Key result
Sotagliflozin did not alter suPAR levels compared to placebo at 1 year, but baseline suPAR independently predicted cardiovascular outcomes.
Why the study?
Sotagliflozin improves kidney and heart failure outcomes through incompletely understood mechanisms, and the role of suPAR in these effects is unclear.
Does sotagliflozin reduce suPAR levels, and does baseline suPAR predict cardiovascular outcomes in patients with type 2 diabetes and worsening heart failure?
RCT (n=815)
Does sotagliflozin reduce suPAR levels, and does baseline suPAR predict cardiovascular outcomes in patients with type 2 diabetes and worsening heart failure?
Baseline suPAR is a strong, independent predictor of heart failure outcomes in patients with diabetes and worsening HF, but its levels are not modified by sotagliflozin therapy.
Answers are grounded in this paper and cite their sources.
Baseline suPAR independently predicts outcomes in T2D with worsening HF; confirms prognostic value but leaves modification by SGLT2i open.
OBJECTIVE: 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. RESEARCH DESIGN AND METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.
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Ismail et al. (2026) conducted an RCT in type 2 diabetes and worsening heart failure (n=815). Sotagliflozin vs. Placebo was evaluated on change in suPAR levels at 1 year (p=0.69). Sotagliflozin did not alter suPAR levels compared to placebo at 1 year, but baseline suPAR independently predicted cardiovascular outcomes.
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