SGLT1/2 Inhibitor Cut Stroke, Heart Attack Risk in Diabetic Kidney Disease

The dual SGLT1/2 inhibitor sotagliflozin (Inpefa) reduced the risk for myocardial infarction (MI) and stroke in high-risk patients with type 2 diabetes (T2D), chronic kidney disease (CKD), and cardiovascular risk factors, a prespecified secondary analysis of the SCORED trial found.

Among 10,584 patients, those assigned to sotagliflozin had 4.8 major adverse cardiovascular events (MACE) — a composite of cardiovascular death, non-fatal MI, and non-fatal stroke — compared with 6.3 events per 100 person-years in the placebo group (HR 0.77, 95% CI 0.65-0.91, P=0.0020), reported Deepak Bhatt, MD, of the Icahn School of Medicine at Mount Sinai in New York City, and colleagues.

This corresponded to 1.6 MACE events avoided per 100 patients up to 24 months, they wrote in Lancet Diabetes & Endocrinology.

When the composite components were separated, sotagliflozin significantly reduced the rate of MI and stroke compared with placebo over a median 14.2-month follow-up:

• MI: 1.8 vs 2.7 per 100 person-years (HR 0.68, 95% CI 0.52-0.89, P=0.0041)
• Stroke: 1.2 vs 1.8 events per 100 person-years (HR 0.66, 95% CI 0.48-0.91, P=0.012)

This corresponded to 0.7 MIs and 1.2 strokes avoided per 100 patients up to 24 months.

“Sotagliflozin is the first SGLT inhibitor to provide a significant reduction in both myocardial infarction and stroke,” the researchers noted. “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.”

“These results demonstrate a new mechanism of action — combined blockade with sotagliflozin of the SGLT1 receptors found in the kidney, gut, heart, and brain and SGLT2 receptors found in the kidney — to reduce heart attack and stroke risk,” Bhatt added in a statement. “The benefits seen here are distinct from those seen with the other very popular SGLT2 inhibitors in widespread clinical use for diabetes, heart failure, and kidney disease.”

“Few people had predicted the broad effects of the SGLT inhibitor class when initially developing a diabetes drug that increased glucose excretion in urine,” said accompanying commentary authors Anna Norhammar, MD, PhD, and Viveca Ritsinger, MD, PhD, both of the Karolinska Institutet in Stockholm.

Approved in 2023, sotagliflozin holds indications for heart failure in patients with or without diabetes, as well as in adults with T2D, CKD, and other cardiovascular risk factors based on the SCORED and SOLOIST-WHF trials.

In SCORED, 5,292 participants across 44 countries were randomized to sotagliflozin or placebo from 2017 to 2020. Median age was 69 years, 55% were male, all had T2D and an estimated glomerular filtration rate (eGFR) between 25 and 60 mL/min per 1.73 m². Nearly half had a history of cardiovascular disease and 19.9% of the total population had a history of MI, 8.9% had a history of stroke, and 22.4% had a previous coronary revascularization.

Oral sotagliflozin was prescribed at 200 mg/day and the dose increased to 400 mg/day within the first 6 months if tolerated.

During follow-up, there were 343 MACE events in 286 sotagliflozin-treated patients and 442 events in 334 placebo patients. Similar to the overall MACE rate, the sotagliflozin group also had a 16% lower rate of first-occurrence MACE than placebo (4.0 vs 4.8 events per 100 person-years; HR 0.84, 95% CI 0.72-0.99, P=0.035).

There was a numerical difference for first occurrence of stroke, but this didn’t reach statistical significance (1.0 vs 1.4 events per 100 person-years; HR 0.74, 95% CI 0.55-1.01, P=0.054).

A total of 155 and 170 cardiovascular deaths occurred in the sotagliflozin and placebo groups, respectively. There was no difference in the rate of cardiovascular deaths between the two groups (HR 0.90, 95% CI 0.73-1.12).

Bhatt and colleagues said, “this study was not powered for the subgroup analyses, although we found no formal evidence of heterogeneity in the effect of sotagliflozin on total MACE among the stratified subgroups.”

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