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

21 1.5%, 95% CI -1.7 to -1.4) significantly more than did sitagliptin (-0.9%, -1.1 to -0.7) or pioglitazone (-1.2%, -1.4 to -1.0). Treatment differences were -0.6% (95% CI -0.9 to -0.4, p<0.0001) for exenatide versus sitagliptin, and -0.3% (-0.6 to -0.1, p=0.0165) for exenatide versus pioglitazone. Weight loss with exenatide (-2.3 kg, 95% CI-2.9 to -1.7) was significantly greater than with sitagliptin (difference -1.5 kg, 95% CI -2.4 to -0.7, p=0.0002) or pioglitazone (difference -5.1 kg, -5.9 to -4.3, p<0.0001). No episodes of major hypoglycaemia occurred. The most frequent adverse events with exenatide and sitagliptin were nausea (n=38, 24%, and n=16, 10%, respectively) and diarrhoea (n=29, 18%, and n=16, 10%, respectively); upper-respiratory-tract infection (n=17, 10%) and peripheral oedema (n=13, 8%) were the most frequent events with pioglitazone. INTERPRETATION: The goal of many clinicians who manage diabetes is to achieve optimum glucose control alongside weight loss and a minimum number of hypoglycaemic episodes. Addition of exenatide once weekly to metformin achieved this goal more often than did addition of maximum daily doses of either sitagliptin or pioglitazone. FUNDING: Amylin Pharmaceuticals and Eli Lilly. Blevins, T., J. Pullman, et al. (2011). "DURATION-5: exenatide once weekly resulted in greater improvements in glycemic control compared with exenatide twice daily in patients with type 2 diabetes." J Clin Endocrinol Metab 96(5): CONTEXT: We wanted to understand the effects of once-weekly vs. twice-daily glucagon-like peptide-1 receptor agonism for treatment of patients with type 2 diabetes. OBJECTIVE: The objective of the study was to compare effects of exenatide once weekly (ExQW) and exenatide twice daily (ExBID) on glycemic control, body weight, and safety. DESIGN: This was a 24-wk, randomized, open-label, comparator-controlled study. SETTING: The study was conducted at 43 sites in the United States. PATIENTS: The study population was 252 intent-to-treat patients with type 2 diabetes [baseline (mean +/- SD): glycosylated hemoglobin (HbA1c) 8.4 +/- 1.2%, fasting plasma glucose 171 +/- 47 mg/dl, weight 96 +/- 20 kg] that were drug naive (19%) or previously treated with one (47%) or multiple (35%) oral antidiabetic medications. INTERVENTIONS: Interventions included ExQW 2 mg for 24 wk or ExBID 5 mug for 4 wk followed by ExBID 10 mug for 20 wk. MAIN OUTCOME MEASURE: The change in HbA1c from baseline to wk 24 was measured. RESULTS: At 24 wk, ExQW produced significantly greater changes from baseline (least squares mean +/- SE) vs. ExBID in HbA1c (-1.6 +/- 0.1% vs /- 0.1%; P < ) and fasting plasma glucose (-35 +/- 5 mg/dl vs /- 5 mg/dl; P = ). Similar reductions in mean body weight from baseline to wk 24 were observed in both groups (-2.3 +/- 0.4 kg and /- 0.4 kg). Both treatments were generally well tolerated. Transient and predominantly mild to moderate nausea, the most frequent adverse event, was less common with ExQW (14%) than with ExBID (35%). Injection-site reactions were infrequent, but more common with ExQW. No major hypoglycemia occurred. CONCLUSIONS: Continuous glucagon-like peptide-1 receptor agonism with ExQW resulted in superior glycemic control, with less nausea, compared with ExBID in patients with type 2 diabetes. Both groups lost weight. Borges, J. L., J. P. Bilezikian, et al. (2011). "A randomized, parallel group, double-blind, multicentre study comparing the efficacy and safety of Avandamet (rosiglitazone/metformin) and metformin on long-term glycaemic control and bone mineral density after 80 weeks of treatment New Diabetes Medications, TZDs, and Combinations Update #1 Page 21 of 71

22 in drug-naive type 2 diabetes mellitus patients." Diabetes Obes Metab 13(11): AIM: The purpose of this study was to evaluate if superior glycaemic control could be achieved with Avandamet(R) (rosiglitazone/metformin/avm) compared with metformin (MET) monotherapy, and if glycaemic effects attained with AVM are durable over 18 months of treatment. Bone mineral density (BMD) and bone biomarkers were evaluated in a subgroup of patients. METHODS: This was a phase IV, randomized, double-blind, multi-centre study in 688, drug naive, male and female patients who had an established clinical diagnosis of type 2 diabetes mellitus (T2DM). Patients were randomized in a 1 : 1 ratio either to AVM or MET. RESULTS: As initial therapy in patients with T2DM, AVM was superior to MET in achieving statistically significant reductions in glycated haemoglobin (HbA1c) (p < ) and fasting plasma glucose (FPG) (p < 0.001), with more patients reaching recommended HbA1c and FPG targets for intensive glycaemic control. The glycaemic effects attained with AVM compared to MET monotherapy were durable over 18 months of treatment. In the bone substudy, AVM was associated with a significantly lower BMD in comparison with MET at week 80 in the lumbar spine and total hip (p < and p = , respectively). Between-treatment differences were not statistically significant for distal one-third of radius BMD, femoral neck BMD or total BMD. CONCLUSION: Superior glycaemic control was achieved with AVM compared with MET monotherapy. The superior glycaemic effects were shown to be durable over 18 months of treatment. AVM was associated with a significantly reduced BMD in comparison with MET at week 80 in the lumbar spine and total hip. Bosi, E., G. C. Ellis, et al. (2011). "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, double-blind, active-controlled, parallel-group study." Diabetes Obes Metab 13(12): AIM: To assess the efficacy and safety of adding alogliptin versus uptitrating pioglitazone in patients with type 2 diabetes and inadequate glycaemic control on metformin and pioglitazone. METHODS: In this randomized, double-blind, activecontrolled, parallel-group study, patients with type 2 diabetes and A1c >/=7.0 and </=10.0% on metformin (>/=1500 mg or maximum tolerated dose; Met) and pioglitazone 30 mg (Pio30) received alogliptin 25 mg (Alo25; n = 404) or pioglitazone 15 mg (n = 399) added to Met+Pio30 for 52 weeks. The primary endpoint was change from baseline (CFB) in A1c at weeks 26 and 52, with sequential testing for non-inferiority of Met+Pio30+Alo25 at weeks 26 and 52 and then for superiority at week 52. RESULTS: Met+Pio30+Alo25 showed superior glycaemic control versus Met+Pio45 at week 52 [least squares (LS) mean CFB in A1c, vs %; p < 0.001]. At week 52, Met+Pio30+Alo25 resulted in greater CFB in A1c regardless of baseline A1c (p < 0.001); higher proportions of patients achieving A1c </=7.0 (33.2 vs. 21.3%) and </=6.5% (8.7 vs. 4.3%; p < 0.001); greater CFB in fasting plasma glucose (FPG; LS mean CFB, -0.8 vs mmol/l; p < 0.001); and greater improvements in measures of beta-cell function (p < 0.001). Hypoglycaemia incidence was low (Met+Pio30+Alo25, 4.5%; Met+Pio45, 1.5%), mostly mild to moderate, but with two severe events in the Met+Pio30+Alo25 group. No meaningful differences in incidences of individual adverse events were observed between treatments. CONCLUSIONS: Adding alogliptin to an existing metformin-pioglitazone regimen provided superior glycaemic control and potentially New Diabetes Medications, TZDs, and Combinations Update #1 Page 22 of 71

23 improved beta-cell function versus uptitrating pioglitazone in patients with type 2 diabetes, with no clinically important differences in safety. Bunck, M. C., A. Corner, et al. (2011). "Effects of exenatide on measures of beta-cell function after 3 years in metformin-treated patients with type 2 diabetes." Diabetes Care 34(9): OBJECTIVE: We previously showed that exenatide (EXE) enhanced insulin secretion after 1 year of treatment, relative to insulin glargine (GLAR), with a similar glucoselowering action. These effects were not sustained after a 4-week off-drug period. This article reports the results after additional 2 years of exposure. RESEARCH DESIGN AND METHODS: Sixty-nine metformin-treated patients with type 2 diabetes were randomized to EXE or GLAR. Forty-six patients entered the 2-year extension study in which they continued their allocated therapy. Thirty-six completed (EXE: n = 16; GLAR: n = 20) the 3-year exposure period. Insulin sensitivity (M value) and beta-cell function were measured by euglycemic hyperinsulinemic clamp followed by hyperglycemic clamp with arginine stimulation at pretreatment (week 52) and 4 weeks after discontinuation of study medication (week 56 and week 172). First-phase glucose stimulated C-peptide secretion was adjusted for M value and calculated as the disposition index (DI). RESULTS: At 3 years, EXE and GLAR resulted in similar levels of glycemic control: 6.6 +/- 0.2% and 6.9 +/- 0.2%, respectively (P = 0.186). EXE compared with GLAR significantly reduced body weight (-7.9 +/- 1.8 kg; P < 0.001). After the 4-week off-drug period, EXE increased the M value by 39% (P = 0.006) while GLAR had no effect (P = 0.647). Following the 4-week off-drug period, the DI, compared with pretreatment, increased with EXE, but decreased with GLAR (1.43 +/ and /- 0.65, respectively; P = 0.028). CONCLUSIONS: EXE and GLAR sustained HbA(1c) over the 3-year treatment period, while EXE reduced body weight and GLAR increased body weight. Following the 3-year treatment with EXE, the DI was sustained after a 4-week off-drug period. These findings suggest a beneficial effect on beta-cell health. DeFronzo, R. A., C. F. Burant, et al. (2012). "Efficacy and tolerability of the DPP-4 inhibitor alogliptin combined with pioglitazone, in metformin-treated patients with type 2 diabetes." J Clin Endocrinol Metab 97(5): CONTEXT: Optimal management of type 2 diabetes remains an elusive goal. Combination therapy addressing the core defects of impaired insulin secretion and insulin resistance shows promise in maintaining glycemic control. OBJECTIVE: The aim of the study was to assess the efficacy and tolerability of alogliptin combined with pioglitazone in metformin-treated type 2 diabetic patients. DESIGN, SETTING, AND PATIENTS: We conducted a multicenter, randomized, double-blind, placebo-controlled, parallel-arm study in patients with type 2 diabetes. INTERVENTIONS: The study consisted of 26-wk treatment with alogliptin (12.5 or 25 mg qd) alone or combined with pioglitazone (15, 30, or 45 mg qd) in 1554 patients on stable-dose metformin monotherapy (>/=1500 mg) with inadequate glycemic control. MAIN OUTCOME MEASURE: The primary endpoint was change in glycosylated hemoglobin (HbA(1c)) from baseline to wk 26. Secondary endpoints included changes in fasting plasma glucose and beta-cell function. Primary analyses compared pioglitazone therapy [all doses pooled, pioglitazone alone (Pio alone); n = 387] with alogliptin 12.5 mg plus any dose of pioglitazone (A12.5+P; n = 390) or alogliptin 25 mg plus any dose of pioglitazone (A25+P; n = 390). RESULTS: When New Diabetes Medications, TZDs, and Combinations Update #1 Page 23 of 71

24 added to metformin, the least squares mean change (LSMDelta) from baseline HbA(1c) was /- 0.05% in the Pio-alone group and /- 0.05% in both the A12.5+P and A25+P groups (P < for both comparisons). A12.5+P and A25+P produced greater reductions in fasting plasma glucose (LSMDelta = /- 0.1 mmol/liter for both) than Pio alone (LSMDelta = /- 0.1 mmol/liter; P < 0.001). A12.5+P and A25+P significantly improved measures of beta-cell function (proinsulin:insulin and homeostasis model assessment of beta-cell function) compared to Pio alone, but had no effect on homeostasis model assessment of insulin resistance. The LSMDelta body weight was 1.8 +/- 0.2, 1.9 +/- 0.2, and 1.5 +/- 0.2 kg in A12.5+P, A25+P, and Pio-alone groups, respectively. Hypoglycemia was reported by 1.0, 1.5, and 2.1% of patients in the A12.5+P, A25+P, and Pio-alone groups, respectively. CONCLUSIONS: In type 2 diabetic patients inadequately controlled by metformin, the reduction in HbA(1c) by alogliptin and pioglitazone was additive. The decreases in HbA(1c) with A12.5+P and A25+P were similar. All treatments were well tolerated. Derosa, G., P. Maffioli, et al. (2010). "Effects of one year treatment of vildagliptin added to pioglitazone or glimepiride in poorly controlled type 2 diabetic patients." Horm Metab Res 42(9): The aim of the study was to compare the effects of vildagliptin added to pioglitazone or glimepiride on metabolic and insulin resistance related-indices in poorly controlled type 2 diabetic patients (T2DM). 168 patients with T2DM were randomized to take either pioglitazone 30 mg once a day plus vildagliptin 50 mg twice a day or glimepiride 2 mg 3 times a day plus vildagliptin 50 mg twice a day. We evaluated body weight, body mass index (BMI), glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), postprandial plasma glucose (PPG), fasting plasma insulin (FPI), homeostasis model assessment insulin resistance index (HOMA-IR), homeostasis model assessment beta-cell function index (HOMA-beta), fasting plasma proinsulin (FPPr), proinsulin/fasting plasma insulin ratio (Pr/FPI ratio), adiponectin (ADN), resistin (R), tumor necrosis factor-alpha (TNFalpha), and high sensitivity C-reactive protein (Hs-CRP) at their baseline values, and after 3, 6, 9, and 12 months of treatment. We observed a similar improvement of HbA1c, FPG, PPG, and Hs-CRP compared to baseline in the 2 groups. Fasting plasma insulin, FPPr, Pr/FPI ratio, R, and TNF-alpha were significantly decreased and ADN was significantly increased with pioglitazone plus vildagliptin, but not with glimepiride plus vildagliptin. HOMA-IR, and HOMA-beta values obtained with pioglitazone plus vildagliptin were significantly better than the values obtained with glimepiride plus vildagliptin. Pioglitazone plus vildagliptin were found to be more effective in preserving beta-cell function, and in reducing insulin resistance, and inflammatory state parameters. Derosa, G., R. Mereu, et al. (2010). "Effect of pioglitazone and acarbose on endothelial inflammation biomarkers during oral glucose tolerance test in diabetic patients treated with sulphonylureas and metformin." Journal of Clinical Pharmacy & Therapeutics 35(5): WHAT IS KNOWN: The increased risk of cardiovascular events in diabetic patients has been related to numerous metabolic and haemoreological factors. Some of these factors appear to be particularly evident during the post-prandial phases and to be related to peak plasma glucose level. AIM: To compare the effect of addition of pioglitazone and acarbose to sulphonylureas and metformin therapy on metabolic parameters and on New Diabetes Medications, TZDs, and Combinations Update #1 Page 24 of 71

25 markers of endothelial dysfunction and vascular inflammation in type 2 diabetic patients. MATERIALS AND METHODS: We enrolled 473 caucasian type 2 diabetic patients. All patients underwent measurements of height and body weight, body mass index (BMI), glycated haemoglobin (HbA1c), fasting plasma glucose (FPG), post-prandial plasma glucose (PPG), fasting plasma insulin (FPI), post-prandial plasma insulin (PPI), homeostasis model assessment (HOMA index), systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol (TC), low density lipoprotein-cholesterol (LDL- C), high density lipoprotein-cholesterol (HDL-C), triglycerides (Tg), sicam-1, IL-6, high-sensitivity C reactive protein (hscrp), svcam-1, se-selectin and tumour necrosis factor (TNF-alpha). Assessments were made at start of titration, after 3 months [before a first oral glucose tolerance test (OGTT)], after 6 months and at the study end (before a second OGTT). RESULTS: Two-hundred and seventy four patients completed the study: 138 were randomized to double-blind treatment with pioglitazone and 136 with acarbose. Significant BMI and weight increase were observed after full treatment in the pioglitazone group relative to the acarbose group. A decrease in glycated haemoglobin was observed after the titration period in the pioglitazone group compared to both baseline value and the acarbose group. A decrease in glycated haemoglobin was also obtained after full treatment in the pioglitazone group when compared to the end of titration period and to the acarbose group. Significant decrease in FPG was obtained in the pioglitazone group after full treatment compared to the end of titration period. Postprandial plasma glucose decrease was observed in acarbose group compared to the baseline value and to the end of titration period. Fasting plasma insulin decreased in the pioglitazone group after both the titration period and the full treatment period compared to both the baseline value and the acarbose group. The HOMA index decreased significantly after the full treatment in pioglitazone group compared to the end of titration period and to the acarbose group. Interleukin-6 and tumour necrosis factor-alpha decreased after full treatment in the pioglitazone group relative to the end of titration period. Significant hscrp decrease was obtained after the titration period when compared to the baseline value in the pioglitazone group. High-sensitivity C reactive protein decreased in the pioglitazone group after full treatment compared to the end of titration period and to the acarbose group. WHAT IS NEW AND CONCLUSION: Pioglitazone reduces the inflammatory response to a glucose challenge more than acarbose in type 2 diabetic patients, already treated with maximal doses of sulphonylureas and metformin. Derosa, G., P. Putignano, et al. (2011). "Exenatide or glimepiride added to metformin on metabolic control and on insulin resistance in type 2 diabetic patients." Eur J Pharmacol 666(1-3): The aim of this study was to evaluate the effect of exenatide compared to glimepiride on body weight, glycemic control and insulin resistance in type 2 diabetic patients taking metformin. One hundred and eleven patients with uncontrolled type 2 diabetes mellitus and intolerant to metformin at the highest dosages ( mg/day) were enrolled in this study. Patients were randomized to receive exenatide 5 mug twice a day or glimepiride 1mg three times a day and titrated after 1 month to exenatide 10 mug twice a day or glimepiride 2mg three times a day for 12 months in a randomized, single-blind, controlled study. We evaluated at the baseline and after 3, 6, 9, and 12 months these New Diabetes Medications, TZDs, and Combinations Update #1 Page 25 of 71

26 parameters: body weight, body mass index (BMI), HbA(1c), glycemic control, fasting plasma insulin, homeostasis model assessment insulin resistance index (HOMA-IR) index, adiponectin, tumor necrosis factor-alpha, and high sensitivity-c reactive protein. Both treatments gave a similar improvement of glycemic control, without any differences between the two groups. Only exenatide gave a decrease of BMI, insulin resistance parameters such as fasting plasma insulin, HOMA-IR, and adiponectin and a decrease of inflammatory parameters such as tumor necrosis factor-alpha, and high sensitivity-c reactive protein. Furthermore, the values obtained with exenatide were significantly better than the values recorded with glimepiride. We can conclude that exenatide was better than glimepiride in improving insulin resistance and inflammatory state. Furthermore, adiponectin increase, and tumor necrosis factor-alpha reduction seem to be related to weight loss obtained with exenatide. Diamant, M., L. Van Gaal, et al. (2012). "Safety and efficacy of once-weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes over 84 weeks." Diabetes Care 35(4): OBJECTIVE: We recently reported that after 26 weeks, exenatide once weekly (EQW) resulted in superior A1C reduction, reduced hypoglycemia, and progressive weight loss compared with daily insulin glargine (IG) in patients with type 2 diabetes who were taking metformin alone or with sulfonylurea. This 84-week extension study assessed the long-term safety and efficacy of EQW versus IG. RESEARCH DESIGN AND METHODS: This multicenter, open-label, randomized, two-arm, parallel trial assessed change in A1C, proportions of patients achieving A1C <7.0 and </=6.5%, body weight, incidence of hypoglycemia, and overall safety. RESULTS: Of 415 patients who completed 26 weeks, 390 (194 EQW and 196 IG patients) entered the extension study. At 84 weeks, A1C decreased from baseline (8.3%) by -1.2% for EQW vs. -1.0% for IG (P = 0.029). The proportions of patients who achieved end point A1C targets <7.0 and </=6.5% were 44.6% for EQW patients vs. 36.8% for IG patients (P = 0.084) and 31.3% for EQW patients vs. 20.2% for IG patients (P = 0.009), respectively. Patients taking EQW lost 2.1 kg of body weight, whereas those taking IG gained 2.4 kg (P < 0.001). Among patients taking metformin plus sulfonylurea, the incidence of minor hypoglycemia was 24% for EQW patients vs. 54% for IG patients (P < 0.001); among patients taking metformin alone, it was 8% for EQW patients vs. 32% for IG patients (P < 0.001). Among adverse events occurring in >/=5% of patients, diarrhea and nausea occurred more frequently (P < 0.05) in the EQW group than in the IG group (12 vs. 6% and 15 vs. 1%, respectively). CONCLUSIONS: After 84 weeks, patients treated with EQW continued to experience better glycemic control with sustained overall weight loss and a lower risk of hypoglycemia than patients treated with IG. Diamant, M., L. Van Gaal, et al. (2010). "Once weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes (DURATION-3): an open-label randomised trial." Lancet 375(9733): BACKGROUND: Diabetes treatments are needed that are convenient, provide effective glycaemic control, and do not cause weight gain. We aimed to test the hypothesis that improvement in haemoglobin A(1c) (HbA(1c)) achieved with once weekly exenatide was superior to that achieved with insulin glargine titrated to glucose targets. METHODS: In New Diabetes Medications, TZDs, and Combinations Update #1 Page 26 of 71

