medwireNews: The dual sodium–glucose co-transporter (SGLT)1/2 inhibitor sotagliflozin significantly reduces the risk for major adverse cardiac events (MACE) in people with type 2 diabetes, chronic kidney disease, and additional cardiovascular disease risk, SCORED study data show.
Sotagliflozin also significantly reduced individual rates of both total myocardial infarction (MI) and total stroke, a dual benefit that “has not been previously observed with other SGLT inhibitors and warrants investigation of combined SGLT1 and SGLT2 inhibition as a possible underlying mechanism,” say Deepak Bhatt (Icahn School of Medicine at Mount Sinai, New York, USA) and co-investigators.
The primary analysis of the SCORED trial showed that sotagliflozin significantly reduced heart failure-related outcomes. The current, prespecified secondary analysis focused on total MACE, which was defined as a composite of cardiovascular death, nonfatal MI, and nonfatal stroke.
The study included 10,584 adults (median age 69 years, 55% men) with type 2 diabetes, chronic kidney disease, and additional cardiovascular risk factors. Of these, 22.4% had a history of coronary revascularization, 19.9% had a history of MI, and 8.9% had a history of stroke.
The researchers report in The Lancet Diabetes & Endocrinology that during a median 14.2 months of follow-up, 785 total MACE occurred in 620 patients.
The risk for total MACE was a significant 23% lower among the 5292 patients randomly assigned to receive oral sotagliflozin 200 mg/day (increasing to 400 mg/day within 6 months, if tolerated) than among the 5292 individuals given placebo. Specifically, the event rates were 4.8 and 6.3 per 100 person–years in the sotagliflozin and placebo arms, respectively, with the difference corresponding to 1.6 events avoided per 100 patients up to 24 months in the sotagliflozin arm.
Furthermore, the benefit of sotagliflozin on total MACE reduction was consistent across subgroups stratified by baseline demographic and clinical features such as sex, age, geographic region, heart failure-related criteria, estimated glomerular filtration rate, urine albumin–creatinine ratio, and cardiovascular disease history.
The investigators also found that people given sotagliflozin had a significant 32% lower risk for total MI than those given placebo (1.8 vs 2.7 events per 100 person–years) and a significant 34% lower risk for total stroke (1.2 vs 1.8 events per 100 person–years) when the two events when assessed as individual post-hoc outcomes. In these analyses, use of sotagliflozin amounted to 0.7 MI events and 1.2 stroke events avoided per 100 patients up to 24 months.
Bhatt and colleagues note: “The stroke benefit observed in the present study appears to be unique to sotagliflozin, as it has not been observed in trials of selective SGLT2 inhibitors.”
However, they add that “the underlying mechanisms for this activity are unclear. One possible explanation is SGLT1 inhibition.”
In an accompanying comment, Anna Norhammar and Viveca Ritsinger, both from Karolinska Institutet in Stockholm, Sweden, explain: “The major difference between the dual SGLT1/2 inhibitor sotagliflozin and selective SGLT2 inhibitors is that sotagliflozin has more inhibitory effects on the SGLT1 transporter in the intestines, contributing to reduced blood glucose concentrations, especially postprandial, by reducing glucose absorption during meals.”
They suggest that this could partly explain the “mechanism behind the novel data.”
Regardless of the mechanism, Norhammar and Ritsinger say that sotagliflozin’s potential to prevent ischemic events is “of importance for patients with type 2 diabetes.”
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Lancet Diabetes Endocrinol 2025; doi:10.1016/S2213-8587(24)00362-0
Lancet Diabetes Endocrinol 2025; doi:10.1016/S2213-8587(25)00001-4
