Incretin Therapies: Clinical Updates for Type 2 Diabetes

Transcription

1 Incretin Therapies: Clinical Updates for Type 2 Diabetes Jessica L. Kerr, Pharm.D, CDE Assistant Chair, Pharmacy Practice Associate Professor Jennifer Rosselli, Pharm.D., BCPS, BCACP Clinical Associate Professor Southern Illinois University Edwardsville

2 Disclosures/Conflict of Interest Drs. Jessica Kerr and Jennifer Rosselli have received community and patient health education grants from Novo Nordisk during years 2014 and Dr. Jessica Kerr has provided CPE credits for unrestricted educational grants sponsored by Sanofi.

3 Objectives At the conclusion of this program, the pharmacist/technicians will be able to: Describe glycemic effects of incretin-based therapies. Compare and contrast the efficacy and safety concerns of individual incretin medications. Describe the role of incretin-based medicines in diabetes management. Explain injection administration clinical pearls for GLP-1 receptor agonists.

4 Pre-Session Assessment #1 Which of the following is a mechanism of action for GLP-1 receptor agonists? SELECT ALL THAT APPLY A. decrease insulin secretion B. enhance glucagon secretion C. increase amylin secretion D. slow gastric emptying E. both B and D are mechanisms of action for GLP-1 receptor agonists

5 Pre-Session Assessment #2 DPP-4 inhibitors have been clinically assessed for cardiovascular outcomes. Which of the following DPP-4 inhibitors has been associated with a clinical concern of heart failure? A. alogliptin B. omargliptin C. sitagliptin D. saxagliptin

6 Pre-Session Assessment #3 A 48 y/o WM with a 10-year history of diabetes has an A1C of 8.4% and BMI of 32 kg/m 2 on metformin 1000 mg BID, glipizide ER 20 mg daily, and citalopram 20 mg daily. He has declined to start insulin per last PCM note. PMH: depression. estcrcl > 90 ml/min. Family history: CVA, DM Which of the following is an ideal add-on therapy to better control his diabetes? A. exenatide 5 mcg BID x 4 weeks, then 10 mcg BID B. liraglutide 0.6 mg daily x 1 week, then 1.2 mg daily C. linagliptin 5 mg daily D. sitaglitpin 50 mg daily

7 Pathophysiology of T2DM Increased hepatic glucose production Neurotransmitter dysfunction Decreased glucose uptake Increased lipolysis Decreased insulin secretion Impaired incretin function Increased glucagon secretion Hyperglycemia Increased glucose reabsorption Defronzo RA. Diabetes 2009;58:

8 Incretin System Incretins are naturally occurring glucoregulatory hormones. Glucose-dependent release by the gut Glucagon-like peptide-1 (GLP-1) Glucose-dependent insulinotropic peptide (GIP) Incretin hormones are rapidly degraded by dipeptidyl peptidase 4 (DPP-4)

9 Physiologic Affects of the Incretin System DPP-4 GLP-1 and GIP Food intake Small intestines Release of incretin hormones Insulin release Glucagon suppression Decreases GI motility Reduces appetite Slows glucose absorption Increases cardiac output Brain, GI Tract, Heart, Pancreas

10 DPP-4 Inhibitors

11 Incretin Enhancement by DPP-4 Inhibitors DPP-4 Inhibition DPP-4 GLP-1 and GIP Food intake Small intestines Release of incretin hormones Insulin release Glucagon suppression Decreases GI motility Reduces appetite Slows glucose absorption Increases cardiac output Brain, GI Tract, Heart, Pancreas

12 Alogliptin (Nesina ) Linagliptin (Tradjenta ) Saxagliptin (Onglyza ) Sitagliptin (Januvia ) Vildagliptin (Galvus )* Current DPP-4 Inhibitors *Approved for use in Europe

13 Overview of DPP-4 Inhibitors Supplied as oral formulations Currently, once daily administration, without regards to meals A1C reduction % Minimal weight loss to weight neutral Low incidence of hypoglycemia Studied as combination and monotherapy

