Sotagliflozin, suPAR, and Cardiovascular Outcomes in Patients With Diabetes and Heart Failure: A SOLOIST-WHF...

Sotagliflozin, a dual sodium-glucose cotransporter 1 and 2 (SGLT1/2) inhibitor, improves kidney and heart failure (HF) outcomes through incompletely understood mechanisms. Soluble urokinase plasminogen activator receptor (suPAR), an immune-derived glycoprotein, is implicated in kidney and cardiovascular disease pathogenesis. We investigated whether sotagliflozin reduces suPAR levels; whether baseline suPAR predicts cardiovascular outcomes; and whether baseline suPAR modifies sotagliflozin's treatment effect.

We measured suPAR levels at baseline and at 1-year follow-up in a subset of patients from the SOLOIST-WHF (Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening HF) trial, which evaluated sotagliflozin's effect on the composite outcome of cardiovascular death, HF hospitalization, and urgent HF visits in patients with type 2 diabetes and worsening HF. Cox proportional hazards modeling assessed associations between baseline suPAR and outcomes and tested for treatment-by-suPAR interaction. Analysis of covariance (ANCOVA) compared changes in suPAR between treatment groups.

In the main SOLOIST-WHF trial, sotagliflozin reduced the primary composite outcome (HR 0.67, 95% CI 0.52-0.85). In this ancillary analysis (n = 815 with available samples), the median baseline suPAR level was 4.7 ng/mL (IQR 3.7-6.1). SuPAR levels decreased similarly in both treatment groups at 1 year: sotagliflozin (n = 97, -6.2%, 95% CI [-12.0, -0.04]) vs placebo (n = 101, -7.9%, 95% CI [-13.5-2.0]; P = 0.69). Baseline suPAR was strongly associated with the primary outcome in a graded, dose-response manner, independent of treatment, systolic function, kidney function, and NT-proBNP levels: adjusted hazard ratio 2.21 (95% CI 1.36-3.60) for the fourth quartile (>6.06 ng/mL) vs the first quartile (≤3.67 ng/mL). The treatment effect of sotagliflozin was consistent across suPAR quartiles (P interaction = 0.90).

The cardiovascular benefits of sotagliflozin are unlikely to be related to suPAR reduction, because sotagliflozin did not significantly alter suPAR levels, and treatment efficacy was consistent across suPAR strata. However, suPAR remains a strong, independent predictor of HF outcomes. Further studies are needed to determine whether suPAR-targeted therapies can improve HF outcomes.