SCORED/SOLOIST: Dual SGLT inhibitor shows new CV benefits in type 2 diabetes
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Adults with type 2 diabetes and worsening HF or at CV risk assigned the dual SGLT1/SGLT2 inhibitor sotagliflozin saw reduced risk for CV death and hospitalization or urgent visits for HF compared with placebo.
In two randomized controlled trials assessing more than 11,000 participants, researchers also observed a reduction in stroke among those assigned sotagliflozin (approved in the European Union as Zynquista and developed by Lexicon) compared with placebo, a first for an SGLT inhibitor trial.
“SOLOIST and SCORED advance our understanding of the expanding role of SGLT2 inhibition, now including in acute heart failure, the full range of proteinuria, and heart failure with preserved ejection fraction,” Cardiology Today Intervention Section Editor Deepak L. Bhatt, MD, MPH, executive director of interventional cardiovascular programs at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, told Healio. “Additionally, the ability to reduce HbA1c in patients with both moderate and severe kidney disease reflects the value of SGLT1 inhibition. The reductions in MI and stroke are also of great interest.”
A growing amount of clinical trial data now support the CV and renal benefits of SGLT2 inhibitors for adults with and without type 2 diabetes, Bhatt said during a presentation at the virtual American Heart Association Scientific Sessions. The combination of SGLT2 and SGLT1 blocking abilities in sotagliflozin, specifically, also leads to enhanced elimination of glucose in the digestive tract, a benefit that was observed even in trial participants with severe renal impairment, Bhatt said.
Parallel SGLT studies
Researchers conducted two parallel trials of sotagliflozin in adults with type 2 diabetes with and without CVD. For SOLOIST, researchers analyzed data from 1,222 participants with type 2 diabetes recently hospitalized for worsening HF, randomly assigned sotagliflozin (n = 608) or placebo (n = 614) and followed for a median of 9 months. The primary endpoint was total number of deaths from CV causes and hospitalizations and urgent visits for HF (first and subsequent events). The SOLOIST trial ended early due to loss of funding from the sponsor.
For SCORED, researchers analyzed data from 10,584 participants with type 2 diabetes and chronic kidney disease at risk for CVD, randomly assigned sotagliflozin (n = 5,292) or placebo (n = 5,292) and followed for a median of 16 months. The primary endpoint was changed during the trial to the composite of the total number of deaths from CV causes, hospitalizations for HF and urgent visits for HF. SCORED also ended early due to loss of funding.
The findings for SCORED and SOLOIST were both simultaneously published in The New England Journal of Medicine.
In SOLOIST, researchers 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 number needed to treat of just 4, Bhatt said.
In SCORED, researchers observed a 26% reduction in the same primary endpoint among participants assigned sotagliflozin vs. placebo (HR = 0.74; 95% CI, 0.63-0.88; P = .0004), with a higher number needed to treat of 54.
“These were stable outpatients unlike the first trial, SOLOIST, which included patients admitted to the hospital with HF,” Bhatt said. “In SOLOIST, the benefits kicked in and were statistically significant by about 1 month in an acute population. Here, in this more chronic outpatient population, the benefits still kicked in early, by about 3 months or so.”
Assessing the rate of CV death, nonfatal MI and nonfatal stroke in SCORED, researchers observed a 23% RR reduction with sotagliflozin vs. placebo (HR = 0.77; 95% CI, 0.65-0.91; P = .002), with benefit seen approximately 3 months after initiating therapy, Bhatt said.
In post hoc analyses for SCORED assessing total fatal or nonfatal MI, or total fatal or nonfatal stroke, researchers also saw significant reductions with sotagliflozin vs. placebo, Bhatt said.
“This is the first time that an SGLT2 inhibitor trial shows a reduction in stroke as an endpoint,” Bhatt said.
The lower rate of MI and stroke seen among participants assigned sotagliflozin also suggests a possible anti-ischemic effect with SGLT1 inhibition, Bhatt said, adding this observation should be explored further in future trials.
Adverse event rates in both trials were low, though those assigned sotagliflozin had higher rates of diarrhea than those assigned placebo, according to the researchers.
‘A new role’ for sotagliflozin
Sotagliflozin is a novel compound — SGLT2 acting on the kidney and SGLT1 acting on the gut — which may explain the observed reductions across the spectrum of estimated glomerular filtration rate levels, Jane E. Wilcox, MD. MSc, assistant professor of medicine and director of the Myocardial Recovery Program at Northwestern University Feinberg School of Medicine, said during a discussion after the presentation.
“The reduction in risk for the composite outcome was 26%, and it should be noted that this benefit was seen early, within 3 months of [initiating] sotagliflozin,” Wilcox said during the press conference.
Wilcox said sotagliflozin adds to the continuing SGLT2 inhibitor story, which now includes a series of large CV outcomes trials demonstrating class benefits in patients with high risk for CV events and in those with overt CVD.
“For most of these trials, there is a clear signal for reduction of HF events as opposed to vascular or atherosclerotic events,” Wilcox said. “The SCORED trial shows sotagliflozin seems to influence HF and a 23% reduction in total CV deaths, MI and stroke on secondary analysis. Additionally, in pooled analyses of over 700 patients from both SOLOIST and SCORED, there was a 37% reduction among patients with HF with preserved ejection fraction in total CV death or HF outcomes.”
Wilcox called the signals for HFpEF and reduction in atherosclerotic CVD hypothesis-generating, adding more study is needed to determine whether the SGLT1 mechanism plays a role.
“The implications are clear that sotagliflozin adds to the SGLT story among patients with diabetes where the aggregate evidence favors treatment to reduce HbA1c, preserve renal function and prevent CV events in early treatment,” Wilcox said. “As well, in SOLOIST, we may have a new role for sotagliflozin in the acute HF space.”
References:
- Bhatt DL, et al. N Engl J Med. 2020;doi:10.1056/NEJMoa2030186.
- Bhatt DL, et al. N Engl J Med. 2020;doi:10.1056/NEJMoa2030183.
Perspective
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Seth J. Baum, MD, FACC, FAHA, FNLA, FASPC
CVD prevention was transformed by the accumulation of consistently favorable data demonstrating that, in patients with diabetes, SGLT2 inhibitors decrease the risk for CV death, hospitalization for HF, and renal decompensation. Cardiologists are now re-engaged in the management of diabetes — for risk reduction — and the management of HF has added another excellent tool to its tool chest. SCORED and SOLOIST portend a similar drug being added to our CVD risk-reducing armamentarium. The studies evaluated a first-in-class dual SGLT2/SGLT1 inhibitor. Unfortunately, both trials were limited by a COVID-19-related loss of funding; however, they succeeded in meeting endpoints that will ultimately make this novel drug a genuine game-changer.
For the first time, SGLT inhibition reduced stroke in addition to MI; also, HFpEF — not just HFrEF — patients experienced a reduction in the composite of CV death, hospitalization for HF, and urgent HF visits. Both findings have heretofore been unattainable with SGLT inhibition, or with any drug as far as HFpEF is concerned. The fact that SOLOIST’s primary efficacy endpoint became statistically significant in just 28 days and the ultimate number needed to treat was an astounding 4 greatly amplified the study’s success.
Fully examining the studies’ data and conducting additional trials will now become the investigators’ task and will likely lead to a novel drug that can help mitigate challenging CV risks.
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Bhatt DL, et al. LBS.07: Randomized trials — brain, kidney and heart. Presented at: American Heart Association Scientific Sessions; Nov. 13-17, 2020 (virtual meeting).
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