Sodium-glucose co-transporter 2 (SGLT2) inhibitors as a class have demonstrated benefit for preventing heart failure hospitalizations in stable outpatients with diabetes mellitus type 2. 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 made the choice to deviate from the original study protocol when they found themselves without enough money to complete the trial as originally designed. The original trial started in 2018 and was planned to enroll 4,000 patients with diabetes hospitalized for heart failure and given sotaglifozin or placebo at hospital discharge. The researchers needed 1,341 events of either cardiovascular death or first heart failure hospitalization to achieve the 85 percent power needed to see the anticipated 19 percent improvement. Recall that power is the ability to detect a difference between a drug and a placebo if such a difference in outcomes exists. When enrollment was closed, researchers were following 1,222 patients (608 taking sotaglifozin and 614 taking placebo). They 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 in order to increase the overall event rate. In another important difference between the original protocol and the modified one, outcomes were not adjudicated but rather were reported by the researchers.
Based on this modified research protocol, there were 600 reported events 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 0.67, 95% CI 0.52-0.85). However, there was no significant difference in death between the two groups (hazard ratio 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. Researchers reported they added additional outcomes because the trial would have been underpowered as originally executed. 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 have benefits in treating patients with heart failure, but the extent of benefit remains uncertain.
For more information, see the topic Heart Failure With Reduced Ejection Fraction in DynaMed®.