Drug Class Review. Newer Diabetes Medications and Combinations

Transcription

1 Drug Class Review Newer Diabetes Medications and Combinations Final Streamlined Update 1 Report June 2014 The purpose of Drug Effectiveness Review Project reports is to make available information regarding the comparative clinical effectiveness and harms of different drugs. Reports are not usage guidelines, nor should they be read as an endorsement of or recommendation for any particular drug, use, or approach. Oregon Health & Science University does not recommend or endorse any guideline or recommendation developed by users of these reports. Agency for Healthcare Research and Quality does not commission, review, or approve reports conducted by Evidence-based Practice Centers for the Drug Effectiveness Review Project. Original Report: February 2011 The literature on this topic is scanned periodically Cynthia Feltner, MD, MPH Roberta Wines, MPH Jennifer Simon, PharmD Cassandra Rowe, BA Rachael E. Posey, MSLS Daniel E. Jonas, MD, MPH Produced by RTI-UNC Evidence-based Practice Center Cecil G. Sheps Center for Health Services Research University of North Carolina at Chapel Hill Daniel E. Jonas, M.D., M.P.H., Director Drug Effectiveness Review Project Marian McDonagh, PharmD, Principal Investigator Pacific Northwest Evidence-based Practice Center Roger Chou, MD, Director Marian McDonagh, PharmD, Associate Director Copyright 2014 by Oregon Health & Science University Portland, Oregon All rights reserved.

2 STRUCTURED ABSTRACT Purpose To compare the effectiveness and adverse event profiles of amylin agonists, DPP-4 inhibitors, GLP-1 analogs, SGLT2 inhibitors, and certain drug combinations (administered as dual therapy or fixed dose combination products) for people with type 2 diabetes and for people with type 1 diabetes for pramlintide only. Data Sources To identify published studies, we searched MEDLINE, The Cochrane Library, Embase, and International Pharmaceutical Abstracts through November 201. We also reviewed reference lists of recent systematic reviews for studies that our electronic searches may have missed, and we requested relevant information from pharmaceutical manufacturers. Review Methods Study selection, data abstraction, validity assessment, grading the strength of the evidence (strength of evidence), and data synthesis were all carried out according to standard Drug Effectiveness Review Project methods. For this streamlined update report, we included only head-to-head comparisons of newer diabetes drugs (and combinations) and comparisons of newer diabetes drugs with metformin. Results Thirty articles met inclusion criteria for this streamlined update report; all were randomized controlled trials focused on adults with type 2 diabetes. All included trials evaluated intermediate outcomes (HbA1c and weight). Very few trials reported health outcomes, and only seven of the 0 included trials were longer than 6 months. Some trials reported some health outcomes (e.g., all-cause mortality or number of people with macrovascular disease) among secondary outcomes or adverse events, but overall evidence was generally insufficient to determine the comparative efficacy of newer diabetes drugs for improving health outcomes. Five trials assessed within-class comparisons of newer diabetes medications. Our metaanalysis ( trials, N=1225) found a greater reduction in mean HbA1c with exenatide XR than exenatide administered twice daily over 24 to 0 weeks: WMD -0.46%; 95% CI, to -0.2 (low strength of evidence); these drugs did not differ in their effect on weight (low strength of evidence). However, injection site reactions were higher in the group receiving exenatide XR weekly compared with exenatide twice daily (moderate strength of evidence). In one trial (N=464), liraglutide 1.8 mg once daily reduced mean HbA1c more than exenatide 10 µg twice daily (between-group difference: 0.%; 95% CI, 0.47 to 0.18); no difference was noted for weight change (low strength of evidence for both outcomes). Those receiving liraglutide had a lower rate of minor hypoglycemia compared with those receiving exenatide 10 µg twice daily (RR 0.55; 95% CI, 0.4 to 0.88) (low strength of evidence). We found insufficient evidence to determine the comparative efficacy or harms of sitagliptin and saxagliptin (1 trial, unknown consistency).

3 Seven trials compared a drug from one class of newer diabetes medications with a drug from a different class, 4 compared a DPP-4 inhibitor with a GLP-1 analog, and compared a DPP-4 inhibitor with an SGLT2 inhibitor. Pooled data from 2 trials (N=75) found that exenatide XR was more efficacious than sitagliptin 100 mg once daily in reducing mean HbA1c over 12 to 26 weeks (WMD -0.48; 95% CI, to -0.26) and weight (WMD -1.2; 95% CI, to -0.76) (low strength of evidence for both outcomes). Exenatide XR was associated with significantly higher rates of nausea, vomiting, and diarrhea compared with sitagliptin (moderate strength of evidence). One trial (N=665) found liraglutide at both dosages (1.2mg and 1.8mg) to be more efficacious than sitagliptin 100 mg in reducing mean HbA1c; the differences in mean HbA1c were -0.4% (95% CI, to -0.16) and -0.60% (95% CI, to -0.4) for both doses of liraglutide compared with sitagliptin, respectively (low strength of evidence). Rates of nausea were higher in those receiving liraglutide (both doses) than in those receiving sitagliptin (low strength of evidence). We found no difference between canagliflozin at both dosages (100 mg and 00 mg) and sitagliptin in reducing mean HbA1c (low strength of evidence); greater reduction in weight was seen with canagliflozin (at both doses) compared with sitagliptin (low strength of evidence). In one trial, women receiving canagliflozin (at both dosages) experienced a higher rate of genital mycotic infections compared to those receiving sitagliptin (low strength of evidence). Eleven trials compared a newer diabetes drug with metformin. Eight trials compared a DPP-4 inhibitor with metformin: linagliptin (1 trial), alogliptin (1 trial), sitagliptin (4 trials) and saxagliptin (2 trials). Moderate strength of evidence supports the conclusion that metformin in doses greater than1000 mg per day is more efficacious than linagliptin 5 mg, alogliptin 25 mg, and sitagliptin 100 mg in reducing HbA1c (between-group differences range from -0.0% to %). For comparisons between metformin and DPP-4 inhibitors, the rates of adverse events were similar (and low) for the vast majority of adverse events; however, metformin was associated with a higher rate of diarrhea compared with alogliptin and sitagliptin (low strength of evidence for both comparisons). We included 2 trials that compared the addition of saxagliptin to uptitration of metformin (in a population not at goal on submaximal doses of metformin); we found no difference between groups for reducing HbA1c (low strength of evidence). However, the addition of saxagliptin was associated with higher rates of hypoglycemia (low strength of evidence). Metformin 1000 mg per day was associated with a greater reduction in weight in all head-to-head trials of DPP-4 inhibitors. Two trials compared a GLP-1 analog with metformin (exenatide twice daily and exenatide XR); we found insufficient evidence to determine the comparative efficacy of metformin and GLP-1 analogs (1 trial each, unknown consistency). We found no difference between dapagliflozin and metformin for reducing HbA1c at either dose of dapagliflozin; the direction of effect favored dapagliflozin, but overall magnitude of effect was small (-0.11% and %) and not within a range that is considered clinically significant. Dapagliflozin was associated with a greater weight reduction over 24 weeks compared with metformin (low strength of evidence). There was no difference between dapagliflozin and metformin in rates of hypoglycemia or nausea (low strength of evidence). Four trials compared either an FDCP or dual therapy with a DPP-4 inhibitor and metformin: alogliptin (1 trial), linagliptin (1 trial), or sitagliptin (2 trials). Alogliptin plus metformin dual therapy was more efficacious than monotherapy for all dose comparisons; between-group differences ranged from -0.44% to -0.99% for all comparisons (moderate strength of evidence); weight changes were similar across all other groups (moderate strength of evidence

4 for no difference). One trial (N=791) found greater reduction in HbA1c with linagliptin plus metformin dual therapy than with component monotherapy over 24 weeks; between-group differences ranged from 0.50% to 1.10% (moderate strength of evidence). Linagliptin 2.5 mg plus metformin 1000 mg twice daily was associated with greater reduction in weight compared with linagliptin 5 mg daily ( 1.00 kg; 95% CI, 1.59 to 0.41) (low strength of evidence). No other groups experienced a significant change in weight (low strength of evidence). Our metaanalysis (2 trials; N=1478) found greater reduction in HbA1c with sitagliptin100 mg plus metformin 2000 mg daily over 18 to 24 weeks compared with metformin monotherapy (WMD %; 95% CI, to -0.45); there was no difference in weight reduction between sitagliptin plus metformin and component monotherapy. Conclusion We found few head-to-head trials within each category of newer diabetes medications; strength of evidence for conclusions related to head to head evidence is generally low for HbA1c, weight, and harms outcomes. Evidence was insufficient to assess the comparative efficacy of included medications for improving health outcomes. Few trials assessed within-class comparisons; we found exenatide XR to be more efficacious for reducing mean HbA1c than exenatide given twice daily, and also associated with more injection site reactions. Liraglutide was more efficacious than exenatide twice daily for reducing mean HbA1c. Metformin (at doses >1500 mg per day) is more efficacious than most DPP-4 inhibitors for reducing HbA1c and is associated with greater weight loss; in some cases, metformin is associated with higher rates of diarrhea. Exenatide XR and liraglutide are both more efficacious than sitagliptin. We found no difference between canagliflozin and sitagliptin for reducing mean HbA1c; canagliflozin is associated with higher rates of genital mycotic infections in women. We found no trials evaluating the comparative efficacy of included medications for subgroups based on age, gender, comorbidity, or drug-drug interaction.

5 TABLE OF CONTENTS INTRODUCTION... 9 Newer Diabetes Medications... 9 Dual Therapy and Fixed-dose Combination Products Purpose and Limitations of Systematic Reviews Scope and Key Questions METHODS Literature Search Study Selection Data Abstraction Validity Assessment Grading the Strength of Evidence Data Synthesis Public Comment RESULTS Overview Key Question 1. What is the comparative efficacy and effectiveness of newer diabetes medications and drug combinations (administered as fixed dose combination products or dual therapy) for children and adults with diabetes mellitus? I. Intra-class Comparisons (within a class) Key Findings Characteristics of Included Studies Detailed Assessment DPP-4 Inhibitors Study Characteristics GLP-1 analogs II. Between-Class Comparisons Key Findings DPP-4 inhibitors compared with GLP-1 analogs DPP-4 inhibitors compared with SGLT2 inhibitors... 2 Characteristics of Included Studies... 2 Detailed Assessment DPP-4 inhibitors compared with GLP-1 analogs DPP-4 inhibitors compared with SGLT2 inhibitors III. Newer Diabetes Medications compared with Metformin Key Findings DPP-4 inibitors compared with metformin GLP-1 analogs compared with metformin SGLT2 inhibitors compared with metformin Detailed Assessment... DPP-4 inibitors compared with metformin... GLP-1 analogs compared with metformin... 5 SGLT2 inhibitors compared with metformin... 5 IV. Fixed-dose Combination Products (FDCPs) or Dual Therapy... 6 Key Findings... 6 Characteristics of Included Studies... 7 Detailed Assessment Kazano or dual therapy with alogliptin plus metformin Jentadueto or dual therapy with linagliptin plus metformin Janumet or dual therapy with sitagliptin plus metformin Key Question 2. What is the comparative tolerability and frequency of adverse events for newer diabetes medications and drug combinations (administered as fixed dose combination products or dual therapy) for children and adults with diabetes mellitus?... 42

6 I. Intra-class Comparisons (within a class) Key Findings: Harms DPP-4 inhibitors: Sitagliptin compared with saxagliptin GLP1-analogs: Exenatide 10 µg compared with liraglutide 1.8 mg GLP-1 analogs: Exenatide XR compared with exenatide 10 µg Characteristics of Included Studies... 4 Detailed Assessment of for Intra-class Comparisons: Harms... 4 Sitagliptin compared with saxagliptin... 4 Exenatide 10 µg twice daily compared with liraglutide 1.8 mg once daily... 4 Exenatide XR 2 mg once weekly compared with exenatide 10 µg twice daily II. Between-Class Comparisons: Harms Key Findings: Harms DPP-4 inhibitors compared with GLP-1 analogs DPP-4 inhibitors compared with SGLT2 inhibitors Study Characteristics Detailed Assessment for Between-class Comparisons: Harms DPP-4 inhibitors compared with GLP-1 analogs DPP-4 inhibitors compared with SGLT2 inhibitors III. Newer Diabetes Medications compared with metformin: Harms Key Findings: Harms DPP-4 inhibitors compared with metformin GLP-1 analogs compared with metformin SGLT2 inhibitors compared with metformin Study Characteristics Detailed Assessment for Newer Diabetes Medications compared with Metformin: Harms DPP-4 inhibitors compared with metformin Abbreviations: CI, confidence interval; RR, relative risk GLP-1 analogs compared with metformin SGLT2 inhibitor compared with metformin IV. Fixed-dose Combination Products (FDCPs) or Dual Therapy Key Findings: Harms DPP-4 inhibitors in combination with metformin Study Characteristics Detailed Assessment for FDCPs and Dual Therapy Kazano or dual therapy with alogliptin plus metformin Jentadueto or dual therapy with linagliptin plus metformin Janumet or dual therapy with sitagliptin plus metformin Key Question. Are there subgroups of patients based on demographics (age, racial groups, gender), comorbidities (drug-disease interactions, obesity), or other medications (drug-drug interactions) for which newer diabetes medications and drug combinations (administered as fixed dose combination products or dual therapy) differ in efficacy/effectiveness or tolerability and frequency of adverse events? SUMMARY Strength of Evidence Limitations of this Report Applicability Trials in Progress REFERENCES... 69

7 TABLES Table 1. Characteristics of included drugs Table 2. Eligible drugs and comparators... 1 Table. Study inclusion and exclusion criteria Table 4. Definitions of the grades of overall strength of evidence Table 5. Characteristics of included studies: Newer diabetes medications within-class comparisons Table 6. Characteristics of included studies: Newer diabetes medications between-class comparisons.. 24 Table 7. Randomized controlled trials comparing canagliflozin and sitagliptin: Results for hemoglobin A1c and weight Table 8. Characteristics of included studies: Newer diabetes medications compared with metformin... 0 Table 9. Characteristics of included studies: Fixed-dose combination products or dual therapy... 8 Table 10. Adverse events of intra-class comparisons Table 11. Meta-analysis comparing adverse events: Exenatide XR to sitagliptin 100 mg Table 12. Adverse events of between-class comparisons: Sitagliptin compared with exenatide XR or liraglutide Table 1. Adverse events of between-class comparisons: Sitagliptin compared with canagliflozin Table 14. Meta-analysis comparing adverse events: Linagliptin 5 mg compared with metformin 1000 mg twice daily Table 15. Meta-analysis comparing adverse events: Sitagliptin compared with metformin... 5 Table 16. Adverse events of sitagliptin compared with metformin... 5 Table 17. Changes in lipid parameters (mean change from baseline, mg/dl): Sitagliptin compared with metformin Table 18. Meta-analysis comparing adverse events: Saxagliptin compared with metformin Table 19. Meta-analysis comparing adverse events: Dapagliflozin 5 mg compared with metformin XR Table 20. Meta-analysis comparing adverse events: Dapagliflozin 10 mg compared with metformin XR. 56 Table 21. Adverse events of Kazano or dual therapy with alogliptin and metformin compared with metformin monotherapy Table 22. Adverse events of Jentadueto or dual therapy with linagliptin and metformin compared with linagliptin or metformin monotherapy Table 2. Adverse events of Janumet or dual therapy with sitagliptin and metformin compared with sitagliptin or metformin monotherapy Table 24. Changes in lipid parameters (mean change from baseline, mg/dl): sitagliptin plus metformin compared with metformin monotherapy Table 25. Summary of evidence by Key Question FIGURES Figure 1. Results of literature search APPENDIXES Appendix A. Boxed warnings for included drugs... 7 Appendix B. Glossary Appendix C. Search strategies Appendix D. Excluded studies and studies of poor quality Appendix E. Meta-analyses Appendix F. Strength of evidence EVIDENCE TABLES Evidence tables are published in a separate document.

8 Acknowledgments We thank Leah Williams, our publications editor, for putting this report into its present form for you to read. We also thank Ellen Shanahan for assistance with project coordination, Claire Baker for assistance with full-text article identification and retrieval, and Christiane Voisin for assistance with the literature search. Suggested citation for this report Feltner C, Wines R, Simon J, Rowe C, Posey R, Jonas D. Drug class review: Newer diabetes medications and combinations. Prepared by the RTI-UNC Evidence-based Practice Center for the Drug Effectiveness Review Project. Oregon Health & Science University. Portland, OR Funding The funding source, the Drug Effectiveness Review Project, is supported by 12 State Medicaid programs. These organizations selected the topic and had input into the Key Questions for this review. The content and conclusions of the review are entirely determined by the Evidence-based Practice Center researchers. The authors of this report have no financial interest in any company that makes or distributes the products reviewed in this report.

9 INTRODUCTION Diabetes mellitus (diabetes) is a chronic disease associated with significant morbidity and healthcare costs. The prevalence of diabetes has increased substantially over the past 2 decades; in 2010, approximately 21 million adults in the United States had diabetes, based on self-report or hemoglobin A1c (HbA1c) levels 6.5%. 1 Among people diagnosed with diabetes, 90% to 95% have type 2 diabetes, while 5% to 10% have type 1 diabetes. 2 Type 1 diabetes is characterized by autoimmune destruction of beta cells of the pancreas resulting in absolute insulin deficiency. Type 2 diabetes encompasses a heterogeneous group of disorders characterized by slow progressive loss of beta cell function and mass, leading to variable degrees of insulin resistance, impaired insulin secretion, and increased hepatic glucose production. Higher glucagon levels relative to insulin also play a significant role in the pathogenesis and management of type 2 diabetes. The 2014 American Diabetes Association treatment guidelines recommend an HbA1c goal of <7% for most nonpregnant adults in order to prevent adverse microvascular and macrovascular outcomes. The guidelines acknowledge that less stringent (HbA1c <8%) or more stringent (A1c < 6.5%) goals may be appropriate for certain populations. Insulin is the standard treatment for type 1 diabetes. Pharmacologic options for type 2 diabetes include sulfonylureas, biguanides, thiazolidinediones, meglitinides, alpha-glucosidase inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) analogs, sodium-glucose cotransporter 2 (SGLT2) inhibitors, combination products, and insulin. Because of the progressive nature of diabetes, practitioners and patients often experience challenges in reaching and sustaining American Diabetes Association treatment goals. Patients with type 2 diabetes often need to take more than one type of diabetes medication. In 2005 and 2006, 5% of all patients with diabetes were taking 2 classes of antidiabetes medications, and 14% were taking or more classes. 4 Newer Diabetes Medications Within recent years, several new antihyperglycemic agents have been approved (Table 1). These agents offer mechanisms of glycemic control beyond that of traditional oral agents and insulin by targeting alternate gluco-regulatory receptors and hormones such as amylin, GLP-1, glucosedependent insulinotropic peptide (GIP), DPP-4, and sodium-glucose cotransporter 2 (SGLT2). For the purposes of this report, we consider the following to be newer diabetes medications : amylin agonists, DPP-4 inhibitors, GLP-1 analogs, and SGLT2 inhibitors. Amylin is a neuroendocrine hormone co-secreted with insulin from beta cells in response to elevated blood glucose concentrations, and it complements the actions of insulin. GLP-1 and GIP are secreted by L- and K-type cells in the intestinal tract in response to a combination of endocrine and neural signals initiated by the entry of food into the gut. Secretion of GLP-1 and GIP enhance insulin release. Both endogenous GLP-1 and GIP are rapidly degraded by the proteolytic enzyme DPP- 4. SGLT2 is located in the proximal renal tubules and is the main site of filtered glucose reabsorption from the tubular lumen. Inhibition of SGLT2 results in increased urinary excretion of glucose and reduced plasma glucose concentrations.

10 Dual Therapy and Fixed-dose Combination Products For this report, we ve included 5 fixed-dose combination products (FDCPs) approved for the treatment of type 2 diabetes; all combine a DPP-4 inhibitor with metformin (Table 1). In addition to the 5 FDCPs, we ve included studies of the individual components of those FDCPs when used together but in separate pills we refer to this as dual therapy throughout the review. We only evaluate dual therapy when there is a US Food and Drug Administration-approved fixed dose combination product. Table 1. Characteristics of included drugs Drug Class Trade name Administration Labeled indications FDA-approved dosing Type 1: µg with Pramlintide Symlin Type 1 diabetes, meals Type 2 diabetes; Amylin agonist Injectable Type 2: µg with Adjunct with insulin meals Linagliptin DPP-4 Inhibitor Alogliptin DPP-4 Inhibitor Sitagliptin DPP-4 Inhibitor Saxagliptin DPP-4 Inhibitor Exenatide GLP-1 Analog Exenatide XR GLP-1 Analog Liraglutide GLP-1 Analog Canagliflozin SGLT2 Inhibitor Dapagliflozin SGLT2 Inhibitor Alogliptin + Metformin Linagliptin + Metformin Tradjenta Oral tablet Nesina Oral tablet Januvia Oral tablet Onglyza Oral tablet Byetta Injection Bydureon Injection Victoza Injection Invokana Oral tablet Farxiga Oral tablet Kazano Oral tablet Jentadueto Oral tablet Type 2 diabetes; Monotherapy or combination with many antihyperglycemics Type 2 diabetes; Monotherapy or combination with many antihyperglycemics Type 2 diabetes; Monotherapy or combination with many antihyperglycemics Type 2 diabetes; Monotherapy or combination with many antihyperglycemics Type 2 diabetes; Not recommended with insulin, except for insulin glargine Type 2 diabetes; Not recommended with insulin Type 2 diabetes; Not recommended with shortacting insulin (has not been studied) Type 2 diabetes; Monotherapy or combination with many antihyperglycemics Type 2 diabetes; Adjunct to diet and exercise Type 2 diabetes; Adjunct to diet and exercise for patients not adequately controlled on alogliptin or metformin monotherapy Type 2 diabetes; Adjunct to diet and exercise in patients when treatment with both linagliptin and metformin is appropriate 5 mg once daily 25 mg once daily (6.25 or 12.5 mg if renal dysfunction) 100 mg once daily (25 or 50 mg if renal dysfunction) mg once daily (2.5 mg if renal dysfunction) 5 or 10 µg twice daily prior to meals 2 mg once weekly 0.6, 1.2, or 1.8 mg once daily 100 or 00 mg once daily prior to first meal (100 mg if renal dysfunction) 5 or 10 mg once daily in the morning 12.5/ /1000 mg one to two times daily with meals 2.5/500 mg, 2.5/850 mg, or 2.5/1000 mg one to two times daily with meals Sitagliptin + Janumet Type 2 diabetes; 50/500 mg or 50 mg/1000

11 Drug Class Trade name Administration Labeled indications FDA-approved dosing Metformin Oral tablet Adjunct to diet and exercise in adult patients when treatment with both sitagliptin and metformin is appropriate mg once or twice daily with meals Sitagliptin XR + Metformin Saxagliptin + Metformin Janumet XR Oral tablet Kombiglyze XR Oral tablet Type 2 diabetes; Adjunct to diet and exercise in adult patients when treatment with both sitagliptin and metformin is appropriate Type 2 diabetes; Adjunct to diet and exercise when treatment with both saxagliptin and metformin is appropriate 50/500 mg, 50/1000 mg, or 100/1000 mg one to two tablets once daily with meals; Maximum of 100/2000 mg daily 2.5/1000 mg, 5/500, or 5/1000, one to two tablets once daily with evening meal; Maximum of 5/2000 mg daily Abbreviations: DPP-4, Dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; SGLT2, Sodium-glucose cotransporter 2 Purpose and Limitations of Systematic Reviews Systematic reviews, also called evidence reviews, are the foundation of evidence-based practice. They focus on the strength and limits of evidence from studies about the effectiveness of a clinical intervention. Systematic reviews begin with careful formulation of research questions. The goal is to select questions that are important to patients and clinicians, then to examine how well the scientific literature answers those questions. Terms commonly used in systematic reviews, such as statistical terms, are provided in Appendix B and are defined as they apply to reports produced by the Drug Effectiveness Review Project. Scope and Key Questions The purpose of this review is to assist healthcare providers, researchers, and policy makers in making clinical decisions, creating formularies, and developing policies regarding newer medications for the treatment of diabetes based on the most current available literature. We compare the efficacy, effectiveness, and tolerability of newer diabetes medications and combinations, and also look for subgroups that may differ in these areas. In the previous update report, 5 placebo-controlled comparisons were included as part of the evidence base. A new, streamlined approach was used for this update, which focuses on head-to-head studies. We compare efficacy and tolerability both within classes of newer diabetes medications and between the classes of newer diabetes medications; we also compare newer diabetes medications with metformin. For this update, we do not include comparisons of newer diabetes medications with pioglitazone or sulfonylureas. We include trials enrolling populations of diabetes patients who are already on treatment with insulin or other oral medications for diabetes as long as they are randomized to an eligible drug and comparator (Table 2). We developed preliminary key questions to identify the populations, interventions, outcomes of interest, and eligibility criteria for studies. A draft of these questions and inclusion and exclusion criteria were posted on the Drug Effectiveness Review Project (DERP) website for public comment. The draft was reviewed and revised by representatives of the organizations participating in the DERP. These organizations approved the following key questions to guide the review for this report:

12 1. What is the comparative efficacy and effectiveness of newer diabetes medications and drug combinations (administered as fixed dose combination products or dual therapy) for children and adults with diabetes mellitus? 2. What is the comparative tolerability and frequency of adverse events for newer diabetes medications and drug combinations (administered as fixed dose combination products or dual therapy) for children and adults with diabetes mellitus?. Are there subgroups of patients based on demographics (age, racial groups, gender), comorbidities (drug-disease interactions, obesity), or other medications (drug-drug interactions) for which newer diabetes medications and drug combinations (administered as combination products or dual therapy) differ in efficacy/effectiveness or frequency of adverse events? METHODS Literature Search To identify articles relevant to each key question, we searched MEDLINE, Embase, the Cochrane Library, and the International Pharmaceutical Abstracts. To identify new trials of drugs in the last report, we searched from December 1, 2008 (1 year before the final searches were run for the previous report 5 ) through November 5, 201. To identify new trials of linagliptin, we searched from September 1, 2011 (1 year before the final searches were run for the Linagliptin Single Drug Addendum 6 ) through November 5, 201. To identify trials of newly approved drugs, we did not limit the search date. To identify trials of dapagliflozin, we conducted additional searches through February 7, 2014, as dapagliflozin was approved after the original searches were completed. We used the generic and brand names of included drugs, and study designs as search terms, limiting the electronic searches to human and English language. We combined the results of all the searches and removed duplicate references. The full search strategies are presented in Appendix C. We attempted to identify additional studies through hand searches of reference lists of included studies and reviews. In addition, we searched the FDA s Center for Drug Evaluation and Research (CDER) for medical and statistical reviews. Finally, we requested dossiers of published and unpublished information from the relevant pharmaceutical companies for this review. All received dossiers were screened for studies or data not found through other searches. All citations were imported into an electronic database (Endnote X.0.2, Thomson Reuters). Study Selection Selection of included studies was based on the inclusion criteria in Table. Studies meeting these criteria and comparing at least one of the drugs of interest with an eligible comparator were included. Eligible drugs and comparators are listed in Table 2. Two reviewers independently assessed titles and abstracts of citations identified through literature searches for eligibility using the criteria below. Full-text articles of potentially relevant citations were retrieved and were

13 again assessed for eligibility by both reviewers. Disagreements were resolved by consensus. Results published only in abstract form were not included because inadequate details were available for quality assessment. Table 2. Eligible drugs and comparators Drug class or drug a Eligible comparators Amylin Agonists DPP-4 Inhibitors, GLP-1 Analog, SGLT2 Inhibitors, Fixed dose combination products, Dual therapy with the component Pramlintide vs. medications of fixed dose combination products, Biguanides (metformin) DPP-4 Inhibitors Each other, Amylin Agonists, GLP-1 Analog, SGLT2 Inhibitors, Sitagliptin, Saxagliptin, Linagliptin, Fixed dose combination products, Dual therapy with the component or Alogliptin vs. medications of fixed dose combination products, Biguanides (metformin) GLP-1 Analog Exenatide, Exenatide XR, or Liraglutide vs. SGLT2 Inhibitors Canagliflozin or Dapagliflozin vs. Fixed-dose Combination Products b Janumet (Metformin + Sitagliptin), Janumet XR (Metformin + Sitagliptin XR), Kombiglyze XR (Metformin + Saxagliptin), Kazano (Metformin + Alogliptin), or Jentadueto (Metformin + Linagliptin) vs. Dual Therapy Metformin + Sitagliptin, Metformin + Sitagliptin XR, Metformin + Saxagliptin, Metformin + Alogliptin, or Metformin + Linagliptin vs. Each other, DPP-4 Inhibitors, Amylin agonists, SGLT2 Inhibitors, Fixed dose combination products, Dual therapy with the component medications of fixed dose combination products, Biguanides (metformin) Each other, Amylin agonists, DPP-4 Inhibitors, GLP-1 Analogs, Fixed dose combination products, Dual therapy with the component medications of included fixed dose combination products, Biguanides (metformin) Monotherapy with one of the component medications of the product or head to head studies comparing 2 fixed dose combination products Monotherapy with one of the component medications Abbreviations: DPP-4, Dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; SGLT2, Sodium-glucose cotransporter 2 a Evidence of these interventions (left column) used as monotherapy or as add-on therapy will be included when available. b In Drug Effectiveness Review Project reports, we traditionally refer to the drug products by their generic names wherever possible. For this report, however, we are using the trade names for the FDCPs in an effort to make reading easier.

14 Table. Study inclusion and exclusion criteria Included populations Adults with type 2 diabetes for all included medications Adults and children with type 1 diabetes for Pramlintide (Symlin ) only Excluded populations Individuals with gestational diabetes, pre-diabetes (impaired fasting glucose or impaired glucose tolerance), metabolic syndrome without diabetes, or polycystic ovary syndrome Included intermediate outcomes Hemoglobin A1c (HbA1c) Changes in weight Included health outcomes All-cause mortality Microvascular disease: chronic kidney disease, including renal dialysis, renal transplantation, end-stage renal disease; renal failure with proteinuria, retinopathy including proliferative retinopathy and blindness; peripheral neuropathy Macrovascular disease: cardiovascular events, cardiovascular morbidity (e.g. myocardial infarction and peripheral arterial disease), cardiovascular mortality, stroke/transient ischemic attack, coronary heart disease, cardiovascular procedures, extremity amputation Included harms/adverse events outcomes Overall adverse events Withdrawals due to adverse events Major adverse events (for example diabetic ketoacidosis, non-ketotic hyperosmolar coma) Specific adverse events (for example cancers/neoplasms, infections, hypoglycemia, liver toxicity, liver function abnormalities, gastrointestinal effects, congestive heart failure, adverse changes in lipid concentrations, pancreatitis, weight gain, fractures) Included study designs For intermediate outcomes: randomized controlled trials a For health outcomes: randomized controlled trials For harms: randomized controlled trials, controlled clinical trials, population-based comparative cohort studies focused on adverse events, case-control studies, and reports from voluntary adverse event reporting systems. Duration: 12 weeks of follow-up Sample size: No limit for randomized controlled trials, observational studies with at least 100 subjects a We included extension trials (e.g., longer term follow-up) of randomized controlled trials when patients were maintained on the treatment they were initially randomized to. We considered groups that were switched from one treatment to another during the follow-up period to be an ineligible comparison. Data Abstraction The following data were abstracted from included trials: study design; population characteristics, including sex, age, and ethnicity; eligibility and exclusion criteria; interventions; comparisons; numbers randomized or treated, and the numbers analyzed; and results for each outcome. We recorded intention-to-treat results when reported. If true intention-to-treat results were not reported, but loss to follow-up was very small, we recorded these results and noted that they were modified intention-to-treat results. In cases where only per protocol results were reported, we recorded these results and noted that they were per protocol results. We considered whether results were intention-to-treat, modified intention-to-treat, or per protocol when assessing the internal validity of studies (as described below). Data abstraction was performed by one reviewer and independently checked by a second reviewer, and differences were resolved by consensus. When studies reported duration in number of months, we converted this to number of weeks by multiplying months by 4. and rounding up or down. Number of weeks is presented in the tables of study characteristics throughout the report. When recording data on lipids, we

15 converted mmol/l to mg/dl. To convert total cholesterol and HDL and LDL cholesterol, we used the following formula: divide mmol/l by to get mg/dl. To convert triglycerides, we used the following formula: divide mmol/l by to get mg/dl. When included trials had non-eligible comparators (e.g., placebo comparisons or non-fda approved dosages), we extracted that data into evidence tables (published in a separate document) but did not synthesize or report that data in the results. Validity Assessment Two reviewers independently assessed each study, and differences were resolved by consensus. We assessed the internal validity (quality) of trials based on the predefined criteria (see These criteria are based on those developed by the US Preventive Services Task Force and the National Health Service Centre for Reviews and Dissemination (United Kingdom). 7,8 We rated the internal validity of each trial based on the methods used for randomization, allocation concealment, and blinding; the similarity of compared groups at baseline; maintenance of comparable groups; adequate reporting of dropouts and attrition; loss to follow-up; and the use of intention-to-treat analysis. Trials that had a fatal flaw were rated poor quality; trials that met all criteria were rated good quality; the remainder were rated fair quality. As the fair-quality category is broad, studies with this rating vary in their strengths and weaknesses: The results of some fair-quality studies are likely to be valid, while others are only possibly valid. A poor-quality trial is not valid; the results are at least as likely to reflect flaws in the study design as a true difference between the compared drugs. A fatal flaw may be reflected by one aspect introducing a high risk of bias or by failure to meet combinations of items of the quality assessment checklist. We did not include poor quality studies in our qualitative or quantitative analyses; however, data from poor quality trials is reported in evidence tables (Evidence Tables are published in a separate document). A particular randomized trial might receive 2 different ratings (e.g., one rating efficacy/effectiveness outcomes and one for harms). In these cases, data from one study may be included for one KQ but not included in another KQ. We only rated the quality of trials; although observational studies were eligible for outcomes related to adverse events, we did not identify any that met our inclusion criteria. Grading the Strength of Evidence We graded strength of evidence based on the guidance established for the Evidence-based Practice Center Program of the Agency for Healthcare Research and Quality. 9 Developed to grade the overall strength of a body of evidence, this approach incorporates 4 key domains: risk of bias (includes study design and aggregate quality), consistency, directness, and precision of the evidence. It also considers other optional domains that may be relevant for some scenarios, such as a dose-response association, or plausible confounding that would decrease the observed effect, strength of association (magnitude of effect), publication bias, and selective analysis reporting (e.g. presenting a point estimate without providing a measure of dispersion). We considered all evidence from intermediate outcomes (e.g. HbA1c and weight) to be indirect (not directly reporting health outcomes). Table 4 describes the grades of evidence that can be assigned. Grades reflect the strength of the body of evidence to answer key questions on the comparative effectiveness, efficacy, and harms of the drugs included in this review. Grades do not refer to the general efficacy or effectiveness of pharmaceuticals. Two reviewers assessed

16 each domain for each outcome and differences were resolved by consensus. For this streamlined update report, we did not modify SOE grades for comparisons assessed in prior DERP reports when we found no new trials relevant to a particular comparison. In these cases, SOE grades may reflect evidence that was previously reviewed but not part of the scope of this review (e.g., doseresponse association). We reference the prior DERP for these SOE grades in a footnote to the SOE appendix. We graded the strength of evidence for the outcomes deemed to be of greatest importance to decision makers and those most commonly reported in the literature. For example, these included HbA1c and weight changes, among others. Because of time and resource constraints, we did not grade the strength of evidence for every possible outcome reported everywhere in the included literature. Table 4. Definitions of the grades of overall strength of evidence Grade Definition 9 We are very confident that the estimate of effect lies close to the true effect for High this outcome. The body of evidence has few or no deficiencies. We believe that the findings are stable, i.e., another study would not change the conclusions We are moderately confident that the estimate of effect lies close to the true Moderate effect for this outcome. The body of evidence has some deficiencies. We believe that the findings are likely to be stable, but some doubt remains. We have limited confidence that the estimate of effect lies close to the true effect for this outcome. The body of evidence has major or numerous deficiencies (or both). We believe that additional evidence is needed before concluding either that the findings are stable or that the estimate of effect is close to the true effect. We have no evidence, we are unable to estimate an effect, or we have no Insufficient confidence in the estimate of effect for this outcome. No evidence is available or the body of evidence has unacceptable deficiencies, precluding reaching a conclusion. Data Synthesis We constructed evidence tables showing the study characteristics, quality ratings, and results for all included studies (published in a separate document). We conducted meta-analyses of outcomes reported by at least 2 studies that were homogeneous enough to justify combining their results. In order to determine whether metaanalysis could be meaningfully performed, we considered the quality of the studies and the heterogeneity among studies in design, patient population, interventions, and outcomes. When meta-analysis could not be performed, the data were summarized qualitatively. Random-effects models were used to estimate pooled effects. 10 Forest plots graphically summarize results of individual studies and of the pooled analysis. 11 For continuous outcomes (e.g., HbA1c and weight) measured with the same scale, we report the weighted mean difference (WMD) between intervention and control subjects. For binary outcomes, we report the relative risk (RR) and 95% confidence interval (CI). The Chi-squared statistic and the I 2 statistic (the proportion of variation in study estimates due to heterogeneity) were calculated to assess heterogeneity in effects between studies. 12,1 An I 2 from 0 to 40% might not be important, 0% to 60% may represent moderate heterogeneity, 50% to 90% may represent substantial heterogeneity, and 75% represents considerable heterogeneity. 14 The importance of the observed value of I 2 depends on the magnitude and

17 direction of effects and on the strength of evidence for heterogeneity (e.g. P value from the chisquared test, or a confidence interval for I 2 ). Whenever including a meta-analysis with considerable statistical heterogeneity in this report, we provide an explanation for doing so, considering the magnitude and direction of effects. 14 Potential sources of heterogeneity were examined by analysis of subgroups of study design, study quality, patient population, and variation in interventions. Quantitative analyses were conducted using Stata version When meta-analysis could not be performed, the data were summarized qualitatively. For continuous outcomes (changes in HbA1c and weight), we report both the mean change from baseline for both groups and the between-group difference when these were reported. When only mean change in hemoglobin A1c from baseline and standard error or standard deviation were reported for 2 comparisons, we calculated the difference in means (linagliptin-placebo) and 95% confidence interval if not already reported by the included trials. When describing conclusions and key findings in this report, we sometimes refer to no difference between 2 treatments. We use this wording to indicate that the available evidence did not support a statistically or clinically significant difference between the 2 treatments. For HbA1c outcomes, we note whether differences between groups were statistically significant. When between-group differences in HbA1c were less than 0.%, we did not consider this a clinically meaningful difference; this cut-off value is consistent with what was considered clinically significant in prior DERP reports. 5 For weight outcomes, we did not set a cut off at which we considered a change in weight to be clinically meaningful. We note the magnitude of effect and describe the SOE for the observed effect as discussed above. Public Comment This report was posted to the Drug Effectiveness Review Project website for public comment. We received comments from 5 persons representing pharmaceutical companies. RESULTS Overview Literature searches through November 4, 201 for the current report identified 749 unduplicated citations. We received dossiers from 5 pharmaceutical manufacturers: AstraZeneca, Boehringer- Ingelheim, Janssen, Novo Nordisk, and Merck. Ninety-six additional references were identified through hand searches of systematic reviews and other sources, and 52 additional articles were identified from the dossiers, 17 from the exenatide (Byetta ) dossier (AstraZeneca), from the exenatide XR (Bydureon ) dossier (AstraZeneca), 8 from the liraglutide (Victoza ) dossier (Novo Nordisk), 2 from the canagliflozin (Invokana ) dossier (Janssen), 1 from the Jentadueto dossier (Boehringer-Ingelheim), 1 from the Kombiglyze TM dossier (AstraZeneca), 2 from the pramlintide (Symlin ) dossier (AstraZeneca), 4 from the saxagliptin (Onglyza ) dossier (AstraZeneca), 7 from the sitagliptin (Januvia ) dossier (Merck), and 7 from the dapagliflozin (Farxiga TM ) dossier (AstraZeneca ). We also retrieved 4 excluded references from the reference database of the Newer Diabetes Medications, TZDs, and Combinations DERP report 5 in order to review these publications using new inclusion criteria. From all of these sources, we had a total of 1024 references. In addition to these, we carried forward 12 of the included studies from 5

18 previous DERP reports: Newer Drugs for the Treatment of Diabetes Mellitus, 15 Fixed Dose Combination Drug Products for the Treatment of Type 2 Diabetes and Hyperlipidemia, 16 and the Drug Class Review on Thiazolidinediones, 17 Newer Diabetes Medications, TZDs, and Combinations, 5 Newer Diabetes Medications, TZDs, and Combinations Single Drug Addendum: Linagliptin. 6 By applying the eligibility and exclusion criteria to titles and abstracts of all identified citations, we obtained full-text copies of 266 citations. After re-applying the criteria for inclusion, we ultimately included 21 new publications from our recent literature searches and other sources, plus the 9 includes from previous reports. See Appendix D for a list of excluded studies and reasons for exclusion at the full text stage. Figure 1 shows the flow of study selection. Among the 21 includes from our recent searches, all 21 were randomized controlled trials. Among these, we rated 2 as good quality, 18 as fair quality, and 1 as poor quality. Poor-quality studies are listed in Appendix D. Figure 1. Results of literature search 749 unduplicated references identified from recent searches 275 additional references identified through other sources (127 included references from previous reports, 148 from dossiers and hand searches) 1024 titles and abstracts screened for report 758 references excluded at abstract level 266 full text articles assessed for eligibility in current report (12 references carried forward from previous reports + 14 full-text includes from recent searches) 0 articles (26 studies) included in the review 8 (5) from previous reports, 22 (21) from recent searches 26 full-text articles excluded 17 ineligible publication type ineligible drug or duplicate publication already included in earlier diabetes medication reports 184 ineligible comparison 11 no eligible outcomes reported 8 ineligible study design 6 ineligible population 7 full text not available The 22 articles from recent searches included: 21 trials (22 articles), and 0 observational studies (2 good, 18 fair, 1 poor)

19 Key Question 1. What is the comparative efficacy and effectiveness of newer diabetes medications and drug combinations (administered as fixed dose combination products or dual therapy) for children and adults with diabetes mellitus? I. Intra-class Comparisons (within a class) Key Findings We found 5 fair-quality trials comparing 2 medications within the same class: one compared saxagliptin with sitagliptin and 4 compared 2 different GLP-1 analogs. No trial assessed health outcomes as a primary outcome or evaluated outcomes beyond 6 months; we found insufficient evidence to determine the comparative efficacy for improving health outcomes for all intra-class comparisons. One trial (N=801) found no difference between sitagliptin and saxagliptin for reducing HbA1c or weight over 18 weeks. Evidence was insufficient to determine the comparative efficacy of sitagliptin and saxagliptin for reducing HbA1c or weight (1 trial; unknown consistency). We pooled data from trials (N=1225) comparing exenatide XR with exenatide administered twice daily over 24-0 weeks. Exenatide XR was more efficacious in reducing mean HbA1c than exenatide twice daily: WMD -0.46%; 95% CI, to -0.2 (moderate strength of evidence). Three trials found no difference between exenatide XR and exenatide administered twice daily for weight changes over 24-0 weeks; 1 trial (N=252) two trials found no statistically significant difference between groups, the third trial (N=678) found a small reduction in weight (-0.kg; p<0.001) favoring exenatide twice daily (low strength of evidence for no difference). One trial (N=464) compared liraglutide 1.8 mg once daily with exenatide 10 µg twice daily over 26 weeks. Liraglutide was more efficacious than exenatide in reducing mean HbA1c: -0.%; 95% CI, to -0.18; P< (low strength of evidence). There was no difference in weight loss between liraglutide and exenatide twice daily: 0.8 kg; 95% CI, 0.99 to 0.2, P=0.225 (low strength of evidence). Characteristics of Included Studies Six trials compared 2 drugs within the same class. One trial compared saxagliptin with sitagliptin, 18 one compared liraglutide with exenatide XR, 19 and trials compared exenatide XR (given once weekly) with exenatide given twice daily We rated one trial comparing liraglutide with exenatide XR as poor quality, primarily due to inadequate handling of missing data; study characteristics and results of that trial are provided in evidence tables (published in a separate document). 2 Table 5 presents study characteristics for the 5 trials that we rated as fair quality and included in our analyses. We found no trials assessing intra-class comparisons of amylin agonists or SGLT2 inhibitors.

