Incretin Therapies: ClinicalUpdates for Type 2 Diabetes

Jessica L. Kerr, Pharm.D, CDEAssistant Chair, Pharmacy Practice

Associate Professor

Jennifer Rosselli, Pharm.D., BCPS, BCACPClinical Associate Professor

Southern Illinois University Edwardsville

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 2015.

• Dr. Jessica Kerr has provided CPE credits for unrestricted educational grants sponsored by Sanofi.

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.

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

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

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/m2 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

Pathophysiology of T2DM

HyperglycemiaIncreased glucagon secretion

Decreased insulin

secretion

Increased hepatic glucose

production

Neurotransmitter dysfunction

Decreased glucose uptake

Increased lipolysis

Impaired incretin function

Increased glucose

reabsorption

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

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)

Physiologic Affects of the Incretin System

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

GLP-1 and GIPDPP-4

DPP-4 Inhibitors

Incretin Enhancement by DPP-4 Inhibitors

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

GLP-1 and GIPDPP-4DPP-4

Inhibition

Current DPP-4 Inhibitors

• Alogliptin (Nesina®)

• Linagliptin (Tradjenta®)

• Saxagliptin (Onglyza®)

• Sitagliptin (Januvia®)

• Vildagliptin (Galvus®)*

*Approved for use in Europe

Overview of DPP-4 Inhibitors

• Supplied as oral formulations

• Currently, once daily administration, without regards to meals

• A1C reduction 0.2-1.15%

• Minimal weight loss to weight neutral

• Low incidence of hypoglycemia

• Studied as combination and monotherapy

Comparison of DPP-4 InhibitorsMedication Usual Dose Dose Adjustment Unique

WarningsA1C Change(%)

FPGChange (mg/dl)

2h PPG Change (mg/dl)

Alogliptin6.25 mg, 12.5 mg, 25 mg

25 mg/d Renal impairment CrCl: 30-60 ml/min=12.5 mg< 30 ml/min=6.25 mg

Hepaticfailure

-0.5 to -1.0 -8 to -26 -43

Linagliptin5 mg

5 mg/d None(Decreased effectiveness with P-glycoproteins/CYP 3A4 inducers)

-0.2 to -0.6 -5 to -13 -34 to -49

Saxagliptin2.5 mg, 5 mg

2.5 or 5 mg/d Renal impairment CrCl:< 50 ml/min=2.5 mgStrong CYP 3A4 inhibitors=2.5 mg dose

Increased edema with TZDs

-0.4 to -0.9 -7 to -22 -12 to -65

Sitagliptin25 mg, 50 mg,100 mg

100 mg/d Renal impairment CrCl:30-49 ml/min=50 mg< 30 ml/min=25 mg

Acute renal failurePruritis

-0.3 to -1.15 -1 to -30 -31 to -62

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

DPP-4 Inhibitor Cardiovascular (CV) Outcomes Studies

N Engl J Med 2015;373:232-42.

EXAMINE

SAVOR –TIMI 53

TECOS

Median Follow Up0 3yr

ACSA1c 6.5% to 11%

n = 5380

R

Alogliptin

PLACEBO

CVD or RFA1c 6.5 to 12%

n = 16,422R

PLACEBO

Saxagliptin

CVDA1c 6.5 to 8.0%

n = 14,671

R

PLACEBO

Sitagliptin

CV death, nonfatal CVA or

nonfatal MI

CV death, nonfatal CVA or

nonfatal MI

CV death, nonfatal CVA or

nonfatal MI or UA requiring

hospitalization

Trial Name Primary Outcomes Population

N Engl J Med 2013;369:1317-26.

N Engl J Med 2013;369:1327-35

Baseline Characteristics from DPP-4 Inhibitor Cardiovascular Outcomes Studies

N Engl J Med 2013;369:1327-35.N Engl J Med 2013;369:1317-26.N Engl J Med 2015;373:232-42.