27 this 26-week, open-label, randomised, parallel study, we compared exenatide with insulin glargine in adults with type 2 diabetes who had suboptimum glycaemic control despite use of maximum tolerated doses of blood-glucose-lowering drugs for 3 months or longer. Patients were randomly assigned to add exenatide (2 mg, once-a-week injection) or insulin glargine (once-daily injection, starting dose 10 IU, target glucose range mmol/l) to their blood-glucose-lowering regimens. Randomisation was with a one-toone allocation and block size four, stratified according to country and concomitant treatment (70% metformin only; 30% metformin plus sulphonylurea). Participants and clinical investigators were not masked to assignment, but investigators analysing data were. The primary endpoint was change in HbA(1c) from baseline, and analysis of this outcome was by modified intention to treat for all patients who received at least one dose of study drug. This trial is registered at ClinicalTrials.gov, number NCT FINDINGS: 456 patients were randomly allocated to treatment and were included in the modified intention-to-treat analysis (233 exenatide, 223 insulin glargine). Participants who received at least one dose of study drug and for whom baseline and at least one postbaseline measurement of HbA(1c) were available were included in the primary efficacy analysis. Change in HbA(1c) at 26 weeks was greater in patients taking exenatide (n=228; -1.5%, SE 0.05) than in those taking insulin glargine (n=220; -1.3%, 0.06; treatment difference -0.16%, 0.07, 95% CI to -0.03). 12 (5%) of 233 patients allocated to exenatide and two (1%) of 223 taking insulin glargine discontinued participation because of adverse events (p=0.012). A planned extension period (up to 2.5 years' duration) is in progress. INTERPRETATION: Once weekly exenatide is an important therapeutic option for patients for whom risk of hypoglycaemia, weight loss, and convenience are particular concerns. FUNDING: Amylin Pharmaceuticals; Eli Lilly and Company. Fidan, E., H. Onder Ersoz, et al. (2011). "The effects of rosiglitazone and metformin on inflammation and endothelial dysfunction in patients with type 2 diabetes mellitus." Acta Diabetol 48(4): Diabetic patients have a markedly increased risk of cardiovascular disease compared with non-diabetics. Two drug groups today target insulin resistance; biguanides and thiazolidinediones. In addition, these may have other effects on cardiovascular risk factors. The aim of this study was to evaluate the effects of metformin and rosiglitazone on non-traditional cardiovascular risk factors. Forty type 2 diabetic patients were randomized into metformin and rosiglitazone groups. After receiving the optimal doses, the patients were monitored for 12 weeks. Biochemical parameters, lipid parameters, CRP, insulin, c-peptide, and HbA1c levels were analyzed. VWF, PAI-1, ICAM-1, TNFalpha, IL-6, E-selectin, and fibrinogen levels were measured in order to assess coagulation status and endothelial dysfunction. In the metformin group, body mass index, PPG, HbA1c, IL-6, ICAM-1, and TNF-alpha levels were significantly decreased after 12 weeks compared with the basal levels. IL-6 levels decreased from 75 pg/ml +/- 20 to 42 pg/ml +/- 9 (P 0.023) and TNF- alpha levels from 61 pg/ml +/- 31 to 39 pg/ml +/- 10 (P 0.018). In the rosiglitazone group, FPG, PPG, HbA1c, insulin, HOMA-IR, IL-6, and TNF-alpha levels decreased significantly after 12 weeks compared with the basal levels. IL-6 levels decreased from 78 pg/ml +/- 21 to 41 pg/ml +/- 9 (P 0.028) and TNF-alpha levels from 62 pg/ml +/- 19 to 37 pg/ml +/- 10 (P 0.012). At the end of the study, no New Diabetes Medications, TZDs, and Combinations Update #1 Page 27 of 71

28 significant differences were determined between groups. Insulin resistance and type 2 diabetes are strongly associated with low grade inflammation. Both metformin and rosiglitazone were effective in controlling inflammatory markers in addition to metabolic parameters. Fonseca, V., T. Zhu, et al. (2012). "Adding saxagliptin to extended-release metformin vs. uptitrating metformin dosage." Diabetes Obes Metab 14(4): AIM: To investigate whether patients taking metformin for type 2 diabetes mellitus (T2DM) have improved glycaemic control without compromising tolerability by adding an agent with a complementary mechanism of action vs. uptitrating metformin. METHODS: Adults with T2DM and glycated haemoglobin (HbA1c) between 7.0 and 10.5% receiving metformin extended release (XR) 1500 mg/day for >/=8 weeks were randomized to receive saxagliptin 5 mg added to metformin XR 1500 mg (n = 138) or metformin XR uptitrated to 2000 mg/day (n = 144). Endpoints were change from baseline to week 18 in HbA1c (primary), 120-min postprandial glucose (PPG), fasting plasma glucose (FPG) and the proportion of patients achieving HbA1c <7%. RESULTS: At week 18, the adjusted mean reduction from baseline HbA1c was -0.88% for saxagliptin + metformin XR and -0.35% for uptitrated metformin XR (difference, -0.52%; p < ). For 120-min PPG and FPG, differences in adjusted mean change from baseline between saxagliptin + metformin XR and uptitrated metformin XR were -1.3 mmol/l ( mg/dl) (p = ) and mmol/l ( mg/dl) (p = ), respectively. More patients achieved HbA1c <7.0% with saxagliptin + metformin XR than with uptitrated metformin XR (37.2 vs. 26.1%; p = ). The proportions of patients experiencing any adverse events (AEs) were generally similar between groups; neither group showed any notable difference in hypoglycaemia or gastrointestinal AEs. CONCLUSION: Adding saxagliptin to metformin XR provided superior glycaemic control compared with uptitrating metformin XR without the emergence of additional safety concerns. Forst, T., M. M. Weber, et al. (2010). "Pioglitazone in addition to metformin improves erythrocyte deformability in patients with Type 2 diabetes mellitus." Clin Sci (Lond) 119(8): The aim of the present study was to compare the effect of PIO (pioglitazone) or GLIM (glimepiride) on erythrocyte deformability in T2DM (Type 2 diabetes mellitus). The study covered 23 metformin-treated T2DM patients with an HbA1c (glycated haemoglobin) >6.5%. Patients were randomized to receive either PIO (15 mg, twice a day) or GLIM (1 mg, twice a day) in combination with metformin (850 mg, twice a day) for 6 months. Blood samples were taken for the measurement of fasting glucose, HbA1c, fasting insulin, intact proinsulin, adiponectin and Hct (haematocrit). In addition, the erythrocyte EI (elongation index) was measured using laser diffractoscopy. Both treatments significantly improved HbA1c levels (PIO, -0.9+/-1.1%; GLIM, -0.6+/-0.4%; both P<0.05) and resulted in comparable HbA1c levels after 6 months (PIO, 6.5+/-1.2%; GLIM, 6.2+/-0.4%) Treatment with PIO reduced fasting insulin levels (-8.7+/-15.8 milliunits/l; P=0.098), intact proinsulin levels (-11.8+/-9.5 pmol/l; P<0.05) and Hct (-1.3+/- 2.3%; P=0.09), whereas adiponectin levels increased (8.2+/-4.9 microg/ml; P<0.05). No significant change in these parameters was observed during GLIM treatment. PIO improved the EI, resulting in a significant increase in EI at all physiological shear stress New Diabetes Medications, TZDs, and Combinations Update #1 Page 28 of 71

29 ranges ( Pa; P<0.05). The improvement in EI correlated with the increase in adiponectin levels (r=0.74; P<0.001), and inversely with intact proinsulin levels (r=-0.47; P<0.05). This is the first study showing an improvement in EI during treatment with PIO, which was associated with an increase in adiponectin and a decrease in intact proinsulin levels, but independent of glycaemic control. Fujitaka, K., H. Otani, et al. (2011). "Comparison of metabolic profile and adiponectin level with pioglitazone versus voglibose in patients with type-2 diabetes mellitus associated with metabolic syndrome." Endocr J 58(6): Type 2 diabetes mellitus (T2DM) associated with metabolic syndrome (MetS) represents a high risk of cardiovascular disease. We compared the effect of early intervention with pioglitazone versus voglibose on physical and metabolic profiles and serum adiponectin level in patients with T2DM associated with MetS. Sixty patients who were diagnosed for the first time as T2DM associated with MetS were analyzed for insulin sensitivity, lipid profile, serum adiponectin and systemic inflammation. Those patients were randomly assigned to oral pioglitazone group (n = 30) or voglibose group (n = 30) in addition to conventional diet and exercise training. Body mass index and waist circumference did not change in the pioglitazone group, whereas these physical parameters significantly decreased in the voglibose group during a 6-month follow-up period. However, glycosylated hemoglobin, fasting plasma glucose, and HOMA-IR more significantly decreased in the pioglitazone group. The level of serum adiponectin especially highmolecular weight adiponectin markedly increased in the pioglitazone group. Moreover, high sensitive CRP significantly decreased only in the pioglitazone group. These results suggest that voglibose is superior in improving obesity, while pioglitazone is superior in ameliorating insulin sensitivity and increasing serum adiponectin in patients with an early stage of T2DM associated with MetS. Gallwitz, B., M. Bohmer, et al. (2011). "Exenatide twice daily versus premixed insulin aspart 70/30 in metformin-treated patients with type 2 diabetes: a randomized 26-week study on glycemic control and hypoglycemia." Diabetes Care 34(3): OBJECTIVE: Hypoglycemia causes recurrent morbidity in patients with type 2 diabetes. This study evaluated if exenatide twice daily (BID) was noninferior to premixed insulin aspart 70/30 BID (PIA) for glycemic control and associated with less hypoglycemia. RESEARCH DESIGN AND METHODS: In this open-label study, metformin-treated adults with type 2 diabetes were randomized to 26-week treatment with exenatide BID (4 weeks 5 mug, then 10 mug) or PIA. RESULTS: Exenatide BID (n = 181) was noninferior to PIA (n = 173) for A1C control (least squares [LS] mean change -1.0 vs %; difference [95% CI] 0.14 [ to 0.291]) and associated with a lower risk for hypoglycemia (8.0 vs. 20.5%, P < 0.05). LS mean weight decreased by 4.1 kg and increased by 1.0 kg with PIA (P < 0.001). A total of 39.2 vs. 20.8% of patients reached the composite end point of A1C <7.0%, no weight gain, and no hypoglycemia (P < 0.001; post hoc analysis). CONCLUSIONS: In metformin-treated patients, exenatide BID was noninferior to PIA for glycemic control but superior for hypoglycemia and weight control. Gallwitz, B., J. Guzman, et al. (2012). "Exenatide twice daily versus glimepiride for prevention New Diabetes Medications, TZDs, and Combinations Update #1 Page 29 of 71

30 of glycaemic deterioration in patients with type 2 diabetes with metformin failure (EUREXA): an open-label, randomised controlled trial." Lancet 379(9833): BACKGROUND: Glycaemic control deteriorates progressively over time in patients with type 2 diabetes. Options for treatment escalation remain controversial after failure of first-line treatment with metformin. We compared add-on exenatide with glimepiride for durability of glycaemic control in patients with type 2 diabetes inadequately controlled by metformin alone. METHODS: We did an open-label, randomised controlled trial at 128 centres in 14 countries between Sept 5, 2006, and March 29, Patients aged years with type 2 diabetes inadequately treated by metformin were randomly assigned via a computer-generated randomisation sequence to receive exenatide twice daily or glimepiride once daily as add-on to metformin. Randomisation was stratified by predetermined categories of glycated haemoglobin (HbA(1C)) concentration. The primary outcome was time to inadequate glycaemic control and need for alternative treatment, defined as an HbA(1c) concentration of more than 9% after the first 3 months of treatment, or more than 7% at two consecutive visits after the first 6 months. Analysis was by intention to treat. This trial is registered with EudraCT, number , and ClinicalTrials.gov, number NCT FINDINGS: We randomly assigned 515 patients to the exenatide group and 514 to the glimepiride group, of whom 490 versus 487 were the intention-to-treat population. 203 (41%) patients had treatment failure in the exenatide group compared with 262 (54%) in the glimepiride group (risk difference 12.4 [95% CI ], hazard ratio [ ]; p=0.002). 218 (44%) of 490 patients in the exenatide group, and 150 (31%) of 487 in the glimepiride group achieved an HbA(1c) concentration of less than 7% (p<0.0001), and 140 (29%) versus 87 (18%) achieved concentrations of 6.5% and less (p=0.0001). We noted a significantly greater decrease in bodyweight in patients given exenatide than in those given glimepiride (p<0.0001). Five patients in each treatment group died from causes unrelated to treatment. Significantly fewer patients in the exenatide group than in the glimepiride group reported documented symptomatic (p<0.0001), nocturnal (p=0.007), and nonnocturnal (p<0.0001) hypoglycaemia. Discontinuation because of adverse events (mainly gastrointestinal) was significantly higher (p=0.0005) in the exenatide group than in the glimepiride group in the first 6 months of treatment, but not thereafter. INTERPRETATION: These findings provide evidence for the benefits of exenatide versus glimepiride for control of glycaemic deterioration in patients with type-2 diabetes inadequately controlled by metformin alone. FUNDING: Eli Lilly and Company; Amylin Pharmaceuticals. Garber, A., R. R. Henry, et al. (2011). "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 13(4): AIMS: Most treatments for type 2 diabetes fail over time, necessitating combination therapy. We investigated the safety, tolerability and efficacy of liraglutide monotherapy compared with glimepiride monotherapy over 2 years. METHODS: Participants were randomized to receive once-daily liraglutide 1.2 mg, liraglutide 1.8 mg or glimepiride 8 mg. Participants completing the 1-year randomized, double-blind, double-dummy period could continue open-label treatment for an additional year. Safety data were evaluated for New Diabetes Medications, TZDs, and Combinations Update #1 Page 30 of 71

31 the full population exposed to treatment, and efficacy data were evaluated for the full intention-to-treat (ITT) and 2-year completer populations. Outcome measures included change in glycosylated haemoglobin (HbA1c), fasting plasma glucose (FPG), body weight and frequency of nausea and hypoglycaemia. RESULTS: For patients completing 2 years of therapy, HbA1c reductions were -0.6% with glimepiride versus -0.9% with liraglutide 1.2 mg (difference: -0.37, 95% CI: to -0.02; p = ) and -1.1% with liraglutide 1.8 mg (difference: -0.55, 95% CI: to -0.21; p = ). In the ITT population, HbA1c reductions were -0.3% with glimepiride versus -0.6% with liraglutide 1.2 mg (difference: -0.31, 95% CI: to -0.08; p = ) and -0.9% with liraglutide 1.8 mg (difference: -0.60, 95% CI: to -0.38; p < ). For both ITT and completer populations, liraglutide was more effective in reducing HbA1c, FPG and weight. Over 2 years, rates of minor hypoglycaemia [self-treated plasma glucose <3.1 mmol/l (<56 mg/dl)] were significantly lower with liraglutide 1.2 mg and 1.8 mg compared with glimepiride (p < ). CONCLUSION: Liraglutide monotherapy for 2 years provides significant and sustained improvements in glycaemic control and body weight compared with glimepiride monotherapy, at a lower risk of hypoglycaemia. Goke, B., B. Gallwitz, et al. (2010). "Saxagliptin is non-inferior to glipizide in patients with type 2 diabetes mellitus inadequately controlled on metformin alone: a 52-week randomised controlled trial." Int J Clin Pract 64(12): AIM: To assess the efficacy and safety of saxagliptin vs. glipizide as add-on therapy to metformin in patients with type 2 diabetes mellitus and inadequate glycaemic control on metformin alone. METHODS AND PATIENTS: A total of 858 patients [age >/= 18 years; glycated haemoglobin (HbA(1c) ) > %; on stable metformin doses >/= 1500 mg/day] were randomised 1 : 1 to saxagliptin 5 mg/day or glipizide up-titrated as needed from 5 to 20 mg/day for 52 weeks. The primary objective was to assess if the change from baseline HbA(1c) achieved with saxagliptin plus metformin was noninferior to glipizide plus metformin. RESULTS: The per-protocol analysis demonstrated non-inferiority of saxagliptin vs. glipizide; adjusted mean changes from baseline HbA(1c) were -0.74% vs %, respectively; the between-group difference was 0.06% (95% CI, -0.05% to 0.16%). Treatment with saxagliptin vs. glipizide was associated with a significantly smaller proportion of patients with hypoglycaemic events (3.0% vs. 36.3%; p < ) and a divergent impact on body weight (adjusted mean change from baseline -1.1 kg with saxagliptin vs. 1.1 kg with glipizide; p < ). There was a significantly smaller rise in HbA(1c) (%/week) from week 24 to 52 with saxagliptin vs. glipizide (0.001% vs %; p = 0.04) indicating a sustained glycaemic effect beyond week 24. Excluding hypoglycaemic events, the proportion of patients experiencing adverse events (AEs) was similar (60.0% saxagliptin vs. 56.7% glipizide); treatmentrelated AEs were less common with saxagliptin vs. glipizide (9.8% vs. 31.2%), attributable to the higher frequency of hypoglycaemia in glipizide patients. Discontinuation rates resulting from AEs were similar ( approximately 4%). CONCLUSION: Saxagliptin plus metformin was well tolerated, provided a sustained HbA(1c) reduction over 52 weeks, and was non-inferior to glipizide plus metformin, with reduced body weight and a significantly lower risk of hypoglycaemia. Gram, J., J. E. Henriksen, et al. (2011). "Pharmacological treatment of the pathogenetic defects New Diabetes Medications, TZDs, and Combinations Update #1 Page 31 of 71

32 in type 2 diabetes: the randomized multicenter South Danish Diabetes Study." Diabetes Care 34(1): OBJECTIVE: To determine the effect of treatment with insulin aspart compared with NPH insulin, together with metformin/placebo and rosiglitazone/placebo. The hypothesis was that combined correction of major pathogenetic defects in type 2 diabetes would result in optimal glycemic control. RESEARCH DESIGN AND METHODS: This study was a 2-year investigator-driven randomized partly placebo-controlled multicenter trial in 371 patients with type 2 diabetes on at least oral antiglycemic treatment. Patients were assigned to one of eight treatment groups in a factorial design with insulin aspart at mealtimes versus NPH insulin once daily at bedtime, metformin twice daily versus placebo, and rosiglitazone twice daily versus placebo. The main outcome measurement was change in A1C. RESULTS: A1C decreased more in patients treated with insulin aspart compared with NPH ( /- 0.10%, P < 0.001). Metformin decreased A1C compared with placebo ( /- 0.10%, P < 0.001), as did rosiglitazone ( /- 0.10%, P < 0.001). Triple therapy (rosiglitazone, metformin, and any insulin) resulted in a greater reduction in A1C than rosiglitazone plus insulin ( /- 0.14%, P < 0.001) and metformin plus insulin ( /- 0.14%, P < 0.001). Aspart was associated with a higher increase in body weight (1.6 +/- 0.6 kg, P < 0.01) and higher incidence of mild daytime hypoglycemia (4.9 +/- 7.5 vs /- 5.4 number/person/year, P < 0.001) compared with NPH. CONCLUSIONS: Insulin treatment of postprandial hyperglycemia results in lower A1C than treatment of fasting hyperglycemia, at the expense of higher body weight and hypoglycemic episodes. However, insulin therapy has to be combined with treatment of both peripheral and liver insulin resistance to normalize blood glucose, and in this case, the insulin regimen is less important. Hanefeld, M., A. Pfutzner, et al. (2011). "Double-blind, randomized, multicentre, and active comparator controlled investigation of the effect of pioglitazone, metformin, and the combination of both on cardiovascular risk in patients with type 2 diabetes receiving stable basal insulin therapy: the PIOCOMB study." Cardiovasc Diabetol 10(65. BACKGROUND: We analyzed specific effects of an add-on therapy with pioglitazone compared to metformin and their combination in patients with basal insulin treatment on biomarkers of CV risk. METHODS: In this double-blind, randomized, multicentre, active comparator controlled trial, 121 patients with type 2 diabetes were enrolled. Inclusions: treatment with basal insulin, HbA(1C) 6.5%-8.5%, age years. After glargine therapy over 2 weeks for titration towards FBG </= 7.8 mmol/l, patients received either (A) bid 850 mg metformin (n = 42), (B) bid 15 mg pioglitazone (n = 40), or (C) 30 mg pioglitazone plus 1.7 g metformin (n = 39) over 6 months. Matrix Metal Proteinase 9 (MMP-9) was primary objective, together with biomarkers of CV risk. RESULTS: Pioglitazone (B) reduced MMP-9 versus baseline by / ng/ml, with metformin (A) it was increased by / ng/ml (p = ; B vs. A), and with the combination of both (C) it was decreased by / ng/ml (A vs. C: p = ; B vs. C: p = ). After logarithmic transformation due to high variances the exploratory results showed significance for A vs. B (p = ) and for A vs. C (p = ).Insulin dosage was reduced by 7.3 units in group B (p < ), by 6.0 units in C (p = ), but was increased by 2.5 units (p = ) in A at follow up. Reduction in hs-crp was significant within treatment groups for B (p = ) and C (p < ), New Diabetes Medications, TZDs, and Combinations Update #1 Page 32 of 71

33 and between the groups for A vs. C (p = ). All three single regimens reduced PAI- 1. Adiponectin was significantly elevated in B and C (p < ) and between-groups. HbA(1C) was only significantly decreased in the combination group. No significant effects were observed for NFkB and PGFalpha. peripheral edema were seen in 11.9% vs. 40.0% vs. 20.5%, and weight change was -0.7 kg vs kg vs kg (A vs. B vs. C). CONCLUSIONS: Addition of pioglitazone but not of metformin reduces MMP-9, hs- CRP and increased insulin sensitivity and adiponectin in this study. The combination of both had no additional effect on inflammation. Pioglitazone is suggested to be a rational add-on therapy to basal insulin in patients with high CV risk. Hong, E. S., A. R. Khang, et al. (2012). "Comparison between sitagliptin as add-on therapy to insulin and insulin dose-increase therapy in uncontrolled Korean type 2 diabetes: CSI study." Diabetes Obes Metab 14(9): AIM: Individuals requiring insulin therapy for type 2 diabetes often require escalation of their regimen to achieve glycaemic control. Optimal management strategies for uncontrolled type 2 diabetes would improve glycaemic control without hypoglycaemia and weight gain. This study compared the efficacy and tolerability of adding sitagliptin, an oral dipeptidyl peptidase-4 inhibitor, and an up to 20% increase in insulin dose in patients with uncontrolled type 2 diabetes on insulin therapy. METHODS: We conducted a 24-week, randomized, active-competitor, parallel-group study in subjects with uncontrolled type 2 diabetes [haemoglobin A1c (HbA1c) = %] currently using insulin therapy. Subjects were randomly assigned to either the sitagliptin adding (100 mg daily, n = 70) or an insulin-increasing arm (>/= 10% at week 12 and >/= 10% at week 24, n = 70) while continuing other medications. RESULTS: Average baseline HbA1c was 9.2% in both groups. HbA1c decreased more at 24 weeks in the sitagliptin adding than the insulin-increasing arm (-0.6 +/- 0.1% vs /- 0.1%, p < 0.01). Insulin was increased by 25% at 24 weeks in the insulin-increasing group. Hypoglycaemic events were less common and less severe in sitagliptin adding arm than insulin-increasing arm (7.0 vs events per patient-year, p < 0.05). Weight was stable in the sitagliptin adding subjects (68.6 +/ vs / kg) but increased in the insulin-increasing subjects (66.2 +/ vs /- 9.7 kg, p < 0.05). Other adverse events occurred at similar rates in both arms. CONCLUSIONS: Compared to a 25% increase in insulin dose, adding sitagliptin to an insulin-based regimen was more effective at lowering HbA1c and associated with less hypoglycaemia and weight gain over 24 weeks. Clinical trial number: NCT Iwamoto, Y., N. Tajima, et al. (2010). "Efficacy and safety of sitagliptin monotherapy compared with voglibose in Japanese patients with type 2 diabetes: a randomized, double-blind trial." Diabetes Obes Metab 12(7): OBJECTIVE: To compare the efficacy and safety of sitagliptin (a dipeptidyl peptidase-4 inhibitor) and voglibose (an alpha-glucosidase inhibitor) monotherapy in Japanese patients with type 2 diabetes who have inadequate glycaemic control (HbA1c > or =6.5% and <10.0%) on diet and exercise. METHODS: In a multi-center, randomized, doubleblind, parallel-group study, 319 patients were randomized (1:1) to 12-week treatment with sitagliptin 50 mg once daily or voglibose 0.2 mg thrice daily before meals. The primary analysis assessed whether sitagliptin was non-inferior to voglibose in lowering New Diabetes Medications, TZDs, and Combinations Update #1 Page 33 of 71