20 Table 5. Characteristics of included studies: Newer diabetes medications within-class comparisons Author, Year Trial Name Arm Dose, mg/day (N) Scheen, SAXA 5 mg (40) SITA 100 mg (98) EXE 20 µg a (12) Blevins, EXE XR 2 mg/w (129) EXE 20 µg a (147) Drucker, EXE XR 2 mg/w (148) EXE XR 2 mg/w (40) Ji, EXE 20 µg a (8) LIR 1.8 mg (2) Buse, EXE 10 µg (21) Follow-up (weeks) 18 Country Mean Age, years %W %F Base-line HgA1c Baseline Weight (kg) Back-ground Therapy Quality NR Metformin Fair 24 US Multinational Multinational Multinational b Multinational Metformin, sulfonylurea, TZD, or combination Metformin, sulfonylurea, thiazolidinedione, or metformin plus either sulfonylurea or thiazolidinedione Metformin, sulfonylurea, TZD, or combination Metformin +/- sulfonylurea Abbreviations: %F, percent female; %W, percent white; EXE, exenatide; EXE XR, exenatide extended release; mg, milligrams; N, number; SAXA, saxagliptin; TZD, thiazolidinedione; µg, micrograms a In these trials, patients were given exenatide 10 µg/day for 4 weeks followed by20 µg/day for the remainder of the trial period. b Population in this trial was 100% Asian. Fair Fair Fair Fair

21 All 5 trials enrolled adults with type 2 diabetes not adequately controlled on metformin alone or in combination with a sulfonylurea, pioglitazone, or both. Study duration ranged from 18 to 0 weeks; none included health outcomes as a primary outcome of interest. Most trials excluded persons with significant comorbid conditions (including liver, kidney, and cardiovascular disease) and older persons. A more detailed description of study characteristics and included populations is given below by drug comparison. Detailed Assessment DPP-4 Inhibitors Study characteristics One trial (N=801) compared sitagliptin 100 mg once daily with saxagliptin 5 mg once daily over 18 weeks. 18 The study population included adults with type 2 diabetes who were not at goal on metformin monotherapy alone; patients on other diabetes medications were excluded. Patients were excluded if they had a diagnosis of heart failure or recent myocardial infarction. Mean age was 58; most participants were white (65% to 68%) and approximately half were women (Table 5). Baseline HbA1c was 7.7% for both groups; baseline weight was not reported. Participants continued on background therapy of metformin mg per day throughout the trial. The trial was conducted in multinational settings and sponsored by AstraZeneca and Bristol-Myers Squibb. We rated the trial as fair quality. Sitagliptin compared with saxagliptin No deaths occurred in either group. One person in the sitagliptin group had a myocardial infarction and one person had a transient ischemic attack, compared with no events in the saxagliptin group. 18 Saxagliptin and sitagliptin produced similar reductions in mean HbA1c over 18 weeks (saxagliptin -0.52% [SE 0.09] compared with sitagliptin -0.62% [SE 0.08]); the estimated between group treatment difference was 0.09% (95% CI, to 0.2). 18 There was no difference in weight loss between the 2 groups; both groups experienced a mean weight loss of 0.4 kg from baseline. GLP-1 analogs Study characteristics Four fair-quality trials compared different GLP-1 analogs (Table 5). Three compared exenatide XR 2 mg once weekly with exenatide 10 µg twice daily; in all trials, exenatide was initially given as 5 µg twice daily for 4 weeks, then increased to 10 µg twice daily. 20,21 One trial compared liraglutide 1.8 mg once daily with exenatide 10 µg twice daily over 26 weeks. 19 All trials included adults with type 2 diabetes inadequately controlled on metformin, a sulfonylurea, a TZD, or combinations of these drugs. Mean ages ranged from 55 to 57 and 40% to 51% of participants were women. Baseline HbA1c ranged from 8.1 to 8.5. In one trial, the baseline weight of participants was 70kg; 21 in the other 2 trials, baseline weight ranged from 9 kg to 102 kg. One trial was conducted exclusively in an Asian population (Chinese, Indian, Japanese, Korean participants); 21 the majority of participants in the other trials were white. One trial was conducted within the United States; 20 the others were conducted in multinational settings. All 4 trials were industry sponsored.

22 Exenatide XR compared with exenatide Three trials compared exenatide XR (administered once weekly) with twice daily formulation. 20,21 Two trials reported the incidence of fatal myocardial infarction over 24 to 0 weeks. In one trial, one patient receiving exenatide twice daily experienced a fatal myocardial infarction, compared with no persons receiving exenatide XR. 20 In the second trial, one patient receiving exenatide XR experienced a myocardial infarction, compared with no persons receiving exenatide XR. 22 The trial by Ji and colleagues did not report health outcomes. 21 Our meta-analysis ( trials, N=1225; Appendix E) found that exenatide XR 2 mg once weekly was more efficacious than exenatide 10 µg twice daily in reducing mean HbA1c over 24 to 0weeks (WMD -0.46%; 95% CI, to -0.2). Two trials found no statistically significant difference between the two drugs for changes in weight; both drugs were associated with weight loss. 20,22 The trial by Ji et al. found a greater reduction in weight with exenatide 10 µg twice daily than with exenatide XR (-2.45 kg, 95% CI, to 2.62 versus -1.6, 95% CI, 1.47 to 1.79, respectively, P<0.001). 21 Exenatide compared with liraglutide One trial (N=464) compared liraglutide 1.8 mg once daily with exenatide 10 µg twice daily over 26 weeks; persons on a maximally tolerated doses of metformin, a sulfonylurea, or both were included. 19 No health outcomes were reported. Liraglutide was more efficacious than exenatide in reducing mean HbA1c (-1.12% [SE 0.08] compared with -0.79% [SE 0.08]; estimated treatment difference -0.%; 95% CI, to -0.18; P<0.0001). 19 No difference was found in weight loss between the 2 groups (liraglutide -.24 kg [0.] compared with exenatide 2.87 kg [0.]; estimated treatment difference 0.8 kg; 95% CI, 0.99 to 0.2; P=0.225). 19 II. Between-Class Comparisons Key Findings Seven trials compared a drug from one class of newer diabetes medications with a drug from a different class; 4 compared a DPP-4 inhibitor with a GLP-1 analog and compared a DPP-4 inhibitor with an SGLT2 inhibitor. We found no other between-class comparisons. No trial assessed health outcomes as a primary outcome; we found no evidence or insufficient evidence to determine the comparative efficacy for improving health outcomes for most between-class comparisons. DPP-4 inhibitors compared with GLP-1 analogs Pooled data from 2 trials (N=75) found that exenatide XR was more efficacious than sitagliptin 100 mg once daily in reducing mean HbA1c over 12 to 26 weeks (WMD ; 95% CI, to -0.26) and weight (WMD -1.2; 95% CI, to -0.76) (low strength of evidence for both outcomes). One trial (N=665) found liraglutide at both dosages (1.2 mg and 1.8 mg) to be more efficacious than sitagliptin 100 mg once daily in reducing mean HbA1c at 26 and 52 weeks. The differences in mean HbA1c at 26 weeks were as follows: -0.4% (95% CI, to -0.16) for liraglutide 1.2 mg compared with sitagliptin 100 mg and -0.60% (95%

23 CI, to -0.4) for liraglutide 1.8 mg compared with sitagliptin 100 mg (low strength of evidence). One trial (N=665) found liraglutide at both dosages (1.2 mg and 1.8 mg) to be more efficacious than sitagliptin 100 mg once daily in reducing weight at 26 and 52 weeks. Change in weight at 26 weeks for each group was as follows: liraglutide 1.2 mg kg, liraglutide 1.8 mg -.8 kg, sitagliptin kg, P< for both comparisons (low strength of evidence). DPP-4 inhibitors compared with SGLT2 inhibitors We found no difference between canagliflozin 100 mg and sitagliptin 100 mg in reducing mean HbA1c over 12 to 52 weeks (low strength of evidence); one trial (N=74) found no between-group difference (0%; 95% CI, to 0.12), and another trial (N=129) reported similar reductions in HbA1c but did not report a measure of variance (-0.76% vs %). We found no difference between canagliflozin 00 mg and sitagliptin 100 mg in reducing mean HbA1c over 52 weeks (low strength of evidence). Canagliflozin 00mg once daily led to a greater reduction in mean HbA1c, however, the between-group differences in HbA1c was small (-0.15% to -0.7%) and below what is considered to be clinically significant (low strength of evidence for no difference between groups). Greater reduction in weight was seen with canagliflozin (at both doses) compared with sitagliptin (low strength of evidence). One trial found a between-group difference of - 2.4% (-.0 to -1.8) for canagliflozin 100 mg compared with sitagliptin 100 mg; a second trial found a between-group difference of -0.4% over 12 weeks (favoring canagliflozin), but did not report a measure of variance. Three trials found greater reduction in weight with canagliflozin 00 mg compared with sitagliptin 100 mg daily. Characteristics of Included Studies Seven trials compared a drug from one class of newer diabetes medications with a drug from a different class (Table 6). Four trials compared a DPP-4 inhibitor with a GLP-1 analog, and compared a DPP-4 inhibitor with an SGLT2 inhibitor All trials enrolled adults with type 2 diabetes; most included patients who were not at goal on metformin monotherapy prior to randomization. Study duration ranged from 12 to 52 weeks; no trials included health outcomes as a primary outcome of interest. Most trials excluded persons with significant comorbid conditions (including liver, kidney, and cardiovascular disease). A more detailed description of study characteristics and included populations by drug comparison is given below.

24 Table 6. Characteristics of included studies: Newer diabetes medications between-class comparisons Author, Year Trial Name Arm Dose, mg/day (N) EXE XR 2 mg/w (170) Bergenstal, SITA100 mg (172) Russell-Jones, EXE XR 2.0 mg/w (248) MET 2,000 mg (246) SITA 100 mg (16) SITA 100 mg (26) Charbonnel, LIRA mg (27) LIRA 1.2 mg (225) a Pratley, Pratley, Multinational Lavalle- Gonzalez, Rosenstock, ,Nicolle, LIRA 1.8 mg (221) SITA 100 mg (219) SITA 100 mg (66) CANA 100 mg (68) CANA 00 mg (67) SITA 100 mg (65) CANA 100 mg (64) CANA 00 mg (64) SITA 100 mg (78) Schernthaner, CANA 00 mg (78) Follow-up (weeks) Country , Multinational Multinational Multinational Mean age, Years %W % F Base-line HgA1c Base-line Weight (kg) Back-ground Therapy Quality Metformin Fair None Fair Metformin Fair Metformin Fair Metformin Good Multinational Multinational 52-5 NR Metformin Fair Multinational Metformin + Sulfonylurea Abbreviations: %F, percent female; %W, percent white; CANA, canagliflozin; EXE XR, exenatide extended release; LIRA, liraglutide; MET, metformin; mg, milligrams; N, number; SITA, sitagliptin a N in the extension study included 155 in the liraglutide 1.2 mg group, 176 in the liraglutide 1.8 mg group, and 166 in the sitagliptin 100 mg group Good

25 Detailed Assessment DPP-4 inhibitors compared with GLP-1 analogs Study characteristics Four trials compared a DPP-4 inhibitor with a GLP-1 analog Two trials compared sitagliptin 100 mg once daily with exenatide XR 2.0 mg weekly. 24,25 Two trials compared sitagliptin 100 mg once daily with liraglutide at various doses. 26,27 All trials included adults with type 2 diabetes; one trial only enrolled people who were not taking a medication for diabetes; 25 the other trials enrolled people who were not at goal on metformin monotherapy. Mean ages ranged from 52 to 58 years; 7% to 44% of participants were women. A majority of patients in most trials were white; one trial enrolled a minority of white participants (0% to %). 24 Baseline HbA1c was similar across all 4 trials (8.1% to 8.5%); baseline weight ranged from 87 kg to 95 kg. All trials were conducted in multinational settings, and all were industry sponsored. Sitagliptin compared with exenatide XR Two trials compared sitagliptin with exenatide XR over 26 weeks (Table 6). 24,25 One trial reported on macrovascular outcomes; no patients experienced coronary artery occlusion or unstable angina, one person receiving sitagliptin experienced a cerebrovascular event. 24 The trial by Russell-Jones and colleagues reported mortality rate over 26 weeks; there were no deaths in either group. 25 Our meta-analysis (2 trials N=75; Appendix E) found that exenatide XR was more efficacious than sitagliptin 100 mg once daily in reducing mean HbA1c over 26 weeks (WMD ; 95% CI, to -0.26). Our meta-analysis (2 trials N=75; Appendix E) found that exenatide XR was associated with greater weight loss over 26 weeks compared with sitagliptin 100 mg once daily (WMD - 1.2; 95% CI, to -0.76). 25 Sitagliptin compared with liraglutide One trial (N=665) compared liraglutide 1.2 mg daily, liraglutide 1.8 mg daily, and sitagliptin 100 mg daily over 26 weeks; 27 this trial included an extension period at 52 weeks. 1 All study participants were on metformin 1500 mg daily as background therapy. Over 52 weeks, there was one death in the group randomized to liraglutide 1.2 mg once daily, no deaths among those randomized to 1.8 mg once daily, and 2 deaths among those randomized to sitagliptin 100 mg daily. Liraglutide (at both dosages) was more efficacious in reducing mean HbA1c compared with sitagliptin over 26 weeks (change in HbA1c: liraglutide 1.2 mg -1.24%; liraglutide 1.8 mg - 1.5%; sitagliptin -0.6%; P< for both doses of liraglutide compared with sitagliptin). The differences in mean HbA1c at 26 weeks were -0.4% (95% CI, to -0.16) for liraglutide 1.2 mg once daily compared with sitagliptin 100 mg once daily and -0.60% (95% CI, to -0.4) for liraglutide 1.8 mg once daily compared with sitagliptin 100 mg once daily. Liraglutide was associated with greater weight loss (at both dosages) compared with sitagliptin over 26 weeks (change in weight: liraglutide 1.2 mg, kg; liraglutide 1.8 mg, -.8 kg; sitagliptin, kg; P< for both comparisons). Similarly, at 52 weeks, both dosages of liraglutide were more efficacious in reducing mean HbA1c compared with sitagliptin: liraglutide 1.2 mg daily, % (95% CI, -1.4 to ); liraglutide 1.8 mg daily, -1.51% (95% CI, to -1.7); sitagliptin 100 mg daily, -0.88%

26 (95% CI, to -0.74), P< for both comparisons. The differences in mean HbA1c at 52 weeks were -0.40% (95% CI, to -0.22) for liraglutide 1.2 mg once daily compared with sitagliptin 100 mg once daily and -0.6% (95% CI, to -0.44) for liraglutide 1.8 mg once daily compared with sitagliptin. At 52 weeks, liraglutide (at both doses) was associated with greater weight loss than sitagliptin 100 mg daily; between-group difference for liraglutide 1.2 mg compared with sitagliptin 100 mg daily was kg (95% CI, -2.4 to -0.82) and for liraglutide 1.8 mg compared with sitagliptin 100 mg daily, the difference was -2.5 kg (95% CI, -. to 1.72), P<0.001 for both comparisons. DPP-4 inhibitors compared with SGLT2 inhibitors Study characteristics Three trials (described in 4 publications) compared sitagliptin to canagliflozin (Table 6). 28-0,2 Two trials compared sitagliptin 100 mg with 2 different doses of canagliflozin (100 mg and 00 mg), 28,29,2 and one trial compared sitagliptin 100 mg to canagliflozin 00 mg. 0 Two trials reported outcomes at 52 weeks 28,0 and one reported outcomes at 12 weeks. 29 All trials included adults with type 2 diabetes not at goal on metformin 28,29 or metformin and a sulfonylurea. 0 Mean ages ranged from 52 to 57 years; 42% to 55% of participants were women. One trial did not report on race or ethnicity; 29,2 a majority of participants in 2 trials were white. 28,0 Across all trials, baseline HbA1c was 7.6 to 8.1, and mean weight ranged from 85 kg to 89 kg. All trials were conducted in multinational settings and sponsored by the same pharmaceutical company (Janssen Global Services, LLC.). Two trials were rated as good quality, 28,0 and one was rated as fair. 29,2 Sitagliptin compared with canagliflozin Two trials reported mortality rates. In one trial, one person receiving sitagliptin and one person receiving canagliflozin 00mg died over 52 weeks, compared with no deaths in the group receiving canagliflozin 100mg daily. 28 In the other trial, no deaths occurred among persons receiving sitagliptin, and 2 deaths occurred among persons receiving canagliflozin 00 mg over 52 weeks. 0 Results for HbA1c and weight are presented in Table 7. One trial reported outcomes at 12 weeks, but did not provide a measure of variance (e.g., standard error or confidence interval) or P-value for the difference between groups. 29,2 Over 52 weeks, one trial found no difference between canagliflozin 100 mg and sitagliptin 100 mg in reducing mean HbA1c. 28 Canagliflozin 00 mg was associated with a greater reduction in HbA1c than sitagliptin in two trials; one trial found a small but statistically significant difference favoring canagliflozin over 52 weeks (- 0.15%; 95% CI, to -0.0). 28 The second trial also found a greater reduction in mean HbA1c favoring canagliflozin 00mg over sitagliptin 100mg (-0.7%; 95% CI, to -0.25). 0 Two trials found that canagliflozin was associated with a greater reduction in weight (at both doses) at 52 weeks. 28,0

27 Table 7. Randomized controlled trials comparing canagliflozin and sitagliptin: Results for hemoglobin A1c and weight Author, year Comparison (N) Duration (weeks) Change in HbA1c Change in Weight Rosenstock, ,Nicoll e, CANA 100 mg (64) SITA 100 mg (65) 12 CANA: -0.76% SITA: -0.74% No variance reported CANA: -2.7% a SITA: -2.% No variance reported Rosenstock, ,Nicoll e, Lavalle- Gonzalez, Lavalle- Gonzalez, CANA 00 mg (64) SITA 100 mg (65) CANA 100 mg (68) SITA 100 mg (66) CANA 00 mg (67) SITA 100 mg (66) CANA 00 mg (77) Schernthaner, SITA 100 mg (78) CANA: -0.92% SITA: -0.74% No variance reported Between-group difference: 0% (95%CI to 0.12) Between-group difference: -0.15% (95% CI, to -0.0) Between-group difference: -0.7% CANA: -.4% a SITA: -2.% No variance reported Between-group difference: -2.4% (95% CI, -.0 to -1.8) Between-group difference: -2.9% (95% CI, -.4 to -2.) Between-group difference: -2.4 kg, P<0.001 (95% CI, to -0.25) Abbreviations: CANA, canagliflozin; kg, kilograms; SITA, sitagliptin a Data on weight was given as percent change in body weight from baseline for each group; data was presented in a figure only and no measure of variance was reported in the text (e.g., p-value or confidence interval). III. Newer Diabetes Medications compared with Metformin Key Findings Twelve trials compared a newer diabetes drug with metformin. Eight compared a DPP-4 inhibitor with metformin: linagliptin (1 trial), alogliptin (1 trial), sitagliptin (4 trials), and saxagliptin (2 trials). No trial assessed health outcomes as a primary outcome; we found insufficient evidence to determine the comparative efficacy for improving health outcomes for most between class comparisons. DPP-4 inhibitors compared with metformin One trial (N=4) found no difference between linagliptin 5 mg and metformin 500 mg twice daily for reduction in HbA1c (low strength of evidence). Metformin 1,000 mg twice daily was more efficacious than linagliptin in reducing mean HbA1c (moderate strength of evidence), between-group difference: -0.60% (95% CI, -0.2 to -0.88). One trial (N=4) found greater weight reduction with metformin (at 500mg and 1000mg twice daily) compared with linagliptin at 24 weeks in one trial (low strength of evidence). The difference in mean change from baseline for metformin 500 mg twice daily compared with linagliptin 5 mg once daily was kg (95% CI, -0.1 to -1.49); and kg (95% CI, to -1.29) for linagliptin compared with metformin 1000 mg twice daily.

28 One trial (N=7) found no difference between alogliptin 12.5 mg twice daily and metformin 500 mg twice daily at 26 weeks for reducing mean HbA1c, between-group difference: 0.09%; 95% CI, to 0.5 (low strength of evidence). However, metformin 1000 mg twice daily was more efficacious compared with alogliptin 12.5 mg twice daily (moderate strength of evidence): between-group difference, -0.55% (95% CI, to -0.81). One trial (N=7) found greater weight reduction with metformin (at both doses) compared with alogliptin 12 mg twice daily (low strength of evidence). The difference in mean weight change from baseline for metformin 500 mg twice daily compared with alogliptin 12.5 mg twice daily was kg (95% CI, to -1.58), and for metformin 1000 mg twice daily compared with alogliptin 12.5 mg twice daily, the difference in mean weight change from baseline was -1.4 kg (95% CI, to -0.45). Metformin 2000 mg daily was more efficacious than sitagliptin 100mg daily in reducing mean HbA1c (moderate SOE). Our meta-analysis ( trials; N=1655) found that metformin 2000mg per day was more efficacious than sitagliptin 100mg daily (WMD - 0.0%; 95% CI, to -0.09, I 2= 84.7%); all trials found a statistically significant benefit favoring metformin, one trial found a smaller magnitude of effect (-0.14%) than the other 2 trials (-0.% and -0.47%). Metformin 2000 mg was associated with a greater reduction in weight compared with sitagliptin 100 mg over 24 to 54 weeks (low strength of evidence); mean difference between groups ranged from -1.2 kg to -1.7 kg. Our meta-analysis (2 trials; N=1677) found no difference in HbA1c with the addition of saxagliptin 5 mg compared with uptitration of metformin in patients not at goal on submaximal doses of metformin (WMD, -0.1; 95% CI, to 0.1) (low strength of evidence). Two trials found inconsistent results; one trial found greater reduction in HbA1c with the addition of saxagliptin 5 mg compared with uptitration of metformin (between-group difference: -0.5; 95% CI, to -0.2) and another trial found no difference in the change from baseline (between-group difference: -0.09%; 95% CI, to 0.08). In one trial (N=282), the uptitration of metformin was associated with a greater reduction in weight compared with adding saxagliptin 5 mg, between-group difference: -0.9kg (95% CI, to -1.56). GLP-1 analogs compared with metformin One trial (N=59) found greater reduction in HbA1c with exenatide twice daily compared with metformin 500mg times daily over 26 weeks: -2.6% vs. -1.6%, respectively; P <0.045 (insufficient strength of evidence; 1 trial, unknown consistency). The same trial found greater reduction in weight with exenatide (-5.8 kg) compared with metformin (-.81 kg) over 26 weeks, P <0.01 (insufficient strength of evidence; 1 trial, unknown consistency). One trial (N=494) found no difference for reducing HbA1c between exenatide XR and metformin 1,000 mg twice daily: -1.5% vs.-1.48%, P=0.62 (insufficient strength of evidence; 1 trial, unknown consistency). The same trial found no difference in weight reduction between exenatide XR and metformin; both groups lost an average of 2 kg over 24 weeks (insufficient strength of evidence; 1 trial, unknown consistency).

29 SGLT2 inhibitors compared with metformin Three trials found no difference in mortality rates between groups receiving metformin XR 1500 mg to 2000 mg daily and dapagliflozin at both doses (low strength of evidence over 12 to 26 weeks). We found no difference between dapagliflozin and metformin for reducing HbA1c. We pooled 2 trials (N=505) in a meta-analysis; there was no difference between dapagliflozin 5 mg compared with metformin XR 1500 mg to 2000 mg daily (WMD -0.12; 95% CI, to -0.08) Our meta-analysis of 2 trials (N=522) found that dapagliflozin 10 mg was associated with a small but statistically significant greater reduction in HbA1c compared with metformin XR 1500 mg to 2000 mg daily found (WMD %; 95% CI, to ). The direction of effect favored dapagliflozin, but overall magnitude of effect was small and not within a range that is considered clinically significant. Dapagliflozin is associated with greater weight reduction over 24 weeks compared with metformin (low strength of evidence). Our meta-analysis (2 trials; N=505) found a greater reduction with dapagliflozin 5 mg compared with metformin XR 1500 mg to 2000 mg daily (WMD kg; 95% CI, to -0.26); similarly, a greater reduction in weight was seen with dapagliflozin 10 mg compared with metformin XR 1500 mg to 2000 mg (WMD -1. kg; 95% CI, -1.8 to -0.7). Twelve trials (described in 12 publications) compared a newer diabetes drug with metformin. Of these, 8 trials compared a DPP-4 inhibitor with metformin: linagliptin (1 trial), alogliptin (1 trial), 4 sitagliptin (4 trials), 25,5-7 and saxagliptin (2 trials). 8,9 Two trials compared metformin with a GLP-1 analog; 1 trial compared metformin with exenatide administered twice daily over 26 weeks, 40 and the other -arm trial that compared exenatide XR with metformin and sitagliptin. 25 Three trials compared an SGLT2 inhibitor (dapagliflozin) with metformin; the publication by Henry et al. describes the results of two separate trials. 41,42 Table 8 presents study characteristics for included trials comparing newer diabetes drugs with metformin.

30 Table 8. Characteristics of included studies: Newer diabetes medications compared with metformin Author, Year Trial Name Arm Dose, mg/day (N) LINA 5 mg (142) Follow-up (weeks) Country Mean age, Years %W %F Base-line HgA1c Base-line Weight (kg) Background Therapy Quality MET 1000 mg (144) Haak, 2012 MET 2000 mg (147) LINA 5 mg +MET 1000 mg (14) 24 Multinational None Fair LINA 5 mg + MET 2000 mg (14) LINA 5 mg (55) Haag, MET 1000 mg 2000 mg (65) ALO 25 mg a (112) 12 Multinational NR NR None Fair ALO 25 mg b (11) MET 1000 mg (114) Pratley, MET 2000 mg (111) 26 Multinational None Fair ALO 25 mg + MET 1000 mg (111) ALO 25 mg + MET 2000 mg (114) Aschner, SITA 100 mg 455) MET 2000 mg (49) c Derosa, SIT 100 mg (75) MET 1700 mg (76) Multinational NR NR None Fair 52 Italy NR PIO d Fair

31 Author, Year Trial Name Goldstein, Williams- Herman, Williams- Herman, Russell-Jones, Fonseca, Arm Dose, mg/day (N) SITA 100 mg (179) MET 1000 mg (82) MET 2000 mg (182) SITA 100 mg+ MET 1000 mg (190) SITA 100 mg+ MET 1000 mg (182) EXE 2.0 mg/w MET 2,000 mg Follow-up (weeks) Country 26 SITA 100 mg SAXA 5 mg + MET XR 1500 mg (18) 18 MET XR uptitrated to 2000 mg e (144) SAXA 5 mg (147) Hermans, MET uptitrated to 2000 mg f (19) 24 24, 54, 104 Multinational Multinational Multinational Multinational Mean age, Years %W %F Base-line HgA1c Base-line Weight (kg) Background Therapy Quality NR None Fair None Fair NR NR MET XR 1500 mg MET 1500 mg 40 EXE 10 µg () Yuan, China NR None Fair MET1500 mg (25) g DAPA 5 mg (20) Fair Fair Henry, h MET XR 2000 mg (201) i DAPA 5 mg+ MET XR 2000 mg (194) 24 Multinational 52 NR None Fair

32 Author, Year Trial Name Arm Dose, mg/day (N) DAPA 10 mg (219) Follow-up (weeks) Country Mean age, Years %W %F Base-line HgA1c Base-line Weight (kg) Background Therapy Quality Henry, 2012 h42 MET XR 2000 mg (208) i List, DAPA 10 mg+ MET XR 2000 mg (211) DAPA 5 mg (58) DAPA 10 mg (47) MET XR 1500 mg (56) j Multinational Multinational 52 NR None Fair NR None Fair Abbreviations: %F, percent female; %W, percent white; ALO, alogliptin; DAPA, dapagliflozin; EXE, exenatide; LINA, linagliptin; MET, metformin; MET XR, metformin extended release; mg, milligrams; N, number; PIO, pioglitazone; SAXA, saxagliptin; SITA, sitagliptin; µg, micrograms a Patients in this group were randomized to alogliptin 12.5 mg twice daily. b Patients in this group were randomized to alogliptin 25 mg once daily. c Eligible patients were started on metformin 500mg once daily and up-titrated to metformin 1000mg twice daily during the initial 5 weeks of the study. d This trial enrolled patients not at goal on pioglitazone 0mg/day. The group randomized to sitagliptin continued pioglitazone 0mg/d and the group randomized to metformin received pioglitazone 15mg/day. The reason for the discrepancy in pioglitazone doses was not explained. e Eligible patients were stabilized on metformin XR 1500 mg daily during a lead-in period; those who had a HbA1c between 7.0 and 10.5 were randomized to receive to either the addition of saxagliptin 5 mg or uptitration of metformin XR to 2000 mg daily. f Eligible patients were stabilized on metformin 1500 mg daily during a lead-in period; those who had a HbA1c between 7.0 and 10.5 were randomized to receive either the addition of saxagliptin 5 mg or uptitration of metformin to 2000 mg daily. g Metformin was started at a dose of 500 mg twice daily for 4 weeks, then increased to 500 mg times a day during weeks h The publication by Henry et. al. reports results from two separate trials, each with three arms. In one trial dapagliflozin was dosed at 5mg and in the other trial dapagliflozin was dosed at 10mg. i Starting dose of metformin XR was 500 mg daily and increased to 2000mg daily over the initial 8 weeks of the study period. j Starting dose of metformin XR was 750 mg daily and increased to1500mg at week 2.

33 All trials enrolled adults with type 2 diabetes. Most included people who were not previously taking a medication for diabetes; one included patients not at goal on pioglitazone. 6 Two trials compared the addition of a newer diabetes drug to uptitration of metformin in patients not at glycemic control on a submaximal dose of metformin. 8,9 Study duration ranged from 12 to 26 weeks in most trials; 1 trial only reported outcomes at 52 weeks, and 1 trial included an extension period that reported outcomes at 54 and 102 weeks. Most excluded those with significant comorbid conditions or those who had an HbA1c >11.0. A more detailed description of study characteristics and included populations is given below by drug comparison. Detailed Assessment DPP-4 inhibitors compared with metformin Study characteristics Eight trials compared a DPP-4 inhibitor with metformin: linagliptin (1 trial), alogliptin (1 trial), 4 sitagliptin (4 trials), 25,5-7 and saxagliptin (2 trials). 8,9 One trial compared sitagliptin 100 mg daily to metformin 850 mg twice daily as add-on therapy in a population not controlled with pioglitazone monotherapy; 6 2 trials compared the addition of sitagliptin to uptitration of metformin in patients who were not controlled on a submaximal dose of metformin. 8,9 The other 5 trials included people who were not taking any other medication for diabetes. Mean ages ranged from 52 to 59. In trials, less than half of participants were women; 25,,9 across all other trials, women made up approximately half of the included population. Two trials did not report patient race or ethnicity, 5,6 one trial included a majority of Hispanic participants, 8 and another included a majority of white participants. Baseline HbA1c ranged from 8. to 8.9 in most trials; one trial included a population with a baseline HbA1c of Baseline weight ranged from 77 kg to 89 kg in most trials; 4 trials did not report baseline weight. 5,7-9 One trial was conducted in Italy, 6 and all others were conducted in multinational settings. Most trials were funded by industry; 2 were not. 4,6 All trials were rated as fair quality. Linagliptin compared with metformin At 24 weeks, there was no significant difference in mean change from baseline hemoglobin A1c between those receiving linagliptin 5 mg daily and those receiving metformin 500 mg twice daily (-0.10%; 95% CI, 0.18 to -0.0). Metformin 1000 mg twice daily was more efficacious in reducing mean HbA1c than linagliptin 5 mg daily (-0.60%; 95% CI, to -0.2). Greater weight loss was seen with metformin (at both doses) compared with linagliptin at 24 weeks. The difference in mean change from baseline for metformin 500 mg twice daily and linagliptin 5 mg once daily was kg (95% CI, to -0.1); and kg (95% CI, to -1.11) for linagliptin compared with metformin 1000 mg twice daily. Alogliptin compared with metformin One trial compared alogliptin 25 mg daily (2 arms: one received 12.5 mg twice daily and the other received 25 mg once daily) with 2 doses of metformin (500 mg twice daily and 1000 mg twice daily) over 26 weeks. 4 No deaths or heart failure-related events were reported in any group. Two patients receiving alogliptin 12.5 mg twice daily suffered an ischemic stroke (one was noted to have an ischemic stroke and the other a cerebrovascular accident, but the

34 difference in classification was not provided), and 1 patient receiving alogliptin 25 mg once daily suffered a myocardial infarction. Alogliptin produced similar reductions in mean HbA1c regardless of schedule (alogliptin 25 mg once daily: -0.52% [no variance reported] and alogliptin 12.5 mg twice daily: -0.56% [SE 0.09]). The trial did not compare alogliptin directly to metformin (only to a fixed drug combination, discussed in a separate section). We calculated the between-group difference for alogliptin 12.5 mg compared with metformin 500 mg at 26 weeks; there was no difference between groups (0.09%; 95% CI, to 0.5). Metformin 1000 mg twice daily was more efficacious than alogliptin 12.5 mg twice daily in reducing mean HbA1c (between-group difference: -0.55%; 95% CI, to -0.81). For weight outcomes, metformin (at both dosages) was associated with greater weight loss than alogliptin 12.5 mg twice daily; kg (95% CI, to 1.58) for metformin 500 mg twice daily compared with alogliptin 12.5 mg twice daily and -1.4 kg (95% CI, to 2.02) for metformin 1000 mg twice daily compared with alogliptin 12.5 mg once daily. Sitagliptin compared with metformin Four trials compared sitagliptin with metformin. 25,5-7 One trial did not report health outcomes. 6 The other trials reported mortality over 24 to 26 weeks. In 1 trial, one patient receiving sitagliptin died and there were no deaths in the metformin group. 5 In the other 2 trials, 1 death occurred among those taking metformin and no deaths occurred in the sitagliptin group. 25,7 Three trials reported mean change from baseline HbA1c over 24 to 26 weeks. 25,5,7 One of these also reported outcomes from an extension trial over 54 and 102 weeks. 7,44,45 The fourth trial reported outcomes at 52 weeks only. 6 Our meta-analysis ( trials; N=1655) found that metformin 2000 mg per day was more efficacious than sitagliptin 100 mg daily (WMD -0.0%; 95% CI, to -0.09, I %). All trials found a statistically significant benefit favoring metformin; one trial found a smaller magnitude of effect (-0.14%) than the other 2 trials (-0.% and -0.47%). A fourth trial found no difference in HbA1c at 52 weeks between the 2 groups, but did not report a measure of variance. 6 Two trials reported the mean change in weight between the two groups, neither reported a measure of variance. Both found a greater weight loss with metformin compared with sitagliptin, the between group differences were 1. kg and 1.2 kg. 5,6 The trial by Goldstein et al. includes extension studies reporting efficacy outcomes over 52 and 104 weeks. 44,45 This data is limited by high attrition and possible contamination due to the high percentage of patients who received a sulfonylurea for HbA1c >7.5% after week 54. Overall the extension trials found that improvements in glycemic control were sustained. Data for these extension trials is provided in the Evidence Tables published as a separate document. Saxagliptin compared with uptitrated metformin Two trials compared saxagliptin 5 mg to metformin. 8,9 Both enrolled patients who were not at goal on submaximal dosages of metformin; patients were randomized to receive either the addition of saxagliptin 5 mg to metformin or uptitration of metformin from 1500 mg daily to 2000 mg daily. In one trial, one person receiving saxagliptin experienced myocardial ischemia, compared with no events in the metformin group; in the same trial, one person in the metformin group experienced a myocardial infarction compared with no events in the saxagliptin group. 8 One reported mortality over 24 weeks, one patient died in each group: aortic dissection (saxagliptin) and malignant tongue neoplasm (metformin). 9

35 Our meta-analysis (2 trials; N=1677) found no difference between the addition of saxagliptin 5 mg and the uptitration of metformin for reduction in HbA1c over 18 to 24 weeks (WMD, -0.1; 95% CI, -0.74% to 0.1, I 2 =84.7%). The 2 trials found inconsistent results; the trial by Fonseca et al., the addition of saxagliptin 5 mg was more efficacious in reducing mean HbA1c compared with uptitrating metformin (between-group difference: -0.5; 95% CI, to -0.2). 8 In the trial by Hermans et al., there was no difference in the mean HbA1c change from baseline (between-group difference: -0.09; 95% CI, to 0.08). 9 The heterogeneity in findings could be due to differences in included populations: the trial Fonseca et al. was conducted primarily in a Hispanic population (67%), while the trial by Hermans et. al included a population that was 99% white. One trial reported changes in weight; 8 the uptitration of metformin was associated with a greater reduction in weight compared with adding saxagliptin 5 mg (between-group difference: kg; 95% CI, to -1.56). GLP-1 analogs compared with metformin Study characteristics Two trials compared a GLP-1 analog with metformin. In one trial, participants received either exenatide10 µg twice daily or metformin 1000 mg to 1500 mg daily 40 and in the other trial, participants received either exenatide XR 2 mg weekly or metformin 2000 mg daily; 25 both trials measured outcomes at 26 weeks. 25 Patients in both trials were not taking other medications for diabetes at baseline. Mean ages ranged from 7 to 54; 7% to 54% of participants were women. One trial was set in China; 40 the other was set in multinational settings and included a majority of white participants. Mean HbA1c ranged from 8.1% to 8.9%; baseline weight ranged from 82 kg to 89 kg. Both trials were rated as fair quality. Exenatide compared with metformin One trial (N=59) set in China compared exenatide10 µg twice daily to metformin over 26 weeks. 40 No health outcomes were reported. Exenatide was more efficacious in reducing mean HbA1c (-2.10%; SD 1.79) compared with metformin 500 mg twice daily (-1.66%; SD 1.8), P= Treatment with exenatide resulted in greater weight loss than metformin; -5.8 kg (SD 1.66) vs kg (SD 1.8) respectively, P< Exenatide XR compared with metformin One trial (N=820) compared exenatide XR 2 mg weekly to metformin 2000 mg per day over 26 weeks. 25 One person in the metformin group died, compared with no patients in the exenatide group. There was no difference between exenatide XR and metformin for reducing HbA1c over 26 weeks (exenatide XR -1.5% [SE 0.07] compared with metformin -1.48% [SE 0.07]; P=0.62). No difference was found in weight loss between the 2 groups; both groups experienced a mean weight loss of 2 kg from baseline (p=0.892). 25 SGLT2 inhibitors compared with metformin Study characteristics Three trials compared dapagliflozin with metformin in patients not taking other medications for diabetes (Table 8). Two trials compared dapagliflozin with metformin XR 2000 mg over 24 weeks; one evaluated dapagliflozin at 5 mg and the second evaluated dapagliflozin at 10 mg,

36 both trials were reported in one publication. 42 In both trials by Henry et.al, patients randomized to metformin started at 500 mg, and the dose was uptitrated to a maximum of 2000 mg over the initial 8 week study period. The other trial compared dapagliflozin at 2 doses (5 mg and 10 mg) with metformin XR 1500 mg over 12 weeks; 41 similarly, in this trial, patients were started at a lower dose of metformin XR (750 mg), which was uptitrated to 1500 mg during the study period. Mean ages ranged from 52 to 54; approximately half of participants were women. Race or ethnicity was not reported by either trial. Mean HbA1c ranged from 7.6% to 8.0% in one trial 41 and from 9.1% to 9.2% in the other. 42 Baseline weight ranged from 86 kg to 89 kg. Both trials were conducted in multinational settings, and both were rated as fair quality. Dapagliflozin compared with metformin One trial reported no deaths at 12 weeks. 41 In the trial by Henry et al comparing dapagliflozin 5mg with metformin, one person receiving dapagliflozin died compared with no deaths in the metformin group. In the trial by Henry et al. comparing dapagliflozin 10mg with metformin, there were no deaths in the dapagliflozin group compared with one death in the metformin group. 42 Our meta-analyses found that dapagliflozin (at both dosages) was associated with greater reduction in HbA1c than metformin XR 1500 mg to 2000 mg daily. However, the difference between groups was small, and not within a range generally considered to be a clinically significant change in HbA1c; for dapagliflozin 5 mg compared with metformin XR (2 trials; N=505), WMD -0.12% (95% CI, to -0.08), and for dapagliflozin 10 mg compared with metformin XR (2 trials; N=522), WMD -0.11% (95% CI, to -0.05). 41,42 In the two trials led by Henry et al., no difference was found for reduction in HbA1c between dapagliflozin (at either dose) and metformin XR 2000 mg daily over 26 weeks. 42 The trial by List et al. was shorter in duration (12 weeks); patients randomized to metformin were started at a dose of 750 mg, which was titrated to 1500 mg at week Our meta-analysis (2 trials; N=505) found that dapagliflozin 5 mg was associated with greater weight loss than metformin XR 1500 mg to 2000 mg daily (WMD kg; 95% CI, to -0.26); similarly, dapagliflozin 10 mg was associated with a greater weight loss than metformin XR 1500 mg to 2000 mg daily (WMD -1. kg; 95% CI, -1.8 to -0.7). IV. Fixed-dose Combination Products (FDCPs) or Dual Therapy Key Findings Four trials compared either an FDCP or dual therapy with a DPP-4 inhibitor and metformin with the individual components. No trials reported a health outcome as a primary outcome; evidence was general insufficient to determine whether FDCP or dual therapy led to improved health outcomes compared with component monotherapy. Kazano (FDCP of alogliptin plus metformin) was more efficacious than monotherapy for all dose comparisons; between-group differences ranged from -0.44% to -0.99%, P<0.001 for all comparisons (moderate strength of evidence). Greater reduction in weight was seen with Kazano 12.5 mg/1000 mg twice daily than component monotherapy with alogliptin 12.5 mg twice daily: kg (p<0.00), moderate strength of evidence. Weight changes were similar across all other groups (moderate strength of evidence for no difference). One trial (N=791) found greater reduction in HbA1c with linagliptin plus metformin dual

37 therapy than with component monotherapy over 24 weeks. Between-group difference for linagliptin 2.5 mg plus metformin 500 mg and component monotherapy ranged from 0.60% to 0.70%; between-group differences for linagliptin 2.5 mg twice daily plus metformin 1000 mg twice daily and component monotherapy ranged from -0.5% to %, P<0.001 for all comparisons (moderate strength of evidence). Linagliptin 2.5 mg plus metformin 1000 mg twice daily was associated with greater reduction in weight than linagliptin 5 mg daily ( 1.00 kg; 95% CI, 1.59 to 0.41), low strength of evidence. No other groups experienced a significant change in weight (low strength of evidence). The group receiving linagliptin 2.5 mg twice daily plus metformin 500 mg had a small but statistically significant weight gain compared to patients receiving metformin 500 mg twice daily (0.60 kg; 95% CI, 0.01 to 1.19). Two trials assessed dual therapy with sitagliptin plus metformin. One compared dual therapy to monotherapy with metformin (but not a sitagliptin arm). Our meta-analysis (2 trials; N=1478) found greater reduction in HbA1c with sitagliptin100 mg plus metformin 2000 mg over 18 to 24 weeks compared with metformin monotherapy (WMD -0.60%; 95% CI, to -0.45). In one trial, greater reduction in HbA1c was found with dual therapy (both dosages of metformin plus sitagliptin) than with component monotherapy at 24 weeks, and in a 0 and 52-week extension period (range -0.4% to -1.2%). Two trials found no difference in weight change between sitagliptin plus metformin and component monotherapy. In one trial, sitagliptin plus metformin 200 mg was associated with greater weight loss than metformin alone at 18 weeks (between-group difference: kg; 95% CI, -2.1 to -1.1). The second trial found a similar reduction in weight with both dosages of sitagliptin plus metformin (-0.7 kg to -1.7 kg), metformin monotherapy (- 1.0 kg to -1.7 kg), and sitagliptin (-0.8 kg) over 26 weeks. Characteristics of Included Studies Four trials compared either an FDCP or dual therapy with a DPP-4 inhibitor and metformin with the individual components (Table 9). For this report, dual therapy was defined as using the individual components of an FDCP in separate pills/tablets. Studies were required to randomize subjects to the components of an FDCP or to monotherapy with one of the components of the FDCP to be eligible for this report. Studies continuing a background therapy (e.g., with metformin) and randomizing subjects to add-on one medication (e.g., saxagliptin) or to add-on placebo were classified as comparing that medication (e.g., saxagliptin) with placebo; we excluded these placebo comparisons from this updated report.

