Drug Class Review Newer Diabetes Medications, TZDs, and Combinations

Transcription

1 Drug Class Review Newer Diabetes Medications, TZDs, and Combinations Preliminary Scan Report #1 Update #1 February 2013 The purpose of 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. Scan conducted by: Rachael Posey, MSLS Roberta Wines, MPH Cynthia Feltner, MD, MPH RTI-UNC Evidence-based Practice Center Cecil G. Sheps Center for Health Services Research University of North Carolina at Chapel Hill 725 MLK Blvd, CB# 7590 Chapel Hill, NC Marian McDonagh, PharmD, Principal Investigator Pacific Northwest Evidence-based Practice Center Roger Chou, MD, Director Marian McDonagh, PharmD, Associate Director Oregon Health & Science University Copyright 2013 by Oregon Health & Science University Portland, Oregon All rights reserved.

2 OBJECTIVE The purpose of this preliminary updated literature scan process is to provide the Participating Organizations with a preview of the volume and nature of new research that has emerged subsequent to the previous full review process. Provision of the new research presented in this report is meant to assist with Participating Organizations consideration of allocating resources toward a full report update, a single drug addendum, or a summary review. Comprehensive review, quality assessment, and synthesis of evidence from the full publications of the new research presented in this report would follow only under the condition that the Participating Organizations ruled in favor of a full update. The literature search for this preliminary update scan focuses only on new randomized controlled trials, comparative effectiveness reviews, and actions taken by the U.S. Food and Drug Administration (FDA) since the last report. Other important studies could exist. Date of Last Report Original Report on Newer Diabetes Medications, TZDs, and Combinations: February 2011 (searches through July 2010) Single Drug Addendum on Linagliptin: December 2012 (searches through September 2012) Date of Last Preliminary Update Scan Report None since most recent report Scope and Key Questions Researchers at the University of North Carolina wrote preliminary key questions and the eligibility criteria for studies based on the populations, interventions, and outcomes of interest. These were reviewed by representatives of organizations participating in the Drug Effectiveness Review Project (DERP) and posted to the DERP website for public comment. The participating organizations of DERP are responsible for ensuring that the scope of the review reflects the populations, drugs, and outcome measures of interest to both clinicians and patients. The participating organizations approved the following key questions to guide this review: 1. What is the comparative efficacy and effectiveness of newer diabetes medications, TZDs, 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, TZDs, and drug combinations (administered as fixed dose combination products or dual therapy) for children and adults with diabetes mellitus? 3. 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, TZDs, and drug combinations (administered as combination products or dual therapy) differ in efficacy/effectiveness or frequency of adverse events? New Diabetes Medications, TZDs, and Combinations Update #1 Page 2 of 71

3 Inclusion Criteria Populations Adults and children with diabetes o Type 2 diabetes for all included medications o Type 1 diabetes for pramlintide (Symlin ) only Exclusions: Individuals with gestational diabetes, pre-diabetes (impaired fasting glucose or impaired glucose tolerance), metabolic syndrome without diabetes, or polycystic ovary syndrome Interventions Table 1. Included interventions Drug Class Pramlintide Amylin agonist Sitagliptin DPP-4 Inhibitor Saxagliptin DPP-4 Inhibitor Linagliptin DPP-4 Inhibitor Exenatide GLP-1 Agonists (Incretin mimetics) Liraglutide GLP-1 Agonists (Incretin mimetics) Pioglitazone Thiazolidinediones Rosiglitazone Thiazolidinediones Trade name Administration Symlin Injectable Januvia Oral tablet Onglyza Oral tablet Tradjenta Oral tablet Byetta Injection Victoza Injection Actos Oral tablet Avandia Oral tablet Rosiglitazone + Avandamet Metformin a Oral tablet Pioglitazone + Actoplus Met Metformin a Actoplus Met Labeled indications Type 1 diabetes, Type 2 diabetes; Adjunct with insulin Type 2 diabetes; Monotherapy or combination with any antihyperglycemic Type 2 diabetes; Monotherapy or combination with any antihyperglycemic Type 2 diabetes; Monotherapy or combination therapy with any antihyperglycemic Type 2 diabetes; Not recommended with insulin (not studied) Type 2 diabetes; Not recommended with insulin (not studied) Type 2 diabetes; Monotherapy or combination with sulfonylurea, metformin, insulin Type 2 diabetes; Monotherapy or combination with sulfonylurea, metformin Type 2 diabetes; Adjunct to diet and exercise in patients with type 2 diabetes mellitus when treatment with dual rosiglitazone and metformin therapy is appropriate. Type 2 diabetes; Adjunct to diet and exercise to Dosing Type 1: mcg with meals Type 2: mcg with meals 100 mg once daily (25 or 50 mg if renal dysfunction) mg once daily (2.5 mg if renal dysfunction) 5 mg once daily 5 or 10 mcg twice daily prior to meals 0.6, 1.2, or 1.8 mg once daily mg once daily 4-8 mg once daily 2 mg/500 mg; 2 mg/1000 mg; 4 mg/500 mg; 4 mg/1000 mg 15 mg/500 mg; 15 mg/850 mg for Actoplus Met ; 15 New Diabetes Medications, TZDs, and Combinations Update #1 Page 3 of 71