34 HbA1c. RESULTS: After 12 weeks, sitagliptin was non-inferior to voglibose for HbA1clowering efficacy. Furthermore, sitagliptin was superior to voglibose, providing significantly greater reductions in HbA1c from baseline [least squares mean changes in HbA1c [95% confidence intervals (CI)] = -0.7% (-0.8 to -0.6) and -0.3% (-0.4 to -0.2), respectively; between-group difference = -0.4% (-0.5 to -0.3), p < 0.001]. Sitagliptin was also superior to voglibose on other key efficacy endpoints, including change from baseline in 2-h postmeal glucose (-2.8 mmol/l vs mmol/l, p < 0.001) and fasting plasma glucose (-1.1 mmol/l vs mmol/l, p < 0.001). After 12 weeks, the incidences of clinical adverse experiences (AEs), drug-related AEs and gastrointestinal AEs in the sitagliptin group (48.5, 10.4 and 18.4%, respectively) were significantly (p < 0.05) lower than those in the voglibose group (64.7, 26.3 and 34.6%, respectively). The incidences of hypoglycaemia, serious AEs and discontinuations due to AEs were low and similar in both groups. CONCLUSIONS: In Japanese patients with type 2 diabetes, once-daily sitagliptin monotherapy showed greater efficacy and better tolerability than thrice-daily voglibose over 12 weeks. Jonker, J. T., Y. Wang, et al. (2010). "Pioglitazone decreases plasma cholesteryl ester transfer protein mass, associated with a decrease in hepatic triglyceride content, in patients with type 2 diabetes." Diabetes Care 33(7): OBJECTIVE: Thiazolidinediones reduce hepatic steatosis and increase HDL cholesterol levels. In mice with human-like lipoprotein metabolism (APOE*3-Leiden.CETP transgenic mice), a decrease in hepatic triglyceride content is associated with a decrease in plasma cholesteryl ester transfer protein (CETP) mass and an increase in HDL levels. Therefore, the aim of the present study was to assess the effects of pioglitazone on CETP mass in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: We included 78 men with type 2 diabetes (aged /- 0.6 years; HbA1c 7.1 +/- 0.1%) who were randomly assigned to treatment with pioglitazone (30 mg/day) or metformin (2000 mg/day) and matching placebo, in addition to glimepiride. At baseline and after 24 weeks of treatment plasma HDL cholesterol levels and CETP mass were measured, and hepatic triglyceride content was assessed by proton magnetic resonance spectroscopy. RESULTS Pioglitazone decreased hepatic triglyceride content (5.9 [interquartile range ] versus 4.1 [ ]%, P < 0.05), decreased plasma CETP mass (2.33 +/ vs / microg/ml, P < 0.05), and increased plasma HDL cholesterol level (1.22 +/ vs / mmol/l, P < 0.05). Metformin did not significantly change any of these parameters. CONCLUSIONS: A decrease in hepatic triglyceride content by pioglitazone is accompanied by a decrease in plasma CETP mass and associated with an increase in HDL cholesterol levels. These results in patients with type 2 diabetes fully confirm recent findings in mice. Joya-Galeana, J., M. Fernandez, et al. (2011). "Effects of insulin and oral anti-diabetic agents on glucose metabolism, vascular dysfunction and skeletal muscle inflammation in type 2 diabetic subjects." Diabetes/Metabolism Research Reviews 27(4): BACKGROUND: To test potential differences between the actions of anti-diabetic medications, we examined the effects of oral hypoglycaemic agents versus glargineapidra insulin therapy in T2DM. METHODS: T2DM subjects were randomized to either oral hypoglycaemic agents (pioglitazone, metformin and glipizide, n = 9) or insulin New Diabetes Medications, TZDs, and Combinations Update #1 Page 34 of 71

35 therapy (n = 12) for 6 months. Carotid intimal media thickness, vascular reactivity (flowmediated vasodilatation; percent change in brachial artery basal diameter post-ischaemia) and sublingual nitrate were measured with ultrasonography. Euglycemic hyperinsulinemic (80 mu/m(2) ) clamp with [3]-3H-glucose and muscle biopsies were performed. RESULTS: Fasting plasma glucose (~257 to ~124 mg/dl, oral hypoglycaemic agents and ~256 to ~142 mg/dl, IT) and HbA(1c) (~10.3 to ~6.4%, OHA and ~10.7 to ~7.1%, IT) improved comparably. Endogenous glucose production (~2.1 to ~1.7 mg/kg/min, oral hypoglycaemic agents and ~2.3 to ~2.0 mg/kg/min, insulin therapy) and endogenous glucose production suppression by insulin (~0.4 to ~0.3 mg/kg min, oral hypoglycaemic agents and ~0.5 to ~0.7 mg/kg min, insulin therapy) were different. Total glucose disposal x 100 increased in the oral hypoglycaemic agents group (~5.2 to ~8.1; p = 0.03), but not in insulin therapy (~6.0 to ~5.4 mg/kg/min/microu/ml x 100). OHA reduced CIMT (~0.080 to ~0.068 cm; p < 0.05), whereas insulin therapy did not (~0.075 to ~0.072 cm). After sublingual nitrate, brachial artery basal diameter increased in the OHA group (~8.7 to ~18.2%), but not in insulin therapy (~11.2 to ~15.0%; p < 0.02). Except for plasma adiponectin (~7 to ~15, oral hypoglycaemic agents versus ~6 to ~10, IT), changes in inflammatory markers in the circulation and in muscle (IkappaBalpha, super-oxidase dismutase 2, monocyte-chemo-attractant protein 1, p-erk and JNK) were equivalent. CONCLUSIONS: Oral hypoglycaemic agents and insulin therapy treated patients achieved adequate glycemic control and the effects on circulating and muscle inflammatory biomarkers were similar, but only oral hypoglycaemic agents improved insulin sensitivity, vascular function and carotid intimal media thickness. These findings in a small sample suggest that the use of oral hypoglycaemic agents provides additional benefits to patients with T2DM. Kadoglou, N. P., A. Kapelouzou, et al. (2011). "Effects of rosiglitazone/metformin fixed-dose combination therapy and metformin monotherapy on serum vaspin, adiponectin and IL-6 levels in drug-naive patients with type 2 diabetes." Exp Clin Endocrinol Diabetes 119(2): OBJECTIVE: Vaspin, adiponectin and interleukin-6 (IL-6) constitute novel adiposetissue derivatives, known as adipokines, which mediate insulin resistance. The aim of the present study was to evaluate the effects of metformin and rosiglitazone on serum levels of those novel adipokines in drug-naive patients with type 2 diabetes mellitus (T2DM). METHODS: 140 patients with T2DM, already treated with diet, but without adequate glycemic control (HbA1c > 7%), were randomly assigned to: RSG+MET group, (n = 70): Combination therapy with fixed dose of 4 mg rosiglitazone plus 500 mg metformin. MET group, (n = 70): Half-maximum dose of metformin monotherapy (1 700 mg/day). Before and after 6-month treatment, body-mass index (BMI), blood pressure (BP), fat-mass, fasting plasma glucose (FPG), HbA1c, insulin resistance indexes (HOMA-IR, insulin), lipids, high-sensitivity CRP (hscrp), vaspin, adiponectin, and interleukin-6 (IL-6) were measured. RESULTS: Glucose regulation and insulin resistance were equivalently improved from baseline within both groups (p < 0.05). There was a considerable amelioration of hscrp, WBC, adiponectin, IL-6, systolic and diastolic BP with rosiglitazone/metformin combined treatment as compared to baseline (p < 0.05) and MET group (p < 0.05). In contrast, metformin monotherapy significantly reduced BMI (p < 0.001), total-cholesterol (p = 0.012) and LDL (p = 0.020) levels compared to RSG+MET group. Importantly, serum vaspin concentration was equivalently decreased from baseline New Diabetes Medications, TZDs, and Combinations Update #1 Page 35 of 71

36 in both RSG+MET ( / ng/ml, p < 0.001) and MET ( / ng/ml, p=0.001) group. The aforementioned vaspin changes correlated with changes in WHR, HbA1c, FPG, HOMA-IR, insulin, IL-6 (only in the RSG+MET group) and fat-mass. In standard multiple regression analysis, FPG, HbA1c, HOMA-IR and insulin remained independent determinants of serum vaspin levels changes (R(2) = 0.836, p = 0.004). CONCLUSIONS: Both rosiglitazone/metformin combination therapy and metformin monotherapy decreased serum vaspin levels through glucose and insulin sensitivity regulation, while they exerted differential effects on adiponectin, IL-6 and other cardiovascular risk factors in drug-naive patients with T2DM. Kikuchi, M., K. Kaku, et al. (2012). "Efficacy and tolerability of rosiglitazone and pioglitazone in drug-naive Japanese patients with type 2 diabetes mellitus: a double-blind, 28 weeks' treatment, comparative study." Curr Med Res Opin 28(6): OBJECTIVE: A 28-week, randomized, placebo-controlled study was performed to evaluate efficacy and tolerability of rosiglitazone in Japanese type 2 diabetes patients. RESEARCH AND DESIGN METHODS: 373 patients were randomized to rosiglitazone (4-8 mg/day), pioglitazone (15-45 mg/day) or placebo. Agents were titrated to maximum doses at fixed time points in a pre-defined manner. Primary endpoints were superiority of each active treatment compared to placebo in HbA(1c) at week 16, and non-inferiority between active agents in HbA(1c) at week 28, based on a -0.45% margin. RESULTS: At week 16, improvements versus placebo were observed with rosiglitazone 4 mg/day (- 0.96%, p < 0.001) and pioglitazone 30 mg/day (-1.26%, p < 0.001). At week 28, rosiglitazone and pioglitazone were associated with significant changes from baseline of % and -1.35%, respectively and rosiglitazone produced statistically and clinically significant improvement versus placebo (-1.29%, CI: -1.62, -0.97). Pioglitazone also showed significant improvement versus placebo (-1.64%, CI: -1.96, -1.31). Noninferiority of rosiglitazone (4-8 mg/day) to pioglitazone (30-45 mg/day) was not demonstrated (treatment-difference: -0.41%, 95% CI: -0.64, -0.18). More patients treated with pioglitazone were withdrawn from the study by adverse events compared with rosiglitazone (14 vs. 4, p = 0.015). Pioglitazone was associated with higher incidences of adverse events relating to edema and weight gain compared with rosiglitazone (edema: 25.2 vs. 11.3%, weight gain: 9.4 vs. 4.4%). There were no reports of ischemic heart disease or congestive heart failure in any treatment group. CONCLUSION: Although non-inferiority to pioglitazone up to 45 mg in efficacy was not shown, rosiglitazone was confirmed to have clinically meaningful efficacy over placebo and fewer fluid-related events than pioglitazone. The study is registered on ClinicalTrials.gov as protocol NCT Kong, A. P., A. Yamasaki, et al. (2011). "A randomized-controlled trial to investigate the effects of rivoglitazone, a novel PPAR gamma agonist on glucose-lipid control in type 2 diabetes." Diabetes Obes Metab 13(9): AIM: To examine the efficacy, safety and tolerability of rivoglitazone, a novel thiazolidinedione (TZD), and explore its effects on glucose and lipid control compared to placebo and pioglitazone in Chinese type 2 diabetic patients who are treatment naive or treated with a single oral blood glucose-lowering drug. METHODS: This was a doubleblind, randomized, placebo- and active-controlled study. A total of 287 Chinese type 2 New Diabetes Medications, TZDs, and Combinations Update #1 Page 36 of 71

37 diabetic patients with suboptimal glycaemic control (defined as HbA1c >/=6.5 to <10% and fasting plasma glucose >/=7 to </=15 mmol/l) were enrolled. One hundred and seventy-four eligible patients were randomized into one of the five treatment arms for 12 weeks: placebo, pioglitazone 30 mg daily, rivoglitazone of dose 0.5, 1.0 or 1.5 mg daily. In a full set analysis, we used analysis of covariance to compare the primary endpoint defined as change in HbA1c from baseline to week 12/last observation carried forward in the rivoglitazone group at each dose level with the placebo group. RESULTS: Changes in HbA1c were -0.11% in the 0.5-mg group; -0.22% in the 1-mg group and -0.17% in the 1.5-mg rivoglitazone group; -0.06% in the 30-mg pioglitazone group and 0.61% in the placebo group. Compared to placebo, changes were significant in all active treatment groups (all p < 0.05). Increase in high-density lipoprotein cholesterol and decrease in triglyceride were observed in the rivoglitazone 1 and 1.5 mg groups, respectively, compared to placebo from baseline to week 12 (p < 0.05). Drug-related oedema was reported in eight patients (7.7%) in all rivoglitazone groups compared to six patients (16.2%) in the pioglitazone group and one patient (3.0%) in the placebo group. CONCLUSIONS: Rivoglitazone is an efficacious, safe and well-tolerated TZD which improved glycaemic control in Chinese type 2 diabetic patients up to 3 months. Koren, S., L. Shemesh-Bar, et al. (2012). "The effect of sitagliptin versus glibenclamide on arterial stiffness, blood pressure, lipids, and inflammation in type 2 diabetes mellitus patients." Diabetes Technol Ther 14(7): AIM: This study evaluated the effect of sitagliptin versus glibenclamide on arterial stiffness, blood pressure, lipid profile, oxidative stress, and high-sensitivity C-reactive protein (hscrp) in type 2 diabetes mellitus patients. SUBJECTS AND METHODS: Forty diabetes patients, inadequately controlled on metformin, were randomly assigned to either sitagliptin (100 mg/day) or glibenclamide (5 mg/day) for 3 months. Following a 1- month washout period, a crossover switch from glibenclamide to sitagliptin and vice versa was performed for an additional 3 months. Arterial stiffness, 24-h ambulatory blood pressure monitoring, lipids, hscrp, glycated hemoglobin, fasting glucose, STAT-8- isoprostane (a measure of oxidative stress), body mass index (BMI), and waist circumference were measured at baseline and at 3 months with each of the study drugs. RESULTS: Thirty-four patients completed the study. Glibenclamide had a better glucoselowering effect than sitagliptin, but this was associated with more hypoglycemic events. BMI increased following glibenclamide treatment, whereas sitagliptin proved weightneutral. Mean BMI gain was +0.5+/-1.0 kg/m(2) for glibenclamide versus /-0.9 kg/m(2) for sitagliptin (P<0.001). Triglyceride levels significantly dropped following sitagliptin, although they remained unaltered after glibenclamide treatment. Mean triglyceride decrease was /-45 mg/ml after sitagliptin but -0.2+/-57 mg/dl following glibenclamide treatment (P=0.018). There was no change in low-density lipoprotein, high-density lipoprotein, arterial stiffness, blood pressure monitoring, hscrp, or STAT-8-isoprostane with each of the study drugs. CONCLUSIONS: Sitagliptin, but not glibenclamide, demonstrated a significant beneficial effect on BMI and triglyceride levels. However, arterial stiffness, blood pressure, oxidative stress, and inflammatory status were not significantly affected by adding sitagliptin or glibenclamide to metformin-treated type 2 diabetes patients. New Diabetes Medications, TZDs, and Combinations Update #1 Page 37 of 71

38 Meneghini, L. F., L. Traylor, et al. (2010). "Improved glycemic control with insulin glargine versus pioglitazone as add-on therapy to sulfonylurea or metformin in patients with uncontrolled type 2 diabetes mellitus." Endocr Pract 16(4): OBJECTIVE: To compare glycemic control with add-on insulin glargine versus pioglitazone treatment in patients with type 2 diabetes. METHODS: This 48-week, multicenter, parallel-group, open-label study randomized 389 adults with poorly controlled type 2 diabetes (glycated hemoglobin A1c [A1C], 8.0% to 12.0%), despite > or =3 months of sulfonylurea or metformin monotherapy, to receive add-on therapy with insulin glargine or pioglitazone. Outcomes included A1C change from baseline to end point (primary), percentage of patients achieving A1C levels < or =7.0%, and changes from baseline in fasting plasma glucose, body mass index, weight, and serum lipids. The safety analysis included incidence of adverse events and rates of hypoglycemia. RESULTS: At end point, insulin glargine yielded a significantly greater reduction in A1C in comparison with pioglitazone (-2.48% versus -1.86%, respectively; 95% confidence interval, to -0.31; P =.0001, 48-week modified intent-to-treat population). Insulin glargine also yielded significantly greater reductions in fasting plasma glucose at all time points (end point difference, mg/dl; 95% confidence interval, to -22.2; P<.0001). In comparison with pioglitazone, insulin glargine resulted in a lower overall incidence of possibly related treatment-emergent adverse events (12.0% versus 20.7%) and fewer study discontinuations (2.2% versus 9.1%), but a higher rate (per patient-year) of confirmed clinically relevant hypoglycemic episodes (blood glucose <70 mg/dl and all severe hypoglycemia) (4.97 versus 1.04; P<.0001) and severe hypoglycemia (0.07 versus 0.01; P =.0309). Weight and body mass index changes were similar between the 2 treatment groups. CONCLUSION: The addition of insulin glargine early in the diabetes treatment paradigm in patients for whom sulfonylurea or metformin monotherapy had failed resulted in significantly greater improvements in glycemic control in comparison with the addition of pioglitazone. Although severe hypoglycemia was more frequent in patients with insulin glargine therapy, hypoglycemic events occurred in <5% of patients in the insulin glargine treatment group. Mizoguchi, M., N. Tahara, et al. (2011). "Pioglitazone attenuates atherosclerotic plaque inflammation in patients with impaired glucose tolerance or diabetes a prospective, randomized, comparator-controlled study using serial FDG PET/CT imaging study of carotid artery and ascending aorta." JACC Cardiovasc Imaging 4(10): OBJECTIVES: The aim of this study was to compare the effect of pioglitazone, an insulin sensitizer, with glimepiride, an insulin secretagogue, on atherosclerotic plaque inflammation by using serial (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) imaging. BACKGROUND: Atherosclerosis is intrinsically an inflammatory disease. Although hyperglycemia is associated with an increased risk of atherosclerotic cardiovascular disease, there are no clinical data to show the preference of any specific oral hypoglycemic agents to prevent atherosclerotic plaque inflammation. METHODS: A total of 56 impaired glucose tolerant or diabetic patients with carotid atherosclerosis underwent a complete history, determinations of blood chemistries, anthropometric variables, and FDG-PET. They were randomly assigned to receive either pioglitazone (15 to 30 mg) or glimepiride (0.5 to 4.0 mg) for 4 months with titration to optimal dosage. Effects of the drugs on atherosclerotic plaque inflammation were evaluated by FDG-PET New Diabetes Medications, TZDs, and Combinations Update #1 Page 38 of 71

39 at study completion. Plaque inflammation was measured by blood-normalized standardized uptake value, known as a target-to-background ratio. RESULTS: The study was completed in 31 pioglitazone-treated patients and 21 glimepiride-treated patients. Although both treatments reduced fasting plasma glucose and hemoglobin A1c values comparably, pioglitazone, but not glimepiride, decreased atherosclerotic plaque inflammation. Compared with glimepiride, pioglitazone significantly increased highdensity lipoprotein cholesterol level. High-sensitivity C-reactive protein was decreased by pioglitazone, whereas it was increased by glimepiride. Multiple stepwise regression analysis revealed that the increase in high-density lipoprotein cholesterol level was independently associated with the attenuation of plaque inflammation. CONCLUSIONS: Our present study suggests that pioglitazone could attenuate atherosclerotic plaque inflammation in patients with impaired glucose tolerance or in diabetic patients independent of glucose lowering effect. Pioglitazone may be a promising strategy for the treatment of atherosclerotic plaque inflammation in impaired glucose tolerance or diabetic patients. (Detection of Plaque Inflammation and Visualization of Anti- Inflammatory Effects of Pioglitazone on Plaque Inflammation in Subjects With Impaired Glucose Tolerance and Type 2 Diabetes Mellitus by FDG-PET/CT; NCT ). Naka, K. K., K. Papathanassiou, et al. (2012). "Effects of pioglitazone and metformin on vascular endothelial function in patients with type 2 diabetes treated with sulfonylureas." Diabetes & Vascular Disease Research 9(1): Pioglitazone and metformin are insulin sensitisers used for the treatment of T2DM. The effects of pioglitazone and metformin on endothelial function, assessed by FMD, in T2DM patients treated with sulfonylureas were compared. Patients were randomised to receive pioglitazone (n = 15) 30 mg once daily or metformin (n = 16) 850 mg twice daily for six months. Pioglitazone significantly decreased fasting insulin, HbA(1C) and HOMA-IR (p < 0.05 for all) and increased FMD (p = 0.002). Metformin induced a significant decrease in HbA(1C) (p = 0.02) and only a trend for increase in FMD (p = 0.08). The greater improvement in FMD with pioglitazone, compared with metformin, did not reach significance (p = 0.11). Treatment-induced changes in FMD were not associated with the effects of the two insulin sensitisers on glycaemic control or insulin resistance. The beneficial effects of pioglitazone and metformin on endothelial function in T2DM patients did not differ greatly. Larger studies are needed to explore whether a potentially greater benefit with pioglitazone may exist. Olansky, L., C. Reasner, et al. (2011). "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 13(9): AIMS: Combination therapy with sitagliptin and metformin has shown superior efficacy compared with metformin monotherapy. In this study, we compare two strategies: initial combination therapy with sitagliptin/metformin as a fixed-dose combination (FDC) and initial metformin monotherapy, with the option to add additional antihyperglycaemic agents (AHAs) in either treatment arm during the second phase of the study in order to reach adequate glycaemic control. METHODS: We evaluated the sitagliptin and metformin FDC compared with metformin monotherapy over 44 weeks in 1250 patients New Diabetes Medications, TZDs, and Combinations Update #1 Page 39 of 71

