Safety and Tolerability of Glucagon-Like Peptide-1 Receptor Agonists Utilizing Data from the Exenatide Clinical Trial Development Program
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Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have demonstrated benefits for patients with type 2 diabetes including A1C reduction and weight loss with minimal risk of hypoglycemia. This article provides an evidence-based update of safety and tolerability considerations for the clinical use of GLP-1RAs as a class, with a specific detailed review of data from the exenatide clinical trial development program, which has the longest history and availability of safety and tolerability data as the first-approved GLP-1RA. Specific areas covered include comparative risk of hypoglycemia, as well as pancreatic, thyroid, and cardiovascular safety data; clinical guidance regarding current safety and tolerability data is also reviewed.
KeywordsGLP-1 receptor agonists Incretin Exenatide Safety Pancreatitis Cardiovascular
The authors wish to acknowledge Róisín O’Connor and Amanda Sheldon of inScience Communications, Springer Healthcare, for medical writing assistance, which was funded by AstraZeneca.
Compliance with Ethical Standards
Conflict of Interest
Hui Peng declares that he has no conflict of interest.
Laura L. Want has been involved in clinical research trials for AstraZeneca, Sanofi, NovoNordisk, Hanmi, Halozyme, Calibra, and Janssen.
Vanita R. Aroda has served as a consultant for Janssen, Novo Nordisk, and Sanofi-Aventis on behalf of Medstar Health Research Institute. She has been involved in clinical research trials for AstraZeneca/Bristol-Myers Squibb/Amylin, Boehringer-Ingelheim, Eisai, GI Dynamics, Halozyme, Hanmi, Intarcia, Janssen, Novo Nordisk, Sanofi-Aventis, and Takeda. She is an employee of MedStar Health Research Institute.
Human and Animal Rights and Informed Consent
This review article does not contain any new studies with human or animal subjects performed by any of the authors.
Papers of particular interest, published recently, have been highlighted as: • Of importance,•• Of major importance
- 2.Inzucchi SE, Bergenstal RM, Buse JB, et al. 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;35:1364–79.CrossRefPubMedPubMedCentralGoogle Scholar
- 3.Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38:140–9.CrossRefPubMedGoogle Scholar
- 4.American Diabetes Association. Standards of medical care in diabetes. Diabetes Care. 2015;38 Suppl 1:S1–93.Google Scholar
- 5.BYETTA [package insert]. Wilmington, DE, AstraZeneca Pharmaceuticals LP, 2015Google Scholar
- 6.BYDUREON [package insert]. Wilmington, DE, AstraZeneca Pharmaceuticals LP, 2015Google Scholar
- 7.Victoza [package insert]. Bagsvaerd, Denmark, Novo Nordisk A/S, 2015Google Scholar
- 8.TANZEUM [package insert]. Research Triangle Park, NC, GlaxoSmithKline, 2015Google Scholar
- 9.TRULICITY [package insert]. Indianapolis, IN, Eli Lilly and Company, 2015Google Scholar
- 17.Barnett AH, Burger J, Johns D, et al. Tolerability and efficacy of exenatide and titrated insulin glargine in adult patients with type 2 diabetes previously uncontrolled with metformin or a sulfonylurea: a multinational, randomized, open-label, two-period, crossover noninferiority trial. Clin Ther. 2007;29:2333–48.CrossRefPubMedGoogle Scholar
- 21.Davies MJ, Donnelly R, Barnett AH, Jones S, Nicolay C, Kilcoyne A. Exenatide compared with long-acting insulin to achieve glycaemic control with minimal weight gain in patients with type 2 diabetes: results of the Helping Evaluate Exenatide in patients with diabetes compared with Long-Acting insulin (HEELA) study. Diabetes Obes Metab. 2009;11:1153–62.CrossRefPubMedPubMedCentralGoogle Scholar
- 22.Apovian CM, Bergenstal RM, Cuddihy RM, et al. Effects of exenatide combined with lifestyle modification in patients with type 2 diabetes. Am J Med. 2010;123(468):e469–17.Google Scholar
- 24.Riddle M, Ahmann A, Basu A, Aroda V, Ratner R. Metformin+exenatide+basal insulin vs metformin+placebo+basal insulin: reaching A1c <6.5% without weight-gain or serious hypoglycemia (abstract). Diabetes. 2010;59(Suppl 1A):LB6.Google Scholar
