Sotagliflozin SCORED favourably in patients with T2D, CKD

Use of the sodium-glucose cotransporter 2 (SGLT2) inhibitor sotagliflozin led to a reduction in the risk of deaths from cardiovascular (CV) causes, hospitalizations for heart failure (HF), and urgent visits for HF compared with placebo among patients with type 2 diabetes (T2D) and chronic kidney disease (CKD) regardless of the degree of albuminuria, the SCORED* trial has shown.

“Sotagliflozin provides some degree of SGLT1 inhibition as well, slowing intestinal glucose absorption and reducing post-prandial glycaemia,” noted the researchers. “Mendelian randomization data have raised the possibility that SGLT1 inhibition might be associated with decreased rates of CV events.” [J Am Coll Cardiol 2018;72:1763-1773]

A total of 10,584 T2D patients with CKD with or without albuminuria (median age 69 years, 44.9 percent female) were randomized 1:1 to receive sotagliflozin 200 mg QD or placebo. More than two-thirds of participants in the sotagliflozin arm (74 percent) had their dose increased to 400 mg. Median follow-up duration was 16 months. [N Engl J Med 2020;doi:10.1056/NEJMoa2030186]

Compared with placebo, the sotagliflozin arm had significantly lower incidences of the primary endpoint (total number of deaths from CV causes, hospitalizations for HF, and urgent visits for HF; 5.6 vs 7.5 events/100 patient-years [PY]; hazard ratio [HR], 0.74) and the first secondary endpoint events (total number of hospitalizations for HF and urgent visits for HF; 3.5 vs 5.1 events/100 PY; HR, 0.67; p<0.001 for both).

However, the number of HF events might have been overestimated, as nearly a third (~31 percent) of adjudicated HF hospitalizations or urgent visits were not confirmed to be primary events, the researchers pointed out.

Despite the low estimated glomerular filtration rate (eGFR) among participants (median 44.5 mL/min/1.73 m²), renal** events did not differ significantly between the sotagliflozin and the placebo arms (0.5 vs 0.7 events/100 PY).

There were similar fractions of sotagliflozin and placebo recipients who experienced serious adverse events (AEs; 23 percent vs 25 percent). AEs of special interest more common in the sotagliflozin vs the placebo arm were diarrhoea (8.5 percent vs 6.0 percent), diabetic ketoacidosis (0.6 percent vs 0.3 percent), and genital mycotic infections (2.4 percent vs 0.9 percent).

The proportion of participants who developed hypertension was lower in the sotagliflozin vs the placebo arm (2.6 percent vs 4.1 percent). Conversely, hypotension was more frequent in the sotagliflozin vs the placebo arm (2.6 percent vs 1.9 percent).

“The SGLT1 blockade may have contributed to the increased reports of diarrhoea. Whether additional CV benefit is provided from SGLT1 inhibition above that provided by SGLT2 inhibition remains to be determined,” said the researchers.

However, the trial was prematurely terminated due to loss of funding, hence the inability to complete the intended follow-up duration. Nonetheless, instead of the original coprimary endpoints, the primary endpoint was adjusted in hopes of preserving statistical power, the researchers explained. “[Although] the power to show a difference between the trial groups was not recalculated with the change of the endpoint, the trial remained adequately powered for the original and revised primary endpoints.”

As in the revised primary endpoints, HRs for the original coprimary endpoints also favoured the study drug over placebo (HRs, 0.84 [for first occurrence of major adverse CV event***] and 0.77 [for first occurrence of death from CV causes or hospitalization for HF]).

Nonetheless, the researchers called for longer trials to ascertain the efficacy and safety of sotagliflozin in this setting.