38 Table 9. Characteristics of included studies: Fixed-dose combination products or dual therapy Author, Year Trial Name Arm Dose, mg/day (N) LINA 5 mg (142) Follow-up (weeks) Country Mean age, Years %W %F Base-line HgA1c Base-line Weight (kg) Background Therapy Quality MET 1000 mg (144) Haak, 2012,46 MET 2000 mg (147) LINA 5 mg + MET 1000 mg (14) 24, 54 Multinational None Fair LINA 5 mg + MET 2000 mg (14) ALO 25 mg a (112) ALO 25 mg b (11) MET 1000 mg (114) Pratley, MET 2000 mg (111) 26 Multinational None Fair ALO 25 mg + MET 1000 mg (111) ALO 25 mg + MET 2000 mg (114) SITA 100 mg (179) Goldstein, MET 1000 mg (82) Williams-Herman, MET 2000 mg (182) Williams-Herman, SITA 100 mg+ MET 1000 mg (190) SITA 100 mg+ MET 1000 mg (182) 24, 54, 104 Multinational NR None Fair

39 Author, Year Trial Name Reasner, Arm Dose, mg/day (N) SITA 100 +MET 2000 mg FDCP (626) MET 2000 mg (624) Follow-up (weeks) Country Mean age, Years %W %F Base-line HgA1c Base-line Weight (kg) Background Therapy 18 US None Fair Abbreviations: %F, percent female; %W, percent white; ALO, alogliptin; LINA, linagliptin; MET, metformin; mg, milligrams; N, number; SITA, sitagliptin a Patients in this group were randomized to alogliptin 12.5 mg twice daily. b Patients in this group were randomized to alogliptin 25 mg once daily. Quality

40 Each FDCP or dual therapy included metformin with either alogliptin, 4 linagliptin, or sitagliptin. 7,47 In the 2 trials assessing dual therapy or FDCP of sitagliptin plus metformin, one compared dual therapy with both sitagliptin and metformin, 7 and the other trial compared dual therapy with metformin but not sitagliptin. 47 Mean ages ranges from 49 to 56. The majority of participants across all trials were white. Women made up a minority in 2 trials.,47 Baseline HbA1c ranged from 8. to 9.9. One trial did not report baseline weight; 7 across all other trials, baseline weight ranged from 79 kg to 97 kg. Across all trials, patients were not taking additional (i.e., background) medication for diabetes. One trial was set in the United States; 47 all others were set in multinational settings. All trials were rated fair quality. Detailed Assessment Kazano or dual therapy with alogliptin plus metformin One trial (N=784) compared 2 doses of Kazano (12.5/500 mg twice daily and 12.5/1000 mg twice daily) to various doses of its component monotherapies (alogliptin 25 mg once daily, alogliptin 12.5 mg twice daily, metformin 500 mg twice daily, metformin 1000 mg twice daily) 4 over 26 weeks. Participants were treatment naïve prior to entering the study. Both Kazano 12.5/500 mg twice daily and 12.5/1000 mg twice daily were more efficacious than component monotherapies in reducing mean HbA1c: alogliptin 25 mg daily: %, alogliptin 12.5 mg twice daily: 0.56% [SE 0.09], metformin 500 mg twice daily: 0.65% [SE 0.094], metformin 1000 mg twice daily: 1.11% [SE 0.092], Kazano 12.5/500 twice daily: 1.22% [SE 0.094], Kazano 12.5/1000 mg twice daily: 1.55% [SE 0.090]; P < for all comparisons of combination therapy compared with component monotherapies. Kazano 12.5/1000 mg twice daily resulted in greater weight loss than treatment with alogliptin 12.5 mg twice daily alone (-1.17 kg [SE 0.268] compared with kg [SE 0.288]; P=0.00). No difference in weight was found between the remaining comparators (alogliptin 25 mg daily: 0.1 kg, metformin 500 mg twice daily: kg [SE 0.28], metformin 1000 mg twice daily: kg [SE 0.270], Kazano 12.5/500 twice daily: kg [SE 0.28]). Jentadueto or dual therapy with linagliptin plus metformin One trial compared initial dual therapy with linagliptin plus metformin (at 2 dosages) to each component monotherapy over 24 weeks with an optional extension trial to 54 weeks. 46 Participants were randomized to 1 of 2 combinations of linagliptin 2.5 mg twice daily combined with metformin at either 500 mg or 1000 mg twice daily, or the respective monotherapies. At both doses, dual therapy was more efficacious than component monotherapies. The mean change from baseline HbA1c with dual therapy compared with each component is as follows: 0.70% (95% CI, 0.98 to 0.42) for linagliptin 2.5 mg twice daily plus metformin 500 mg twice daily compared with linagliptin 5 mg once daily; 0.60% (95% CI, 0.88 to 0.2) for linagliptin 2.5 mg twice daily plus metformin 500 mg twice daily compared with metformin 500 mg twice daily; 1.10% (95% CI, 1.8 to 0.82) for linagliptin 2.5 mg twice daily plus metformin 1000 mg twice daily compared with linagliptin 5 mg daily; and 0.50% (95% CI, 0.78 to 0.22) for linagliptin 2.5 mg twice daily plus metformin 1000 mg twice daily compared with metformin 1000 mg twice daily. In the extension trial, patients initially randomized to either metformin 500 mg or linagliptin 5 mg were reallocated to another arm; patients participating in the extension trial who continued in the original randomized groups were analyzed separately (e.g., non-switched

41 groups). 46 No further reduction in HbA1c or weight occurred over 24 to 54 weeks. Across all groups, the mean change in HbA1c from 26 to 54 weeks ranged from 0.12% to 0.% across both dual therapy groups and those taking metformin 100 mg twice daily. No difference was seen in the mean weight change from baseline in patients receiving linagliptin 2.5 mg twice daily plus metformin 500 mg twice daily compared with linagliptin 5 mg ( 0.0 kg; 95% CI, 0.89 to 0.29) or between the groups receiving linagliptin 2.5 mg twice daily plus metformin 1000 mg twice daily compared with metformin 1000 mg twice daily ( 0.0 kg; 95% CI, 0.89 to 0.29). Patients receiving linagliptin 2.5 mg twice daily plus metformin 1000 mg twice daily experienced greater weight loss than those receiving linagliptin 5 mg daily ( 1.00 kg; 95% CI, 1.59 to 0.41). Linagliptin 2.5 mg twice daily plus metformin 500 mg twice daily was associated with a small but statistically significant weight gain compared to patients receiving metformin 500 mg twice daily (0.60 kg; 95% CI, 0.01 to 1.19). Janumet or dual therapy with sitagliptin plus metformin Two trials compared sitagliptin plus metformin to at least one component monotherapy. 7,47 One 24 week trial 7 with an optional additional 0 weeks 44 and further additional 50 week extension 45 (Table10) compared initial dual therapy of sitagliptin plus metformin to sitagliptin monotherapy and metformin monotherapy. Patients were followed initially for 24 weeks, and then had the option to continue for 0 additional weeks and then an additional 50 weeks. In the second trial, patients received sitagliptin 50 mg plus metformin 500 mg twice daily in an FDCP twice daily (uptitrated to sitagliptin 50 mg plus metformin 1000 mg twice daily) or metformin 500 mg twice daily (uptitrated to 1000 mg twice daily) over 18 weeks; there was no arm that received sitagliptin monotherapy. 47 Our meta-analysis (2 trials) found that sitagliptin 100 mg plus metformin 2000 mg per day was more efficacious in reducing mean HbA1c over 18 to 24 weeks compared with metformin monotherapy (WMD -0.60%; 95% CI, to -0.45). Additional results from the trial by Goldstein et al. for the extension studies are provided in the Evidence Tables; as mentioned previously, this data is limited by high attrition and contamination due to multiple participants receiving a sulfonylurea for HbA1c >7.5% after week Across all outcome timings, dual therapy with sitagliptin plus metformin was more efficacious than component monotherapy. In one trial, sitagliptin plus metformin was associated with greater weight loss than metformin alone at 18 weeks (between-group difference: -1.6 kg; 95% CI, -2.1 to -1.1). 47 The second trial found a similar reduction in weight with both dosages of sitagliptin plus metformin, (-0.7 kg to -1.7 kg), metformin monotherapy (-1.0 kg to -1.7 kg), and sitagliptin (-0.8 kg) over 26 weeks. 7

42 Key Question 2. What is the comparative tolerability and frequency of adverse events for newer diabetes medications and drug combinations (administered as fixed dose combination products or dual therapy) for children and adults with diabetes mellitus? I. Intra-class Comparisons (within a class) Key Findings: Harms DPP-4 inhibitors: Sitagliptin compared with saxagliptin In 1 trial, rates of adverse events and withdrawals from adverse events were similar between groups over 18 weeks. The most commonly reported adverse events occurring in 2% or more of participants in either group were influenza, urinary tract infection, and nasopharyngitis. Overall, 24 people experienced hypoglycemia, 1 (.2%) in the saxagliptin group and 11 (2.8%) in the sitagliptin group. Most of the hypoglycemic events were considered mild; there were major hypoglycemic events in the sitagliptin group. GLP1-analogs: Exenatide 10 µg compared with liraglutide 1.8 mg In 1 trial, rates of withdrawal because of adverse events were similar between groups over 26 weeks. The incidence of nausea was similar between the groups initially, but was more persistent over time in the exenatide group. The proportion of patients who reported minor hypoglycemia was less in the liraglutide group than the exenatide group (26% compared with 4%, 1.9 compared with 2.60 events per patient per year, rate ratio 0.55, CI 0.4 to 0.88; P=0.011) (low strength of evidence). Neither group experienced adverse changes in lipid levels GLP-1 analogs: Exenatide XR compared with exenatide 10 µg Three trials compared exenatide 2 mg once weekly with exenatide 10 µg twice daily over 24 to 0 weeks. Our meta-analysis found no difference between groups for rates of withdrawals because of adverse events ( trials, N=1,22; RR 0.72; 95% CI, 0.5 to 1.50) (low strength of evidence for no difference) Our meta-analyses found a lower rate of nausea ( trials, N=1,22; RR 0.51; 95% CI 0. to 0.79) and vomiting ( trials N=1,22; RR 0.62; 95% CI, 0.45 to 0.87) with exenatide once weekly (low strength of evidence), but found no significant difference between groups for rates diarrhea ( trials N=1,22; RR 1.21; 95% CI, 0.86 to 1.72). (low strength of evidence for no difference) Injection site reactions were defined and reported differently in trials comparing exenatide 2 mg once weekly with exenatide 10 µg twice daily over 24 to 0 weeks. In all trials, patients receiving the exenatide once weekly dose experienced higher rates of injection site reactions. (moderate strength of evidence) No adverse lipid changes occurred in either group.

43 Characteristics of Included Studies We included 5 fair quality trials comparing drugs within the same class for key question 2. One compared saxagliptin with sitagliptin; 18 the other 4 compared 2 different GLP-1 analogs We rated 1 additional trial comparing different GLP-1 analogs poor for harms outcomes and did not include it in this section. 2 Details of the study characteristics for these 6 trials are presented in Table 5 in the corresponding section of KQ 1 and in the Evidence Tables (included in a separate file). Harms outcomes for the 5 trials eligible for this key question are summarized in Table 10. We found no trials assessing intra-class comparisons of amylin agonists or SGLT2 inhibitors. Detailed Assessment of for Intra-class Comparisons: Harms Sitagliptin compared with saxagliptin One trial compared sitagliptin 100 mg once daily with saxagliptin 5 mg once daily in adults already on stable doses of mg of metformin daily over 18 weeks. 18 There were no statistically significant differences in rates of adverse events or withdrawals from adverse events between the 2 groups. Nine participants in each group withdrew from the study because of adverse events. The most commonly reported adverse events occurring in 2% or more of participants in either group were influenza, urinary tract infection, and nasopharyngitis. Overall, 24 people experienced hypoglycemia, 1 (.2%) in the saxagliptin plus metformin group and 11 (2.8%) in the sitagliptin plus metformin group. Most of the hypoglycemic events were considered mild; there were major hypoglycemic events in the sitagliptin group. Exenatide 10 µg twice daily compared with liraglutide 1.8 mg once daily In 1 trial (N=464) comparing exenatide 10 µg twice daily with liraglutide 1.8 mg once daily, among patients who were not adequately controlled on background therapy with metformin, a sulfonylurea, or both, withdrawal rates because of adverse events were not significantly different between groups over 26 weeks. 19 In the liraglutide arm, 10% of participants withdrew because of adverse events, compared with 1% of participants in the exenatide arm. The incidence of nausea was similar between the groups initially, but was more persistent over time in the exenatide group. Otherwise, the distribution of adverse events was similar between the study arms. There were 2 major episodes of hypoglycemia in patients in the exenatide arm of the study who were also on a sulfonylurea. No major episodes of hypoglycemia occurred in the liraglutide arm of the study. The proportion of patients who reported minor hypoglycemia was significantly less in the liraglutide group than the exenatide group (26% compared with 4%, rate ratio 0.55, CI 0.4 to 0.88; P=0.011). Neither group experienced adverse changes in lipid levels. There was no significant difference in change in total cholesterol, LDL cholesterol, or HDL cholesterol between the exenatide and the liraglutide treatment arms. Reduction in triglycerides was significantly greater in the liraglutide group than the exenatide group ( 15.8 mg/dl [.9] compared with 8.9 mg/dl [.9] estimated treatment difference 6.9 mg/dl, CI 14. to 0.0; P=0.0485)

44 Exenatide XR 2 mg once weekly compared with exenatide 10 µg twice daily Three trials compared exenatide 2 mg once weekly with exenatide 10 µg twice daily over 24 to 0 weeks. Our meta-analysis showed no difference between groups for rates of withdrawals because of adverse events ( trials, N=1,22; RR 0.72; 95% CI, 0.5 to 1.50) (Appendix E). In the 26-week trial, the exenatide 10 µg twice daily group had a higher rate of withdrawal because of adverse events compared with the exenatide 2 mg once weekly group (10.4% vs. 4.4%). However rates between the groups were similar in the other two trials (Table 10). The most commonly reported adverse events included gastrointestinal events such as nausea, vomiting, and diarrhea. In the 26-week trial, rates of nausea and vomiting peaked between weeks 4 and 8 in both treatment groups and then decreased over the remaining weeks of the treatment period. Our meta-analyses found a lower rate of vomiting in the exenatide once weekly group ( trials, N=1,22; RR 0.62; 95% CI, 0.45 to 0.87) and a lower rate of nausea in the exenatide once weekly group ( trials, N=1,22; RR 0.51; 95% CI 0. to 0.79), but found no significant difference between groups for rates diarrhea ( trials N=1,22; RR 1.21; 95% CI, 0.86 to 1.72) (Appendix E). In the 26-week trial, injection site reactions, including induration, pruritus, and nodules occurred in 74 (21.8%) participants in the exenatide 2 mg once weekly group compared with 11 (.%) participants in the exenatide 10 µg twice daily group. Injection site pruritus occurred in 26 (17.6%) participants in the exenatide once weekly group and in 2 (1.4%) participants in the exenatide twice daily group in the 0-week trial. In the 24-week trial, injection site erythema occurred in 7 (5.4%) participants in the exenatide once weekly group and in (2.4%) participants in the exenatide twice daily group. Neither group experienced an adverse change in lipid levels in any of the trials.

45 Table 10. Adverse events of intra-class comparisons Ji, Drucker, Scheen, Blevins, Buse, Adverse event S100 Sax5 EXR Ex10 L1.8 Ex10 N (%) WD due to AE 9(2.) 9(2.2) 15(4) 9(6.1) 5(10) 7(4.8) 2(10) 1(1) 6(4.6) 6(4.9) Hypoglycemia 11(2.8) 1(.2) NR NR 60(26) 78(4) 7(11) 89(26) 60(26) 65(28) Nausea 9(2.) 4(1.0) 9(26.4) 18(14) 50(4.5) 4(5) 28(8) 41(12) 14(6) 2(9.9) Vomiting NR NR 16(10.8) 6(4.7) 27(18.6) 11(8.9) (10) 28(8) 29(12) 28(12) Diarrhea 10(2.5) 10(2.5) 20(1.5) 12(9.) 19(1.1) 5(4.1) Nasopharyngitis 16(4.0) 16(4.0) NR NR 27(12) 1(1) NR NR Upper respiratory 4(1.0) 9(2.2) 12(8.1) 25(17.2) tract infection 9(7) 5(4.1) 15(6) 14(6) Influenza 2(5.8) 2(5.7) NR NR NR NR Headaches 9(2.) 11(2.7) Urinary tract infections 21(5.) 2(5.7) NR NR 6(4.7) NR 15(10.1) NR NR 10(8.1) NR 12(8.) 21(9) 24(10) NR NR Pancreatitis NR NR --- b 0 0 a 0 Abbreviations: S100=sitagliptin 100 mg; Sax5=saxagliptin 5 mg; EXR=exenatide XR; Ex10=exenatide 10 µg; L1.8=liraglutide 1.8 mg; NR=not reported; a One episode of mild pancreatitis occurred in one patient taking liraglutide. Investigators considered this unlikely to be related to study medication. It was diagnosed in a person with a history of abdominal distension and hypercholesterolemia. b The study authors report that acute pancreatitis occurred in the exenatide 2 mg once weekly group, however the number of patients who experienced acute pancreatitis is not explicitly stated. NR NR II. Between-Class Comparisons: Harms Key Findings: Harms DPP-4 inhibitors compared with GLP-1 analogs Two trials compared exenatide 2 mg once weekly to sitagliptin 100 mg once daily over 26 weeks. The rate of withdrawals because of adverse events was higher with exenatide 2 mg once weekly than with sitagliptin 100 mg once daily (pooled relative risk 2.54; 95% CI, 1.00 to 6.4). Rates of nausea, vomiting, and diarrhea were higher with exenatide 2 mg once weekly than with sitagliptin 100 mg (pooled relative risks for nausea (2.62; 95% CI, 1.66 to

46 4.15), vomiting (.67; 95% CI, 1.6 to 8.24), and diarrhea (1.91; 95% CI, 1.22 to.00) (moderate strength of evidence). Neither drug caused adverse changes in lipid levels over 26 weeks. One trial compared liraglutide (1.2 mg or 1.8 mg daily) with sitagliptin 100 mg daily over 26 weeks and then continued the same treatment in a 26-week extension. At 26 weeks, the rate of withdrawal because of adverse events was higher in both liraglutide groups than in the sitagliptin group, 6.2% for liraglutide 1.2 mg, 6.8% for liraglutide 1.8 mg, and 1.8% for sitagliptin. Nausea occurred more frequently with liraglutide than with sitagliptin (21.7% liraglutide 1.2 mg; 27.5% liraglutide 1.8 mg, and 5.5% sitagliptin). The incidence of nausea was highest for the first weeks of treatment and then declined and remained low for weeks 26 through 52 (low strength of evidence). DPP-4 inhibitors compared with SGLT2 inhibitors Three trials (represented by 4 publications) compared sitagliptin 100 mg to canagliflozin 100 mg or 00 mg. The rate of withdrawal because of adverse events in the trials ranged from 0% to 5% and was similar between the sitagliptin groups and both doses of canagliflozin. Only 1 of the trials reported any gastrointestinal adverse event outcomes such as nausea or diarrhea. There were no significant differences between groups for these outcomes (low strength of evidence). None of the trials found significant differences between the sitagliptin groups and either dose of canagliflozin for urinary tract infections. Two of the trials reported higher incidences of genital mycotic infections in men and women taking canagliflozin compared to those taking sitagliptin, but neither study reported whether the differences between the groups were statistically significant. The third study reported higher rates of genital mycotic infections among women between the treatment groups (low strength of evidence). Rates of hypoglycemia were low (ranging from 0% to 7%) in the trials of canagliflozin 100 mg, canagliflozin 00 mg, and sitagliptin 100 mg (insufficient strength of evidence). In the 52-week trial in which patients were on a background treatment of metformin plus sulfonylurea, the rate of hypoglycemia was high in both the canagliflozin 00 mg and sitagliptin 100 mg arms with no difference between the groups (4% and 41% respectively) (low strength of evidence). A larger increase in LDL cholesterol occurred with canagliflozin 00 mg (11.7%) than with sitagliptin 100 mg (5.2%) (difference in least square means 6.4%; 95% CI, 1.7 to 11.2) (low strength of evidence). Study Characteristics For harms outcomes, we included 6 trials (8 articles) comparing a medication from one class of new diabetes medications with another. 24,25,27-2 We found 1 additional study that is not included in this section because it was rated poor for harms. 26 Details of these 7 trials (represented by 9 articles) are presented in Table 6 in the corresponding section of KQ 1 and in the Evidence Tables (included in a separate file).

47 Detailed Assessment for Between-class Comparisons: Harms DPP-4 inhibitors compared with GLP-1 analogs Sitagliptin compared with exenatide XR Two trials compared exenatide 2 mg once weekly to sitagliptin 100 mg daily over 26 weeks. 24,25 Our meta-analysis of withdrawals because of adverse events showed that patients receiving exenatide 2 mg once weekly were more likely to withdraw because of adverse events than patients receiving sitagliptin (N=2, RR for withdrawals because of adverse events 2.54; 95% CI, 1.00 to 6.4). Pooled relative risks for nausea (2.62; 95% CI, 1.66 to 4.15), vomiting (.67; 95% CI, 1.6 to 8.24), and diarrhea (1.91; 95% CI, 1.22 to.00) showed statistically significant higher risks of these adverse events with exenatide once weekly than with sitagliptin 100 mg one time daily. There were no statistically significant differences between exenatide XR and sitagliptin 100 mg for hypoglycemia (major or minor events), headache, or pancreatitis (Table 11 and Appendix E). One of the trials reported no significant changes from baseline in fasting serum lipid concentrations in either group. 25 The other study reported a significant improvement from baseline in HDL cholesterol in both groups, but no significant difference between the groups for changes in total cholesterol, HDL cholesterol, LDL cholesterol, or triglycerides. 24 Table 11. Meta-analysis comparing adverse events: Exenatide XR to sitagliptin 100 mg Outcome N Heterogeneity Measure Estimate 95% CI P value I 2 WD due to adverse event 2 RR , % Hypoglycemia a 2 RR , % Nausea 2 RR , % Vomiting 2 RR , % Diarrhea 2 RR , % Headache 2 RR , % Pancreatitis 2 RR , % a Results shown are for major hypoglycemia. See Appendix E for results of meta-analysis of minor hypoglycemia. Sitagliptin compared with liraglutide One trial compared liraglutide (1.2 mg or 1.8 mg daily) with sitagliptin 100 mg daily over 26 weeks and then continued the same treatment in a 26-week extension. 27,1 All participants were on metformin 1500 mg daily as background therapy. Sixty percent of the original 225 patients randomized to the liraglutide 1.2 mg group, 68% of the original 221 patients randomized to the liraglutide 1.2 mg group, and 69% of the original 219 randomized to the sitagliptin 100 mg group completed 52 weeks. The authors reported rates of adverse events based on the number of patients in each group who received at least one dose of study medication; this was 221 patients

48 in the liraglutide 1.2 mg group, 218 in the liraglutide 1.8 mg group, and 219 in the sitagliptin 100 mg group. At 26 weeks, the rate of withdrawal because of adverse events was higher in both liraglutide groups than in the sitagliptin group, 6.2% for liraglutide 1.2 mg, 6.8% for liraglutide 1.8 mg, and 1.8% for sitagliptin. The cumulative rate of withdrawal because of adverse events was not reported at 52 weeks. Gastrointestinal events and infections and infestation events were the most commonly reported adverse events (Table 12). Nausea occurred more frequently with either dose of liraglutide than with sitagliptin and was the most common gastrointestinal adverse event with liraglutide. The incidence of nausea declined after the first weeks, then remained low throughout weeks 26 through 52. One patient in the liraglutide 1.2 mg group experienced an episode of major hypoglycemia. Minor hypoglycemia events occurred at a rate of 0.14, 0.154, and 0.17 per person per year for the liraglutide 1.2 mg, 1.8 mg, and sitagliptin groups, respectively. One incidence of non-acute pancreatitis occurred in a patient in the liraglutide 1.8 mg group. Changes in lipid parameters were not significantly different between sitagliptin and either dose of liraglutide. Table 12. Adverse events of between-class comparisons: Sitagliptin compared with exenatide XR or liraglutide Russell-Jones, Bergenstal, Pratley, ,1 Adverse event N (%) S100 EXR S100 EXR S100 L1.2 L1.8 WD because of adverse events 5() 11(7) 6(2) 6(2) 4(2) a 14(6) 15(7) Hypoglycemia 5() 2(1) 0 5(2) Nausea 16(10) 8(24) 6(4) 28(11) 12(6) 48(22) 60(28) Vomiting 4(2) 18(11) (5) 18(8) 2(11) Diarrhea 16(10) 29(18) 9(6) 27(11) 14(6) 20(9) 27(12) Abdominal pain Nasopharyngitis (10) 19(8) 1(14) 27(12) 2(14) Upper respiratory tract infection 15(9) 6(4) Influenza Headaches 15(9) 15(9) 15(9) 20(8) 27(12) 21(10) 29(1) Urinary tract infections 9(5) 10(6) Abbreviation: EXR=exenatide XR; L1.2=liraglutide 1.2 mg; L1.8=liraglutide 1.8 mg, S100=sitagliptin 100 mg; WD=withdrawal a Withdrawals because of adverse events from Pratley, 2010 are from the original 26-week treatment period, other outcomes data are from 52 weeks. DPP-4 inhibitors compared with SGLT2 inhibitors Sitagliptin compared with canagliflozin Three trials (represented by 4 publications) compared sitagliptin 100 mg to canagliflozin 100 mg or 00 mg over 12 and 52 weeks. 28-0,2 Patients in 1 of the 52-week trials comparing canagliflozin 00 mg with sitagliptin 100 mg were on a background therapy of metformin plus sulfonylurea. Patients in the other 2 trials were taking metformin monotherapy. Results for specific adverse events are shown in Table 1. The rate of withdrawal because of adverse events was low in the trials. Rates ranged from 0% to 4% for sitagliptin 100 mg and % to 5% for canagliflozin 00 mg. In the 2 trials also comparing canagliflozin 100 mg with sitagliptin 100 mg, withdrawal from adverse events was 5% in both trials. Only one of the trials reported any

49 gastrointestinal adverse event outcomes such as nausea or diarrhea. There were no significant differences between groups for these outcomes. 29 In the 52-week trials, hypoglycemia was slightly more common in the canagliflozin arms than in the sitagliptin arms (Table 1). The 12- week trial reported more hypoglycemic events in the sitagliptin group (5%) than either canagliflozin group (2% for canagliflozin 100 mg and 0% for canagliflozin 00 mg). None of the trials found significant differences between the sitagliptin groups and either dose of canagliflozin for urinary tract infections. Two of the trials reported higher incidences of genital mycotic infections after 52 weeks of treatment in men and women taking canagliflozin compared to those taking sitagliptin, but neither study reported whether the differences between the groups were significant. 28,0 The third trial also reported higher rates of genital infections after 12 weeks of treatment (including vulvovaginal mycotic infection and vulvovaginal candidiasis) among women between the treatment groups. 29 Changes in lipid concentrations were not statistically significant between sitagliptin and either dose of canagliflozin at 12 or 52 weeks in 2 of the trials. 28,29 The third trial reported significant differences between sitagliptin 100 mg and canagliflozin 00 mg after 52 weeks of treatment for changes in HDL cholesterol and LDL cholesterol. HDL cholesterol increased significantly more with canagliflozin 00 mg (7.6%) than with sitagliptin 100 mg (0.6%) (difference in least square means 7.0%, 95% CI, 4.6 to 9.). Similarly, a larger increase in LDL cholesterol occurred with canagliflozin 00 mg (11.7%) than with sitagliptin 100 mg (5.2%) (difference in least square means 6.4%, 95% CI, 1.7 to 11.2). Increases in triglycerides were similar between groups. Table 1. Adverse events of between-class comparisons: Sitagliptin compared with canagliflozin Schernthaner, Lavalle-Gonzalez, Rosenstock, ,2 Adverse event S100 C00 S100 C100 C00 S100 C100 C00 WD because of adverse events 11() 20(5) 16(4) 19(5) 12() 0 (5) 2() Hypoglycemia 155(41) 162(4) (4) (7) (7) (5) 1(2) 0 Nausea (2) 1(2) (5) Diarrhea () 1(2) 2() Nasopharyngitis (5) 0 1(2) Headaches (2) 5(8) (5) Urinary tract infections 21(6) 15(4) 2(6) 29(8) 18(5) 1(2) 2() 2() Genital mycotic infection a 1(0.5) 19(9.2) 2(1.2) 9(5.2) 4(2.4) Males 7(4. 26(15.) 5(2.6) 22(11.) 20(9.9) 2(7) 7(25) 4(14) Females Abbreviation: C100=canagliflozin 100 mg; C00=canagliflozin 00 mg; S100=sitagliptin 100 mg; WD=withdrawal a. Data from Rosenstock et al, 2012 represent all vulvovaginal adverse events in female patients, of which the most commonly reported were vulvovaginal mycotic infection and vulvovaginal candidiasis.

50 III. Newer Diabetes Medications compared with metformin: Harms Key Findings: Harms DPP-4 inhibitors compared with metformin Two trials compared linagliptin 5 mg with either metformin 500 mg twice daily or 1000 mg twice daily. Our meta-analyses showed no difference between linagliptin 5 mg and metformin 1000 mg twice daily for withdrawals because of adverse events (N=2, RR for withdrawals because of adverse events % CI, 0.52 to 2.78) or diarrhea (N=2, RR for diarrhea % CI, 0.19 to 1.50) (low strength of evidence) (Table 14). In 1 trial, at 24 weeks, there were no significant differences between groups for other adverse events; however, compared with patients receiving linagliptin, patients receiving metformin 1000 mg twice daily experienced higher rates of nausea (.4% compared with 0.7%) (low strength of evidence), hypoglycemia (.4% compared with 0%) (low strength of evidence), and upper respiratory tract infections (4.2% compared with 0.7%). Rates of other adverse events such as vomiting, urinary tract infections, influenza, and headaches were similar between groups. No cases of pancreatitis occurred during the 24-week treatment period. In 1 trial comparing alogliptin 25 mg with metformin 500 mg and 1000 mg twice daily over 26 weeks, rates of withdrawal because of adverse events were similar across groups. Metformin 1000 mg twice daily was associated with higher rates of hypoglycemia, diarrhea, and nausea than the metformin 500 mg twice daily and alogliptin 25 mg once daily groups (low strength of evidence). Compared with metformin monotherapy, sitagliptin was associated with lower incidence of nausea and diarrhea (N=, RR for nausea % CI, 0.24 to 0.84; N=, RR for diarrhea % CI, 0.24 to 0.51) (low strength of evidence). Two trials compared saxagliptin 5 mg to metformin over 18 and 24 weeks. 8,9 Our metaanalyses showed no difference between saxagliptin and metformin for the following harms outcomes: withdrawals because of adverse events, nausea, vomiting, diarrhea, urinary tract infections, and nasopharyngitis (low strength of evidence). Compared with metformin, saxagliptin was associated with an increased risk of hypoglycemia (N=2, RR 2.9; 95% CI, 1.08 to 7.97) (low strength of evidence). Results of our meta-analyses are summarized in Table 18 and shown in Appendix E. Results from individual trials are summarized in the Evidence Tables (included in a separate file). GLP-1 analogs compared with metformin Rates of withdrawal because of adverse events were not reported in the single trial comparing exenatide 10 µg twice daily to metformin over 26 weeks. The most commonly reported event was nausea, which occurred in a significantly greater number of patients receiving exenatide than in those receiving metformin (0% and 8%, respectively P=0.010). Hypoglycemia was also reported significantly more often in the exenatide arm than in the metformin arm (12% compared with.2%, P<0.05). One trial compared exenatide XR 2 mg weekly to metformin 2000 mg per day over 26 weeks. Withdrawals because of adverse events occurred at similar rates in the exenatide and metformin arms. Nausea, nasopharyngitis, and constipation were more common

51 among those receiving exenatide than among those receiving metformin Headache and diarrhea, occurred more often in the metformin group than in the exenatide group. Vomiting was uncommon and the percent of patients reporting vomiting was similar in both groups. Differences between the groups were not statistically significant. SGLT2 inhibitors compared with metformin Three trials described in 2 publications compared dapagliflozin 5 mg and 10 mg with metformin XR daily over 12 and 24 weeks. Our meta-analyses showed a significant difference in the rate of diarrhea between dapagliflozin 10 mg and metformin XR (N=2 RR % CI, 0.12 to 0.60) (moderate strength of evidence). We did not find any significant differences between dapagliflozin 5 mg and metformin XR for any of the outcomes for which we conducted meta-analysis (low strength of evidence for no difference). Study Characteristics For harms outcomes, we identified 12 trials (described in 15 publications) comparing a newer diabetes drug with metformin. Of these, 8 compared a DPP-4 inhibitor with metformin: linagliptin (2 trials),4,46, alogliptin (1 trial), 4 sitagliptin (4 trials), 25,5,7,44,45 and saxagliptin (2 trials). 8,9 Two trials compared metformin with a GLP-1 analog. 25,40 One trial compared metformin with exenatide over 26 weeks; 40 the other arm trial comparing exenatide XR with metformin and sitagliptin. 25 Three trials compared the SGLT2 inhibitor dapagliflozin with metformin. 41,42 Details of these trials are presented in Table 8 in the corresponding section of KQ 1 and in the Evidence Tables (included in a separate file). Detailed Assessment for Newer Diabetes Medications compared with Metformin: Harms DPP-4 inhibitors compared with metformin Linagliptin compared with metformin Two trials (described in 2 published articles and 1 unpublished trial synopsis) compared linagliptin 5 mg with either metformin 500 mg twice daily or 1000 mg twice daily.,4,46 For linagliptin 5 mg compared with metformin 1000 mg twice daily, our meta-analyses of 2 trials showed no difference for withdrawals because of adverse events (N=2, RR for withdrawals because of adverse events 1.21; 95% CI, 0.52 to 2.78) or diarrhea (N=2, RR for diarrhea 0.54; 95% CI, 0.19 to 1.50) (Table 14). In 1 trial, at 24 weeks the rate of withdrawal because of adverse events was higher in the linagliptin 5 mg arm than in the metformin 500 mg twice daily arm (4.2% compared with 2.1%). Only 1 of the trials reported rates for other adverse events for linagliptin and both doses of metformin. At 24 weeks, rates of specific adverse events were generally low in all groups. The most commonly reported adverse events occurring in % of patients or more in any group were nasopharyngitis, diarrhea, hypoglycemia, nausea, influenza, upper respiratory tract infection, and headache. Compared with patients receiving linagliptin, patients receiving metformin 1000 mg twice daily experienced higher rates of nausea (.4% compared with 0.7%) and hypoglycemia (.4% compared with 0%). Nasopharyngitis occurred more frequently in the

52 linagliptin group than in either the metformin 500 mg or 1000 mg twice daily groups (5.6%, 2.8%, and 2.7%, respectively). Upper respiratory tract infections occurred more frequently in the metformin 500 mg twice daily group than in the linagliptin group (4.2% compared with 0.7%). Rates of other adverse events such as vomiting, urinary tract infections, influenza, and headaches were similar between groups. No cases of pancreatitis occurred during the 24 week treatment period. Table 14. Meta-analysis comparing adverse events: Linagliptin 5 mg compared with metformin 1000 mg twice daily # of Studies Heterogeneity Outcome # of Participants Measure Estimate 95% CI P value I 2 WD due to 2 adverse event 409 RR , % Diarrhea RR , % Abbreviations: CI, confidence interval; RR, relative risk; WD, withdrawal Alogliptin compared with metformin In the 1 trial comparing alogliptin 25 mg once daily with metformin 500 mg and 1000 mg twice daily over 26 weeks, rates of withdrawal because of adverse events were similar, with a slightly higher percentage of patients in the alogliptin 25 mg once daily arm (.6%) withdrawing because of adverse events than in the 2 metformin monotherapy arms (2.8% in the metformin 500 mg twice daily arm and 1.8% in the metformin 1000 mg twice daily arm). Hypoglycemia was more common among patients receiving metformin 1000 mg twice daily than among those receiving alogliptin (6.% compared with 1.8%). Skin reactions occurred at similar rates in the alogliptin 25 mg, metformin 500 mg twice daily, and metformin 1000 mg twice daily group, with the highest rate occurring in the metformin 1000 mg twice daily arm (2.7%,.7%, 5.4%, respectively). Nine percent of patients in the metformin 1000 mg twice daily group reported having diarrhea compared with 0.9% in the alogliptin 25 mg once daily group. Similarly, nausea was more common in the higher dose metformin group (5.4%) than in the alogliptin group (0%). 4 Sitagliptin compared with metformin We included trials (described in 5 publications) for harms that compared sitagliptin with metformin, 25,5,7,44,45 Results from our meta-analyses are summarized in Table 15 and results from individual trials are summarized in Table 16 and the Evidence Tables (included in a separate file). Changes in lipid concentrations reported in each trial are summarized in Table 17. Compared with metformin monotherapy, sitagliptin was associated with lower incidence of nausea and diarrhea (N=, RR for nausea % CI, 0.24 to 0.84; N=, RR for diarrhea % CI, 0.24 to 0.51). We found no statistically significant difference between sitagliptin and metformin for other harms outcomes for which suitable data were available for analysis.

