sign in sign up
<<
Home , Incretin

9/21/2015

Disclosures/Conflict of Interest Incretin Therapies: Clinical • Drs. Jessica Kerr and Jennifer Rosselli have received community Updates for and patient health education grants from Novo Nordisk during years 2014 and 2015. Jessica L. Kerr, Pharm.D, CDE Assistant Chair, Pharmacy Practice • Dr. Jessica Kerr has provided CPE credits for unrestricted Associate Professor educational grants sponsored by Sanofi. Jennifer Rosselli, Pharm.D., BCPS, BCACP Clinical Associate Professor Southern Illinois University Edwardsville

Objectives Pre-Session Assessment #1 • At the conclusion of this program, the pharmacist/technicians will Which of the following is a mechanism of action for GLP-1 receptor agonists? be able to: SELECT ALL THAT APPLY • Describe glycemic effects of incretin-based therapies. A. decrease secretion • Compare and contrast the efficacy and safety concerns of individual incretin medications. B. enhance secretion • Describe the role of incretin-based medicines in diabetes management. C. increase secretion • Explain injection administration clinical pearls for GLP-1 receptor agonists. D. slow gastric emptying E. both B and D are mechanisms of action for GLP-1 receptor agonists

Pre-Session Assessment #2 Pre-Session Assessment #3

DPP-4 inhibitors have been clinically assessed for cardiovascular outcomes. A 48 y/o WM with a 10-year history of diabetes has an A1C of 8.4% and BMI Which of the following DPP-4 inhibitors has been associated with a clinical of 32 kg/m 2 on metformin 1000 mg BID, glipizide ER 20 mg daily, and concern of heart failure? citalopram 20 mg daily. He has declined to start insulin per last PCM note. A. alogliptin PMH: depression. estCrCl > 90 ml/min. Family history: CVA, DM B. omargliptin C. Which of the following is an ideal add-on therapy to better control his diabetes? D. A. 5 mcg BID x 4 weeks, then 10 mcg BID B. 0.6 mg daily x 1 week, then 1.2 mg daily C. linagliptin 5 mg daily D. sitaglitpin 50 mg daily

1 9/21/2015

Pathophysiology of T2DM

Decreased Incretin System Neurotransmitter dysfunction uptake Increased hepatic Increased • Incretins are naturally occurring glucoregulatory . glucose lipolysis production • Glucose-dependent release by the gut • Decreased Impaired Glucagon-like -1 (GLP-1) insulin incretin • Glucose-dependent insulinotropic peptide (GIP) secretion function • Incretin hormones are rapidly degraded by dipeptidyl peptidase 4 (DPP-4)

Increased Increased glucagon Hyperglycemia glucose secretion reabsorption

Defronzo RA. Diabetes 2009;58:773-95 .

Physiologic Affects of the Incretin System

DPP-4 GLP-1 and GIP

Small • Insulin release DPP-4 Inhibitors intestines • Glucagon suppression • Decreases GI motility • Release of incretin • Reduces appetite hormones • Slows glucose absorption • Increases cardiac output Food intake Brain, GI Tract, Heart,

Incretin Enhancement by DPP-4 Inhibitors Current DPP-4 Inhibitors

DPP-4 DPP-4 GLP-1 and GIP Inhibition • Alogliptin (Nesina®) • Linagliptin (Tradjenta®) • Small • Insulin release Saxagliptin (Onglyza®) intestines • Glucagon suppression • Sitagliptin (Januvia®) • Decreases GI motility • Release of incretin • Reduces appetite • Vildagliptin (Galvus®)* hormones • Slows glucose absorption • Increases cardiac output Food intake Brain, GI Tract, Heart, Pancreas *Approved for use in Europe

2 9/21/2015

Comparison of DPP-4 Inhibitors

Medication Usual Dose Dose Adjustment Unique A1C Change FPG 2h PPG Warnings (%) Change Change Overview of DPP-4 Inhibitors (mg/dl) (mg/dl) Alogliptin 25 mg/d Renal impairment CrCl: Hepatic -0.5to -1.0 -8 to -26 -43 • 6.25 mg, 12.5 30-60 ml/min=12.5 mg failure Supplied as oral formulations mg, 25 mg < 30 ml/min=6.25 mg • Currently, once daily administration, without regards to meals Linagliptin 5 mg/d None -0.2 to -0.6 -5 to -13 -34 to -49 • A1C reduction 0.2-1.15% 5 mg (Decreased effectiveness with P-glycoproteins/CYP • Minimal weight loss to weight neutral 3A4 inducers) • Low incidence of hypoglycemia Saxagliptin 2.5 or 5 mg/d Renal impairment CrCl: Increased -0.4 to -0.9 -7 to -22 -12 to -65 2.5 mg, 5 mg < 50 ml/min=2.5 mg edema with • Studied as combination and monotherapy Strong CYP 3A4 TZDs inhibitors=2.5 mg dose

