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Safety and Efficacy of Dulaglutide, a Once Weekly GLP-1 Receptor Agonist, for the Management of Type 2 Diabetes Louis Kuritzky, MD 1 ; Guillermo Umpierrez,

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Presentation on theme: "Safety and Efficacy of Dulaglutide, a Once Weekly GLP-1 Receptor Agonist, for the Management of Type 2 Diabetes Louis Kuritzky, MD 1 ; Guillermo Umpierrez,"— Presentation transcript:

1 Safety and Efficacy of Dulaglutide, a Once Weekly GLP-1 Receptor Agonist, for the Management of Type 2 Diabetes Louis Kuritzky, MD 1 ; Guillermo Umpierrez, MD 2 ; Jean Marie Ekoé, MD 3 ; Leonardo Mancillas-Adame, MD 4 ; Laura Fernandez Lando, MD 5 1 Department of Community Health and Family Medicine, University of Florida, Gainesville, FL, USA; 2 Emory University School of Medicine, Division of Endocrinology, Atlanta, GA, USA; 3 Chum Hôpital Hôtel-Dieu, Montreal, Québec, CAN; 4 Lilly Diabetes, Eli Lilly Canada, Toronto, Ontario, CAN; 5 Lilly Diabetes, Eli Lilly and Company, Indianapolis, IN, USA

2 Type 2 Diabetes Background Type 2 diabetes is an increasingly common endocrine disorder characterized by chronic hyperglycemia and consequences in multiple tissue compartments, including macrovascular and microvascular complications. 1 More than 90% of patients with type 2 diabetes will be diagnosed and initially treated by primary care physicians (PCPs) Stratton IM et al. BMJ. 2000;321(7258): Siminerio LM et al. Diabetes Educ. 2008;34(3):

3 Major Metabolic Defects in Type 2 Diabetes Physiopathology of diabetes includes multiple metabolic defects: 1-4 –Progressive β-cell failure/decreased insulin secretion –Insulin resistance –α-cell dysfunction (hyperglucagonemia) –Increased liver glucose output –Decreased incretin effects –Decreased muscle glucose uptake –Increased glucose renal reabsorption –Increased lypolysis 1. Schwartz SS. Curr. Med. Res. Opin. 2013;29(7): Nathan DM et al. Diabetes Care. 2009;32(1): Ahrén B. Diabetes Metab. 2013;39(3): DeFronzo RA et al. Diabetes Care. 2013;36 (Suppl2):S

4 Hyperglycemia in Type 2 Diabetes Results from Major Metabolic Defects. 1,2 1. DeFronzo RA. Diabetes. 1988;37(6): Holst JJ and Gromada J. Am. J. Physiol. Endocrinol. Metab. 2004;287(2):E

5 The Incretin Effect and the Role of Incretin Hormones The incretin effect is the increased insulin release observed after oral glucose ingestion compared with after IV glucose infusion. 1 2 hormones released after food ingestion are responsible: 2,3 –GLP-1 –GIP GLP-1 1 Released mostly from L-cells located in ileum and colon Sites of action include: pancreatic β- and α-cells, GI tract, CNS, and heart GIP 1 Released mostly from K-cells of the duodenum and jejunum Sites of action include: pancreatic β-cells, adipocytes, and neural progenitor cells 4 1. Baggio LL and Drucker DJ. Gastroenterology 2007;132: Drucker DJ. Diabetes Care 2003;26: Thorens B. Diabetes Metab 1995;21: Nyberg J et al. J Neurosci 2005;25: CNS = central nervous system; GI = gastrointestinal; GIP = glucose-dependent insulinotropic polypeptide; GLP-1 = glucagon-like peptide-1; IV = intravenous