53 Table 15. Meta-analysis comparing adverse events: Sitagliptin compared with metformin # of Studies Heterogeneity Outcome # of Patients Measure Estimate 95% CI P value I 2 WD due to adverse event 1,820 RR , % Hypoglycemia 1,820 RR , % Nausea 1,820 RR , % Vomiting 2 1,411 RR , % Diarrhea 1,820 RR , % Headache 2 1,459 RR , % Nasopharyngitis 2 1,459 RR , % Abbreviations: CI, confidence interval; RR, relative risk Table 16. Adverse events of sitagliptin compared with metformin Goldstein, Williams- Herman, 2009 a44 Williams- Herman, 2010 a45 Aschner, Russell- Jones, Adverse event (%) S100 M1 M2 S100 M1 M2 S100 M1 M2 S100 M2 S100 M2 Hypoglycemia , Nausea Vomiting Diarrhea Abdominal pain Nasopharyngitis Upper respiratory tract infection Influenza Headaches Urinary tract infections Abbreviations: M1, metformin 500 mg twice daily; M2, metformin 1000 mg twice daily; S100, sitagliptin 100 mg a Williams-Herman et al., 2009 and Williams-Herman et al., 2010 are extensions of Goldstein et al., 2007

54 Table 17. Changes in lipid parameters (mean change from baseline, mg/dl): Sitagliptin compared with metformin Total cholesterol Aschner, Goldstein, a Williams-Herman, 2009 c44 Williams- Herman, 2010 c 45b S100 M2 S100 M1 M2 S100 M1 M2 S100 M1 M NR NR NR HDL LDL TG -2.0 b 0 b b +6.0 b b Abbreviations: HDL, high-density lipoprotein cholesterol; LDL, low-density lipoprotein cholesterol; M1, metformin 1000 mg/d; M2, metformin 2000 mg/d; S100, sitagliptin 100 mg; TG, triglycerides. a Data received from manufacturer. b Reported as median change from baseline c Williams-Herman et al., 2009 and Williams-Herman et al., 2010 are extensions of Goldstein et al., 2007 Saxagliptin compared with uptitrated metformin Two trials compared saxagliptin 5 mg to metformin over 18 and 24 weeks. 8,9 Compared with metformin, saxagliptin was associated with an increased risk of hypoglycemia (N=2, RR % CI, 1.08 to 7.97). There were no significant differences between saxagliptin and metformin based on pooled estimates for the following harms outcomes: withdrawals because of adverse events, nausea, vomiting, diarrhea, urinary tract infections, and nasopharyngitis. Results of our meta-analyses are summarized in Table 18, and results from individual trials are summarized in the Evidence Tables (included in a separate file). Table 18. Meta-analysis comparing adverse events: Saxagliptin compared with metformin Outcome WD due to adverse event Hypoglycemia Nausea Vomiting Diarrhea # of Studies # of Patients Abbreviations: CI, confidence interval; RR, relative risk GLP-1 analogs compared with metformin Heterogeneity Measure Estimate 95% CI P value I 2 RR , % RR , % RR , % RR , % RR , % Exenatide compared with metformin One trial set in China compared exenatide 10 µg twice daily to metformin over 26 weeks. 40 The rates of withdrawal because of adverse events were not reported. The most commonly reported event was nausea, which occurred in a significantly greater number of patients receiving exenatide than in those receiving metformin (0% and 8%, respectively P=0.010). Hypoglycemia

55 was also reported significantly more often in the exenatide arm than in the metformin arm (12% compared with.2%, P<0.05). Exenatide XR compared with metformin One trial compared exenatide XR 2 mg weekly to metformin 2000 mg per day 25 over 26 weeks. Withdrawals because of adverse events occurred at similar rates in the exenatide and metformin arms (2.4% in each group). Among the most commonly reported adverse events, occurring in >5% of patients in any group, nausea, nasopharyngitis, and constipation were more common among those receiving exenatide than among those receiving metformin (nausea: 11.% compared with 6.9%; nasopharyngitis: 7.7% compared with 4.5%; constipation 8.5% compared with.%). Both headache and diarrhea occurred more often in the metformin group than in the exenatide group (headache: 12.2% and 8.1%; diarrhea: 12.6% and 10.9%). Vomiting was uncommon, and the percent of patients reporting vomiting was similar in both groups (exenatide, 4.8%; metformin,.%). Differences between the groups were not statistically significant. SGLT2 inhibitor compared with metformin Dapagliflozin compared with metformin Three trials described in 2 publications compared dapagliflozin 5 mg and 10 mg with metformin XR daily over 12 and 24 weeks. 41,42 Results of our meta-analyses are summarized in Table 19 and Table 20. Results from individual trials are summarized in the Evidence Tables (included in a separate file). Our meta-analyses showed a significant difference in the rate of diarrhea between dapagliflozin 10 mg and metformin XR (N=2 RR 0.26; 95% CI, 0.12 to 0.60). We did not find any significant differences between dapagliflozin 5 mg and metformin XR for any of the outcomes for which we conducted meta-analysis. Table 19. Meta-analysis comparing adverse events: Dapagliflozin 5 mg compared with metformin XR # of Studies Heterogeneity Outcome # of Patients Measure Estimate 95% CI P value I 2 WD due to 2 adverse event 518 RR , % Hypoglycemia RR , % Nausea RR , % Diarrhea RR , % Urinary tract 2 RR , % infection 518 Abbreviations: CI, confidence interval; RR, relative risk; WD, withdrawal

56 Table 20. Meta-analysis comparing adverse events: Dapagliflozin 10 mg compared with metformin XR # of Studies Heterogeneity Outcome # of Patients Measure Estimate 95% CI P value I 2 WD due to 2 adverse event 50 RR , % Hypoglycemia 2 50 RR , % Nausea 2 50 RR , % Diarrhea 2 50 RR , % Urinary tract 2 RR % infection 50 Abbreviations: CI, confidence interval; RR, relative risk IV. Fixed-dose Combination Products (FDCPs) or Dual Therapy Key Findings: Harms DPP-4 inhibitors in combination with metformin At 26 weeks, rates of withdrawals because of adverse events in 1 trial of Kazano or dual therapy with alogliptin and metformin ranged from 1.8% in the metformin 1000 mg twice daily group to 9.6% in the alogliptin 12.5 mg plus metformin 500 mg twice daily group. Hypoglycemia, nausea, and diarrhea occurred more frequently in the groups receiving the highest doses of metformin (1000 mg twice daily either as monotherapy or in combination with alogliptin) than in the other groups (low strength of evidence). The rates of withdrawal because of adverse events in 1 trial of Jentadueto or dual therapy with linagliptin plus metformin ranged from 2.1% in the higher-dose metformin combination therapy group to 4.2% in the linagliptin monotherapy group. Diarrhea was the only gastrointestinal adverse event occurring in more than 4% of patients in any group. Rates of hypoglycemia were low across all treatment groups ranging from 0% to.5%. There were no significant differences between the groups for harms outcomes (low strength of evidence). Two trials of Janumet or dual therapy with sitagliptin and metformin met our inclusion criteria. Incidences of adverse events were generally similar between treatment arms in both trials and the rate of withdrawals due to adverse events was low. Hypoglycemic events were rare across treatment groups and none were severe. Our meta-analysis for sitagliptin 50 mg plus metformin 100 mg twice daily compared with metformin 1000 mg twice daily found no difference between groups for hypoglycemia (N=2, pooled RR 1.75; 95% CI, 0.50 to 6.10) (low strength of evidence). Our meta-analyses comparing sitagliptin 50 mg plus metformin 1000 mg twice daily with metformin 1000 mg twice daily found statistically significant differences in favor of combination therapy for diarrhea and abdominal pain (N=2, pooled RR for diarrhea 0.74; 95% CI, 0.58 to 0.95; pooled RR for abdominal pain 0.42; 95% CI, 0.19 to 0.99) (low strength of evidence). Neither group experienced adverse changes in lipid levels.

57 Study Characteristics We included trials (described in 7 publications) for harms specifically using fixed dose combination products or dual therapy with individual components of fixed dose combination products.,4,7,44-47 Detailed Assessment for FDCPs and Dual Therapy Kazano or dual therapy with alogliptin plus metformin We identified 1 trial of Kazano or dual therapy with alogliptin and metformin. 4 At 26 weeks, rates of withdrawals because of adverse events in each group ranged from 1.8% in the metformin 1000 mg twice daily group to 9.6% in the alogliptin 12.5 mg plus metformin 500 mg twice daily group. Hypoglycemia occurred more frequently in the groups receiving the highest doses of metformin (6.% in the metformin 1000 mg twice daily group and 5.% in the alogliptin 12.5 mg plus metformin 1000 mg twice daily group), and occurred in less than 2% of patients in the other groups. Similarly, those who received higher doses of metformin either as monotherapy or in combination with alogliptin experienced higher rates of nausea and diarrhea than those in the alogliptin monotherapy or the lower dose metformin monotherapy groups (Table 21). None of the participants experienced severe hypoglycemia. There were no significant differences between the combination therapies and either metformin or alogliptin monotherapy with respect to changes in total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides. Table 21. Adverse events of Kazano or dual therapy with alogliptin and metformin compared with metformin monotherapy Adverse event (%) Author, Year Pratley, Alo25 Met1 Met2 Alo/Met1 Alo/Met2 Withdrawal due to adverse event Hypoglycemia Severe Hypoglycemia Skin reactions Nausea Diarrhea Nasopharyngitis Upper respiratory tract infection Headaches Abbreviations: Alo25, alogliptin 25 mg; Met1, metformin 1000 mg; Met2, metformin 2000 mg. Jentadueto or dual therapy with linagliptin plus metformin One trial meeting inclusion criteria compared Jentadueto or dual therapy with linagliptin plus metformin, linagliptin monotherapy or metformin monotherapy. The rates of withdrawal because of adverse events ranged from 2.1% in the higher-dose metformin combination therapy group to 4.2% in the linagliptin monotherapy group. The only gastrointestinal adverse event occurring in more than 4% of patients in any group was diarrhea, which was most frequent in the

58 metformin 1000 mg twice daily group (5.4%). Rates of hypoglycemia were low across all treatment groups ranging from 0% to.5% (Table 22). Table 22. Adverse events of Jentadueto or dual therapy with linagliptin and metformin compared with linagliptin or metformin monotherapy Author, Year Haak, 2012 Lin Met1 Met2 Lin/Met1 Lin/Met2 Adverse event (%) Withdrawal due to adverse event Hypoglycemia Severe Hypoglycemia Nausea Vomiting Diarrhea Nasopharyngitis Upper respiratory tract infection Influenza Headaches Urinary tract infections Abbreviations: Lin, linagliptin; Met1, metformin 500 mg twice daily; Met2, metformin 1000 mg twice daily. Janumet or dual therapy with sitagliptin plus metformin Two trials of Janumet or dual therapy with sitagliptin and metformin met our inclusion criteria. 7,44,45,47 One trial resulted in publications; 1 reporting results after 24 weeks, 7 1 reporting results after 54 weeks, 44 and the other after a total of 104 weeks. 45 Our meta-analyses of 2 trails comparing sitagliptin 50 mg plus metformin 1000 mg twice daily with metformin 1000 mg twice daily found statistically significant differences in favor of combination therapy for diarrhea and abdominal pain (pooled RR for diarrhea 0.74; 95% CI, 0.58 to 0.95; pooled RR for abdominal pain 0.42; 95% CI, 0.19 to 0.99) (Appendix E). Other meta-analyses showed no differences between treatment groups. Table 2 summarizes adverse events of metformin/sitagliptin dual therapy in adults with type 2 diabetes. Incidences of adverse events were generally similar between treatment arms in both trials. Withdrawals due to adverse events were low, ranging from 1.1% to 2.8% during the first 24 weeks and 2% to 4% during the entire study period in 1 trial, and reaching 4% in the other trial at 18 weeks. (Table 2). Hypoglycemic events were rare across treatment groups in both trials at 18, 24, 54, and 104 weeks and were of mild or moderate severity. Gastrointestinal events were reported with similar frequency across treatment arms in both trials, with the higher-dose metformin monotherapy patients reporting the highest rates (24.6% at 18 weeks, 25.% at 24 weeks, 1% at 54 weeks, and % at 104 weeks). Patients in either dual therapy arm reported adverse gastrointestinal events more frequently than patients on sitagliptin monotherapy or lower-dose metformin. Nausea/vomiting and abdominal pain were reported most frequently in the higher-dose metformin monotherapy group, and diarrhea was reported most frequently by higher-dose dual therapy patients. In 1 trial, the only arm in which total cholesterol changed significantly from baseline was higher-dose dual therapy; total cholesterol decreased by.0 mg/dl on average. In the second

59 trial, both the metformin monotherapy and dual therapy groups showed improvements from baseline in total cholesterol, HDL cholesterol, and triglycerides and a small decrease in LDL cholesterol. The between-group difference for changes in triglycerides was statistically significant for dual therapy compared with metformin monotherapy (P=0.049) (Table 24).

60 Table 2. Adverse events of Janumet or dual therapy with sitagliptin and metformin compared with sitagliptin or metformin monotherapy Withdrawal due to adverse event (%) Hypoglycemia Gastrointestinal Nausea/ Vomiting Diarrhea Abdominal pain Reasner, Goldstein, Williams-Herman, 2009 b44 Williams-Herman, 2010 b 45 M2 S/M2 S1 M1 M2 S/M1 S/M2 S1 M1 M2 S/M1 S/M2 S1 M1 M2 S/M1 S/M (1.8) 15 (24.6) 1 (2.1) 129 (20.6) 1 (0.6) 27 (15.1) (6.) a (5.6) a (1.1) 10 (16.6) 24 (.9) 75 (12.0) 7 (1.1) 5 (2.8) 6 (.4) 1 (0.5) 29 (15.9) 5 (2.7) 9 (4.9) 5 (2.7) 2 (1.1) 46 (25.) 17 (9.) 19 (10.4) 15 (8.2) 2 (1.1) 4 (17.9) 10 (5.) 12 (6.) 8 (4.2) 4 (2.2) 45 (24.7) 16 (8.8) 16 (8.8) 10 (5.5) 2 (1) 6 (20) (2) 7 (4) 8 (5) 2 (1) 7 (20) 6 () 1 (7) 7 (4) Abbreviations: M1, metformin 1000 mg/d; M2, metformin 2000 mg/d; S, sitagliptin a Data received from manufacturer. b Reported as median change from baseline. c Williams-Herman et al., 2009 and Williams-Herman et al., 2010 are extensions of Goldstein et al., (1) 57 (1) 24 (1) 22 (12) 10 (6) 4 (2) 5 () 50 (26) 14 (7) 17 (9) 5 () 5 (29) 18 (10) 2 (1) 7 (4) 2 (1.1) 7 (20.7) (1.6) 8 (20.9) 4 (2.2) 60 () 5 (2.6) 56 (29.5) 9 (4.9) 60 () Table 24. Changes in lipid parameters (mean change from baseline, mg/dl): sitagliptin plus metformin compared with metformin monotherapy Reasner, Goldstein, a Williams-Herman, 2009 c44 Williams-Herman, 2010 c 45b M2 S/M2 M1 M2 S/M1 S/M2 M1 M2 S/M1 S/M2 M1 M2 S/M1 S/M2 Total cholesterol -.8% -4.2% HDL 5.8% 4.8% LDL -4.2% -1.% TG -2.1% -8.4% b b -8.0 b -15 b (4.5) 9 (5.0) 14 (7.7) 7 (.8) 2 (12.6) 12 (6.6) Abbreviations: HDL, high-density lipoprotein cholesterol; LDL, low-density lipoprotein cholesterol; M1, metformin 1000 mg/d; M2, metformin 2000 mg/d; TG, triglycerides. a. Data received from manufacturer. b. Reported as median change from baseline. c. Williams-Herman et al., 2009 and Williams-Herman et al., 2010 are extensions of Goldstein et al. 19 (10.0) 7 (.7) 25 (1.7) 9 (4.9)

61 Key Question. Are there subgroups of patients based on demographics (age, racial groups, gender), comorbidities (drug-disease interactions, obesity), or other medications (drug-drug interactions) for which newer diabetes medications and drug combinations (administered as fixed dose combination products or dual therapy) differ in efficacy/effectiveness or tolerability and frequency of adverse events? We did not identify any trials meeting inclusion criteria that reported on efficacy/effectiveness or harms for subgroups of patients based on demographics, comorbidities, or other medications (drug-drug interactions). SUMMARY Strength of Evidence All evidence was limited to adult populations with type 2 diabetes; no trials including children or people with type 1 diabetes were identified. All of the included trials evaluated intermediate outcomes, such HbA1c or weight, as primary outcomes, and few trials were longer than 24 weeks. Only a few trials reported health outcomes (such as number of people with macrovascular disease among secondary outcomes or adverse events); overall evidence was insufficient to determine the comparative effectiveness of newer diabetes medications in improving long-term health outcomes. Table 25 provides a detailed summary of our strength of evidence grades for efficacy and harms by drug comparison. In general, we found few head-to-head trials within each category of newer diabetes medications; strength of evidence for conclusions related to head to head evidence is generally low for HbA1c, weight and harms outcomes.. Included medications appear to be weight neutral or associated with weight loss. Most studies evaluating weight change were 6 months or less in duration and it is uncertain whether weight loss is sustained long term. Evidence was generally insufficient to assess the comparative efficacy of included medications for improving health outcomes. Few trials assessed within-class comparisons; we found exenatide XR to be more efficacious for reducing mean HbA1c than exenatide given twice daily, and also associated with more injection site reactions. Liraglutide was more efficacious than exenatide twice daily for reducing mean HbA1c. Metformin (at dosages > 1500 mg) is more efficacious than DPP-4 inhibitors for reducing HbA1c and is associated with greater weight loss; in some cases metformin is associated with higher rates of diarrhea. Exenatide XR and liraglutide are both more efficacious than sitagliptin. We found no difference between canagliflozin and sitagliptin for reducing HbA1c; canagliflozin is associated with higher rates of genital mycotic infections in women. We found no trials evaluating the comparative efficacy of included medications for subgroups based on age, gender, comorbidity or drug-drug interaction. Limitations of this Report Methodological limitations of the review within the defined scope included the exclusion of trials published in languages other than English and not being able to search additional electronic databases or gray literature. We received and searched published and unpublished information in

62 a dossier from 5 manufacturers to ensure the inclusion of eligible unpublished data and recently published trials. In addition, the data from randomized controlled trials included in this report have limited utility for assessing real-world adherence to medications. This is largely because they enrolled selected populations, often requiring adherence during a run-in period before randomization. For this streamlined update, our scope was limited to head-to-head trials of included drugs and comparisons with metformin only. The evidence base was inadequate to draw conclusions for some key questions (subgroups of patients) and drug comparisons. Applicability Most trials represented a selected population: primarily white, middle-aged, obese adults with moderately elevated baseline hemoglobin A1c (< 9%) and diabetes for less than 10 years. No trials included populations with a mean age above 60. It is unclear if the reductions in hemoglobin A1c found in the included trials would be consistent with what is expected in general practice. Many trials included narrowly defined populations of patients who had to undergo placebo run-in periods prior to randomization. Minorities and patients with comorbidities were generally underrepresented. Trials in Progress We identified 8 trials that are currently in progress and which appear to meet inclusion criteria. These trials may allow us to make strength of evidence conclusions about the efficacy, effectiveness, and relative safety of sitagliptin compared within-class to saxagliptin and between classes to liraglutide, as well as the comparative efficacy, effectiveness, and safety of canagliflozin and alogliptin in combination with metformin, in comparison to each drug individually. Table 25. Summary of evidence by Key Question Key Question 1. What is the comparative efficacy and effectiveness of newer diabetes medications and drug combinations (administered as fixed dose combination products or dual therapy) for children and adults with diabetes mellitus? Key Question 2. What is the comparative tolerability and frequency of adverse events for newer diabetes medications and drug combinations (administered as fixed dose combination products or dual therapy) for children and adults with diabetes mellitus? Strength of evidence a Conclusions Within Class Comparisons: Saxagliptin vs. Sitagliptin Insufficient One trial (N=801) found no difference between sitagliptin and saxagliptin for improving the following health outcomes: mortality rate, myocardial infarction, and transient ischemic attack (1 trial; unknown consistency; imprecise findings). Insufficient One trial (N=801) found no difference between sitagliptin and saxagliptin for reducing HbA1c or weight over 18 weeks. Evidence was insufficient to determine the comparative efficacy of sitagliptin and saxagliptin for reducing HbA1c or weight (1 trial; unknown consistency).

63 Key Question 1. What is the comparative efficacy and effectiveness of newer diabetes medications and drug combinations (administered as fixed dose combination products or dual therapy) for children and adults with diabetes mellitus? Key Question 2. What is the comparative tolerability and frequency of adverse events for newer diabetes medications and drug combinations (administered as fixed dose combination products or dual therapy) for children and adults with diabetes mellitus? Strength of evidence a Conclusions Within Class Comparisons: Exenatide XR vs. Exenatide Insufficient Two trials (N=547) found no difference between exenatide XR and exenatide for improving cardiovascular events. One trial measured myocardial infarction and the other fatal myocardial infarction. (1 trial for each measurement; unknown consistency; imprecise findings). Moderate We pooled data from trials (N=1225) comparing exenatide XR with exenatide administered twice daily over 24 to 0 weeks. Exenatide XR was more efficacious in reducing mean HbA1c than exenatide twice daily: WMD -0.46%; 95% CI, to Three trials found no difference between exenatide XR and exenatide administered twice daily for weight changes over 24 to 0 weeks; 2 trials found no difference between groups and one trial found a small reduction in weight (-0.kg; P<0.001) favoring exenatide twice daily (low strength of evidence for no difference). There was no difference between groups for rates of withdrawals because of adverse events ( trials, N=1,22; RR 0.72; 95% CI, 0.5 to 1.50). We pooled trials (N=1,22) comparing exenatide XR with exenatide administered twice daily over 24 to 0 weeks. Rates of nausea and vomiting were lower with exenatide XR that with exenatide twice daily (Nausea, RR0.51; 95% CI 0. to 0.79; Vomiting RR 0.62; 95% CI, 0.45 to 0.87) Our meta-analyses found no difference between exenatide XR and exenatide administered twice daily for rates diarrhea (RR 1.21; 95% CI, 0.86 to 1.72) over 24 to 0 weeks (low strength of evidence for no difference). Moderate In 1 trial, injection site reactions were defined as inclusive of induration, pruritus, and nodules. Another trial reported only pruritus at the injection site. The third trial reported only erythema at the injection site. In all cases, exenatide XR was associated with a higher rate of injection site reactions. Within Class Comparisons: Exenatide vs. Liraglutide In 1 trial (N=464), liraglutide 1.8 mg once daily reduced mean HbA1c more than exenatide 10 µg twice daily (between-group difference: 0.%; 95% CI, 0.47 to 0.18). One trial (N=464) found no difference between exenatide and liraglutide 1.8mg for weight changes. Both drugs were associated with weight loss. The proportion of patients who reported minor hypoglycemia was less in the liraglutide group than the exenatide group (26% compared with 4%, 1.9 compared with 2.60 events per patient per year, rate ratio 0.55, CI 0.4 to 0.88; P=0.011) Between Class Comparisons: Sitagliptin vs. Exenatide XR Insufficient One trial (N=411) found no difference between sitagliptin and exenatide XR in mortality over 26 weeks (unknown consistency; imprecise findings). Insufficient One trial (N=42) found no difference between sitagliptin and exenatide XR in cardiovascular events over 26 weeks (unknown consistency; imprecise findings). Our meta-analysis (2 trials; N=75) found that exenatide XR was more efficacious than sitagliptin 100 mg once daily in reducing mean HbA1c over 26 weeks (WMD -0.48; 95% CI, to -0.26).

64 Key Question 1. What is the comparative efficacy and effectiveness of newer diabetes medications and drug combinations (administered as fixed dose combination products or dual therapy) for children and adults with diabetes mellitus? Key Question 2. What is the comparative tolerability and frequency of adverse events for newer diabetes medications and drug combinations (administered as fixed dose combination products or dual therapy) for children and adults with diabetes mellitus? Strength of evidence a Conclusions Our meta-analysis (2 trials; N=75) found that exenatide XR was more efficacious than sitagliptin 100 mg once daily in reducing weight over 26 weeks (WMD -1.2; 95% CI, to -0.76). Moderate Rates of nausea, vomiting, and diarrhea were higher with exenatide XR than with sitagliptin 100 mg; pooled relative risks for nausea 2.62; 95% CI, 1.66 to 4.15, vomiting.67; 95% CI, 1.6 to 8.24, and diarrhea 1.91; 95% CI, 1.22 to.00. Between Class Comparisons: Sitagliptin vs. Liraglutide Insufficient One trial (N=665) found no difference in mortality between liraglutide and sitagliptin over 52 weeks. One death occurred in the group randomized to liraglutide 1.2 mg once daily, no deaths occurred in patients randomized to 1.8mg once daily, and 2 deaths occurred among patients randomized to sitagliptin 100 mg daily (unknown consistency; imprecise findings). One trial (N=665) found liraglutide at both dosages (1.2 mg and 1.8 mg) to be more efficacious than sitagliptin 100 mg once daily in reducing mean HbA1c at 26 and 52 weeks. The differences in mean HbA1c at 26 weeks were -0.4% (95% CI, to -0.16) for liraglutide 1.2 mg once daily compared with sitagliptin 100 mg once daily and -0.60% (95% CI, to -0.4) for liraglutide 1.8 mg once daily compared with sitagliptin. One trial (N=665) found liraglutide at both dosages (1.2 mg and 1.8 mg) to be more efficacious than sitagliptin 100 mg once daily in reducing weight at 26 and 52 weeks. Change in weight at 26 weeks: liraglutide 1.2 mg kg, liraglutide 1.8 mg -.8 kg; sitagliptin kg; P< for both comparisons. Nausea occurred more frequently with liraglutide than with sitagliptin (21.7% liraglutide 1.2 mg; 27.5% liraglutide 1.8 mg, and 5.5% sitagliptin). The incidence of nausea was highest for the first weeks of treatment and then declined and remained low for weeks 26 to 52. Between Class Comparisons: Canagliflozin vs. Sitagliptin Two trials found no difference in mortality rates between canagliflozin 00 mg and sitagliptin 100 mg in 52 weeks. One trial found no difference in mortality between groups receiving canagliflozin 100 mg and sitagliptin 100mg. We found no difference between canagliflozin 100 mg and sitagliptin 100 mg in reducing mean HbA1c. One trial found no between-group difference (0%; 95% CI, to 0.12), and another trial reported similar reductions in HbA1c but did not report a measure of variance (-0.76% vs %). Two trials compared canagliflozin 00 mg to sitagliptin 100 mg over 52 weeks; canagliflozin 00 mg once daily led to a greater reduction in mean HbA1c. However, the difference between groups was small (between-group differences in HbA1c ranged from -0.15% to -0.7%) and below what is considered to be clinically significant (low strength of evidence for no difference between groups). Greater reduction in weight was seen with canagliflozin (at both doses) compared with sitagliptin. One trial found a between-group difference of -2.4% (-.0 to -1.8) for canagliflozin 100 mg compared with sitagliptin 100 mg; a second trial found a between-group difference of -0.4% over 12 weeks (favoring canagliflozin) but did not report a measure of variance. Three trials found greater reduction in weight with canagliflozin 00 mg compared with sitagliptin 100 mg daily (between-group differences ranged from -2.4% to -2.9% of body weight from baseline in two trials and a difference of 2.4 kg in one trial).

65 Key Question 1. What is the comparative efficacy and effectiveness of newer diabetes medications and drug combinations (administered as fixed dose combination products or dual therapy) for children and adults with diabetes mellitus? Key Question 2. What is the comparative tolerability and frequency of adverse events for newer diabetes medications and drug combinations (administered as fixed dose combination products or dual therapy) for children and adults with diabetes mellitus? Strength of evidence a Conclusions There were no significant differences between groups for nausea or diarrhea outcomes. The incidence of genital mycotic infections was higher with canagliflozin than with sitagliptin, and rates of urinary tract infections were similar between groups. Rates of hypoglycemia were low (0% to 7%) in the 12 and 52-week trials in which canagliflozin was added to metformin monotherapy and higher in the 52-week trial in which canagliflozin was added to metformin plus sulfonylurea (41% for sitagliptin 100 mg and 4% for canagliflozin 00 mg). For canagliflozin 00 mg compared with sitagliptin, there was no difference in 2 trials at 12 or 52 weeks when canagliflozin was added to metformin monotherapy. At 52 weeks, 1 trial found a greater increase in LDL cholesterol in the canagliflozin group (mean difference 6.4%; 95% CI, 1.7 to 11.2). No difference between groups for changes in triglycerides. Newer Diabetes Medications compared with Metformin: Linagliptin vs. Metformin One trial (N=286) found no difference between linagliptin 5 mg and metformin 500 mg for reduction in HbA1c. Moderate Metformin 1000 mg was more efficacious than linagliptin in reducing mean HbA1c: between-group difference: -0.60%; 95% CI, -0.2 to One trial (N=7) found a greater reduction in weight with metformin 500 mg than linagliptin 5 mg daily (-0.9 kg; -0.1 to -1.49) and metformin 1000 mg twice daily compared with linagliptin 5 mg daily (-0.70kg; to -1.29). In 1 trial, there were no significant differences between groups for specific adverse events; however, rates of nausea (.4% compared with 0.7%) and hypoglycemia (.4% compared with 0%) were higher with metformin 1000 mg twice daily than with linagliptin. Our meta-analysis of 2 trials showed no significant difference between groups for rates of diarrhea, pooled relative risk 0.54; 95% CI, 0.19 to Newer Diabetes Medications compared with Metformin: Alogliptin vs. Metformin Insufficient One trial (N=7) found no difference between alogliptin and metformin (at either dose) for improving the following health outcomes: mortality, ischemic stroke, heart failure related events, and myocardial infarction (1 trial; unknown consistency; imprecise findings). Moderate One trial (N=7) found no difference between alogliptin 12.5 mg and metformin 500 mg at 26 weeks (0.09%; 95% CI, to 0.5). One trial (N=7) found a greater reduction in HbA1c with metformin 1000 mg than alogliptin 12.5 mg twice daily (between-group difference, -0.55; 95% CI, to -0.81). One trial (N=7) found a greater reduction in weight with metformin 500 mg than alogliptin 12.5mg twice daily (-0.79kg; 95% CI, to -1.58) and metformin 1000 mg twice daily compared with alogliptin 12.5 mg twice daily (-1.4kg; 95% CI, to -0.45). Metformin 1000 mg twice daily was associated with higher rates of hypoglycemia, diarrhea, and nausea than the metformin 500 mg twice daily and alogliptin 25 mg once daily groups.

66 Key Question 1. What is the comparative efficacy and effectiveness of newer diabetes medications and drug combinations (administered as fixed dose combination products or dual therapy) for children and adults with diabetes mellitus? Key Question 2. What is the comparative tolerability and frequency of adverse events for newer diabetes medications and drug combinations (administered as fixed dose combination products or dual therapy) for children and adults with diabetes mellitus? Strength of evidence a Conclusions Newer Diabetes Medications compared with Metformin: Sitagliptin vs. Metformin Three trials reported mortality over 24 to 26 weeks; there was no difference between groups. Moderate Our meta-analysis ( trials; N=1655) found that metformin 2000 mg per day was more efficacious for reducing HbA1c than sitagliptin 100 mg daily (WMD -0.0%; 95% CI, to -0.09, I2 84.7%); all trials found a statistically significant benefit favoring metformin; 1 trial found a smaller magnitude of effect (-0.14%) than the other 2 trials (-0.% and -0.47%). Metformin was associated with a greater reduction in weight compared with sitagliptin over 24 to 54 weeks (2 trials). Mean difference between groups ranged from -1.2 kg to -1.7 kg. Compared with metformin monotherapy, sitagliptin was associated with lower incidence of nausea and diarrhea (N=, RR for nausea 0.45; 95% CI, 0.24 to 0.84; N=, RR for diarrhea 0.5; 95% CI, 0.24 to 0.51). Newer Diabetes Medications compared with Metformin: Saxagliptin vs. Uptitrated Metformin Insufficient One trial (N=286) found no difference in mortality between the addition of saxagliptin and uptitration of metformin in patients not at goal on submaximal metformin (over 24 weeks); a second trial (N=282) found no difference between saxagliptin and uptitration of metformin for improving cardiovascular events (myocardial infarction and myocardial ischemia). Our meta-analysis (2 trials; N=1677) found no difference in HbA1c with the addition of saxagliptin 5 mg compared with uptitration of metformin in patients not at goal on submaximal doses of metformin (WMD, -0.1; 95% CI, to 0.1) (low strength of evidence). Two trials found inconsistent results. One trial found greater reduction in HbA1c with the addition of saxagliptin 5 mg compared with uptitration of metformin (between-group difference: -0.5; 95% CI, to -0.2). A second trial and another trial found no difference in the change from baseline (between-group difference: -0.09%; 95% CI, to 0.08). In 1 trial (N=282), the uptitration of metformin was associated with a greater reduction in weight compared with adding saxagliptin 5 mg (between-group difference: -0.9kg; 95% CI, to -1.56). Compared with metformin, saxagliptin was associated with an increased risk of hypoglycemia (N=2, RR 2.9; 95% CI, 1.08 to 7.97), but no differences between groups were found with our metaanalyses for nausea, vomiting, diarrhea, or urinary tract infections. Newer Diabetes Medications compared with Metformin: Exenatide twice daily vs. Metformin Insufficient One trial (N=59) found greater reduction in HbA1c with exenatide twice daily compared with metformin: -2.6% vs. -1.6%; P<0.045 (1 trial; unknown consistency). Insufficient One trial found greater reduction in weight with exenatide (-5.8 kg) compared with metformin (-.81 kg) over 26 weeks, P<0.01 (1 trial; unknown consistency). Newer Diabetes Medications compared with Metformin: Exenatide XR vs. Metformin Insufficient One trial (N=494) found no difference in mortality between exenatide XR and metformin over 24 weeks (1 trial; unknown consistency; imprecise findings). One trial (N=494) found no difference for reducing HbA1c between exenatide XR and metformin: - 1.5% vs.-1.48%, P=0.62.

67 Key Question 1. What is the comparative efficacy and effectiveness of newer diabetes medications and drug combinations (administered as fixed dose combination products or dual therapy) for children and adults with diabetes mellitus? Key Question 2. What is the comparative tolerability and frequency of adverse events for newer diabetes medications and drug combinations (administered as fixed dose combination products or dual therapy) for children and adults with diabetes mellitus? Strength of evidence a Conclusions One trial (N=494) found no difference in weight reduction between exenatide XR and metformin; both groups lost an average of 2 kg over 24 weeks. Newer Diabetes Medications Compared with Metformin: Dapagliflozin vs. Metformin Three trials found no difference in mortality rates between groups receiving metformin XR mg daily and dapagliflozin. Moderate We pooled 2 trials (N=522) in a meta-analysis; there was no difference between dapagliflozin 5 mg compared with metformin XR 1500 mg-2000 mg daily (WMD -0.12; 95% CI, to -0.08). For dapagliflozin 10 mg compared with metformin XR 1500 mg-2000 mg daily there was a statistically significant reduction in HbA1c favoring dapagliflozin but the overall magnitude of effect was small and not within a range considered clinically significant (WMD %; 95% CI, to -0.05). Dapagliflozin (at both dosages) is associated with greater weight reduction than metformin XR 1500 mg-2000 mg over 24 weeks. Our meta-analysis (2 trials; N=522) found a greater reduction with dapagliflozin 5 mg compared with metformin XR 1500 mg-2000 mg daily(wmd kg; 95% CI, to -0.26); similarly, across two trials (N=505) a greater reduction in weight was seen with dapagliflozin 10 mg compared with metformin XR 1500 mg-2000mg (WMD -1.kg; 95% CI, -1.8 to - 0.7). Our meta-analyses showed a significant difference in favor of dapagliflozin in the rate of diarrhea between dapagliflozin 10 mg and metformin XR (N=2, RR 0.26; 95% CI, 0.12 to 0.60). Meta-analyses showed no significant differences between dapagliflozin 5 mg and metformin XR for any of the outcomes for which we conducted meta-analysis (withdrawals because of adverse events, hypoglycemia, nausea, diarrhea, and urinary tract infection) Fixed dose combination products or dual-therapy; Kazano or dual therapy with alogliptin plus metformin One trial (N=784) compared 2 doses of Kazano (12.5/500 mg twice daily and 12.5/1000 mg twice daily) to various doses of its component monotherapies. Both Kazano 12.5/500 mg twice daily and 12.5/1000 mg twice daily were more efficacious than component monotherapies in reducing mean HbA1c over 26 weeks. Mean HbA1c change from baseline HbA1c changes from baseline were 1.22% (0.094) and 1.55% (0.090) with 12.5/500 and 12.5/1000 twice daily combination therapies, respectively, versus 0.56% (0.09) with alogliptin 12.5 twice daily, and 0.65% (0.094) and 1.11% (0.092) with metformin 500 and 1000 twice daily monotherapies (P< for all comparisons of combination therapy vs. component monotherapies). Kazano 12.5/1000 mg twice daily resulted in greater weight loss than treatment with alogliptin 12.5 mg twice daily alone (-1.17 kg vs kg P=0.00). No difference in weight was found between the remaining comparators: alogliptin 25 mg daily: 0.1 kg, metformin 500 mg twice daily: kg, metformin 1000 mg twice daily: kg, Kazano 12.5/500 twice daily: kg. Those receiving metformin 1000 mg either as monotherapy or in combination with alogliptin had higher rates of hypoglycemia, nausea, and diarrhea compared with those receiving alogliptin 25 mg monotherapy or lower doses of metformin.

68 Key Question 1. What is the comparative efficacy and effectiveness of newer diabetes medications and drug combinations (administered as fixed dose combination products or dual therapy) for children and adults with diabetes mellitus? Key Question 2. What is the comparative tolerability and frequency of adverse events for newer diabetes medications and drug combinations (administered as fixed dose combination products or dual therapy) for children and adults with diabetes mellitus? Strength of evidence a Conclusions Fixed-dose combination products or dual-therapy: Jentadueto or dual therapy with linagliptin plus metformin Moderate One trial (N=791) found greater reduction in HbA1c with linagliptin plus metformin dual therapy than with component monotherapy over 24 weeks. Between-group difference for linagliptin 2.5mg plus metformin 500 mg and component monotherapy ranged from 0.60% to 0.70%; between-group differences for linagliptin 2.5 mg twice daily plus metformin 1000 mg twice daily and component monotherapy ranged from -0.5% to -1.10%, P<0.001 for all comparisons. Linagliptin 2.5 mg plus metformin 1000 mg twice daily was associated with greater reduction in weight compared with linagliptin 5 mg daily ( 1.00 kg; 95% CI, 1.59 to 0.41). No other groups experienced a significant change in weight. The group receiving linagliptin 2.5 mg twice daily plus metformin 500 mg had a small but statistically significant weight gain compared to patients receiving metformin 500 mg twice daily (0.60 kg; 95% CI, 0.01 to 1.19). Rates of hypoglycemia and gastrointestinal events such as nausea, vomiting, and diarrhea were low in all groups, and there were no significant differences between groups for these outcomes. Fixed-dose combination products or dual-therapy: Janumet or dual therapy with sitagliptin plus metformin Moderate Two trials assessed an FDCP or dual therapy with sitagliptin plus metformin. One compared dual therapy to monotherapy with metformin (but not a sitagliptin arm). Our meta-analysis (2 trials; N=1478) found greater reduction in HbA1c with sitagliptin100mg plus metformin 2000 mg over 18 to 24 weeks compared with metformin monotherapy (WMD -0.60%; 95% CI, to -0.45). Greater reduction in HbA1c with dual therapy with metformin and sitagliptin than with component monotherapy in a 24-week trial with additional 0 and 52 week extensions (range 0.4% to 1.2%). Two trials found no difference in weight reduction between sitagliptin plus metformin and component monotherapy. In 1 trial, sitagliptin plus metformin was associated with greater weight loss than metformin alone at 18 weeks (between-group difference: -1.6 kg; 95% CI, -2.1 to -1.1). The second trial found a similar reduction in weight with both dosages of sitagliptin plus metformin (-0.7 kg to -1.7 kg), metformin monotherapy (-1.0 kg to -1.7 kg), and sitagliptin (-0.8 kg) over 26 weeks. Gastrointestinal events were reported with similar frequency across treatment arms in both trials, with the higher-dose metformin monotherapy patients reporting the highest rates. Our meta-analyses of 2 trials comparing the combination of sitagliptin 50 mg plus metformin 1000 mg twice daily with monotherapy of metformin 1000mg twice daily found a significant difference in favor of combination therapy for diarrhea outcomes (RR 0.74; 95% CI, 0.58 to 0.95). Meta-analyses for hypoglycemia (RR 1.75; 95% CI, 0.50 to 6.10), nausea (RR 0.8; 95% CI, 0.57 to 1.22), and vomiting (RR 1.9; 95% CI, 0.62 to.1) were not statistically significant.