Sitagliptin 100 mg/d Renal impairment CrCl: Acute renal -0.3 to -1.15 -1 to -30 -31 to -62 25 mg, 50 mg, 30-49 ml/min=50 mg failure 100 mg < 30 ml/min=25 mg Pruritis

DPP-4 Inhibitor Cardiovascular (CV) Outcomes Studies Safety Concerns of DPP-4 Inhibitors PLACEBO CV death, CVD or RF SAVOR –TIMI 53 nonfatal CVA or A1c 6.5 to 12% R • Most common ADRs: upper respiratory infection, nasopharyngitis, nonfatal MI n = 16,422 Saxagliptin headache N Engl J Med 2013;369:1317-26. • Hypersensitivity reactions: angioedema, anaphylaxis, Steven’s-Johnson PLACEBO syndrome CV death, ACS EXAMINE nonfatal CVA or A1c 6.5% to 11% R • Acute pancreatitis nonfatal MI n = 5380 N Engl J Med 2013;369:1327-35 Alogliptin • Arthralgias: severe and disabling have been reported PLACEBO CV death, CVD R TECOS nonfatal CVA or A1c 6.5 to 8.0% nonfatal MI or UA n = 14,671 Sitagliptin N Engl J Med 2015;373:232-42 . requiring hospitalization

Trial Name Primary Outcomes Population 0 Median Follow Up 3yr

Baseline Characteristics from DPP -4 Inhibitor Incidence of Hospitalization for Heart Failure in Cardiovascular Outcomes Studies DPP-4 Inhibitor Cardiovascular Outcomes Studies Trait SAVOR-TIMI 53 EXAMINE TECOS Clinical Trial Study Drug Placebo Hazard Ratio 95% CI Mean age, years 65 61 66

Mean duration diabetes, years 10.3 7.3 10 SAVOR-TIMI 53 3.5% 2.8% 1.27 1.07-1.51

Mean baseline A1c, % 8.0 8.0 7.2 EXAMINE 3.9% 3.3% 1.19 0.89-1.58 Dyslipidemia, % 71 Not reported 77

Active smokers, % Not reported 14 11 TECOS 3.1% 3.1% 1.00 0.83-1.20

Previous heart failure, % 13 28 18

Mean duration of follow up, years 2.1 1.5 3.0 0 1 2 Favors Treatment Favors Placebo N Engl J Med 2013;369:1327-35. N Engl J Med 2013;369:1327-35. N Engl J Med 2013;369:1317-26. N Engl J Med 2013;369:1317-26. N Engl J Med 2015;373:232-42. N Engl J Med 2015;373:232-42.

3 9/21/2015

Grab a Partner Ongoing Trials to Evaluate CV Outcomes 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. • Linagliptin: CARMELINA, CAROLINA (both to be completed in 2018) 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?

clinicaltrials.gov

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 GLP-1 Agonists • Renal dosing with all, except for linagliptin • Pancreatitis warnings • No long term outcomes • Choice likely dependent on formulary/cost

Incretin Mimetic Current GLP-1 Agonists

GLP-1 and GIP Exogenous GLP-1

• Exenatide (Byetta®) 2005

Small • Insulin release • Liraglutide (Victoza®) 2010 intestines • Glucagon suppression • • Decreases GI motility Exenatide extended-release (Bydureon®) 2012 • Release of incretin • Reduces appetite • (Tanzeum®) 2014 hormones • Slows glucose absorption • Increases cardiac output • (Trulicity®) 2014 Food intake Brain, GI Tract, Heart, Pancreas

