Efficacy and safety of DPP-4 inhibitors in patients with type 2 diabetes: Meta-analysis of placebo-controlled randomized clinical trials

Background: Guidelines for type 2 diabetes (T2D) recommend reducing HbA_1c through lifestyle interventions and glucose-lowering drugs (metformin, then combination with dipeptidyl peptidase-4 inhibitors [DPP-4Is] among other glucose-lowering drugs). However, no double-blind randomized clinical trial (RCT) compared with placebo has so far demonstrated that DDP-4Is reduce micro- and macrovascular complications in T2D. Moreover, the safety of DPP-4Is (with increased heart failure and acute pancreatitis) remains controversial.

Methods: A systematic review of the literature (PubMed, Cochrane Library Central Register of Controlled Trials [CENTRAL] and https://clinicaltrials.gov), including all RCTs vs placebo published up to May 2015 and the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), published June 2015, was performed. Primary endpoints were all-cause mortality and death from cardiovascular causes; secondary endpoints were macrovascular and microvascular events. Safety endpoints were acute pancreatitis, pancreatic cancer, serious adverse events and severe hypoglycaemia.

Results: A total of 36 double-blind RCTs were included, allowing analyses of 54,664 patients. There were no significant differences in all-cause mortality (RR=1.03, 95% confidence interval [CI]=0.95-1.12), cardiovascular mortality (RR=1.02, 95% CI=0.92-1.12), myocardial infarction (RR=0.98, 95% CI=0.89-1.08), strokes (RR=1.02, 95% CI=0.88-1.17), renal failure (RR=1.06, 95% CI=0.88-1.27), severe hypoglycaemia (RR=1.14, 95% CI=0.95-1.36) and pancreatic cancer (RR=0.54, 95% CI=0.28-1.04) with the use of DPP-4Is. However, DDP-4Is were associated with an increased risk of heart failure (RR=1.13, 95% CI=1.01-1.26) and of acute pancreatitis (RR=1.57, 95% CI=1.03-2.39).

Conclusion: There is no significant evidence of short-term efficacy of DPP-4Is on either morbidity/mortality or macro-/microvascular complications in T2D. However, there are warning signs concerning heart failure and acute pancreatitis. This suggests a great need for additional relevant studies in future.