Exploring Heterogeneities of Cardiovascular Efficacy and Effectiveness of SGLT2 Inhibitors in Patients with Type 2 Diabetes: an Umbrella Review of Evidence from Randomized Clinical Trials Versus Real-World Observational Studies.

PURPOSE:We aimed to explore possible contributors to discrepancies between randomized controlled trials (RCTs) and real-world observational studies (OS) in cardiovascular benefits of sodium-glucose cotransporter 2 (SGLT2) inhibitors in type 2 diabetes (T2D) patients.METHODS:We searched PubMed and EMBASE to identify meta-analyses of RCTs and OS on cardiovascular effects of SGLT2 inhibitors in T2D patients. Cardiovascular outcomes included major adverse cardiovascular events (MACE), myocardial infarction (MI), stroke, cardiovascular mortality (CVM), all-cause mortality (ACM), hospitalization for heart failure (HHF), and atrial fibrillation (AF). We examined the summary relative risk (RR) and 95% confidence interval (CI) for each endpoint from meta-analyses of RCTs.RESULTS:We identified and included 15 eligible meta-analyses, 13 for RCTs and 2 for OS, with moderately strong evidence. The results revealed a significant discrepancy between RCTs and OS for MI (RR, 95% CI 1.05, 0.82-1.38; I = 91.5% versus odds ratio (OR), 95% CI 0.77, 0.73-0.81; I = 15.0%), stroke (RR, 95% CI 0.99, 0.76-1.29; I = 93.4% versus OR, 95% CI 0.75, 0.72-0.78; I = 23.0%), and AF (RR, 95% CI 0.72, 0.62-0.85; I = 0.0% versus OR, 95% CI 0.92, 0.83-1.02; I = 0.0%).CONCLUSION:OS presented significant benefits of SGLT2 inhibitors both on primary and secondary preventions of MACE, MI, stroke, ACM, CVM, and HHF; RCTs did not. Given the spectrum of T2D patient characteristics and the strength of overall evidence, our review underscored the importance of constant integration of all available information and critical interpretation of all inconsistencies to optimize evidence-based diabetes care.