- 32.Russell-Jones D, Cuddihy RM, Hanefeld M, et al. Efficacy and safety of exenatide once weekly versus metformin, pioglitazone, and sitagliptin used as monotherapy in drug-naive patients with type 2 diabetes (DURATION-4): a 26-week double-blind study. Diabetes Care. 2012;35:252–8.CrossRefPubMedPubMedCentralGoogle Scholar
- 46.•Alves C, Batel-Marques F, Macedo AF. A meta-analysis of serious adverse events reported with exenatide and liraglutide: acute pancreatitis and cancer. Diabetes Res Clin Pract. 2012;98:271–84. This study describes a large meta-analysis (25 studies), reporting that exenatide and liraglutide are not associated with an increased risk for thyroid cancer. CrossRefPubMedGoogle Scholar
- 48.•Grimm M, Han J, Weaver C, et al. Efficacy, safety, and tolerability of exenatide once weekly in patients with type 2 diabetes mellitus: an integrated analysis of the DURATION trials. Postgrad Med. 2013;125:47–57. This pooled analysis describes the overall efficacy (detailing improvements in A1C, fasting blood glucose, blood pressure, lipids, and weight) and safety and tolerability (including hypoglycemia, gastrointestinal events, and injection site reactions) findings of exenatide treatment in a large (n = 1379) and varied patient population. CrossRefPubMedGoogle Scholar
- 49.MacConell L, Brown C, Gurney K, Han J. Safety and tolerability of exenatide twice daily in patients with type 2 diabetes: integrated analysis of 5594 patients from 19 placebo-controlled and comparator-controlled clinical trials. Diabetes Metab Syndr Obes. 2012;5:29–41.PubMedPubMedCentralGoogle Scholar
- 52.•Ratner R, Han J, Nicewarner D, Yushmanova I, Hoogwerf BJ, Shen L. Cardiovascular safety of exenatide BID: an integrated analysis from controlled clinical trials in participants with type 2 diabetes. Cardiovasc Diabetol 2011;10:22. This large, pooled, post hoc analysis (~4000 patients from 12 clinical studies) reports that exenatide does not increase the risk of major adverse cardiovascular events compared with comparator treatment (placebo or insulin).Google Scholar
- 53.Ridge T, Moretto T, Macconell L, et al. Comparison of safety and tolerability with continuous (exenatide once weekly) or intermittent (exenatide twice daily) GLP-1 receptor agonism in patients with type 2 diabetes. Diabetes Obes Metab. 2012;26:1463–326.Google Scholar
- 55.Hegedus L, Moses AC, Zdravkovic M, Le Thi T, Daniels GH. GLP-1 and calcitonin concentration in humans: lack of evidence of calcitonin release from sequential screening in over 5000 subjects with type 2 diabetes or nondiabetic obese subjects treated with the human GLP-1 analog, liraglutide. J Clin Endocrinol Metab. 2011;96:853–60.CrossRefPubMedGoogle Scholar
- 75.••Egan AG, Blind E, Dunder K, et al. Pancreatic safety of incretin-based drugs—FDA and EMA assessment. N Engl J Med. 2014;370:794–7. This report describes the joint position of the regulatory bodies in the United States and Europe, summarizing a review of safety data on incretin-based drugs and pancreatic effects. CrossRefPubMedGoogle Scholar
- 78.European Medicines Agency. Assessment report: Eperzan. Procedure No. EMEA/H/C/002735/0000, 2014. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002735/WC500165119.pdf. Accessed 3 June 2015.
- 84.US Food and Drug Administration. Guidance for industry. Diabetes mellitus—evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes, 2008. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm071627.pdf. Accessed 3 June 2015
- 89.US Food and Drug Administration. NDA: 21-919. BYETTA (exenatide), 2005. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/021919s000pharmr.pdf. Accessed 3 June 2015
- 90.Chilton RJ, MacConell LA, Han J, Marso SP. Characterization of heart rate increases with glucagon-like peptide-1 agonist therapy (abstract). Circulation. 2013;128:A16290.Google Scholar
- 96.US Food and Drug Administration. Application number: 022200orig1s000. Clinical pharmacology and biopharmaceutics review(s), 2011. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/022200Orig1s000PharmR.pdf. Accessed 3 June 2015