6 ADA/EASD Joint Position Statement: General Therapy Recommendations in Type 2 Diabetes 1 Healthy eating, weight control, increased physical activity SUTZDDPP-4 inhibitorGLP-1 receptor agonistInsulin (usually basal) Metformin + If combination therapy that includes basal insulin has failed to achieve HbA 1c target after 3-6 months, proceed to a more complex insulin strategy, usually in combination with 1 or 2 non-insulin agents: Insulin (multiple daily doses) Insulin + TZD DPP-4 inhibitor or + SU DPP-4 inhibitor or + SU TZD Insulin or + SU TZD Insulin or + TZD DPP-4 inhibitor GLP-1 receptor agonist or Insulin Initial drug monotherapy Efficacy (↓ HbA 1c ) ………..… Hypoglycemia …………….... Weight ………………………. Major side effect(s) ……..…. Costs ……………………..…. 2-drug combinations 3-drug combinations More complex insulin strategies Efficacy (↓ HbA 1c ) ……….. Hypoglycemia ……………. Weight ……………………. Side effects …………….... Costs …………………..… SUTZDDPP-4 inhibitorInsulin (usually basal) high …………………….. moderate risk …………. gain ………… hypoglycemia……….... low ……………………… Metformin + high …………………….. low risk ………………… gain ………… edema, HF, Fx……... high …………………….. intermediate …………… low risk …………………. neutral ……… rare ……… high..……………………. highest ………………….. high risk ………………... gain ………… hypoglycemia……….... variable ………………… If needed to reach individualization HbA 1c target after ~3 months, proceed to 3-drug combination (order not meant to denote any specific preference): Metformin If needed to reach individualization HbA 1c target after ~3 months, proceed to 2-drug combination (order not meant to denote any specific preference): High Low risk Neutral / loss GI / lactic acidosis Low …………………………………………………………………… ………………………………………………….…………………………….. ………………………………………………………………………………… ………………………………………………………………………………… ………………………………………………………..……………………….. ADA = American Diabetes Association; DPP-4 = dipeptidyl peptidase-4; EASD = European Association for the Study of Diabetes; Fx = bone fracture; GI = gastrointestinal; GLP-1 = glucagon-like peptide 1; HF = heart failure; SU = sulfonylurea; TZD = thiazolidinedione 1. Inzucchi SE et al. Diabetes Care 2012;35(6): GLP-1 receptor agonist high ……………………... low risk …………………. loss ………… GI……… high ……………………... GLP-1 receptor agonist

7 Comparison of GLP-1 Receptor Agonists 1-6 The structure of GLP-1 receptor agonists are based on two distinct homologies, referred to as human GLP-1s and exendin-4s. Human GLP-1s are homologous to endogenous GLP-1s with limited amino acid substitutions whereas exendin-4s are approximately 50% homologous to human GLP-1 and are based on a protein found in the saliva of the Gila monster. GLP-1 receptor agonists based on the exendin-4 backbone may be more likely to elicit antibodies. In the small percentage of patients developing high titers of antibodies (approximately 10%), a negative clinical impact may be observed with a decrease in HbA 1c reduction in comparison to those with no antibodies or low titers Peña A et al. ADA – 74 th Annual Scientific Sessions. Diabetes 2014;(suppl1):A GlaxoSmithKline. TANZEUM (albiglutide) US Package Insert AstraZeneca. BYETTA (exenatide) US Package Insert AstraZeneca. BYDUREON (exenatide extended-release) US Package Insert NovoNordisk. VICTOZA (liraglutide) US Package Insert Sanofi. LYXUMIA (lixisenatide) EMA Package Insert Diamant M et al. Lancet. 2010;375(9733): BID = twice daily; DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide 1; Fc = fragment crystalizable; IgG4 = Immunoglobulin G4; t 1/2 = half-life; QW = once weekly

8 Structure of Dulaglutide and IgG4 A) The Fc (fragment crystalizable) region in dulaglutide is altered at two amino acid residues to reduce binding to cellular Fc receptors and prevent dimerization of the dulaglutide molecule with endogenous IgG4 (half-antibodies). A disulfide linker acts to dimerize dulaglutide molecules. 1 Fab = Fragment antigen binding B) The amino acid composition of the GLP-1 (7-37) and linker region of dulaglutide. Striped positions indicate modified amino acids and their position from wild type human GLP-1. 1 Color code in B is representative of region color in A. 1. Glaesner W et al. Diabetes Metab Res Rev 2010;26:287-96

