Sotagliflozin (INPEFA®) is Associated with Improving Heart Failure, Atherosclerotic Events

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FDA approved sotaglifozin (INPEFA®) on May 26, 2023, to treat heart failure. Also, a phase 3 trial shows the clinical benefits of the drug by the 3-month mark.

On November 12, 2023, Lexicon Pharmaceuticals, Inc. announced a post hoc analysis of clinical data from the SCORED trial, which showcased the clinical benefit from sotagliflozin (INPEFA®) to treat heart failure and major adverse cardiovascular events as early as about 3 months.

“We are pleased to support research in areas important to heart failure clinicians and payors, and we are confident that the early clinical benefit of INPEFA observed in the SCORED post hoc analysis will play a role in care decisions made by these stakeholders,” said Craig Granowitz, MD, PhD, Lexicon’s senior vice president and chief medical officer, in a press release. “Avoiding a stroke or myocardial infarction can have great benefit to both patients and the healthcare system, and we believe that the observed reductions in [major adverse cardiovascular events] as early as approximately three months are additional points of differentiation for INPEFA.”

The U.S. Food and Drug Administration (FDA) approved INPEFA® on May 26, 2023, to lower the risk of cardiovascular death, hospitalization or urgent doctor visits for patients with either heart failure or type 2 diabetes mellitus, chronic kidney disease, and other cardiovascular risk factors. INPEFA® is an oral inhibitor of 2 proteins responsible for glucose regulation, occurring with sodium-glucose cotransporter types 2 and 1 (SGLT2 and SGLT1). SGLT2 is responsible for glucose reabsorption in the kidney, and SGLT2 is responsible for glucose reabsorption in the gastrointestinal tract.

SCORED, a multi-center, randomized, double-blinded, placebo-controlled phase 3 study, evaluated the cardiovascular benefits of sotagliflozin versus placebo of 10,584 patients with type 2 diabetes, chronic kidney disease with an estimated glomerular filtration rate (eGFR) of 25 ml to 60 ml per minute per 1.73 m2 of body-surface area, and risks for cardiovascular disease. Rahul Aggarwal, MD, of Brigham and Women’s Hospital in Boston, Massachusetts presented the study at the American Heart Association (AHA) Scientific Sessions 2023 in Philadelphia, Pennsylvania.

In the post-hoc analysis at AHA 2023, the relative risk in patients with heart failure treated with INPEFA® vs. placebo was 26% (hazard ratio [HR], 0.74; 95% CI, 0.63 – 0.88; P < .001). At the 95-day mark after randomization, the investigators found a significant sustained reduction in the primary endpoint (hazard ratio [HR], 0.70; 95% CI, 0.50 – 0.98).

The secondary endpoint looked at major adverse cardiovascular events, and the investigators found, for this, the relative risk reduction in patients treated sotagliflozin vs placebo was 23% (95% CI, 0.65 – 0.91; P <.001), and there was a statistically significant sustained reduction at 94 days after randomization (hazard ratio [HR], 0.69; 95% CI, 0.47 – 0.99).

The press release ended with warnings of adverse effects, such as:

  • Risk of Ketoacidosis: The press warned INPEFA® increases the risk of ketoacidosis in patients with type 1 diabetes mellitus. People with type 2 diabetes mellitus are also at risk of ketoacidosis if on INPEFA®. There have been reports of fatal events of ketoacidosis in patients with type 2 diabetes taking sodium glucose transporter 2 (SGLT2 inhibitors), and thus Lexicon informs people to access risk factors for ketoacidosis before taking INPEFA®.
  • Risk of intravascular volume depletion: This can cause symptomatic hypotension or acute transient changes in creatinine. People with impaired retinal function (eGFR < 60 mL/min/1.73 m2), older adults, or patients on loop diuretics could be at an increased risk.
  • Risk of Urinary Tract Infections: Doctors are urged to evaluate patients on INPEFA® for signs and symptoms of the infection.
  • Risk of hypoglycemia: This one is when taking INPEFA® is combined with insulin or insulin secretagogue. In this case, a lower dose of insulin or insulin secretagogue may be needed to lower the risk of hypoglycemia.
  • Risk of Fournier Gangrene: This is a rare life-threatening infection associated in patients with diabetes mellitus receiving SGLT2. Doctors are advised to access patients with a fever or malaise, as well as pain, tenderness, erythema, or swelling in the genital or perineal area.
  • Risk of genital mycotic infection

The common adverse reactions of INPEFA® with an incidence of > 5% was urinary tract infection, volume depletion, diarrhea, and hypoglycemia. INPEFA® is not recommended during the second or third pregnancy of pregnancy or while breastfeeding. It is also not recommended for patients with moderate or severe hepatic impairment. The INPEFA® dose does not change for age, although elderly patients may be at increased risk for volume depletion or hypotension.

Patients with a chronic kidney disease who had an estimated glomerular filtration rate (eGFR) of <30 mL/min/1.73 m2 had an increase in volume-related adverse events like hypotension and dizziness. Patients were discontinued if their eGFR fell below 15 mL/min/1.73 m2 or started chronic dialysis.


INPEFA® (sotagliflozin) Use Associated with Early Clinical Benefit in Heart Failure and Atherosclerotic Events in Analysis of Clinical Data. Lexicon Pharmaceuticals. November 12, 2023. Accessed November 13, 2023.