4 Drug Class Trade name Administration XR Oral tablet Rosiglitazone + Avandaryl Glimepiride a Oral tablet Pioglitazone + Duetact Glimepiride a Oral tablet Linagliptin + Jentadueto Metformin a Oral tablet Labeled indications improve glycemic control in patients with type 2 diabetes who are already treated with a combination of pioglitazone and metformin or whose diabetes is not adequately controlled with metformin alone, or for those patients who have initially responded to pioglitazone alone and require additional glycemic control. Type 2 diabetes; Adjunct to diet and exercise, to improve glycemic control in patients with type 2 diabetes mellitus when treatment with dual rosiglitazone and glimepiride therapy is appropriate. Type 2 diabetes; Adjunct to diet and exercise as a once-daily combination therapy to improve glycemic control in patients with type 2 diabetes who are already treated with a combination of pioglitazone and a sulfonylurea or whose diabetes is not adequately controlled with a sulfonylurea alone, or for those patients who have initially responded to pioglitazone alone and require additional glycemic control. Type 2 diabetes; adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both linagliptin and metformin is appropriate Dosing mg/1000 mg; 30 mg/1000 mg for Actoplus Met XR 4 mg/1 mg; 4 mg/2 mg; 4 mg/4 mg; 8 mg/2 mg; 8 mg/4 mg 30 mg/2 mg; 30 mg/4 mg 2.5 mg/500 mg; 2.5 mg/850 mg; 2.5 mg/1000 mg Abbreviations: DPP-4, Dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1. a In addition to the fixed-dose combination products (FDCPs) listed above, we have included studies of the individual components of those FDCPs when used together but in separate pills. Study designs For intermediate outcomes, 1) randomized controlled trials 2) good-quality systematic reviews For health and utilization outcomes: 1) In addition to the above, observational studies (cohort studies with a comparison group or case-control studies) New Diabetes Medications, TZDs, and Combinations Update #1 Page 4 of 71

5 For harms: 1) randomized controlled trials, controlled clinical trials 2) good-quality systematic reviews 3) population-based comparative cohort studies focused on adverse events, case-control studies, reports from voluntary adverse event reporting systems Comparators For amylin agonists, DPP-4 inhibitors, GLP-1 agonists, and TZDs: o Any other hypoglycemic agent including: other DPP-4 Inhibitors (Sitagliptin, Saxagliptin, and Linagliptin), Thiazolidinediones (TZDs [Pioglitazone and Rosiglitazone]), Amylin Agonists (Pramlintide), or GLP-1 Agonists (Exenatide and Liraglutide); Fixed Dose Combination Products (Avandamet, Actoplus Met, Avandaryl, Duetact, and Jentadueto, which are combinations of Metformin + Rosiglitazone, Metformin + Pioglitazone, Glimepiride + Rosiglitazone, Glimepiride + Pioglitazone, and Linagliptin + Metforminrespectively); Dual therapy with the component medications of fixed dose combination products, Insulin, Second generation Sulfonylureas and beyond, Biguanides (Metformin), Meglitinides, Alpha Glucosidase Inhibitors For FDCPs: o Monotherapy with a component medication or head-to-head studies comparing 2 FDCPs For dual therapy: o Monotherapy with one of the component medications Placebo Effectiveness outcomes Intermediate outcomes: o Hemoglobin A1c o Changes in weight o Changes in lipid concentrations Health outcomes: o Microvascular disease: chronic kidney disease, including renal dialysis, renal transplantation, end-stage renal disease; retinopathy including proliferative retinopathy and blindness; peripheral neuropathy o Macrovascular disease: cardiovascular morbidity (e.g., myocardial infarction and peripheral artery disease), cardiovascular mortality, stroke/tia, coronary heart disease, cardiovascular procedures, extremity amputation o Lower extremity ulcers o All-cause mortality o Quality of life Utilization outcomes: o Hospitalization and medical visits related to diabetes care New Diabetes Medications, TZDs, and Combinations Update #1 Page 5 of 71

6 Harms outcomes Overall adverse events Withdrawals due to adverse events Major adverse events (including 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) METHODS Literature Search To identify relevant citations, we searched PubMed using terms for included drugs and indications and limits for humans, English language, and randomized controlled trials or controlled clinical trials. To identify new trials of drugs in the original report, we searched from January 28, 2010 through January 11, To identify trials of newly-approved drugs, we searched from database inception (i.e., did not limit the search start date) through January 11, 2013 (but through February 4, 2013 for alogliptin, as it was approved after the other searches had been completed). We also searched the FDA website ( for identification of new drugs, indications, and safety alerts. To identify comparative effectiveness reviews, we searched the websites of the Agency for Healthcare Research and Quality ( and the Canadian Agency for Drugs and Technology in Health ( All citations were imported into an electronic database (EndNote X4) and duplicate citations were removed. Study Selection One reviewer assessed abstracts of citations identified from literature searches for inclusion, using the criteria described above. RESULTS New Drugs New drugs identified in this Preliminary Update Scan 11/5/2010: Kombiglyze XR, an extended-release, fixed dose combination product of saxagliptin and metformin hydrochloride, was approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both saxagliptin and metformin is appropriate. 1/27/2012: Bydureon, an extended-release formulation of exenatide, was approved for the treatment of adults with type 2 diabetes mellitus in multiple clinical settings. New Diabetes Medications, TZDs, and Combinations Update #1 Page 6 of 71

7 2/2/2012: Janumet XR, an extended release formulation of Janumet (sitagliptin + metformin HCl), was approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with sitagliptin and metformin is appropriate. 1/10/2013: Invokana (canagliflozin), a sodium-glucose co-transporter-2 inhibitor, was recommended for approval by the FDA's endocrinologic and metabolic drugs advisory committee for the treatment of adults with type 2 diabetes mellitus, approval is pending final FDA action scheduled for March /25/2013: Nesina (alogliptin), a dipeptidyl peptidase 4 inhibitor, was approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. 1/25/2013: Kazano (alogliptin + metformin), a fixed dose combination product of alogliptin and metformin hydrochloride, was approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. 1/25/2013: Oseni (alogliptin + pioglitazone), a fixed dose combination product of alogliptin and pioglitazone, was approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. New Indications None identified. New Safety Alerts Identified in this Preliminary Update Scan VICTOZA (LIRAGLUTIDE) 6/13/2011; VICTOZA (LIRAGLUTIDE [RDNA ORIGIN]) INJECTION: REMS - RISK OF THYROID C-CELL TUMORS, ACUTE PANCREATITIS AUDIENCE: ENDOCRINOLOGY, FAMILY PRACTICE ISSUE: Novo Nordisk reminded healthcare professionals of important safety information about Victoza (liraglutide [rdna origin]) injection required in a Risk Evaluation and Mitigation Strategy (REMS). The letter is being sent because a recent assessment of healthcare providers showed that some primary care providers are not fully aware of the serious risks associated with the use of Victoza. Liraglutide causes dose-dependent and treatment-duration-dependent 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. Additionally, in clinical trials studying Victoza, there were more cases of pancreatitis in patients treated with Victoza than in patients treated with comparators. RECOMMENDATION: Patients with thyroid nodules noted on physical examination or neck imaging obtained for other reasons should be referred to an endocrinologist for further evaluation. Although routine monitoring of serum calcitonin is of uncertain value in patients New Diabetes Medications, TZDs, and Combinations Update #1 Page 7 of 71

