Lexicon's Sotagliflozin Meets Mark in T2D With Moderate Renal Impairment, but Misses on Sicker Patients

Sotagliflozin, which acts on both the sodium glucose co-transporter 1 and 2 proteins (SGLT1 and SGLT2), produced mixed results at last week’s 80th American Diabetes Association Scientific Sessions—hitting the mark with one group of type 2 (T2D) patients but missing its end point on a group with more severe kidney disease.

Separate abstracts presented at ADA highlighted results from 2 groups of patients: those with severe renal impairment—stage 4 chronic kidney disease, or CKD—and those with moderate impairment, or stage 3 CKD.

Both studies evaluated how well the dual inhibitor reduced glycated hemoglobin (A1C) while measuring instances of hypoglycemia and other safety measures. Cardiovascular and renal outcomes are being measured separately and will be reported later.

Researchers presented the pair of late-breaking abstracts on Lexicon’s sotagliflozin, marketed in Europe as Zynquista, more than a year after FDA rejected its bid as an add-on therapy in type 1 diabetes (T1D), and after partner Sanofi paid $260 million to sever the relationship.

The more ubiquitous SGLT2 inhibitors target the SGLT2 protein in the kidney, while the dual inhibitor also targets the SGLT1 protein in gastrointestinal tract to expel glucose; the theory is that the dual inhibitor should allow the drug to give patients glycemic control even when they are experiencing renal decline.

Stage 3 CKD Results.¹ In a phase 3, 52-week double-blind randomized clinical trial involving 787 patients with stage 3 CKD (eGFR ≥30-60 mL/min/1.73m²) sotagliflozin was tested for superiority compared with placebo in reducing A1C after 26 weeks. The 400 mg dose met the primary end point, significantly reducing A1C; the difference in least square (LS) mean change in baseline compared with placebo was —0.24% (P = 0.0021). The change in A1C from baseline did not meet statistical significance for those taking the 200 mg dose (P = 0.2085).

Researchers reported that the safety profile of the study drug was similar to placebo. Episodes of symptomatic hypoglycemia (with blood glucose ≤70 mg/dL) were 20.4% for sotagliflozin 400 mg and 27.3% on sotagliflozin 200 mg, compared with 25% on placebo. Rates of symptomatic hypoglycemia per 100 patient years of exposure were 114.0 on sotagliflozin 400 mg, 140.5 on sotagliflozin 200 mg and 175.4 on placebo.

Reductions in the urinary albumin-to-creatinine ratio (UACR) were —38% (P < .001) with sotagliflozin 400 mg and —31% (P = .001) with sotagliflozin 200 mg. An expected drop in eGFR occurred when the study drug was initiated, which then returned toward baseline. At week 52, rates of adverse events, including mycotic infections and volume depletion, were low, and rates of severe hypoglycemia (≤54 mg/dL) for sotagliflozin were half that of placebo (5.4% vs 10.8%).

Stage 4 CKD Results.² A similar phase 3 study failed to meet its primary end point of demonstrating superiority of sotagliflozin at either the 400 mg or 200 mg dose in reducing A1C at 26 weeks, but did find meaningful glycemic control at 52 weeks among patients with stage 4 CKD (mean eGFR, 23.6 mL/min/1.73 m²).

Researchers reported that the placebo-adjusted difference in A1C from baseline for those treated with sotagliflozin 400 mg compared with placebo was —0.29% (P = .0962); for the 200 mg dose, the difference was 0.05% (P = .8124).

However, findings at week 52 were more favorable to sotagliflozin. The reduction for 400 mg dose was —0.69% (95% CI: –0.23, –1.15), and at this point, 20.7% of the patients achieved at A1C of ≤ 7%, compared with 6.5% on placebo.Over this same period, use of rescue therapy for hyperglycemia was 7.6% on sotagliflozin 400 mg and 15.1% on placebo.

A dose-related response was seen, as results for the 200 mg group at 52 weeks showed a placebo-adjusted A1C reduction of —0.32%; 19.6% of patients at this dose achieved A1C ≤ 7%, and 10.9% needed rescue therapy.

As with the Stage 3 CKD patients, the safety profile of sotagliflozin was generally similar to that of placebo. Of note, this group faced higher cardiovascular risk, and the rates of major adverse cardiovascular events (myocardial infarction, stroke, and cardiovascular death) were 4.4% on sotagliflozin 400 mg, 1.1% on sotagliflozin 200 mg, and 11.9% on placebo.

Symptomatic hypoglycemia (blood glucose ≤70 mg/dL) occurred with 27.8% of patients on sotagliflozin 400 mg, 28.7% on sotagliflozin 200 mg and 35.5% on placebo. Rates per 100 patient years of exposure were 171.6 on sotagliflozin 400 mg, 226.9 on sotagliflozin 200 mg, and 269.8 on placebo.

References

1. Cherney D, Ferrannini E, Guillermo E, et al. Efficacy and safety of sotagliflozin (SOTA) in patients with type 2 Diabetes (T2D) and moderate renal impairment. Presented at the 80^th Ameircan Diabetes Association Scientific Sessions, June 12-16, 2020. Abstract 136-LB.
2. Cherney D, Ferrannini E, Guillermo E, et al. Efficacy and safety of sotagliflozin (SOTA) in patients with type 2 Diabetes (T2D) and severe renal impairment. Presented at the 80^th Ameircan Diabetes Association Scientific Sessions, June 12-16, 2020. Abstract 135-LB.