Obesity is a central contributor to the development and progression of cardio‑reno‑metabolic (CRM) disease. Whether excess adiposity, commonly quantified by body mass index (BMI), modifies the therapeutic benefits of sodium–glucose cotransporter 2 inhibitors (SGLT2i) across CRM conditions has remained uncertain. SGLT2i have established outcome benefits in heart failure (HF), chronic kidney disease (CKD), and type 2 diabetes (T2D). The present meta‑analysis sought to determine if BMI (using a 30 kg/m2 cutoff) changes the magnitude of these benefits when pooling randomized controlled trials (RCTs) spanning a broad CRM population.
The authors performed a meta‑analysis of randomized, placebo‑controlled clinical trials of SGLT2i that reported outcomes stratified by BMI using a prespecified cutoff of 30 kg/m2. Eight RCTs met inclusion criteria and were pooled. The combined dataset included 57,356 patients with a mean BMI of 29.95 kg/m2. Patient populations across the trials comprised individuals with HF, CKD, and/or T2D.
Reported outcomes included the composite of cardiovascular death or heart failure hospitalization as well as the individual components of that composite and all‑cause death. The investigators used random‑effects meta‑analyses and reported risk ratios (RR) with 95% confidence intervals (CI) to quantify treatment effects within BMI subgroups (<30 kg/m2 and ≥30 kg/m2). Additional analyses included meta‑regression to explore heterogeneity and sensitivity, cumulative, and bootstrap analyses to test robustness.
Across the pooled trials, SGLT2i significantly reduced the risk of the composite outcome of cardiovascular death or HF hospitalization in both BMI strata. For participants with BMI <30 kg/m2 the risk ratio was 0.80 (95% CI 0.72–0.89), and for those with BMI ≥30 kg/m2 the risk ratio was 0.80 (95% CI 0.75–0.85). There was no evidence that BMI modified the effect of SGLT2i on this composite endpoint.
The composite benefit was driven primarily by reductions in heart failure hospitalization, with RRs of 0.75 for BMI <30 kg/m2 and 0.74 for BMI ≥30 kg/m2. Benefits for all‑cause mortality were also consistent across BMI categories: RR 0.83 for BMI <30 kg/m2 and RR 0.89 for BMI ≥30 kg/m2.
Meta‑regression identified the underlying disease category (HF, CKD, or T2D) and the specific SGLT2i molecule used in the trials as contributors to between‑study heterogeneity. Importantly, exploration of these sources of heterogeneity did not change the principal finding of no interaction between BMI and SGLT2i benefit. The authors report that sensitivity analyses, cumulative analyses, and bootstrap procedures confirmed the stability and robustness of the pooled results.
In a pooled analysis of eight randomized trials including more than 57,000 participants across a spectrum of cardio‑reno‑metabolic disease, treatment with SGLT2 inhibitors reduced the incidence of cardiovascular death or HF hospitalization and lowered all‑cause mortality irrespective of BMI when comparing patients with BMI <30 kg/m2 to those with BMI ≥30 kg/m2. The observed effects were particularly driven by reductions in HF‑related hospitalizations. Although disease category and specific SGLT2i agent introduced heterogeneity, they did not alter the overall absence of a BMI interaction. These findings suggest that BMI alone, using a 30 kg/m2 threshold, should not be considered a determinant of SGLT2i treatment effect across the CRM populations represented in these trials.
The published conflict of interest disclosures note that several authors reported lecture or advisory board honoraria, trial committee memberships, or grants from multiple industry sources and that research grants from the European Union were reported. Specific company names and the nature of relationships are provided in the source document.
The meta‑analysis provides trial‑level evidence that SGLT2i improve key cardiovascular and mortality outcomes across HF, CKD, and T2D populations regardless of BMI category defined at 30 kg/m2, with robustness across multiple sensitivity analyses.