9 Dulaglutide A recombinant GLP-1 Fc fusion protein linking a human GLP-1 peptide analog and a variant of a human IgG4 Fc fragment 1,2 – Extended plasma half-life (~5 days) – Minimal renal clearance – Once-weekly dosing – Solution injection: no reconstitution needed – Low immunogenic potential 1. Glaesner W et al. Diabetes Metab Res Rev 2010;26: Peña A et al. ADA – 74 th Annual Scientific Sessions. Diabetes 2014;(suppl1):A251 Linker Modified IgG4 Fc domain GLP-1 analog

10 Dulaglutide 1.5 mg SC Concentration-Time Profile* *Black line and blue shaded area represent model-estimated mean plasma dulaglutide concentrations and 90% CI; symbols are mean observed data; whiskers represent ± SE. CI = confidence interval; SC = subcutaneous 1. Peña A et al. ADA – 74 th Annual Scientific Sessions. Diabetes 2014;(suppl1):A251

11 The AWARD Program (Assessment of Weekly AdministRation of Dulaglutide in Diabetes): Phase 3 Data Efficacy

12 Dulaglutide: Across the Type 2 Diabetes Treatment Continuum The Phase 3 studies (AWARD-1 through AWARD-6) are completed Monotherapy 2 drug combinations More complex insulin strategies AWARD-3 vs. metformin Drug naïve or washout from 1 OAM AWARD-5 vs. sitagliptin Add-on to metformin AWARD-6 vs. liraglutide Add-on to metformin AWARD-8* vs. placebo Add-on to SU AWARD-1 vs. exenatide BID Add-on to metformin and TZD AWARD-2 vs. glargine Add-on to metformin and SU AWARD-4 vs. glargine Both with mealtime insulin lispro with or without metformin AWARD-7* vs. BBT in CKD AWARD-9* vs. Placebo Both with titrated insulin glargine with or without metformin BBT = basal/bolus therapy; BID = twice daily; CKD = chronic kidney disease; OAM = oral antidiabetic medication; SU = sulfonylurea; TZD = thiazoladinedione 3 drug combinations * Indicates ongoing study

13 AWARD-5: An Adaptive, Double-blind Phase 3 Study 1,2 a Lead-in period lasted from 2 weeks up to 11 weeks. b Metformin concomitant therapy from lead-in period through treatment period. c All patients on non-selected arms were discontinued. d After 26 weeks, patients in the placebo arm transitioned to sitagliptin (100 mg/day) in a blinded fashion. e Randomization, after dose selection, used a fixed allocation scheme (2:2:2:1 for dulaglutide 0.75 mg:dulaglutide 1.5 mg:sitagliptin:placebo/sitagliptin). 1.Skrivanek Z et al. Diabetes Obes. Metab. 2014;16(8): Nauck MA et. Al. Diabetes Care. 2014;37(8):

14 AWARD-3 Study Design Through 52 Weeks 1 a Patients received 2000 mg/day or 1500 mg/day according to tolerability. Key inclusion criteria Type 2 Diabetes (≥3 months and ≤5 years) HbA 1c ≥6.5% (≥48 mmol/mol) and ≤9.5% (≤80 mmol/mol) Treatment-naïve or on 1 OAM (except TZDs) ≤50% of the approved maximum daily dose ≥3 months 1. Umpierrez G et al. Diabetes Care. 2014;37(8) BID = twice daily; OAM = oral antidiabetic medication; TZD = thiazoladinedione

15 AWARD-1 Study Design Through 52 Weeks 1 Key inclusion criteria Type 2 Diabetes not well controlled on 1, 2, or 3 OAM - HbA 1c ≥7.0% (53 mmol/mol) and ≤11.0% (97 mmol/mol) on OAM monotherapy or - HbA 1c ≥7.0% (53 mmol/mol) and ≤10.0% (86 mmol/mol) on combination OAM therapy Placebo patients continued until 26 weeks, and then switched to dulaglutide 1.5 mg or dulaglutide 0.75 mg 1. Wysham C et al. Diabetes Care. 2014;37(8):

