The double SGLT inhibitor shows new CV benefits in type 2 diabetes

Adults with type 2 diabetes and worsening heart failure or CV risk who were assigned the dual SGLT1 / SGLT2 sotagliflozin inhibitor had a reduced risk of CV death and hospitalization or urgent visits for HF compared to placebo.

In two randomized controlled trials that evaluated more than 11,000 participants, the researchers also observed a reduction in stroke among those assigned sotagliflozin (approved in the European Union as Zynquista and developed by Lexicon) compared to placebo, the former. for a study on SGLT inhibitors.

Deepak L. Bhatt

“With careful patient selection and monitoring, I would say that, as a class, SGLT2 inhibitors should be strongly considered in most patients with type 2 diabetes, including those admitted with acute decompensated HF, in HF patients with reduced or preserved ejection fraction, and also in patients with chronic kidney disease through the full range of protein losses in the urine “, Cardiology today Intervention Section Editor Deepak L. Bhatt, MD, MPH, Executive director of interventional cardiovascular programs at Brigham and Women’s Hospital and a professor of medicine at Harvard Medical School, he said during a press conference at the American Heart Association’s virtual science sessions.

An increasing amount of clinical trial data now supports CV and kidney benefits of SGLT2 inhibitors for adults with and without type 2 diabetes, Bhatt said during a presentation. The combination of SGLT2 and SGLT1 blocking abilities in sotagliflozin, in particular, also leads to increased glucose clearance in the digestive tract, a benefit that was also seen in study participants with severe kidney failure, Bhatt said.

Parallel Studies SGLT

The researchers conducted two parallel studies of sotagliflozin in adults with type 2 diabetes with and without CVD. For SOLOSIT, the researchers analyzed data from 1,222 participants with type 2 diabetes recently hospitalized for worsening heart failure, sotagliflozin (n = 608) or placebo (n = 614) randomly assigned and followed for a median of 9 months. The primary endpoint was the total number of deaths from cardiovascular causes and urgent hospitalizations and visits for HF (first and subsequent events). The SOLOIST study ended early due to the loss of funds from the sponsor.

For SCORED, the researchers analyzed data from 10,584 participants with type 2 diabetes and chronic kidney disease at risk of CVD, sotagliflozin (n = 5,292) or placebo (n = 5,292) randomly assigned and followed for a median of 16 months. The primary endpoint was changed during the study to comprise the total number of CV-related deaths, HF hospitalizations, and urgent HF visits. SCORED also ended early due to the loss of funds.

The results of SCORED and SOLOIST were both published simultaneously in The New England Journal of Medicine.

In SOLOIST, investigators observed 245 primary endpoint events in the sotagliflozin group and 355 events in the placebo group, for an event rate of 51 vs 76.3 per 100 patient-years, an HR of 0.67 (95% CI 0.52-0.85; P. .001) and a necessary number to deal with of just 4, Bhatt said.

In SCORED, the researchers observed a 26% reduction in the same primary endpoint among participants assigned to sotagliflozin compared to placebo (HR = 0.74; 95% CI, 0.63-0.88; P = .0004), with a higher number to be treated equal to 54.

“These were stable outpatients unlike the first study, SOLOIST, which included patients admitted to hospital with HF,” Bhatt said. “In SOLOIST, the benefits kicked in and were statistically significant for approximately 1 month in an acute population. Here, in this more chronic outpatient population, the benefits still increased in the beginning, by around 3 months. “

When evaluating the rate of CV death, non-fatal MI, and non-fatal stroke in SCORED, the researchers observed a 23% reduction in RR with sotagliflozin compared with placebo (HR = 0.77; 95% CI, 0.65-0, 91; P = .002), with benefit seen about 3 months after starting therapy, Bhatt said.

In post hoc analyzes for SCORED evaluating total fatal or non-fatal MI, or total fatal or non-fatal stroke, the investigators also saw significant reductions with sotagliflozin compared to placebo (HR = 0.77; 95% CI, 0.65- 0.91; P = .002).

“This is the first time that a study with an SGLT2 inhibitor shows a reduction in stroke as an endpoint,” Bhatt said.

The lower rate of MI and stroke observed among participants who were assigned sotagliflozin also suggests a possible anti-ischemic effect with SGLT1 inhibition, Bhatt said, adding that this observation should be explored further in future studies.

‘A new role’ for sotagliflozin

Jane E. Wilcox

Sotagliflozin is a new compound – SGLT2 which acts on the kidneys and SGLT1 which acts on the gut – which may explain the reductions observed across the spectrum of estimated levels of glomerular filtration rate. Jane E. Wilcox, MD. MSc, assistant professor of medicine and director of the Myocardial Recovery Program at Northwestern University Feinberg School of Medicine, he said during a discussion after the presentation.

“The risk reduction for the composite outcome was 26% and it should be noted that this benefit was seen early, within 3 months. [initiating] sotagliflozin, “Wilcox said at the press conference.

Wilcox said sotagliflozin adds to the continuing history of the SGLT2 inhibitor, which now includes a number of large CV outcome studies demonstrating class benefits in patients at high risk for CV events and those with overt CVD.

“For most of these studies, aside from VERTIS-CV, there is a clear signal for reduction in HF events compared to vascular or atherosclerotic events,” Wilcox said. “The SCORED study shows that sotagliflozin appears to affect heart failure and a 23% reduction in total CV, MI and stroke deaths at secondary analysis. Additionally, in pooled analyzes of over 700 patients from both SOLOIST and SCORED, there was a 37% reduction among HF patients with preserved ejection fraction in total CV death or HF outcomes. “

Wilcox defined the signals for HFpEF and reduced generation of atherosclerotic CVD hypothesis, adding further studies to determine if the SGLT1 mechanism plays a role.

“The implications are clear that sotagliflozin adds to the SGLT history among patients with diabetes in whom the pooled evidence favors treatment to reduce HbA1c, preserve renal function and prevent CV events in early treatment,” Wilcox said. “Furthermore, in SOLOIST, we may have a new role for sotagliflozin in acute HF space.”

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