Abstract
Inhibitors of dipeptidyl peptidase-4 (DPP-4) enzyme are one of the commonly recommended hypoglycemic agents. Although efficient in controlling hyperglycemia, their cardiovascular (CV) safety has been debated for long-term use, particularly in relation to heart failure risk. This review analyzed the cardiovascular safety profile after the consumption of various DPP-4 inhibitors in hyperglycemic patients. The systematic review and meta-analysis was conducted by utilizing widespread empirical research and randomized control trials (RCTs), evaluating sitagliptin, saxagliptin, alogliptin, and linagliptin. Databases searched included PubMed, Embase, Cochrane CENTRAL, and Clinical Trials.gov through September 2025. Outcomes assessed were: HHF, i.e., hospitalization for heart failure, MACE, i.e., major adverse cardiovascular events (CV death, nonfatal myocardial infarction (MI), nonfatal cerebrovascular attack (CVA), all-cause mortality, and cardiovascular mortality. Random-effects metHFa-analyses were conducted, with heterogeneity assessed via I² statistics. Seven large RCTs (n > 70,000 participants) were included, along with supporting observational data. Pooled analysis demonstrated no significant increase in MACE intake of DPP-4 inhibitors when compared to placebo (hazard ratio (HR) 0.99, 95% confidence interval (CI) 0.93-1.05, heterogeneity (I²) = 5%). However, an increased probability of HHF was found (HR 1.14, 95% CI 1.02-1.27, I² = 28%), largely driven by saxagliptin (HR 1.27, 95% CI 1.07-1.51) and, to a lesser extent, alogliptin. While no significant heart failure (HF) risk was observed by the intake of drugs sitagliptin (HR 1.00, 95% CI 0.83-1.20) and linagliptin (HR 1.02, 95% CI 0.89-1.17), no differences were noted in all-cause or CV mortality across the class. DPP-4 inhibitors, as a group of drugs, are safe with respect to MACE, but saxagliptin and possibly alogliptin are linked with an increased risk of HHF. Sitagliptin and linagliptin appear neutral regarding HF risk. These findings highlight the importance of drug-specific evaluation when selecting a DPP-4 inhibitor for type-2 diabetic patients, particularly those having an elevated risk of heart failure.