4 9/21/2015

Comparison of GLP-1 Agonists Medication Injection Dosing Regimen Product Preparation and Storage Overview of GLP-1 Agonists schedule Administration Exenatide BID 5 mcg BID x 1 month, increase to Administer within 60 min Refrigerate until opened. (Multi-dose pen) 10 mcg BID based on clinical prior to 2 biggest meals (6 Good for 30 days once response. hours apart) opened. • Supplied as subcutaneous injections Liraglutide Daily 0.6 mg daily x 1 week, then Administer regardless of Refrigerate until opened. • Twice daily, once daily, or once weekly administration depending on (Multi-dose pen) 1.2 mg daily x at least 1 week, meal timing Good for 30 days once medication can increase up to 1.8 mg based opened. on response. • Product preparation required of patient varies by medication Exenatide ER Weekly 2 mg once weekly. Administer immediately Refrigerate until opened. (Single-dose tray and after reconstituting. Rotate Discard after 4 weeks of • A1C reduction varies by medication (-0.5% to -1.9%) single-dose pen) injection sites room temperature. • Weight loss of 1.5-3 kg on average Albiglutide Weekly 30 mg once weekly. Can increase Wait 15-30 minutes for Refrigerate until opened. (Single-dose pen) to 50 mg after 4 weeks for reconstituted solution to Discard after 4 weeks of • Low incidence of hypoglycemia additional glycemic control. mix. Use within 8 hours of room temperature. reconstitution. • Studied as monotherapy and in combination Dulaglutide Weekly 0.75 mg once weekly. Can Single-use pen device Refrigerate. Discard 14 (Single-dose pen) increase to 1.5 mg for additional supplied with non-visible days after product is left glycemic control. needle attached and does at room temperature. not require reconstitution

Comparison of GLP -1 Agonists Summary of GLP -1 Agonist Head -to -Head Clinical Trials Drug Unique Warnings Dose Adjustment A1C Change FPG 2h PPG Weight Trial Treatment A1c Change (%) Weight Change (kg) (%) Change Change Change (mg/dl) (mg/dl) (kg) Pratley et al. Albiglutide 30 mg, up to 50 mg weekly Albiglutide: -0.78 Albiglutide: -0.6 (HARMONY 7) Liraglutide 1.8 mg daily Liraglutide: -0.99* Liraglutide: -2.2* Exenatide Increased INR with Renal impairment -0.5to -1.2 -5 to -21 -63 to -71 -1.1 to -2.9 warfarin Avoid if CrCl < 30 ml/min Administer oral Wysham et al. Dulaglutide 0.75 mg weekly Dulaglutide 0.75 mg: -1.3 Dulaglutide 0.75 mg: 0.2 contraceptive 1 hour prior (AWARD-1) Dulaglutide 1.5 mg weekly Dulaglutide 1.5 mg: -1.5 Dulaglutide 1.5 mg: -1.3 Exenatide 10 mcg BID Exenatide: -0.99 Exenatide: -1.07 Liraglutide None -0.8 to –1.5 -15 to -36 -2.1to -2.6 Dungan, et al. Dulaglutide 1.5 mg weekly Dulaglutide:-1.42 Dulaglutide: - 2.9 (AWARD-6) Liraglutide 1.8 mg daily Liraglutide: -1.36 Liraglutide: -3.61 Exenatide ER Injection site reactions Renal impairment -0.8 to -1.9 -25 -2.5 (subcutaneous nodules, Avoid if CrCl < 30 ml/min Buse et al. Liraglutide 1.8 mg daily vs. Liraglutide: -1.12* Liraglutide: -3.24 cellulitis, abscess, Takes up to 9 (LEAD-6) Exenatide 10 mcg BID Exenatide: -0.79 Exenatide: -2.87 necrosis) weeks to Buse et al. Exenatide ER 2 mg weekly Exenatide ER: -1.9* Exenatide ER:-3.6 Monitor for increased INR reach full (DURATION-1) Exenatide 10 mcg BID Exenatide: -1.5 Exenatide: -3.7 with warfarin efficacy Not studied in Blevins et al. Exenatide ER 2 mg weekly Exenatide ER: -1.6* Exenatide ER: -2.3 combination with insulin (DURATION-5) Exenatide 10 mcg BID Exenatide: -0.9 Exenatide: -1.4 Albiglutide None -0.7 to -1.0 -12 to -26 -0.4 to -1.2 Buse et al. Exenatide ER 2 mg weekly vs. Exenatide ER: -1.28 Exenatide: -2.68 (DURATION-6) Liraglutide 1.8 mg daily Liraglutide: –1.48* Liraglutide: -3.57* Dulaglutide Not studied in combo None -0.7 to -1.6 4 to -41 0.2 to -3.1 with basal insulin *Statistically significant