40 with type 2 diabetes mellitus in a two-part, double-blind, randomized, controlled clinical trial. The initial 18-week portion (Phase A) of this study in which additional AHAs were only allowed based on prespecified glycaemic criteria, has been previously reported. Here, we present results from the 26-week Phase B portion of the study during which double-blind study medication continued; however, unlike Phase A, during Phase B investigators were unmasked to results for haemoglobin A1C (HbA1c) and fasting plasma glucose (FPG) and directed to manage glycaemic control by adding incremental AHA(s) as deemed clinically appropriate. RESULTS: There were 1250 patients randomized in the study with 965 completing Phase A and continuing in Phase B. Among patients receiving sitagliptin/metformin FDC or metformin monotherapy, 8.8% and 16.7% received additional AHA therapy, respectively. Although glycaemic therapy in both groups was to have been managed to optimize HbA1c reductions with the option for investigators to supplement with additional AHAs during Phase B, patients randomized to initial therapy with sitagliptin/metformin FDC had larger reductions of HbA1c from baseline compared with patients randomized to initial metformin monotherapy [least squares (LS) mean change: -2.3% and -1.8% (p < for difference) for sitagliptin/metformin FDC and metformin monotherapy groups, respectively]. A significantly larger reduction in FPG from baseline was observed in the sitagliptin/metformin FDC group compared with the metformin monotherapy group (p = 0.001). Significantly more patients in the sitagliptin/metformin FDC group had an HbA1c of less than 7.0% or less than 6.5% compared with those on metformin monotherapy. Both treatment strategies were generally well tolerated, with a low and similar incidence of hypoglycaemia in both groups and lower incidences of abdominal pain and diarrhoea in the sitagliptin/metformin FDC group compared with the metformin monotherapy group. CONCLUSIONS: A strategy initially implementing combination therapy with sitagliptin/metformin FDC was superior to a strategy initially implementing metformin monotherapy, even when accounting for the later addition of supplemental AHAs. Sitagliptin/metformin FDC was generally well tolerated. Perez, A., R. Jacks, et al. (2010). "Effects of pioglitazone and metformin fixed-dose combination therapy on cardiovascular risk markers of inflammation and lipid profile compared with pioglitazone and metformin monotherapy in patients with type 2 diabetes." J Clin Hypertens (Greenwich) 12(12): Type 2 diabetes mellitus (T2DM) treatment should not increase cardiovascular (CV) risk and at best could provide benefit beyond lowering glucose. Pioglitazone has demonstrated a favorable CV profile relative to other oral antidiabetic drugs (OADs) in outcome and observational studies. This randomized, double-blind, parallel-group controlled study examined circulating biomarkers of CV risk in T2DM patients receiving a fixed-dose combination (FDC) of pioglitazone/metformin compared with the respective monotherapies. Patients with stable glycosylated hemoglobin (HbA(1c) ) for 3 months taking no OADs were treated with pioglitazone 15mg/metformin 850mg FDC twice daily (bid), pioglitazone 15mg bid, or metformin 850mg bid for 24 weeks. FDC and pioglitazone increased high-density lipoprotein cholesterol by 14.20% and 9.88%, respectively, vs an increase of 6.09% with metformin (P<.05, metformin vs FDC). Triglycerides decreased with all three treatments -5.95%, -5.54% and -1.78%, respectively; P=not significant). FDC and pioglitazone significantly decreased small low- New Diabetes Medications, TZDs, and Combinations Update #1 Page 40 of 71

41 density lipoprotein and increased large low-density lipoprotein particle concentrations. Reductions in high-sensitivity C-reactive protein were greater in the FDC and pioglitazone groups. Increases in adiponectin were significant in the FDC and pioglitazone groups (P<.0001 vs metformin). Overall, adverse events were not higher with the FDC. Thus, treatment with the FDC resulted in improved levels of CV biomarkers, which were better than or equal to monotherapy. Perez-Monteverde, A., T. Seck, et al. (2011). "Efficacy and safety of sitagliptin and the fixeddose combination of sitagliptin and metformin vs. pioglitazone in drug-naive patients with type 2 diabetes." Int J Clin Pract 65(9): AIM: The efficacy and safety of sitagliptin (SITA) monotherapy and SITA/metformin (MET) vs. pioglitazone (PIO) were assessed in patients with type 2 diabetes and moderate-to-severe hyperglycaemia (A1C = %). METHODS: In an initial 12- week phase (Phase A), 492 patients were randomised 1 : 1 in a double-blind fashion to SITA (100 mg qd) or PIO (15 mg qd, up-titrated to 30 mg after 6 weeks). In Phase B (28 additional weeks), the SITA group was switched to SITA/MET (up-titrated to 50/1000 mg bid over 4 weeks) and the PIO group was up-titrated to 45 mg qd RESULTS: At the end of Phase A, mean changes from baseline were -1.0% and -0.9% for A1C; mg/dl and mg/dl for fasting plasma glucose; and mg/dl and mg/dl for 2-h postmeal glucose for SITA and PIO, respectively. At the end of Phase B, improvements in glycaemic parameters were greater with SITA/MET vs. PIO: -1.7% vs. -1.4% for A1C (p = 0.002); mg/dl vs mg/dl for fasting plasma glucose (p = 0.03); mg/dl vs mg/dl for 2-h postmeal glucose (p = 0.001); and 55.0% vs. 40.5% for patients with A1C < 7% (p = 0.004). A numerically higher incidence of gastrointestinal adverse events and a significantly lower incidence of oedema were observed with SITA/MET vs. PIO. The incidence of hypoglycaemia was similarly low in both groups. Body weight decreased with SITA/MET and increased with PIO (-1.1 kg vs. 3.4 kg; p < 0.001). CONCLUSION: Improvements in glycaemic control were greater with SITA/MET vs. PIO, with weight loss vs. weight gain. Both treatments were generally well tolerated. Petrica, L., A. Vlad, et al. (2011). "Pioglitazone delays proximal tubule dysfunction and improves cerebral vessel endothelial dysfunction in normoalbuminuric people with type 2 diabetes mellitus." Diabetes Res Clin Pract 94(1): AIM: The renal and cerebral protective effects of pioglitazone were assessed in normoalbuminuric patients with type 2 diabetes mellitus (DM). METHODS: A total of 68 normoalbuminuric type 2 DM patients were enrolled in a one-year open-label randomized controlled trial: 34 patients (pioglitazone-metformin) vs. 34 patients (glimepiride-metformin). All patients were assessed concerning urinary albumin: creatinine ratio (UACR), urinary alpha1-microglobulin, urinary beta2-microglobulin, plasma asymmetric dymethyl-arginine (ADMA), GFR, hsc-reactive protein, fibrinogen, HbA1c; pulsatility index, resistance index in the internal carotid artery and middle cerebral artery, intima-media thickness in the common carotid artery; cerebrovascular reactivity was evaluated through the breath-holding test. RESULTS: At 1 year there were differences between groups regarding ADMA, urinary beta2-microglobulin, urinary alpha1-microglobulin, parameters of inflammation, serum creatinine, GFR, UACR, the cerebral haemodynamic indices. Significant correlations were found between alpha 1- New Diabetes Medications, TZDs, and Combinations Update #1 Page 41 of 71

42 microglobulin-uacr (R(2)=0.143; P=0.001) and GFR (R(2)=0.081; P=0.01); beta2- microglobulin-uacr (R(2)=0.241; P=0.0001) and GFR (R(2)=0.064; P=0.036); ADMA-GFR (R(2)=0.338; P=0.0001), parameters of inflammation, HbA1c, duration of DM, cerebral indices. There were no correlations between ADMA-UACR, urinary alpha1-microglobulin and beta2-microglobulin. CONCLUSION: Proximal tubule (PT) dysfunction precedes albuminuria and is dissociated from endothelial dysfunction in patients with type 2 DM. Pioglitazone delays PT dysfunction and improves cerebral vessels endothelial dysfunction in normoalbuminuric patients with type 2 DM. Pfutzner, A., E. Paz-Pacheco, et al. (2011). "Initial combination therapy with saxagliptin and metformin provides sustained glycaemic control and is well tolerated for up to 76 weeks." Diabetes Obes Metab 13(6): AIM: To assess the efficacy and safety of saxagliptin + metformin initial combination therapy compared with saxagliptin or metformin alone over 76 weeks (24-week shortterm + 52-week long-term extension) in treatment-naive type 2 diabetes mellitus patients with inadequate glycaemic control. METHODS: In this phase 3, parallel-group, doubleblind, active-controlled study, 1306 patients years of age (HbA1c %) were randomized to saxagliptin 5 mg mg metformin, saxagliptin 10 mg mg metformin, saxagliptin 10 mg + placebo or 500 mg metformin + placebo. Blinded metformin was titrated during weeks 1-5 of the short-term treatment period in 500 mg/day increments to 2000 mg/day maximum in the metformin-based treatment groups. No titration of metformin was permitted during the long-term treatment period. A total of 888 patients completed the study (76 weeks), 613 without being rescued. Changes in HbA1c, fasting plasma glucose, 120-min postprandial glucose (PPG) and PPG-area under the curve (AUC) from baseline to week 76 were analysed using a repeated-measures model. RESULTS: At 76 weeks, adjusted mean changes from baseline HbA1c (95% CI) for saxagliptin 5 mg + metformin, saxagliptin 10 mg + metformin, saxagliptin 10 mg and metformin were (-2.44, -2.18), (-2.46, -2.20), (-1.70, -1.40) and -1.79% (-1.93, -1.65), respectively (post hoc and nominal p < vs. metformin and saxagliptin monotherapies for saxagliptin 5 mg + metformin and saxagliptin 10 mg + metformin). The proportions of patients requiring rescue or discontinuation for insufficient glycaemic control were lower for saxagliptin + metformin than for either monotherapy. Little or no attenuation in PPG-AUC or 120-min PPG was observed between weeks 24 and 76 for saxagliptin + metformin, indicating persistent efficacy. Adverse event rates were similar across groups; hypoglycaemic events occurred at a low frequency. CONCLUSION: Saxagliptin + metformin initial combination therapy was well tolerated and produced sustained glycaemic control for up to 76 weeks, with greater improvements in glycaemic parameters compared with either drug alone. Pratley, R., M. Nauck, et al. (2011). "One year of liraglutide treatment offers sustained and more effective glycaemic control and weight reduction compared with sitagliptin, both in combination with metformin, in patients with type 2 diabetes: a randomised, parallel-group, open-label trial." Int J Clin Pract 65(4): AIM: The aim of this study was to compare the efficacy and safety of once-daily human glucagon-like peptide-1 analogue liraglutide with dipeptidyl peptidase-4 inhibitor sitagliptin, each added to metformin, over 52 weeks in individuals with type 2 diabetes. New Diabetes Medications, TZDs, and Combinations Update #1 Page 42 of 71

43 METHODS: In an open-label, parallel-group trial, metformin-treated participants were randomised to liraglutide 1.2 mg/day (n=225), liraglutide 1.8 mg/day (n=221) or sitagliptin 100 mg/day (n=219) for 26 weeks (main phase). Participants continued the same treatment in a 26-week extension. RESULTS: Liraglutide (1.2 or 1.8 mg) was superior to sitagliptin for reducing HbA(1c) from baseline ( %) to 52 weeks: % and -1.51% vs % respectively. Estimated mean treatment differences between liraglutide and sitagliptin were as follows: -0.40% (95% confidence interval to -0.22) for 1.2 mg and -0.63% (-0.81 to -0.44) for 1.8 mg (both p<0.0001). Weight loss was greater with liraglutide 1.2 mg (-2.78 kg) and 1.8 mg (-3.68 kg) than sitagliptin (-1.16 kg) (both p<0.0001). Diabetes Treatment Satisfaction Questionnaire scores increased significantly more with liraglutide 1.8 mg than with sitagliptin (p=0.03). Proportions of participants reporting adverse events were generally comparable; minor hypoglycaemia was 8.1%, 8.3% and 6.4% for liraglutide 1.2 mg, 1.8 mg and sitagliptin respectively. Gastrointestinal side effects, mainly nausea, initially occurred more frequently with liraglutide, but declined after several weeks. CONCLUSION: Liraglutide provides greater sustained glycaemic control and body weight reduction over 52 weeks. Treatment satisfaction was significantly greater with 1.8 mg liraglutide, similar to 26- week results. The safety profiles of liraglutide and sitagliptin are consistent with previous reports. Pratley, R. E., J. E. Reusch, et al. (2009). "Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin added to pioglitazone in patients with type 2 diabetes: a randomized, doubleblind, placebo-controlled study." Curr Med Res Opin 25(10): OBJECTIVES: To evaluate the efficacy and safety of alogliptin in patients with type 2 diabetes inadequately controlled by therapy with a thiazolidinedione (TZD). RESEARCH DESIGN AND METHODS: In a multicenter, double-blind, placebo-controlled clinical study, 493 patients years old with inadequate glycemic control after stabilization (i.e., glycosylated hemoglobin [HbA(1c)] %) despite ongoing treatment with a TZD were randomly assigned (2:2:1) to treatment with pioglitazone plus alogliptin 12.5 mg, alogliptin 25 mg or placebo once daily. Concomitant therapy with metformin or sulfonylurea at prestudy doses was permitted. MAIN OUTCOME MEASURES: The primary efficacy endpoint was change in HbA(1c) from baseline to Week 26. Secondary endpoints included changes in fasting plasma glucose (FPG) and body weight, and incidences of marked hyperglycemia (FPG > or = 200 mg/dl [11.10 mmol/l]) and rescue for hyperglycemia. RESULTS: Least squares (LS) mean change in HbA(1c) was significantly (p < 0.001) greater for alogliptin 12.5 mg (-0.66%) or 25 mg (-0.80%) than for placebo (-0.19%). A significantly (p < or = 0.016) larger proportion of patients achieved HbA(1c) < or = 7% with alogliptin 12.5 mg (44.2%) or 25 mg (49.2%) than with placebo (34.0%). LS mean decreases in FPG were significantly (p = 0.003) greater with alogliptin 12.5 mg (-19.7 mg/dl [-1.09 mmol/l]) or 25 mg (-19.9 mg/dl [-1.10 mmol/l]) than with placebo (-5.7 mg/dl [-0.32 mmol/l]). The percentage of patients with marked hyperglycemia was significantly (p < 0.001) lower for alogliptin (< or =25.0%) than placebo (44.3%). The incidences of overall adverse events and hypoglycemia were similar across treatment groups, but cardiac events occurred more often with active treatment than placebo. CONCLUSIONS: Addition of alogliptin to pioglitazone therapy significantly improved glycemic control in patients with type 2 New Diabetes Medications, TZDs, and Combinations Update #1 Page 43 of 71

44 diabetes and was generally well tolerated. The study did not evaluate the effect of combination therapy on long-term clinical outcomes and safety. CLINICAL TRIAL REGISTRATION: NCT , clinicaltrials.gov. Punthakee, Z., J. Bosch, et al. (2012). "Design, history and results of the Thiazolidinedione Intervention with vitamin D Evaluation (TIDE) randomised controlled trial." Diabetologia 55(1): AIMS/OBJECTIVE: Conflicting data regarding cardiovascular effects of thiazolidinediones (TZDs) and extra-skeletal effects of vitamin D supported the need for a definitive trial. The Thiazolidinedione Intervention with vitamin D Evaluation (TIDE) trial aimed to assess the effects of TZDs (rosiglitazone and pioglitazone) on cardiovascular outcomes and the effects of vitamin D (cholecalciferol) on cancers and mortality. METHODS: A large multicentre 3 x 2 factorial double-blind placebocontrolled randomised trial recruited from outpatient primary care and specialty clinics in 33 countries. From June 2009 to July 2010, 1,332 people with type 2 diabetes and other cardiovascular risk factors aged >/= 50 years whose HbA(1c) was % (48-80 mmol/mol) when using two or fewer glucose-lowering drugs were randomised by a central computer system to placebo (n = 541), rosiglitazone 4-8 mg/day (n = 399) or pioglitazone mg/day (n = 392); 1,221 participants were randomised to placebo (n = 614) or vitamin D 1,000 IU/day (n = 607). Participants and all study personnel were blind to treatment allocation. The primary outcome for the TZD arm was the composite of myocardial infarction, stroke or cardiovascular death, and for the vitamin D arm it was cancer or all-cause death. All randomised participants were included in the primary analysis. RESULTS: From the study design, 16,000 people were to be followed for approximately 5.5 years. However, the trial was stopped prematurely because of regulatory concerns after a mean of 162 days without consideration of the accrued data. In the TZD arm, the cardiovascular outcome occurred in five participants (0.9%) in the placebo groups and three participants (0.4%) in the TZD groups (two allocated to pioglitazone, one to rosiglitazone). In the vitamin D arm, the primary outcome occurred in three participants (0.5%) in the placebo group and in two participants (0.3%) receiving vitamin D. Adverse events were comparable in all groups. CONCLUSIONS/INTERPRETATION: Uncertainty persists regarding the clinically relevant risks and benefits of TZDs and vitamin D because of the early cancellation of this comprehensive trial. Reasner, C., L. Olansky, et al. (2011). "The effect of initial therapy with the fixed-dose combination of sitagliptin and metformin compared with metformin monotherapy in patients with type 2 diabetes mellitus." Diabetes Obes Metab 13(7): AIMS: This study was conducted to compare the glycaemic efficacy and safety of initial combination therapy with the fixed-dose combination of sitagliptin and metformin versus metformin monotherapy in drug-naive patients with type 2 diabetes. METHODS: This double-blind study (18-week Phase A and 26-week Phase B) randomized 1250 drugnaive patients with type 2 diabetes [mean baseline haemoglobin A1c (HbA1c) 9.9%] to sitagliptin/metformin 50/500 mg bid or metformin 500 mg bid (uptitrated over 4 weeks to achieve maximum doses of sitagliptin/metformin 50/1000 mg bid or metformin 1000 bid). Results of the primary efficacy endpoint (mean HbA1c reductions from baseline at New Diabetes Medications, TZDs, and Combinations Update #1 Page 44 of 71

45 the end of Phase A) are reported herein. RESULTS: At week 18, mean change from baseline HbA1c was -2.4% for sitagliptin/metformin FDC and -1.8% for metformin monotherapy (p < 0.001); more patients treated with sitagliptin/metformin FDC had an HbA1c value <7% (p < 0.001) versus metformin monotherapy. Changes in fasting plasma glucose were significantly greater with sitagliptin/metformin FDC (-3.8 mmol/l) versus metformin monotherapy (-3.0 mmol/l; p < 0.001). Homeostasis model assessment of beta-cell function (HOMA-beta) and fasting proinsulin/insulin ratio were significantly improved with sitagliptin/metformin FDC versus metformin monotherapy. Baseline body weight was reduced by 1.6 kg in each group. Both treatments were generally well tolerated with a low and similar incidence of hypoglycaemia. Abdominal pain (1.1 and 3.9%; p = 0.002) and diarrhoea (12.0 and 16.6%; p = 0.021) occurred significantly less with sitagliptin/metformin FDC versus metformin monotherapy; the incidence of nausea and vomiting was similar in both groups. CONCLUSION: Compared with metformin monotherapy, initial treatment with sitagliptin/metformin FDC provided superior glycaemic improvement with a similar degree of weight loss and lower incidences of abdominal pain and diarrhoea. Rosenstock, J., N. Aggarwal, et al. (2012). "Dose-ranging effects of canagliflozin, a sodiumglucose cotransporter 2 inhibitor, as add-on to metformin in subjects with type 2 diabetes." Diabetes Care 35(6): OBJECTIVE: To evaluate the effects of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, in type 2 diabetes mellitus inadequately controlled with metformin monotherapy. RESEARCH DESIGN AND METHODS: This was a double-blind, placebo-controlled, parallel-group, multicenter, dose-ranging study in 451 subjects randomized to canagliflozin 50, 100, 200, or 300 mg once daily (QD) or 300 mg twice daily (BID), sitagliptin 100 mg QD, or placebo. Primary end point was change in A1C from baseline through week 12. Secondary end points included change in fasting plasma glucose (FPG), body weight, and overnight urinary glucose-to-creatinine ratio. Safety and tolerability were also assessed. RESULTS: Canagliflozin was associated with significant reductions in A1C from baseline ( %) to week 12: -0.79, -0.76, -0.70, -0.92, and % for canagliflozin 50, 100, 200, 300 mg QD and 300 mg BID, respectively, versus % for placebo (all P < 0.001) and -0.74% for sitagliptin. FPG was reduced by -16 to - 27 mg/dl, and body weight was reduced by -2.3 to -3.4%, with significant increases in urinary glucose-to-creatinine ratio. Adverse events were transient, mild to moderate, and balanced across arms except for a non-dose-dependent increase in symptomatic genital infections with canagliflozin (3-8%) versus placebo and sitagliptin (2%). Urinary tract infections were reported without dose dependency in 3-9% of canagliflozin, 6% of placebo, and 2% of sitagliptin arms. Overall incidence of hypoglycemia was low. CONCLUSIONS: Canagliflozin added onto metformin significantly improved glycemic control in type 2 diabetes and was associated with low incidence of hypoglycemia and significant weight loss. The safety/tolerability profile of canagliflozin was favorable except for increased frequency of genital infections in females. Rosenstock, J., S. E. Inzucchi, et al. (2010). "Initial combination therapy with alogliptin and pioglitazone in drug-naive patients with type 2 diabetes." Diabetes Care 33(11): OBJECTIVE: To assess the efficacy and tolerability of alogliptin plus pioglitazone for New Diabetes Medications, TZDs, and Combinations Update #1 Page 45 of 71