8 treated with Victoza, if serum calcitonin is measured and found to be elevated, the patient should be referred to an endocrinologist for further evaluation. After initiation of Victoza, and after dose increases, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back, and which may or may not be accompanied by vomiting). Healthcare professionals and patients are encouraged to report adverse events, side effects, or product quality problems related to the use of these products to the FDA's MedWatch Safety Information and Adverse Event Reporting Program. ACTOS (PIOGLITAZONE) 8/4/2011; ONGOING SAFETY REVIEW - POTENTIAL INCREASED RISK OF BLADDER CANCER The U.S. Food and Drug Administration (FDA) is informing the public that the Agency has approved updated drug labels for the pioglitazone-containing medicines to include safety information that the use of pioglitazone for more than one year may be associated with an increased risk of bladder cancer. AVANDIA (ROSIGLITAZONE), AVANDAMET (ROSIGLITAZONE + METFORMIN), AVANDARYL (ROSIGLITAZONE + GLIMEPIRIDE) 5/18/2011; DRUG SAFETY COMMUNICATION: UPDATED RISK EVALUATION AND MITIGATION STRATEGY (REMS) TO RESTRICT ACCESS TO ROSIGLITAZONE- CONTAINING MEDICINES INCLUDING AVANDIA, AVANDAMET, AND AVANDARYL The U.S. Food and Drug Administration (FDA) is informing the public of new restrictions to the prescribing and use of rosiglitazone-containing medicines. These medicines to treat type II diabetes are sold under the names Avandia, Avandamet, and Avandaryl. Healthcare providers and patients must enroll in a special program in order to prescribe and receive these drugs. The new restrictions are part of a Risk Evaluation and Mitigation Strategy (REMS) a program FDA may require to manage serious risks of marketed drugs. The restrictions are based on data that suggested an elevated risk of heart attacks in patients treated with rosiglitazone. The decision to restrict access to rosiglitazone medicines was made on September 23, FDA has modified the REMS for Avandamet and Avandaryl because previously, the REMS consisted of only a Medication Guide. The REMS, which now includes a restricted access and distribution program, applies to all three rosiglitazone products. The REMS, called the Avandia-Rosiglitazone Medicines Access Program, limits the use of rosiglitazone medicines to: Patients already being successfully treated with these medicines. Patients whose blood sugar cannot be controlled with other anti-diabetic medicines and who, after consulting with their healthcare provider, do not wish to use pioglitazone-containing medicines (Actos, Actoplus Met, Actoplus Met XR, or Duetact). Healthcare providers and patients must be enrolled in the Avandia-Rosiglitazone Medicines Access Program in order to prescribe and receive rosiglitazone medicines. After November 18, 2011, rosiglitazone medicines will no longer be available through retail pharmacies. Patients who New Diabetes Medications, TZDs, and Combinations Update #1 Page 8 of 71

9 are enrolled in the Avandia-Rosiglitazone Medicines Access Program will receive their medicine by mail order through specially certified pharmacies participating in the program. Identified in previous Preliminary Update Scan(s) No scan since most recent report Comparative Effectiveness Reviews Reviews identified in this Preliminary Update Scan We identified 1 potentially relevant comparative effectiveness review, Oral Diabetes Medications for Adults with Type 2 Diabetes: An Update conducted by AHRQ in March 2011 (See Appendix A for abstract). This review summarizes the benefits and harms of oral medications for the treatment of type 2 diabetes mellitus in mono- and combination therapy, including metformin, second-generation sulfonylureas, thiazolidinediones, meglitinides, dipeptidyl peptidase-4 inhibitors, and glucagon-like peptide-1 receptor agonists, covering the period from inception through April Two additional reports from CAD-TH, Second-Line Pharmacotherapy for Type 2 Diabetes and Third-Line Pharmacotherapy for Type 2 Diabetes are currently in progress and are scheduled for publication in Reviews identified in previous Preliminary Update Scan(s) No scans have been conducted since the original report. Randomized Controlled Trials Trials identified since the most recent Full Report Medline searches for randomized controlled trials resulted in 325 citations. Of those, there are 91 potentially relevant new publications, including 57 trials comparing an included medication with eligible active comparators, 30 placebo-controlled trials, and 4 subgroup or secondary analyses of trials included in existing reports (see Appendix B for abstracts). Among the 57 trials comparing included medications with eligible active comparators, 18 included comparisons between two included medications, and 46 of them included comparisons between included medications and other active comparators such as insulin, metformin, or a sulfonylurea. Characteristics of these trials are shown in Tables 2, 3, and 4, below. Table 5 is a matrix showing the studies comparing two included medications. Table 2. New trials comparing included medications with eligible active comparators Author, year Intervention and Comparison Population N Duration Amylin Agonists None DPP-4 Inhibitors DeFronzo, 2012 Alogliptin vs. alogliptin + pioglitazone Patients with T2DM weeks Pratley, 2009 Alogliptin vs. alogliptin + pioglitazone Adults with T2DM weeks Bosi, 2011 Alogliptin vs. pioglitazone Patients with T2DM 803 New Diabetes Medications, TZDs, and Combinations Update #1 Page 9 of 71

