Clinical Pearls & Morning Reports
Published January 13, 2021
Bhatt et al. conducted a phase 3, randomized, placebo-controlled trial that assessed whether sotagliflozin, administered soon after an episode of decompensated heart failure, reduced the risks of death from cardiovascular causes and hospitalizations and urgent visits for heart failure among patients with type 2 diabetes mellitus. The trial ended early because of loss of funding from the sponsor. Read the NEJM Original Article here.
Q: What is the mechanism of action of sotagliflozin?
A: Sotagliflozin is a sodium–glucose cotransporter 2 (SGLT2) inhibitor that also provides some gastrointestinal SGLT1 inhibition. SGLT2 inhibition increases glucose excretion in the urine, whereas SGLT1 inhibition reduces the postprandial glucose level by delaying intestinal glucose absorption.
Q: Describe some of the findings regarding the use of SGLT2 inhibitors in patients with or without diabetes.
A: SGLT2 inhibitors represent a major therapeutic advance. They were initially developed to treat hyperglycemia in patients with diabetes mellitus. Subsequently, several SGLT2 inhibitors were shown to lower the risk of hospitalization for heart failure among patients with type 2 diabetes, who are at substantial risk for this complication. In addition, some SGLT2 inhibitors have been shown to reduce the risk of death from cardiovascular causes or hospitalization for heart failure in patients with heart failure (with or without diabetes) and a reduced ejection fraction. The safety and potential efficacy of initiating SGLT2 inhibition soon after an episode of decompensated heart failure remain uncertain.
A: The trial showed that among patients with diabetes who had worsening heart failure, the primary end point of the total number of cardiovascular deaths and hospitalizations and urgent visits for heart failure was significantly lower with sotagliflozin than with placebo. The trial had intended to evaluate whether the benefits of SGLT2 inhibition extend to patients with heart failure with preserved ejection fraction. However, although such patients were enrolled in the trial and there was no evidence of heterogeneity of treatment effect according to ejection fraction, early termination of the trial and the small sample size of this subgroup made it difficult to draw any firm conclusion in this regard.
A: The results of the analysis of the first secondary end point (the total number of hospitalizations and urgent visits for heart failure) were consistent with the results of the primary end-point analysis. The incidence of death from cardiovascular causes or of death from any cause did not differ significantly between the trial groups. The between-group difference in the change in the Kansas City Cardiomyopathy Questionnaire–12 item score was 4.1 points (95% CI, 1.3 to 7.0) in favor of the sotagliflozin group, and the between-group difference in the change in the estimated glomerular filtration rate during follow-up was −0.16 ml per minute per 1.73 m2 (95% CI, −1.30 to 0.98) in favor of the placebo group. The most common adverse events other than heart failure that occurred in the sotagliflozin group and the placebo group were hypotension (6.0% vs. 4.6%), urinary tract infection (4.8% vs. 5.1%), and diarrhea (6.1% vs. 3.4%).