46 initial combination therapy in drug-naive type 2 diabetic patients. RESEARCH DESIGN AND METHODS: This 26-week, double-blind, parallel-group study randomized 655 patients with inadequately controlled type 2 diabetes to four arms: 25 mg alogliptin (A25) q.d. monotherapy, 30 mg pioglitazone (P30) q.d. monotherapy, or 12.5 (A12.5) or 25 mg alogliptin q.d. plus pioglitazone (P30) q.d. combination therapy. Primary efficacy was A1C change from baseline with the high-dose combination (A25+P30) versus each monotherapy. RESULTS: Combination therapy with A25+P30 resulted in greater reductions in A1C (-1.7+/-0.1% from an 8.8% mean baseline) vs. A25 (-1.0+/-0.1%, P<0.001) or P30 (-1.2+/-0.1%, P<0.001) and in fasting plasma glucose (-2.8+/-0.2 mmol/l) vs. A25 (-1.4+/-0.2 mmol/l, P<0.001) or P30 (-2.1+/-0.2 mmol/l, P=0.006). The A25+P30 safety profile was consistent with those of its component monotherapies. CONCLUSIONS: Alogliptin plus pioglitazone combination treatment appears to be an efficacious initial therapeutic option for type 2 diabetes. Russell-Jones, D., R. M. Cuddihy, et al. (2012). "Efficacy and safety of exenatide once weekly versus metformin, pioglitazone, and sitagliptin used as monotherapy in drug-naive patients with type 2 diabetes (DURATION-4): a 26-week double-blind study." Diabetes Care 35(2): OBJECTIVE: To test the safety and efficacy of exenatide once weekly (EQW) compared with metformin (MET), pioglitazone (PIO), and sitagliptin (SITA) over 26 weeks, in suboptimally treated (diet and exercise) drug-naive patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Patients were randomized to subcutaneous (SC) EQW 2.0 mg + oral placebo (n = 248), MET 2,000 mg/day + SC placebo (n = 246), PIO 45 mg/day + SC placebo (n = 163), or SITA 100 mg/day + SC placebo (n = 163) for 26 weeks. MET and PIO therapies were increased to maximum-tolerated dosages. Injections with EQW or placebo were administered weekly, while oral medication or placebo was administered daily. RESULTS: Baseline characteristics were as follows: 59% men, 67% Caucasian, mean age 54 years, HbA(1c) 8.5%, fasting serum glucose 9.9 mmol/l, body weight 87.0 kg, and diabetes duration 2.7 years. HbA(1c) reductions (%) at 26 weeks (least-squares means) with EQW versus MET, PIO, and SITA were vs (P = 0.620), (P = 0.328), and (P < 0.001), respectively. Weight changes (kg) were -2.0 vs (P = 0.892), +1.5 (P < 0.001), and -0.8 (P < 0.001), respectively. Common adverse events were as follows: EQW, nausea (11.3%) and diarrhea (10.9%); MET, diarrhea (12.6%) and headache (12.2%); PIO, nasopharyngitis (8.6%) and headache (8.0%); and SIT, nasopharyngitis (9.8%) and headache (9.2%). Minor (confirmed) hypoglycemia was rarely reported. No major hypoglycemia occurred. CONCLUSIONS: EQW was noninferior to MET but not PIO and superior to SITA with regard to HbA(1c) reduction at 26 weeks. Of the agents studied, EQW and MET provided similar improvements in glycemic control along with the benefit of weight reduction and no increased risk of hypoglycemia. Scheen, A. J., G. Charpentier, et al. (2010). "Efficacy and safety of saxagliptin in combination with metformin compared with sitagliptin in combination with metformin in adult patients with type 2 diabetes mellitus." Diabetes/Metabolism Research Reviews 26(7): BACKGROUND: Dipeptidyl peptidase-4 inhibitors improve glycaemic control in patients with type 2 diabetes mellitus when used as monotherapy or in combination with other anti-diabetic drugs (metformin, sulphonylurea, or thiazolidinedione). This 18-week, New Diabetes Medications, TZDs, and Combinations Update #1 Page 46 of 71

47 phase 3b, multicentre, double-blind, noninferiority trial compared the efficacy and safety of two dipeptidyl peptidase-4 inhibitors, saxagliptin and sitagliptin, in patients whose glycaemia was inadequately controlled with metformin. METHODS: Adult type 2 diabetes mellitus patients (N = 801) with glycated haemoglobin (HbA(1c)) % on stable metformin doses ( mg/day) were randomized 1 : 1 to add-on 5 mg saxagliptin or 100 mg sitagliptin once daily for 18 weeks. The primary efficacy analysis was a comparison of the change from baseline HbA(1c) at week 18 in per-protocol patients. Noninferiority was concluded if the upper limit of the two-sided 95% confidence interval of the HbA(1c) difference between treatments was < 0.3%. RESULTS: The adjusted mean changes in HbA(1c) following the addition of saxagliptin or sitagliptin to stable metformin therapy were and %, respectively. The between-group difference was 0.09% (95% confidence interval, to 0.20%), demonstrating noninferiority. Both treatments were generally well tolerated; incidence and types of adverse events were comparable between groups. Hypoglycaemic events, mostly mild, were reported in approximately 3% of patients in each treatment group. Body weight declined by a mean of 0.4 kg in both groups. CONCLUSIONS: Saxagliptin added to metformin therapy was effective in improving glycaemic control in patients with type 2 diabetes mellitus inadequately controlled by metformin alone; saxagliptin plus metformin was noninferior to sitagliptin plus metformin, and was generally well tolerated. Seino, Y., T. Fujita, et al. (2011). "Efficacy and safety of alogliptin in Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, dose-ranging comparison with placebo, followed by a long-term extension study." Curr Med Res Opin 27(9): OBJECTIVE: To compare the efficacy and safety of different dosages of alogliptin with that of placebo and voglibose in drug-naive Japanese patients with type 2 diabetes inadequately controlled by diet and exercise. Research design and methods: In the double-blind, placebo-controlled phase of this two-part study, 480 patients aged >/=20 years with type 2 diabetes mellitus (HbA1c >/=6.9% to <10.4%) were randomized to monotherapy with alogliptin 6.25, 12.5, 25 or 50 mg once daily, placebo, or voglibose 0.2 mg three times daily for a period of 12 weeks. In a subsequent open-label, long-term extension phase, patients continued on the same treatment for an additional 40 weeks (patients in the placebo group were reassigned equally to one of the four alogliptin dosages). MAIN OUTCOME MEASURES: The primary efficacy endpoint was the change in HbA1c from the baseline value at week 12 of treatment. Safety endpoints were the occurrence of adverse events, vital sign measurements, physical examination and ECG findings, and laboratory test results recorded over the entire 52-week period. RESULTS: HbA1c was dose-dependently reduced by alogliptin, and the changes versus baseline were statistically significant with all four dosages in comparison with both placebo and voglibose. In addition, changes in fasting plasma glucose and postprandial plasma glucose AUC(0-2h) values were significantly greater with all four dosages of alogliptin in comparison with placebo. The incidence of adverse events with alogliptin over 52 weeks was not dose-dependent and was lower than with voglibose. Hypoglycemia occurred infrequently and was generally rated as mild. Changes in body weight with alogliptin were minimal (<0.5 kg) and not clinically meaningful. CONCLUSIONS: Alogliptin was well tolerated and dose-dependently improved New Diabetes Medications, TZDs, and Combinations Update #1 Page 47 of 71

48 glycemic parameters in patients with type 2 diabetes inadequately controlled on diet and exercise. Seino, Y., M. F. Rasmussen, et al. (2010). "Efficacy and safety of the once-daily human GLP-1 analogue, liraglutide, vs glibenclamide monotherapy in Japanese patients with type 2 diabetes." Curr Med Res Opin 26(5): OBJECTIVE: Liraglutide is a once-daily human glucagon-like peptide-1 (GLP-1) analogue developed for the treatment of type 2 diabetes mellitus (T2DM). In Phase 2 and Phase 3 trials, largely conducted in populations of European descent, liraglutide has been shown to lower HbA(1C), weight and systolic blood pressure with a low risk of hypoglycaemia. This Phase 3, 24-week, multi-centre, double-blind, double dummy, randomised parallel-group trial compared the efficacy and safety of liraglutide and glibenclamide monotherapy in Japanese subjects with T2DM, inadequately controlled with diet therapy or oral antidiabetic drug (OAD) monotherapy. RESEARCH DESIGN AND METHODS: A total of 411 Japanese subjects were randomised 2:1 to liraglutide (n = 272) or glibenclamide (n = 139). Liraglutide was administered at a maximum planned dose of 0.9 mg once daily. Glibenclamide was administered once or twice daily at a planned maximum dose of 2.5 mg/day, before or after meals. CLINICAL TRIAL REGISTRATION: NCT RESULTS: After 24 weeks, glycaemic control with liraglutide was non-inferior/superior to glibenclamide, with HbA(1C) at 24 weeks of 6.99% (SE +/- 0.07) with liraglutide and 7.50% (+/-0.09) with glibenclamide (difference, -0.5%; 95% CI to 0.30; p < ). Mean fasting plasma glucose (FPG) levels at 24 weeks were significantly lower with liraglutide (7.6 mmol/l [SE +/- 0.1]) vs glibenclamide (8.3 mmol/l [+/-0.1]; difference, mmol/l; 95% CI -1.0 to -0.4; p < ). Weight was reduced by kg from a baseline of 65.2 kg in liraglutide-treated patients, compared with weight gain of kg from a baseline of 64.8 kg with glibenclamide (difference, kg; 95% CI to -1.48; p < ). A significantly lower rate of minor hypoglycaemic episodes was achieved with liraglutide compared with glibenclamide (p < ), and no major hypoglycaemic episodes were reported in either treatment group. The most common gastrointestinal AEs were diarrhoea (liraglutide, 6.3%; glibenclamide, 3.8%) and constipation (liraglutide, 5.6%; glibenclamide, 3.8%). Nausea was infrequent (liraglutide, 4.5%; glibenclamide, 1.5%). CONCLUSIONS: Liraglutide monotherapy, administered once daily for 24 weeks in Japanese subjects with T2DM, was well tolerated. Compared with glibenclamide monotherapy, liraglutide achieved superior glycaemic control and weight outcome, and a significantly lower incidence of hypoglycaemia. Future studies, comprising a greater proportion of true therapy-naive Japanese patients, will be beneficial in order to establish the true add-on efficacy of liraglutide monotherapy in patients with T2DM. Srivastava, S., G. N. Saxena, et al. (2012). "Comparing the efficacy and safety profile of sitagliptin versus glimepiride in patients of type 2 diabetes mellitus inadequately controlled with metformin alone." J Assoc Physicians India 60( OBJECTIVE: To compare the efficacy and safety of sitagliptin and glimepiride in treatment of patients with type 2 diabetes mellitus inadequately controlled with metformin alone. RESEARCH DESIGN AND METHODS: In an 18 week, randomized parallel group interventional trial, 50 subjects who were only on metformin as New Diabetes Medications, TZDs, and Combinations Update #1 Page 48 of 71

49 antidiabetic agent, with inadequate glycemic control, were randomized to either sitagliptin 50/100mg or glimepiride 1/2 mg per day. Dose of drugs was adjusted after 4 weeks if glycemic control was not reached. RESULTS: At 18 weeks both groups (sitagliptin and glimepiride) produced significant (P < 0.001) reduction in HbA1C ( % and % respectively), with 12% patients in sitagliptin group and 36% patients in glimepiride group achieving target HbA1C. Reduction was also significant (P < 0.001) in both groups in FPG ( mg and mg respectively) and 2HPPG ( mg and mg respectively). Sitagliptin group showed net decrease in bodyweight by kg whereas glimepiride group showed net increase in body weight by kg. Incidence of hypoglycemia was 4% in sitagliptin group and 8% in glimepiride group. CONCLUSION: In this study addition of sitagliptin and glimepiride to metformin monotherapy, produced significant improvement in glycemic control. Benefits were more with glimepiride in comparison to sitagliptin. Sitagliptin was well tolerated, with lower risk of hypoglycemia than glimepiride, and produced weight loss as compared to weight gain with glimepiride. Wainstein, J., L. Katz, et al. (2012). "Initial therapy with the fixed-dose combination of sitagliptin and metformin results in greater improvement in glycaemic control compared with pioglitazone monotherapy in patients with type 2 diabetes." Diabetes Obes Metab 14(5): AIMS: To evaluate the efficacy and safety of initial therapy with a fixed-dose combination (FDC) of sitagliptin and metformin compared with pioglitazone in drugnaive patients with type 2 diabetes. METHODS: After a 2-week single-blind placebo run-in period, patients with type 2 diabetes, HbA1c of % and not on antihyperglycaemic agent therapy were randomized in a double-blind manner to initial treatment with a FDC of sitagliptin/metformin 50/500 mg twice daily (N = 261) or pioglitazone 30 mg per day (N = 256). Sitagliptin/metformin and pioglitazone were uptitrated over 4 weeks to doses of 50/1000 mg twice daily and 45 mg per day, respectively. Both treatments were then continued for an additional 28 weeks. RESULTS: From a mean baseline HbA1c of 8.9% in both groups, least squares (LS) mean changes in HbA1c at week 32 were -1.9 and -1.4% for sitagliptin/metformin and pioglitazone, respectively (between-group difference = -0.5%; p < 0.001). A greater proportion of patients had an HbA1c of <7% at week 32 with sitagliptin/metformin vs. pioglitazone (57% vs. 43%, p < 0.001). Compared with pioglitazone, sitagliptin/metformin treatment resulted in greater LS mean reductions in fasting plasma glucose (FPG) [-56.0 mg/dl (-3.11 mmol/l) vs mg/dl (-2.45 mmol/l), p < 0.001] and in 2-h post-meal glucose [ mg/dl (-5.68 mmol/l) vs mg/dl (-4.56 mmol/l), p < 0.001] at week 32. A substantially greater reduction in FPG [-40.5 mg/dl (-2.25 mmol/l) vs mg/dl (-0.72 mmol/l), p < 0.001] was observed at week 1 with sitagliptin/metformin vs. pioglitazone. A greater reduction in the fasting proinsulin/insulin ratio and a greater increase in homeostasis model assessment of beta-cell function (HOMA-beta) were observed with sitagliptin/metformin than with pioglitazone, while greater decreases in fasting insulin and HOMA of insulin resistance (HOMA-IR), and a greater increase in quantitative insulin sensitivity check index (QUICKI) were observed with pioglitazone than with sitagliptin/metformin. Both sitagliptin/metformin and pioglitazone were generally well tolerated. Sitagliptin/metformin led to weight loss (-1.4 kg), while pioglitazone led to weight gain (3.0 kg) (p < for the between-group difference). Higher incidences of diarrhoea New Diabetes Medications, TZDs, and Combinations Update #1 Page 49 of 71

50 (15.3% vs. 4.3%, p < 0.001), nausea (4.6% vs. 1.2%, p = 0.02) and vomiting (1.9% vs. 0.0%, p = 0.026), and a lower incidence of oedema (1.1% vs. 7.0%, p < 0.001), were observed with sitagliptin/metformin vs. pioglitazone. The between-group difference in the incidence of hypoglycaemia did not reach statistical significance (8.4 and 4.3% with sitagliptin/metformin and pioglitazone, respectively; p = 0.055). CONCLUSION: Compared with pioglitazone, initial therapy with a FDC of sitagliptin and metformin led to significantly greater improvement in glycaemic control as well as a higher incidence of prespecified gastrointestinal adverse events, a lower incidence of oedema and weight loss vs. weight gain. Xing, Y., S. Ye, et al. (2012). "Podocyte as a potential target of inflammation: role of pioglitazone hydrochloride in patients with type 2 diabetes." Endocr Pract 18(4): OBJECTIVE: To observe the effects of pioglitazone hydrochloride on urinary sediment podocalyxin and monocyte chemoattractant protein-1 (MCP-1) excretion in patients with type 2 diabetes and to explore its possible renoprotective mechanisms. METHODS: Ninety-eight patients with uncontrolled type 2 diabetes, who were previously prescribed metformin, acarbose, or both, were randomly assigned to a DP group (add-on pioglitazone; n = 49) or a DS group (add-on sulfonylurea; n = 49). RESULTS: After 12 weeks of treatment, both add-on pioglitazone therapy (the DP group) and add-on sulfonylurea therapy (the DS group) demonstrated a similar improvement in fasting blood glucose and hemoglobin A1c, but systolic and diastolic blood pressure declined significantly in only the DP group. Moreover, the DP group showed significantly better efficacy in reducing urinary MCP-1 excretion in comparison with the DS group. Furthermore, both urinary albumin and urinary sediment podocalyxin excretion decreased significantly in the DP group but not in the DS group. The urinary sediment podocalyxin to creatinine ratio had a positive correlation with urinary albumin to creatinine ratio (r = 0.624; P<.01) and urinary MCP-1 to creatinine ratio (r = 0.346; P<.01). CONCLUSION: Pioglitazone treatment revealed a podocyte-protective capacity in patients with type 2 diabetes, and the underlying mechanisms may be partly attributed to its effective suppression of excessive local renal inflammation. Yang, W., L. Chen, et al. (2011). "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 13(1): AIM: To assess and compare the efficacy and safety of liraglutide with those of glimepiride, both in combination with metformin for the treatment of type 2 diabetes in Asian population from China, South Korea and India. METHODS: A 16-week, randomized, double-blind, double-dummy, four-arm, active control trial was carried out. In total, 929 subjects with type 2 diabetes with a mean (+/-s.d.) age of /- 9.5 years, HbA(1)(c) of 8.6 +/- 1.0% and body weight of / kg were randomized (liraglutide 0.6, 1.2 or 1.8 mg once daily or glimepiride 4 mg once daily all in combination with metformin: 1 : 1 : 1 : 1). One subject withdrew immediately after randomization and before exposure. RESULTS: HbA(1)(c) was significantly reduced in all groups compared with baseline. Treatment with liraglutide 1.2 and 1.8 mg was noninferior to glimepiride (mean HbA(1)(c) reduction: 1.36% points, 1.45% points and New Diabetes Medications, TZDs, and Combinations Update #1 Page 50 of 71

51 1.39% points, respectively). No significant difference was shown in the percentage of subjects reaching American Diabetes Association HbA(1)(c) target <7% or American Association of Clinical Endocrinologists target </=6.5% between liraglutide 1.2 and 1.8 mg and glimepiride. Liraglutide was associated with a kg mean weight reduction, compared with a 0.1 kg mean weight gain with glimepiride. Liraglutide led to a significantly greater reduction in systolic blood pressure (SBP) compared with glimepiride. Two subjects in the glimepiride group reported major hypoglycaemia while none in the liraglutide groups. Liraglutide was associated with about 10-fold lower incidence of minor hypoglycaemia than glimepiride. Gastrointestinal disorders were the most common adverse events (AEs) for liraglutide, but were transient and resulted in few withdrawals. CONCLUSIONS: In Asian subjects with type 2 diabetes, once-daily liraglutide led to improvement in glycaemic control similar to that with glimepiride but with less frequent major and minor hypoglycaemia. Liraglutide also induced a significant weight loss and reduced SBP and was generally well tolerated. The most frequently reported AE was transient nausea. The effect of liraglutide in this Asian population is comparable to the effects seen in Caucasian, African American and Hispanic populations in global liraglutide phase 3 trials. Zeitler, P., K. Hirst, et al. (2012). "A clinical trial to maintain glycemic control in youth with type 2 diabetes." N Engl J Med 366(24): BACKGROUND: Despite the increasing prevalence of type 2 diabetes in youth, there are few data to guide treatment. We compared the efficacy of three treatment regimens to achieve durable glycemic control in children and adolescents with recent-onset type 2 diabetes. METHODS: Eligible patients 10 to 17 years of age were treated with metformin (at a dose of 1000 mg twice daily) to attain a glycated hemoglobin level of less than 8% and were randomly assigned to continued treatment with metformin alone or to metformin combined with rosiglitazone (4 mg twice a day) or a lifestyle-intervention program focusing on weight loss through eating and activity behaviors. The primary outcome was loss of glycemic control, defined as a glycated hemoglobin level of at least 8% for 6 months or sustained metabolic decompensation requiring insulin. RESULTS: Of the 699 randomly assigned participants (mean duration of diagnosed type 2 diabetes, 7.8 months), 319 (45.6%) reached the primary outcome over an average follow-up of 3.86 years. Rates of failure were 51.7% (120 of 232 participants), 38.6% (90 of 233), and 46.6% (109 of 234) for metformin alone, metformin plus rosiglitazone, and metformin plus lifestyle intervention, respectively. Metformin plus rosiglitazone was superior to metformin alone (P=0.006); metformin plus lifestyle intervention was intermediate but not significantly different from metformin alone or metformin plus rosiglitazone. Prespecified analyses according to sex and race or ethnic group showed differences in sustained effectiveness, with metformin alone least effective in non-hispanic black participants and metformin plus rosiglitazone most effective in girls. Serious adverse events were reported in 19.2% of participants. CONCLUSIONS: Monotherapy with metformin was associated with durable glycemic control in approximately half of children and adolescents with type 2 diabetes. The addition of rosiglitazone, but not an intensive lifestyle intervention, was superior to metformin alone. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; TODAY ClinicalTrials.gov number, NCT ). New Diabetes Medications, TZDs, and Combinations Update #1 Page 51 of 71