10 Author, year Intervention and Comparison Population N Duration 52 weeks Rosenstock, 2010 Alogliptin vs. pioglitazone vs. alogliptin + pioglitazone Patients with T2DM weeks Seino, 2011 Alogliptin vs. voglibose Japanese adult patients with T2DM weeks Goke, 2010 Saxagliptin vs. glipizide Adults with T2DM weeks Pfutzner, 2011 Saxagliptin vs. saxagliptin + metformin vs. metformin Patients with T2DM weeks Scheen, 2010 Saxagliptin vs. sitagliptin Adults with T2DM weeks Rosenstock, 2012 Sitagliptin vs. canagliflozen Patients with T2DM weeks Arnolds, 2010 Sitagliptin vs. exenatide twice daily Adults with T2DM weeks Bergenstal, 2010 Sitagliptin vs. exenatide weekly vs. pioglitazone Patients with T2DM weeks Russell-Jones, 2012 Sitagliptin vs. exenatide weekly vs. pioglitazone vs. metformin Patients with T2DM weeks Koren, 2012 Sitagliptin vs. glibenclamide Patients with T2DM 40 3 months Arechavaleta, 2011 Sitagliptin vs. glimepiride Patients with T2DM weeks Srivastava, 2012 Sitagliptin vs. glimepiride Patients with T2DM weeks Hong, 2012 Sitagliptin vs. insulin Korean patients with T2DM weeks Aschner, 2012 Sitagliptin vs. insulin glargine Adults with T2DM weeks Pratley, 2011 Sitagliptin vs. liraglutide Patients with T2DM weeks Perez-Monteverde, 2011 Sitagliptin vs. pioglitazone Patients with T2DM weeks Aravind, 2012 Sitagliptin vs. sulfonylureas Muslim patients with T2DM months Al Sifri, 2011 Sitagliptin vs. sulphonylurea Muslim patients with T2DM months Iwamoto, 2010 Sitagliptin vs. voglibose Japanese patients with T2DM weeks GLP-1 Agonists Derosa, 2011 Exenatide twice daily vs. glimepiride Patients with T2DM months Gallwitz, 2012 Exenatide twice daily vs. glimepiride Adults with T2DM months Gallwitz, 2011 Exenatide twice daily vs. insulin aspart Patients with T2DM weeks Bunck, 2011 Exenatide twice daily vs. insulin glargine Patients with T2DM 46 2 years Arnolds, 2010 Exenatide twice daily vs. sitagliptin Adults with T2DM weeks Blevins, 2011 Exenatide weekly vs. exenatide twice daily Patients with T2DM weeks Diamant, 2010 Exenatide weekly vs. insulin glargine Adults with T2DM weeks Diamant, 2012 Exenatide weekly vs. insulin glargine Patients with T2DM weeks Bergenstal, 2010 Exenatide weekly vs. pioglitazone vs. sitagliptin Patients with T2DM weeks New Diabetes Medications, TZDs, and Combinations Update #1 Page 10 of 71

11 Author, year Intervention and Comparison Population N Duration Russell-Jones, 2012 Exenatide weekly vs. pioglitazone vs. sitagliptin vs. metformin Patients with T2DM weeks Seino, 2010 Liraglutide vs. glibenclamide Japanese patients with T2DM weeks Garber, 2011 Liraglutide vs. glimepiride Patients with T2DM years Yang, 2011 Liraglutide vs. glimepiride Asian patients with T2DM weeks Thiazolidinediones Derosa, 2010 Pioglitazone vs. acarbose Caucasian patients with T2DM months Perez, 2010 Pioglitazone vs. Actoplus Met vs. metformin Patients with T2DM weeks Bosi, 2011 Pioglitazone vs. alogliptin Patients with T2DM weeks Rosenstock, 2010 Pioglitazone vs. alogliptin vs. alogliptin + pioglitazone Patients with T2DM weeks Bergenstal, 2010 Pioglitazone vs. exenatide weekly vs. sitagliptin Patients with T2DM weeks Russell-Jones, 2012 Pioglitazone vs. exenatide weekly vs. sitagliptin vs. metformin Patients with T2DM weeks Derosa, 2010 Pioglitazone vs. glimepiride Patients with T2DM months Forst, 2010 Pioglitazone vs. glimepiride Patients with T2DM 23 6 months Mizoguchi, 2011 Pioglitazone vs. glimepiride Patients with T2DM with carotid atherosclerosis 56 4 months Petrica, 2011 Pioglitazone vs. glimepiride Normoalbuminuric patients with T2DM 68 1 year Meneghini, 2010 Pioglitazone vs. insulin glargine Patients with T2DM weeks Wainstein, 2012 Pioglitazone vs. Janumet Patients with T2DM weeks Hanefeld, 2011 Pioglitazone vs. metformin vs. pioglitazone + metformin Patients with T2DM months Jonker, 2010 Pioglitazone vs. metformin Men with T2DM weeks Naka, 2012 Pioglitazone vs. metformin Patients with T2DM 31 6 months Joya-Galeana, 2011 Pioglitazone vs. metformin vs. glipizide Patients with T2DM 21 6 months Kong, 2011 Pioglitazone vs. rivoglitazone Chinese patients with T2DM weeks Kikuchi, 2012 Pioglitazone vs. rosiglitazone Japanese patients with T2DM weeks Punthakee, 2012 Pioglitazone vs. rosiglitazone Patients with T2DM and other cardiovascular risk years factors Perez-Monteverde, 2011 Pioglitazone vs. sitagliptin Patients with T2DM weeks Xing, 2012 Pioglitazone vs. sulfonylureas Patients with T2DM 98 Fujitaka, 2011 Pioglitazone vs. voglibose Patients with T2DM associated with metabolic syndrome 12 weeks 60 6 months Fidan, 2011 Rosiglitazone vs. metformin Patients with T2DM weeks Gram, 2011 Rosiglitazone vs. metformin vs. Patients with T2DM 371 New Diabetes Medications, TZDs, and Combinations Update #1 Page 11 of 71

