Sotagliflozin may reduce the risk for cardiovascular (CV) deaths and and hospitalization and urgent visits for heart failure compared with placebo among patients with type 2 diabetes mellitus and chronic kidney disease, with or without albuminuria, according to new study findings published online ahead of print in the New England Journal of Medicine.
Sotagliflozin inhibits sodium-glucose cotransporter 2 (SGLT2) in the proximal convoluted tubule of the nephron, which increases urinary glucose, and also SGLT1 in the gastrointestinal tract, which appears to delay glucose absorption and reduce postprandial glucose, according to investigators.
In the Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk (SCORED; NCT03315143) trial, investigators randomly assigned 10,584 patients (mean age 69 years; 45% women; 17% non-White) to receive sotagliflozin (200 mg once daily, increased to 400 mg once daily if tolerated) or placebo. Patients had glycated hemoglobin of 7% or greater, an estimated glomerular filtration rate (eGFR) of 25 to 60 mL/min/1.73 m2, and at least 1 major CV risk factor or at least 2 minor CV risk factors in those 55 years of age or older. Unlike some previous trials, only 19.9% of the cohort had an ejection fraction of 40% or less within the past year or hospitalization for heart failure during the previous 2 years. Also, unlike some previous trials, albuminuria was not an eligibility requirement. Roughly a third of the cohort each had no albuminuria, a urinary albumin-to-creatinine ratio (UACR) of 30 to less than 300 mg/g, or a UACR of 300 mg/g or greater.
The trial’s primary endpoint was changed on August 21, 2020 due to a loss of funding, which is a limitation. The revised endpoint was a composite of deaths from CV causes and hospitalizations or urgent visits for heart failure.
Over a median 16 months, 5.6 events per 100 patient-years occurred in the sotagliflozin group compared with 7.5 events per 100 patient-years in the placebo group, for a significant 26% reduction in risk with sotagliflozin, Deepak L. Bhatt, MD, MPH, of Brigham and Women’s Hospital Heart and Vascular Center, Harvard Medical School in Boston, Massachusetts, and colleagues reported. Deaths from CV causes were nonsignificantly different: 2.2 vs 2.4 per 100 patient-years, respectively.
Sotagliflozin users also had a significant 16% reduced risk for the trial’s original coprimary endpoint of the first occurrence of death from CV causes, nonfatal myocardial infarction, or nonfatal stroke and a significant 23% reduction in the risk for the original coprimary endpoint of the first occurrence of death from cardiovascular causes or hospitalization for heart failure, Dr Bhatt’s team reported.
Adverse events (AEs) of special interest that were significantly more common with sotagliflozin than with placebo included diarrhea (8.5% vs 6.0%), diabetic ketoacidosis (0.6% vs 0.3%), genital mycotic infections (2.4% vs 0.9%), and volume depletion (5.3% vs 4.0%). The team found no significant between-group differences in acute kidney injury, however, bone fractures, urinary tract infections, severe hypoglycemia, or amputations. Hypertension developed in a lower proportion of the sotagliflozin than placebo group (2.6% vs 4.1%), whereas hypotension developed in a significantly higher proportion of sotagliflozin recipients (2.6% vs 1.9%). There were no significant between-group differences in overall AEs or regimen withdrawal. Serious AEs occurred in a slightly lower proportion of the sotagliflozin group 23.4% vs 25.2%.
“Sotagliflozin is the first SGLT2 inhibitor to show a beneficial effect on stroke among patients with diabetes, suggesting that it may also affect atherosclerosis, or plaque build-up in the coronary and brain arteries,” Dr Bhatt stated in a news release from the American Heart Association. “SCORED is also the first trial to show the benefits of SGLT2 inhibitors across the full range of albuminuria, or leakage of protein in the urine, which is common in people with Type 2 diabetes.
“This is a major advance for patients with Type 2 diabetes and advanced kidney disease, and these results clearly demonstrate that SGLT2 inhibitors should become part of the standard of care,” he stated.
Disclosure: This clinical trial was supported by Sanofi and Lexicon Pharmaceuticals. Please see the original reference for a full list of authors’ disclosures.
Bhatt DL, Szarek M, Pitt B, et al; for the SCORED investigators. Sotagliflozin in patients with diabetes and chronic kidney disease. N Engl J Med. doi:10.1056/NEJMoa2030186
New diabetes medication reduced heart event risk in those with diabetes and kidney disease [news release]. Dallas, Texas: American Heart Association; November 17, 2020.