52 Placebo-controlled trials Aaboe, K., F. K. Knop, et al. (2010). "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 12(4): AIM: To examine the effects of 12 weeks of treatment with the DPP-4 inhibitor, sitagliptin, on gastrointestinal hormone responses to a standardized mixed meal and beta cell secretory capacity, measured as glucose and non-glucose induced insulin secretion during a hyperglycaemic clamp, in patients with type 2 diabetes. METHOD: A doubleblinded, placebo-controlled study over 12 weeks in which 24 patients with T2DM were randomized to receive either sitagliptin (Januvia) 100 mg qd or placebo as an add-on therapy to metformin. In week 0, 1 and 12 patients underwent a meal test and a 90-min 20 mm hyperglycaemic clamp with 5 g of l-arginine infusion. Main outcome measure was postprandial total glucagon-like peptide 1 (GLP-1) concentration. Additional measures were insulin and C-peptide, glycaemic control, intact and total peptide YY (PYY) and glucose-dependent insulinotropic polypeptide (GIP), and intact glucagon-like peptide 2 (GLP-2) and GLP-1. RESULTS: All patients [sitagliptin n = 12, age: 59.5 (39-64) years, HbA1c: 8.0 ( )%, BMI: 33.2 ( ); placebo n = 12, age: 60 (31-72) years, HbA1c: 7.7 ( )%, BMI: 30.7 ( )] [median (range)] completed the trial. Sitagliptin treatment improved glycaemic control, had no effect on total GLP-1, GIP or intact GLP-2, but reduced total PYY and PYY(3-36), and increased PYY(1-36) and intact incretin hormones. Sitagliptin improved first and second phases of beta cell secretion and maximal secretory capacity. All effects were achieved after 1 week. No significant changes occurred in the placebo group. CONCLUSION: The postprandial responses of total GLP-1 and GIP and intact GLP-2 were unaltered. PYY degradation was prevented. Glucose and non-glucose induced beta cell secretion was improved. There was no difference in responses to sitagliptin between 1 and 12 weeks of treatment. Abe, M., K. Okada, et al. (2010). "Clinical effectiveness and safety evaluation of long-term pioglitazone treatment for erythropoietin responsiveness and insulin resistance in type 2 diabetic patients on hemodialysis." Expert Opin Pharmacother 11(10): BACKGROUND: We aimed to assess the effect of long-term pioglitazone treatment on erythropoietin responsiveness and insulin resistance in type 2 diabetic patients on hemodialysis. METHODS: We conducted a prospective, open-label, parallel-group, controlled study of 63 type 2 diabetic hemodialysis patients who were randomly assigned to two groups: pioglitazone group (P-group; mg/day pioglitazone plus conventional oral hypoglycemic agents) and control group (C-group; conventional oral hypoglycemic agents alone). We determined the efficacy of pioglitazone by monitoring anemia, glycemic control, insulin resistance, and levels of inflammatory cytokines and highmolecular-weight (HMW) adiponectin for 96 weeks. RESULTS: Pioglitazone effectively reduced erythropoietin dose and maintained the target hemoglobin levels by improving insulin resistance up to the end of the study. In the P-group, hemoglobin A(1c), glycated albumin, and triglycerides significantly decreased compared with the C-group. There was a significant reduction in homeostasis model assessment for insulin resistance and the level of high-sensitivity C-reactive protein, and a significant increase in HMW New Diabetes Medications, TZDs, and Combinations Update #1 Page 52 of 71

53 adiponectin level in the P-group; these changes were significantly different compared with values for the C-group. No serious adverse effects such as hypoglycemia, liver impairment, or heart failure were observed in any of the patients. CONCLUSION: Pioglitazone treatment resulted in better glycemic control, improved lipid levels, an increase in insulin sensitivity and adiponectin levels, and a decrease in inflammatory markers, thus improving the risk factors of cardiovascular disease. Erythropoietin responsiveness improved with a reduction in erythropoietin dose and may be associated with the improvement in insulin resistance due to long-term pioglitazone treatment. Barnett, A. H., B. Charbonnel, et al. (2012). "Effect of saxagliptin as add-on therapy in patients with poorly controlled type 2 diabetes on insulin alone or insulin combined with metformin." Curr Med Res Opin 28(4): OBJECTIVE: To evaluate efficacy and safety of saxagliptin as add-on therapy in patients with type 2 diabetes (T2D) with inadequate glycemic control on insulin alone or combined with metformin. METHODS: Adults (n = 455) with HbA(1c) % on stable insulin therapy ( U/day +/- metformin) for at least 8 weeks were stratified by metformin use and randomly assigned 2:1 to receive saxagliptin 5 mg or placebo once daily for 24 weeks. Patients were to maintain stable insulin doses but these could be decreased to reduce risk of hypoglycemia. Patients with hyperglycemia or substantially increased insulin use were rescued with a flexible insulin regimen and remained in the study. Metformin doses were kept stable. The primary efficacy endpoint was change in HbA(1c) from baseline to week 24 (or rescue). RESULTS: Patients treated with saxagliptin versus placebo had significantly greater reductions in adjusted mean HbA(1c) (difference: -0.41%, p < ), postprandial glucose (PPG) 180-minute area under the curve ( mg.min/dl, p = ), and 120-minute PPG (-23.0 mg/dl, p = ) at 24 weeks. Treatment with saxagliptin resulted in similar reductions in HBA(1c) relative to placebo, irrespective of metformin treatment. At 24 weeks, difference in adjusted mean fasting plasma glucose for saxagliptin versus placebo was mg/dl (p = ); 17.3% and 6.7% of patients in the saxagliptin and placebo groups, respectively, achieved HbA(1c) < 7%. Mean change from baseline in body weight at week 24 was 0.39 kg for saxagliptin and 0.18 kg for placebo. Hypoglycemia was reported in 18.4% and 19.9% of patients in the saxagliptin and placebo groups, respectively (confirmed hypoglycemia: 5.3%, 3.3%). Other adverse events reported in at least 5% of patients were urinary tract infection (saxagliptin, placebo: 5.9%, 6.0%), influenza (3.0%, 6.6%), and pain in extremity (1.6%, 6.0%). CONCLUSIONS: Saxagliptin 5-mg oncedaily add-on therapy improves glycemic control in T2D patients on insulin alone or combined with metformin and is generally well-tolerated. NCT Barzilai, N., H. Guo, et al. (2011). "Efficacy and tolerability of sitagliptin monotherapy in elderly patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial." Curr Med Res Opin 27(5): OBJECTIVE: Type 2 diabetes in the elderly is an important and insufficiently studied public health problem. This study evaluated sitagliptin monotherapy in patients with type 2 diabetes aged >/= 65 years. RESEARCH DESIGN AND METHODS: This was a randomized, double-blind, placebo-controlled, parallel-group study conducted at 52 sites in the United States. Patients were treated with once-daily sitagliptin (100 or 50 mg, New Diabetes Medications, TZDs, and Combinations Update #1 Page 53 of 71

54 depending on renal function) or placebo for 24 weeks. Key endpoints included change from baseline in glycated hemoglobin (HbA(1c)), 2-hour post-meal glucose (2-h PMG) and fasting plasma glucose (FPG) at week 24, and average blood glucose on treatment days 3 and 7. CLINICAL TRIAL REGISTRATION: NCT RESULTS: Among randomized patients (N = 206), mean age was 72 years and mean baseline HbA(1c) was 7.8%. At week 24, HbA(1c) decreased by 0.7%, 2-h PMG by 61 mg/dl, and FPG by 27 mg/dl in sitagliptin-treated patients compared with placebo (all p < 0.001). On day 3 of treatment, mean average blood glucose was decreased from baseline by 20.4 mg/dl in sitagliptin-treated patients compared with placebo (p < 0.001). In subgroups defined by baseline HbA(1c) <8.0% (n = 132), >/= 8.0% to <9.0% (n = 42), and >/= 9.0% (n = 18), the placebo-adjusted reductions in HbA(1c) with sitagliptin treatment were 0.5%, 0.9%, and 1.6%, respectively. Patients in the sitagliptin and placebo groups had similar rates of adverse events overall (46.1% and 52.9%, respectively); serious adverse events were reported in 6.9% and 13.5%, respectively. No adverse events of hypoglycemia were reported. Potential study limitations include a relatively small number of patients with more severe hyperglycemia (HbA(1c) >/= 9.0%) and the exclusion of patients with severe renal insufficiency. CONCLUSION: In this study, sitagliptin treatment significantly and rapidly improved glycemic measures and was well tolerated in patients aged >/= 65 years with type 2 diabetes. Bertrand, O. F., P. Poirier, et al. (2010). "Cardiometabolic effects of rosiglitazone in patients with type 2 diabetes and coronary artery bypass grafts: A randomized placebo-controlled clinical trial." Atherosclerosis 211(2): OBJECTIVES: To assess the efficacy and safety of rosiglitazone on saphenous vein graft (SVG) atherosclerosis prevention and on modification of the global cardiometabolic risk profile. METHODS AND RESULTS: This was a double-blind, randomized, placebocontrolled, multicenter trial which enrolled 193 post-cabg patients with type 2 diabetes. Atherosclerosis changes in one SVG were assessed with intravascular ultrasound at baseline and at 12 months. Serial cardiometabolic assessments were performed. At baseline, both groups had mean HbA(1C)<7%, LDL-cholesterol (LDL-C)<2.3 mmol/l, HDL-cholesterol (HDL-C)>1.0 mmol/l and blood pressure<130/75 mmhg. After 12 months, plaque volume in SVG had increased (median [interquartile range]) by 7.7 mm(3) (-17.2 to 37.9) in the placebo group and decreased by 0.3mm(3) (-19.1 to 22.3) in the rosiglitazone group (P=0.22). Compared to placebo, rosiglitazone treated patients had a higher (mean + or - SD) body weight (89 + or - 15 kg vs or - 15 kg, P=0.02) at the end of the study, mostly related to an increment in subcutaneous adipose tissue. Rosiglitazone treated patients also displayed further improvements in glycemic control compared to placebo (HbA(1C): or - 0.7% vs or - 0.9%, P<0.001) as well as in several cardiometabolic parameters such as lipids (HDL-C: or mmol/l vs or mmol/l, P=0.003), inflammatory profile (C-reactive protein: 0.92 mg/l [ ] vs mg/l [ ], P=0.02), and adiponectin levels (11.1 microg/ml [ ] vs microg/ml [ ], P<0.001). There was no significant difference in the incidence of serious adverse cardiovascular events. However, more patients in the rosiglitazone group had peripheral oedema (33% vs. 18%, P=0.0019). CONCLUSION: After a 12-month follow-up, we found no evidence for a statistically significant effect of rosiglitazone on SVG atherosclerosis whereas significant effects on glycemic control and New Diabetes Medications, TZDs, and Combinations Update #1 Page 54 of 71

55 on the cardiometabolic risk profile appeared to be modulated in part by changes in subcutaneous adiposity. Buse, J. B., R. M. Bergenstal, et al. (2011). "Use of twice-daily exenatide in Basal insulin-treated patients with type 2 diabetes: a randomized, controlled trial." Ann Intern Med 154(2): BACKGROUND: Insulin replacement in diabetes often requires prandial intervention to reach hemoglobin A(1)(c) (HbA(1)(c)) targets. OBJECTIVE: To test whether twice-daily exenatide injections reduce HbA(1)(c) levels more than placebo in people receiving insulin glargine. DESIGN: Parallel, randomized, placebo-controlled trial, blocked and stratified by HbA(1)(c) level at site, performed from October 2008 to January Participants, investigators, and personnel conducting the study were masked to treatment assignments. (ClinicalTrials.gov registration number: NCT ) SETTING: 59 centers in 5 countries. PATIENTS: Adults with type 2 diabetes and an HbA(1)(c) level of 7.1% to 10.5% who were receiving insulin glargine alone or in combination with metformin or pioglitazone (or both agents). INTERVENTION: Assignment by a centralized, computer-generated, random-sequence interactive voice-response system to exenatide, 10 microg twice daily, or placebo for 30 weeks. MEASUREMENTS: The primary outcome was change in HbA(1)(c) level. Secondary outcomes included the percentage of participants with HbA(1)(c) values of 7.0% or less and 6.5% or less, 7- point self-monitored glucose profiles, body weight, waist circumference, insulin dose, hypoglycemia, and adverse events. RESULTS: 112 of 138 exenatide recipients and 101 of 123 placebo recipients completed the study. The HbA(1)(c) level decreased by 1.74% with exenatide and 1.04% with placebo (between-group difference, -0.69% [95% CI, % to -0.46%]; P < 0.001). Weight decreased by 1.8 kg with exenatide and increased by 1.0 kg with placebo (between-group difference, -2.7 kg [CI, -3.7 to -1.7]). Average increases in insulin dosage with exenatide and placebo were 13 U/d and 20 U/d. The estimated rate of minor hypoglycemia was similar between groups. Thirteen exenatide recipients and 1 placebo recipient discontinued the study because of adverse events (P < 0.010); rates of nausea (41% vs. 8%), diarrhea (18% vs. 8%), vomiting (18% vs. 4%), headache (14% vs. 4%), and constipation (10% vs. 2%) were higher with exenatide than with placebo. LIMITATIONS: The study was of short duration. There were slight imbalances between groups at baseline in terms of sex, use of concomitant glucoselowering medications, and HbA(1)(c) levels, and more exenatide recipients than placebo recipients withdrew because of adverse events. CONCLUSION: Adding twice-daily exenatide injections improved glycemic control without increased hypoglycemia or weight gain in participants with uncontrolled type 2 diabetes who were receiving insulin glargine treatment. Adverse events of exenatide included nausea, diarrhea, vomiting, headache, and constipation. PRIMARY FUNDING SOURCE: Alliance of Eli Lilly and Company and Amylin Pharmaceuticals. Chacra, A. R., G. H. Tan, et al. (2011). "Safety and efficacy of saxagliptin in combination with submaximal sulphonylurea versus up-titrated sulphonylurea over 76 weeks." Diabetes & Vascular Disease Research 8(2): To assess the long-term efficacy and safety of saxagliptin in patients with type 2 diabetes mellitus inadequately controlled on sulphonylurea monotherapy, 768 patients were randomised to saxagliptin 2.5 or 5 mg in combination with glyburide 7.5 mg versus New Diabetes Medications, TZDs, and Combinations Update #1 Page 55 of 71

56 placebo added to up-titrated glyburide over 76 weeks (24 weeks plus 52-week extension) in this phase 3, double-blind, placebo-controlled trial; 557 patients completed the study, 142 without being rescued. At 76 weeks, adjusted mean changes from baseline HbA(1C) (repeated measures model) (95% confidence interval) for saxagliptin 2.5 mg, saxagliptin 5 mg, and up-titrated glyburide were 0.11% (-0.05, 0.27), 0.03% (-0.14, 0.19), and 0.69% (0.47, 0.92), respectively (post hoc and nominal p < for saxagliptin 2.5 and 5 mg vs. up-titrated glyburide). Adverse event frequency was similar in all treatment groups; reported hypoglycaemia event rates were 24.2%, 22.9%, and 20.6% with saxagliptin 2.5 mg, saxagliptin 5 mg, and up-titrated glyburide, respectively. Saxagliptin plus glyburide provided sustained incremental efficacy compared with up-titrated glyburide over 76 weeks, and was generally well tolerated. DeFronzo, R. A., P. R. Fleck, et al. (2008). "Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes and inadequate glycemic control: a randomized, double-blind, placebo-controlled study." Diabetes Care 31(12): OBJECTIVE: To evaluate the dipeptidyl peptidase-4 (DPP-4) inhibitor alogliptin in drugnaive patients with inadequately controlled type 2 diabetes. RESEARCH DESIGN AND METHODS: This double-blind, placebo-controlled, multicenter study included 329 patients with poorly controlled diabetes randomized to once-daily treatment with 12.5 mg alogliptin (n = 133), 25 mg alogliptin (n = 131), or placebo (n = 65) for 26 weeks. Primary efficacy end point was mean change from baseline in A1C at the final visit. RESULTS: At week 26, mean change in A1C was significantly greater (P < 0.001) for 12.5 mg (-0.56%) and 25 mg (-0.59%) alogliptin than placebo (-0.02%). Reductions in fasting plasma glucose were also greater (P < 0.001) in alogliptin-treated patients than in those receiving placebo. Overall, incidences of adverse events ( %) and hypoglycemia ( %) were similar across treatment groups. CONCLUSIONS: Alogliptin monotherapy was well tolerated and significantly improved glycemic control in patients with type 2 diabetes, without raising the incidence of hypoglycemia. Hollander, P. L., J. Li, et al. (2011). "Safety and efficacy of saxagliptin added to thiazolidinedione over 76 weeks in patients with type 2 diabetes mellitus." Diabetes & Vascular Disease Research 8(2): To assess the long-term efficacy and safety of saxagliptin in patients with type 2 diabetes mellitus inadequately controlled with thiazolidinedione monotherapy, 565 patients were randomised to saxagliptin (2.5 mg or 5 mg) or placebo added to thiazolidinedione over 76 weeks (24-week short-term + 52-week long-term extension period) in this phase 3, double-blind, placebo-controlled trial; 360 patients completed the study. At 76 weeks, adjusted mean changes from baseline HbA(1C) (repeated measures model; 95% CI) for saxagliptin 2.5 mg, 5 mg, and placebo were -0.59% (-0.75, -0.43), -1.09% (-1.26, -0.93), and -0.20% (-0.39, -0.01), respectively (post hoc and nominal p= and p< for saxagliptin 2.5 mg and 5 mg vs. placebo, respectively). Adverse event frequency was similar between groups. Confirmed hypoglycaemic events were 1.0% and 0% vs. 0.5% for saxagliptin 2.5 mg and 5 mg vs. placebo, respectively. Results should be interpreted with caution given the proportion of patients who discontinued or required glycaemic rescue therapy during the 76-week course of study. Saxagliptin added to New Diabetes Medications, TZDs, and Combinations Update #1 Page 56 of 71

57 thiazolidinedione provided sustained incremental efficacy vs. placebo with little hypoglycaemia for up to 76 weeks and was generally well tolerated. Iwamoto, Y., T. Taniguchi, et al. (2010). "Dose-ranging efficacy of sitagliptin, a dipeptidyl peptidase-4 inhibitor, in Japanese patients with type 2 diabetes mellitus." Endocr J 57(5): Sitagliptin is an oral, potent, highly selective, once-daily DPP-4 inhibitor indicated for the treatment of type 2 diabetes mellitus (T2DM). To assess the dose-ranging efficacy and safety/tolerability profile of once-daily sitagliptin 25, 50, 100, and 200 mg in Japanese patients with T2DM. In this randomized, double-blind, placebo-controlled study, 363 Japanese patients with inadequate glycemic control (HbA(1c)=6.5-10%; FPG< or =270 mg/dl) were randomized (1:1:1:1:1) to placebo, sitagliptin 25, 50, 100, or 200 mg q.d. for 12 weeks. The primary endpoint was change from baseline in HbA(1c) at Week 12. At Week 12, treatment with sitagliptin at all doses tested provided significant (p<0.001) reductions in HbA(1c) (-0.69 to -1.04%) from baseline (7.49 to 7.65%) relative to placebo. Sitagliptin significantly (p<0.001) reduced fasting plasma glucose (FPG; to mg/dl) and 2-hour postprandial glucose (2-hr PPG; to mg/dl) relative to placebo, in a dose-dependent manner. At doses > or =50 mg, differences in HbA(1c), FPG, and 2-hr PPG between the sitagliptin groups were not statistically significant. Sitagliptin was generally well tolerated with a low and similar incidence of hypoglycemia and minimal weight gain relative to placebo. Treatment with sitagliptin for 12 weeks provided significant and clinically meaningful reductions in HbA(1c), FPG, and 2-hr PPG across the dose range studied and was generally well tolerated in Japanese patients with T2DM. Kaku, K., T. Itayasu, et al. (2011). "Efficacy and safety of alogliptin added to pioglitazone in Japanese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial with an open-label long-term extension study." Diabetes Obes Metab 13(11): AIM: To assess the efficacy and safety of alogliptin added to pioglitazone versus pioglitazone monotherapy, in Japanese patients with type 2 diabetes who achieved inadequate glycaemic control on pioglitazone plus diet/exercise. METHODS: Patients were stabilized on pioglitazone 15 or 30 mg/day plus diet/exercise during a 16-week screening period. Patients with HbA1c of % were randomized to 12 weeks' double-blind treatment with alogliptin 12.5 or 25 mg once daily or placebo, added to their stable pioglitazone regimen. The primary endpoint was the change in HbA1c from baseline to week 12. Patients had an option to continue in a 40-week, open-label extension study, with those originally randomized to alogliptin remaining on the same dosage regimen while patients treated with placebo were randomly allocated to alogliptin 12.5 or 25 mg (added to their stable pioglitazone). RESULTS: The change from baseline in HbA1c after 12 weeks was significantly greater with alogliptin 12.5 mg added to pioglitazone and alogliptin 25 mg added to pioglitazone than with placebo added to pioglitazone (-0.91 and -0.97% vs %; p < ). Responder rates (HbA1c <6.9% and HbA1c <6.2%) and changes in fasting and postprandial blood glucose levels showed a similar positive trend in terms of glycaemic control. The benefits seen with alogliptin were sustained during the 40-week extension period. Alogliptin added to pioglitazone was generally well tolerated; hypoglycaemia was infrequent and increases in body weight were minor. CONCLUSIONS: Once-daily alogliptin was effective and generally well New Diabetes Medications, TZDs, and Combinations Update #1 Page 57 of 71