14 Comparison of DPP-4 Inhibitors Medication Usual Dose Dose Adjustment Unique Warnings Alogliptin 6.25 mg, 12.5 mg, 25 mg 25 mg/d Renal impairment CrCl: ml/min=12.5 mg < 30 ml/min=6.25 mg Hepatic failure A1C Change (%) FPG Change (mg/dl) -0.5 to to h PPG Change (mg/dl) Linagliptin 5 mg 5 mg/d None (Decreased effectiveness with P-glycoproteins/CYP 3A4 inducers) -0.2 to to to -49 Saxagliptin 2.5 mg, 5 mg 2.5 or 5 mg/d Renal impairment CrCl: < 50 ml/min=2.5 mg Strong CYP 3A4 inhibitors=2.5 mg dose Increased edema with TZDs -0.4 to to to -65 Sitagliptin 25 mg, 50 mg, 100 mg 100 mg/d Renal impairment CrCl: ml/min=50 mg < 30 ml/min=25 mg Acute renal failure Pruritis -0.3 to to to -62

15 Safety Concerns of DPP-4 Inhibitors Most common ADRs: upper respiratory infection, nasopharyngitis, headache Hypersensitivity reactions: angioedema, anaphylaxis, Steven s-johnson syndrome Acute pancreatitis Arthralgias: severe and disabling have been reported

16 DPP-4 Inhibitor Cardiovascular (CV) Outcomes Studies SAVOR TIMI 53 N Engl J Med 2013;369: CV death, nonfatal CVA or nonfatal MI CVD or RF A1c 6.5 to 12% n = 16,422 R PLACEBO Saxagliptin EXAMINE N Engl J Med 2013;369: CV death, nonfatal CVA or nonfatal MI ACS A1c 6.5% to 11% n = 5380 R PLACEBO Alogliptin TECOS N Engl J Med 2015;373: CV death, nonfatal CVA or nonfatal MI or UA requiring hospitalization CVD A1c 6.5 to 8.0% n = 14,671 R PLACEBO Sitagliptin Trial Name Primary Outcomes Population Median Follow Up 0 3yr

17 Baseline Characteristics from DPP-4 Inhibitor Cardiovascular Outcomes Studies Trait SAVOR-TIMI 53 EXAMINE TECOS Mean age, years Mean duration diabetes, years Mean baseline A1c, % Dyslipidemia, % 71 Not reported 77 Active smokers, % Not reported Previous heart failure, % Mean duration of follow up, years N Engl J Med 2013;369: N Engl J Med 2013;369: N Engl J Med 2015;373:

18 Incidence of Hospitalization for Heart Failure in DPP-4 Inhibitor Cardiovascular Outcomes Studies Clinical Trial Study Drug Placebo Hazard Ratio 95% CI SAVOR- TIMI % 2.8% EXAMINE 3.9% 3.3% TECOS 3.1% 3.1% Favors Treatment Favors Placebo N Engl J Med 2013;369: N Engl J Med 2013;369: N Engl J Med 2015;373:

19 Ongoing Trials to Evaluate CV Outcomes Linagliptin: CARMELINA, CAROLINA (both to be completed in 2018) clinicaltrials.gov

20 Grab a Partner Mr. Starch is a 49 y/o who was recently discharged from the hospital for his 1 st episode of acute pancreatitis. You two are pharmacists at his home pharmacy where presents to refill his routine diabetes medications (metformin, saxagliptin, and glimepiride). Mr. Starch tells you that he remembers the doctor at the hospital telling him to stop taking one of his medications, but he isn t sure which one that is and he has misplaced the papers they gave him. What questions do you have for Mr. Starch? What additional information would you like to have? What is your recommendation even if you don t get answers to the above questions?

21 Summary of DPP-4 Inhibitors Can be used in combination with orals or basal insulin Similar A1c reduction (up to ~1%) between individual drugs Linagliptin lowest A1c reduction (max 0.6%) No head-to-head trials Renal dosing with all, except for linagliptin Pancreatitis warnings No long term outcomes Choice likely dependent on formulary/cost

22 GLP-1 Agonists

23 Incretin Mimetic GLP-1 and GIP Exogenous GLP-1 Food intake Release of incretin hormones Small intestines Insulin release Glucagon suppression Decreases GI motility Reduces appetite Slows glucose absorption Increases cardiac output Brain, GI Tract, Heart, Pancreas

24 Current GLP-1 Agonists Exenatide (Byetta ) 2005 Liraglutide (Victoza ) 2010 Exenatide extended-release (Bydureon ) 2012 Albiglutide (Tanzeum ) 2014 Dulaglutide (Trulicity ) 2014

