Incretin-based anti-diabetic therapies: a pharmacovigilance perspective
Incretin-based therapies have advanced treatment of type 2 diabetes but have been linked to pancreatitis and pancreatic cancer in some patients. Conflicting evidences for and against this suspicious link has generated controversy among the medical community around the globe.
Glucagon-like peptide-1 (GLP-1) receptor agonists as incretin mimetics and dipeptidyl peptidase-4 (DPP-4) inhibitors as incretin enhancers are the two classes of incretin-based treatments available for type 2 diabetes mellitus. While these classes of drugs have proven their efficacy and tolerability in the majority of the populations who consumed the drug, the suspicion of pancreatitis and pancreatic cancer thought to be associated with the use of these drugs has resulted in concerns about the safety of these drugs.
Approximately 347 million people in the world are currently diagnosed with type 2 diabetes, and there is an ever-growing range of treatments for these patients. The recent shift towards wider clinical use of the newer classes of drugs, collectively referred to as incretin-based therapies, warrants a strong and ongoing pharmacovigilance activity to evaluate their benefit-risk ratio and establish the complete safety profile of these drugs, over time.
Dipeptidyl peptidase-4 (DPP-4) inhibitors are a class of oral antidiabetic drugs that work by inhibiting the action of DPP-4, an enzyme (exopeptidase) which inactivates the hormone incretin. Currently, four DPP-4 inhibitors: Sitagliptin, Saxagliptin, Linagliptin and Alogliptin are approved by the US Food and Drug Administration (FDA), whereas in the European Union (EU), an additional DPP-4 inhibitor, Vildagliptin, is also available. All of these drugs except Alogliptin are also available in India and other developing countries.
Glucagon like peptide (GLP-1) receptor agonists are peptide-based therapies that mimic the action of GLP-1 and increase the incretin effect, thereby stimulating the release of insulin. At present, there are three GLP-1 agonists (Exenatide, Liraglutide, Exenatide extended-release) approved by the FDA and the fourth drug (Lixisenatide) is approved only in Europe. Exenatide and Liraglutide are also available for use in India and other developing countries.
Clinical use of incretin-based glucose-lowering medications
The benefits of incretin-based therapies ranging from their core clinical effectiveness (lowering of blood glucose especially control of postprandial plasma glucose [PPG], prevention of weight gain and complications of diabetes) and additional beneficial effects or the extra glycemic effects in type 2 diabetic patients (improvements in cardiovascular risk profile such as weight loss and reduction in blood pressure) makes them a more convincing therapeutic option compared to other diabetes treatments, especially insulin. Furthermore, both of these drug classes seem to be associated with better tolerability, compliance to therapy and improved patient-reported outcomes.
The safety and efficacy of GLP-1 receptor agonists and DPP-4 inhibitors have been well-demonstrated in clinical trials and initial post-marketing surveillance. Considering the overall safety aspects of these drugs, the most common adverse events reported in clinical studies with incretin-based therapies mainly involve the gastrointestinal system. Nausea, vomiting, diarrhoea, indigestion and upper abdominal discomfort have been reported.
Acute pancreatitis and incretin-based therapies
Acute pancreatitis, which was not identified during the clinical trials of GLP-1 receptor agonists and DPP-4 inhibitors, was spotlighted during post marketing pharmacovigilance activities such as analysis of spontaneously reported adverse reactions – commonly referred as individual case safety reports of acute pancreatitis. Following reports of acute pancreatitis in patients receiving GLP-1 receptor agonists and DPP-4 inhibitors, the European Medicines Agency (EMA) and FDA have conducted independent reviews of the clinical studies, non-clinical studies and the post marketing reports of acute pancreatitis.
Based on the review, the EMA and FDA have established a possible causal relationship between incretin-based therapy and acute pancreatitis, and have instructed the Marketing Authorisation Holders (MAHs) to include information about acute pancreatitis as an identified risk in the PRECAUTIONS/WARNINGS section of the product label.
Furthermore, they have recommended that healthcare professionals should be aware of the possible signs and symptoms of acute pancreatitis, and to discontinue the use of these drugs if acute pancreatitis is suspected or confirmed. In addition, the public have been warned about post marketing reports of acute pancreatitis, including fatal and serious non-fatal cases, associated with the use of incretin mimetic drugs, namely Exenatide and Sitagliptin, and to promptly seek medical care if they experience unexplained severe abdominal pain with or without nausea and vomiting.
So despite their benefits, there are grounds for trepidation around the drugs, including suspicion that they may increase the risk of pancreatitis and, over time in some individuals, induce pancreatic cancer.
A recent finding reported that pancreas specimens from organ donors with type 2 diabetes, who had received treatment with the DPP-4 inhibitor Sitagliptin (n57) or Exenatide (n51), relative to patients with type 2 diabetes treated with other agents, had concluded an increased prevalence of pre-neoplastic lesions in the pancreas.