58 tolerated when given as add-on therapy to pioglitazone in Japanese patients with type 2 diabetes who achieved inadequate glycaemic control on pioglitazone plus lifestyle measures. Clinical benefits were maintained for 52 weeks. Kaku, K., M. F. Rasmussen, et al. (2010). "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 12(4): AIM: Sulphonylureas (SUs) are often used as first-line treatments for type 2 diabetes in Japan, hence it is important to study new antidiabetic drugs in combination with SUs in Japanese patients. METHODS: The efficacy and safety of the once-daily human glucagon-like peptide-1 (GLP-1) analogue liraglutide were compared in 264 Japanese subjects [mean body mass index (BMI) 24.9 kg/m(2); mean glycated haemoglobin (HBA1c) 8.4%] randomized and exposed to receive liraglutide 0.6 mg/day (n = 88), 0.9 mg/day (n = 88) or placebo (n = 88) each added to SU monotherapy (glibenclamide, glicazide or glimeprimide) in a 24-week, double-blind, parallel-group trial. RESULTS: The mean change in HBA1c from baseline to week 24 (LOCF) was (s.d. 0.84) and (s.d. 0.95) with liraglutide 0.9 and 0.6 mg respectively, and (s.d. 0.93) with placebo. HBA1c decreased in the placebo group from 8.45 to 8.06%, while liraglutide reduced HBA1c from 8.60 to 7.14%, and from 8.23 to 6.67% at the 0.6 and 0.9 mg doses respectively. Mean HBA1c at week 24 of the two liraglutide groups were significantly lower than the placebo group (p < for both). More subjects reached HBA1c < 7.0% with liraglutide (0.6 mg: 46.5%; 0.9 mg: 71.3%) vs. placebo (14.8%). Fasting plasma glucose (FPG) levels were significantly improved with liraglutide (difference mmol/l and mmol/l with 0.6 and 0.9 mg vs. placebo; p < ). Overall safety was similar between treatments: no major hypoglycaemic episodes were reported, while 84/77/38 minor hypoglycaemic episodes occurred in the 0.6 mg/0.9 mg and placebo treatment groups (all in combination with SU), reflecting lower ambient glucose levels. No relevant change in mean body weight occurred in subjects receiving liraglutide (0.6 mg: 0.06 kg; 0.9 mg: kg), while mean body weight decreased in subjects receiving placebo (-1.12 kg). CONCLUSIONS: The addition of liraglutide to SU treatment for 24 weeks dose-dependently improved glycaemic control vs. SU monotherapy, without causing major hypoglycaemia or weight gain or loss. Kutoh, E.Y. Ukai. (2012). "Alogliptin as an initial therapy in patients with newly diagnosed, drug naive type 2 diabetes: a randomized, control trial." Endocrine 41(3): The objectives of this study is to evaluate the efficacy and safety of alogliptin versus very low fat/calorie traditional Japanese diet (non-inferiority trial) as an initial therapy for newly diagnosed, drug naive subjects with type 2 diabetes (T2DM). Study design was prospective, randomized, non-double-blind, controlled trial. The study was conducted at outpatient units of municipal hospital. Patients were newly diagnosed, drug naive patients who visited the outpatient units. The patients randomly received mg/day alogliptin (n = 25) or severe low calorie traditional Japanese diet (n = 26). The procedure of this trial was assessed by the consolidated standards of reporting trials statement. The primary end point was the change of HbA1c at 3 months. Secondary end points included the changes of fasting blood glucose, insulin, homeostasis model assessment-r (HOMA- New Diabetes Medications, TZDs, and Combinations Update #1 Page 58 of 71

59 R), HOMA-B, body mass index (BMI), and lipid parameters. Similar, significant reductions of HbA1c levels were observed in both groups (from to 8.74% for alogliptin and from to 8.39% for traditional Japanese diet) without any clinically significant adverse events. In the alogliptin group, some subjects (16%) had mild hypoglycemic evens which could be managed by taking glucose drinks by themselves. HOMA-B significantly increased in both groups with varying degrees, whereas HOMA- R significantly decreased only in the Japanese diet group. Atherogenic lipids, such as, total cholesterol, non-high density lipoprotein cholesterol, and low density lipoprotein cholesterol levels significantly decreased in both groups. BMI had no change in the alogliptin group, whereas it significantly decreased in the Japanese diet group. (1) Concerning its glycemic efficacy, alogliptin is effective and non-inferior to traditional Japanese diet as an initial therapeutic option for newly diagnosed T2DM. However, regarding the reductions of body weight and insulin resistance, traditional Japanese diet is superior. (2) Both alogliptin and traditional Japanese diet have favorable effects on atherogenic lipid profiles. Liutkus, J., J. Rosas Guzman, et al. (2010). "A placebo-controlled trial of exenatide twice-daily added to thiazolidinediones alone or in combination with metformin." Diabetes Obes Metab 12(12): AIM: To test the hypothesis that glycaemic control with exenatide added to thiazolidinediones (TZDs) with or without metformin was superior to placebo. METHODS: A 26-week, multi-country (Canada, Mexico, Romania, South Africa and the USA), randomized, double-blind, placebo-controlled study compared exenatide twicedaily vs. placebo in 165 subjects suboptimally controlled with TZDs with or without metformin [HbA(1c) 8.2% (s.d. 0.9), fasting serum glucose 9.1 (2.6) mmol/l, body weight 93.9 (17.8) kg, diabetes duration 6.4 (4.3) years]. After a 2-week, single-blind, lead-in period, subjects were randomly assigned (2 : 1) to add exenatide or placebo to current regimens. The primary endpoint was HbA(1c) change at endpoint (Week 26 or lastobservation-carried-forward). RESULTS: Only 8 subjects were treated with concomitant TZD alone. Exenatide reduced HbA(1c) significantly more than placebo [-0.84% (s.e. 0.20) vs % (0.23), treatment difference -0.74% (0.16), p < 0.001)]. Mean reductions in body weight were similar in both treatments at endpoint [exenatide, -1.4 (s.e. 0.6) kg vs. placebo, -0.8 (0.7) kg, p = 0.176)]. Nearly 71% of subjects had both a reduction in HbA(1c) and body weight with exenatide compared with 54% with placebo. The most common adverse events (exenatide vs. placebo) were nausea (12% vs. 2%, p = 0.037), vomiting (8% vs. 0%, p = 0.031) and headache (4% vs. 4%). Confirmed (blood glucose <3.0 mmol/l) minor hypoglycaemia was experienced by 4 and 2% of subjects treated with exenatide and placebo, respectively. Incidence of hypoglycaemia was not significantly different between groups. CONCLUSIONS: Exenatide added to TZDs alone or in combination with metformin significantly improved glycaemic control as determined by significant improvement in HbA(1c) without associated hypoglycaemia. Makdissi, A., H. Ghanim, et al. (2012). "Sitagliptin exerts an antinflammatory action." J Clin Endocrinol Metab 97(9): CONTEXT: Sitagliptin is an inhibitor of the enzyme dipeptidyl peptidase-iv (DPP-IV), which degrades the incretins, glucagon-like peptide-1 and glucose-dependent New Diabetes Medications, TZDs, and Combinations Update #1 Page 59 of 71

60 insulinotropic polypeptide, and thus, sitagliptin increases their bioavailability. The stimulation of insulin and the suppression of glucagon secretion that follow exert a glucose lowering effect and hence its use as an antidiabetic drug. Because DPP-IV is expressed as CD26 on cell membranes and because CD26 mediates proinflammatory signals, we hypothesized that sitagliptin may exert an antiinflammatory effect. PATIENTS AND METHODS: Twenty-two patients with type 2 diabetes were randomized to receive either 100 mg daily of sitagliptin or placebo for 12 wk. Fasting blood samples were obtained at baseline and at 2, 4, and 6 hours after a single dose of sitagliptin and at 2, 4, 8, and 12 wk of treatment. RESULTS: Glycosylated hemoglobin fell significantly from 7.6 +/- 0.4 to 6.9 +/- 3% in patients treated with sitagliptin. Fasting glucagon-like peptide-1 concentrations increased significantly, whereas the mrna expression in mononuclear cell of CD26, the proinflammatory cytokine, TNFalpha, the receptor for endotoxin, Toll-like receptor (TLR)-4, TLR-2, and proinflammatory kinases, c-jun N-terminal kinase-1 and inhibitory-kappab kinase (IKKbeta), and that of the chemokine receptor CCR-2 fell significantly after 12 wk of sitagliptin. TLR-2, IKKbeta, CCR-2, and CD26 expression and nuclear factor-kappab binding also fell after a single dose of sitagliptin. There was a fall in protein expression of c-jun N-terminal kinase-1, IKKbeta, and TLR-4 and in plasma concentrations of C-reactive protein, IL-6, and free fatty acids after 12 wk of sitagliptin. CONCLUSIONS: These effects are consistent with a potent and rapid antiinflammatory effect of sitagliptin and may potentially contribute to the inhibition of atherosclerosis. The suppression of CD26 expression suggests that sitagliptin may inhibit the synthesis of DPP-IV in addition to inhibiting its action. Naka, K. K., K. Papathanassiou, et al. (2011). "Rosiglitazone improves endothelial function in patients with type 2 diabetes treated with insulin." Diabetes & Vascular Disease Research 8(3): An increased incidence of myocardial infarction with rosiglitazone in patients with type 2 diabetes mellitus (T2DM) has been reported. This study aimed to assess the effect of rosiglitazone on endothelial function, assessed by flow-mediated dilation (FMD), in 34 patients with advanced T2DM treated with insulin without known cardiovascular disease. Patients were randomised into two groups: no additional treatment was given in 17 patients, while 17 patients were given rosiglitazone for 6 months. Addition of rosiglitazone significantly reduced glycosylated haemoglobin (HbA(1c)) (p < ) and fasting glucose (p < 0.05) and improved FMD (p < 0.005). No significant changes were observed in the insulin-only group. The single independent predictor of FMD improvement was rosiglitazone treatment (p = 0.048). These results show that, in patients with advanced T2DM treated with insulin, addition of rosiglitazone may have a beneficial effect on endothelial function. Further research is needed to investigate why this beneficial effect does not translate into improved cardiovascular prognosis in these patients. Nauck, M. A., G. C. Ellis, et al. (2009). "Efficacy and safety of adding the dipeptidyl peptidase-4 inhibitor alogliptin to metformin therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a multicentre, randomised, double-blind, placebo-controlled study." Int J Clin Pract 63(1): New Diabetes Medications, TZDs, and Combinations Update #1 Page 60 of 71

61 AIMS: To evaluate the efficacy and safety of alogliptin, a new dipeptidyl peptidase-4 inhibitor, for 26 weeks at once-daily doses of 12.5 and 25 mg in combination with metformin in patients whose HbA(1c) levels were inadequately controlled on metformin alone. METHODS AND PATIENTS: Patients with type 2 diabetes and inadequate glycaemic control (HbA(1c) %) were randomised to continue a stable daily metformin dose regimen (> or = 1500 mg) plus the addition of placebo (n = 104) or alogliptin at once-daily doses of 12.5 (n = 213) or 25 mg (n = 210). HbA(1c), insulin, proinsulin, C-peptide and fasting plasma glucose (FPG) concentrations were determined over a period of 26 weeks. RESULTS: Alogliptin at either dose produced least squares mean (SE) decreases from baseline in HbA(1c) of -0.6 (0.1)% and in FPG of (2.5) mg/dl [-1.0 (0.1) mmol/l], decreases that were significantly (p < 0.001) greater than those observed with placebo. The between treatment differences (alogliptin - placebo) in FPG reached statistical significance (p < 0.001) as early as week 1 and persisted for the duration of the study. Overall, adverse events (AEs) observed with alogliptin were not substantially different from those observed with placebo. This includes low event rates for gastrointestinal side effects and hypoglycaemic episodes. There was no dose-related pattern of AE reporting between alogliptin groups and few serious AEs were reported. CONCLUSION: Alogliptin is an effective and safe treatment for type 2 diabetes when added to metformin for patients not sufficiently controlled on metformin monotherapy. Nowicki, M., I. Rychlik, et al. (2011). "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 65(12): OBJECTIVE: Therapeutic options are limited for diabetes patients with renal disease. This report presents 52-week results from a study assessing the dipeptidyl peptidase-4 inhibitor saxagliptin in patients with type 2 diabetes mellitus (T2DM) and renal impairment. DESIGN: Double-blind study in patients stratified by baseline renal impairment (moderate, severe or end-stage renal disease [ESRD] on haemodialysis) randomised to saxagliptin 2.5 mg once daily or placebo added to other antidiabetic drugs in use at baseline, including insulin. PATIENTS: A total of 170 adults with glycated haemoglobin (HbA(1c) ) 7-11% and creatinine clearance < 50 ml/min or ESRD were randomised and treated. MEASUREMENTS: Absolute changes in HbA(1c) and fasting plasma glucose (FPG) from baseline to week 52 were evaluated using analysis of covariance (ANCOVA) with last observation carried forward. Repeated-measures analyses were also performed. RESULTS: Adjusted mean decrease in HbA(1c) was greater with saxagliptin than placebo (difference, -0.73%, p < [ANCOVA]). Reductions in adjusted mean HbA(1c) were numerically greater with saxagliptin than placebo in patients with renal impairment rated as moderate (-0.94% vs. 0.19% respectively) or severe (-0.81% vs %), but similar to placebo for those with ESRD (-1.13% vs %). Reductions in adjusted mean FPG were numerically greater with saxagliptin in patients with moderate or severe renal impairment. Saxagliptin was generally well tolerated; similar proportions of patients in the saxagliptin and placebo groups reported hypoglycaemic events (28% and 29% respectively). CONCLUSIONS: Saxagliptin 2.5 mg once daily offers sustained efficacy and good tolerability for patients with T2DM and renal impairment. New Diabetes Medications, TZDs, and Combinations Update #1 Page 61 of 71

62 Nowicki, M., I. Rychlik, et al. (2011). "Saxagliptin improves glycaemic control and is well tolerated in patients with type 2 diabetes mellitus and renal impairment." Diabetes Obes Metab 13(6): AIM: To evaluate the efficacy and safety of saxagliptin vs. placebo in patients with type 2 diabetes mellitus (T2DM) and renal impairment. METHODS: In this multicentre, randomized, parallel-group, double-blind, placebo-controlled study, patients with glycated haemoglobin (HbA1c) 7-11% and creatinine clearance <50 ml/min were stratified by baseline renal impairment (moderate, severe or end-stage on haemodialysis), and randomized (1 : 1) to saxagliptin 2.5 mg once daily or placebo for 12 weeks. Oral antihyperglycaemic drugs and insulin therapy present at enrolment were continued throughout the study. The absolute change in HbA1c from baseline to week 12 (primary efficacy end-point) was analysed using an analysis of covariance model with last observation carried forward methodology. RESULTS: A total of 170 patients were randomized and treated. The adjusted mean decrease from baseline to week 12 in HbA1c was statistically significantly greater in the saxagliptin group than in the placebo group; the difference between treatments was -0.42% (95% confidence interval: to -0.12%, p = 0.007). Adjusted mean HbA1c decreases from baseline to week 12 were numerically greater with saxagliptin than with placebo in the subgroups of patients with moderate ( vs %) and severe (-0.95 vs %) renal impairment. HbA1c reductions were similar between saxagliptin and placebo in the subgroup with end-stage renal disease on haemodialysis (-0.84 vs %). Saxagliptin was generally well tolerated; incidences of adverse events and hypoglycaemic events were similar to placebo. CONCLUSIONS: Saxagliptin 2.5 mg once daily is a well-tolerated treatment option for patients with inadequately controlled T2DM and renal impairment. Oz, O., S. Kiyici, et al. (2011). "Effect of sitagliptin monotherapy on serum total ghrelin levels in people with type 2 diabetes." Diabetes Res Clin Pract 94(2): AIM: Sitagliptin is not associated with weight gain and has neutral effects on body weight. It is unclear whether sitagliptin treatment alters serum ghrelin levels in people with type 2 diabetes. METHODS: Forty-four subjects with type 2 diabetes were randomly assigned to receive sitagliptin or medical nutrition therapy (MNT) for 12 weeks. Changes in anthropometric variables, glycemic control, insulin resistance, lipid parameters, and total ghrelin levels were evaluated at baseline and following 12 weeks of treatment. RESULTS: Significant decreases in body weight and body mass index were observed over the entire study period in both treatment groups. Glycosylated hemoglobin and postprandial plasma glucose levels were statistically significant decreased in the groups receiving sitagliptin compared with baseline values (p=0.021 and p=0.021, respectively), while they were unchanged in the groups receiving MNT. There was a significant decrease in total ghrelin in the groups receiving sitagliptin (p=0.04) compared with baseline values but not in the groups receiving MNT (p=0.46) at the end of the 12 weeks. CONCLUSIONS: In this study of patients with type 2 diabetes, treatment with sitagliptin was associated with a significant decrease in serum ghrelin levels. These results suggest that the neutral effect of sitagliptin on weight might be associated with the suppression of fasting serum ghrelin levels. New Diabetes Medications, TZDs, and Combinations Update #1 Page 62 of 71

63 Pan, C. Y., W. Yang, et al. (2012). "Efficacy and safety of saxagliptin in drug-naive Asian patients with type 2 diabetes mellitus: a randomized controlled trial." Diabetes/Metabolism Research Reviews 28(3): BACKGROUND: Few studies have assessed the use of new oral anti-diabetic agents in Asian populations. This study assesses the efficacy and safety of saxagliptin versus placebo in Asian patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: Five hundred sixty-eight drug-naive adult patients with T2DM and glycated haemoglobin levels (HbA(1c)) of % (53-86 mmol/mol) were randomized 1 : 1 to receive saxagliptin 5 mg daily or placebo. Efficacy endpoints included changes from baseline to week 24 in HbA(1c), fasting plasma glucose (FPG), post-prandial glucose area under the curve from 0 to 180 min (PPG AUC(0-180)), and the proportion of patients achieving HbA(1c) <7.0% (53 mmol/mol). Adverse events (AEs) and serious AEs (SAEs) were evaluated. RESULTS: Saxagliptin provided statistically significant adjusted mean decreases from baseline to week 24 compared with placebo, respectively, in HbA(1c) (-0.84% [-9 mmol/mol] versus -0.34% [-4 mmol/mol]; p < ), FPG ( versus mmol/l; p < ), and PPG AUC(0-180) (-417 versus -235 mmol. min/l; p = ). A significantly greater proportion of patients achieved a therapeutic glycaemic response (HbA(1c) <7.0% [53 mmol/mol]) with saxagliptin (45.8%) versus placebo (28.8%; p < ). The proportions of patients who experienced >/=1 AE (excluding hypoglycaemia) was 43.3% for saxagliptin and 35.6% for placebo. Few patients in either treatment group experienced an SAE (2.8%, saxagliptin; 1.4%, placebo). A low proportion of patients reported hypoglycaemic events (1.8%, saxagliptin; 0.7%, placebo). CONCLUSIONS: Saxagliptin improved glycaemic control and was well tolerated in drug-naive Asian patients with T2DM. Pratley, R. E., M. S. Kipnes, et al. (2009). "Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes inadequately controlled by glyburide monotherapy." Diabetes Obes Metab 11(2): AIM: To evaluate the efficacy and safety of alogliptin, a potent and highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor, in combination with glyburide in patients with type 2 diabetes inadequately controlled by sulphonylurea monotherapy. METHODS: After a 2-week screening period, adult patients years of age entered a 4-week runin/stabilization period in which they were switched from their own sulphonylurea medication to an equivalent dose of glyburide (open label) plus placebo (single blind). After the run-in period, patients were randomly assigned to double-blind treatment with alogliptin 12.5 mg (n = 203), alogliptin 25 mg (n = 198), or placebo (n = 99) for 26 weeks. The primary end-point was change from baseline to week 26 in glycosylated haemoglobin (HbA1c). Secondary end-points included clinical response rates and changes in fasting plasma glucose, beta-cell function (fasting proinsulin, insulin, proinsulin/insulin ratio, and C-peptide, and homeostasis model assessment beta-cell function), body weight, and safety end-points [adverse events (AEs), clinical laboratory tests, vital signs and electrocardiographic readings]. RESULTS: The study population had a mean age of 57 years and a mean disease duration of 8 years; it was well balanced for gender (52% women) and was mainly white (71%). The mean baseline HbA1c was approximately 8.1% in each group. Significantly greater least squares (LS) mean reductions in HbA1c were seen at week 26 with alogliptin 12.5 mg (-0.38%) and 25 mg (- New Diabetes Medications, TZDs, and Combinations Update #1 Page 63 of 71

64 0.52%) vs. placebo (+0.01%; p < 0.001), and more patients in the alogliptin 25-mg group had HbA1c levels < or =7.0% at week 26 (34.8%, p = 0.002) vs. placebo (18.2%). Proportionately more patients in the alogliptin 12.5 mg (47.3%) and 25 mg (50.5%) groups had an HbA1c reduction > or =0.5% from baseline compared with patients in the placebo group (26.3%; p < 0.001). Minor improvements in individual markers of betacell function were seen with alogliptin, but no significant treatment group differences were noted relative to placebo. Minor LS mean changes in body weight were noted across groups (placebo, kg; alogliptin 12.5 mg, kg; alogliptin 25 mg, kg). AEs were reported for 63-64% of patients receiving alogliptin and 54% of patients receiving placebo. Few AEs were treatment limiting ( % across groups), and serious AEs ( %) were infrequent, similar across groups, and generally considered not related to treatment. The incidences of hypoglycaemia for placebo, alogliptin 12.5 mg and alogliptin 25 mg groups were 11.1, 15.8 and 9.6% respectively. CONCLUSIONS: In patients with type 2 diabetes inadequately controlled by glyburide monotherapy, the addition of alogliptin resulted in clinically significant reductions in HbA1c without increased incidence of hypoglycaemia. Rennings, A. J., P. Smits, et al. (2010). "Autonomic neuropathy predisposes to rosiglitazoneinduced vascular leakage in insulin-treated patients with type 2 diabetes: a randomised, controlled trial on thiazolidinedione-induced vascular leakage." Diabetologia 53(9): AIMS/HYPOTHESIS: The mechanism of fluid-related complications caused by thiazolidinedione derivatives is unclear. One potential mechanism is thiazolidinedioneinduced arterial vasodilatation, which results in vascular leakage and a fall in blood pressure, normally counterbalanced by sympathetic activation and subsequent renal fluid retention. We hypothesised that thiazolidinedione-induced vascular leakage will be particularly prominent in patients with autonomic neuropathy. METHODS: We conducted a randomised, double-blind, placebo-controlled, parallel study in 40 patients with type 2 diabetes on insulin treatment recruited from a university medical centre. The randomisation was performed by a central office using a randomisation schedule. Both treatment groups, placebo (n = 21) and rosiglitazone (n = 19), were stratified for sex and level of autonomic neuropathy as assessed by Ewing score (<2.5 or >or=2.5). We investigated the effects of 16 weeks of treatment with rosiglitazone 4 mg twice daily on vascular leakage (transcapillary escape rate of albumin, TERalb), body weight, extracellular volume and plasma volume. RESULTS: Thirty-nine patients were included in the analysis. In patients with high Ewing scores (n = 16), rosiglitazone increased TERalb significantly (DeltaTERalb: rosiglitazone /- 0.45%/h, placebo /- 0.15%/h, p = 0.002), while rosiglitazone had no effect in the patients with low Ewing scores (n = 23). Rosiglitazone-induced increases in TERalb and Ewing score at baseline were correlated (r = 0.65, p = 0.02). There was no correlation between Ewing score and rosiglitazone-induced changes in fluid variables. One subject was withdrawn from the study because of atrial fibrillation. CONCLUSIONS/INTERPRETATION: Rosiglitazone may increase vascular leakage in insulin-treated patients with type 2 diabetes with autonomic neuropathy. Autonomic neuropathy did not exaggerate rosiglitazone-induced fluid retention. Therefore, autonomic neuropathy should be considered as a risk factor for thiazolidinedione-induced oedema, not for thiazolidinedione-induced fluid retention. New Diabetes Medications, TZDs, and Combinations Update #1 Page 64 of 71