25 Overview of GLP-1 Agonists Supplied as subcutaneous injections Twice daily, once daily, or once weekly administration depending on medication Product preparation required of patient varies by medication A1C reduction varies by medication (-0.5% to -1.9%) Weight loss of kg on average Low incidence of hypoglycemia Studied as monotherapy and in combination

26 Medication Injection schedule Comparison of GLP-1 Agonists Dosing Regimen Product Preparation and Administration Storage Exenatide (Multi-dose pen) BID 5 mcg BID x 1 month, increase to 10 mcg BID based on clinical response. Administer within 60 min prior to 2 biggest meals (6 hours apart) Refrigerate until opened. Good for 30 days once opened. Liraglutide (Multi-dose pen) Exenatide ER (Single-dose tray and single-dose pen) Daily 0.6 mg daily x 1 week, then 1.2 mg daily x at least 1 week, can increase up to 1.8 mg based on response. Administer regardless of meal timing Weekly 2 mg once weekly. Administer immediately after reconstituting. Rotate injection sites Refrigerate until opened. Good for 30 days once opened. Refrigerate until opened. Discard after 4 weeks of room temperature. Albiglutide (Single-dose pen) Weekly 30 mg once weekly. Can increase to 50 mg after 4 weeks for additional glycemic control. Wait minutes for reconstituted solution to mix. Use within 8 hours of reconstitution. Refrigerate until opened. Discard after 4 weeks of room temperature. Dulaglutide (Single-dose pen) Weekly 0.75 mg once weekly. Can increase to 1.5 mg for additional glycemic control. Single-use pen device supplied with non-visible needle attached and does not require reconstitution Refrigerate. Discard 14 days after product is left at room temperature.

27 Comparison of GLP-1 Agonists Drug Unique Warnings Dose Adjustment A1C Change (%) Exenatide Increased INR with warfarin Administer oral contraceptive 1 hour prior Renal impairment Avoid if CrCl < 30 ml/min FPG Change (mg/dl) 2h PPG Change (mg/dl) Weight Change (kg) -0.5 to to to to -2.9 Liraglutide None -0.8 to to to -2.6 Exenatide ER Injection site reactions (subcutaneous nodules, cellulitis, abscess, necrosis) Monitor for increased INR with warfarin Not studied in combination with insulin Renal impairment Avoid if CrCl < 30 ml/min -0.8 to -1.9 Takes up to 9 weeks to reach full efficacy Albiglutide None -0.7 to to to -1.2 Dulaglutide Not studied in combo with basal insulin None -0.7 to to to -3.1

28 Summary of GLP-1 Agonist Head-to-Head Clinical Trials Trial Treatment A1c Change (%) Weight Change (kg) Pratley et al. (HARMONY 7) Albiglutide 30 mg, up to 50 mg weekly Liraglutide 1.8 mg daily Albiglutide: Liraglutide: -0.99* Albiglutide: -0.6 Liraglutide: -2.2* Wysham et al. (AWARD-1) Dulaglutide 0.75 mg weekly Dulaglutide 1.5 mg weekly Exenatide 10 mcg BID Dulaglutide 0.75 mg: -1.3 Dulaglutide 1.5 mg: -1.5 Exenatide: Dulaglutide 0.75 mg: 0.2 Dulaglutide 1.5 mg: -1.3 Exenatide: Dungan, et al. (AWARD-6) Dulaglutide 1.5 mg weekly Liraglutide 1.8 mg daily Dulaglutide:-1.42 Liraglutide: Dulaglutide: Liraglutide: Buse et al. (LEAD-6) Liraglutide 1.8 mg daily vs. Exenatide 10 mcg BID Liraglutide: -1.12* Exenatide: Liraglutide: Exenatide: Buse et al. (DURATION-1) Exenatide ER 2 mg weekly Exenatide 10 mcg BID Exenatide ER: -1.9* Exenatide: -1.5 Exenatide ER:-3.6 Exenatide: -3.7 Blevins et al. (DURATION-5) Exenatide ER 2 mg weekly Exenatide 10 mcg BID Exenatide ER: -1.6* Exenatide: -0.9 Exenatide ER: -2.3 Exenatide: -1.4 Buse et al. (DURATION-6) Exenatide ER 2 mg weekly vs. Liraglutide 1.8 mg daily Exenatide ER: Liraglutide: 1.48* Exenatide: Liraglutide: -3.57* *Statistically significant