The FDA and EMA have also independently reviewed a number of observational studies using a variety of large administrative claims databases, to explore a possible association between incretin-based drugs and pancreatic cancer, which yielded inconsistent results. However, it was identified that the studies suffered from methodological shortcomings, including limited power, inadequate outcome validation, incomplete covariate ascertainment, and inadequate confounding control.
In addition, there is currently no support from clinical trials that GLP-1 based therapies increase the risk and the number of spontaneous reports to strengthen the evidence are limited. Nevertheless, long-term consequences of stimulation of beta-cells and suppression of alpha cells as well as possible effects on exocrine pancreas are largely unknown and therefore some uncertainties exist, as in the case of any novel therapy.
The controversy surrounding the long-term side effects of GLP-1 receptor agonists and DPP-4 inhibitors means that diabetologists, physicians, endocrinologists and general practitioners should ensure that the anticipated benefits outweigh the potential risks when they prescribe these drugs. The FDA and the EMA have not yet reached a final conclusion regarding a causal relationship between incretin-based drugs and pancreatitis or pancreatic cancer, which indicates that ongoing pharmacovigilance is imperative in order to identify the general benefit-risk ratio of these drugs.
Both the FDA and EMA have suggested that the conclusions are premature and they will continue to monitor post-marketing data for safety signals. Wrapping up its review, the EMA said that ‘presently available data do not confirm recent concerns over an increased risk of pancreatic adverse events with these medicines’.
The challenge in pharmacovigilance while evaluating the safety signals, therefore, is to analyse ‘signal versus noise’ and draw well-founded conclusions from spontaneous adverse events reported on a periodic basis, which highlights the significant role played by pharmacovigilance in the life cycle of any drug.
Cefalu, T M, 2013. A Critical Analysis of the Clinical Use of Incretin-Based Therapies. Journal of Diabetes Care, [Online]. 36, 2126-2132. Available at: http://care.diabetesjournals.org/content/36/7/2118.long [Accessed 3 July 2014].
Garg, W, et al. 2010. Acute Pancreatitis in Type 2 Diabetes Treated with Exenatide or Sitagliptin. Journal of Diabetes Care, [Online].33, 2349–2354. http://care.diabetesjournals.org/content/33/11/2349.long [Accessed 3 July 2014].
Egan, G.A, et al. 2014. Pancreatic Safety of Incretin-Based Drugs — FDA and EMA Assessment. The New England Journal of Medicine, [online]. 370, 794-79. Available at: http://www.nejm.org/doi/full/10.1056/NEJMp1314078 [Accessed 4 July 2014].
Podcast: FDA investigating reports of possible increased risk of pancreatitis and pre-cancerous findings of the pancreas from incretin mimetic drugs for type 2 diabetes (14 March 13), via: http://www.fda.gov/Drugs/DrugSafety/DrugSafetyPodcasts. Accessed 4 July 2014.
European Medicines Agency. 2013. Assessment report for GLP – 1 based therapies. [Online] Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Report/2013/08/WC500147026.pdf. [Accessed 5 July 14].
Butler, C P, et al. 2010. GLP-1–Based Therapy for Diabetes: What You Do Not Know Can Hurt You. Journal of Diabetes Care, [Online]. 33(2), 453-455. Available at: http://care.diabetesjournals.org/content/33/2/453.long [Accessed 7 July 2014].
Butler, C P, et al. 2013. 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. Journal of Diabetes Care [Online]. 62(7), 2595–2604. Available at: http://diabetes.diabetesjournals.org/content/62/7/2595.long [Accessed 7 July 2014].
Drucker, J D, et al. 2010. Incretin-Based Therapies for the Treatment of Type 2 Diabetes: Evaluation of the Risks and Benefits. Journal of Diabetes Care [Online]. 33(2), 428–433. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2809297/ [Accessed 4 July 2014].
Nauck, A M, et al. 2009. Incretin-Based Therapies: Viewpoints on the way to consensus. Journal of Diabetes Care, [Online]. 32, S223-S231. Available at: http://care.diabetesjournals.org/content/32/suppl_2/S223.long [Accessed 4 July 2014].
About the Author:
Dr J Vijay Venkatraman is managing director and chief executive officer of Oviya MedSafe, a pharmacovigilance company with operations in Coimbatore, India, and London, UK.
A diabetologist and drug safety physician, he has 13 years’ experience in medicine, the last seven in the pharmacovigilance sector. He also holds an MBA degree in Services Management.
With acknowledgement to colleagues at Oviya MedSafe for their contributions to this article: Kabila Balakumar, Pharmacovigilance Associate; Gayathri Subramani, Pharmacovigilance Associate, and Ganesan Ramakrishnan – Senior Drug Safety Manager.
Have your say: Have the regulators got the balance right in assessing the safety of the incretin-based therapies?