Safety Concerns GLP-1 Agonists and Thyroid Carcinoma

• Most common ADRs: nausea, vomiting, • All GLP-1 agonists except for exenatide IR have black box warning for diarrhea, headache, injection site reaction thyroid carcinoma • • Contraindicated with a personal or family history of medullary thyroid Hypersensitivity reactions: Black Box Warning* angioedema, anaphylaxis, rash, pruritis cancer (MTC) or multiple endocrine neoplasia syndrome type 2 (MEN 2) • Acute pancreatitis Risk of thyroid C-cell tumors • Thyroid C-cell tumors observed in animal studies • Severe gastrointestinal disease (ex. *Warning of liraglutide, exenatide ER, albiglutide, and • Cases of MTC in humans treated with liraglutide have been reported in post gastroparesis) dulaglutide marketing period • Hypoglycemia risk increased when used • Counsel patients regarding risks and symptoms of MTC with insulin or sulfonylurea • Refer to endocrinologist if thyroid nodules are present • Renal impairment

U.S. Food and Drug Administration Website. http://www.fda.gov/safety/medwatch/safetyinformation/ucm400570.htm.

5 9/21/2015

GLP-1 Agonist Cardiovascular Outcomes Studies GLP-1 Agonists Cardiovascular Outcomes Studies Bentley-Lewis et al. ELIXA Monami et al. Trial design Randomized, placebo controlled, parallel-group, Trial design Meta-analysis multinational Trials included 37 Intervention Lixisenatide 10-20 mcg/day Subjects, No. N=15,398 Subjects N=6,068, T2DM and discharge in recent 180 days for ACS GLP-1 agonists Albiglutide Baseline characteristics Mean age 60 years, 69% male, 75% white, duration of Exenatide T2DM 9 years, BMI 30 kg/m 2, A1c 7.7%, history of HF 12% Exenatide LAR Mean follow-up 2 years Liraglutide Results [Hazard Ratio (95% CI)] • Primary outcome: CV death, non-fatal MI, Duration of included trials (mean) 42 weeks non-fatal stroke, and hospitalization for 1.017 (0.886 to 1.168) Results Odds Ratio (95% CI) unstable angina Primary outcome: CV death, non-fatal 0.78 (0.54 to 1.13) • Secondary outcome: HF 0.96 (0.75 to 1.23) MI and stroke, and ACS and/or HF 0 1 2 Diabetes Obes Metab 2014;16:38-47. Favors lixisenatide Favors placebo Am Heart J 2015;169:631-38, http://www.medscape.com/viewarticle/841761

Ongoing Trials to Evaluate Major CV Outcomes Help Mrs. Sugar Mrs. Sugar calls for your advice. She is scheduled to take her weekly dulaglutide Study Drug Primary Outcome Measure Estimated Completion tomorrow and she just found her medication in the kitchen cabinet with 2 Date remaining pens. She picked up the medication September 12th and assumes they • Liraglutide CV death, non-fatal MI, non-fatal stroke 2016 have been out of the fridge since then. Which of the following is correct? • Death, HF hospitalization, change in pro- 2016 B-type Exenatide ER CV death, non-fatal MI, or non-fatal stroke 2018 a. She should discard all remaining pens and obtain a new supply today prior to administration. Albiglutide CV death, MI, or stroke 2019 b. She may use the remaining 2 pens for tomorrow and next Saturday’s Dulaglutide CV death, non-fatal MI, or non-fatal stroke 2019 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. clinicaltrials.gov

Summary of GLP-1 Agonists

• Can be used in combination with orals or insulin (exenatide ER not studied Pancreatic Concerns with with insulin) • Dulaglutide, exenatide ER, and liraglutide result in largest A1c lowering Incretin-based Therapies • 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

6 9/21/2015

If Pancreatitis Occurs While Taking Pancreatic Pathology and Incretin Therapies Incretin Therapy

• Population-based, rodent, and human autopsy studies caused concern • Discontinue the DPP-4 inhibitor or GLP-1 agonist that incretin-based therapy may be associated with pancreatic changes. • Do not restart incretin medications • Since March 2013, FDA has been evaluating this information • Consider other antidiabetic therapies if patient has a history of pancreatitis • Cases of pancreatitis in humans have been associated with DPP-4 inhibitors and GLP-1 agonists.

U.S. Food and Drug Administration Website. http://www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalproducts/ucm343805.htm . U.S. Food and Drug Administration Website. http://www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalproducts/ucm343805.htm .

