Cardiovascular Effects of Alogliptin, Linagliptin, Saxagliptin, and Sitagliptin: A Target Trial Emulation of a Comparative Effectiveness Study

Objective: To compare major adverse cardiovascular event (MACE) risks among available dipeptidyl peptidase-4 inhibitors among adults with type 2 diabetes at moderate cardiovascular risk. Methods: Using claims data of enrollees in commercial, Medicare Advantage, and traditional Medicare plans between 2014 and 2021, we identified adults (≥21 years) with type 2 diabetes, moderate cardiovascular risk, and not requiring insulin who initiated alogliptin, linagliptin, saxagliptin, or sitagliptin. Random treatment assignment was emulated using propensity scores estimated using the super learner ensemble and incorporated as inverse probability of treatment weights into Cox models examining MACE (myocardial infarction, stroke, all-cause mortality), heart failure hospitalization (HHF), arterial revascularization, and hypoglycemia requiring emergency department/hospital use, with weighted median follow-up times calculated for each treatment arm. Results: The weighted study cohort included 184,660 patients starting alogliptin (N= 2541), linagliptin (N= 42,433), saxagliptin (N= 15,649), and sitagliptin (N= 124,038) with median weighted follow-up of 39.5 (95% CI 35.8-41.6), 40.9 (95% CI 40.5-41.3), 42.6 (95% CI 41.7-43.3), and 42.4 (95% CI 42.2-42.6) months, respectively. One year after DDP4i initiation, MACE rates were 2.2%, 2.2%, 2.0%, and 1.7% for sitagliptin, linagliptin, saxagliptin, and alogliptin, respectively; HHF rates were 0.42%, 0.41%, 0.41%, and 0.37%; and hypoglycemia rates were 0.2%, 0.2%, 0.2%, and 0.2%. Saxagliptin was associated with modestly decreased risk of MACE vs sitagliptin (HR 0.94; 95% CI 0.88-0.99) and linagliptin (HR 0.94; 95% CI 0.87-1.00). There was no significant difference in HHF or hypoglycemia risk among the study drugs. Conclusion: Risks of MACE, HHF, and hypoglycemia were comparable with all DPP4i. Choice of medication may be determined based on local availability.