A systematic review and meta-analysis of 29 randomised controlled trials (n=67,873) evaluated the association between DPP-4 inhibitors and heart failure in adults with type 2 diabetes. Overall, DPP-4 inhibitor use was not significantly associated with an increased risk of heart failure (RR 1.06; 95% CI 0.94–1.12), although subgroup analysis identified a significant risk increase specifically with saxagliptin. These findings reinforce existing safety warnings and support current guidelines recommending caution or alternative agents in patients with established or high risk of heart failure.
DPP-4 inhibitors use has been reported to cause heart failure events in patients with type-2 diabetes. The FDA had also issued warnings concerning increased risk of heart failure events for alogliptin, saxagliptin and their combination with metformin.
Randomized controlled trials (RCTs) involving adult patients with type-2 diabetes patients with or without history of cardio-vascular disorders were included in the review. Cohort studies, case-control studies and other non-RCTs, and studies involving paediatric patients were excluded. Data bases searched were PubMed/Medline, DOAJ, MDPI, Google Scholar and clinicaltrails.gov. The search was conducted in late January of 2026. Risk of bias was assessed using RoB-2 tool for RCTs. Individual study outcomes were tabulated and summary measure was synthesized by meta-analysis under random effect model; GRADE certainty of evidence was used; sub-group analysis based on individual DPP-4 inhibitors, follow-up duration and placebo or other controls was done; systematic review was done under PRISMA 2020 Guidelines.
The meta-analysis was done under random effect computation model for all 29 included studies. The analysis for total of pooled 67,873 patients showed statistically insignificant association between the use of DPP-4 inhibitors and heart failure with Risk Ratio (RR) = 1.06, 95% Confidence Interval (CI) 0.94-1.12. Sub-group analysis found significant association of saxagliptin use with increased heart failure risk.
Results should be interpreted with caution because of several limitations of the study. TRIAL REGISTRATION: PROSPERO, CRD420261288081.
