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Novel SGLT1 and SGLT2 inhibitor sotagliflozin reduced cardiovascular events in particularly high-risk type 2 diabetes patients with worsening heart failure or chronic kidney disease, two trials showed.

Among the 1,222 patients recently hospitalized for worsening heart failure, sotagliflozin reduced the composite of cardiovascular death and hospitalizations and urgent visits for heart failure (first and subsequent events) by a relative 33% compared with placebo (51.0 vs 76.3 events per 100 patient-years, P<0.001).

In the , the rate of that same primary endpoint came out a relative 26% lower (5.6 vs 7.5 events per 100 patient-years, P<0.001) with sotagliflozin versus placebo in its 10,584 patients with type 2 diabetes, an estimated glomerular filtration rate of 25 to 60 mL/min/1.73 m², and risks for cardiovascular disease.

Both trials were reported by Deepak Bhatt, MD, of Brigham and Women's Hospital and Harvard Medical School in Boston, at the virtual American Heart Association meeting and online in the New England Journal of Medicine.

Both trials ended early after the funding dried up, with Bhatt citing the . Also in March, the FDA declined to approve the drug in type 1 diabetes and of the drug with partner Lexicon Pharmaceuticals. Lexicon has said it still hopes for regulatory filing for an .

SCORED had its original co-primary endpoints changed to that above while the data were still blinded to maximize statistical power with the smaller number of events. However, both the original endpoints came out significantly in favor of sotagliflozin as well:

• First occurrence of cardiovascular death, nonfatal MI, or nonfatal stroke (HR 0.84, 95% CI 0.72-0.99)
• First occurrence of cardiovascular death or hospitalization for heart failure (HR 0.77, 95% CI 0.66-0.91)

Overall, "the data are consistent with type of data that we have in terms of the class effect of SGLT2 inhibitors," commented Robert Eckel, MD, of the University of Colorado in Aurora and a past president of the American Heart Association.

AHA session study discussant Jane Wilcox, MD, of Northwestern University in Chicago, agreed.

"Most of these trials, save for VERTIS-CV, when we look at the cardiovascular system, there's a clear signal in reduction of heart failure events as opposed to vascular events or atherosclerotic events," she said at a press conference. "The implications are really clear that sotagliflozin adds to the SGLT2 story among diabetic patients, where the aggregate evidence favors treatment to reduce A1c, preserve renal function, and prevent cardiovascular events."

"With careful patient selection and monitoring, I would say, as a class, SGLT2 inhibitors should be strongly considered in the majority of patients with type 2 diabetes, including ... now with the knowledge from SOLOIST and SCORED, in those admitted with acute decompensated heart failure ... and patients with either reduced or preserved ejection fraction," Bhatt concluded.

Almost 21% of SOLOIST-WHF participants had heart failure with preserved ejection fraction (HFpEF), and the benefit of sotagliflozin appeared consistent across the range of ejection fractions, he said.

Bhatt also pointed to a significant effect on composite endpoints that included stroke in SCORED. "In fact, this is the first time an SGLT2 inhibitor trial showed a reduction in stroke as an endpoint," he said.

However, Eckel cautioned that both of those unique features were somewhat hypothesis generating.

SCORED lacked a significant impact on cardiovascular death as a sole endpoint, which stopped the hierarchical analysis before it could reach the composite endpoints that included stroke.

And, "the HFpEF results are of interest but will require validation," he told 番茄社区. Although a prespecified subgroup, Eckel suggested waiting on trials designed to test the effect of SGLT2 inhibition in HFpEF, including the soon-to-be-completed trial with empagliflozin (Jardiance) and the with dapagliflozin (Farxiga) expected in 2021.

"For the first time we've actually demonstrated prospectively that an SGLT2 inhibitor, with SGLT1 inhibition capability as well, is something that is useful for heart failure with preserved ejection fraction," Bhatt noted. "I will predict based on the results of SOLOIST and combined SOLOIST and SCORED that those trials will also be positive."

Bhatt noted that sotagliflozin does have some uniqueness due to its dual target with SGLT1, which acts on the gut to reduce glucose even when kidney function is severely impaired.

Not surprisingly, there were more gastrointestinal adverse events in terms of diarrhea with sotagliflozin than placebo in both trials, and more volume depletion, genital mycotic infections, and diabetic ketoacidosis with the drug in the SCORED trial but not SOLOIST-WHF.

Diabetic ketoacidosis risk was the safety issue that tripped up sotagliflozin approval in type 1 diabetes.

While commenting at the session on the safety of the strategy used, Bhatt noted that it does have to be done carefully. "One shouldn't be cavalier about instituting any medication, especially in a patient who has just presented with acute decompensated heart failure. We did monitor their GFR," he said.

There was an initial decrement in kidney function, as seen with other SGLT2 inhibitors, which then switches to an improvement after 4 weeks, he added. "For sure when initiating these therapies, as we did in the trial, you need to monitor the GFR but it's really no different than when one initiates an ACE inhibitor or an ARB or switches to sacubitril-valsartan."