16 AWARD-1, -3, and -5 Trials Achieving Primary Endpoints Treatment Type BackgroundComparatorTrial Alias*Subjects a Results (primary endpoint) MonotherapyN/AMetforminAWARD-3807 Change in HbA 1c (26 wks) 2 drug combinations MetforminSitagliptinAWARD Change in HbA 1c (52 wks) 3 drug combinations Metformin Pioglitazone ExenatideAWARD-1976 Change in HbA 1c (26 wks) *Dulaglutide 1.5 and 0.75 once weekly a Intent-to Treat population

17 Baseline Characteristics, AWARD-1, -3, and -5 trials Abbreviations: BMI = body mass index; N = number of patients randomized; SD = standard deviation;

18 HbA 1c Reduction Across Trials at Primary Endpoint † p <0.025, superiority vs. metformin †† p <0.001, superiority vs. exenatide ‡‡ p <0.001, superiority vs. placebo **p <0.001 vs. placebo † Baseline HbA 1c HbA 1c, Change from Baseline (%) AWARD-3 (26-week) 7.6% (59.6 mmol/mol) AWARD-1 (26-week) 8.1% (65.0 mmol/mol) Dulaglutide 1.5 mgDulaglutide 0.75 mgComparatorPlacebo † ††‡‡ ** vs. metformin †† p <0.001, superiority vs. sitagliptin AWARD-5 (52-week) 8.1% (65.0 mmol/mol) †† vs. sitagliptinvs. exenatide 1.Nauck MA et. Al. Diabetes Care. 2014;37(8): Umpierrez G et al. Diabetes Care. 2014;37(8) Wysham C et al. Diabetes Care. 2014;37(8): Data presented are LS means ± SE of the intent-to-treat population

19 Proportion of Patients Achieving HbA 1C Target of <7% at Primary Endpoint # p <0.05 vs. metformin ## 2-sided p <0.001 vs. exenatide *p <0.05 vs. placebo **p <0.001 vs. placebo 1 3 AWARD-3 (26-week) AWARD-5 (52-week) AWARD-1 (26-week) # # ##** * Dulaglutide 1.5 mgDulaglutide 0.75 mgComparatorPlacebo vs. metformin ## p <0.001 vs. sitagliptin 2 ## vs. sitagliptin vs. exenatide Patients (%) Data presented are LS means ± SE of the intent-to-treat population 1.Nauck MA et. Al. Diabetes Care. 2014;37(8): Umpierrez G et al. Diabetes Care. 2014;37(8) Wysham C et al. Diabetes Care. 2014;37(8):

20 Weight Change from Baseline at Study Endpoint # p <0.001, superiority vs. metformin ## p <0.001, superiority vs. sitagliptin ## p <0.001, superiority vs. exenatide *p <0.05, vs. placebo **p <0.001 vs. placebo AWARD-1 (26-week) ** ## * ** AWARD-3 (26-week) # vs. metformin AWARD-5 (52-week) ## vs. sitagliptin vs. exenatide Data presented are LS means ± SE of the intent-to-treat population 12 Dulaglutide 1.5 mgDulaglutide 0.75 mgComparatorPlacebo Body Weight Change (kg) 1.Nauck MA et. Al. Diabetes Care. 2014;37(8): Umpierrez G et al. Diabetes Care. 2014;37(8) Wysham C et al. Diabetes Care. 2014;37(8):

21 Dulaglutide Phase 3 Clinical Trial Efficacy Data at Primary Endpoint Abbreviations: BID = twice daily; FBG = fasting blood glucose; LOCF = last observation carried forward; LS = least squares; MMRM = mixed-effect model repeated measure; SE = standard error; SMPG = self-monitored plasma glucose; wk = week. Analysis methods: change in HbA 1C and weight, ANCOVA (LOCF); percentage patients achieving HbA 1C target, logistic regression (LOCF); change in plasma glucose, MMRM. †,†† multiplicity adjusted 1-sided p <0.025 for noninferiority and superiority, respectively, vs active comparator for HbA 1C only. ‡‡ multiplicity adjusted 1-sided p <0.001 for superiority vs placebo for HbA 1C only. *p <0.05, **p <0.001 for dulaglutide or active comparator vs placebo #p <0.05, ##p <0.001 for dulaglutide vs active comparator

