Abstract

Background: To test the hypothesis that patients treated with sodium-glucose cotransporter 2 (SGLT2) inhibitors or glucagon-like peptide 1 receptor agonists (GLP1RA) was associated with lower risk of cardiovascular endpoints vs dipeptidyl peptidase 4 inhibitors (DPP4). Methods: A retrospective cohort combined Veterans Administration, Medicare, and National Death Index databases. Patients using metformin, sulfonylurea or insulin alone or in combination were followed until a new fill of one of the following classes: SGLT2; GLP1RA; or DPP4. The index date and start of follow-up was the new prescription fill date. The composite outcome was major adverse cardiovascular event (MACE) or heart failure (HF) hospitalization: acute myocardial infarction (AMI), stroke, acute HF or cardiovascular (CV) death. Cox Proportional Hazards models compared MACE and HF for the comparison groups of interest, separately, in propensity score (PS) weighted cohorts adjusted for clinical covariates, laboratory data, ejection fraction (EF), smoking, and selected medications. Results: After PS weighting the cohorts included 46018 GLP1RA vs 45814 DPP4 and 36646 SGLT2 vs 36261 DPP4 participants. Median age was 69 years and diabetes duration of 9.0 (5.2, 13.4) years for GLP1RA vs DPP4 and 9.3 (5.7, 13.8) years for SGLT2 vs DPP4 users. Most new agents were added as third drug to either metformin + sulfonylurea or metformin + insulin regimen. GLP1RA was associated with lower hazard of MACE/HF vs DPP4 (0.73 [0.68, 0.78]) (panel A) yielding an adjusted risk difference (aRD) of 10.5 events [8.5, 12.4]); results were consistent for all outcome components. SGLT2 was associated with a lower hazard of MACE and HF (0.76 [0.69, 0.85]) (panel B) (aRD 8.1 [5.2, 10.7]); primarily due to reduction in CV death (0.71 [0.56, 0.90]) and HF hospitalization with reduced EF (0.40 [0.26, 0.62]). Conclusions: Use of GLP1RA or SGLT2 for diabetes treatment was associated with reduced risk of MACE and HF hospitalization vs DPP4.

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