12 Author, year Intervention and Comparison Population N Duration insulin aspart vs. NPH insulin 2 years SGLT2 Inhibitors a Rosenstock, 2012 Canagliflozin vs. sitagliptin Patients with T2DM weeks Fixed Dose Combination Products Perez, 2010 Actoplus Met vs. pioglitazone vs. Metformin Patients with T2DM weeks Borges, 2011 Avandamet vs. metformin Patients with T2DM weeks Kadoglou, 2011 Avandamet vs. metformin Patients with T2DM months Olansky, 2011 Janumet vs. metformin Patients with T2DM weeks Reasner, 2011 Janumet vs. metformin Patients with T2DM weeks Wainstein, 2012 Janumet vs. pioglitazone Patients with T2DM weeks Dual Therapy DeFronzo, 2012 Alogliptin + pioglitazone vs. alogliptin Patients with T2DM weeks Pratley, 2009 Alogliptin + pioglitazone vs. alogliptin Adults with T2DM weeks Rosenstock, 2010 Alogliptin + pioglitazone vs. alogliptin vs. pioglitazone Patients with T2DM weeks Hanefeld, 2011 Pioglitazone + metformin vs. pioglitazone vs. metformin Patients with T2DM months Zeitler, 2012 Rosiglitazone + metformin vs. metformin Patients aged 10 to 17 years with T2DM years Pfutzner, 2011 Saxagliptin + metformin vs. saxagliptin vs. metformin Patients with T2DM weeks Fonseca, 2012 Saxagliptin + metformin vs. metformin Adults with T2DM weeks a Canagliflozin, a sodium-glucose co-transporter-2 inhibitor (SGLT2), was recommended for approval by the FDA's endocrinologic and metabolic drugs advisory committee for the treatment of adults with type 2 diabetes mellitus, approval is pending final FDA action scheduled for March Abbreviations: DPP-4, Dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; SGLT2, sodium-glucose cotransporter-2 inhibitor; T2DM, type 2 diabetes mellitus. Table 3. New placebo-controlled trials Author, year Intervention Population N Duration Amylin agonists None DPP-4 Inhibitors DeFronzo, 2008 Alogliptin Patients with T2DM weeks Kaku, 2011 Alogliptin Japanese patients with T2DM NR 52 weeks Kutoh, 2012 Alogliptin Newly diagnosed patients with T2DM 51 3 months Nauck, 2009 Alogliptin Patients with T2DM weeks Pratley, 2009 Alogliptin Adults with T2DM weeks Rosenstock, 2009 Alogliptin Patients with T2DM weeks Seino, 2011 Alogliptin Japanese adult patients with T2DM NR New Diabetes Medications, TZDs, and Combinations Update #1 Page 12 of 71

13 Author, year Intervention Population N Duration 52 weeks Barnett, 2012 Saxagliptin Adults with T2DM weeks Hollander, 2011 Saxagliptin Patient with T2DM weeks Nowicki, 2011 Saxagliptin Adults with T2DM and renal impairment weeks Nowicki, 2011 Saxagliptin Adults with T2DM and renal impairment weeks Pan, 2012 Saxagliptin Asian patients with T2DM weeks Yang, 2011 Saxagliptin Asian adults with T2DM weeks Chacra, 2011 Saxagliptin Patients with T2DM weeks Aaboe, 2010 Sitagliptin Patient with T2DM 24 patients 12 weeks Iwamoto, 2010 Sitagliptin Japanese patients with T2DM weeks Makdissi, 2012 Sitagliptin Patients with T2DM weeks Oz, 2011 Sitagliptin Patients with T2DM weeks Barzilai, 2011 Sitagliptin Elderly patients with T2DM weeks GLP-1 Agonists Buse, 2011 Exenatide twice daily Adults with T2DM weeks Liutkus, 2010 Exenatide twice daily Patients with T2DM weeks Wu, 2011 Exenatide twice daily Patients with T2DM weeks Kaku, 2010 Liraglutide Japanese patients with T2DM weeks Thiazolidinediones Abe, 2010 Pioglitazone Patients with T2DM on hemodialysis weeks Saiki, 2010 Pioglitazone Japanese patients with T2DM weeks Shah, 2011 Pioglitazone Obese patients with T2DM weeks Truitt, 2010 Pioglitazone Patients with T2DM weeks Bertrand, 2010 Rosiglitazone Patients with T2DM and coronary artery bypass grafts months Naka, 2011 Rosiglitazone Patients with advanced T2DM without known cardiovascular disease 34 6 months Rennings, 2010 Rosiglitazone Patients with T2DM weeks SGLT2 Inhibitors None Abbreviations: DPP-4, Dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; SGLT2, sodium-glucose cotransporter-2 inhibitor; T2DM, type 2 diabetes mellitus. New Diabetes Medications, TZDs, and Combinations Update #1 Page 13 of 71

14 Table 4. Secondary analyses of included primary trial publications Author, year Intervention Comparator Population N Duration Karyekar, 2011 Saxagliptin Placebo Adults with T2DM weeks Erdmann, 2010 Pioglitazone Placebo Patients with T2DM and macrovascular months disease Komajda, 2010 Rosiglitazone Metformin + Patients with T2DM 4447 sulfonylurea Home, 2010 Rosiglitazone Metformin Abbreviations: T2DM, type 2 diabetes mellitus. Glyburide 5.5 years Patients with T2DM years Table 5. Breakdown of potentially relevant RCTs comparing two included medications: Alogliptin Sitagliptin Saxagliptin Exenatide Exenatide XR Liraglutide Pioglitazone Rosiglitazone Canagliflozin Actoplus Met Janumet Alogliptin + Pioglitazone Pioglitazone + Metformin Saxaglitpin + Met-formin Sitagliptin + Metformin Alogliptin 2 3 Sitagliptin Saxagliptin 1 1 Exenatide 1 2 Exenatide XR Liraglutide 1 Pioglitazone Rosiglitazone 2 Canagliflozin 1 Actoplus Met 1 Janumet 1 Alogliptin + Pioglitazone Pioglitazone + Metformin Saxaglitpin + Metformin Sitagliptin + Metformin New Diabetes Medications, TZDs, and Combinations Update #1 Page 14 of 71