65 TRIAL REGISTRATION: ClinicalTrials.gov NCT FUNDING: GlaxoSmithKline. Rosenstock, J., M. S. Rendell, et al. (2009). "Alogliptin added to insulin therapy in patients with type 2 diabetes reduces HbA(1C) without causing weight gain or increased hypoglycaemia." Diabetes Obes Metab 11(12): AIMS: To assess the efficacy and safety of alogliptin added to insulin in patients with type 2 diabetes inadequately controlled with insulin alone or combined with metformin. METHODS: In this 26-week, double-blind, placebo-controlled study, 390 patients were randomized to receive alogliptin 12.5 mg (n = 131), alogliptin 25 mg (n = 129) or placebo (n = 130) once daily, as add-on to stable insulin therapy with or without metformin. The primary endpoint was change in haemoglobin A(1C) (HbA(1C)) at week 26. RESULTS: At week 26, mean HbA(1C) changes from the mean baseline value of 9.3% were significantly greater for alogliptin 12.5 mg ( /- 0.08%) and alogliptin 25 mg ( /- 0.08%) than placebo ( /- 0.08%; p < 0.001). Significantly greater proportions of patients receiving alogliptin 12.5 or 25 mg than placebo had HbA(1C) decreases of > or =0.5, > or =1.0 and > or =1.5%. Insulin doses remained unchanged, and there were no differences in the proportions of patients experiencing hypoglycaemia among placebo (24%), alogliptin 12.5 mg (27%) and alogliptin 25 mg (27%). Mean weight increases from baseline at week 26 were similar for placebo (0.6 +/- 0.2 kg), alogliptin 12.5 mg (0.7 +/- 0.2 kg) and alogliptin 25 mg (0.6 +/- 0.2 kg). Incidences of overall adverse events, and of gastrointestinal, dermatological and infection-related events, were similar among groups. CONCLUSIONS: Adding alogliptin to previous insulin therapy (with or without metformin) significantly improved glycaemic control in patients with type 2 diabetes inadequately controlled on insulin, without causing weight gain or increasing the incidence of hypoglycaemia. Further studies are warranted to explore the role of alogliptin added to optimized basal insulin regimens. Saiki, A., M. Ohira, et al. (2010). "Pioglitazone decreases plasma angiotensin II concentration in type 2 diabetes." J Atheroscler Thromb 17(6): AIM: Adipocytes express all components of the renin-angiotensin system (RAS), and adipocyte RAS regulates adipocyte differentiation and metabolism. Plasma angiotensin II (AII) is a putative marker of adipocyte RAS production. The aim of this study was to investigate the effect of pioglitazone on plasma AII in type 2 diabetes (T2D). METHODS: Fifty Japanese subjects with T2D were randomly allocated to two groups. One group was administered pioglitazone 30 mg/day (pioglitazone group) and the other group was not given pioglitazone (control group) for 16 weeks. Lipoprotein lipase mass in preheparin serum (LPL mass) was measured as an adipocyte-derived factor and a marker of insulin sensitivity. RESULTS: In the pioglitazone group, the mean HbA1c decreased (p<0.0001), LPL mass increased (p<0.0001), and plasma AII decreased (p=0.0007), whereas these parameters were unchanged in the control group. The change in plasma AII correlated negatively with the change in LPL mass (r=-0.312) in the pioglitazone group. In the pioglitazone group, the decrease in plasma AII was higher (p=0.0002) and the increase in LPL mass tended to be higher (p=0.0941) in the subgroup with higher baseline plasma AII than that with lower plasma AII. CONCLUSIONS: The present study indicates that pioglitazone decreases plasma AII associated with an increase New Diabetes Medications, TZDs, and Combinations Update #1 Page 65 of 71

66 in LPL mass in T2D. The insulin-sensitizing effect of pioglitazone may be involved in suppressing adipocyte RAS. Seino, Y., T. Fujita, et al. (2011). "Alogliptin plus voglibose in Japanese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial with an open-label, long-term extension." Curr Med Res Opin 27 Suppl 3(21-9. OBJECTIVE: To compare the efficacy and safety of alogliptin and placebo as add-on therapy in Japanese patients with type 2 diabetes who experienced inadequate glycemic control on voglibose plus diet/exercise therapy. RESEARCH DESIGN AND METHODS: During an 8 week screening phase, patients aged >/= 20 years were stabilized on voglibose 0.2 mg three times daily plus diet/exercise therapy. Those with HbA1c between >/= 6.9% and <10.4% were randomly assigned to 12 weeks' doubleblind treatment with once daily alogliptin 12.5 or 25 mg, or placebo. The primary endpoint was the change in HbA1c at 12 weeks from baseline. Patients then entered an open-label, 40 week extension trial (patients in the placebo group were randomly allocated to alogliptin 12.5 or 25 mg). CLINICAL TRIALS REGISTRATION: ; pivotal trial NCT ; Long term trial NCT RESULTS: Least square mean change in HbA1c after 12 weeks' therapy from baseline (primary endpoint) was significantly greater in the alogliptin 12.5 mg (-0.96%; P < ) and 25 mg (-0.93%; P < ) groups compared with placebo (+0.06%). This was associated with statistically significant improvements in other measures of glycemic control, in particular sustained reductions in fasting plasma glucose and postprandial plasma glucose. These benefits were maintained for the duration of the 1 year study and, importantly, they were achieved without detrimental effects on tolerability/safety. In particular, there was no increase in the rate of hypoglycemia and almost no changes in mean body weight. CONCLUSIONS: Addition of once daily alogliptin to voglibose monotherapy in Japanese patients with uncontrolled type 2 diabetes produced clinically significant improvements in glycemic control, and was well tolerated. Shah, P. K., S. Mudaliar, et al. (2011). "Effects of intensive insulin therapy alone and in combination with pioglitazone on body weight, composition, distribution and liver fat content in patients with type 2 diabetes." Diabetes Obes Metab 13(6): AIM: To evaluate the effects of intensive insulin therapy alone and with added pioglitazone on body weight, fat distribution, lean body mass (LBM) and liver fat in type 2 diabetic patients. METHODS: Twenty-five insulin-treated, obese patients with type 2 diabetes were randomized to addition of pioglitazone 45 mg (n = 12) or placebo (n = 13) and treated intensively for weeks. Dual-energy X-ray absorptiometry/abdominal computed tomography scans were performed before/after treatment. LBM, visceral/subcutaneous adipose tissue (VAT/SAT) and liver/spleen (L/S) attenuation ratios were measured pre-/posttreatment (a ratio <1 represents fatty liver). RESULTS: Intensive insulin alone and insulin + pioglitazone significantly improved glycaemic control (7.8 +/- 0.3 to 7.2 +/- 0.3% and 7.6 +/- 0.3 to 7.1 +/- 0.4%, respectively). Body weight gain was greater with insulin + pioglitazone (4.9 +/- 4.5 kg) versus insulin therapy alone (1.7 +/- 0.7 kg). SAT increased significantly with pioglitazone + insulin therapy ( / to / cm(2), p < 0.01) compared to a non-significant increase with insulin therapy alone ( / to / cm(2) ). VAT decreased non-significantly New Diabetes Medications, TZDs, and Combinations Update #1 Page 66 of 71

67 in both groups ( / to / cm(2) with insulin + pioglitazone and / to / cm(2) with insulin therapy). LBM increased significantly by / kg with insulin + pioglitazone treatment. The L/S attenuation ratio in the placebo + insulin group decreased from /- 0.1 to /- 0.1 (p = ns) and increased from /- 0.1 to / (p = 0.06) in the pioglitazone + insulin group. CONCLUSIONS: Intensification of insulin therapy in type 2 diabetic patients causes modest weight gain and no change in body fat distribution, LBM or liver fat. In contrast, the addition of pioglitazone, at equivalent glycaemia, increases weight gain, fat mass and SAT; increases LBM and tends to decrease liver fat. These changes in fat distribution may contribute to the beneficial effects of pioglitazone, despite greater weight gain. Truitt, K. E., R. B. Goldberg, et al. (2010). "A 26-week, placebo- and pioglitazone-controlled, dose-ranging study of rivoglitazone, a novel thiazolidinedione for the treatment of type 2 diabetes." Curr Med Res Opin 26(6): OBJECTIVE: To examine the efficacy and general safety of rivoglitazone, a novel thiazolidinedione, as a treatment for type 2 diabetes in a dose-ranging study over a period of up to 6 months. RESEARCH DESIGN AND METHODS: A 26-week, randomized, double-blind, double-dummy, placebo- and active comparator (pioglitazone 45 mg)- controlled study designed to evaluate the efficacy and safety of once-daily rivoglitazone 1, 2, or 3 mg in subjects with type 2 diabetes. The study was conducted in adults with type 2 diabetes (glycated hemoglobin [HbA(1c)] >or=7.0% and <10.5%) who were either naive to prior antidiabetes drug treatment or discontinued pre-study antidiabetes medications and were switched to study medication. A total of 441 subjects were randomized, using an equal allocation schedule to one of five treatment arms, including placebo. The primary efficacy measurement was the change in HbA(1c) from baseline to week 26 in the intent-to-treat population (last observation carried forward), for drug treatments minus placebo (placebo-subtracted). Clinical Trial Registration: ClinicalTrials.gov Identifier NCT RESULTS: The incidence of early discontinuations was >50%, with most cases being related to a lack of efficacy (highest on placebo) or adverse experiences (highest on rivoglitazone 3 mg). Rivoglitazone 1, 2, and 3 mg and pioglitazone 45 mg were more effective than placebo in reducing HbA(1c) from baseline to week 26 (placebo-subtracted change from baseline: -0.55% [p = ], -0.99% [p < ], -1.10% [p < ], and -0.59% [p = ], respectively). In general, all treatments were safe. The most common drug-related adverse events reported with rivoglitazone were peripheral edema and weight gain; incidences increased with dose and were higher with rivoglitazone 2 and 3 mg than with pioglitazone or rivoglitazone 1 mg. CONCLUSIONS: Rivoglitazone is a potent thiazolidinedione agent with demonstrated glycemic benefits over a 6-month period in subjects with type 2 diabetes. Once-daily doses of 1, 2, and 3 mg rivoglitazone demonstrated HbA(1c) reduction similar or superior to those observed for pioglitazone 45 mg. Limitations in generalizing from this study include a modest sample size and a high rate of discontinuation prior to the last scheduled visit. Wu, J. D., X. H. Xu, et al. (2011). "Effect of exenatide on inflammatory and oxidative stress markers in patients with type 2 diabetes mellitus." Diabetes Technol Ther 13(2): New Diabetes Medications, TZDs, and Combinations Update #1 Page 67 of 71

68 AIM: This study was designed to determine the effect of exenatide on inflammatory and oxidative stress markers in type 2 diabetes mellitus (T2DM) patients who were suboptimally controlled with metformin and/or sulfonylurea. SUBJECTS AND METHODS: Twenty-three patients with T2DM with inadequate glucose control were randomly divided into two groups: exenatide group (E group) (12 patients, 5 mug b.d. x 4 weeks followed by 10 mug b.d. x 12 weeks) and placebo group (P group) (11 patients). Glycosylated hemoglobin (HbA1c), the seven-point glucose profile, daily mean glucose, and glycemic excursion were determined. The effects of exenatide on 8-iso-prostaglandin F2alpha (PGF2alpha), monocyte chemoattractant protein-1 (MCP-1), and high-sensitivity C-reactive protein (hs-crp) were investigated. RESULTS: Exenatide treatment reduced body weight and body mass index (BMI) and improved HbA1c, the seven-point glucose profile, and daily mean glucose compared with placebo (P < 0.05). Limited glycemic excursion was found in the E group compared with the P group (P < 0.05), including a smaller SD and postprandial glucose excursion. In addition, the oxidative stress maker PGF2alpha was significantly reduced by exenatide treatment (P < 0.05). The inflammatory markers hs-crp and MCP-1 were also significantly reduced in the E group compared with the P group (P < 0.05). PGF2alpha was significantly correlated with glycemic excursion (P < 0.05), whereas MCP-1 was significantly correlated with body weight, BMI, glycemic excursion, and HbA1c (P < 0.05 for all). CONCLUSIONS: Exenatide treatment reduced patient body weight and BMI, improved HbA1c and the seven-point glucose profile, reduced daily mean glucose, limited glycemic excursion, and reduced oxidative stress and inflammatory markers in patients of T2DM having inadequate glucose control. Yang, W., C. Y. Pan, et al. (2011). "Efficacy and safety of saxagliptin added to metformin in Asian people with type 2 diabetes mellitus: a randomized controlled trial." Diabetes Res Clin Pract 94(2): AIM: To assess efficacy and safety of saxagliptin added to metformin versus placebo plus metformin in Asian patients with type 2 diabetes mellitus (T2DM) and inadequate glycemic control on metformin alone. METHODS: Adults (HbA(1c) %, on stable metformin >/= 1500 mg/day) were randomized 1:1 to saxagliptin 5mg daily plus metformin (n = 283) or placebo plus metformin (n = 287). The primary end point was HbA(1c) change from baseline to Week 24. RESULTS: Saxagliptin plus metformin provided significant adjusted mean decreases versus placebo plus metformin (p </= ) in HbA(1c) (-0.78% versus -0.37%), fasting plasma glucose (-1.14 mmol/l versus mmol/l), and postprandial glucose area under the curve from 0 to 180 min (- 315 mmol min/l versus -160 mmol min/l). Significantly more saxagliptin-treated patients achieved a therapeutic glycemic response (HbA(1c)<7.0%) (46.5% versus 30.5%; p = ). The proportion of patients experiencing adverse events (excluding hypoglycemia) was similar for saxagliptin plus metformin (42.8%) versus placebo plus metformin (40.8%). Hypoglycemic events were reported in 1.4% of patients in each group. CONCLUSION: Saxagliptin added to metformin significantly improved glycemic control and was well tolerated in Asian patients with T2DM who had inadequate glycemic control with metformin and diet and lifestyle modification. Secondary analyses of included primary trial publications New Diabetes Medications, TZDs, and Combinations Update #1 Page 68 of 71

69 Erdmann, E., R. Spanheimer, et al. (2010). "Pioglitazone and the risk of cardiovascular events in patients with Type 2 diabetes receiving concomitant treatment with nitrates, renin-angiotensin system blockers, or insulin: results from the PROactive study (PROactive 20)." J Diabetes 2(3): BACKGROUND: Patients with Type 2 diabetes mellitus (T2DM) are often treated with multiple glucose-lowering and cardiovascular agents. The concomitant use of nitrates, renin-angiotensin system (RAS) blockers, or insulin has been linked to a potential increase in myocardial ischemic risk with rosiglitazone. The PROactive database provides an opportunity to investigate the effects of these medications on the potential macrovascular benefits reported with pioglitazone. METHODS: The PROactive study was a randomized double-blind prospective trial that evaluated mortality and cardiovascular morbidity in 5238 patients with T2DM and macrovascular disease. Patients received pioglitazone or placebo in addition to their baseline glucose-lowering and cardiovascular medications. The effect of pioglitazone on composite endpoints was evaluated, including all-cause death, myocardial infarction (MI), and stroke, as well as safety events of edema and serious heart failure, in subgroups using nitrates, RAS blockers, or insulin at baseline. RESULTS: The risk of all-cause death, MI, and stroke for pioglitazone versus placebo was similar regardless of the baseline use of nitrates, RAS blockers, or insulin, with hazard ratios ranging from 0.81 to Similar results were obtained for the other composite endpoints analyzed. There were no significant interactions between baseline medication subgroups and treatment. The increased risk of edema and serious heart failure was consistent across the baseline medication subgroups. CONCLUSIONS: This post hoc analysis did not reveal an increased risk of macrovascular events with pioglitazone in patients receiving nitrates, RAS blockers, or insulin. Rather, all patients realized the same trend towards benefit with pioglitazone, and adverse events of edema and heart failure were predictable. Home, P. D., S. E. Kahn, et al. (2010). "Experience of malignancies with oral glucose-lowering drugs in the randomised controlled ADOPT (A Diabetes Outcome Progression Trial) and RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycaemia in Diabetes) clinical trials." Diabetologia 53(9): AIMS/HYPOTHESIS: Observational and mechanistic studies have suggested a possible relationship between treatment with metformin and decreased incidence of cancer in participants with type 2 diabetes. We extracted data for malignancies from the ADOPT (A Diabetes Outcome Progression Trial) and RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycaemia in Diabetes) randomised controlled clinical trials, in which the efficacy and/or safety of metformin was assessed in comparison with sulfonylureas and rosiglitazone. METHODS: Neoplasm occurrences were collected as adverse events in these studies. We reviewed and re-analysed the individual participant data in both studies for serious adverse events, malignancies reported as adverse events and related neoplasms of special interest. RESULTS: In ADOPT, 50 participants (3.4%) on metformin and 55 (3.8%) on each of rosiglitazone and glibenclamide (known as glyburide in the USA and Canada) developed serious adverse event malignancies (excluding non-melanoma skin cancers). This corresponds to 1.03, 1.12 and 1.31 per 100 person-years, giving hazard ratios for metformin of 0.92 (95% CI New Diabetes Medications, TZDs, and Combinations Update #1 Page 69 of 71

70 ) vs rosiglitazone and 0.78 ( ) vs glibenclamide. In RECORD, on a background of sulfonylurea, 69 (6.1%) participants developed malignant neoplasms in the metformin group, compared with 56 (5.1%) in the rosiglitazone group (HR 1.22 [ ]). On a background of metformin, 74 (6.7%) participants in the sulfonylurea group developed malignant neoplasms, compared with 57 (5.1%) in the rosiglitazone group (HR 1.33 [ ]). CONCLUSIONS/INTERPRETATION: The malignancy rates in these two randomised controlled clinical trials do not support a view that metformin offers any particular protection against malignancy compared with rosiglitazone. However, they do not refute the possibility of a difference compared with sulfonylureas. Karyekar, C., M. Donovan, et al. (2011). "Efficacy and safety of saxagliptin combination therapy in US patients with type 2 diabetes." Postgrad Med 123(4): BACKGROUND: The mechanism of action of dipeptidyl peptidase-4 inhibitors, such as saxagliptin, makes them suitable for combination therapy in type 2 diabetes mellitus (T2DM). Genetic, cultural, and environmental differences in individuals from different regions of the world may result in differences in treatment response to oral antidiabetic drugs (OADs). This post-hoc subanalysis assessed the efficacy and safety of saxagliptin as add-on therapy to metformin, glyburide, or a thiazolidinedione in patients with inadequately controlled T2DM in the United States. METHODS: In 3 phase 3 studies of patients with T2DM uncontrolled on monotherapy, 547 adult US patients were randomized to receive saxagliptin (2.5 or 5 mg/d) or placebo as add-on to metformin, glyburide, or a thiazolidinedione (pioglitazone or rosiglitazone). Efficacy was assessed as the change from baseline to week 24 in glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), and postprandial glucose area under the curve (PPG-AUC) and the proportion of patients achieving HbA1c<7.0%. Pooled safety and tolerability data across trials were also analyzed. RESULTS: Reductions from baseline to week 24 in HbA1c were observed in all saxagliptin treatment groups versus placebo: saxagliptin 2.5 or 5 mg plus metformin (mean difference from placebo, -0.87% and -0.89%, respectively), glyburide (-0.51% and -0.52%), or thiazolidinedione (-0.45% and -0.60%). Improvement was also observed in FPG and PPG-AUC. Adverse events for the US cohort were consistent with previously reported data from the 3 trials. The pooled incidence of reported hypoglycemia was 5.3% and 11.4% with saxagliptin 2.5 and 5 mg/d add-on, respectively, versus 6.8% with placebo add-on. CONCLUSIONS: This post-hoc analysis in a cohort of US patients with T2DM uncontrolled on monotherapy suggests that saxagliptin 2.5 or 5 mg as add-on therapy to OADs results in improvement across key glycemic parameters compared with placebo add-on and was generally safe and well tolerated. Komajda, M., J. J. McMurray, et al. (2010). "Heart failure events with rosiglitazone in type 2 diabetes: data from the RECORD clinical trial." European Heart Journal 31(7): AIMS: Thiazolidinediones are insulin sensitizers, and are associated with fluid retention and increased risk of heart failure (HF) in people with type 2 diabetes. We assessed fatal and non-fatal HF events and their outcome, and identified HF predictors in the RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycaemia in Diabetes) trial population. METHODS AND RESULTS: In a multicentre, open-label New Diabetes Medications, TZDs, and Combinations Update #1 Page 70 of 71

71 study, we randomized 4447 people with type 2 diabetes on metformin or sulfonylurea monotherapy with a mean HbA(1c) of 7.9% to add-on rosiglitazone (n = 2220) or to a combination of metformin and sulfonylurea (n = 2227) and followed them over 5.5 years on average. Heart failure hospitalizations and deaths were adjudicated by a Clinical Endpoint Committee using pre-specified criteria. Independent predictors of HF events were identified out of a group of 30 pre-specified clinical, demographic, and biological variables. In the rosiglitazone group, the risk of HF death or hospitalization was doubled: HR = 2.10 (95% CI, ): the excess HF event rate was 2.6 ( ) per 1000 person-years. An excess in HF deaths was observed (10 vs. two), including four HF deaths as first HF events. By contrast, there was no increase in cardiovascular mortality or hospitalization (HR = 0.99, 95% CI, ) or in cardiovascular deaths (60 vs. 71). Independent predictors of HF were rosiglitazone assignment, age, urinary albumin : creatinine ratio, body mass index, and systolic blood pressure at baseline. A history of previous cardiovascular disease was not predictive of HF. Duration of HF hospitalization and rate of HF re-hospitalization were similar in the two groups. CONCLUSION: These findings confirm the increased risk of HF events in people treated with rosiglitazone and support the recommendation that this agent should not continue to be used in people developing symptomatic HF while using the medication. Close follow-up for the risk of HF should be offered to elderly people, people with markedly increased body mass index, people with microalbuminuria/proteinuria, and people with increased systolic blood pressure. New Diabetes Medications, TZDs, and Combinations Update #1 Page 71 of 71