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73 Appendix A. Boxed warnings for included drugs Trade name Active ingredient(s) Boxed warnings SYMLIN is used with insulin and has been associated with an increased risk of insulin induced severe hypoglycemia, particularly in patients with type 1 diabetes. When severe hypoglycemia associated with SYMLIN use occurs, it is Symlin seen within hours following a SYMLIN injection. If severe Pramlintide Acetate hypoglycemia occurs while operating a motor vehicle, heavy machinery, or while engaging in other high-risk activities, serious injuries may occur. Appropriate patient selection, careful patient instruction, and insulin dose adjustments are critical elements for reducing this risk. Tradjenta Linagliptin No boxed warning Nesina Alogliptin Benzoate No boxed warning Januvia Sitagliptin Phosphate No boxed warning Onglyza Saxagliptin Hydrochloride No boxed warning Byetta Exenatide Synthetic No boxed warning Bydureon Exenatide Synthetic Exenatide extended-release causes an increased incidence in thyroid C-cell tumors at clinically relevant exposures in rats compared to controls. It is unknown whether BYDUREON causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as human relevance could not be determined by clinical or nonclinical studies. BYDUREON is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Routine serum calcitonin or thyroid ultrasound monitoring is of uncertain value in patients treated with BYDUREON. Patients should be counseled regarding the risk and symptoms of thyroid tumors

74 Trade name Active ingredient(s) Boxed warnings Victoza Liraglutide Recombinant Liraglutide causes dose-dependent and treatment-durationdependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether Victoza causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as human relevance could not be ruled out by clinical or nonclinical studies. Victoza is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Based on the findings in rodents, monitoring with serum calcitonin or thyroid ultrasound was performed during clinical trials, but this may have increased the number of unnecessary thyroid surgeries. It is unknown whether monitoring with serum calcitonin or thyroid ultrasound will mitigate human risk of thyroid C-cell tumors. Patients should be counseled regarding the risk and symptoms of thyroid tumor. Invokana Canagliflozin No boxed warning Farxiga TM Dapagliflozin No boxed warning Kazano Jentadueto Alogliptin Benzoate Metformin Hydrochloride Linagliptin Metformin Hydrochloride Lactic acidosis is a rare, but serious complication that can occur due to metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic impairment, renal impairment, and acute congestive heart failure. The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. Laboratory abnormalities include low ph, increased anion gap and elevated blood lactate. If acidosis is suspected, KAZANO (alogliptin and metformin HCl) should be discontinued and the patient hospitalized immediately. Lactic acidosis is a rare, but serious, complication that can occur due to metformin accumulation. The risk increases with conditions such as renal impairment, sepsis, dehydration, excess alcohol intake, hepatic impairment, and acute congestive heart failure. The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. Laboratory abnormalities include low ph, increased anion gap, and elevated blood lactate. If acidosis is suspected, JENTADUETO should be discontinued and the patient hospitalized immediately

75 Trade name Active ingredient(s) Boxed warnings Janumet Janumet XR Kombiglyze TM Metformin Hydrochloride Sitagliptin Phosphate Metformin Hydrochloride Sitagliptin Phosphate Saxagliptin Hydrochloride Metformin Hydrochloride Lactic acidosis is a rare, but serious complication that can occur due to metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic insufficiency, renal impairment, and acute congestive heart failure. The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. Laboratory abnormalities include low ph, increased anion gap and elevated blood lactate. If acidosis is suspected, JANUMET 1 should be discontinued and the patient hospitalized immediately. Lactic acidosis is a rare, but serious complication that can occur due to metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic impairment, renal impairment, and acute congestive heart failure. The onset of lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. Laboratory abnormalities include low ph, increased anion gap and elevated blood lactate. If acidosis is suspected, JANUMET XR (sitagliptin and metformin HCl extended-release) tablets should be discontinued and the patient hospitalized immediately. Lactic acidosis is a rare, but serious complication that can occur due to metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic impairment, renal impairment, and acute congestive heart failure. The onset of lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. Laboratory abnormalities include low ph, increased anion gap, and elevated blood lactate. If acidosis is suspected, saxagliptin hydrochloride/ metformin hydrochloride extended-release combination should be discontinued and the patient hospitalized immediately.

76 Appendix B. Glossary This glossary defines terms as they are used in reports produced by the Drug Effectiveness Review Project. Some definitions may vary slightly from other published definitions. Absolute risk: The probability or chance that a person will have a medical event. Absolute risk is expressed as a percentage. It is the ratio of the number of people who have a medical event divided by all of the people who could have the event because of their medical condition. Add-on therapy: An additional treatment used in conjunction with the primary or initial treatment. Adherence: Following the course of treatment proscribed by a study protocol. Adverse drug reaction: An adverse effect specifically associated with a drug. Adverse event: A harmful or undesirable outcome that occurs during or after the use of a drug or intervention but is not necessarily caused by it. Adverse effect: An adverse event for which the causal relation between the intervention and the event is at least a reasonable possibility. Active-control trial: A trial comparing a drug in a particular class or group with a drug outside of that class or group. Allocation concealment: The process by which the person determining randomization is blinded to a study participant s group allocation. Applicability: see External Validity Before-after study: A type nonrandomized study where data are collected before and after patients receive an intervention. Before-after studies can have a single arm or can include a control group. Bias: A systematic error or deviation in results or inferences from the truth. Several types of bias can appear in published trials, including selection bias, performance bias, detection bias, and reporting bias. Bioequivalence: Drug products that contain the same compound in the same amount that meet current official standards, that, when administered to the same person in the same dosage regimen result in equivalent concentrations of drug in blood and tissue. Black box warning: A type of warning that appears on the package insert for prescription drugs that may cause serious adverse effects. It is so named for the black border that usually surrounds the text of the warning. A black box warning means that medical studies indicate that the drug carries a significant risk of serious or even life-threatening adverse effects. The US Food and Drug Administration (FDA) can require a pharmaceutical company to place a black box warning on the labeling of a prescription drug, or in literature describing it. It is the strongest warning that the FDA requires. Blinding: A way of making sure that the people involved in a research study participants, clinicians, or researchers do not know which participants are assigned to each study group. Blinding usually is used in research studies that compare two or more types of treatment for an illness. Blinding is used to make sure that knowing the type of treatment does not affect a participant's response to the treatment, a health care provider's behavior, or assessment of the treatment effects.

77 Case series: A study reporting observations on a series of patients receiving the same intervention with no control group. Case study: A study reporting observations on a single patient. Case-control study: A study that compares people with a specific disease or outcome of interest (cases) to people from the same population without that disease or outcome (controls). Clinical diversity: Differences between studies in key characteristics of the participants, interventions or outcome measures. Clinically significant: A result that is large enough to affect a patient s disease state in a manner that is noticeable to the patient and/or a caregiver. Cohort study: An observational study in which a defined group of people (the cohort) is followed over time and compared with a group of people who were exposed or not exposed to a particular intervention or other factor of interest. A prospective cohort study assembles participants and follows them into the future. A retrospective cohort study identifies subjects from past records and follows them from the time of those records to the present. Combination Therapy: The use of two or more therapies and especially drugs to treat a disease or condition. Confidence interval: The range of values calculated from the data such that there is a level of confidence, or certainty, that it contains the true value. The 95% confidence interval is generally used in Drug Effectiveness Review Project reports. If the report were hypothetically repeated on a collection of 100 random samples of studies, the resulting 95% confidence intervals would include the true population value 95% of the time. Confounder: A factor that is associated with both an intervention and an outcome of interest. Controlled clinical trial: A clinical trial that includes a control group but no or inadequate methods of randomization. Control group: In a research study, the group of people who do not receive the treatment being tested. The control group might receive a placebo, a different treatment for the disease, or no treatment at all. Convenience sample: A group of individuals being studied because they are conveniently accessible in some way. Convenience samples may or may not be representative of a population that would normally be receiving an intervention. Crossover trial: A type of clinical trial comparing two or more interventions in which the participants, upon completion of the course of one treatment, are switched to another. Direct analysis: The practice of using data from head-to-head trials to draw conclusions about the comparative effectiveness of drugs within a class or group. Results of direct analysis are the preferred source of data in Drug Effectiveness Review Project reports. Dosage form: The physical form of a dose of medication, such as a capsule, injection, or liquid. The route of administration is dependent on the dosage form of a given drug. Various dosage forms may exist for the same compound, since different medical conditions may warrant different routes of administration. Dose-response relationship: The relationship between the quantity of treatment given and its effect on outcome. In meta-analysis, dose-response relationships can be investigated using metaregression.

78 Double-blind: The process of preventing those involved in a trial from knowing to which comparison group a particular participant belongs. While double-blind is a frequently used term in trials, its meaning can vary to include blinding of patients, caregivers, investigators, or other study staff. Double-dummy: The use of two placebos in a trial that match the active interventions when they vary in appearance or method of administrations (for example, when an oral agent is compared with an injectable agent). Effectiveness: The extent to which a specific intervention used under ordinary circumstances does what it is intended to do. Effectiveness outcomes: Outcomes that are generally important to patients and caregivers, such as quality of life, responder rates, number and length of hospitalizations, and ability to work. Data on effectiveness outcomes usually comes from longer-term studies of a real-world population. Effect size/estimate of effect: The amount of change in a condition or symptom because of a treatment (compared to not receiving the treatment). It is commonly expressed as a risk ratio (relative risk), odds ratio, or difference in risk. Efficacy: The extent to which an intervention produces a beneficial result under ideal conditions in a selected and controlled population. Equivalence level: The amount which an outcome from two treatments can differ but still be considered equivalent, as in an equivalence trial, or the amount which an outcome from treatment A can be worse than that of treatment B but still be considered noninferior, as in a noninferiority trial. Equivalence trial: A trial designed to determine whether the response to two or more treatments differs by an amount that is clinically unimportant. This lack of clinical importance is usually demonstrated by showing that the true treatment difference is likely to lie between a lower and an upper equivalence level of clinically acceptable differences. Exclusion criteria: The criteria, or standards, set out before a study or review. Exclusion criteria are used to determine whether a person should participate in a research study or whether an individual study should be excluded in a systematic review. Exclusion criteria may include age, previous treatments, and other medical conditions. Criteria help identify suitable participants. External validity: The extent to which results provide a correct basis for generalizations to other circumstances. For instance, a meta-analysis of trials of elderly patients may not be generalizable to children. (Also called generalizability or applicability.) Fixed-effect model: A model that calculates a pooled estimate using the assumption that all observed variation between studies is due to by chance. Studies are assumed to be measuring the same overall effect. An alternative model is the random-effects model. Fixed-dose combination product: A formulation of two or more active ingredients combined in a single dosage form available in certain fixed doses. Forest plot: A graphical representation of the individual results of each study included in a metaanalysis and the combined result of the meta-analysis. The plot allows viewers to see the heterogeneity among the results of the studies. The results of individual studies are shown as squares centered on each study s point estimate. A horizontal line runs through each square to show each study s confidence interval usually, but not always, a 95% confidence interval. The overall estimate from the meta-analysis and its confidence interval are represented as a diamond.

79 The center of the diamond is at the pooled point estimate, and its horizontal tips show the confidence interval. Funnel plot: A graphical display of some measure of study precision plotted against effect size that can be used to investigate whether there is a link between study size and treatment effect. Generalizability: See External Validity. Half-life: The time it takes for the plasma concentration or the amount of drug in the body to be reduced by 50%. Harms: See Adverse Event Hazard ratio: The increased risk with which one group is likely to experience an outcome of interest. It is similar to a risk ratio. For example, if the hazard ratio for death for a treatment is 0.5, then treated patients are likely to die at half the rate of untreated patients. Head-to-head trial: A trial that directly compares one drug in a particular class or group with another in the same class or group. Health outcome: The result of a particular health care practice or intervention, including the ability to function and feelings of well-being. For individuals with chronic conditions where cure is not always possible results include health-related quality of life as well as mortality. Heterogeneity: The variation in, or diversity of, participants, interventions, and measurement of outcomes across a set of studies. I 2 : A measure of statistical heterogeneity of the estimates of effect from studies. Values range from 0% to 100%. Large values of I 2 suggest heterogeneity. I 2 is the proportion of total variability across studies that is due to heterogeneity and not chance. It is calculated as (Q-(n- 1))/Q, where n is the number of studies. Incidence: The number of new occurrences of something in a population over a particular period of time, e.g. the number of cases of a disease in a country over one year. Indication: A term describing a valid reason to use a certain test, medication, procedure, or surgery. In the United States, indications for medications are strictly regulated by the Food and Drug Administration, which includes them in the package insert under the phrase "Indications and Usage". Indirect analysis: The practice of using data from trials comparing one drug in a particular class or group with another drug outside of that class or group or with placebo and attempting to draw conclusions about the comparative effectiveness of drugs within a class or group based on that data. For example, direct comparisons between drugs A and B and between drugs B and C can be used to make an indirect comparison between drugs A and C. Intention to treat: The use of data from a randomized controlled trial in which data from all randomized patients are accounted for in the final results. Trials often incorrectly report results as being based on intention to treat despite the fact that some patients are excluded from the analysis. Internal validity: The extent to which the design and conduct of a study are likely to have prevented bias. Generally, the higher the interval validity, the better the quality of the study publication. Inter-rater reliability: The degree of stability exhibited when a measurement is repeated under identical conditions by different raters.

80 Intermediate outcome: An outcome not of direct practical importance but believed to reflect outcomes that are important. For example, blood pressure is not directly important to patients but it is often used as an outcome in clinical trials because it is a risk factor for stroke and myocardial infarction (heart attack). Logistic regression: A form of regression analysis that models an individual's odds of disease or some other outcome as a function of a risk factor or intervention. Masking: See Blinding Mean difference: A method used to combine measures on continuous scales (such as weight) where the mean, standard deviation, and sample size are known for each group. Meta-analysis: The use of statistical techniques in a systematic review to integrate the results of included studies. Although the terms are sometimes used interchangeably, meta-analysis is not synonymous with systematic review. However, systematic reviews often include meta-analyses. Meta-regression: A technique used to explore the relationship between study characteristics (for example, baseline risk, concealment of allocation, timing of the intervention) and study results (the magnitude of effect observed in each study) in a systematic review. Mixed treatment comparison meta-analysis: A meta-analytic technique that simultaneously compares multiple treatments (typical or more) using both direct and indirect evidence. The multiple treatments form a network of treatment comparisons. Also called multiple treatment comparisons, network analysis, or umbrella reviews. Monotherapy: the use of a single drug to treat a particular disorder or disease. Multivariate analysis: Measuring the impact of more than one variable at a time while analyzing a set of data. N-of-1 trial: A randomized trial in an individual to determine the optimum treatment for that individual. Noninferiority trial: A trial designed to determine whether the effect of a new treatment is not worse than a standard treatment by more than a prespecified amount. A one-sided version of an equivalence trial. Nonrandomized study: Any study estimating the effectiveness (harm or benefit) of an intervention that does not use randomization to allocate patients to comparison groups. There are many types of nonrandomized studies, including cohort studies, case-control studies, and beforeafter studies. Null hypothesis: The statistical hypothesis that one variable (for example, treatment to which a participant was allocated) has no association with another variable or set of variables. Number needed to harm: The number of people who would need to be treated over a specific period of time before one bad outcome of the treatment will occur. The number needed to harm (NNH) for a treatment can be known only if clinical trials of the treatment have been performed. Number needed to treat: An estimate of how many persons need to receive a treatment before one person would experience a beneficial outcome. Observational study: A type of nonrandomized study in which the investigators do not seek to intervene, instead simply observing the course of events. Odds ratio: The ratio of the odds of an event in one group to the odds of an event in another group. An odds ratio of 1.0 indicates no difference between comparison groups. For undesirable

81 outcomes an odds ratio that is <1.0 indicates that the intervention was effective in reducing the risk of that outcome. Off-label use: When a drug or device is prescribed outside its specific FDA-approved indication, to treat a condition or disease for which it is not specifically licensed. Outcome: The result of care and treatment and/ or rehabilitation. In other words, the change in health, functional ability, symptoms or situation of a person, which can be used to measure the effectiveness of care/treatment/rehabilitation. Researchers should decide what outcomes to measure before a study begins; outcomes are then assessed at the end of the study. Outcome measure: Is the way in which an outcome is evaluated---the device (scale) used for measuring. With this definition YMRS is an outcome measure, and a patient's outcome after treatment might be a 12-point improvement on that scale. One-tailed test (one-sided test): A hypothesis test in which the values that reject the null hypothesis are located entirely in one tail of the probability distribution. For example, testing whether one treatment is better than another (rather than testing whether one treatment is either better or worse than another). Open-label trial: A clinical trial in which the investigator and participant are aware which intervention is being used for which participant (that is, not blinded). Random allocation may or may not be used in open-label trials. Per protocol: The subset of participants from a randomized controlled trial who complied with the protocol sufficiently to ensure that their data would be likely to exhibit the effect of treatment. Per protocol analyses are sometimes misidentified in published trials as intention-totreat analyses. Pharmacokinetics: the characteristic interactions of a drug and the body in terms of its absorption, distribution, metabolism, and excretion. Placebo: An inactive substance commonly called a "sugar pill." In a clinical trial, a placebo is designed to look like the drug being tested and is used as a control. It does not contain anything that could harm a person. It is not necessarily true that a placebo has no effect on the person taking it. Placebo-controlled trial: A study in which the effect of a drug is compared with the effect of a placebo (an inactive substance designed to resemble the drug). In placebo-controlled clinical trials, participants receive either the drug being studied or a placebo. The results of the drug and placebo groups are then compared to see if the drug is more effective in treating the condition than the placebo is. Point estimate: The results (e.g. mean, weighted difference, odds ratio, relative risk or risk difference) obtained in a sample (a study or a meta-analysis) which are used as the best estimate of what is true for the relevant population from which the sample is taken. A confidence interval is a measure of the uncertainty (due to the play of chance) associated with that estimate. Pooling: The practice of combing data from several studies to draw conclusions about treatment effects. Power: The probability that a trial will detect statistically significant differences among intervention effects. Studies with small sample sizes can frequently be underpowered to detect difference. Precision: The likelihood of random errors in the results of a study, meta-analysis, or measurement. The greater the precision, the less the random error. Confidence intervals around

82 the estimate of effect are one way of expressing precision, with a narrower confidence interval meaning more precision. Prospective study: A study in which participants are identified according to current risk status or exposure and followed forward through time to observe outcome. Prevalence: How often or how frequently a disease or condition occurs in a group of people. Prevalence is calculated by dividing the number of people who have the disease or condition by the total number of people in the group. Probability: The likelihood (or chance) that an event will occur. In a clinical research study, it is the number of times a condition or event occurs in a study group divided by the number of people being studied. Publication bias: A bias caused by only a subset of the relevant data being available. The publication of research can depend on the nature and direction of the study results. Studies in which an intervention is not found to be effective are sometimes not published. Because of this, systematic reviews that fail to include unpublished studies may overestimate the true effect of an intervention. In addition, a published report might present a biased set of results (for example, only outcomes or subgroups for which a statistically significant difference was found). P value: The probability (ranging from zero to one) that the results observed in a study could have occurred by chance if the null hypothesis was true. A P value of 0.05 is often used as a threshold to indicate statistical significance. Q-statistic: A measure of statistical heterogeneity of the estimates of effect from studies. Large values of Q suggest heterogeneity. It is calculated as the weighted sum of the squared difference of each estimate from the mean estimate. Random-effects model: A statistical model in which both within-study sampling error (variance) and between-studies variation are included in the assessment of the uncertainty (confidence interval) of the results of a meta-analysis. When there is heterogeneity among the results of the included studies beyond chance, random-effects models will give wider confidence intervals than fixed-effect models. Randomization: The process by which study participants are allocated to treatment groups in a trial. Adequate (that is, unbiased) methods of randomization include computer generated schedules and random-numbers tables. Randomized controlled trial: A trial in which two or more interventions are compared through random allocation of participants. Regression analysis: A statistical modeling technique used to estimate or predict the influence of one or more independent variables on a dependent variable, for example, the effect of age, sex, or confounding disease on the effectiveness of an intervention. Relative risk: The ratio of risks in two groups; same as a risk ratio. Retrospective study: A study in which the outcomes have occurred prior to study entry. Risk: A way of expressing the chance that something will happen. It is a measure of the association between exposure to something and what happens (the outcome). Risk is the same as probability, but it usually is used to describe the probability of an adverse event. It is the rate of events (such as breast cancer) in the total population of people who could have the event (such as women of a certain age). Risk difference: The difference in size of risk between two groups.

83 Risk Factor: A characteristic of a person that affects that person's chance of having a disease. A risk factor may be an inherent trait, such as gender or genetic make-up, or a factor under the person's control, such as using tobacco. A risk factor does not usually cause the disease. It changes a person's chance (or risk) of getting the disease. Risk ratio: The ratio of risks in two groups. In intervention studies, it is the ratio of the risk in the intervention group to the risk in the control group. A risk ratio of 1 indicates no difference between comparison groups. For undesirable outcomes, a risk ratio that is <1 indicates that the intervention was effective in reducing the risk of that outcome. Run-in period: Run in period: A period before randomization when participants are monitored but receive no treatment (or they sometimes all receive one of the study treatments, possibly in a blind fashion). The data from this stage of a trial are only occasionally of value but can serve a valuable role in screening out ineligible or non-compliant participants, in ensuring that participants are in a stable condition, and in providing baseline observations. A run-in period is sometimes called a washout period if treatments that participants were using before entering the trial are discontinued. Safety: Substantive evidence of an absence of harm. This term (or the term safe ) should not be used when evidence on harms is simply absent or is insufficient. Sample size: The number of people included in a study. In research reports, sample size is usually expressed as "n." In general, studies with larger sample sizes have a broader range of participants. This increases the chance that the study's findings apply to the general population. Larger sample sizes also increase the chance that rare events (such as adverse effects of drugs) will be detected. Sensitivity analysis: An analysis used to determine how sensitive the results of a study or systematic review are to changes in how it was done. Sensitivity analyses are used to assess how robust the results are to uncertain decisions or assumptions about the data and the methods that were used. Side effect: Any unintended effect of an intervention. Side effects are most commonly associated with pharmaceutical products, in which case they are related to the pharmacological properties of the drug at doses normally used for therapeutic purposes in humans. Standard deviation (SD): A measure of the spread or dispersion of a set of observations, calculated as the average difference from the mean value in the sample. Standard error (SE): A measure of the variation in the sample statistic over all possible samples of the same size. The standard error decreases as the sample size increases. Standard treatment: The treatment or procedure that is most commonly used to treat a disease or condition. In clinical trials, new or experimental treatments sometimes are compared to standard treatments to measure whether the new treatment is better. Statistically significant: A result that is unlikely to have happened by chance. Study: A research process in which information is recorded for a group of people. The information is known as data. The data are used to answer questions about a health care problem. Study population: The group of people participating in a clinical research study. The study population often includes people with a particular problem or disease. It may also include people who have no known diseases. Subgroup analysis: An analysis in which an intervention is evaluated in a defined subset of the participants in a trial, such as all females or adults older than 65 years.

84 Superiority trial: A trial designed to test whether one intervention is superior to another. Surrogate outcome: Outcome measures that are not of direct practical importance but are believed to reflect outcomes that are important; for example, blood pressure is not directly important to patients but it is often used as an outcome in clinical trials because it is a risk factor for stroke and heart attacks. Surrogate endpoints are often physiological or biochemical markers that can be relatively quickly and easily measured, and that are taken as being predictive of important clinical outcomes. They are often used when observation of clinical outcomes requires long follow-up. Survival analysis: Analysis of data that correspond to the time from a well-defined time origin until the occurrence of some particular event or end-point; same as time-to-event analysis. Systematic review: A review of a clearly formulated question that uses systematic and explicit methods to identify, select, and critically appraise relevant research and to collect and analyze data from the studies that are included in the review. Tolerability: For therapeutic drugs, it refers a drug's lack of "nuisance side effects," side effects that are thought to have no long-term effect but that are unpleasant enough to the patient that adherence to the medication regimen is affected. The extent to which a drug s adverse effects impact the patient s ability or willingness to continue taking the drug as prescribed. These adverse effects are often referred to as nuisance side effects, because they are generally considered to not have long-term effects but can seriously impact compliance and adherence to a medication regimen. Treatment regimen: The magnitude of effect of a treatment versus no treatment or placebo; similar to effect size. Can be calculated in terms of relative risk (or risk ratio), odds ratio, or risk difference. Two-tailed test (two-sided test): A hypothesis test in which the values that reject the null hypothesis are located in both tails of the probability distribution. For example, testing whether one treatment is different than another (rather than testing whether one treatment is either better than another). Type I error: A conclusion that there is evidence that a treatment works, when it actually does not work (false-positive). Type II error: A conclusion that there is no evidence that a treatment works, when it actually does work (false-negative). Validity: The degree to which a result (of a measurement or study) is likely to be true and free of bias (systematic errors). Variable: A measurable attribute that varies over time or between individuals. Variables can be Discrete: taking values from a finite set of possible values (e.g. race or ethnicity) Ordinal: taking values from a finite set of possible values where the values indicate rank (e.g. 5-point Likert scale) Continuous: taking values on a continuum (e.g. HbA1c values). Washout period: [In a cross-over trial] The stage after the first treatment is withdrawn, but before the second treatment is started. The washout period aims to allow time for any active effects of the first treatment to wear off before the new one gets started

85 Appendix C. Search strategies Diabetes Medications Search Update PubMed November 5, 201 Search Query Result #1 Search (pramlintide OR Symlin OR [rn]) 275 #2 Search "Diabetes Mellitus, Type 1"[Mesh] # Search (#1 AND #2) 102 Search (sitagliptin OR Januvia OR dipeptidyl peptidase OR cd26 inhibitor OR gliptins OR [rn] OR saxagliptin OR Onglyza OR [rn] OR exenatide OR Byetta OR exendin-4 OR glp-1 OR [rn] OR "liraglutide"[substance Name] OR liraglutide OR Victoza OR [rn] OR "janumet"[substance Name] OR "janumet"[all #4 Fields]) 728 Search ("Diabetes Mellitus/drug therapy"[mesh] OR "diabetes mellitus, type #5 2"[MeSH Terms]) #6 Search ((#1 OR #4) AND #5) 2450 #7 Search (# OR #6) 2456 Search ("case reports"[publication Type] OR "editorial"[publication Type] OR #8 "news"[publication Type]) 2154 #9 Search (#7 NOT #8) 2299 #10 Search (#7 NOT #8) Filters: Humans 2059 #11 Search (#7 NOT #8) Filters: Humans; English 1878 #12 Search ("Randomized Controlled Trial"[Publication Type] OR "Single-Blind Method"[MeSH] OR "Double-Blind Method"[MeSH] OR "Random Allocation"[MeSH]) #1 Search (#11 AND #12) 444 #14 Search (#11 AND #12) Filters: Publication date from 2008/12/01 00 #15 Search (#7 NOT #8) Filters: Systematic Reviews; Humans; English 150 #16 Search (#15 NOT #1) 140 #17 Search (#15 NOT #1) Filters: Publication date from 2008/12/ #18 Search (linagliptin[supplementary Concept] OR "Linagliptin"[All Fields] OR "bi156"[all Fields] OR [rn] OR "tradjenta"[all Fields] OR trajenta OR trazenta OR "jentadueto"[all Fields] OR ondero) 200 #19 Search (#18 AND #5) 109 #20 Search (#19 NOT #8) 105 #21 Search (#19 NOT #8) Filters: Humans 97 #22 Search (#19 NOT #8) Filters: Humans; English 88 #2 Search (#22 AND #12) 20 #24 Search (#22 AND #12) Filters: Publication date from 2011/09/01 10 #25 Search (#19 NOT #8) Filters: Systematic Reviews; Humans; English 12 #26 Search (#25 NOT #2) 11 #27 Search (#25 NOT #2) Filters: Publication date from 2011/09/01 10 Search ("alogliptin" [Supplementary Concept] OR alogliptin OR #28 5[rn] OR Nesina OR [rn] OR "canagliflozin"[supplementary 1812

86 Concept] OR canagliflozin OR [rn] OR Invokana OR exenatide XR OR exenatide extended release OR bydureon OR [rn] OR kombiglyze OR [rn] OR kazano OR janumet xr OR janumet extended release ) #29 Search (#28 AND #5) 924 #0 Search (#29 NOT #8) 852 #1 Search (#29 NOT #8) Filters: Humans 755 #2 Search (#29 NOT #8) Filters: Humans; English 682 # Search (#2 AND #12) 14 #4 Search (#29 NOT #8) Filters: Systematic Reviews; Humans; English 68 #5 Search (#4 NOT #) 66 #6 Search (#1 OR #4 OR #18 OR #28) 7577 #7 Search (#7 OR #19 OR #29) 2482 #8 Search ("Diabetic Ketoacidosis"[Mesh] OR "Hyperglycemic Hyperosmolar Nonketotic Coma"[Mesh] OR "Neoplasms"[Mesh] OR "Infection"[Mesh] OR "Communicable Diseases"[Mesh] OR "Hypoglycemia"[Mesh] OR "Massive Hepatic Necrosis"[Mesh] OR "Liver Function Tests"[Mesh] OR "Gastrointestinal Diseases/drug effects"[mesh] OR "Heart Failure"[Mesh] OR "Lipids"[Mesh] OR "Pancreatitis"[Mesh] OR "Weight Gain"[Mesh] OR "Fractures, Bone"[Mesh] OR adverse effects [sh] OR overall adverse events OR withdrawal due to adverse events ) #9 Search (#7 AND #8) 926 #40 Search (#9 NOT #8) 860 #41 Search (#9 NOT #8) Filters: Humans 804 #42 Search (#9 NOT #8) Filters: Humans; English 744 #4 Search ( prospective cohort OR prospective studies [MeSH] OR (prospective*[all Fields] AND cohort[all Fields] AND (study[all Fields] OR studies[all Fields])) OR "case-control" OR "case control") #44 Search (#42 AND (#12 OR #4)) 262 #45 Search (#9 NOT #8) Filters: Systematic Reviews; Humans; English 84 #46 Search (#45 NOT #44) 76 #47 Search (#14 OR #24 OR # OR #44) 418 #48 Search (#17 OR #27 OR #5 OR #46) 12 #49 Search (#47 OR #48) 548 Diabetes Medications Search Update Embase November 5, 201 No. Query Results #1 'pramlintide'/exp OR 'symlin'/exp 1002 #2 'diabetes mellitus, type 1'/exp OR 'type 1 diabetes mellitus'/exp OR 'insulin dependent diabetes mellitus'/exp # #1 AND #2 25 #4 'sitagliptin'/exp OR 'januvia'/exp OR 'dipeptidyl peptidase'/exp OR 'gliptins'/exp OR 'saxagliptin'/exp OR 'onglyza'/exp OR 'exenatide'/exp OR 'byetta'/exp OR 'liraglutide'/exp OR 'victoza'/exp OR 'janumet'/exp OR 'metformin plus sitagliptin'/exp #5 'diabetes mellitus, type 2'/exp OR 'type 2 diabetes mellitus'/exp OR 'non insulin dependent diabetes mellitus'/exp

87 #6 #7 #8 #9 #10 #11 #12 #1 #14 #15 #16 #17 #18 #19 #20 #21 #22 #2 #24 #25 #26 #27 #5 AND (#1 OR #4) # OR #6 [conference abstract]/lim OR [conference paper]/lim OR [conference review]/lim OR [editorial]/lim OR [erratum]/lim OR [letter]/lim OR [note]/lim OR [short survey]/lim #7 NOT #8 #9 AND [humans]/lim AND [english]/lim #10 AND [randomized controlled trial]/lim 'randomized controlled trial'/exp OR 'single blind procedure'/exp OR 'double blind procedure'/exp OR 'random allocation'/exp #10 AND #12 #11 OR #1 #14 AND [ ]/sd #15 AND [medline]/lim #15 NOT #16 #10 AND ([meta analysis]/lim OR [systematic review]/lim) 'systematic review'/exp OR 'systematic review (topic)'/exp OR 'metaanalysis'/exp OR 'meta analysis (topic)'/exp OR 'meta analysis'/exp #10 AND #19 #18 OR #20 #21 NOT #14 #22 AND [ ]/sd #2 AND [medline]/lim #2 NOT #24 'linagliptin'/exp OR 'bi156'/exp OR 'tradjenta'/exp OR 'trajenta'/exp OR trazenta OR 'jentadueto'/exp OR 'ondero'/exp OR 'linagliptin plus metformin'/exp #26 AND # #28 #29 #0 #1 #2 # #4 #5 #6 #7 #8 #9 #40 #41 #27 NOT #8 #28 AND [humans]/lim AND [english]/lim #29 AND [randomized controlled trial]/lim #29 AND #12 #0 OR #1 #2 AND [ ]/sd # AND [medline]/lim # NOT #4 #29 AND ([meta analysis]/lim OR [systematic review]/lim) #29 AND #19 #6 OR #7 #8 AND [ ]/sd #9 AND [medline]/lim #9 NOT #

88 #42 #4 #44 #45 #46 #47 #48 #49 #50 #51 #52 #5 #54 #55 #56 #57 #58 #59 #60 #61 #62 #6 #64 #65 #66 #67 #68 #69 #70 #71 #72 #7 #74 'alogliptin'/exp OR 'nesina'/exp OR 'canagliflozin'/exp OR 'invokana'/exp OR 'bydureon'/exp OR 'kombiglyze'/exp OR 'metformin plus saxagliptin'/exp OR 'kazano'/exp OR 'alogliptin plus metformin'/exp #42 AND #5 #4 NOT #8 #44 AND [humans]/lim AND [english]/lim #45 AND [randomized controlled trial]/lim #45 AND #12 #46 OR #47 #48 AND [medline]/lim #48 NOT #49 #45 AND ([meta analysis]/lim OR [systematic review]/lim) #45 AND #19 #51 OR #52 #5 AND [medline]/lim #5 NOT #54 #7 OR #27 OR #4 'diabetic ketoacidosis'/exp OR 'nonketotic diabetic coma'/exp OR 'neoplasm'/exp OR 'infection'/exp OR 'communicable disease'/exp OR 'hypoglycemia'/exp OR 'liver necrosis'/exp OR 'liver function test'/exp OR 'gastrointestinal disease'/exp OR 'heart failure'/exp OR 'lipid'/exp OR 'pancreatitis'/exp OR 'weight gain'/exp OR 'fracture'/exp OR (adverse AND effects) OR (overall AND adverse AND events) OR (withdraw al AND due AND to AND adverse AND events) #51 AND #52 #5 AND [humans]/lim AND [english]/lim 'prospective cohort' OR 'prospective study'/exp OR (prospective* AND cohort AND ('study'/exp OR studies)) OR 'casecontrol' OR 'case control' OR 'case control study'/exp #59 AND (#60 OR #12) #59 AND [randomized controlled trial]/lim #61 OR #62 #6 AND [medline]/lim #6 NOT #64 #59 AND ([meta analysis]/lim OR [systematic review]/lim) #59 AND #19 #66 OR #67 #68 AND [medline]/lim #68 NOT #69 #17 OR #5 OR #50 OR #65 #25 OR #41 OR #55 OR #70 #71 OR #72 'pioglitazone'/exp OR 'actos'/exp AND ('metformin'/exp OR 'glucophage'/exp)

89 #75 #76 #77 #78 #79 #80 #81 #82 #8 #84 #85 #86 #5 AND #74 #75 NOT #8 #76 AND #57 #76 AND #12 #76 AND [randomized controlled trial]/lim #78 OR #79 #60 AND #77 #80 OR #81 #76 AND ([meta analysis]/lim OR [systematic review]/lim) #8 NOT #82 #82 AND [ ]/sd #84 AND [ ]/sd Diabetes Medications Search Update Cochrane November 5, 201 No. Query Results #1 pramlintide or Symlin 65 #2 [mh "Diabetes Mellitus, Type 1"] 029 # #1 and #2 0 #4 sitagliptin or Januvia or "dipeptidyl peptidase" or "cd26 inhibitor" or gliptins or saxagliptin or Onglyza or exenatide or Byetta or exendin-4 or glp-1 or liraglutide or Victoza or janumet 586 #5 [mh "Diabetes Mellitus/drug therapy"] or [mh "diabetes mellitus, type 2"] 7916 #6 (#1 or #4) and #5 44 #7 # or #6 471 #8 #7 from 2008, in Trials 257 #9 #7 from 2008, in Trials 257 #10 #7 in Cochrane Reviews (Reviews and Protocols) 8 #11 #7 from 2008, in Cochrane Reviews (Reviews and Protocols) 8 #12 #7 in Other Reviews 51 #1 #7 from 2008, in Other Reviews 50 #14 #11 or #1 58 #15 #8 or #14 15 #16 linagliptin or bi156 or tradjenta or trajenta or trazenta or jentadueto or ondero 41 #17 #16 and #5 26 #18 #17 in Trials 17 #19 #17 from 2011, in Trials 1 #20 #17 in Cochrane Reviews (Reviews and Protocols) 0 #21 #17 from 2011, in Cochrane Reviews (Reviews and Protocols) 0 #22 #17 in Other Reviews 6 #2 #17 from 2011, in Other Reviews 6 #24 #21 or #2 6

90 #25 #19 or #24 19 #26 alogliptin or Nesina or canagliflozin or Invokana or "exenatide XR" or "exenatide extended release" or bydureon or kombiglyze or kazano or "janumet xr" or "janumet extended release" 4 #27 #26 and #5 26 #28 #27 in Trials 19 #29 #27 in Cochrane Reviews (Reviews and Protocols) 1 #0 #27 in Other Reviews 5 #1 #29 or #0 6 #2 #28 or #1 25 # #7 or #17 or # #4 [mh "Diabetic Ketoacidosis"] or [mh "Hyperglycemic Hyperosmolar Nonketotic Coma"] or [mh Neoplasms] or [mh Infection] or [mh "Communicable Diseases"] or [mh Hypoglycemia] or [mh "Massive Hepatic Necrosis"] or [mh "Liver Function Tests"] or [mh "Gastrointestinal Diseases"/DE] or [mh "Heart Failure"] or [mh Lipids] or [mh Pancreatitis] or [mh "Weight Gain"] or [mh "Fractures, Bone"] or [mh /AE] or "overall adverse events" or "withdrawal due to adverse events" #5 # and #4 222 #6 #5 in Trials 191 #7 #5 in Cochrane Reviews (Reviews and Protocols) #8 #5 in Other Reviews 24 #9 #7 or #8 27 #40 #6 or #9 218 #41 #9 or #19 or #28 or #6 16 #42 #14 or #24 or #1 or #9 59 #4 #41 or #42 75 #44 (pioglitazone or actos) and (metformin or Glucophage) 256 #45 #44 and #5 185 #46 #44 and #5 in Trials 15 #47 #44 and #5 from 2008, in Trials 8 #48 #44 and #5 in Cochrane Reviews (Reviews and Protocols) 12 #49 #44 and #5 from 2008, in Cochrane Reviews (Reviews and Protocols) 10 #50 #44 and #5 in Other Reviews 0 #51 #44 and #5 from 2008, in Other Reviews 24 Diabetes Medications Search Update International Pharmaceutical Abstracts November 5, 201 # Query Results S1 TX pramlintide OR Symlin 90 S2 SU insulin-dependent diabetes OR TX ("type 1 diabetes" OR "diabetes mellitus, type 1") 815