15 Summary and Recommendations Since the original report and single drug addendum were completed, there are many new trials comparing an included medication with an eligible active comparator. Recent publications include studies for two newly-approved drugs, Bydureon (extended-release formulation of exenatide) and Nesina (alogliptin), and several studies comparing two included medications. An update that includes only trials comparing an included medication with any active comparator would likely be of jumbo size. If placebo-controlled trials are included in an update, it would be even larger. The original report was the result of combining three separate reports (newer diabetes drugs, TZDs, and fixed dose combination products [FDCPs]), resulting in a very large, complex report. We think that the current scope of the report is quite large and that future reports could probably be improved by focusing the inclusion criteria on the information needed most. For example, depending on needs, the Participants could consider producing an update focused only on the newer diabetes drugs. This would capture studies of Bydureon, the new exenatide formulation, and all the new trials of DPP-4 inhibitors and GLP-1 agonists and the new canagliflozin, if it is approved. Depending on the needs of all the Participants regarding issues surrounding TZDs and FDCPs, updating those portions of this report might be lower priority. New Diabetes Medications, TZDs, and Combinations Update #1 Page 15 of 71

16 Appendix A. Abstracts of potentially relevant new comparative effectiveness reviews of newer diabetes medications, TZDs, and combinations Bennett, W. L., L. M. Wilson, et al. (2011). Oral Diabetes Medications for Adults With Type 2 Diabetes: An Update. Rockville MD. Given the number of medications available for type 2 diabetes mellitus, clinicians and patients need information about their effectiveness and safety to make informed choices. The objective of this review was to summarize the benefits and harms of medications (metformin, second-generation sulfonylureas, thiazolidinediones, meglitinides, dipeptidyl peptidase-4 [DPP-4] inhibitors, and glucagon-like peptide-1 [GLP-1] receptor agonists), as monotherapy and in combination, for the treatment of adults with type 2 diabetes. We searched the MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases from inception through April 2010 for original English-language articles and sought unpublished data from the Food and Drug Administration and others. Two reviewers independently screened titles to identify studies that assessed intermediate outcomes (e.g., hemoglobin A1c [HbA1c]), long-term clinical outcomes (e.g., mortality), and harms (e.g., hypoglycemia) in head-to-head monotherapy or combination therapy comparisons. Two reviewers serially extracted data for each article using standardized protocols, assessed applicability, and independently evaluated study quality. The review included 140 randomized controlled trials and 26 observational studies. We graded evidence as low or insufficient for long-term clinical outcomes of all-cause mortality, cardiovascular disease, nephropathy, and neuropathy. Most medications lowered HbA1c on average by 1 absolute percentage point, but metformin was more efficacious than the DPP-4 inhibitors. Two-drug combinations had similar HbA1c reduction. Compared with metformin, thiazolidinediones and sulfonylureas had a more unfavorable effect on weight (mean difference of +2.6 kg). Metformin decreased low density lipoprotein cholesterol relative to pioglitazone, sulfonylureas, and DPP-4 inhibitors. Sulfonylureas had a fourfold higher risk of mild/moderate hypoglycemia compared with metformin alone, and, in combination with metformin, had more than a fivefold increased risk compared with metformin plus thiazolidinediones. Thiazolidinediones had an increased risk of congestive heart failure relative to sulfonylureas and bone fractures relative to metformin. Diarrhea occurred more often for metformin compared with thiazolidinedione users. Comprehensive information comparing benefits and harms of diabetes medications can facilitate personalized treatment choices for patients. Although the long-term benefits and harms of diabetes medications remain unclear, the evidence supports use of metformin as a first-line agent. Comparisons of two-drug combinations showed little to no difference in HbA1c reduction, but some combinations increased risk for hypoglycemia and other adverse events. New Diabetes Medications, TZDs, and Combinations Update #1 Page 16 of 71

17 Appendix B. Abstracts of potentially relevant new trials of newer diabetes medications, TZDs, and combinations New trials comparing included medications with eligible active comparators Al Sifri, S., A. Basiounny, et al. (2011). "The incidence of hypoglycaemia in Muslim patients with type 2 diabetes treated with sitagliptin or a sulphonylurea during Ramadan: a randomised trial." Int J Clin Pract 65(11): AIMS: To compare the incidence of symptomatic hypoglycaemia in fasting Muslim patients with type 2 diabetes treated with sitagliptin or a sulphonylurea during Ramadan. METHODS: Patients with type 2 diabetes (age >/= 18 years) who were treated with a stable dose of a sulphonylurea with or without metformin for at least 3 months prior to screening, who had an HbA(1c) < 10% and who expressed their intention to daytime fast during Ramadan were eligible for this open-label study. Patients were randomised in a 1 : 1 ratio to either switch to sitagliptin 100 mg qd or to remain on their prestudy sulphonylurea. Patients completed daily diary cards to document information on hypoglycaemic symptoms and complications. The primary end-point was the overall incidence of symptomatic hypoglycaemia recorded during Ramadan. RESULTS: Of the 1066 patients randomised, 1021 (n = 507 for sitagliptin and n = 514 for sulphonylurea) returned at least one completed diary card and were included in the analysis. The proportion of patients who recorded one or more symptomatic hypoglycaemic events during Ramadan was lower in the sitagliptin group (6.7%) compared with the sulphonylurea group (13.2%). The risk of symptomatic hypoglycaemia was significantly decreased with sitagliptin relative to sulphonylurea treatment (Mantel-Haenszel relative risk ratio [95% CI] = 0.51 [0.34, 0.75]; p < 0.001). There were no reported events that required medical assistance (i.e. visits to physician or emergency room or hospitalisations) or were considered severe (i.e. events that caused loss of consciousness, seizure, coma or physical injury) during Ramadan. CONCLUSIONS: In Muslim patients with type 2 diabetes who observed the fast during Ramadan, switching to a sitagliptinbased regimen decreased the risk of hypoglycaemia compared with remaining on a sulphonylurea-based regimen. The incidence of hypoglycaemia was lower with gliclazide relative to the other sulphonylurea agents and similar to that observed with sitagliptin. Aravind, S. R., S. B. Ismail, et al. (2012). "Hypoglycemia in patients with type 2 diabetes from India and Malaysia treated with sitagliptin or a sulfonylurea during Ramadan: a randomized, pragmatic study." Curr Med Res Opin 28(8): OBJECTIVE: To compare the incidence of symptomatic hypoglycemia between sitagliptin and sulfonylurea in Muslim patients with type 2 diabetes who fasted during Ramadan. METHODS: In a multicenter, pragmatic, randomized study, patients with type 2 diabetes were recruited from clinical centers in India (n = 765) and Malaysia (n = 105). Eligible patients (age >/= 18 yrs) expressed their intention to daytime fast during Ramadan, were treated with a stable dose of sulfonylurea with or without metformin for >/=3 months prior to screening visit, and had an HbA(1c) </= 10%. Patients were randomized in a 1:1 ratio to either switch to sitagliptin 100 mg q.d. or remain on their pre-study sulfonylurea. Daily diary cards were completed to document information on hypoglycemic symptoms and complications. The primary endpoint was the overall New Diabetes Medications, TZDs, and Combinations Update #1 Page 17 of 71