29 Safety Concerns Most common ADRs: nausea, vomiting, diarrhea, headache, injection site reaction Hypersensitivity reactions: angioedema, anaphylaxis, rash, pruritis Acute pancreatitis Severe gastrointestinal disease (ex. gastroparesis) Hypoglycemia risk increased when used with insulin or sulfonylurea Renal impairment Black Box Warning* Risk of thyroid C-cell tumors *Warning of liraglutide, exenatide ER, albiglutide, and dulaglutide

30 GLP-1 Agonists and Thyroid Carcinoma All GLP-1 agonists except for exenatide IR have black box warning for thyroid carcinoma Contraindicated with a personal or family history of medullary thyroid cancer (MTC) or multiple endocrine neoplasia syndrome type 2 (MEN 2) Thyroid C-cell tumors observed in animal studies Cases of MTC in humans treated with liraglutide have been reported in post marketing period Counsel patients regarding risks and symptoms of MTC Refer to endocrinologist if thyroid nodules are present U.S. Food and Drug Administration Website.

31 GLP-1 Agonists Cardiovascular Outcomes Studies Monami et al. Trial design Trials included Subjects, No. GLP-1 agonists Duration of included trials (mean) Results Primary outcome: CV death, non-fatal MI and stroke, and ACS and/or HF Meta-analysis 37 N=15,398 Albiglutide Exenatide Exenatide LAR Liraglutide Taspoglutide 42 weeks Odds Ratio (95% CI) 0.78 (0.54 to 1.13) Diabetes Obes Metab 2014;16:38-47.

32 GLP-1 Agonist Cardiovascular Outcomes Studies Bentley-Lewis et al. ELIXA Trial design Intervention Subjects Baseline characteristics Mean follow-up Results [Hazard Ratio (95% CI)] Primary outcome: CV death, non-fatal MI, non-fatal stroke, and hospitalization for unstable angina Secondary outcome: HF Randomized, placebo controlled, parallel-group, multinational Lixisenatide mcg/day N=6,068, T2DM and discharge in recent 180 days for ACS Mean age 60 years, 69% male, 75% white, duration of T2DM 9 years, BMI 30 kg/m 2, A1c 7.7%, history of HF 12% 2 years (0.886 to 1.168) 0.96 (0.75 to 1.23) Am Heart J 2015;169:631-38, Favors lixisenatide Favors placebo

33 Ongoing Trials to Evaluate Major CV Outcomes Study Drug Primary Outcome Measure Estimated Completion Date Liraglutide CV death, non-fatal MI, non-fatal stroke Death, HF hospitalization, change in pro- B-type natriuretic peptide Exenatide ER CV death, non-fatal MI, or non-fatal stroke 2018 Albiglutide CV death, MI, or stroke 2019 Dulaglutide CV death, non-fatal MI, or non-fatal stroke 2019 clinicaltrials.gov

34 Help Mrs. Sugar Mrs. Sugar calls for your advice. She is scheduled to take her weekly dulaglutide tomorrow and she just found her medication in the kitchen cabinet with 2 remaining pens. She picked up the medication September 12th and assumes they have been out of the fridge since then. Which of the following is correct? a. She should discard all remaining pens and obtain a new supply today prior to administration. b. She may use the remaining 2 pens for tomorrow and next Saturday s injections. c. She may use 1 pen tomorrow but will need a new supply prior to next Saturday. d. She may use 1 pen tomorrow and 1 pen next Saturday if she refrigerates it between now and then.

35 Summary of GLP-1 Agonists Can be used in combination with orals or insulin (exenatide ER not studied with insulin) Dulaglutide, exenatide ER, and liraglutide result in largest A1c lowering Similar cancer and pancreatitis profiles (no cancer warning for exenatide IR) No long term CV outcomes with available medications Choice likely dependent on formulary, cost, and patient preferences

36 Pancreatic Concerns with Incretin-based Therapies 36

37 Pancreatic Pathology and Incretin Therapies Population-based, rodent, and human autopsy studies caused concern that incretin-based therapy may be associated with pancreatic changes. Since March 2013, FDA has been evaluating this information Cases of pancreatitis in humans have been associated with DPP-4 inhibitors and GLP-1 agonists. U.S. Food and Drug Administration Website.

