A systematic review of the safety of incretin-based therapies in type 2 diabetes

ABSTRACT

Introduction: Large randomized clinical trials have demonstrated that incretin-based therapies provide effective glycemic control in type 2 diabetes. Long-term safety assessments are ongoing.

Methods: This systematic review of incretin-based therapy safety is based on 112 randomized clinical trials of duration ≥26 weeks published between January 2000 and February 2015 in patients with type 2 diabetes.

Results: As expected, hypoglycemia rates were lower with dipeptidyl peptidase-4 inhibitors (DPP-4is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) versus other oral antidiabetic drugs and insulin. The most common adverse events were infection and infestation (DPP-4is) and gastrointestinal (GLP-1 RAs). Pancreatitis cases were rare across all studies and, in the SAVOR-TIMI and EXAMINE trials, pancreatitis rates were similar in DPP-4i- and placebo-treated patients. No thyroid tumors were reported, and increased risk of cardiovascular events was not associated with DPP-4is in SAVOR-TIMI and EXAMINE, albeit over a short follow-up period.

Conclusions: Overall, incretin-based therapies were well tolerated; however, their long-term safety profile should continue to be periodically assessed.

KEYWORDS:

• Type 2 diabetes (T2D)
• glucagon-like peptide-1 receptor agonist (GLP-1 RA)
• dipeptidyl peptidase (DPP)-4inhibitor
• clinical trials
• safety
• adverse event

Financial & competing interests disclosure

This study was funded by Novo Nordisk. M. Evans is an advisory panel member and receives speaker fees from Novo Nordisk, Sanofi Aventis, Novartis and MSD. S.C Bain is on the advisory panels for AstraZeneca, Boerhinger Ingelheim, BMS, Jannsen, Lilly, MSD, Novo Nordisk, Omnia-Med, Sanofi & Cellnovo. S.C Bain is a board member for Glycosmedia. J. Vora has received support for research and attendance for national and international educational meetings and honoraria for lecturing and advisory boards from Novo Nordisk, Lilly, Sanofi, MSD, Takeda, Novartis, and Abbott. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Writing assistance was utilized in the production of this manuscript and was funded by Novo Nordisk and provided by R. Ferguson from Watermeadow Medical, Witney, UK. Novo Nordisk had a role in the review of the manuscript for scientific accuracy.

Supplementary Appendix for this article can be accessed here

Key issues

• Since 2005, several different incretin-based therapies have been approved by the US FDA and the European Medicines Agency (EMA).

• As with all newly approved drugs, the benefits of incretin-based therapies for patients must be balanced against the risk of any associated adverse events (AEs); thus, it is important to periodically assess their safety profile.

• The action of both dipeptidyl peptidase-4 inhibitors (DPP-4is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) is glucose dependent and, thus, these therapies carry a lower risk of hypoglycemia compared to insulin and traditional oral antidiabetic drugs.

• The use of DPP-4is and GLP-1 RAs is linked to other AEs. These principally include infections and infestations for DPP-4is and transient gastrointestinal AEs for GLP-1 RAs.

• More serious AEs such as pancreatitis and pancreatic cancer have also been suggested to be associated with incretin-based therapies; however, in response, an assessment from the FDA/EMA has concluded that such a causal association is inconsistent with currently available data.

• A large proportion of patients with type 2 diabetes (T2D) are at high risk of cardiovascular disease, and some previous therapies have been withdrawn due to their elevated cardiovascular event risk profile. The long-term cardiovascular safety of incretin-based therapies must, therefore, be assessed. To date, two long-term studies on the use of DPP-4is have provided evidence that these therapies are not associated with an increased risk of cardiovascular events, and for other DPP-4is and GLP-1 RAs, long-term cardiovascular risk studies are ongoing.

• Since the approval of the first incretin-based therapy in 2005, a large number of clinical trials have provided a consistently favorable safety profile for both GLP-1 RAs and DPP-4is. Further long-term trials will continue to assess the safety of incretin therapies, which is of great importance due to the chronic nature of T2D and the associated long-term therapy requirements of patients with this disease.