91 S SU S1 AND S2 18 TX sitagliptin OR Januvia OR dipeptidyl peptidase OR cd26 S4 inhibitor OR gliptins OR saxagliptin OR Onglyza OR exenatide OR 77 Byetta OR exendin-4 OR glp-1 OR liraglutide OR Victoza OR "janumet" OR metformin plus sitagliptin S5 SU non insulin dependent diabetes mellitus OR TX ( "diabetes mellitus, type 2" OR "type 2 diabetes" ),827 S6 (S1 OR S4) AND S5 542 S7 S OR S6 55 S8 S OR S6 Limiters - Language: English; Articles about Human Studies 501 S9 S OR S6 Limiters - Published Date: ; Language: English; Articles about Human Studies 27 S10 TX linagliptin OR "bi156" OR "tradjenta" OR trajenta OR trazenta OR "jentadueto" OR ondero OR linagliptin plus metformin 51 S11 S10 AND S5 40 S12 S10 AND S5 Limiters - Language: English; Articles about Human Studies 8 S1 S10 AND S5 Limiters - Published Date: ; Language: English; Articles about Human Studies 24 TX alogliptin OR Nesina OR canagliflozin OR Invokana OR exenatide S14 XR OR exenatide extended release OR bydureon OR kombiglyze OR metformin plus saxagliptin OR kazano OR alogliptin 48 plus metformin OR janumet xr OR janumet extended release S15 S14 AND S5 40 S16 S14 AND S5 Limiters - Language: English; Articles about Human Studies 40 SU ( ("Diabetic Ketoacidosis" OR "nonketotic diabetic coma" OR "Neoplasm" OR "Infection" OR "Communicable Disease" OR "Hypoglycemia" OR "liver necrosis" OR "Liver Function Test" OR "Gastrointestinal Disease" OR "Heart Failure" OR "Lipid" OR "Pancreatitis" OR "Weight Gain" OR "Fracture" OR adverse effects OR overall adverse events OR withdrawal due to adverse events ) S17 ) OR TX ( ("Diabetic Ketoacidosis" OR "nonketotic diabetic coma" OR 78,928 "Neoplasm" OR "Infection" OR "Communicable Disease" OR "Hypoglycemia" OR "liver necrosis" OR "Liver Function Test" OR "Gastrointestinal Disease" OR "Heart Failure" OR "Lipid" OR "Pancreatitis" OR "Weight Gain" OR "Fracture" OR adverse effects OR overall adverse events OR withdrawal due to adverse events ) ) S18 S7 OR S11 OR S S19 S17 AND S18 21 S20 S17 AND S18 Limiters - Language: English; Articles about Human Studies 06 S21 (S9 OR S1 OR S16 OR S20) 49 S22 (pioglitazone or actos) and (metformin or Glucophage) 264 S2 S22 AND S5 186 S24 S22 AND S5 Limiters - Language: English; Articles about Human Studies 181 S25 S22 AND S5 Limiters - Published Date: ; Language: English; Articles about Human Studies 75

92 Dapagliflozin Search PubMed Pharmaceutical Abstracts February 7, 2014 Search Query Items found #1 Search (("2-(-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2Hpyran-,4,5-triol"[Supplementary 15 Concept] OR "2-(-(4-ethoxybenzyl)-4- chlorophenyl)-6-hydroxymethyltetrahydro-2h-pyran-,4,5-triol"[all Fields] OR "dapagliflozin"[all Fields]) OR Forxiga[All Fields]) #2 Search (("Diabetes Mellitus/drug therapy"[mesh] OR "diabetes mellitus, type "[MeSH Terms])) # Search (("case reports"[publication Type] OR "editorial"[publication Type] OR "news"[publication Type])) #4 Search (#1 AND #2) 82 #5 Search (#4 NOT #) 76 #6 Search (#4 NOT #) Filters: Humans 75 #7 Search (#4 NOT #) Filters: Humans; English 65 #8 Search (("Randomized Controlled Trial"[Publication Type] OR "Single-Blind Method"[MeSH] OR "Double-Blind Method"[MeSH] OR "Random Allocation"[MeSH])) #9 Search (#7 AND #8) 19 #10 Search (#4 NOT #) Filters: Systematic Reviews; Humans; English 5 #11 Search (#10 NOT #9) 5 #12 Search (("Diabetic Ketoacidosis"[Mesh] OR "Hyperglycemic Hyperosmolar Nonketotic Coma"[Mesh] OR "Neoplasms"[Mesh] OR "Infection"[Mesh] OR "Communicable Diseases"[Mesh] OR "Hypoglycemia"[Mesh] OR "Massive Hepatic Necrosis"[Mesh] OR "Liver Function Tests"[Mesh] OR "Gastrointestinal Diseases/drug effects"[mesh] OR "Heart Failure"[Mesh] OR "Lipids"[Mesh] OR "Pancreatitis"[Mesh] OR "Weight Gain"[Mesh] OR "Fractures, Bone"[Mesh] OR adverse effects [sh] OR overall adverse events OR withdrawal due to adverse events )) #1 Search (#4 AND #12) 6 #14 Search (#1 NOT #) 4 #15 Search (#1 NOT #) Filters: Humans 4 #16 Search (#1 NOT #) Filters: Humans; English 27 #17 Search (( prospective cohort OR prospective studies [MeSH] OR (prospective*[all Fields] AND cohort[all Fields] AND (study[all Fields] OR studies[all Fields])) OR "case-control" OR "case control")) #18 Search (#16 AND (#17 OR #8)) 6 #19 Search (#1 NOT #) Filters: Systematic Reviews; Humans; English 4 #20 Search (#19 NOT #18) 4 #21 Search (#9 OR #11 OR #18 OR #20) 24 Dapagliflozin Search Embase Pharmaceutical Abstracts February 7, 2014 Search Query Items found #1 #2 dapagliflozin/exp OR forxiga/exp OR farxiga 'diabetes mellitus, type 2'/exp OR 'type 2 diabetes mellitus'/exp OR 'non insulin dependent diabetes mellitus'/exp 478 1,8

93 # #4 #5 #6 #7 #8 #9 #10 #11 #12 #1 #14 #15 #16 #1 AND #2 [conference abstract]/lim OR [conference paper]/lim OR [conference review]/lim OR [editorial]/lim OR [erratum]/lim OR [letter]/lim OR [note]/lim OR [short survey]/lim # NOT #4 'diabetic ketoacidosis'/exp OR 'nonketotic diabetic coma'/exp OR 'neoplasm'/exp OR 'infection'/exp OR 'communicable disease'/exp OR 'hypoglycemia'/exp OR 'liver necrosis'/exp OR 'liver function test'/exp OR 'gastrointestinal disease'/exp OR 'heart failure'/exp OR 'lipid'/exp OR 'pancreatitis'/exp OR 'weight gain'/exp OR 'fracture'/exp OR (adverse AND effects) OR (overall AND adverse AND events) OR (withdrawal AND due AND to AND adverse AND events) #5 AND #6 'randomized controlled trial'/exp OR 'single blind procedure'/exp OR 'double blind procedure'/exp OR 'random allocation'/exp #5 AND #8 #5 AND [randomized controlled trial]/lim #9 OR #10 'prospective cohort' OR 'prospective study'/exp OR (prospective* AND cohort AND ('study'/exp OR studies)) OR 'case-control' OR 'case control' OR 'case control study'/exp #7 AND #12 #11 OR #1 #5 AND ([meta analysis]/lim OR [systematic review]/lim) #15 NOT # ,488,25 2 7,56, , , Dapagliflozin Search Cochrane Pharmaceutical Abstracts February 7, 2014 Search Query Items found #1 (dapagliflozin or forxiga or farxiga) 44 #2 [mh "Diabetes Mellitus/drug therapy"] or [mh "diabetes mellitus, type 2"] 809 # #1 and #2 26 #4 #1 and #2 in Trials 19 #5 #1 and #2 in Cochrane Reviews (Reviews and Protocols) 1 #6 #1 and #2 in Other Reviews Dapagliflozin Search International Pharmaceutical Abstracts February 7, 2014 Search Query Items found S1 (dapagliflozin or forxiga or farxiga) 6 S2 SU non insulin dependent diabetes mellitus OR TX ( "diabetes mellitus, type 2" OR "type 2 diabetes" ),900 S S1 AND S2 28 S4 S1 AND S2 Limiters - Language: English; Articles about Human Studies 24

94 Appendix D. Excluded studies and studies of poor quality The following full-text publications were considered for inclusion but failed to meet the criteria for this report. The list does not include the publications excluded for wrong publication type (e.g. letter, editorial, non-systematic reviews, case reports, case series). See previous reports on newer diabetes medications, TZDs, and fixed dose combination products on the Drug Effectiveness Review Project website for studies excluded previously. 1 = Ineligible publication type 2 = Ineligible drug = Ineligible comparison or no comparison 4 = Ineligible outcome 5 = Ineligible study design 6 = Ineligible duration (< 12 weeks) 7 = Ineligible population P = Poor quality rating Exclusion Excluded References Code Aaboe K, Knop FK, Vilsboll T, Deacon CF, Holst JJ, Madsbad S and Krarup T. Twelve weeks treatment with the DPP-4 inhibitor, sitagliptin, prevents degradation of peptide YY and improves glucose and non-glucose induced insulin secretion in patients with type 2 diabetes mellitus. Diabetes Obes Metab Apr;12(4):2-. PMID: Anonymous. liraglutide Type 2 diabetes: more prudent to continue using exenatide. p Apovian CM, Bergenstal RM, Cuddihy RM, Qu Y, Lenox S, Lewis MS and Glass LC. Effects of exenatide combined with lifestyle modification in patients with type 2 diabetes. Am J Med May;12(5):468 e9-17. PMID: Araki E, Kawamori R, Inagaki N, Watada H, Hayashi N, Horie Y, Sarashina A, Thiemann S, von Eynatten M, Dugi K and Woerle HJ. Long-term safety of linagliptin monotherapy in Japanese patients with type 2 diabetes. Diabetes Obes Metab. 201 Apr;15(4): PMID: Aroda VR and DeYoung MB. Clinical Implications of Exenatide as a Twice-Daily or Once-Weekly Therapy for 1 Type 2 Diabetes. p Asche CV, McAdam-Marx C, Shane-McWhorter L, Sheng XM and Plauschinat CA. Evaluation of adverse events of oral antihyperglycaemic monotherapy experienced by a geriatric population in a real-world setting - A retrospective cohort analysis. Drugs and Aging (New Zealand). 2008;25(Jul)PMID: Accession Number: ; Language: English; Chemical Name: Metformin ; Therapeutic Class: (68:20); AHFS Class: Antidiabetic agents Metformin; References: 4; Journal Coden: DRAGE6; Human Indicator: Yes; Section Heading: Toxicity; Drug EvaluationsAdverse Drug Reactions. Aston-Mourney K, Subramanian SL, Zraika S, Samarasekera T, Meier DT, Goldstein LC and Hull RL. One year of sitagliptin treatment protects against islet amyloid-associated beta-cell loss and does not induce 4 pancreatitis or pancreatic neoplasia in mice. Am J Physiol Endocrinol Metab. 201 Aug 15;05(4):E Bailey CJ, Gross JL, Hennicken D, Iqbal N, Mansfield TA and List JF. Dapagliflozin add-on to metformin in type 2 diabetes inadequately controlled with metformin: a randomized, double-blind, placebo-controlled 102- week trial. BMC Med. 201;11:4. PMID: Bailey CJ, Gross JL, Pieters A, Bastien A and List JF. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet Jun 26;75(97):222-. PMID: Balkrishnan R, Arondekar BV, Camacho FT, Shenolikar RA, Horblyuk R and Anderson RT. Comparisons of rosiglitazone versus pioglitazone monotherapy introduction and associated health care utilization in Medicaidenrolled patients with type 2 diabetes mellitus. Clin Ther Jun;29(6 Pt 1): PMID: Bao Y, Zhao T, Wang X, Qiu Y, Su M, Jia W and Jia W. Metabonomic variations in the drug-treated type 2 diabetes mellitus patients and healthy volunteers. J Proteome Res Apr;8(4): PMID:

95 Exclusion Excluded References Code Barnett A. A Phase III randomised, double-blind, placebo-controlled, parallel group, efficacy and safety study of linagliptin (5 mg), administered orally once daily over 24 weeks in type 2 diabetic patients (age 70 years) with insufficient glycaemic control (HbA1c 7.0%) despite metformin and/or sulphonylurea and/or insulin therapy Boehringer Ingelheim Pharmaceuticals. BI Trial No Barnett AH, Charbonnel B, Li J, Donovan M, Fleming D and Iqbal N. Saxagliptin add-on therapy to insulin with or without metformin for type 2 diabetes mellitus: 52-week safety and efficacy. Clinical Drug Investigation. 201 October;(10): PMID: FULL TEXT LINK Barnett AH, Huisman H, Jones R, Von Eynatten M, Patel S and Woerle HJ. Linagliptin for patients aged 70 years or older with type 2 diabetes inadequately controlled with common antidiabetes treatments: A randomised, double-blind, placebo-controlled trial. The Lancet ;82(9902): PMID: FULL TEXT LINK Barnett AH, Patel S, Harper R, Toorawa R, Thiemann S, von Eynatten M and Woerle HJ. Linagliptin monotherapy in type 2 diabetes patients for whom metformin is inappropriate: an 18-week randomized, double-blind, placebo-controlled Phase III trial with a 4-week active-controlled extension. Diabetes Obes Metab Sep 1PMID: Bergenstal R, Lewin A, Bailey T, Chang D, Gylvin T and Roberts V. Efficacy and safety of biphasic insulin aspart 70/0 versus exenatide in subjects with type 2 diabetes failing to achieve glycemic control with metformin and a sulfonylurea. Curr Med Res Opin Jan;25(1): PMID: Bergenstal RM, Forti A, Chiasson JL, Woloschak M, Boldrin M and Balena R. Efficacy and safety of taspoglutide versus sitagliptin for type 2 diabetes mellitus (T-Emerge 4 Trial). Diabetes Therapy ;(1):1-19. PMID: FULL TEXT LINK Berneis K, Rizzo M, Stettler C, Chappuis B, Braun M, Diem P and Christ ER. Comparative effects of rosiglitazone and pioglitazone on fasting and postprandial low-density lipoprotein size and subclasses in patients with Type 2 diabetes. Expert Opin Pharmacother Feb;9():4-9. PMID: Best JH, Rubin RR, Peyrot M, Li Y, Yan P, Malloy J and Garrison LP. Weight-related quality of life, health utility, psychological well-being, and satisfaction with exenatide once weekly compared with sitagliptin or 4 pioglitazone after 26 weeks of treatment. Diabetes Care Feb;4(2):14-9. PMID: Beysen C, Murphy EJ, Nagaraja H, Decaris M, Riiff T, Fong A, Hellerstein MK and Boyle PJ. A pilot study of the effects of pioglitazone and rosiglitazone on de novo lipogenesis in type 2 diabetes. J Lipid Res Dec;49(12): PMID: Bhatnagar D. New treatments and new choices for type 2 diabetes mellitus. Journal of the Royal College of Physicians of Edinburgh ;40(4): PMID: FULL TEXT LINK 1 Blonde L, Klein EJ, Han J, Zhang B, Mac SM, Poon TH, Taylor KL, Trautmann ME, Kim DD and Kendall DM. Interim analysis of the effects of exenatide treatment on A1C, weight and cardiovascular risk factors over 82 weeks in 14 overweight patients with type 2 diabetes. Diabetes Obes Metab Jul;8(4): PMID: Bode B, Stenlof K, Sullivan D, Fung A and Usiskin K. Efficacy and safety of canagliflozin treatment in older subjects with type 2 diabetes mellitus: a randomized trial. Hosp Pract (1995). 201 Apr;41(2): PMID: Bode BW, Testa MA, Magwire M, Hale PM, Hammer M, Blonde L and Garber A. Patient-reported outcomes following treatment with the human GLP-1 analogue liraglutide or glimepiride in monotherapy: results from a randomized controlled trial in patients with type 2 diabetes. Diabetes Obes Metab Jul;12(7): PMID: Bolinder J, Ljunggren O, Johansson L, Wilding J, Langkilde AM, Sjostrom CD, Sugg J and Parikh S. Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin. Diabetes, Obesity and Metabolism February;16(2): PMID: FULL TEXT LINK Bolinder J, Ljunggren O, Kullberg J, Johansson L, Wilding J, Langkilde AM, Sugg J and Parikh S. Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin. J Clin Endocrinol Metab Mar;97(): PMID: Bosi E, Ellis GC, Wilson CA and Fleck PR. Alogliptin as a third oral antidiabetic drug in patients with type 2 diabetes and inadequate glycaemic control on metformin and pioglitazone: a 52-week, randomized, doubleblind, active-controlled, parallel-group study. Diabetes Obes Metab Dec;1(12): PMID: Brackenridge AL, Jackson N, Jefferson W, Stolinski M, Shojaee-Moradie F, Hovorka R, Umpleby AM and

96 Excluded References Russell-Jones D. Effects of rosiglitazone and pioglitazone on lipoprotein metabolism in patients with Type 2 diabetes and normal lipids. Diabet Med May;26(5):52-9. PMID: Brazg R, Xu L, Dalla Man C, Cobelli C, Thomas K and Stein PP. Effect of adding sitagliptin, a dipeptidyl peptidase-4 inhibitor, to metformin on 24-h glycaemic control and beta-cell function in patients with type 2 diabetes. Diabetes Obes Metab Mar;9(2): PMID: Brodows RG, Qu Y, Johns D, Kim D and Holcombe JH. Quantifying the effect of exenatide and insulin glargine on postprandial glucose excursions in patients with type 2 diabetes. Curr Med Res Opin May;24(5): PMID: Brunetti L and Kalabalik J. Management of type-2 diabetes mellitus in adults: Focus on individualizing noninsulin therapies. P and T December;7(12): PMID: Buse JB, Drucker DJ, Taylor KL, Kim T, Grp D-S and et al. DURATION-1 Exenatide Once Weekly Produces Sustained Glycemic Control and Weight Loss Over 52 Weeks. p Buse JB, Klonoff DC, Nielsen LL, Guan X, Bowlus CL, Holcombe JH, Maggs DG and Wintle ME. Metabolic effects of two years of exenatide treatment on diabetes, obesity, and hepatic biomarkers in patients with type 2 diabetes: an interim analysis of data from the open-label, uncontrolled extension of three double-blind, placebo-controlled trials. Clin Ther Jan;29(1):19-5. PMID: Buse JB, Sesti G, Schmidt WE, Montanya E, Chang CT, Xu Y, Blonde L and Rosenstock J. Switching to oncedaily liraglutide from twice-daily exenatide further improves glycemic control in patients with type 2 diabetes using oral agents. Diabetes Care Jun;(6):100-. PMID: Chacra AR, Tan GH, Apanovitch A, Ravichandran S and al. e. Saxagliptin added to a submaximal dose of sulphonylurea improves glycaemic control compared with uptitration of sulphonylurea in patients with type 2 diabetes: a randomised controlled trial. International Journal of Clinical Practice Sep;6(9): Chacra AR, Tan GH, Ravichandran S, List J and Chen R. Safety and efficacy of saxagliptin in combination with submaximal sulphonylurea versus up-titrated sulphonylurea over 76 weeks. Diab Vasc Dis Res Apr;8(2): PMID: Chan JC, Scott R, Arjona Ferreira JC, Sheng D, Gonzalez E, Davies MJ, Stein PP, Kaufman KD, Amatruda JM and Williams-Herman D. Safety and efficacy of sitagliptin in patients with type 2 diabetes and chronic renal insufficiency. Diabetes Obes Metab Jul;10(7): PMID: Chawla S, Kaushik N, Singh NP, Ghosh RK and Saxena A. Effect of addition of either sitagliptin or pioglitazone in patients with uncontrolled type 2 diabetes mellitus on metformin: A randomized controlled trial. Journal of Pharmacology and Pharmacotherapeutics. 201 January-March;4(1):27-2. PMID: FULL TEXT LINK Chien MN, Lee CC, Chen WC, Liu SC, Leung CH and Wang CH. Effect of sitagliptin as add-on therapy in elderly type 2 diabetes patients with inadequate glycemic control in Taiwan. International Journal of Gerontology June;5(2):10-6. PMID: FULL TEXT LINK Chilton R. Trading glucose control for hypertension: Lessons from mother nature. Clinical Diabetes ;1(1):21-4. PMID: FULL TEXT LINK Chogtu B, Singh NP, Chawla S and Gupta U. Impact of glitazones on metabolic and haemodynamic parameters in patients with type 2 diabetes mellitus. Singapore Med J Apr;50(4):95-9. PMID: Chou HS, Palmer JP, Jones AR, Waterhouse B, Ferreira Cornwell C, Krebs J and Goldstein BJ. Initial treatment with fixed-dose combination rosiglitazone/glimepiride in patients with previously untreated type 2 diabetes. Diabetes, obesity & metabolism. 2008;10(8): Davies M, Pratley R, Hammer M, Thomsen AB and Cuddihy R. Liraglutide improves treatment satisfaction in people with Type 2 diabetes compared with sitagliptin, each as an add on to metformin. Diabet Med Mar;28():-7. PMID: Deeg MA, Buse JB, Goldberg RB, Kendall DM, Zagar AJ, Jacober SJ, Khan MA, Perez AT, Tan MH and Investigators GS. Pioglitazone and rosiglitazone have different effects on serum lipoprotein particle concentrations and sizes in patients with type 2 diabetes and dyslipidemia. Diabetes care. 2007;0(10): DeFronzo RA, Burant CF, Fleck P, Wilson C, Mekki Q and Pratley RE. Efficacy and tolerability of the DPP-4 inhibitor alogliptin combined with pioglitazone, in metformin-treated patients with type 2 diabetes. J Clin Endocrinol Metab May;97(5): PMID: DeFronzo RA, Hissa MN, Garber AJ, Luiz Gross J, Yuyan Duan R, Ravichandran S and Chen RS. The efficacy and safety of saxagliptin when added to metformin therapy in patients with inadequately controlled type 2 diabetes with metformin alone. Diabetes Care Sep;2(9): PMID: DeFronzo RA, Triplitt C, Qu Y, Lewis MS, Maggs D and Glass LC. Effects of exenatide plus rosiglitazone on beta-cell function and insulin sensitivity in subjects with type 2 diabetes on metformin. Diabetes Care Exclusion Code

97 Excluded References May;(5): PMID: Derosa G and Maffioli P. Dipeptidyl peptidase-4 inhibitors: years of experience. Diabetes Technol Ther Apr;14(4): PMID: Derosa G, Carbone A, D'Angelo A, Querci F, Fogari E, Cicero AF and Maffioli P. A randomized, double-blind, placebo-controlled trial evaluating sitagliptin action on insulin resistance parameters and beta-cell function. Expert Opin Pharmacother Dec;1(17): PMID: Derosa G, Carbone A, Franzetti I, Querci F, Fogari E, Bianchi L, Bonaventura A, Romano D, Cicero AF and Maffioli P. Effects of a combination of sitagliptin plus metformin vs metformin monotherapy on glycemic control, beta-cell function and insulin resistance in type 2 diabetic patients. Diabetes Res Clin Pract Oct;98(1): PMID: Derosa G, Cicero AFG, Franzetti IG, Querci F, Carbone A, Ciccarelli L, D'Angelo A, Fogari E and Maffioli P. Effects of exenatide and metformin in combination on some adipocytokine levels: A comparison with metformin monotherapy. Canadian Journal of Physiology and Pharmacology ;91(9): PMID: FULL TEXT LINK Derosa G, Franzetti IG, Querci F, Carbone A, Ciccarelli L, Piccinni MN, Fogari E and Maffioli P. Exenatide plus metformin compared with metformin alone on beta-cell function in patients with Type 2 diabetes. Diabet Med Dec;29(12): PMID: Derosa G, Franzetti IG, Querci F, Carbone A, Ciccarelli L, Piccinni MN, Fogari E and Maffioli P. Variation in inflammatory markers and glycemic parameters after 12 months of exenatide plus metformin treatment compared with metformin alone: A randomized placebo-controlled trial. Pharmacotherapy. 201 August;(8): PMID: FULL TEXT LINK Derosa G, Gaddi AV, Ciccarelli L, Fogari E, Ghelfi M, Ferrari I and Cicero AF. Long-term effect of glimepiride and rosiglitazone on non-conventional cardiovascular risk factors in metformin-treated patients affected by metabolic syndrome: a randomized, double-blind clinical trial. The Journal of international medical research. 2005;(): Derosa G, Maffioli P, Salvadeo SA, Ferrari I, Gravina A, Mereu R, Palumbo I, D'Angelo A and Cicero AF. Direct comparison among oral hypoglycemic agents and their association with insulin resistance evaluated by euglycemic hyperinsulinemic clamp: the 60's study. Metabolism Aug;58(8): PMID: Derosa G, Maffioli P, Salvadeo SA, Ferrari I, Ragonesi PD, Querci F, Franzetti IG, Gadaleta G, Ciccarelli L, Piccinni MN, D'Angelo A and Cicero AF. Exenatide versus glibenclamide in patients with diabetes. Diabetes Technol Ther Mar;12():2-40. PMID: Derosa G, Putignano P, Bossi AC, Bonaventura A, Querci F, Franzetti IG, Guazzini B, Testori G, Fogari E and Maffioli P. Exenatide or glimepiride added to metformin on metabolic control and on insulin resistance in type 2 diabetic patients. Eur J Pharmacol Sep;666(1-): PMID: Derosa G, Ragonesi PD, Carbone A, Fogari E, Bianchi L, Bonaventura A, Romano D, Cicero AF and Maffioli P. Vildagliptin added to metformin on beta-cell function after a euglycemic hyperinsulinemic and hyperglycemic clamp in type 2 diabetes patients. Diabetes Technol Ther Jun;14(6): PMID: Diamond GA, Bax L and Kaul S. Uncertain effects of rosiglitazone on the risk for myocardial infarction and cardiovascular death. Ann Intern Med Oct 16;147(8): PMID: Dluhy RG and McMahon GT. Intensive glycemic control in the ACCORD and ADVANCE trials. N Engl J Med Jun 12;58(24):260-. PMID: Dobs AS, Goldstein BJ, Aschner P, Horton ES, Umpierrez GE, Duran L, Hill JS, Chen Y, Golm GT, Langdon RB, Williams-Herman DE, Kaufman KD, Amatruda JM and Ferreira JC. Efficacy and safety of sitagliptin added to ongoing metformin and rosiglitazone combination therapy in a randomized placebo-controlled 54-week trial in patients with type 2 diabetes. J Diabetes. 201 Mar;5(1): PMID: Eaton-Maxwell A and Tran T. Cinnamon - More than just a flavoring agent. U.S. Pharmacist ;2(12):8-42. PMID: Edelman S, Garg S, Frias J, Maggs D, Wang Y, Zhang B, Strobel S, Lutz K and Kolterman O. A double-blind, placebo-controlled trial assessing pramlintide treatment in the setting of intensive insulin therapy in type 1 diabetes. Diabetes Care Oct;29(10): PMID: Eliasson B, Moller-Goede D, Eeg-Olofsson K, Wilson C, Cederholm J, Fleck P, Diamant M, Taskinen MR and Smith U. ering of postprandial lipids in individuals with type 2 diabetes treated with alogliptin and/or pioglitazone: a randomised double-blind placebo-controlled study. Diabetologia Apr;55(4): PMID: Engel S, Seck TL, Golm GT, Meehan AG, Kaufman KD and Goldstein BJ. Assessment of AACE/ACE recommendations for initial dual antihyperglycemic therapy using the fixed-dose combination of sitagliptin and metformin versus metformin. Endocrine Practice ;19(5): PMID: FULL TEXT LINK Exclusion Code

98 Excluded References Erdem G, Dogru T, Tasci I, Bozoglu E, Muhsiroglu O, Tapan S, Ercin CN and Sonmez A. The effects of pioglitazone and metformin on plasma visfatin levels in patients with treatment naive type 2 diabetes mellitus. Diabetes Res Clin Pract Nov;82(2): PMID: Fabunmi R, Nielsen LL, Quimbo R, Misurski D, Wade R and al. e. Patient characteristics, drug adherence patterns, and hypoglycemia costs for patients with type 2 diabetes mellitus newly initiated on exenatide or insulin glargine. Current Medical Research and Opinion (England). 2009;25(Mar): Farshchi A, Nikfar S and Abdollahi M. Concerns on the use of chromium in type 2 diabetes mellitus; needs to conduct major meta-analysis. International Journal of Pharmacology ;8(6): PMID: FULL TEXT LINK Feinglos MN, Saad MF, Pi-Sunyer FX, An B and Santiago O. Effects of liraglutide (NN2211), a long-acting GLP-1 analogue, on glycaemic control and bodyweight in subjects with Type 2 diabetes. Diabet Med Aug;22(8): PMID: Fineman MS, Bicsak TA, Shen LZ, Taylor K, Gaines E, Varns A, Kim D and Baron AD. Effect on glycemic control of exenatide (synthetic exendin-4) additive to existing metformin and/or sulfonylurea treatment in patients with type 2 diabetes. Diabetes Care. 200 Aug;26(8): PMID: Fonseca V, Staels B, Morgan JD, 2nd, Shentu Y, Golm GT, Johnson-Levonas AO, Kaufman KD, Goldstein BJ and Steinberg H. Efficacy and safety of sitagliptin added to ongoing metformin and pioglitazone combination therapy in a randomized, placebo-controlled, 26-week trial in patients with type 2 diabetes. J Diabetes Complications. 201 Mar-Apr;27(2): PMID: Forst T, Michelson G, Ratter F, Weber MM, Anders S, Mitry M, Wilhelm B and Pfutzner A. Addition of liraglutide in patients with Type 2 diabetes well controlled on metformin monotherapy improves several markers of vascular function. Diabet Med Sep;29(9): PMID: Forst T, Uhlig-Laske B, Ring A, Graefe-Mody U, Friedrich C, Herbach K, Woerle HJ and Dugi KA. Linagliptin (BI 156), a potent and selective DPP-4 inhibitor, is safe and efficacious in combination with metformin in patients with inadequately controlled Type 2 diabetes. Diabet Med Dec;27(12): PMID: Gallwitz B, Bohmer M, Segiet T, Molle A, Milek K, Becker B, Helsberg K, Petto H, Peters N and Bachmann O. Exenatide twice daily versus premixed insulin aspart 70/0 in metformin-treated patients with type 2 diabetes: a randomized 26-week study on glycemic control and hypoglycemia. Diabetes Care Mar;4(): PMID: Gallwitz B, Guzman J, Dotta F, Guerci B, Simo R, Basson BR, Festa A, Kiljanski J, Sapin H, Trautmann M and Schernthaner G. Exenatide twice daily versus glimepiride for prevention of glycaemic deterioration in patients with type 2 diabetes with metformin failure (EUREXA): an open-label, randomised controlled trial. Lancet Jun 16;79(98): PMID: Gallwitz B, Rosenstock J, Rauch T, Bhattacharya S, Patel S, von Eynatten M, Dugi KA and Woerle HJ. 2-year efficacy and safety of linagliptin compared with glimepiride in patients with type 2 diabetes inadequately controlled on metformin: a randomised, double-blind, non-inferiority trial. Lancet Aug 4;80(9840): PMID: Gao W, Dong J, Liu J, Li Y, Liu F, Yang L, Zhou X and Liao L. Efficacy and safety of initial combination of DPP-IV inhibitors and metformin versus metformin monotherapy in type 2 diabetes: A systematic review of randomized controlled trials. Diabetes, Obesity and Metabolism Gao Y, Yoon KH, Chuang LM, Mohan V, Ning G, Shah S, Jang HC, Wu TJ, Johns D, Northrup J and Brodows R. Efficacy and safety of exenatide in patients of Asian descent with type 2 diabetes inadequately controlled with metformin or metformin and a sulphonylurea. Diabetes Res Clin Pract Jan;8(1): PMID: Garber A, Henry R, Ratner R, Garcia-Hernandez PA, Rodriguez-Pattzi H, Olvera-Alvarez I, Hale PM, Zdravkovic M and Bode B. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD- Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet Feb 7;7(9662): PMID: Garber A, Henry RR, Ratner R, Hale P, Chang CT and Bode B. Liraglutide, a once-daily human glucagon-like peptide 1 analogue, provides sustained improvements in glycaemic control and weight for 2 years as monotherapy compared with glimepiride in patients with type 2 diabetes. Diabetes Obes Metab Apr;1(4): PMID: Genovese S, Passaro A, Brunetti P, Comaschi M, Cucinotta D, Egan CG, Chinea B, Bravi F and Di Pietro C. Pioglitazone randomised Italian study on metabolic syndrome (PRISMA): Effect of pioglitazone withmetformin on HDL-C levels in type 2 diabetic patients. Journal of Endocrinological Investigation. 201 September;6(8): PMID: FULL TEXT LINK Gerstein HC, Ratner RE, Cannon CP, Serruys PW, Garcia-Garcia HM, van Es GA, Kolatkar NS, Kravitz BG, Miller DM, Huang C, Fitzgerald PJ and Nesto RW. Effect of rosiglitazone on progression of coronary Exclusion Code 1 6 1

99 Excluded References atherosclerosis in patients with type 2 diabetes mellitus and coronary artery disease: the assessment on the prevention of progression by rosiglitazone on atherosclerosis in diabetes patients with cardiovascular history trial. Circulation Mar 16;121(10): PMID: Giampietro O, Giampietro C, Bartola LD, Masoni MC and Matteucci E. Sitagliptin as add-on therapy in insulin deficiency: biomarkers of therapeutic efficacy respond differently in type 1 and type 2 diabetes. Drug Design, Development and Therapy; 201. p Giles TD, Miller AB, Elkayam U, Bhattacharya M and Perez A. Pioglitazone and heart failure: results from a controlled study in patients with type 2 diabetes mellitus and systolic dysfunction. J Card Fail Aug;14(6): PMID: Gill A, Hoogwerf BJ, Burger J, Bruce S, Macconell L, Yan P, Braun D, Giaconia J and Malone J. Effect of exenatide on heart rate and blood pressure in subjects with type 2 diabetes mellitus: a double-blind, placebocontrolled, randomized pilot study. Cardiovasc Diabetol. 2010;9:6. PMID: Goldstein BJ, Weissman PN, Wooddell MJ, Waterhouse BR and Cobitz AR. Reductions in biomarkers of cardiovascular risk in type 2 diabetes with rosiglitazone added to metformin compared with dose escalation of metformin: an EMPIRE trial sub-study. Current Medical Research & Opinion Sep;22(9): PMID: Goossen K and Graber S. Longer term safety of dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes mellitus: Systematic review and meta-analysis. Diabetes, Obesity and Metabolism Grossman LD, Parlan G, Bailey AL, Yee G, Yu M and Chan JY. Tolerability outcomes of a multicenter, observational, open-label, drug-surveillance study in patients with type 2 diabetes mellitus treated with pioglitazone for 2 years. Clin Ther Jan;1(1): PMID: Habib ZA, Tzogias L, Havstad SL, Wells K, Divine G, Lanfear DE, Tang J, Krajenta R, Pladevall M and Williams LK. Relationship between thiazolidinedione use and cardiovascular outcomes and all-cause mortality among patients with diabetes: a time-updated propensity analysis. Pharmacoepidemiol Drug Saf Jun;18(6): PMID: Hamann A, Garcia-Puig J, Paul G, Donaldson J and Stewart M. Comparison of fixed-dose rosiglitazone/metformin combination therapy with sulphonylurea plus metformin in overweight individuals with Type 2 diabetes inadequately controlled on metformin alone. Exp Clin Endocrinol Diabetes Jan;116(1):6-1. PMID: Hanefeld M, Herman GA, Wu M, Mickel C, Sanchez M and Stein PP. Once-daily sitagliptin, a dipeptidyl peptidase-4 inhibitor, for the treatment of patients with type 2 diabetes. Curr Med Res Opin Jun;2(6): PMID: Harashima SI, Ogura M, Tanaka D, Fukushima T, Wang Y, Koizumi T, Aono M, Murata Y, Seike M and Inagaki N. Sitagliptin add-on to low dosage sulphonylureas: efficacy and safety of combination therapy on glycaemic control and insulin secretion capacity in type 2 diabetes. Int J Clin Pract May;66(5): PMID: Henry RR. Antihyperglycemic drug therapy in patients with diabetes and CKD: A closer look at incretin-based therapies. Endocrine Practice. 201 January-February;19(SUPPL.1): PMID: FULL TEXT LINK Hollander P, Li J, Allen E and Chen R. Saxagliptin added to a thiazolidinedione improves glycemic control in patients with type 2 diabetes and inadequate control on thiazolidinedione alone. J Clin Endocrinol Metab Dec;94(12): PMID: Hollander P, Maggs DG, Ruggles JA, Fineman M, Shen L, Kolterman OG and Weyer C. Effect of pramlintide on weight in overweight and obese insulin-treated type 2 diabetes patients. Obes Res Apr;12(4): PMID: Hollander PA, Levy P, Fineman MS, Maggs DG, Shen LZ, Strobel SA, Weyer C and Kolterman OG. Pramlintide as an adjunct to insulin therapy improves long-term glycemic and weight control in patients with type 2 diabetes: a 1-year randomized controlled trial. Diabetes Care. 200 Mar;26(): PMID: Home PD, Pocock SJ, Beck-Nielsen H, Curtis PS, Gomis R, Hanefeld M, Jones NP, Komajda M and McMurray JJ. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet Jun 20;7(9681): PMID: Horowitz M, Vilsbøll T, Zdravkovic M, Hammer M and Madsbad S. Patient-reported rating of gastrointestinal adverse effects during treatment of type 2 diabetes with the once-daily human GLP-1 analogue, liraglutide. Diabetes, obesity & metabolism. 2008;10(7):59-6. Iliadis F, Kadoglou NP, Hatzitolios A, Karamouzis M, Alevizos M and Karamitsos D. Metabolic effects of rosiglitazone and metformin in Greek patients with recently diagnosed type 2 diabetes. In Vivo Nov- Dec;21(6): PMID: Exclusion Code 5 1

100 Excluded References Iwamoto Y, Tajima N, Kadowaki T, Nonaka K, Taniguchi T, Nishii M, Arjona Ferreira JC and Amatruda JM. Efficacy and safety of sitagliptin monotherapy compared with voglibose in Japanese patients with type 2 diabetes: a randomized, double-blind trial. Diabetes Obes Metab Jul;12(7): PMID: Iwamoto Y, Taniguchi T, Nonaka K, Okamoto T, Okuyama K, Arjona Ferreira JC and Amatruda J. Doseranging efficacy of sitagliptin, a dipeptidyl peptidase-4 inhibitor, in Japanese patients with type 2 diabetes mellitus. Endocr J. 2010;57(5):8-94. PMID: Jendle J, Nauck MA, Matthews DR, Frid A, Hermansen K, During M, Zdravkovic M, Strauss BJ and Garber AJ. Weight loss with liraglutide, a once-daily human glucagon-like peptide-1 analogue for type 2 diabetes treatment as monotherapy or added to metformin, is primarily as a result of a reduction in fat tissue. Diabetes Obes Metab Dec;11(12): PMID: Johansen OE, Neubacher D, von Eynatten M, Patel S and Woerle HJ. Cardiovascular safety with linagliptin in patients with type 2 diabetes mellitus: a pre-specified, prospective, and adjudicated meta-analysis of a phase programme. Cardiovasc Diabetol. 2012;11:. PMID: Kadoglou NP, Tsanikidis H, Kapelouzou A, Vrabas I, Vitta I, Karayannacos PE, Liapis CD and Sailer N. Effects of rosiglitazone and metformin treatment on apelin, visfatin, and ghrelin levels in patients with type 2 diabetes mellitus. Metabolism Mar;59():7-9. PMID: Kadowaki T, Namba M, Imaoka T, Yamamura A, Goto W, Boardman MK and Sowa H. Improved glycemic control and reduced bodyweight with exenatide: A double-blind, randomized, phase study in Japanese patients with suboptimally controlled type 2 diabetes over 24 weeks. Journal of Diabetes Investigation June;2(): PMID: FULL TEXT LINK Kadowaki T, Namba M, Yamamura A, Sowa H, Wolka AM and Brodows RG. Exenatide exhibits dosedependent effects on glycemic control over 12 weeks in Japanese patients with suboptimally controlled type 2 diabetes. Endocr J Jun;56(): PMID: Kadowaki T, Tajima N, Odawara M, Nishii M, Taniguchi T and Ferreira JCA. Addition of sitagliptin to ongoing metformin monotherapy improves glycemic control in Japanese patients with type 2 diabetes over 52weeks. Journal of Diabetes Investigation. 201 March;4(2): PMID: FULL TEXT LINK Kahn SE, Zinman B, Lachin JM, Haffner SM, Herman WH, Holman RR, Kravitz BG, Yu D, Heise MA, Aftring RP and Viberti G. Rosiglitazone-associated fractures in type 2 diabetes: an Analysis from A Diabetes Outcome Progression Trial (ADOPT). Diabetes Care May;1(5): PMID: Kaku K, Inoue S, Matsuoka O, Kiyosue A, Azuma H, Hayashi N, Tokudome T, Langkilde AM and Parikh S. Efficacy and safety of dapagliflozin as a monotherapy for type 2 diabetes mellitus in Japanese patients with inadequate glycaemic control: a phase II multicentre, randomized, double-blind, placebo-controlled trial. Diabetes Obes Metab. 201 May;15(5): PMID: Kaku K, Rasmussen MF, Clauson P and Seino Y. Improved glycaemic control with minimal hypoglycaemia and no weight change with the once-daily human glucagon-like peptide-1 analogue liraglutide as add-on to sulphonylurea in Japanese patients with type 2 diabetes. Diabetes Obes Metab Apr;12(4):41-7. PMID: Kane MP, Abu-Baker A and Busch RS. The utility of oral diabetes medications in type 2 diabetes of the young. Curr Diabetes Rev Feb;1(1):8-92. PMID: Karyekar CS, Frederich R and Ravichandran S. Clinically relevant reductions in HbA<INF>1c</INF> without hypoglycaemia: results across four studies of saxagliptin. p Kato T, Sawai Y, Kanayama H, Taguchi H, Terabayashi T, Taki F, Yamada K, Yamazaki Y, Hayakawa N, Suzuki A, Oda N, Katada N and Itoh M. Comparative study of low-dose pioglitazone or metformin treatment in Japanese diabetic patients with metabolic syndrome. Exp Clin Endocrinol Diabetes Nov;117(10):59-9. PMID: Kawamori R, Inagaki N, Araki E, Watada H, Hayashi N, Horie Y, Sarashina A, Gong Y, von Eynatten M, Woerle HJ and Dugi KA. Linagliptin monotherapy provides superior glycaemic control versus placebo or voglibose with comparable safety in Japanese patients with type 2 diabetes: a randomized, placebo and active comparator-controlled, double-blind study. Diabetes Obes Metab Apr;14(4): PMID: Kelly AS, Bergenstal RM, Gonzalez-Campoy JM, Katz H and Bank AJ. Effects of exenatide vs. metformin on endothelial function in obese patients with pre-diabetes: a randomized trial. Cardiovasc Diabetol. 2012;11:64. PMID: Kendall DM, Riddle MC, Rosenstock J, Zhuang D, Kim DD, Fineman MS and Baron AD. Effects of exenatide (exendin-4) on glycemic control over 0 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care May;28(5): PMID: Kim D, MacConell L, Zhuang D, Kothare PA, Trautmann M, Fineman M and Taylor K. Effects of once-weekly dosing of a long-acting release formulation of exenatide on glucose control and body weight in subjects with Exclusion Code 5 5 4