22 Safety The AWARD Program (Assessment of Weekly AdministRation of Dulaglutide in Diabetes): Phase 3 Data

23 Percentage of Patients with Gastrointestinal Events at Primary Endpoint by Study Abbreviations: BID = twice daily; GI = gastrointestinal; wk = week. *p <0.05, **p <0.001 for dulaglutide or active comparator vs placebo # p <0.05, ## p <0.001 for dulaglutide vs active comparator 1.Umpierrez G et al. Diabetes Care. 2014;37(8) Nauck MA et. Al. Diabetes Care. 2014;37(8): Wysham C et al. Diabetes Care. 2014;37(8):

24 Hypoglycemia at Primary Endpoint by Study Abbreviations: BID = twice daily; wk = week. *p <0.05, **p <0.001 for dulaglutide or active comparator vs placebo # p <0.05, ## p <0.001 for dulaglutide vs active comparator Total hypoglycemia was defined as plasma glucose ≤70 mg/dL (≤3.9 mmol/L) and/or symptoms and/or signs attributable to hypoglycemia. Severe hypoglycemia was an episode requiring the assistance of another person to actively administer therapy. 1.Umpierrez G et al. Diabetes Care. 2014;37(8) Nauck MA et. Al. Diabetes Care. 2014;37(8): Wysham C et al. Diabetes Care. 2014;37(8):

25 Thyroid Safety No thyroid safety issues or increases in mean calcitonin were observed in AWARD-1, AWARD-3, or after dose selection in AWARD –One patient in the dulaglutide 2 mg dose group during the dose-finding portion of AWARD-5 was diagnosed with medullary thyroid carcinoma. –This case was determined to be preexisting; the patient had an elevated baseline serum calcitonin (determined retrospectively). –The patient tested positive for the rearranged during transfection (RET) proto-oncogene mutation afterwards. 4,5 1.Umpierrez G et al. Diabetes Care. 2014;37(8) Nauck MA et. Al. Diabetes Care. 2014;37(8): Wysham C et al. Diabetes Care. 2014;37(8): Roy M et al. The Oncologist. 2013;18(10): Moraitis AG et al. Endocr Pract. 2014;20(2):

26 Pancreatic Safety 1-3 In all 3 clinical trials, minor increases were observed in median pancreatic enzymes, but these values did not exceed the normal range. Three cases of acute pancreatitis were confirmed, all in the AWARD-5 trial, and all in comparator groups (2 patients randomized to sitagliptin; 1 patient randomized to placebo/sitagliptin while on sitagliptin). In the AWARD-1 trial, one patient on dulaglutide 1.5 mg was diagnosed with chronic pancreatitis 7 months after treatment initiation. One patient on dulaglutide 1.5 mg was diagnosed with pancreatic cancer after having received dulaglutide for 6 months, and died 9 months after study discontinuation. 1.Umpierrez G et al. Diabetes Care. 2014;37(8) Nauck MA et. Al. Diabetes Care. 2014;37(8): Wysham C et al. Diabetes Care. 2014;37(8):

27 Single-Dose Pen* It contains a single dose of the ready to use dulaglutide solution. The single-dose pen has a small, hidden needle that is already attached, and requires no handling. The single-dose pen automatically injects, and retracts the needle following injection. In a usability clinical trial, 99% of patients successfully injected using the single-dose pen Matfin G et al. ADA 74 th Annual Meeting. 2014; 63(suppl. 1A):LB31 * The single-dose pen was not used in the AWARD studies presented in the review article.

28 Dulaglutide demonstrated significant, sustained glucose lowering with a dose-dependent weight benefit. The safety profile of dulaglutide was comparable to the GLP-1 receptor agonist class, with no new safety signals in up to 2 years of controlled clinical trial data Dulaglutide allows for a once weekly subcutaneous injection that does not require reconstitution or preparation by the patient. The efficacy and safety of once weekly dulaglutide, which lowers HbA 1c and both fasting and postprandial glucose, makes dulaglutide a relevant treatment option for physicians in the busy primary care setting. Summary

