Can Heart Failure Results Create an Alternate Path for Sotagliflozin?

Can sotagliflozin, once seen as a potential blockbuster in both type 1 and type 2 diabetes, get a new lease on life?

The dual inhibitor, which targets the proteins sodium glucose co-transporter 1 (SGLT1) and SGLT2, offered a bright spot during last weekend’s American College of Cardiology Scientific Sessions, which saw a number of trials produce negative or neutral results.

But on Monday, Deepak L. Bhatt, MD, MPH, of Harvard and Brigham and Women’s Hospital followed up on results presented last fall with data that showed the drug developed for patients with diabetes is effective “across the spectrum” of heart failure—including patients with hard-to-treat heart failure with preserved ejection fraction (HFpEF).

It’s still an uphill battle for Lexicon Pharmaceuticals, which stopped funding the research in the wake of regulatory setbacks. At one time, sotagliflozin, which was the be marketed as Zynquista, was projected to be a blockbuster, particularly as an add-on to type 1 diabetes (T1D), where it was seen to improve glycemic control as an add-on to insulin.

But in January 2019, an FDA advisory board split on the issue, and regulators repeatedly turned back Lexicon over concerns about diabetic ketoacidosois (DKA). Patient advocates fumed over these actions, saying that FDA should allow doctors and patients to weigh the benefits and risks, given the paucity of treatments for T1D. Lexicon lost Sanofi as its marketing partner. As recently as March 3, 2021, FDA again rejected Lexicon’s claims.

New Life in Heart Failure

When drug developers were forced to conduct cardiovascular outcomes trials for SGLT2 inhibitors, they found a surprise: the drugs created for T2D had strong benefits for heart failure. And the same has proven true in sotagliflozin. There is a strong relationship between the 2 conditions; patients with diabetes are 2.5 times more likely to develop heart failure than someone without diabetes, and those odds increase among younger adults, according to a study published by Diabetes Care.

Bhatt and his team used pooled data from the SOLOIST-WFH and SCORED trials to produce the findings, which were previously published in the New England Journal of Medicine; the onset of the pandemic was also a factor in hastening the closeout of the trials. But the studies still produced results that showed patients with diabetes and heart failure had reductions of 22% to 43% in the risk of death or worsening heart failure compared with similar patients who were treated with a placebo.

Although the FDA earlier this year approved sacubitril/valsartan, sold as Entresto, to treat HFpEF, it did so despite the lack of a positive trial for this condition. By contrast, Bhatt noted, “This is the first trial to find a significant benefit in this population. We believe that these results merit a recommendation that patients who have both diabetes and HFpEF should be treated with sotagliflozin or another medication in its class.”

Before the FDA’s latest rejection of a T1D indication over DKA concerns, Lexicon had reported positive talks with the agency over the heart failure findings, according to a January press release. The company suggested that despite falling short in diabetes, heart failure could prove a winner: “This regulatory feedback clears a key hurdle for partnership discussions around sotagliflozin in heart failure and enables a potential [new drug application] filing in 2021.”

However, the question is whether Lexicon can pursue the approval—or whether the findings have simply increased speculation about stronger, better financed players such as Boehringer Ingelheim and Eli Lilly’s empagliflozin (Jardiance) or AstraZeneca’s dapagliflozin (Farxiga), a pair of successful SGLT2 inhibitors that are expected to report results on HFpEF trials later this year.

Does the dual mechanism offer something the others don’t? In an interview, Bhatt discussed the advantages of SGLT1 inhibition:

“SGLT1 also has an effect in the kidney, where it does lead to a slight increase in glucose elimination. In that part of the proximal renal tubule where glucose has escaped the SGLT2, SGLT1 is there to do the job SGLT2 was supposed to do. So, SGLT1 inhibition does have some slight incremental effects in the kidney, but perhaps more relevant, there is SGLT1 expressed in the gut, the digestive tract, the intestines, and there SGLT1 inhibition leads to decreases in postprandial glucose.

“That is, if someone, or anybody, eats something, afterwards the blood sugar glucose goes up; if they have diabetes, it can go up a lot. That's believed to be deleterious to health even beyond just having high glucose. That sort of spike in glucose is also believed to be bad for health, and sotagliflozin, via its SGLT1 inhibition, blunts that type of postprandial glucose excursion that would otherwise occur,” Bhatt said.

“That’s believed to be its dual mechanism of action and why it might have something more to offer than an SGLT2 inhibitor,” he said. “Of course, without any head-to-head clinical trials, that's largely speculative.”