Sodium-glucose cotransporter 2 inhibitors across cardio-reno-metabolic disease and body mass index: a meta-analysis of randomized controlled trials.

Abstract

Aims: Obesity is a central driver of cardio-reno-metabolic (CRM) disease and may influence pharmacological responsiveness. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve outcomes in heart failure (HF), chronic kidney disease (CKD), and type 2 diabetes (T2D), but whether body mass index (BMI) modifies these benefits across a broad CRM spectrum remains uncertain.

Methods and results: We performed a meta-analysis of randomized controlled trials (RCTs) comparing SGLT2i with placebo in patients with HF, CKD, and/or T2D and reported BMI-stratified outcomes using a cutoff of 30 kg/m2. Outcomes included the composite of cardiovascular death or HF hospitalization and its components, and all-cause death. Random-effects meta-analyses were performed using risk ratios (RR). Eight RCTs encompassing 57 356 patients were included (mean BMI 29.95 kg/m2). SGLT2i significantly reduced the risk of cardiovascular death or HF hospitalization in patients with BMI <30 kg/m2 (RR 0.80, 95% CI 0.72-0.89) and BMI ≥30 kg/m2 (RR 0.80, 95% CI 0.75-0.85), with no evidence of effect modification by BMI, an effect primarily driven by reductions in heart failure hospitalizations. Consistent benefits were observed for HF hospitalization (RR 0.75 for BMI <30 kg/m2 and 0.74 for BMI ≥30 kg/m2) and all-cause mortality (RR 0.83 for BMI <30 kg/m2 and 0.89 for BMI ≥30 kg/m2). Meta-regression identified disease category and SGLT2i molecule as sources of heterogeneity, without altering the absence of BMI interaction. Sensitivity, cumulative, and bootstrap analyses confirmed the robustness of the results.

Conclusion: Across a broad CRM population, SGLT2i reduce cardiovascular death or HF hospitalization and all-cause death irrespective of BMI.