38 If Pancreatitis Occurs While Taking Incretin Therapy Discontinue the DPP-4 inhibitor or GLP-1 agonist Do not restart incretin medications Consider other antidiabetic therapies if patient has a history of pancreatitis U.S. Food and Drug Administration Website.

39 Pancreatic Pathology and Incretin Therapies June 2013 joint statement from ADA/EASD/IDF: no concern for pancreatic disease with incretins after review of data July 2013 European Medicines Agency: present data do not confirm increased pancreatic risk with incretin-based therapy

40 Summary of GLP-1 Agonists Can be used in combination with orals or basal insulin (exenatide ER not studied with insulin) Liraglutide has better A1c lowering in head-to-head studies (not clinically significant) Similar cancer and pancreatitis profiles (no cancer warning for Byetta) No long term CV outcomes with available medications Choice likely dependent on formulary, cost, and patient preference for dosing

41 Role of Incretin Therapies in Type 2 Diabetes 41

42 Management of Type 2 Diabetes Take a patient-centered approach. Always encourage weight control, healthy eating, and physical activity. ADA: metformin initial monotherapy, add-on with incretin-based therapy, sulfonylurea, thiazolidinedione, or insulin. AACE: depending on A1C, monotherapy, dual, or triple therapy is recommended with incretin-based therapy as an option at any tier. FDA does not recommend GLP-1 agonists as 1 st line therapy because of the risk of pancreatitis and potential risk of MTC.

43 Help Mrs. Candy Mrs. Candy is a 56 y/o with type 2 diabetes and is struggling to gain glycemic control. Recent A1C was 9%. Current meds: metformin 1000 mg BID, glipizide 10 mg BID, insulin glargine 50 units HS. PMH: Hyperlipidemia (LDL 116, TG 290, HDL 30), HTN (current BP 130/80), T2DM x 10 yrs CrCl 48 ml/min. Family history includes unknown thyroid cancer in brother. Denies EtOH, tobacco, or illicit drug use Which of the following is the most appropriate addition to her regimen? A. alogliptin 12.5 mg daily B. dulaglutide 0.75 mg weekly C. exenatide 5 mcg BID D. saxagliptin 5 mg daily

44 Key Points Incretin-based therapies primarily increase glucose-dependent insulin secretion and suppress glucagon release. DPP-4 inhibitors are well tolerated, weight neutral, and have modest effects on A1C. GLP-1 agonists may cause GI upset initially, promote weight loss, and may result in significant A1C reduction. Acute pancreatitis has been associated with use of incretin-based medications in humans. Thyroid cancer is a black box warning for most GLP-1 agonists.

45 Post-Session Assessment #1 Which of the following is a mechanism of action for GLP-1 receptor agonists? SELECT ALL THAT APPLY A. decrease insulin secretion B. enhance glucagon secretion C. increase amylin secretion D. slow gastric emptying E. Both B and D are mechanisms of action for GLP-1 receptor agonists.

46 Post-Session Assessment #2 DPP-4 inhibitors have been clinically assessed for cardiovascular outcomes. Which of the following DPP-4 inhibitors has been associated with a clinical concern of heart failure? A. alogliptin B. omargliptin C. sitagliptin D. saxagliptin

47 Post-Session Assessment #3 A 48 y/o WM with a 10-year history of diabetes has an A1C of 8.4% and BMI of 32 kg/m 2 on metformin 1000 mg BID, glipizide ER 20 mg daily, and citalopram 20 mg daily. He has declined to start insulin per last PCM note. PMH: depression. estcrcl > 90 ml/min. Family history: CVA, DM Which of the following is an ideal add-on therapy to better control his diabetes? A. exenatide 5 mcg BID x 4 weeks, then 10 mcg BID B. liraglutide 0.6 mg daily x 1 week, then 1.2 mg daily C. linagliptin 5 mg daily D. sitaglitpin 50 mg daily