101 Excluded References type 2 diabetes. Diabetes Care Jun;0(6): PMID: Kiyici S, Ersoy C, Kaderli A, Fazlioglu M, Budak F, Duran C, Gul OO, Sigirli D, Baran I, Tuncel E, Erturk E and Imamoglu S. Effect of rosiglitazone, metformin and medical nutrition treatment on arterial stiffness, serum MMP-9 and MCP-1 levels in drug naive type 2 diabetic patients. Diabetes Res Clin Pract Oct;86(1): PMID: Koch L. Pharmacotherapy: GLP-1R agonists - The new weapon against obesity? Nature Reviews Endocrinology April;8(4):196. PMID: FULL TEXT LINK Krobot KJ, Ferrante SA, Davies MJ, Seck T, Meininger GE, Williams-Herman D, Kaufman KD and Goldstein BJ. er risk of hypoglycemia with sitagliptin compared to glipizide when either is added to metformin therapy: a pre-specified analysis adjusting for the most recently measured HbA(1c) value. Curr Med Res Opin Aug;28(8): PMID: Kusaka I, Nagasaka S, Horie H and Ishibashi S. Metformin, but not pioglitazone, decreases postchallenge plasma ghrelin levels in type 2 diabetic patients: a possible role in weight stability? Diabetes Obes Metab Nov;10(11): PMID: Kusama M, Nakashima E, Kouchi Y, Narita M, Imamine R, Kawai M, Watanabe M, Tanaka C, Kanai A, Kawamura T, Sano T and Hotta N. Long-term clinical efficacy and safety of GLP-1 analogue liraglutide vs. DPP-4 inhibitor sitagliptin in Japanese obese adults with type 2 diabetes. J Diabetes. 201;5(S1):19. Kuznar W. 72nd American Diabetes Association Scientific Sessions: Clinical updates review findings on risk of malignancy with pioglitazone, as well as various risk factors associated with insulin glargine use. Formulary ;47(8):287. PMID: Lago RM, Singh PP and Nesto RW. Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomised clinical trials. Lancet Sep 29;70(959): PMID: Levetan C, Want LL, Weyer C, Strobel SA, Crean J, Wang Y, Maggs DG, Kolterman OG, Chandran M, Mudaliar SR and Henry RR. Impact of pramlintide on glucose fluctuations and postprandial glucose, glucagon, and triglyceride excursions among patients with type 1 diabetes intensively treated with insulin pumps. Diabetes Care. 200 Jan;26(1):1-8. PMID: Lewis JD, Capra AM, Achacoso NS, Ferrara A, Levin TR, Quesenberry CP, Jr. and Habel LA. Thiazolidinedione therapy is not associated with increased colonic neoplasia risk in patients with diabetes mellitus. Gastroenterology Dec;15(6):1914-2, 2 e1. PMID: Ljunggren O, Bolinder J, Johansson L, Wilding J, Langkilde AM, Sjostrom CD, Sugg J and Parikh S. Dapagliflozin has no effect on markers of bone formation and resorption or bone mineral density in patients with inadequately controlled type 2 diabetes mellitus on metformin. Diabetes Obes Metab Nov;14(11): PMID: Lofthouse M. Exenatide and insulin glargine are equally effective in patients with suboptimally controlled type 2 diabetes. Nature Clinical Practice Endocrinology and Metabolism ;2(1):7. PMID: FULL TEXT LINK Loke YK, Singh S and Furberg CD. Long-term use of thiazolidinediones and fractures in type 2 diabetes: a meta-analysis. Cmaj Jan 6;180(1):2-9. PMID: Lu CH, Wu TJ, Shih KC, Ni E, Reed V, Yu M, Sheu WHH and Chuang LM. Safety and efficacy of twice-daily exenatide in Taiwanese patients with inadequately controlled type 2 diabetes mellitus. Journal of the Formosan Medical Association. 201 March;112(): PMID: FULL TEXT LINK Ludvik B and Daniela L. [Efficacy and tolerability of sitagliptin in type 2 diabetic patients inadequately controlled with metformin. A prospective observational study in austrian primary care]. Wiener klinische Wochenschrift; p Madsbad S, Schmitz O, Ranstam J, Jakobsen G and Matthews DR. Improved glycemic control with no weight increase in patients with type 2 diabetes after once-daily treatment with the long-acting glucagon-like peptide 1 analog liraglutide (NN2211): a 12-week, double-blind, randomized, controlled trial. Diabetes Care Jun;27(6): PMID: Makdissi A, Ghanim H, Vora M, Green K, Abuaysheh S, Chaudhuri A, Dhindsa S and Dandona P. Sitagliptin exerts an antinflammatory action. J Clin Endocrinol Metab Sep;97(9):-41. PMID: Maniar SU, Biggs NA, Dhanota SK, Gaudet RL, Bala SA and et al. Cost-effectiveness of sitagliptin versus rosiglitazone as adjunct therapy to metformin in adult patients with uncontrolled type 2 diabetes over a 24- week period: a third party payer perspective. ASHP Midyear Clinical Meeting. 2007;42(DEC)PMID: Mannucci E, Monami M, Lamanna C, Gensini GF and Marchionni N. Pioglitazone and cardiovascular risk. A comprehensive meta-analysis of randomized clinical trials. Diabetes Obes Metab Dec;10(12): PMID: Exclusion Code

102 Excluded References Mari A, Nielsen LL, Nanayakkara N, DeFronzo RA, Ferrannini E and Halseth A. Mathematical modeling shows exenatide improved beta-cell function in patients with type 2 diabetes treated with metformin or metformin and a sulfonylurea. Horm Metab Res Dec;8(12): PMID: Marre M, Shaw J, Brandle M, Bebakar WM, Kamaruddin NA, Strand J, Zdravkovic M, Le Thi TD and Colagiuri S. Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with Type 2 diabetes (LEAD-1 SU). Diabet Med Mar;26(): PMID: Marso SP, Poulter NR, Nissen SE, Nauck MA, Zinman B, Daniels GH, Pocock S, Steinberg WM, Bergenstal RM, Mann JFE, Ravn LS, Frandsen KB, Moses AC and Buse J. Design of the liraglutide effect and action in diabetes: Evaluation of cardiovascular outcome results (LEADER) trial. American Heart Journal McCluskey D, Touger MS, Melis R, Schleusener DS and McCluskey D. Results of a randomized, double-blind, placebo-controlled study administering glimepiride to patients with type 2 diabetes mellitus inadequately controlled with rosiglitazone monotherapy. Clinical Therapeutics Nov;26(11): PMID: McDonagh M, Peterson K, Thakurta SG and Dana T. Drug Class Review on Fixed Dose Combination Drug Products for the Treatment of Type 2 Diabetes and Hyperlipidemia. Portland (OR): Oregon Evidence-based Practice Center, Oregon Health & Science University McGill JB, Sloan L, Newman J, Patel S, Sauce C, von Eynatten M and Woerle HJ. Long-Term Efficacy and Safety of Linagliptin in Patients With Type 2 Diabetes and Severe Renal Impairment: A 1-year, randomized, double-blind, placebo-controlled study. Diabetes Care Oct 1PMID: McGill JB, Sloan L, Newman J, Patel S, Sauce C, von Eynatten M and Woerle HJ. Long-term efficacy and safety of linagliptin in patients with type 2 diabetes and severe renal impairment: a 1-year, randomized, double-blind, placebo-controlled study. Diabetes Care. 201 Feb;6(2): PMID: Miyazaki Y and DeFronzo RA. Rosiglitazone and pioglitazone similarly improve insulin sensitivity and secretion, glucose tolerance and adipocytokines in type 2 diabetic patients. Diabetes Obes Metab Dec;10(12): PMID: Mohan V, Yang W, Son HY, Xu L, Noble L, Langdon RB, Amatruda JM, Stein PP and Kaufman KD. Efficacy and safety of sitagliptin in the treatment of patients with type 2 diabetes in China, India, and Korea. Diabetes Res Clin Pract Jan;8(1): PMID: Monami M, Lamanna C, Marchionni N and Mannucci E. Comparison of different drugs as add-on treatments to metformin in type 2 diabetes: a meta-analysis. Diabetes Res Clin Pract Feb;79(2): PMID: Monami M, Lamanna C, Marchionni N and Mannucci E. Rosiglitazone and risk of cancer: a meta-analysis of randomized clinical trials. Diabetes Care Jul;1(7): PMID: Monami M, Marchionni N and Mannucci E. Glucagon-like peptide-1 receptor agonists in type 2 diabetes: a meta-analysis of randomized clinical trials. Eur J Endocrinol Jun;160(6): PMID: Monami M, Marchionni N and Mannucci E. Winners and losers at the rosiglitazone gamble A meta-analytical approach at the definition of the cardiovascular risk profile of rosiglitazone. Diabetes Res Clin Pract Oct;82(1): PMID: Moretto TJ, Milton DR, Ridge TD, Macconell LA, Okerson T, Wolka AM and Brodows RG. Efficacy and tolerability of exenatide monotherapy over 24 weeks in antidiabetic drug-naive patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther Aug;0(8): PMID: Mosenzon O, Raz I, Scirica BM, Hirshberg B, Stahre CI, Steg PG, Davidson J, Ohman P, Price DL, Frederich B, Udell JA, Braunwald E and Bhatt DL. Baseline characteristics of the patient population in the Saxagliptin Assessment of Vascular Outcomes Recorded in patients with diabetes mellitus (SAVOR)-TIMI 5 trial. Diabetes Metab Res Rev. 201 Jul;29(5): PMID: Nagajothi N, Adigopula S, Balamuthusamy S, Velazquez-Cecena JL, Raghunathan K, Khraisat A, Singh S, Molnar J, Khosla S and Benatar D. Pioglitazone and the risk of myocardial infarction and other major adverse cardiac events: a meta-analysis of randomized, controlled trials. Am J Ther Nov-Dec;15(6): PMID: Nauck M and Marre M. Adding liraglutide to oral antidiabetic drug monotherapy: efficacy and weight benefits. Postgrad Med May;121():5-15. Nauck M, Frid A, Hermansen K, Shah NS, Grp L-S and al. e. Efficacy and Safety Comparison of Liraglutide, Glimepiride, and Placebo, All in Combination With Metformin, in Type 2 Diabetes The LEAD (Liraglutide Effect and Action in Diabetes)-2 study. Diabetes Care Jan;2(1): Nauck M, Frid A, Hermansen K, Thomsen AB, During M, Shah N, Tankova T, Mitha I and Matthews DR. Long-term efficacy and safety comparison of liraglutide, glimepiride and placebo, all in combination with metformin in type 2 diabetes: 2-year results from the LEAD-2 study. Diabetes Obes Metab. 201 Mar;15(): Exclusion Code 4 1

103 Excluded References Nauck MA, Del Prato S, Meier JJ, Duran-Garcia S, Rohwedder K, Elze M and Parikh SJ. Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial. Diabetes Care Sep;4(9): Niswender K, Pi-Sunyer X, Buse J, Jensen KH, Toft AD, Russell-Jones D and Zinman B. Weight change with liraglutide and comparator therapies: an analysis of seven phase trials from the liraglutide diabetes development programme. Diabetes Obes Metab. 201 Jan;15(1): Norris SL, Carson S and Roberts C. Comparative effectiveness of pioglitazone and rosiglitazone in type 2 diabetes, prediabetes, and the metabolic syndrome: a meta-analysis. Curr Diabetes Rev May;(2): Norris SL, Carson S, Thakurta S and Chan BKS. Drug class review: Thiazolidinediones. Portland (OR): Oregon Evidence-based Practice Center, Oregon Health & Science University Norris SL, Lee NJ, Severance S, Thakurta S and Chan B. Drug class review on newer drugs for the treatment of diabetes mellitus. Portland (OR): Oregon Evidence-based Practice Center, Oregon Health & Science University Nowicki M, Rychlik I, Haller H, Warren M, Suchower L, Gause-Nilsson I and Schutzer KM. Long-term treatment with the dipeptidyl peptidase-4 inhibitor saxagliptin in patients with type 2 diabetes mellitus and renal impairment: a randomised controlled 52-week efficacy and safety study. Int J Clin Pract Dec;65(12): Nowicki M, Rychlik I, Haller H, Warren ML, Suchower L and Gause-Nilsson I. Saxagliptin improves glycaemic control and is well tolerated in patients with type 2 diabetes mellitus and renal impairment. Diabetes Obes Metab Jun;1(6):52-2. Olansky L, Reasner C, Seck TL, Williams-Herman DE, Chen M, Terranella L, Mehta A, Kaufman KD and Goldstein BJ. A treatment strategy implementing combination therapy with sitagliptin and metformin results in superior glycaemic control versus metformin monotherapy due to a low rate of addition of antihyperglycaemic agents. Diabetes Obes Metab Sep;1(9): Oz Gul O, Tuncel E, Yilmaz Y, Ulukaya E, Gul CB, Kiyici S, Oral AY, Guclu M, Ersoy C and Imamoglu S. Comparative effects of pioglitazone and rosiglitazone on plasma levels of soluble receptor for advanced glycation end products in type 2 diabetes mellitus patients. Metabolism Jan;59(1):64-9. Oz O, Tuncel E, Eryilmaz S, Fazlioglu M, Gul CB, Ersoy C, Ocak N, Dirican M, Cangur S, Baran I and Imamoglu S. Arterial elasticity and plasma levels of adiponectin and leptin in type 2 diabetic patients treated with thiazolidinediones. Endocrine Feb;(1): Papathanassiou K, Naka KK, Kazakos N, Kanioglou C, Makriyiannis D, Pappas K, Katsouras CS, Liveris K, Kolettis T, Tsatsoulis A and Michalis LK. Pioglitazone vs glimepiride: Differential effects on vascular endothelial function in patients with type 2 diabetes. Atherosclerosis Jul;205(1): Paul S, Best J, Klein K, Han J and Maggs D. Effects of HbA1c and weight reduction on blood pressure in patients with type 2 diabetes mellitus treated with exenatide*. Diabetes Obes Metab Sep;14(9): Penfornis A, Bourdel-Marchasson I, Quere S and Dejager S. Real-life comparison of DPP4-inhibitors with conventional oral antidiabetics as add-on therapy to metformin in elderly patients with type 2 diabetes: the HYPOCRAS study. Diabetes Metab Dec;8(6): Perez A, Zhao Z, Jacks R and Spanheimer R. Efficacy and safety of pioglitazone/metformin fixed-dose combination therapy compared with pioglitazone and metformin monotherapy in treating patients with T2DM. Curr Med Res Opin Dec;25(12): Perez-Monteverde A, Seck T, Xu L, Lee MA, Sisk CM, Williams-Herman DE, Engel SS, Kaufman KD and Goldstein BJ. 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105 Exclusion Excluded References Code Jun;28(6): Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, Ohman P, Frederich R, Wiviott SD, Hoffman EB, Cavender MA, Udell JA, Desai NR, Mosenzon O, McGuire DK, Ray KK, Leiter LA and Raz I. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 201 Oct ;69(14): Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, Ohman P, Price DL, Chen R, Udell J and Raz I. The design and rationale of the saxagliptin assessment of vascular outcomes recorded in patients with diabetes mellitus-thrombolysis in myocardial infarction (SAVOR-TIMI) 5 study. Am Heart J Nov;162(5): e6. Seck T, Nauck M, Sheng D, Sunga S, Davies MJ, Stein PP, Kaufman KD and Amatruda JM. Safety and efficacy of treatment with sitagliptin or glipizide in patients with type 2 diabetes inadequately controlled on metformin: a 2-year study. Int J Clin Pract Apr;64(5): Seino Y, Hiroi S, Hirayama M and Kaku K. 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106 Exclusion Excluded References Code mellitus: study design and baseline patient characteristics from a randomized clinical trial of linagliptin. Expert Opin Pharmacother Dec;1(17): Tolman KG, Freston JW, Kupfer S and Perez A. Liver safety in patients with type 2 diabetes treated with pioglitazone: results from a -year, randomized, comparator-controlled study in the US. Drug Saf. 2009;2(9): Tsuchiya K, Akaza I, Yoshimoto T and Hirata Y. Pioglitazone improves endothelial function with increased adiponectin and high-density lipoprotein cholesterol levels in type 2 diabetes. Endocr J Oct;56(5): Turkmen Kemal Y, Guvener Demirag N, Yildirir A, Atar A, Dogruk Unal A and Biyiklioglu Z. Effects of rosiglitazone on plasma brain natriuretic peptide levels and myocardial performance index in patients with type 2 diabetes mellitus. Acta Diabetol Sep;44(): Unger J. Intensification of type 2 diabetes in adolescents: Guess what? Exercise wins! Clinical Diabetes ;0(4): van der Meer RW, Rijzewijk LJ, de Jong HW, Lamb HJ, Lubberink M, Romijn JA, Bax JJ, de Roos A, Kamp O, Paulus WJ, Heine RJ, Lammertsma AA, Smit JW and Diamant M. Pioglitazone improves cardiac function and alters myocardial substrate metabolism without affecting cardiac triglyceride accumulation and high-energy phosphate metabolism in patients with well-controlled type 2 diabetes mellitus. Circulation Apr 21;119(15): Vijay SK, Mishra M, Kumar H and Tripathi K. Effect of pioglitazone and rosiglitazone on mediators of endothelial dysfunction, markers of angiogenesis and inflammatory cytokines in type-2 diabetes. Acta Diabetol Mar;46(1):27-. Vilsboll T, Brock B, Perrild H, Levin K, Lervang HH, Kolendorf K, Krarup T, Schmitz O, Zdravkovic M, Le-Thi T and Madsbad S. Liraglutide, a once-daily human GLP-1 analogue, improves pancreatic B-cell function and arginine-stimulated insulin secretion during hyperglycaemia in patients with Type 2 diabetes mellitus. Diabet Med Feb;25(2): Vilsboll T, Rosenstock J, Yki-Jarvinen H, Cefalu WT, Chen Y, Luo E, Musser B, Andryuk PJ, Ling Y, Kaufman KD, Amatruda JM, Engel SS and Katz L. Efficacy and safety of sitagliptin when added to insulin therapy in patients with type 2 diabetes. Diabetes Obes Metab Feb;12(2): Vilsboll T, Zdravkovic M, Le-Thi T, Krarup T, Schmitz O, Courreges JP, Verhoeven R, Buganova I and Madsbad S. Liraglutide, a long-acting human glucagon-like peptide-1 analog, given as monotherapy significantly improves glycemic control and lowers body weight without risk of hypoglycemia in patients with type 2 diabetes. Diabetes Care Jun;0(6): Violante R, Oliveira JH, Yoon KH, Reed VA, Yu MB, Bachmann OP, Ludemann J and Chan JY. A randomized non-inferiority study comparing the addition of exenatide twice daily to sitagliptin or switching from sitagliptin to exenatide twice daily in patients with type 2 diabetes experiencing inadequate glycaemic control on metformin and sitagliptin. Diabet Med Nov;29(11):e Vlckova V, Cornelius V, Kasliwal R, Wilton L and Shakir SA. Hypoglycaemia with Oral Antidiabetic Drugs Results from Prescription-Event Monitoring Cohorts of Rosiglitazone, Pioglitazone, Nateglinide and Repaglinide. Drug Safety (New Zealand). 2009;2(May): von Bibra H, Diamant M, Scheffer PG, Siegmund T and Schumm-Draeger PM. Rosiglitazone, but not glimepiride, improves myocardial diastolic function in association with reduction in oxidative stress in type 2 diabetic patients without overt heart disease. Diab Vasc Dis Res Nov;5(4):10-8. Watson E, Jonker DM, Jacobsen LV and Ingwersen SH. Population Pharmacokinetics of Liraglutide, a Once- Daily Human Glucagon-Like Peptide-1 Analog, in Healthy Volunteers and Subjects With Type 2 Diabetes, and 5 Comparison to Twice-Daily Exenatide. p Weissman P, Goldstein BJ, Rosenstock J, Waterhouse B, Cobitz AR, Wooddell MJ and Strow LJ. Effects of rosiglitazone added to submaximal doses of metformin compared with dose escalation of metformin in type 2 diabetes: the EMPIRE Study. Current Medical Research & Opinion Dec;21(12): White J. Efficacy and safety of incretin based therapies: clinical trial data. J Am Pharm Assoc (200) Sep-Oct;49 Suppl 1:S0-40. Whitehouse F, Kruger DF, Fineman M, Shen L, Ruggles JA, Maggs DG, Weyer C and Kolterman OG. A randomized study and open-label extension evaluating the long-term efficacy of pramlintide as an adjunct to insulin therapy in type 1 diabetes. Diabetes Care Apr;25(4): Wu JD, Xu XH, Zhu J, Ding B, Du TX, Gao G, Mao XM, Ye L, Lee KO and Ma JH. Effect of exenatide on inflammatory and oxidative stress markers in patients with type 2 diabetes mellitus. Diabetes Technol Ther Feb;1(2):14-8. Wysham C, Bergenstal R, Malloy J, Yan P, Walsh B, Malone J and Taylor K. DURATION-2: efficacy and safety of switching from maximum daily sitagliptin or pioglitazone to once-weekly exenatide. Diabet Med Jun;28(6): Wysham C, Lush C, Zhang B, Maier H and Wilhelm K. Effect of pramlintide as an adjunct to basal insulin on

107 Excluded References markers of cardiovascular risk in patients with type 2 diabetes. Current medical research and opinion. 2008(1): Yang W, Chen L, Ji Q, Liu X, Ma J, Tandon N, Bhattacharyya A, Kumar A, Kim KW, Yoon KH, Bech OM and Zychma M. Liraglutide provides similar glycaemic control as glimepiride (both in combination with metformin) and reduces body weight and systolic blood pressure in Asian population with type 2 diabetes from China, South Korea and India: a 16-week, randomized, double-blind, active control trial(*). Diabetes Obes Metab Jan;1(1):81-8. Yang W, Guan Y, Shentu Y, Li Z, Johnson-Levonas AO, Engel SS, Kaufman KD, Goldstein BJ and Alba M. The addition of sitagliptin to ongoing metformin therapy significantly improves glycemic control in Chinese patients with type 2 diabetes. J Diabetes Sep;4(): Yang W, Pan CY, Tou C, Zhao J and Gause-Nilsson I. Efficacy and safety of saxagliptin added to metformin in Asian people with type 2 diabetes mellitus: a randomized controlled trial. Diabetes Res Clin Pract Nov;94(2): Zeng Z, Yang JK, Tong N, Yan S, Zhang X, Gong Y and Woerle HJ. Efficacy and safety of linagliptin added to metformin and sulphonylurea in Chinese patients with type 2 diabetes: A sub-analysis of data from a randomised clinical trial. Current Medical Research and Opinion. 201 August;29(8): Zinman B, Gerich J, Buse JB, Lewin A, Schwartz S, Raskin P, Hale PM, Zdravkovic M and Blonde L. Efficacy and safety of the human glucagon-like peptide-1 analog liraglutide in combination with metformin and thiazolidinedione in patients with type 2 diabetes (LEAD-4 Met+TZD). Diabetes Care Jul;2(7): Exclusion Code 7 References Rated Poor Buse JB, Nauck M, Forst T, Sheu WH, Shenouda SK, Heilmann CR, Hoogwerf BJ, Gao A, Boardman MK, Fineman M, Porter L and Schernthaner G. Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): a randomised, open-label study. Lancet. 201 Jan 12;81(9861): PMID: Quality Rating P

108 Appendix E. Meta-analyses Figure E-1: Exenatide XR 2 mg weekly compared with exenatide 10 µg twice daily: Mean change in HbA1c over 24-0 weeks Mean Change in HbA1c - Exenatide XR vs. Exenatide % Author,year exenatide exenetide_xr WMD (95% CI) Weight Drucker, (-0.68, -0.12) 0.41 Blevins, (-0.98, -0.42) 0.6 Ji, (-0.50, -0.12) 9.2 Overall (I-squared = 61.2%, p = 0.076) (-0.69, -0.2) NOTE: Weights are from random effects analysis favors Exenatide XR favors Exenatide

109 Figure E-2: Exenatide XR 2 mg weekly compared with Sitagliptin: Mean change in HbA1c over 26 weeks Mean Change in HbA1c - Exenatide XR vs. Sitaglpitin % Author,year N_exenatideXR N_sitagliptin WMD (95% CI) Weight Bergenstal, (-0.85, -0.5) Russel-Jones, (-0.59, -0.17) 55.1 Overall (I-squared = 4.0%, p = 0.185) (-0.69, -0.26) NOTE: Weights are from random effects analysis favors Exenatide XR favors Sitagliptin

110 Figure E-: Exenatide XR 2 mg weekly compared with Sitagliptin: Mean change in weight over 26 weeks Mean Change in Weight - Exenatide XR vs. Sitaglpitin % Author,year N1 N2 WMD (95% CI) Weight Bergenstal, (-2.8, -0.62) 8.96 Russel-Jones (-1.91, -0.49) Overall (I-squared = 0.0%, p = 0.604) -1.2 (-1.87, -0.76) NOTE: Weights are from random effects analysis favors Exenatide XR favors Sitagliptin

111 Figure E-4: Newer Diabetes Medications compared with metformin: Mean change in HbA1c over by outcome timing Mean Change in HbA1c - Newer Diabetes Drugs vs. Metformin Author, Outcome % year Timing drug_n metformin_n WMD (95% CI) Weight Dapagliflozin 5mg vs. Metformin XR* Henry, weeks List, weeks Subtotal (I-squared = 0.0%, p = 0.87). Dapagliflozin 10mg vs. Metformin XR* Henry, weeks List, weeks Subtotal (I-squared = 5.8%, p = 0.0). Saxagliptin 5mg vs. Metformin 2,000mg** Fonseca, weeks Hermans, weeks Subtotal (I-squared = 90.%, p = 0.001). Sitagliptin 100mg vs. Metformin 2,000mg Goldstein, weeks Russell-Jones, weeks Aschner, weeks Subtotal (I-squared = 84.7%, p = 0.001). NOTE: Weights are from random effects analysis (-0.4, 0.14) (-0.15, -0.09) (-0.15, -0.08) (-0.22, 0.20) (-0.16, -0.08) (-0.17, -0.06) (-0.74, -0.2) (-0.26, 0.08) (-0.74, 0.1) (0.29, 0.65) (0.14, 0.52) (0.07, 0.21) (0.09, 0.52) favors Newer Diabetes Drug favors Metformin

112 Figure E-5: Dapagliflozin compared with metformin XR: Mean change in weight over 12 to 26 weeks Mean Change in Weight - Dapagliflozin vs. Metformin Author, Outcome % year Timing drug_n metformin_n WMD (95% CI) Weight Dapagliflozin 5mg vs. Metformin XR* Henry, weeks (-1.98, -0.66) 72.2 List, weeks (-1.86, 0.26) Subtotal (I-squared = 0.0%, p = 0.414) (-1.7, -0.62) Dapagliflozin 10mg vs. Metformin XR* Henry, weeks (-2.0, -0.71) List, weeks (-2.1, 0.1) Subtotal (I-squared = 0.0%, p = 0.580) (-1.85, -0.71) NOTE: Weights are from random effects analysis favors Dapagliflozin favors Metformin

113 Figure E-6: Janumet compared with metformin 2000 mg/day: Mean change in HbA1c over 18 to 26 weeks Mean Change in HbA1c - Janument vs. Metformin Author, Outcome % year Timing drug_n metformin_n WMD (95% CI) Weight Williams-Herman, (-0.8, -0.7) Reasner, (-0.81, -0.9) 5.22 Overall (I-squared = 0.0%, p = 1.000) (-0.75, -0.45) NOTE: Weights are from random effects analysis favors Janumet favors Metformin

114 Figure E-7: Withdrawals because of adverse events Withdrawals because of Adverse Events - Exenatide XR vs. Exenatide 10ug BID % Author_Year Outcome_Timing Drug_N Drug_Events Comp_N Comp_Events RR (95% CI) Weight Blevins, weeks (0.2, 2.88) Drucker, weeks (0.48,.29) Ji, weeks (0.24, 0.77) Overall (I-squared = 5.0%, p = 0.119) 0.72 (0.5, 1.50) NOTE: Weights are from random effects analysis Favors Exenatide Favors XR Exenatide 10ug BID

115 Figure E-8: Nausea Nausea - Exenatide XR vs. Exenatide 10ug BID % Author_Year Outcome_Timing Drug_N Drug_Events Comp_N Comp_Events RR (95% CI) Weight Blevins, weeks (0.24, 0.65) Drucker, weeks (0.54, 1.09) 5.49 Ji, weeks (0.29, 0.59) 5.40 Overall (I-squared = 7.2%, p = 0.024) 0.51 (0., 0.79) NOTE: Weights are from random effects analysis Favors Exenatide Favors XR Exenatide 10ug BID

116 Figure E-9: Vomiting Vomiting - Exenatide XR vs. Exenatide 10ug BID % Author_Year Outcome_Timing Drug_N Drug_Events Comp_N Comp_Events RR (95% CI) Weight Blevins, weeks (0.20, 1.6) Drucker, weeks (0., 1.0) 4.02 Ji, weeks (0.4, 1.07) 5.90 Overall (I-squared = 0.0%, p = 0.848) 0.62 (0.45, 0.87) NOTE: Weights are from random effects analysis Favors Exenatide Favors XR Exenatide 10ug BID

117 Figure E-10: Diarrhea Diarrhea - Exenatide XR vs. Exenatide 10ug BID % Author_Year Outcome_Timing Drug_N Drug_Events Comp_N Comp_Events RR (95% CI) Weight Blevins, weeks (0.8, 6.1) 11.8 Drucker, weeks (0.57, 1.85) 5.55 Ji, weeks (0.72, 1.89) Overall (I-squared = 0.0%, p = 0.401) 1.21 (0.86, 1.72) NOTE: Weights are from random effects analysis Favors Exenatide Favors XR Exenatide 10ug BID

118 Figure E-11. Exenatide XR compared with Sitagliptin 100 mg: Withdrawals because of Adverse Events Withdrawals because of Adverse Events - Exenatide XR vs. Sitagliptin 100mg % Author_Year Outcome_Timing Drug_N Drug_Events Comp_N Comp_Events RR (95% CI) Weight Bergenstal, weeks (0.81, 6.42) Russell-Jones, weeks (0.48, 2.45) Overall (I-squared = 0.0%, p = 0.645) 2.54 (1.00, 6.42) NOTE: Weights are from random effects analysis Favors Exenatide XR Favors Sitagliptin

119 Figure E-12. Exenatide XR compared with Sitagliptin: Hypoglycemia Hypoglycemia - Exenatide XR vs. Sitagliptin 100mg % Author_Year Outcome_Timing Drug_N Drug_Events Comp_N Comp_Events RR (95% CI) Weight Bergenstal, weeks (0.02, 51.97) Russell-Jones, weeks (0.01, 2.96) Overall (I-squared = 0.0%, p = 0.872) 0.8 (0.05, 1.15) NOTE: Weights are from random effects analysis Favors Exenatide XR Favors Sitagliptin Notes: a. Russell-Jones, 2012 data are numbers of participants with major hypoglycemia. The article also reported numbers of participants with minor hypoglycemia and unconfirmed hypoglycemia. (N with minor hypoglycemia = Exe 5, Sita 0; unconfirmed hypoglycemia = Exe 1, Sita 5 b. In the data shown, 0.5 represents 0 events/non-events.

120 Figure E-1. Exenatide XR vs. Sitagliptin: Nausea Nausea - Exenatide XR vs. Sitagliptin 100mg % Author_Year Outcome_Timing Drug_N Drug_Events Comp_N Comp_Events RR (95% CI) Weight Bergenstal, weeks (1.4, 4.24) Russell-Jones, weeks (1.0, 7.24) Overall (I-squared = 0.0%, p = 0.670) 2.62 (1.66, 4.15) NOTE: Weights are from random effects analysis Favors Exenatide XR Favors Sitagliptin Figure E-14. Exenatide XR compared with sitagliptin 100 mg: Vomiting Vomiting - Exenatide XR vs. Sitagliptin 100mg % Author_Year Outcome_Timing Drug_N Drug_Events Comp_N Comp_Events RR (95% CI) Weight Bergenstal, weeks (1.62, 1.49) Russell-Jones, weeks (0.75, 9.17) Overall (I-squared = 0.0%, p = 0.492).67 (1.6, 8.24) NOTE: Weights are from random effects analysis Favors Exenatide XR Favors Sitagliptin

121 Figure E-15. Exenatide XR compared with Sitagliptin: Diarrhea Diarrhea - Exenatide XR vs. Sitagliptin 100mg % Author_Year Outcome_Timing Drug_N Drug_Events Comp_N Comp_Events RR (95% CI) Weight Bergenstal, weeks (1.06,.) Russell-Jones, weeks (0.95, 4.08) 8.04 Overall (I-squared = 0.0%, p = 0.920) 1.91 (1.22,.00) NOTE: Weights are from random effects analysis Favors Exenatide XR Favors Sitagliptin Figure E-16. Exenatide XR compared with Sitagliptin: Headache Headache - Exenatide XR vs. Sitagliptin 100mg % Author_Year Outcome_Timing Drug_N Drug_Events Comp_N Comp_Events RR (95% CI) Weight Bergenstal, weeks (0.52, 2.05) Russell-Jones, weeks (0.46, 1.66) 5.20 Overall (I-squared = 0.0%, p = 0.72) 0.95 (0.59, 1.51) NOTE: Weights are from random effects analysis Favors Exenatide XR Favors Sitagliptin

122 Figure E-17. Exenatide XR compared with Sitagliptin: Pancreatitis Pancreatitis - Exenatide XR vs. Sitagliptin 100mg % Author_Year Outcome_Timing Drug_N Drug_Events Comp_N Comp_Events RR (95% CI) Weight Bergenstal, weeks (0.02, 51.97) Russell-Jones, weeks (0.01, 9.74) Overall (I-squared = 0.0%, p = 0.66) 0.54 (0.04, 6.97) NOTE: Weights are from random effects analysis Favors Exenatide XR Favors Sitagliptin

123 Figure E-18. Newer Diabetes Drugs compared with Metformin: Withdrawals because of Adverse Events Withdrawals because of Adverse Events - Newer Diabetes Drugs vs. Metformin Author, Outcome % Year Timing Drug_N Drug_Events Comp_N Comp_Events RR (95% CI) Weight Dapagliflozin 10mg vs. Metformin XR Henry, weeks (0.42, 2.72) List, weeks (0.8,.2) Subtotal (I-squared = 0.0%, p = 0.26) 1.28 (0.54,.0) Dapagliflozin 5mg vs. Metformin XR Henry, weeks (0.26, 2.66) List, weeks (0.02, 1.99) Subtotal (I-squared = 0.0%, p = 0.765) 0.78 (0.26, 2.5) Linagliptin 5mg vs. Metformin 1000mg bid Haag, weeks (0.42, 5.2) 4.41 Haak, weeks (0.4,.1) Subtotal (I-squared = 0.0%, p = 0.678) 1.21 (0.52, 2.78) Saxagliptin 5mg vs. Metformin Fonseca, weeks (0.02, 1.20) 7.49 Hermans, weeks (0.21, 2.76) Subtotal (I-squared = 4.5%, p = 0.184) 0.41 (0.08, 1.99) Sitagliptin 100mg vs. Meformin 1000mg bid Aschner, weeks (0.21, 1.0) Goldstein, weeks (0.0,.45) Russell-Jones, weeks (0.0, 2.07) 8.92 Subtotal (I-squared = 0.0%, p = 0.44) 0.54 (0.29, 1.02) Sitagliptin 50mg + Metformin 1000mg bid vs. Metformin 1000mg bid Goldstein, weeks (0.08, 2.04) 1.11 Reasner, weeks (0.58, 1.71) Subtotal (I-squared = 7.7%, p = 0.298) 0.88 (0.48, 1.61) NOTE: Weights are from random effects analysis Favors Newer Diabetes Drug Favors Metformin

124 Figure E-19. Newer Diabetes Drugs compared with Metformin: Hypoglycemia Hypoglycemia - Newer Diabetes Drugs vs. Metformin % Author_Year Duration Drug_N Drug_Events Comp_N Comp_Events RR (95% CI) Weight Dapagliflozin 10mg vs. Metformin XR Henry, weeks (0.06, 1.55) List, weeks (0.18, 2.84) Subtotal (I-squared = 0.0%, p = 0.446) 0.50 (0.18, 1.4) Dapagliflozin 5mg vs. Metformin XR Henry, weeks (0.02, 49.66) 7.67 List, weeks (0.7,.58) 92. Subtotal (I-squared = 0.0%, p = 0.940) 1.14 (0.9,.9) Saxagliptin 5mg vs. Metformin Fonseca, weeks (0.51, 1.22) 7.94 Hermans, weeks (0.89, 11.21) Subtotal (I-squared = 0.0%, p = 0.857) 2.9 (1.08, 7.97) Sitagliptin 100mg vs. Metformin Aschner, weeks (0.24, 1.16) Goldstein, weeks (0.05, 5.56) 9.68 Russell-Jones, weeks (0.0, 75.60).61 Subtotal (I-squared = 0.0%, p = 0.87) 0.54 (0.26, 1.14) Sitagliptin 50mg + Metformin 100mg bid vs. M Goldstein, weeks (0.86, 18.58) 6.91 Reasner, weeks (0.50, 2.4) 6.09 Subtotal (I-squared = 55.8%, p = 0.12) 1.75 (0.50, 6.10) NOTE: Weights are from random effects analysis Favors Newer Diabetes Drug Favors Metformin Notes: a. Russell-Jones, 2012 data are numbers of participants with major hypoglycemia. The article also reported numbers of participants with minor hypoglycemia and unconfirmed hypoglycemia. (N with minor hypoglycemia = Exe 5, Sita 0; unconfirmed hypoglycemia = Exe 1, Sita 5 b. In the data shown, 0.5 represents 0 events/non-events.

125 Figure E-20. Newer Diabetes Drugs compared with Metformin: Nausea Nausea - Newer Diabetes Drugs vs. Metformin % Author_Year Outcome_Timing Drug_N Drug_Events Comp_N Comp_Events RR (95% CI) Weight Dapagliflozin 10mg vs. Metformin XR Henry, weeks (0.51, 4.57) List, weeks (0.16, 2.25) Subtotal (I-squared = 11.5%, p = 0.288) 1.0 (0.42, 2.54) Dapagliflozin 5mg vs. Metformin XR Henry, weeks (0.15, 1.62) List, weeks (0.19, 2.16) Subtotal (I-squared = 0.0%, p = 0.761) 0.56 (0.24, 1.1) Saxagliptin 5mg vs. Metformin Fonseca, weeks (0.21, 5.08) Hermans, weeks (0.4,.4) 4.55 Subtotal (I-squared = 0.0%, p = 0.45) 1.6 (0.45, 5.86) Sitagliptin 100mg vs. Metformin Aschner, weeks (0.15, 0.94) Goldstein, weeks (0.05, 5.56) 6.89 Russell-Jones, weeks (0.21, 1.2) Subtotal (I-squared = 0.0%, p = 0.857) 0.45 (0.24, 0.84) Sitagliptin 50mg + Metformin 1000mg bid vs. Metformin 1000mg bid Goldstein, weeks (0.1, 1.44) Reasner, weeks (0.57, 1.9) 75.2 Subtotal (I-squared = 0.0%, p = 0.522) 0.8 (0.57, 1.22) NOTE: Weights are from random effects analysis Favors Newer Diabetes Drug Favors Metformin

126 Figure E-21. Newer Diabetes Drugs compared with Metformin: Vomiting Vomiting - Newer Diabetes Drugs vs. Metformin % Author_Year Outcome_Timing Drug_N Drug_Events Comp_N Comp_Events RR (95% CI) Weight Saxagliptin 5mg vs. Metformin Fonseca, weeks (0.8, ) 1.61 Hermans, weeks (0.19, 4.61) 68.9 Subtotal (I-squared =.6%, p = 0.220) 1.80 (0.27, 12.21) Sitagliptin 100mg vs. Metformin Aschner, weeks (0.06, 1.5) Goldstein, weeks (0.01, 5.60) 20.4 Subtotal (I-squared = 0.0%, p = 0.952) 0.28 (0.07, 1.12) Sitagliptin 50mg + Metformin 1000mg bid vs. Metformin 1000mg bid Goldstein, weeks (0.61, 14.67) 22.8 Reasner, weeks (0.58, 2.17) Subtotal (I-squared = 21.%, p = 0.260) 1.9 (0.62,.1) NOTE: Weights are from random effects analysis Favors Newer Diabetes Drug Favors Metformin Note: In the data shown, 0.5 represents 0 events/non-events.