Pancreatic Pathology and Incretin Therapie s Summary of GLP-1 Agonists

• Can be used in combination with orals or basal insulin (exenatide ER • June 2013 joint statement from ADA/EASD/IDF: no concern for pancreatic not studied with insulin) disease with incretins after review of data • • Liraglutide has better A1c lowering in head-to-head studies (not July 2013 European Medicines Agency: present data do not confirm clinically significant) increased pancreatic risk with incretin-based therapy • 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

http://www.diabetes.org/for-media/2013/recommendations-for.html. http://www.ema.Europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/07/news_detail_001856.jsp&mid=WCobo1ac058004d5c1.

Management of Type 2 Diabetes

Role of IncretinTherapies in • Take a patient-centered approach. Type 2 Diabetes • 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.

41

7 9/21/2015

Help Mrs. Candy Key Points Mrs. Candy is a 56 y/o with type 2 diabetes and is struggling to gain glycemic control. Recent A1C was 9%. • Incretin-based therapies primarily increase glucose-dependent insulin Current meds: metformin 1000 mg BID, glipizide 10 mg BID, insulin glargine 50 units HS. secretion and suppress glucagon release. PMH: Hyperlipidemia (LDL 116, TG 290, HDL 30), HTN (current BP 130/80), T2DM x 10 yrs • DPP-4 inhibitors are well tolerated, weight neutral, and have modest CrCl 48 ml/min. Family history includes unknown thyroid cancer in brother. effects on A1C. Denies EtOH, tobacco, or illicit drug use • GLP-1 agonists may cause GI upset initially, promote weight loss, and may result in significant A1C reduction. Which of the following is the most appropriate addition to her regimen? • Acute pancreatitis has been associated with use of incretin-based A. alogliptin 12.5 mg daily medications in humans. Thyroid cancer is a black box warning for most GLP-1 agonists. B. dulaglutide 0.75 mg weekly C. exenatide 5 mcg BID D. saxagliptin 5 mg daily

Post-Session Assessment #1 Post-Session Assessment #2

DPP-4 inhibitors have been clinically assessed for cardiovascular outcomes. Which of the following is a mechanism of action for GLP-1 receptor agonists? Which of the following DPP-4 inhibitors has been associated with a clinical SELECT ALL THAT APPLY concern of heart failure? A. decrease insulin secretion A. alogliptin B. enhance glucagon secretion B. omargliptin C. increase amylin secretion C. sitagliptin D. slow gastric emptying D. saxagliptin E. Both B and D are mechanisms of action for GLP-1 receptor agonists.

References Post-Session Assessment #3 Defronzo RA. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 2009;58:773-95. Langley AK, Suffoletta TJ, Jennings HR. Dipeptidyl peptidase IV inhibitors and the incretin system in type 2 diabetes mellitus. Pharmacotherapy 2007;27:1163-80. A 48 y/o WM with a 10-year history of diabetes has an A1C of 8.4% and BMI Nisal K, Kela R, Khunti K, Davies MJ. Comparison of efficacy between incretin-based therapies for type 2 diabetes mellitus. BMC Medicine 2012;10:152-62. 2 of 32 kg/m on metformin 1000 mg BID, glipizide ER 20 mg daily, and GolightlyLK, Drayna CC, McDermott MT. Comparative clinical pharmacokinetics of dipeptidyl peptidase-4 inihibitors. Clin Pharmacokinet 2012;51:501-14. citalopram 20 mg daily. He has declined to start insulin per last PCM note. Nesina [package insert]. Deerfield, IL: Takeda Pharmaceuticals America, Inc.; 2015. Tradjenta [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc. and Indianapolis, IN: Eli Lilly and Company; 2015. PMH: depression. estCrCl > 90 ml/min. Family history: CVA, DM Onglyza [package insert]. Wilmington, DE: AstraZenica Pharmceuticals; 2015. Januvia [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2015. White WB, Cannon CP, Heller SR, et al. Alogliptinafter acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013;369:1327-35. Which of the following is an ideal add-on therapy to better control his diabetes? Scirica BM, Bhatt DL, Brauwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369:1317-26. A. exenatide 5 mcg BID x 4 weeks, then 10 mcg BID Green JB, Bethel MA, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015;373:232-42. Clinicaltrials.gov. Accessed September 3, 2015. B. liraglutide 0.6 mg daily x 1 week, then 1.2 mg daily Byetta [package insert]. Wilmington, DE: AstraZenica Pharmaceuticals LP; 2015. C. linagliptin 5 mg daily Bydureon [package insert]. Wilmington, DE. Astra Zenica Pharmaceuticals LP, 2015. Victoza [package insert]. Plainsboro, NJ: Novo Nordisk Inc.; 2015. D. sitaglitpin 50 mg daily Tanzeum [package insert]. Wilmington, DE: GlaxoSmithKlein LLC; 2015. Trulicity [package insert]. Indianapolis, IN. Eli Lilly and Company; 2015.

