Sotagliflozin Reduces Ischemic Risk in SCORED Analysis

Sotagliflozin (Inpefa; Lexicon Pharmaceuticals), a dual sodium-glucose co-transporter 1/2 inhibitor, appears to reduce both MACE and stroke risk among patients with type 2 diabetes, chronic kidney disease (CKD), and additional cardiovascular risk factors compared with placebo, according to new data from the SCORED trial.

The findings offer the tantalizing possibility that dual agents like this one may go beyond the predominantly heart failure (HF)-related and glucose-lowering effects of the SGLT2 inhibitors to also offer some protection from ischemic events.

The SCORED and SOLOIST-WHF trials, in 2020, found that sotagliflozin reduced HF hospitalizations in diabetic patients with CKD and decompensated HF, respectively, despite both studies running short on funds and being stopped prematurely due to the COVID-19 pandemic. A pooled analysis released a year later hinted at a potential reduction in CV mortality with sotagliflozin, even in patients with heart failure and preserved ejection fraction (HFpEF).

The US Food and Drug Administration eventually approved sotagliflozin in 2023 for the full spectrum of LVEF in patients who have heart failure with or without diabetes. The medication joined the two SGLT2 inhibitors already on the market: empagliflozin (Jardiance; Boehringer Ingelheim/Eli Lilly) and dapagliflozin (Farxiga; AstraZeneca).

Neither of the selective SGLT2 inhibitors have yet been shown to reduce MI and stroke events. Sotagliflozin, however, inhibits SGLT2 as well as gastrointestinal SGLT1; the latter effect, the study authors note, reduced carbohydrate absorption and blunts postprandial hyperglycemia, both of which might exert a different influence over ischemic outcomes. 

“The fact that there is a benefit that is seemingly different from the other SGLT2 inhibitors, to me, indicates that likely it’s the SGLT1 mechanism that’s providing these additional benefits in ischemic endpoints,” Deepak Bhatt, MD (Icahn School of Medicine at Mount Sinai, New York, NY), who coauthored the study, told TCTMD. “That is a distinguishing feature from the heart failure-kidney benefits that are shared by sotagliflozin, but also appear to be present with the other SGLT2 inhibitors.”

As such, if ischemic risk was a particular concern and costs were similar, Bhatt said he would “push” to use sotagliflozin ahead of a selective SGLT2 inhibitor.

The predefined post hoc analysis, with first author Rahul Aggarwal, MD (Brigham and Women’s Hospital, Boston, MA), was published online this month in Lancet: Diabetes & Endocrinology.

Fewer MACE

For the analysis of SCORED, researchers included the 10,584 patients with diabetes, CKD, and additional cardiovascular risk factors (median age 69 years; 44.9% women) enrolled in the main trial who were randomized to receive sotagliflozin (n = 5,292) or placebo (n = 5,292) between December 2017 and January 2020. Notably, 48.6% of the total population had a history of cardiovascular disease, including MI in 19.9%, stroke in 8.9%, and coronary revascularization in 22.4%.

Over a median follow-up period of 14.2 months, risk of the composite endpoint of MACE (cardiovascular death, nonfatal MI, and nonfatal stroke) was significantly lower with the sotagliflozin compared with placebo (4.8 vs 6.3 events per 100 person-years; HR 0.77; 95% CI 0.65-0.91), a finding seen across a range of subgroups.

Moreover, the drug appeared to reduce the risks of both MI (1.8 vs 2.7 events per 100 person-years; HR 0.68; 95% CI 0.52-0.89) and stroke (1.2 vs 1.8 events per 100 person-years; HR 0.66; 95% CI 0.48-0.91) compared with placebo. Rates of cardiovascular death, however, were similar between the study groups (2.2 vs 2.4 events per 100 person-years; HR 0.90; 95% CI 0.73-1.12).

The MACE benefit with sotagliflozin emerged after 94 days, then stayed consistent.

“We were fortunate that the effect, both for heart failure and also ischemic endpoints, occurred very, very early,” Bhatt said. “And therefore, even though the trial didn't continue as long as we would have liked, it was still long enough to see significant benefits. . . . [That], to me, is actually quite remarkable and points to some potent effect that the SGLT1 inhibition is having. Exactly what that mechanism is still needs to be teased out.”

A large, head-to-head trial of all three available SGLT2 inhibitors could help clarify the mechanism at play here, but Bhatt acknowledged the unlikeliness of such a study being funded at this point.

Even so, he continued, there are “potential ways to further explore the drug. I certainly hope once investigators see these data, they'll get excited and there might be some investigator-initiated trials looking at sotagliflozin. But what would really help is some company that had the financial resources to really do large-scale further testing.”

Regardless, the new data further emphasize that “there should be even more widespread use of the class of SGLT inhibitors in patients with diabetes, those with heart failure, and those with chronic kidney disease or any combination of those,” Bhatt concluded.

‘Solid and Robust’

Commenting on the study for TCTMD, Carlos Santos-Gallego, MD, PhD (Icahn School of Medicine at Mount Sinai, New York, NY), said he was pleased to see a significant MACE reduction, calling it “the first time that this is confirmed in a solid and robust way.”

Further, Santos-Gallego called it “remarkable” that the researchers showed a solid early improvement in ischemic risk, with these drugs that are already known to reduce heart failure and kidney events. The mechanism of action remains “the million-dollar question,” he continued, suggesting that fewer hyperglycemia spikes with sotagliflozin due to delayed glucose absorption could play a role, as could potential antiplatelet and anti-inflammatory effects.

In an accompanying editorial, Anna Norhammar, MD, PhD, and Viveca Ritsinger, MD, PhD (both Karolinska Institutet, Stockholm, Sweden), explain that there are likely several potential mechanisms leading to ischemic protection with sotagliflozin. They agree that the drug’s ability to reduce glucose absorption likely plays a role, especially for diabetic patients who tend to have fewer microvascular and macrovascular complications by avoiding hyperglycemic spikes.

Compared with previous trials, the editorialists add, this study might have benefitted from the risk profile of its patient population, with just one-fifth having heart failure criteria at baseline, enhancing the opportunity to study ischemic events.

As the data now stand, Santos-Gallego said he wouldn’t necessarily promote using sotagliflozin over other SGLT2 inhibitors in all patients, though he will consider this alongside other factors.

“I always follow the adage: ‘The best drug is the drug that the patient is able to receive,’” he said, adding that lower cost is usually the deciding factor. Otherwise, “in a patient with heart failure or kidney problems, I can go for sotagliflozin, empagliflozin, or dapagliflozin. . . . Now, if the patient has heart failure plus ischemic risk, then yes, that would make me go for sotagliflozin.”