Trait SAVOR-TIMI 53 EXAMINE TECOS

Mean age, years 65 61 66

Mean duration diabetes, years 10.3 7.3 10

Mean baseline A1c, % 8.0 8.0 7.2

Dyslipidemia, % 71 Not reported 77

Active smokers, % Not reported 14 11

Previous heart failure, % 13 28 18

Mean duration of follow up, years 2.1 1.5 3.0

Incidence of Hospitalization for Heart Failure in DPP-4 Inhibitor Cardiovascular Outcomes Studies

0 1 2Favors Treatment Favors Placebo

Clinical Trial Study Drug Placebo Hazard Ratio 95% CI

SAVOR- TIMI 53 3.5% 2.8% 1.27 1.07-1.51

EXAMINE 3.9% 3.3% 1.19 0.89-1.58

TECOS 3.1% 3.1% 1.00 0.83-1.20

N Engl J Med 2013;369:1327-35.N Engl J Med 2013;369:1317-26.N Engl J Med 2015;373:232-42.

Ongoing Trials to Evaluate CV Outcomes

• Linagliptin: CARMELINA, CAROLINA (both to be completed in 2018)

clinicaltrials.gov

Grab a Partner

Mr. Starch is a 49 y/o who was recently discharged from the hospital for his 1st 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?

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

GLP-1 Agonists

Incretin Mimetic

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

Exogenous GLP-1 GLP-1 and GIP

Current GLP-1 Agonists

• Exenatide (Byetta®) 2005

• Liraglutide (Victoza®) 2010

• Exenatide extended-release (Bydureon®) 2012

• Albiglutide (Tanzeum®) 2014

• Dulaglutide (Trulicity®) 2014

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 1.5-3 kg on average

• Low incidence of hypoglycemia

• Studied as monotherapy and in combination

Comparison of GLP-1 AgonistsMedication Injection

scheduleDosing Regimen Product Preparation and

AdministrationStorage

Exenatide(Multi-dose pen)

BID 5 mcg BID x 1 month, increase to10 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)

Daily 0.6 mg daily x 1 week, then1.2 mg daily x at least 1 week, can increase up to 1.8 mg based on response.

Administer regardless of meal timing

Refrigerate until opened. Good for 30 days once opened.

Exenatide ER(Single-dose tray and single-dose pen)

Weekly 2 mg once weekly. Administer immediately after reconstituting. Rotate injection sites

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 15-30 minutes for reconstituted solution tomix. 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.

Comparison of GLP-1 AgonistsDrug Unique Warnings Dose Adjustment A1C Change

(%)FPG Change (mg/dl)

2h PPG Change (mg/dl)

Weight Change(kg)

Exenatide Increased INR with warfarinAdminister oral contraceptive 1 hour prior

Renal impairmentAvoid if CrCl < 30 ml/min

-0.5 to -1.2 -5 to -21 -63 to -71 -1.1 to -2.9

Liraglutide None -0.8 to – 1.5 -15 to -36 -2.1 to -2.6

Exenatide ER Injection site reactions (subcutaneous nodules, cellulitis, abscess, necrosis)Monitor for increased INR with warfarinNot studied in combination with insulin

Renal impairmentAvoid if CrCl < 30 ml/min

-0.8 to -1.9

Takes up to 9 weeks to reach full efficacy

-25 -2.5

Albiglutide None -0.7 to -1.0 -12 to -26 -0.4 to -1.2

Dulaglutide Not studied in combowith basal insulin

None -0.7 to -1.6 4 to -41 0.2 to -3.1

Summary of GLP-1 Agonist Head-to-Head Clinical TrialsTrial Treatment A1c Change (%) Weight Change (kg)

Pratley et al. (HARMONY 7)

Albiglutide 30 mg, up to 50 mg weeklyLiraglutide 1.8 mg daily

Albiglutide: -0.78Liraglutide: -0.99*

Albiglutide: -0.6Liraglutide: -2.2*

Wysham et al.(AWARD-1)

Dulaglutide 0.75 mg weeklyDulaglutide 1.5 mg weeklyExenatide 10 mcg BID

Dulaglutide 0.75 mg: -1.3Dulaglutide 1.5 mg: -1.5Exenatide: -0.99

Dulaglutide 0.75 mg: 0.2Dulaglutide 1.5 mg: -1.3Exenatide: -1.07

Dungan, et al.(AWARD-6)

Dulaglutide 1.5 mg weeklyLiraglutide 1.8 mg daily

Dulaglutide:-1.42Liraglutide: -1.36

Dulaglutide: - 2.9Liraglutide: -3.61

Buse et al.(LEAD-6)

Liraglutide 1.8 mg daily vs.Exenatide 10 mcg BID

Liraglutide: -1.12*Exenatide: -0.79

Liraglutide: -3.24Exenatide: -2.87

Buse et al. (DURATION-1)

