GLP-1 Receptor Agonist Semaglutide and SGLT2 Inhibitors after Acute Coronary Syndrome in Patients with Diabetes: Real-World Comparative Outcomes from an Observational Registry

INTRODUCTION: Patients with type 2 diabetes (T2D) remain at high cardiovascular risk after acute coronary syndrome (ACS), particularly after myocardial infarction (MI). Evidence on the early post-ACS use of glucagon-like peptide-1 receptor agonists (GLP-1RA), particularly semaglutide, and sodium-glucose cotransporter-2 inhibitors (SGLT2i) is limited. METHODS: We analyzed 870 patients in the registry-based T2D cohort discharged after ACS from the single-center CaRD registry (2017-2025). Patients were grouped according to discharge therapy: no GLP-1RA/SGLT2i, GLP-1RA only (semaglutide), SGLT2i only, or combined therapy. Descriptive outcomes included all-cause mortality and a broad registry composite of clinical events. To better address baseline imbalances and unequal group sizes, adjusted Cox models focused on conventional 3-point major adverse cardiovascular events (3P-MACE: cardiovascular death, non-fatal MI, or non-fatal stroke) and included age, sex, ACS type, eGFR, BMI, LVEF, HbA1c, and LDL-C. RESULTS: The median age was 68 years, and 67.5% of participants were male. Discharge therapy included no GLP-1RA/SGLT2i (n = 484), GLP-1RA (n = 35), SGLT2i (n = 277), and combined GLP-1RA+SGLT2i (n = 74), indicating substantial imbalance in subgroup size. During a median follow-up of 37 months, all-cause mortality was highest in the control group (30.2%) and lowest with combined therapy (2.7%), in which no cardiovascular deaths were recorded. However, important baseline differences in BMI, HbA1c, LVEF, age, and socioeconomic characteristics were present across groups. In adjusted 3P-MACE models, adherence to GLP-1RA and/or SGLT2i was associated with lower risk (HR 0.55, 95% CI 0.37-0.82, p = 0.003). When entered separately, SGLT2i remained significant (HR 0.66, 95% CI 0.44-0.99, p = 0.042), whereas GLP-1RA showed a similar direction of association but did not retain statistical significance (HR 0.60, 95% CI 0.28-1.28, p = 0.189). CONCLUSION: In this single-center observational ACS registry, semaglutide and SGLT2i use were associated with more favorable cardiometabolic profiles and lower event rates after discharge. The apparent benefit of combined therapy should be interpreted cautiously because of small subgroup sizes. These results are hypothesis-generating and support further prospective evaluation of combined cardiometabolic therapy after ACS.