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

Year: 2026

Type: article

Abstract: 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.

Source: Journal of Cardiac Failure

DOI: 10.1016/j.cardfail.2026.01.018

Authors: ANIS ISMAIL, GRACE ERNE, ALEXI VASBINDER, CHRISTINA G. HUTTEN, BAHJAT Z. GHAZZAL, IAN PIZZO, KRISTEN MACHADO DIAZ, TONIMARIE CLAIRE CATALAN, THERESA FARHAT, BRENNA KNOTT, PENNELOPE KUNKLE, MICHAEL SZAREK, MICHAEL J. DAVIES, PHILIPPE GABRIEL STEG, BERTRAM PITT, DEEPAK L. BHATT, SALIM S. HAYEK

Institutions: The University of Texas Medical Branch at Galveston, University of Michigan, Michigan Medicine, University of Washington, Rush University Medical Center, University of Massachusetts Chan Medical School, State University of New York, SUNY Downstate Health Sciences University, University of Colorado Anschutz, Lexicon Pharmaceuticals (United States), Inserm, Institut Universitaire de France, Université Paris Cité, Assistance Publique – Hôpitaux de Paris, Laboratoire de Recherche Vasculaire Translationnelle, Hôpital Bichat-Claude-Bernard, Icahn School of Medicine at Mount Sinai

Language: English

Topic: Heart Failure Treatment and Management

Subfield: Cardiology and Cardiovascular Medicine

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $3,970

Awards: Role of SuPAR in the Intersection between Cardiovascular and Kidney Disease, G4922938341, G6971475997, Multidisciplinary Cardiovascular Research Training

OpenAlex ID: W7133123567