18 incidence of symptomatic hypoglycemia during Ramadan. RESULTS: Of the 870 patients randomized, 848 (n = 421 for sitagliptin and 427 for sulfonylurea) returned >/=1 completed diary card and were included in the analysis. The proportion of patients who recorded >/=1 symptomatic hypoglycemic event during Ramadan was lower with sitagliptin (3.8%) compared to sulfonylurea (7.3%). The risk of symptomatic hypoglycemia was significantly lower with sitagliptin (risk ratio [95% CI] = 0.52 [0.29, 0.94]; p = 0.028). By country, the proportions of patients who recorded >/=1 symptomatic hypoglycemic event during Ramadan were 4.1% vs. 7.7% in India and 1.9% vs. 3.8% in Malaysia for sitagliptin and sulfonylurea, respectively. No patient discontinued treatment due to a hypoglycemic event. One patient on sitagliptin and seven on sulfonylurea had an event that required non-medical assistance. No events required medical assistance. Both treatments were generally well tolerated. LIMITATIONS: Symptomatic hypoglycemic events did not require a confirmatory blood glucose measurement, which may have overestimated hypoglycemic events. Measures of glycemic control and body weight were not assessed. CONCLUSION: Switching antihyperglycemic treatment to sitagliptin from a sulfonylurea reduced the risk of symptomatic hypoglycemia by approximately 50% for Muslim patients with type 2 diabetes who fasted during Ramadan. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov: NCT Arechavaleta, R., T. Seck, et al. (2011). "Efficacy and safety of treatment with sitagliptin or glimepiride in patients with type 2 diabetes inadequately controlled on metformin monotherapy: a randomized, double-blind, non-inferiority trial." Diabetes Obes Metab 13(2): AIM: to evaluate the efficacy and safety of adding sitagliptin or glimepiride to the treatment regimen of patients with type 2 diabetes mellitus and inadequate glycaemic control on metformin monotherapy. METHODS: patients with type 2 diabetes and an HbA(1c) of % while on a stable dose of metformin (>/= 1500 mg/day) combined with diet and exercise for at least 12 weeks were randomized in a double-blind manner to receive either sitagliptin 100 mg daily (N = 516) or glimepiride (starting dose 1 mg/day and up-titrated, based upon patient's self-monitoring of blood glucose results, to a maximum dose of up to 6 mg/day) (N = 519) for 30 weeks. The primary analysis assessed whether sitagliptin is non-inferior to glimepiride in reducing HbA(1c) at week 30 (based on the criterion of having an upper bound of the 95% CI less than the prespecified non-inferiority bound of 0.4%). RESULTS: the mean baseline HbA(1c) was 7.5% in both the sitagliptin group (n = 443) and the glimepiride group (n = 436). After 30 weeks, the least squares (LS) mean change in HbA(1c) from baseline was -0.47% with sitagliptin and -0.54% with glimepiride, with a between-group difference (95% CI) of 0.07% (-0.03, 0.16). This result met the prespecified criterion for declaring noninferiority. The percentages of patients with an HbA(1c) < 7.0% at week 30 were 52 and 60% in the sitagliptin and glimepiride groups, respectively. The LS mean change in fasting plasma glucose from baseline (95% CI) was -0.8 mmol/l (-1.0, -0.6) with sitagliptin and -1.0 mmol/l (-1.2, -0.8) with glimepiride, for a between-group difference (95% CI) of 0.2 mmol/l (-0.1, 0.4). The percentages of patients for whom hypoglycaemia was reported were 7% in the sitagliptin group and 22% in the glimepiride group (percentage-point difference = -15, p < 0.001). Relative to baseline, sitagliptin was associated with a mean weight loss (-0.8 kg), whereas glimepiride was associated with a New Diabetes Medications, TZDs, and Combinations Update #1 Page 18 of 71

