Efficacy of sotagliflozin by diabetes duration: a secondary analysis of SCORED

Abstract Background Sotagliflozin is a sodium-glucose cotransporter (SGLT) 1 and SGLT2 inhibitor. SCORED randomized patients with type 2 diabetes (DM) and high cardiovascular (CV) risk to sotagliflozin or placebo. Purpose We evaluated if diabetes duration affects HF and CV outcomes when comparing sotagliflozin with placebo in SCORED, as diabetes duration can modify CV risk. Methods SCORED enrolled patients with DM (hemoglobin A1c ≥7%), chronic kidney disease (glomerular filtration rate of 25-60 mL/minute per 1.73 m2), and CV risk factors. Patients were randomized to sotagliflozin compared with placebo. Patients in SCORED were stratified by diabetes duration, into categories of <10 years, 10-19 years, or ≥20 years. The primary endpoint was total CV death, hospitalization for HF, or urgent visit for HF. Secondary endpoints were total hospitalization for HF or urgent visit for HF, as well as total CV death, nonfatal myocardial infarction, and nonfatal stroke (MACE). Outcomes were assessed using marginal proportional hazard models stratified according to HF criteria and geographic region where non-CV death was a competing terminal event. Subgroup analyses were assessed with natural cubic splines of interaction between treatment and continuous diabetes duration. Results In SCORED, 10,579 (99.9%) of 10,584 patients had complete data on diabetes duration, with 2412 (22.8%), 4424 (41.8%), 3743 (25.9%) having diabetes duration of <10, 10-19, and ≥20 years respectively. Median (Q1, Q3) diabetes duration was 16.4 years (10.4, 22.4 years), while mean hemoglobin A1c was 8.6%, 8.7%, and 8.7% respectively by diabetes duration. The rate of the primary endpoint was lower in the sotagliflozin group (5.6 events per 100 patient-years [p-y]) compared with the placebo group (7.5 events per 100 p-y) (HR: 0.74; 95% CI: 0.63, 0.88). Event rates among diabetes duration subgroups indicated that rates in both the placebo group and relative treatment benefit increased with increasing diabetes duration, with 5.6 vs 5.8 events per 100 p-y, 6.1 vs 7.4 events per 100 p-y, and 4.6 vs 8.5 events per 100 p-y for diabetes duration <10, 10-19, and ≥20 years respectively. Spline analysis indicated increasing treatment benefit with increasing duration when modeled continuously (Figure Panel A; PSpline=0.02). Similar findings were observed for the secondary HF outcome of hospitalization for HF or urgent visit for HF, with increased treatment benefit with duration (Figure Panel B; PSpline=0.10). Total MACE was lower in the sotagliflozin group (4.8 events per 100 patient-years) than in the placebo group (6.3 events per 100 patient-years) (HR: 0.77; 95% CI: 0.65, 0.91), without significant difference in relative treatment benefit by duration (Figure Panel C; PSpline=0.30). Conclusions Sotagliflozin improved HF and MACE outcomes in patients with high CV risk, with increasing treatment benefit for HF outcomes among patients with longer diabetes duration.