Safety of dipeptidyl peptidase-4 inhibitors analyzed in 2 studies

First, in a meta-analysis by Monami and colleagues, 129 trials of dipeptidyl peptidase-4 inhibitors (DPP4is) showed no difference in serious adverse events related to pancreatitis, pancreatic cancer or the treatments in general between active and control groups. Reviewers concluded that DPP4is do not increase risk of pancreatitis in patients with type 2 diabetes. The study was published online first July 28, 2013, and in the January 2014 Diabetes, Obesity and Metabolism, then reviewed in the ACP Journal Club section of the Jan. 21 Annals of Internal Medicine.

Second, the SAVOR-TIMI trial randomized more than 16,000 patients with type 2 diabetes and either cardiovascular disease or at least 1 vascular risk factor to either saxagliptin or placebo. There was no significant difference between groups in overall cardiovascular events, but saxagliptin was associated with more heart failure hospitalizations and hypoglycemic events. The study was published Oct. 3, 2013, in the New England Journal of Medicine, then reviewed in the ACP Journal Club section of the Jan. 21 Annals of Internal Medicine.

The following ACP Journal Club commentary by Oscar L. Morey-Vargas, MD, and Victor M. Montori, MD, MSc, addressed both studies.

DPP4is modestly reduce HbA1c levels without causing weight gain, but their safety is questionable.

In contrast with the signal from observational studies, neither Monami and colleagues' review nor the SAVOR-TIMI 53 trial found an increased risk for pancreatitis associated with DPP4is. Biased documentation of cases and residual confounding in the observational studies, and careful selection of participants into the trials and potential for incomplete or biased reporting of their results, may explain these differences. Therefore, these studies cannot fully settle the issue. In addition, low event rates and short trial duration in both the review and SAVOR-TIMI 53 trial preclude adequate assessment of the risk for pancreatic cancer. These uncertainties complicate the decision to use DPP4is. Patients and clinicians need to consider the benefits that these agents provide (i.e., modest antihyperglycemic effects) and the availability of alternatives. It seems wise to avoid DPP4is in patients with risk factors for (e.g., alcohol abuse, gallbladder stones) or a history of acute pancreatitis.

SAVOR-TIMI 53 was designed to estimate the extent to which DPP4is, specifically saxagliptin, affect the risk for cardiovascular (CV) events. CV disease is a leading cause of death and morbidity in patients with diabetes, yet the effect of glycemic control or antihyperglycemic agents on the risk for CV complications remains uncertain. It is, therefore, important to evaluate the effect of glucose-lowering medications on patient-important CV outcomes (i.e., CV mortality and serious CV events) and not just surrogate endpoints. Since 2008, the US Food and Drug Administration has required that all new therapies for type 2 diabetes be prospectively evaluated for CV safety before approval. Although widely believed to be a step forward in improving our ability to determine risks and benefits of alternative antihyperglycemic agents, this edict does not require interventions to reduce the risk for diabetes complications, but just to avoid increasing it. SAVOR-TIMI 53 did not find a difference between saxagliptin and placebo for ischemic events. This is disappointing because a previous meta-analysis suggested cardiac benefit with DPP4is. In addition, the unexpected increases in hypoglycemic events and heart failure hospitalizations with saxagliptin in SAVOR-TIMI 53 raise new safety concerns that need investigation. For most patients, these findings suggest delaying the use of DPP4is in favor of other drugs with greater glycemic effect and a longer track record of use.