8 9/21/2015

References References Pratley RE, Nauck MA, Barnett AH, et al. Once-weekly albiglutideversus once-daily liraglutidein patients with type 2 diabetes inadequately Singh SS, Chang HY, Richards TM, Weiner JP, Clark JM, Segal JB. Glucagonlike peptide 1-based therapies and risk of hospitalization for acute controlled on oral drugs (HARMONY 7): a randomized, open-label, multicentre, non-inferiority phase 3 study. Lancet Diabetes Endocrinol. pancreatitis in type 2 diabetes mellitus: a population-based matched case-control study. JAMA Intern Med 2013;173:534-9. 2014;2:289-97. ADA/EASD/IDF recommendations for clinicians and people with diabetes concerning the use of incretin therapy and pancreatic disease. Wysham C, Blevins T, Arakaki R, et al. Efficacy and safety of dulaglutideadded onto pioglitazone and metformin versus exenatide in type 2 http://www.diabetes.org/for-media/2013/recommendations-for.html. Accessed August 29, 2015. diabetes in a randomized controlled trial AWARD-1). Diabetes Care 2014;37:2159-67. European Medicines Agency: Investigation into GLP-1 based diabetes therapies concluded. Dungan KM, Povedano ST, ForstT, Gonzalez JG, Atisso C, SeallsW, Fahrbach JL. Once-weekly dulaglutide versus once-daily liraglutide in http://www.ema.Europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/07/news_detail_001856.jsp&mid=WCobo1ac058004d5c1. metformin-treated patients with type 2 diabetes (AWARD-6): a randomized, open-label, phase 3, non-inferiority trial. Lancet 2014;384:1349-57. Accessed August 29, 2015. 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, parallel- Butler AE, Campbell-Thompson M, GurloT, DawsonDW, Atkinson M, Butler PC. Marked expansion of exocrine and endocrine pancreas with group, multinational, open-label trial (LEAD-6). Lancet 2009;374:39-47 incretin therapy in humans with increased exocrine pancreas dysplasia and the potential for glucagon-producing neuroendocrine tumors. Buse JB, Drucker DJ, Taylor KL, et al. DURATION-1: exenatide once weekly produces sustained glycemic control and weight loss over 52 weeks. Diabetes 2013;62:2595-2604. Diabetes Care 2010;33:1255-61. Andersen DK. Diabetes and cancer: placing the association in perspective. Curr Opin Endocrinol Diabetes Obes 2013;20:81-6. Blevins T, Pullman J, Malloy J, et al. DURATION-5: exenatide once weekly resulted in greater improvements in glycemic control compared with Monami M, Dicembrini I, Nardini C, Fiordelli I, Mannucci E. Effects of glucagon-like peptide-1 receptor agonists on cardiovascular risk: a meta- exenatide twice daily in patients with type 2 diabetes. J Clin Endocrin Metab 2011;96:1301-10. analysis of randomized clinical trials. Diabetes Obes Metab 2014;16:38-47. Buse J, Nauck M, ForstT, Sheu W, et al. Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): a Bentley-Lewis R, Aguilar D, Riddle MC, et al. Rationale, design, and baseline characteristics in evaluation of lixisenatide in acute coronary randomised, open-label study. Lancet 2013;381:117-24. syndrome, a long-term cardiovascular end point trial of lixisenatide versus placebo. Am Heart J 2015;169:631-38. U.S. Food and Drug Administration Website. http://www.fda.gov/safety/medwatch/safetyinformation/ucm400570.htm. Accessed August 10, Tucker ME. ELIXA completed; diabetes drug lixisenatide heads back to FDA. http://www.medscape.com/viewarticle/841761. Published March 2015. 19, 2015. Accessed August 30, 2015. U.S. Food and Drug Administration Website. Standards of Medical Care in Diabetes – 2015. Diabetes Care 2015;38(Suppl 1). http://www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalproducts/ucm343805.htm. Accessed August 10, 2015. AACE/ACE Comprehensive Diabetes Management Algorithm 2015. Endocr Pract 2015;21:438-447.

Incretin Therapies: Clinical Updates for Type 2 Diabetes

9