19 mean weight gain (1.2 kg), yielding a between-group difference of -2.0 kg (p < 0.001). CONCLUSIONS: in patients with type 2 diabetes and inadequate glycaemic control on metformin monotherapy, the addition of sitagliptin or glimepiride led to similar improvement in glycaemic control after 30 weeks. Sitagliptin was generally well tolerated. Compared to treatment with glimepiride, treatment with sitagliptin was associated with a lower risk of hypoglycaemia and with weight loss versus weight gain (ClinicalTrials.gov: NCT ). Arnolds, S., S. Dellweg, et al. (2010). "Further improvement in postprandial glucose control with addition of exenatide or sitagliptin to combination therapy with insulin glargine and metformin: a proof-of-concept study." Diabetes Care 33(7): OBJECTIVE: To assess the effect of a 4-week adjunctive therapy of exenatide (EXE) (5-10 microg b.i.d.) or sitagliptin (SITA) (100 mg once daily) in response to a standardized breakfast meal challenge in 48 men or women with type 2 diabetes receiving insulin glargine (GLAR) + metformin (MET). RESEARCH DESIGN AND METHODS: This was a single-center, randomized, open-label, active comparator-controlled study with a three-arm parallel group design, consisting of: screening, 4- to 8-week run-in period, 4- week treatment period, and follow-up. In all three groups, the GLAR dose was titrated according to an algorithm (fasting blood glucose <or=100 mg/dl). RESULTS: The unadjusted 6-h postprandial blood glucose excursion of both GLAR + MET + EXE and GLAR + MET + SITA was statistically significantly smaller than that of GLAR + MET (606 +/- 104 vs /- 133 vs /- 132 mg/dl/h; P = and ). A1C significantly decreased in all three groups (P < ), with the greatest reduction of /- 0.7 under GLAR + MET + EXE (GLAR + MET + SITA /- 0.7; GLAR + MET /- 0.5%-points; GLAR + MET + EXE vs. GLAR + MET P = ). The American Diabetes Association A1C target of <7.0% was reached by 80.0, 87.5, and 62.5% of subjects, respectively. GLAR + MET + EXE had the highest number (47) of adverse events, mostly gastrointestinal (56%) with one dropout. GLAR + MET or GLAR + MET + SITA only had 10 and 12 adverse events, respectively, and no dropouts. Hypoglycemia (blood glucose <50 mg/dl) rates were low and comparable among groups. Weight decreased with GLAR + MET + EXE (-0.9 +/- 1.7 kg; P = ) and increased slightly with GLAR + MET (0.4 +/- 1.5 kg; NS; GLAR + MET + EXE vs. GLAR + MET P = ). CONCLUSIONS: EXE or SITA added to GLAR + MET further substantially reduced postprandial blood glucose excursions. Longer-term studies in a larger population are warranted to confirm these findings. Aschner, P., J. Chan, et al. (2012). "Insulin glargine versus sitagliptin in insulin-naive patients with type 2 diabetes mellitus uncontrolled on metformin (EASIE): a multicentre, randomised open-label trial." Lancet 379(9833): BACKGROUND: In people with type 2 diabetes, a dipeptidyl peptidase-4 (DPP-4) inhibitor is one choice as second-line treatment after metformin, with basal insulin recommended as an alternative. We aimed to compare the efficacy, tolerability, and safety of insulin glargine and sitagliptin, a DPP-4 inhibitor, in patients whose disease was uncontrolled with metformin. METHODS: In this comparative, parallel, randomised, open-label trial, metformin-treated people aged years with glycated haemoglobin A(1c) (HbA(1c)) of 7-11%, diagnosis of type 2 diabetes for at least 6 months, and body- New Diabetes Medications, TZDs, and Combinations Update #1 Page 19 of 71

20 mass index of kg/m(2) were recruited from 17 countries. Participants were randomly assigned (1:1) to 24-week treatment with insulin glargine (titrated from an initial subcutaneous dose of 0.2 units per kg bodyweight to attain fasting plasma glucose of mmol/l) or sitagliptin (oral dose of 100 mg daily). Randomisation (via a central interactive voice response system) was by random sequence generation and was stratified by centre. Patients and investigators were not masked to treatment assignment. The primary outcome was change in HbA(1c) from baseline to study end. Efficacy analysis included all randomly assigned participants who had received at least one dose of study drug and had at least one on-treatment assessment of any primary or secondary efficacy variable. This trial is registered at ClinicalTrials.gov, NCT FINDINGS: 732 people were screened and 515 were randomly assigned to insulin glargine (n=250) or sitagliptin (n=265). At study end, adjusted mean reduction in HbA(1c) was greater for patients on insulin glargine (n=227; -1.72%, SE 0.06) than for those on sitagliptin (n=253; -1.13%, SE 0.06) with a mean difference of -0.59% (95% CI to -0.42, p<0.0001). The estimated rate of all symptomatic hypoglycaemic episodes was greater with insulin glargine than with sitagliptin (4.21 [SE 0.54] vs 0.50 [SE 0.09] events per patient-year; p<0.0001). Severe hypoglycaemia occurred in only three (1%) patients on insulin glargine and one (<1%) on sitagliptin. 15 (6%) of patients on insulin glargine versus eight (3%) on sitagliptin had at least one serious treatment-emergent adverse event. INTERPRETATION: Our results support the option of addition of basal insulin in patients with type 2 diabetes inadequately controlled by metformin. Long-term benefits might be expected from the achievement of optimum glycaemic control early in the course of the disease. FUNDING: Sanofi. Bergenstal, R. M., C. Wysham, et al. (2010). "Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomised trial." Lancet 376(9739): BACKGROUND: Most patients with type 2 diabetes begin pharmacotherapy with metformin, but eventually need additional treatment. We assessed the safety and efficacy of once weekly exenatide, a glucagon-like peptide 1 receptor agonist, versus maximum approved doses of the dipeptidyl peptidase-4 inhibitor, sitagliptin, or the thiazolidinedione, pioglitazone, in patients treated with metformin. METHODS: In this 26-week randomised, double-blind, double-dummy, superiority trial, patients with type 2 diabetes who had been treated with metformin, and at baseline had mean glycosylated haemoglobin (HbA(1c)) of 8.5% (SD 1.1), fasting plasma glucose of 9.1 mmol/l (2.6), and weight of 88.0 kg (20.1), were enrolled and treated at 72 sites in the USA, India, and Mexico. Patients were randomly assigned to receive: 2 mg injected exenatide once weekly plus oral placebo once daily; 100 mg oral sitagliptin once daily plus injected placebo once weekly; or 45 mg oral pioglitazone once daily plus injected placebo once weekly. Primary endpoint was change in HbA(1c) between baseline and week 26. Analysis was by intention to treat, for all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT FINDINGS: 170 patients were assigned to receive once weekly exenatide, 172 to receive sitagliptin, and 172 to receive pioglitazone. 491 patients received at least one dose of study drug and were included in the intention-to-treat analysis (160 on exenatide, 166 on sitagliptin, and 165 on pioglitazone). Treatment with exenatide reduced HbA(1c) (least square mean - New Diabetes Medications, TZDs, and Combinations Update #1 Page 20 of 71