Exenatide ER 2 mg weeklyExenatide 10 mcg BID

Exenatide ER: -1.9*Exenatide: -1.5

Exenatide ER:-3.6Exenatide: -3.7

Blevins et al. (DURATION-5)

Exenatide ER 2 mg weeklyExenatide 10 mcg BID

Exenatide ER: -1.6*Exenatide: -0.9

Exenatide ER: -2.3Exenatide: -1.4

Buse et al.(DURATION-6)

Exenatide ER 2 mg weekly vs.Liraglutide 1.8 mg daily

Exenatide ER: -1.28Liraglutide: –1.48*

Exenatide: -2.68Liraglutide: -3.57*

*Statistically significant

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

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. http://www.fda.gov/safety/medwatch/safetyinformation/ucm400570.htm.

GLP-1 Agonists Cardiovascular Outcomes Studies

Diabetes Obes Metab 2014;16:38-47.

Monami et al.

Trial design Meta-analysis

Trials includedSubjects, No.

37N=15,398

GLP-1 agonists AlbiglutideExenatideExenatide LARLiraglutideTaspoglutide

Duration of included trials (mean) 42 weeks

Results Primary outcome: CV death, non-fatal MI and stroke, and ACS and/or HF

Odds Ratio (95% CI)0.78 (0.54 to 1.13)

GLP-1 Agonist Cardiovascular Outcomes StudiesBentley-Lewis et al.ELIXA

Trial design Randomized, placebo controlled, parallel-group, multinational

Intervention Lixisenatide 10-20 mcg/day

SubjectsBaseline characteristics

N=6,068, T2DM and discharge in recent 180 days for ACSMean age 60 years, 69% male, 75% white, duration of T2DM 9 years, BMI 30 kg/m2, A1c 7.7%, history of HF 12%

Mean follow-up 2 years

Results [Hazard Ratio (95% CI)]• Primary outcome: CV death, non-fatal MI,

non-fatal stroke, and hospitalization for unstable angina

• Secondary outcome: HF

1.017 (0.886 to 1.168)

0.96 (0.75 to 1.23)

Am Heart J 2015;169:631-38, http://www.medscape.com/viewarticle/841761

0 1 2Favors lixisenatide Favors placebo

Ongoing Trials to Evaluate Major CV Outcomes

clinicaltrials.gov

Study Drug Primary Outcome Measure Estimated CompletionDate

Liraglutide • CV death, non-fatal MI, non-fatal stroke• Death, HF hospitalization, change in pro-

B-type natriuretic peptide

20162016

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

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.

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

Pancreatic Concerns with Incretin-based Therapies

36

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. http://www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalproducts/ucm343805.htm.

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. http://www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalproducts/ucm343805.htm.

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

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.

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

Role of Incretin Therapies in Type 2 Diabetes

41

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 1st line therapy because of the risk of pancreatitis and potential risk of MTC.

Help Mrs. CandyMrs. 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

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.

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.

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

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/m2 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

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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.

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ReferencesPratley 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;2:289-97.

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;37:2159-67.

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;384:1349-57.

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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;33:1255-61.

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;96:1301-10.

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;381:117-24.

U.S. Food and Drug Administration Website. http://www.fda.gov/safety/medwatch/safetyinformation/ucm400570.htm. Accessed August 10, 2015.

U.S. Food and Drug Administration Website. http://www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalproducts/ucm343805.htm. Accessed August 10, 2015.

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ADA/EASD/IDF recommendations for clinicians and people with diabetes concerning the use of incretin therapy and pancreatic disease. http://www.diabetes.org/for-media/2013/recommendations-for.html. Accessed August 29, 2015.

European Medicines Agency: Investigation into GLP-1 based diabetes therapies concluded. http://www.ema.Europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/07/news_detail_001856.jsp&mid=WCobo1ac058004d5c1. Accessed August 29, 2015.

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;62:2595-2604.

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Monami M, Dicembrini I, Nardini C, Fiordelli I, Mannucci E. Effects of glucagon-like peptide-1 receptor agonists on cardiovascular risk: a meta-analysis of randomized clinical trials. Diabetes Obes Metab 2014;16:38-47.

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;169:631-38.

Tucker ME. ELIXA completed; diabetes drug lixisenatide heads back to FDA. http://www.medscape.com/viewarticle/841761. Published March 19, 2015. Accessed August 30, 2015.

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