29 References Ahren B. Incretin dysfunction in type 2 diabetes: clinical impact and future perspectives. Diabetes Metab. 2013;39(3):195–201. Baggio LL and Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology. 2007;132(6): Bydureon [package insert]. London, United Kingdom: AstraZeneca; Byetta [package insert]. London, United Kingdom: AstraZeneca; DeFronzo RA, Eldor R, Abdul-Ghani M. Pathophysiologic approach to therapy in patients with newly diagnosed type 2 diabetes. Diabetes Care. 2013;36(suppl 2):S127–S138. DeFronzo RA. Lilly lecture The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes. 1988;37(6): Diamant M, Van Gaal L, Stranks S, et al. Once weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes (DURATION-3): an open-label randomised trial. Lancet. 2010;375(9733):2234–2243. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;26(10): Glaesner W, Vick AM, Millican R, et al. Engineering and characterization of the long-acting glucagon-like peptide-1 analogue LY , an Fc fusion protein. Diabetes Metab Res Rev. 2010;26(4):287–296. Holst JJ, Gromada J. Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans. Am J Physiol Endocrinol Metab. 2004;287(2):E Inzucchi SE, Bergenstal RM, Buse JB, et al. American Diabetes Association (ADA); European Association for the Study of Diabetes (EASD). Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35(6):1364–1379. Lyxumia [package insert]. Paris, France: Sanofi Matfin G, Zimmermann A, Van Brunt K, et al. Safe and effective use of the single-use pen for injection of once weekly dulaglutide in injection-naïve patients with type 2 diabetes. American Diabetes Association. 2014;74th Annual Scientific Sessions. 2014;63(suppl 1A):LB31. Moraitis AG, Martucci VL, Pacak K. Genetics, diagnosis, and management of medullary thyroid carcinoma and pheochromocytoma/paraganglioma. Endocr Pract. 2014;20(2):176–187. Nathan DM, Buse JB, Davidson MB, et al. American Diabetes Association; European Association for Study of Diabetes. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009;32(1):193– 203. Nauck M, Weinstock RS, Umpierrez GE, et al. Efficacy and Safety of Dulaglutide Versus Sitagliptin After 52 Weeks in Type 2 Diabetes in a Randomized Controlled Trial (AWARD-5). Diabetes Care. 2014;37(8):2149–2158. Nyberg J, Anderson MF, Meister B, et al. Glucose-dependent insulinotropic polypeptide is expressed in adult hippocampus and induces progenitor cell proliferation. J Neurosci. 2005;25(7):

30 Peña A, Loghin C, Xuewei C, et al. Pharmacokinetics of once weekly dulaglutide in patients with type 2 diabetes mellitus. American Diabetes Association – 74 th Annual Scientific Sessions. Diabetes. 2014;63(suppl 1):A251. Roy M, Chen H, Sippel RS. Current understanding and management of medullary thyroid cancer. Oncologist. 2013;18(10):1093–1100. Schwartz SS. A practice-based approach to the 2012 position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Curr Med Res Opin. 2013;29(7):793–799. Siminerio LM, Drab SR, Gabbay RA, et al. Diabetes educators: implementing the chronic care model. Diabetes Educ. 2008;34(3):451–456. Skrivanek Z, Gaydos BL, Chien JY, et al. Dose-finding results in an adaptive, seamless, randomized trial of once-weekly dulaglutide combined with metformin in type 2 diabetes patients (AWARD-5). Diabetes Obes Metab. 2014;16(8):748–756. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321(7258):405–412. Tanzeum [package insert]. Research Triangle Park, NC: GlaxoSmithKline Thorens B. Glucagon-like peptide-1 and control of insulin secretion. Diabetes Metab. 1995;21(5): Umpierrez G, Tofé Povedano S, Manghi FP, et al. Efficacy and Safety of Dulaglutide Monotherapy Versus Metformin in Type 2 Diabetes in a Randomized Controlled Trial (AWARD-3). Diabetes Care. 2014;37(8):2168–2176. Victoza [package insert]. Bagsværd, Denmark: Novo Nordisk Wysham C, Blevins T, Arakaki R, et al. Efficacy and Safety of Dulaglutide Added on to Pioglitazone and Metformin Versus Exenatide in Type 2 Diabetes in a Randomized Controlled Trial (AWARD-1). Diabetes Care. 2014;37(8):2159–2167. References Cont’d


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