Sodium-glucose cotransporter 2 (SGLT2) inhibitors as a class have demonstrated benefit for preventing heart failure hospitalizations in stable outpatients with type 2 diabetes. The investigators of a recent randomized trial examined the efficacy of sotagliflozin (a newer combined SGLT2/SGLT1 inhibitor) to prevent rehospitalization in people with diabetes discharged after acute heart failure exacerbations.
The study was defunded in March 2020, after which researchers chose to deviate from the original study protocol because of cost constraints. The original trial started in 2018 and was planned to enroll 4000 patients with diabetes hospitalized for heart failure and given sotaglifozin or placebo at hospital discharge. The trial was designed to have 1341 events of either cardiovascular death or first heart failure hospitalization.
When enrollment was closed, the researchers decided to add all urgent visits and subsequent hospitalizations as components of a composite outcome in addition to the original endpoints of death and first hospitalization to increase the overall event rate. Another difference between the original protocol and the modified one is that outcomes were not adjudicated but rather were reported by the researchers.
Based on this modified research protocol, 600 events were reported during the trial at a rate of 51 per 100 patient-years in the sotaglifozin group vs 76.3 per 100 patient-years in the placebo group (hazard ratio [HR] 0.67; 95% CI 0.52-0.85). However, no significant difference in risk of death was found between the two groups (HR 0.84; 95% CI 0.58-1.22).
Changing a study protocol during trial implementation is a critical threat to internal validity and limits any conclusions that can be drawn from the collected data. By adding in the tally of urgent visits and repeat hospitalizations, the researchers were able to detect a significant difference, but the clinical value of combining unadjudicated urgent visits with hospitalizations and death seems questionable and there is additional bias in the way the data were collected due to deviation from the original protocol. Thus, sotagliflozin may be beneficial in treating patients with heart failure, but the extent of benefit remains uncertain.
Alan Ehrlich, MD, is a deputy editor for DynaMed, Ipswich, Massachusetts, and assistant clinical professor in family medicine, University of Massachusetts Medical School, Worcester.
DynaMed is a database that provides evidence-based information on more than 3000 clinical topics and is updated daily through systematic surveillance covering more than 500 journals.
Bhatt DL, Sarek M, Steg PG, et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med. 2021;384(2):117-128. doi:10.1056/NEJMoa2030183