An FDA panel has recommended against the approval of sotagliflozin, a dual SGLT1/SGLT2 inhibitor, as an adjunct to insulin for patients with type 1 diabetes (T1D) and mild-to-moderate chronic kidney disease (CKD). The Endocrinologic and Metabolic Drugs Advisory Committee voted 11-3 against the drug, citing that the benefits did not outweigh the risks, primarily due to concerns over data uncertainty.
The committee's decision was heavily influenced by the fact that Lexicon Pharmaceuticals' application relied on post-hoc data from three phase III studies (inTandem1, inTandem2, and inTandem3). These trials formed the basis for the original application, which was previously rejected by the FDA five years prior for the broader T1D population due to DKA risks.
Concerns Over Data and DKA Risk
Panel members expressed reservations about the clinical benefit demonstrated in the provided datasets. "We don't have in our datasets of the trials any direct information about the clinical benefit to the patient," said Dr. Marvin Konstam of Tufts University School of Medicine in Boston. He added, "It's very frustrating because there's no easy way to go from glycemic control and jump all the way to mortality benefit."
The post hoc analysis of the InTandem trials indicated that sotagliflozin, at 200 mg and 400 mg daily doses, helped lower HbA1c compared to insulin alone in patients with an eGFR ≥ 60 mL. Specifically, the least squares mean change in HbA1c was -0.39 (95% CI -0.50 to -0.30) and -0.46 (95% CI -0.56 to -0.36) for eGFR 60 to <90 with the two doses, respectively. However, this improvement in glycemic control was accompanied by an increased risk of DKA, with a number needed to harm of 26 (95% CI 20-39) in the overall T1D population.
FDA staff noted that in the CKD subset, seven incident cases of DKA occurred, with no significant treatment difference favoring sotagliflozin for each eGFR subgroup in the pooled inTandem1/inTandem2 data. Among patients with an eGFR of 45 to <60 mL, three DKA events occurred in the sotagliflozin group (n=47) versus none in the placebo group (n=42), which FDA reviewers found "not reassuring."
Unmet Need vs. Patient Safety
While acknowledging the "unmet need" for adjunctive treatments in T1D, particularly for those with CKD, panel members prioritized patient safety. Dr. Connie Newman of the New York University School of Medicine stated, "What I'm struggling with is how to balance that against the real risk of DKA... Whether it has been properly characterized in the different eGFR groups is still uncertain. If we had more data we would know if there is any difference -- but I don't think we see that with the data available."
Currently, dapagliflozin (Farxiga) and empagliflozin (Jardiance) are approved for CKD in adults at risk of progression, which includes some T1D patients with CKD. However, treatment guidelines do not recommend these SGLT2 inhibitors for glycemic control in T1D due to the potential risk of DKA.
Despite the negative vote, some panel members suggested a potential positive benefit/risk profile in patients with an eGFR ≥ 60 mL, contingent upon strict risk mitigation strategies. The FDA is not bound by the advisory committee's recommendation but typically follows its advice.