127 Figure E-22. Newer Diabetes Medications compared with Metformin: Diarrhea Diarrhea - Newer Diabetes Drugs vs. Metformin % Author_Year Outcome_Timing Drug_N Drug_Events Comp_N Comp_Events RR (95% CI) Weight Dapagliflozin 10mg vs Metformin XR Henry, weeks (0.12, 0.70) List, weeks (0.02, 1.) Subtotal (I-squared = 0.0%, p = 0.651). Dapagliflozin 5mg vs Metformin XR 0.26 (0.12, 0.60) Henry, weeks (0.24, 1.2) 72.8 List, weeks (0.02, 1.09) Subtotal (I-squared = 7.1%, p = 0.207). Linagliptin 5mg vs. Metformin 1000mg bid 0.8 (0.11, 1.5) Haag, weeks (0.01, 2.71) 12.1 Haak, weeks (0.22, 1.9) Subtotal (I-squared = 0.0%, p = 0.40). Saxagliptin 5mg vs. Metformin 0.54 (0.19, 1.50) Fonseca, weeks (0.56, 4.98) Hermans, weeks (0.2, 1.09) 55.4 Subtotal (I-squared = 67.8%, p = 0.078). Sitagliptin 100mg vs. Metformin 0.86 (0.27, 2.77) Aschner, weeks (0.20, 0.55) Goldstein, weeks (0.10, 0.70) Russell-Jones, weeks (0.21, 0.90) Subtotal (I-squared = 0.0%, p = 0.695) 0.5 (0.24, 0.51) Sitagliptin 50mg + Metformin 1000mg bid vs. Metformin 1000mg bid Goldstein, weeks (0.45, 1.59) Reasner, weeks (0.55, 0.95) Subtotal (I-squared = 0.0%, p = 0.666). NOTE: Weights are from random effects analysis 0.74 (0.58, 0.95) Favors Newer Diabetes Drug Favors Metformin

128 Figure E-2. Newer Diabetes Drugs compared with Metformin: Gastrointestinal Adverse Events Gastrointestinal Adverse Events - Newer Diabetes Drugs vs. Metformin % Author_Year Outcome_Timing Drug_N Drug_Events Comp_N Comp_Events RR (95% CI) Weight Sitagliptin 50mg + Metformin 1000mg bid vs. Metformin 1000mg bid Reasner, weeks (0.68, 1.0) Goldstein, weeks (0.69, 1.40) Subtotal (I-squared = 0.0%, p = 0.460) 0.87 (0.7, 1.04) NOTE: Weights are from random effects analysis Favors Newer Diabetes Drug Favors Metformin

129 Figure E-24. Newer Diabetes Drugs compared with Metformin: Headache Headache - Newer Diabetes Drugs vs. Metformin % Author_Year Outcome_Timing Drug_N Drug_Events Comp_N Comp_Events RR (95% CI) Weight Sitagliptin 100mg vs. Metformin Aschner, weeks (0.51, 1.92) Russell-Jones, weeks (0.42, 1.6) Subtotal (I-squared = 0.0%, p = 0.549) 0.85 (0.55, 1.2) NOTE: Weights are from random effects analysis Favors Newer Diabetes Drug Favors Metformin Figure E-25. Newer Diabetes Drugs compared with Metformin: Abdominal Pain Abdominal Pain - Newer Diabetes Drugs vs. Metformin % Author_Year Outcome_Timing Drug_N Drug_Events Comp_N Comp_Events RR (95% CI) Weight Sitagliptin 50mg + Metformin 100mg bid vs. Metformin 1000mg bid Goldstein, weeks (0.24, 1.8) 4.88 Reasner, weeks (0.1, 0.67) Subtotal (I-squared = 5.9%, p = 0.212) 0.42 (0.19, 0.94) NOTE: Weights are from random effects analysis Favors Newer Diabetes Drug Favors Metformin

130 Figure E-26. Newer Diabetes Drugs compared with Metformin: Urinary Tract Infection Urinary Tract Infection - Newer Diabetes Drugs vs. Metformin % Author_Year Outcome_Timing Drug_N Drug_Events Comp_N Comp_Events RR (95% CI) Weight Dapagliflizon 10mg vs. Metformin XR Henry, weeks (1.8, 11.80) List, weeks (0.42, 5.2) Subtotal (I-squared = 29.9%, p = 0.22) (0.97, 6.90) Dapagliflizon 5mg vs. Metformin XR Henry, weeks (0.7, 2.15) 67.4 List, weeks (0.4, 4.27) 2.66 Subtotal (I-squared = 0.0%, p = 0.699) (0.48, 2.02) Saxagliptin 5mg vs. Metformin Fonseca, weeks (0.64, 9.2) Hermans, weeks (0.11,.72) Subtotal (I-squared = 29.8%, p = 0.2). NOTE: Weights are from random effects analysis 1.41 (0.9, 5.18) Favors Newer Diabetes Drug Favors Metformin

131 Figure E-27. Newer Diabetes Drugs compared with Metformin: Nasopharyngitis Nasopharyngitis - Newer Diabetes Drugs vs. Metformin % Author_Year Outcome_Timing Drug_N Drug_Events Comp_N Comp_Events RR (95% CI) Weight Saxagliptin 5mg vs. Metformin Fonseca, weeks (0.28, 2.20) Hermans, weeks (0.82, 17.50) 4.9 Subtotal (I-squared = 64.8%, p = 0.092) 1.55 (0., 7.25) Sitagliptin 100mg vs. Metformin Aschner, weeks (0.27, 1.26) Russell-Jones, weeks (0.49, 2.18) Subtotal (I-squared = 11.2%, p = 0.289) 0.78 (0.44, 1.8) NOTE: Weights are from random effects analysis Favors Newer Diabetes Drug Favors Metformin

132 Appendix F. Strength of evidence Table F-1. Sitagliptin compared with saxagliptin Number of Studies; # of Subjects Domains pertaining to strength of evidence Risk of Bias (Design/ Quality) Consistency Directness Precision Magnitude of effect Summary Effect Size (95% Confidence Interval) HbA1c 1;801 Medium Unknown Indirect Precise Between-group difference at 18 weeks: 0.09%; 95% CI, to 0.2 Weight change 1;801 Medium Unknown Indirect Unknown Between-group difference at 18 weeks: 0 kg (no difference between groups; variance not reported) Health outcomes: Myocardial infarction 1;801 Medium Unknown Direct Imprecise 1 event in the sitagliptin group; 0 events in the saxagliptin group Health outcomes: Transient ischemic attack 1:801 Medium Unknown Direct Imprecise 1 event in the sitagliptin group; 0 events in the saxagliptin group Table F-2. Exenatide XR compared with exenatide Number of Studies; # of Subjects Domains pertaining to strength of evidence Risk of Bias (Design/ Quality) Consistency Directness Precision Magnitude of effect Summary Effect Size (95% Confidence Interval) HbA1c ;1225 Medium Consistent Indirect Precise Greater reduction with Exenatide XR: WMD %; 95% CI, to -0.2 Weight change ;1255 Medium Inconsistent Indirect Imprecise No difference was found between groups in two trials. One trial found a small reduction in weight (-0.kg; P<0.001) favoring exenatide twice daily. Health outcomes: myocardial infarction a 2; Medium Unknown Direct Imprecise No difference between groups in either study. Withdrawals because of adverse events :1,22 Medium Inconsistent Direct Imprecise No difference between groups. RR 0.72; 95% CI, 0.5 to 1.50 Injection site reactions Strength of evidence High, Moderate,, Insufficient Insufficient Insufficient Insufficient Insufficient Strength of evidence High, Moderate,, Insufficient Moderate Insufficient

133 Number of Studies; # of Subjects Domains pertaining to strength of evidence Risk of Bias (Design/ Quality) Consistency Directness Precision Magnitude of effect Summary Effect Size (95% Confidence Interval) 1: 678 Medium Consistent b Direct Imprecise Higher in exenatide XR group than exenatide twice daily group (21.8% and.%) GI side effects (nausea and vomiting) :1,22 Medium Consistent Direct Precise er rates of nausea and vomiting with exenatide XR. Nausea, RR0.51; 95% CI 0. to 0.79; Vomiting RR 0.62; 95% CI, 0.45 to 0.87 Diarrhea :1,22 Medium Consistent Direct Imprecise No difference between groups. RR 1.21; 95% CI, 0.86 to 1.72 Strength of evidence High, Moderate,, Insufficient Moderate a One trial reported fatal myocardial infarction and the other myocardial infarction there is not sufficient description of how events were recorded to assess consistency. b We used evidence from two other trials that reported injection site reactions to assess consistency. In 1 trial (N=678), injection site reactions were defined as inclusive of induration, pruritus, and nodules. Another trial (N=29) reported only pruritus at the injection site. The third trial (N=252) reported only erythema at the injection site. In all cases, exenatide XR was associated with a higher rate of injection site reactions. Table F-. Exenatide compared with liraglutide Number of Studies; # of Subjects Domains pertaining to strength of evidence Risk of Bias (Design/ Quality) Consistency Directness Precision Magnitude of effect Summary Effect Size (95% Confidence Interval) HbA1c 1; 464 Medium Unknown Indirect Precise Favors liraglutide at 26 weeks: estimated treatment difference 0.; ( 0.47 to 0.18); P< Weight change 1;464 Medium Unknown Indirect Imprecise No between-group difference at 26 weeks: -0.8 kg (-0.99 to 0.2), P=0.225 Hypoglycemia 1: 464 Medium Unknown Direct Imprecise Less with liraglutide; rate ratio 0.55 for minor hypoglycemia, CI 0.4 to 0.88; P=0.01 Strength of evidence High, Moderate,, Insufficient Table F-4. Sitagliptin compared with exenatide XR Number of Studies; # of Subjects Domains pertaining to strength of evidence Risk of Bias (Design/ Quality) Consistency Directness Precision Magnitude of effect Summary Effect Size (95% Confidence Interval) Strength of evidence High, Moderate,, Insufficient

134 Number of Studies; # of Subjects Domains pertaining to strength of evidence Risk of Bias (Design/ Quality) Consistency Directness Precision Magnitude of effect Summary Effect Size (95% Confidence Interval) HbA1c 2;75 Medium Consistent Indirect Precise Greater reduction with Exenatide XR: WMD (-0.69 to -0.26) Weight change 2;75 Medium Consistent Indirect Precise Greater reduction with Exenatide XR: WMD (-1.87 to -0.76) Health outcomes: Cardiovascular events 1;42 Medium Unknown Direct Imprecise No coronary artery occlusion or unstable angina in either group; one person receiving sitagliptin had a cerebrovascular accident compared with no events in the exenatide group Health outcomes: Mortality 1:411 Medium Unknown Direct Imprecise No deaths in either group over 26 weeks Strength of evidence High, Moderate,, Insufficient Insufficient Insufficient GI side effects 2:77 Medium Consistent Direct Precise Rates of nausea, vomiting, and diarrhea were higher with exenatide 2 mg once weekly than with sitagliptin 100 mg [pooled relative risks for nausea (2.62; 95% CI, 1.66 to 4.15), vomiting (.67; 95% CI, 1.6 to 8.24), and diarrhea (1.91; 95% CI, 1.22 to.00)]. Moderate

135 Table F-5. Sitagliptin 100 mg compared with liraglutide 1.2 mg daily Number of Studies; # of Subjects Domains pertaining to strength of evidence Risk of Bias (Design/ Quality) Consistency Directness Precision Magnitude of effect Summary Effect Size (95% Confidence Interval) HbA1c 1:444 Medium Unknown Indirect Precise Greater reduction with liraglutide at 26 weeks: -0.4% (-0.51 to -0.16) Between-group difference at 52 weeks: -0.40% (-0.59 to -0.22) Weight change 1:444 Medium Unknown Indirect Precise Greater reduction with liraglutide at 26 weeks (-1.90 kg; to ) and 52 weeks ( kg; -.14 to -1.70) Health outcomes: mortality at 52 weeks 1;444 Medium Unknown Direct Imprecise No difference between groups: 1 death in the liraglutide group and 2 deaths in the sitagliptin group GI side effects 1:444 Medium Unknown Direct Imprecise Nausea occurred more frequently with liraglutide 1.2 mg than with sitagliptin (21.7% liraglutide 1.2 mg and 5.5% sitagliptin). The incidence of nausea was highest for the first weeks of treatment and then declined and remained low for weeks Strength of evidence High, Moderate,, Insufficient Insufficient

136 Table F-6. Sitagliptin 100 mg compared with liraglutide 1.8 mg daily Number of Studies; # of Subjects Domains pertaining to strength of evidence Risk of Bias (Design/ Quality) Consistency Directness Precision Magnitude of effect Summary Effect Size (95% Confidence Interval) HbA1c 1:440 Medium Unknown Indirect Precise Greater reduction with liraglutide at 26 weeks: -0.60% (-0.77 to -0.4) and 52 weeks: -0.88% (-1.02 to -0.74) Weight change 1:440 Medium Unknown Indirect Precise Greater reduction with liraglutide at 26 weeks (-2.42 kg; -.14 to ) and 52 weeks (-2.5 kg; -. to ) Health outcomes: Mortality 1;440 Medium Unknown Direct Imprecise No difference between groups: no deaths in the liraglutide group and 1 death in the sitagliptin group GI side effects 1:444 Medium Unknown Direct Imprecise Nausea occurred more frequently with liraglutide 1.8 mg (27.5%) than with sitagliptin (5.5%). The incidence of nausea was highest for the first weeks of treatment and then declined and remained low for weeks Strength of evidence High, Moderate,, Insufficient Insufficient

137 Table F-7. Sitagliptin 100 mg compared with canagliflozin 100 mg Number of Studies; # of Subjects Domains pertaining to strength of evidence Risk of Bias (Design/ Quality) Consistency Directness Precision Magnitude of effect Summary Effect Size (95% Confidence Interval) HbA1c 2;86 Medium Consistent Indirect Imprecise No difference between groups at 52 weeks: 0% (-0.12 to 0.12) One trial reported a similar mean change from baseline for the two groups at 12 weeks, but did not give a measure of variance (-0.76% vs. 0.74%). Weight change 2;86 Medium Consistent Indirect Precise Greater reduction with canagliflozin at 52 weeks: -2.4% (-.0 to - 1.8) in one trial. A second trial found a between-group difference of -0.4% over 12 weeks (favoring canagliflozin) but did not report a measure of variance. Health outcomes: Mortality 1:74 Medium Unknown Direct Imprecise No difference between groups at 52 weeks. Urinary tract infections 2; 86 Medium Consistent Direct Imprecise No difference between groups Genital mycotic infections (women only) b 2; 44 Medium Consistent Direct Imprecise More frequent in canagliflozin 100 mg than sitagliptin 100 Hypoglycemia 2; 86 Medium Inconsistent Direct Imprecise Rates of hypoglycemia were low (2% to 7%), but inconsistent between trials at 12 and 52 weeks. GI side effects 1; 129 Medium Unknown Direct Imprecise At 12 weeks, rates of nausea and diarrhea were similar between groups. Strength of evidence High, Moderate,, Insufficient a Insufficient a This SOE grade takes into consideration the dose-response effect; this trial and one other trial comparing a higher dose of canagliflozin with sitagliptin also found no difference in mortality between groups at 52 weeks. b Data from Rosenstock et al, 2012 represent all vulvovaginal adverse events in female patients (canagliflozin 100mg N=28; sitagliptin 100mg N = 27), of which the most commonly reported were vulvovaginal mycotic infection and vulvovaginal candidiasis.

138 Table F-8. Sitagliptin 100 mg compared with canagliflozin 00 mg Number of Studies; # of Subjects Domains pertaining to strength of evidence Risk of Bias (Design/ Quality) Consistency Directness Precision Magnitude of effect Summary Effect Size (95% Confidence Interval) HbA1c ;1620 Medium Consistent Indirect Precise No difference between groups at 52 weeks: 2 trials found a greater reduction with sitagliptin. However, the difference between groups was small (between-group differences in HbA1c ranged from -0.15% to -0.7%) and below what is considered to be clinically significant. a Weight change ;1620 Medium Consistent Indirect Precise Two trials found greater reduction with canagliflozin: one trial found a between-group difference of -2.9% (-.4 to -2.) at 52 weeks. A second trial found a between-group difference of -2.9 kg (p<0.001) at 52 weeks. b Health outcomes: Mortality 2;1489 Medium Consistent Direct Imprecise One trial over 52 weeks: one death in the sitagliptin group and no deaths in the canagliflozin group. A second trial over 52 weeks: no deaths in the sitagliptin group and 2 deaths in the canagliflozin group Urinary tract infections ; 1617 Medium Consistent Direct Imprecise No difference between groups Genital mycotic infections ; 154 c Medium Consistent Direct Imprecise More frequent in canagliflozin 00 mg than sitagliptin 100 Changes in Lipids Strength of evidence High, Moderate,, Insufficient

139 Number of Studies; # of Subjects Domains pertaining to strength of evidence Risk of Bias (Design/ Quality) Consistency Directness Precision Magnitude of effect Summary Effect Size (95% Confidence Interval) ; 1617 Medium Inconsistent Indirect Imprecise No difference at 12 or 52 weeks when canagliflozin was added to metformin monotherapy. At 52 weeks, one trial found a greater increase in LDL cholesterol in the canagliflozin group (mean difference 6.4%; 95% CI, 1.7 to 11.2). No difference between groups for changes in triglycerides. Hypoglycemia Medium Inconsistent Direct Imprecise Rates of hypoglycemia were low (0% to 7%), in the 12 and 52-week trials in which canagliflozin was added to metformin monotherapy, and higher in the 52-week trial in which canagliflozin was added to metformin plus sulfonylurea (41% for sitagliptin 100 mg and 4% for canagliflozin 00 mg). GI side effects 1; 129 Medium Unknown Direct Imprecise At 12 weeks, rates of nausea and diarrhea were similar between groups. Strength of evidence High, Moderate,, Insufficient a A third trial found a similar reduction in HbA1c between groups at 12 weeks but did not report a measure of variance: -0.92% for canagliflozin and -0.74% for sitagliptin. b A third trial found a greater reduction with canagliflozin at 12 weeks but did not report a measure of variance: -.4kg for canagliflozin and -2.kg for sitagliptin. c Data from Rosenstock et al, 2012 represent all vulvovaginal adverse events in female patients, of which the most commonly reported were vulvovaginal mycotic infection and vulvovaginal candidiasis.

140 Table F-9. Linagliptin 5 mg compared with metformin 500 mg twice daily Number of Studies; # of Subjects Domains pertaining to strength of evidence Risk of Bias (Design/ Quality) Consistency Directness Precision Magnitude of effect Summary Effect Size (95% Confidence Interval) HbA1c 1; 286 Medium Unknown Indirect Imprecise No significant difference between groups: 0.10% ( 0.18 to 0.0) Weight change 1:286 Medium Unknown Indirect Precise Greater weight loss was seen with metformin: kg (-0.1 to -1.49) Hypoglycemia for studies comparing linagliptin to metformin 1; 286 Medium Unknown Direct Imprecise overall, no significant difference between groups. Slightly higher for metformin than linagliptin. GI side effects for studies comparing linagliptin to metformin 1; 286 Medium Unknown Direct Imprecise No difference between groups for diarrhea, nausea, or vomiting a In grading the strength of evidence for these comparisons, we also considered the dose-response effect and evidence from placebo-controlled trials of metformin and linagliptin. 6 Strength of evidence High, Moderate,, Insufficient

141 Table F-10. Linagliptin 5 mg compared with metformin 1000 mg twice daily Number of Studies; # of Subjects Domains pertaining to strength of evidence Risk of Bias (Design/ Quality) Consistency Directness Precision Magnitude of effect Summary Effect Size (95% Confidence Interval) HbA1c 1; 286 Medium Unknown Indirect Precise Greater reduction with metformin: -0.60% ( to -0.2) Weight change 1:286 Medium Unknown Indirect Precise Greater reduction seen with metformin: -0.70kg (-0.11 to -1.29) Hypoglycemia 1; 286 Medium Unknown Direct Imprecise Higher for metformin than linagliptin (.4% and 0% respectively). No significant difference GI side effects (diarrhea) 2; 409 Medium Consistent Direct Precise No difference for diarrhea, pooled RR 0.54; 95% 0.19 to 1.50 GI side effects (nausea and vomiting) 1; 286 Medium Unknown Direct Precise No significant difference. Nausea occurred more frequently among patients receiving metformin 1000 mg twice daily than among those receiving linagliptin (.4% and 0.7% respectively). Rates of vomiting were similar between groups. a In grading the strength of evidence for these comparisons, we also considered the dose-response effect and evidence from placebo-controlled trials of metformin and linagliptin. 6 Strength of evidence High, Moderate,, Insufficient Moderate a

142 Table F-11. Alogliptin compared with metformin 500 mg daily Number of Studies; # of Subjects Domains pertaining to strength of evidence Risk of Bias (Design/ Quality) Consistency Directness Precision Magnitude of effect Summary Effect Size (95% Confidence Interval) HbA1c 1;227 Medium Unknown Indirect Imprecise No difference between groups: 0.09% (-0.17 to 0.5). Weight change 1;227 Medium Unknown Indirect Imprecise Greater weight loss with metformin: -0.79kg (-0.00 to -1.58) Health Outcomes: Mortality at 26 weeks 1:227 Medium Unknown Direct Imprecise No difference between groups (no deaths in any group). Health Outcomes: Ischemic stroke at 26 weeks 1:227 Medium Unknown Direct Imprecise No difference between groups: 2 patients in the alogliptin experienced a stroke compared with no strokes in the metformin group. Health Outcomes: Heart failure related events at 26 weeks 1:227 Medium Unknown Direct Imprecise No difference between groups (no heart failure related events in any group) Health Outcomes: Myocardial infarction at 26 weeks 1:227 Medium Unknown Direct Imprecise No difference between groups (1 patient in the alogliptin 25mg daily group had a myocardial infarction compared with no events in any other group) Hypoglycemia 1; 221 Medium Unknown Direct Imprecise No difference (1.8% in both groups) GI side effects (diarrhea) 1; 221 Medium Unknown Direct Imprecise No significant difference. Diarrhea was more common with metformin than alogliptin 25 mg once daily (.7% and 0.9% respectively). Nausea was also more common with metformin than alogliptin 25 mg once daily (.7% and 0% respectively) Strength of evidence High, Moderate,, Insufficient a Insufficient Insufficient Insufficient Insufficient a In grading the strength of evidence for these comparisons, we also considered the dose-response effect and evidence from placebo-controlled trials of metformin.

143 Table F-12. Alogliptin compared with metformin 1000 mg daily Number of Studies; # of Subjects Domains pertaining to strength of evidence Risk of Bias (Design/ Quality) Consistency Directness Precision Magnitude of effect Summary Effect Size (95% Confidence Interval) HbA1c 1;124 Medium Unknown Indirect Imprecise Greater reduction with metformin: -0.55% (-0.81 to -0.29) Weight change 1;124 Medium Unknown Indirect Imprecise Greater weight loss with metformin: -1.4kg (-2.02 to -0.45) Mortality at 26 weeks 1:124 Medium Unknown Direct Imprecise No difference between groups (no deaths in any group) Ischemic stroke at 26 weeks 1:124 Medium Unknown Direct Imprecise No difference between groups (2 patients in the alogliptin 12.5mg twice daily group had a stroke compared with strokes in any other group) Heart failure related events at 26 1:124 Medium Unknown Direct Imprecise No difference between groups (no heart failure related events in any group) Myocardial infarction at 26 weeks 1:124 Medium Unknown Direct Imprecise No difference between groups (1 patient receiving alogliptin 25mg once daily had a myocardial infarction compared with no events in any other group) Hypoglycemia 1; 22 Medium Unknown Direct Imprecise No significant difference. Higher for metformin than alogliptin 25 mg once daily (6.% and 1.8% respectively) GI side effects (diarrhea and nausea) 1; 22 Medium Unknown Direct Imprecise Diarrhea was more common with metformin than alogliptin 25 mg once daily (9.0% and 0.9% respectively). Nausea also occurred more frequently with metformin than alogliptin 25 mg once daily (5.4% and 0% respectively) a In grading the strength of evidence for these comparisons, we also considered the dose-response effect and evidence from placebo-controlled trials of metformin. Strength of evidence High, Moderate,, Insufficient Moderate a Insufficient Insufficient Insufficient Insufficient

144 Table F-1. Sitagliptin compared with metformin Number of Studies; # of Subjects Domains pertaining to strength of evidence Risk of Bias (Design/ Quality) Consistency Directness Precision Magnitude of effect Summary Effect Size (95% Confidence Interval) HbA1c 4;1664 Medium Consistent Indirect Precise Our meta-analysis ( trials; N=1655) found that metformin 2000 mg per day was more efficacious than sitagliptin 100 mg daily (WMD -0.0%; 95% CI, to -0.09, I2 84.7%); all trials found a statistically significant benefit favoring metformin, one trial found a smaller magnitude of effect (- 0.14%) than the other 2 trials (-0.% and %). Weight change 2; Medium Consistent Indirect Precise Greater reduction with metformin; betweengroup differences ranged from -1.2 to - 1.7kg. Hypoglycemia ; 1,820 Medium Inconsistent Direct Precise No significant difference between groups. Pooled RR 0.54; 95% CI, 0.26, 1.14 GI side effects ; 1820 Medium Consistent Direct Precise Fewer incidences of nausea and diarrhea with sitagliptin than with metformin, no difference between groups for rates of vomiting. Pooled RR for diarrhea 0.5; 95% CI, 0.24 to Pooled RR for nausea 0.45; 95% CI, 0.24 to Pooled RR for vomiting 0.28; 95% CI, 0.07 to Strength of evidence High, Moderate,, Insufficient Moderate

145 Table F-14. Saxagliptin compared with uptitrated metformin Number of Studies; # of Subjects Domains pertaining to strength of evidence Risk of Bias (Design/ Quality) Consistency Directness Precision Magnitude of effect Summary Effect Size (95% Confidence Interval) HbA1c for studies comparing saxagliptin to metformin 2;568 Medium Inconsistent Indirect Imprecise No overall difference; 2 trials found inconsistent results. One found saxagliptin 5mg to be more efficacious: -0.5% (-0.74 to -0.2). A second trial found no difference between groups: -0.09%; (-0.26, 0.08) Weight change 2;568 Medium Unknown Indirect Precise Uptitration of metformin was associated with a greater reduction in weight compared with the addition of saxagliptin 5mg: -0.9kg; (-0.24 to ) Health outcomes: myocardial ischemia or myocardial infarction 2;282 Medium Unknown Direct Imprecise No difference between groups: one person receiving saxagliptin experienced myocardial ischemia and one person in the metformin group had a myocardial infarction compared with no events in the saxagliptin group. Health outcomes: Mortality 2;286 Medium Unknown Direct Imprecise No deaths in either group over 24 weeks. Hypoglycemia 2; 568 Medium Consistent Direct Imprecise Higher incidence of hypoglycemia with saxagliptin. Pooled RR 2.9; 95% CI, 1.08 to GI side effects 2;568 Medium Inconsistent Direct Imprecise No significant difference between groups for incidence of diarrhea, nausea, or vomiting. Pooled RR for diarrhea 0.86; 95% CI, 0.27 to 2.77; Pooled RR for nausea 1.6; 95% CI, 0.45 to Pooled RR for vomiting 1.80; 95% CI, 0.27 to Strength of evidence High, Moderate,, Insufficient Insufficient Insufficient

146 Table F-15. Exenatide twice daily compared with metformin Number of Studies; # of Subjects Domains pertaining to strength of evidence Risk of Bias (Design/ Quality) Consistency Directness Precision Magnitude of effect Summary Effect Size (95% Confidence Interval) HbA1c 1;59 Medium Unknown Indirect Precise Exenatide -2.10% +/ compared with metformin -1.66% +/- 1.8 after 26 weeks; P=0.045 Weight change 1;59 Medium Unknown Indirect Precise Exenatide -5.8 kg +/ kg compared to metformin -.81 kg +/- 1.8 kg after 26 weeks; P<0.01 Strength of evidence High, Moderate,, Insufficient Insufficient Insufficient Table F-16. Exenatide XR compared with metformin Number of Studies; # of Subjects Domains pertaining to strength of evidence Risk of Bias (Design/ Quality) Consistency Directness Precision Magnitude of effect Summary Effect Size (95% Confidence Interval) HbA1c 1;494 Medium Unknown Indirect Imprecise No difference between groups; exenatide XR - 1.5% (SE 0.07) compared with metformin -1.48% (SE 0.07); 98.% CI to 0.17; P=0.62 Weight change 1;494 Medium Unknown Indirect Imprecise No difference between groups: mean weight loss of 2 kg in both groups, P=0.892 Mortality 1;494 Medium Unknown Direct Imprecise No difference between groups: one death in the metformin group; no deaths in the exenatide group Strength of evidence High, Moderate,, Insufficient Insufficient

147 Table F-17. Dapagliflozin 5 mg compared with metformin XR 750 mg-2000 mg Number of Studies; # of Subjects Domains pertaining to strength of evidence Risk of Bias (Design/ Quality) Consistency Directness Precision Magnitude of effect Summary Effect Size (95% Confidence Interval) HbA1c for studies comparing dapagliflozin to metformin HbA1c 2;50 Medium Consistent Indirect Imprecise No difference between groups: WMD -0.12% (-0.16 to -0.08) Weight change 2:50 Medium Consistent Indirect Greater reduction with dapagliflozin: WMD kg (-1.86 to -0.26) Strength of evidence High, Moderate,, Insufficient Mortality 2:50 Medium Consistent Direct Imprecise One trial reported no deaths at 12 weeks; a second trial reported no deaths among the dapagliflozin group compared one death in the metformin group at 26 weeks. Hypoglycemia 2; 518 Medium Inconsistent Direct Imprecise No significant difference between groups. Pooled RR 1.14; 95% CI, 0.9 to.9 GI side effects (nausea and diarrhea) 2; 518 Medium Consistent Direct Imprecise No significant difference between groups. Pooled RR for nausea 0.56; 95% CI, 0.24 to 1.1. Pooled RR for diarrhea 0.8; 95% CI, 0.11 to 1.5.

148 Table F-18. Dapagliflozin 10 mg compared with metformin XR 750 mg mg Number of Studies; # of Subjects Domains pertaining to strength of evidence Risk of Bias (Design/ Quality) Consistency Directness Precision Magnitude of effect Summary Effect Size (95% Confidence Interval) HbA1c 2;50 Medium Consistent Indirect Imprecise Between-group difference not clinically significant (favoring dapagliflozin): WMD % (-0.11 to -0.05) Weight change 2:50 Medium Consistent Indirect Precise Greater reduction with dapagliflozin: WMD -1.kg (-1.8 to -0.7). Mortality 2:50 Medium Consistent Direct Imprecise No difference between groups: one trial reported no deaths at 12 weeks; a second trial reported one death among the metformin group compared with no deaths in the dapagliflozin group at 26 weeks. Hypoglycemia 2; 50 Medium Consistent Direct Precise No significant difference between groups. Pooled RR 0.50; 95% CI, 0.18 to 1.4 GI side effects (nausea) 2; 50 Medium Inconsistent Direct Imprecise No significant difference between groups. Pooled RR 1.0; 95% CI, 0.42 to 2.54 GI side effects (diarrhea) 2; 50 Medium Consistent Direct Precise er incidence with dapagliflozin than with metformin. Pooled RR 0.26; 95% CI, 0.12 to 0.60 Strength of evidence High, Moderate,, Insufficient Moderate

149 Table F-19. Alogliptin + metformin dual therapy compared with component monotherapy Number of Studies; # of Subjects Domains pertaining to strength of evidence Risk of Bias (Design/ Quality) Consistency Directness Precision Magnitude of effect Summary Effect Size (95% Confidence Interval) HbA1c 2;50 Medium Consistent Indirect Imprecise Weight change 2:50 Medium Consistent Indirect Precise Mortality 2:50 Medium Consistent Direct Imprecise Hypoglycemia for alogliptin 12.5 mg bid + metformin 500 mg bid compared with alogliptin 25 mg once daily 1; 218 Medium Unknown Direct Imprecise No difference between groups (1.9% with combination therapy and 1.8% with monotherapy) Hypoglycemia for alogliptin 12.5 mg bid + metformin 500 mg bid compared with metformin 500 mg bid 1; 215 Medium Unknown Direct Imprecise No difference between groups (1.9% with combination therapy and 1.8% with monotherapy) Hypoglycemia for alogliptin 12.5 mg bid + metformin 500 mg bid compared with metformin 1000 mg bid 1; 217 Medium Unknown Direct Imprecise Higher with metformin monotherapy than with combination therapy (6.% and 1.9% respectively). Hypoglycemia for alogliptin 12.5 mg bid + metformin 1000 mg bid compared with alogliptin 25 mg once daily 1; 226 Medium Unknown Direct Imprecise Higher with combination therapy than with monotherapy (5.% and 1.8% respectively). Hypoglycemia for alogliptin 12.5 mg bid + metformin 1000 mg bid compared with metformin 500 mg bid 1; 22 Medium Unknown Direct Imprecise Higher with combination therapy than with monotherapy (5.% and 1.8% respectively). Hypoglycemia for alogliptin 12.5 mg bid + metformin 1000 mg bid compared with metformin 1000 mg bid 1; 225 Medium Unknown Direct Imprecise No difference between groups. Slightly higher with metformin monotherapy than with combination therapy (6.% and 5.% respectively) GI side effects for alogliptin 12.5 mg bid + metformin 500 mg bid compared with alogliptin 25 mg once daily (nausea and diarrhea) 1; 218 Medium Unknown Direct Imprecise No significant difference between groups. Higher Strength of evidence High, Moderate,, Insufficient

150 with combination therapy than with monotherapy (nausea: 2.8% and 0%; diarrhea: 5.7% and 0.9%) GI side effects for alogliptin 12.5 mg bid + metformin 500 mg bid compared with metformin 500 mg bid (nausea and diarrhea) 1; 215 Medium Unknown Direct Imprecise No significant difference between groups. Incidence of nausea slightly higher with monotherapy than with combination therapy (.7% and 2.8%. Incidence of diarrhea higher with combination therapy than with monotherapy (5.7% and.7%). GI side effects for alogliptin 12.5 mg bid + metformin 500 mg bid compared with metformin 1000 mg bid (nausea and diarrhea) 1; 217 Medium Unknown Direct Imprecise No significant difference between groups. Higher with monotherapy than with combination therapy (nausea: 5.4% and 2.8%; diarrhea: 9.0% and 5.7%) GI side effects for alogliptin 12.5 mg bid + metformin 1000 mg bid compared with alogliptin 25 mg once daily (nausea and diarrhea) 1; 226 Medium Unknown Direct Imprecise Higher with combination therapy than with monotherapy (nausea: 5.% and 0%; diarrhea 7.0% and 0.9%). GI side effects for alogliptin 12.5 mg bid + metformin 1000 mg bid compared with metformin 500 mg bid (nausea and diarrhea) 1; 22 Medium Unknown Direct Imprecise Higher with combination therapy than with monotherapy (nausea: 5.% and.7%; diarrhea 7.0% and.7%) GI side effects for alogliptin 12.5 mg bid + metformin 1000 mg bid compared with metformin 1000 mg bid (nausea and diarrhea) 1; 225 Medium Unknown Direct Imprecise No difference between groups for incidence of nausea (5.% with combination therapy and 5.4% with monotherapy). Incidence of diarrhea slightly higher with monotherapy than with combination therapy (9.0% and 7.0%)

151 Table F-20. Linagliptin + metformin dual therapy compared with component monotherapy Number of Studies; # of Subjects Domains pertaining to strength of evidence Risk of Bias (Design/ Quality) Consistency Directness Precision Magnitude of effect Summary Effect Size (95% Confidence Interval) HbA1c for linagliptin 2.5 mg bid + metformin 500 mg bid compared with linagliptin 5 mg 1; 287 Medium Unknown Indirect Precise Greater reduction with dual therapy: 0.70 ( 0.98 to 0.42 HbA1c for linagliptin 2.5 mg bid + metformin 500 mg bid compared with metformin 500mg 1; 287 Medium Unknown (1 study) Indirect Precise Greater reduction with dual therapy: 0.60; 95% CI, 0.88 to 0.2 HbA1c for linagliptin 2.5 mg bid + metformin 1000 mg bid compared with linagliptin 5 mg 1; 285 Medium Unknown Indirect Precise Greater reduction with dual therapy: 1.10; 95% CI, 1.8 to 0.82 HbA1c for linagliptin 2.5 mg bid + metformin 1000 mg bid compared with metformin 1000mg 1; 290 Medium Unknown (1 study) Indirect Precise Greater reduction with dual therapy: 0.50; 95% CI, 0.78 to 0.22 Weight Change for linagliptin 2.5 mg bid + metformin 500 mg bid compared with linagliptin 5 mg 1; 287 Medium Unknown Indirect Imprecise No difference between groups: 0.0 kg; ( 0.89 to 0.29) Weight change for linagliptin 2.5mg bid + metformin 500mg to metformin 500mg 1;287 Medium Unknown Indirect Imprecise Greater weight loss in those taking dual therapy: 0.60kg (0.01 to 1.19) Weight change for linagliptin 2.5mg bid + metformin 1000mg to linagliptin 5mg 1;290 Medium Unknown Indirect Imprecise No difference between groups: -0.0kg (-0.89 to 0.29) Weight change for linagliptin 2.5mg bid + metformin 1000mg to metformin 1000mg 1:290 Medium Unknown Indirect Precise Greater weight loss in those taking dual therapy: kg ( 1.59 to 0.41) Hypoglycemia for linagliptin 2.5 mg bid + metformin 500 mg bid compared with linagliptin 5 mg 1; 285 Medium Unknown Direct Precise No significant difference. Higher with combination therapy than with monotherapy (.5 and 0%) Hypoglycemia for linagliptin 2.5mg bid + metformin 500mg to metformin 500 mg 1; 287 Medium Unknown Direct Precise No significant difference. Higher with combination therapy than with monotherapy (.5 and 1.4%) Hypoglycemia for linagliptin 2.5 mg bid + metformin 1000 mg to linagliptin 5 mg 1; 285 Medium Unknown Direct Precise No difference. Hypoglycemia for linagliptin 2.5mg bid + metformin 1000 mg to metformin 1000 mg Strength of evidence High, Moderate,, Insufficient Moderate Moderate Moderate Moderate

152 Number of Studies; # of Subjects Domains pertaining to strength of evidence Risk of Bias (Design/ Quality) Consistency Directness Precision Magnitude of effect Summary Effect Size (95% Confidence Interval) 1; 290 Medium Unknown Direct Precise No significant difference. Higher with monotherapy than with combination therapy (.4% and 0%) GI side effects for linagliptin 2.5 mg bid + metformin 500 mg bid compared with linagliptin 5 mg 1; 285 Medium Unknown Direct Precise No significant difference. Incidence of nausea, vomiting, and diarrhea higher with combination therapy than with monotherapy. GI side effects for linagliptin 2.5mg bid + metformin 500 mg to metformin 500 mg 1; 287 Medium Unknown Direct Precise No significant difference. Incidence of nausea, vomiting, and diarrhea higher with combination therapy than with monotherapy. GI side effects for linagliptin 2.5mg bid + metformin 1000 mg to linagliptin 5 mg 1; 285 Medium Unknown Direct Precise No significant difference. Incidence of nausea and diarrhea higher with combination therapy than with monotherapy; incidence of vomiting slightly higher with monotherapy than with combination therapy. GI side effects for linagliptin 2.5mg bid + metformin 1000 mg to metformin 1000 mg 1; 290 Medium Unknown Direct Precise No significant difference. Incidence of diarrhea higher with combination therapy than with monotherapy. No difference for nausea and vomiting. Strength of evidence High, Moderate,, Insufficient

153 Table F-21. Janumet FDCP/sitagliptin + metformin dual therapy compared with component monotherapy Number of Studies; # of Subjects Domains pertaining to strength of evidence Risk of Bias (Design/ Quality) Consistency Directness Precision Magnitude of effect Summary Effect Size (95% Confidence Interval) 2; 241 Medium Consistent Indirect Precise Greater reduction with dual therapy than with monotherapy in one trial (range 0.4% to 1.2%) Two trials found greater reduction with dual therapy than with metformin monotherapy: WMD (-0.75 to -0.45) Weight 2:241 Medium Consistent Indirect Precise Similar weight loss of sitagliptin plus metformin ( 0.7 to 1.7 kg) and metformin monotherapy ( 1.0 to 1.5 kg) in one trial. Another trial found greater weight loss with sitagliptin plus metformin compared with metformin alone: between-group difference: -1.6 kg (-2.1 to -1.1) Health outcomes: mortality 1:1250 Medium Unknown Direct Imprecise No difference between groups: one trial found one death In each group over 18 weeks Hypoglycemia for studies comparing Janumet/sitagliptin + metformin to metformin 1000 mg bid 2; 1,610 Medium Consistent Indirect Imprecise No significant difference. Pooled RR 1.75; 95% CI, 0.50, 6.10 GI side effects for studies comparing Janumet/sitagliptin + metformin to metformin 1000 mg bid 2; 1,610 Medium Consistent Indirect Precise Pooled RR for diarrhea 0.74; 95% CI, 0.58, Pooled RR for nausea 0.8; 95% CI, 0.57, Pooled RR for vomiting 1.9; 95% CI, 0.62 to.1. Strength of evidence High, Moderate,, Insufficient Moderate Insufficient