The safety of gliptins : updated data in 2018

ABSTRACT

Introduction: Dipeptidyl peptidase-4 inhibitors (DPP-4is) are generally considered as glucose-lowering agents with a safe profile in type 2 diabetes.

Areas covered: An updated review of recent safety data from randomised controlled trials, observational studies, meta-analyses, pharmacovigilance reports regarding alogliptin, linagliptin, saxagliptin, sitagliptin, and vildagliptin, with a special focus on risks of hypoglycemia, pancreatitis and pancreatic cancer, major cardiovascular events, hospitalisation for heart failure and other new safety issues, such as bone fractures and arthralgia. The safety of DPP-4i use in special populations, elderly patients, patients with renal impairment, liver disease or heart failure, will also be discussed.

Expert opinion: The good tolerance/safety profile of DPP-4is has been largely confirmed, including in more fragile populations, with no gastrointestinal adverse effects and a minimal risk of hypoglycemia. DPP-4is appear to be associated with a small increased incidence of acute pancreatitis in placebo-controlled trials, although most observational studies are reassuring. Most recent studies with DPP-4is do not confirm the increased risk of hospitalisation for heart failure reported with saxagliptin in SAVOR-TIMI 53, but further post-marketing surveillance is still recommended. New adverse events have been reported such as arthralgia, yet a causal relationship remains unclear.

KEYWORDS:

• Cardiovascular disease
• DPP-4 inhibitor
• heart failure
• pancreatitis
• renal impairment
• safety
• type 2 diabetes mellitus

Article highlights

• The overall good tolerance/safety profile of DPP-4 inhibitors is confirmed with the absence of gastrointestinal side effects, a minimal risk of hypoglycemia and no weight gain.

• A slight increase in the incidence of acute pancreatitis was reported when pooling data from CV outcome trials, although this adverse event occurred with a low frequency and was not detected in several observational studies comparing DPP-4i users with nonusers.

• Cardiovascular safety of DPP-4 inhibitors has been demonstrated in meta-analyses of phase III trials and in three large prospective CV outcome placebo-controlled studies

• In observational studies, CV outcomes were more favourable in T2DM patients treated with DPP-4is than in those treated with sulphonylureas or active glucose-lowering agents.

• The higher risk of hospitalization for heart failure reported with saxagliptin in SAVOR TIMI 53 remains unexplained and was not confirmed neither in other RCTs (TECOS with sitagliptin) nor in several observational studies.

• New side effects have been recently reported such as arthralgia (but not bone fractures), although the real incidence of this adverse event and the underlying mechanism remain unknown.

• DPP-4 inhibitors have a good efficacy and safety profile in special populations such as elderly subjects, T2DM patients with renal impairment or liver disturbances.

This box summarizes key points contained in the article.

Declaration of interest

A.J. Scheen has received lecturer, advisor and/or investigator fees from AstraZeneca, Boehringer, Eli Lilly, GlaxoSmithKline, Janssen, Merck Sharp & Dohme, Novartis, NovoNordisk, Sanofi and Servier. 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. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper is not funded.