48 References Defronzo RA. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 2009;58: Langley AK, Suffoletta TJ, Jennings HR. Dipeptidyl peptidase IV inhibitors and the incretin system in type 2 diabetes mellitus. Pharmacotherapy 2007;27: Nisal K, Kela R, Khunti K, Davies MJ. Comparison of efficacy between incretin-based therapies for type 2 diabetes mellitus. BMC Medicine 2012;10: Golightly LK, Drayna CC, McDermott MT. Comparative clinical pharmacokinetics of dipeptidyl peptidase-4 inihibitors. Clin Pharmacokinet 2012;51: Nesina [package insert]. Deerfield, IL: Takeda Pharmaceuticals America, Inc.; Tradjenta [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc. and Indianapolis, IN: Eli Lilly and Company; Onglyza [package insert]. Wilmington, DE: AstraZenica Pharmceuticals; Januvia [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013;369: Scirica BM, Bhatt DL, Brauwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369: Green JB, Bethel MA, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015;373: Clinicaltrials.gov. Accessed September 3, Byetta [package insert]. Wilmington, DE: AstraZenica Pharmaceuticals LP; Bydureon [package insert]. Wilmington, DE. Astra Zenica Pharmaceuticals LP, Victoza [package insert]. Plainsboro, NJ: Novo Nordisk Inc.; Tanzeum [package insert]. Wilmington, DE: GlaxoSmithKlein LLC; Trulicity [package insert]. Indianapolis, IN. Eli Lilly and Company; 2015.

49 References Pratley RE, Nauck MA, Barnett AH, et al. Once-weekly albiglutide versus once-daily liraglutide in patients with type 2 diabetes inadequately controlled on oral drugs (HARMONY 7): a randomized, open-label, multicentre, non-inferiority phase 3 study. Lancet Diabetes Endocrinol. 2014;2: Wysham C, Blevins T, Arakaki R, et al. Efficacy and safety of dulaglutide added onto pioglitazone and metformin versus exenatide in type 2 diabetes in a randomized controlled trial AWARD-1). Diabetes Care 2014;37: Dungan KM, Povedano ST, Forst T, Gonzalez JG, Atisso C, Sealls W, Fahrbach JL. Once-weekly dulaglutide versus once-daily liraglutide in metformin-treated patients with type 2 diabetes (AWARD-6): a randomized, open-label, phase 3, non-inferiority trial. Lancet 2014;384: Buse JB, Rosenstock J, Sesti G, et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomized, parallelgroup, multinational, open-label trial (LEAD-6). Lancet 2009;374:39-47 Buse JB, Drucker DJ, Taylor KL, et al. DURATION-1: exenatide once weekly produces sustained glycemic control and weight loss over 52 weeks. Diabetes Care 2010;33: Blevins T, Pullman J, Malloy J, et al. 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 Endocrin Metab 2011;96: Buse J, Nauck M, Forst T, Sheu W, et al. Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): a randomised, open-label study. Lancet 2013;381: U.S. Food and Drug Administration Website. Accessed August 10, U.S. Food and Drug Administration Website. Accessed August 10, 2015.

50 References Singh SS, Chang HY, Richards TM, Weiner JP, Clark JM, Segal JB. Glucagonlike peptide 1-based therapies and risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus: a population-based matched case-control study. JAMA Intern Med 2013;173: ADA/EASD/IDF recommendations for clinicians and people with diabetes concerning the use of incretin therapy and pancreatic disease. Accessed August 29, European Medicines Agency: Investigation into GLP-1 based diabetes therapies concluded. Accessed August 29, Butler AE, Campbell-Thompson M, Gurlo T, DawsonDW, Atkinson M, Butler PC. Marked expansion of exocrine and endocrine pancreas with incretin therapy in humans with increased exocrine pancreas dysplasia and the potential for glucagon-producing neuroendocrine tumors. Diabetes 2013;62: Andersen DK. Diabetes and cancer: placing the association in perspective. Curr Opin Endocrinol Diabetes Obes 2013;20:81-6. Monami M, Dicembrini I, Nardini C, Fiordelli I, Mannucci E. Effects of glucagon-like peptide-1 receptor agonists on cardiovascular risk: a metaanalysis of randomized clinical trials. Diabetes Obes Metab 2014;16: Bentley-Lewis R, Aguilar D, Riddle MC, et al. Rationale, design, and baseline characteristics in evaluation of lixisenatide in acute coronary syndrome, a long-term cardiovascular end point trial of lixisenatide versus placebo. Am Heart J 2015;169: Tucker ME. ELIXA completed; diabetes drug lixisenatide heads back to FDA. Published March 19, Accessed August 30, Standards of Medical Care in Diabetes Diabetes Care 2015;38(Suppl 1). AACE/ACE Comprehensive Diabetes Management Algorithm Endocr Pract 2015;21:

51 Incretin Therapies: Clinical Updates for Type 2 Diabetes