A new phase 3 study on novel SGLT inhibitor sotagliflozin shows favorable results in those living with severe renal impairment / chronic kidney disease.
Many sodium-glucose cotransporter 2 (SGLT2) inhibitors are currently on the market for patients living with type 2 diabetes (T2D). While these medications have shown to be useful in obtaining glycemic control along with various cardiovascular and renoprotective benefits, their glucose-lowering effect significantly diminishes in patients who have severe chronic kidney disease (CKD). Previous studies have shown that while SGLT2 inhibitors may maintain some of their positive renal effects with reduced kidney function, their glucose-lowering ability becomes less effective in patients with CKD than in patients with normal renal function. Unlike other SGLT2 inhibitors, sotagliflozin was designed to inhibit both the SGLT2 protein in the kidneys and the SGLT1 protein in the gastrointestinal (GI) tract, further enhancing glucose elimination. This dual SGLT inhibitor should, in theory, maintain glucose-lowering efficacy in patients with declining kidney function.
A phase 3, randomized, multicenter, double-blind, placebo-controlled study by Cherney et al. was conducted to demonstrate the superiority of sotagliflozin 400 mg vs. placebo in reducing glycated hemoglobin (A1c) after 26 weeks of treatment. A similar objective was set for analyzing the effects of sotagliflozin 200 mg. The study was designed to look specifically at patients with inadequately controlled T2D and stage 4 CKD (eGFR ≥15 and < 30 mL/min/1.73m2). There were 277 patients with an average eGFR of 23.6 mL/min/1.73 m2 who were randomized to receive sotagliflozin 200 mg, sotagliflozin 400 mg placebo once daily for 52 weeks. The primary efficacy endpoint was the change in A1c from baseline to week 26. Multiple secondary efficacy endpoints were measured, including change in body weight (kg) and fasting plasma glucose (FPG) from baseline to week 26, among various safety considerations (hypoglycemia). An ANCOVA model was used to analyze datasets.
Results showed that the difference in A1c from baseline in those receiving sotagliflozin 400 mg compared with placebo was -0.29% (p=0.0962), and in those who received sotagliflozin 200 mg, the difference was 0.05% (p=0.8124). However, results at week 52 in patients receiving sotagliflozin 400 mg showed a statistically significant difference of -0.69% (95% CI -0.23, -1.15) in A1c from baseline (p=0.0031). Differences in A1c at week 52 in patients receiving sotagliflozin 200 mg were not statistically significant (p=0.3574). Reductions in body weight were modest with -1.48 kg (p=0.0426) in the sotagliflozin 400 mg group at week 26, although this statistical significance was not maintained at week 52: difference of -0.9 kg (p=0.3930). The only significant change in FPG was -23.3 (p=0.0199) at week 52 for patients in the sotagliflozin 400 mg group. No statistically significant differences in weight or FPG were observed in the sotagliflozin 200 mg group.
Documented symptomatic hypoglycemia (blood glucose ≤70 mg/dL) events were similar among patients in the sotagliflozin 400 mg (27.8%), sotagliflozin 200 mg (28.7%), and placebo (35.5%) groups. Results for severe symptomatic hypoglycemia events (blood glucose ≤54 mg/dL) among patients in the sotagliflozin 400 mg (7.8%), sotagliflozin 200 mg (13.8%), and placebo (16.1%) groups were also similar.
While the study failed to meet statistical significance for A1c reduction at week 26, there was a demonstrated benefit in outcomes at week 52 for the sotagliflozin 400 mg vs. placebo group. Currently, SGLT2 inhibitors are not recommended to be initiated, or contraindicated, for use in patients with various CKD (depending on the specific product), primarily due to a decrease in their glucose-lowering efficacy. Inhibiting the SGLT1 protein in the GI tract may potentially open opportunities for patients who require the CV and renoprotective effects to receive and benefit from this class of medications without sacrificing glycemic control. The authors report that this was the first study investigating the glucose-lowering effects of an SGLT inhibitor in patients with T2D and stage 4 CKD. Further studies are needed to investigate the relationship between therapy duration and the glucose-lowering effect dual SGLT inhibitors have in patients with severe CKD.
- Sotagliflozin inhibits both the SGLT2 protein in the kidneys and the SGLT1 protein in the GI tract to enhance glucose elimination.
- There was no statistically significant difference in A1c from baseline in patients with stage 4 CKD receiving sotagliflozin 400 mg compared to placebo at week 26 (p=0.0962); instead, there was an observed difference at week 52 (p=0.0031).
- Further research is needed to determine the significance of inhibiting SGLT2 in patients with CKD.
Kelly, Michael S et al. “Efficacy and renal outcomes of SGLT2 inhibitors in patients with type 2 diabetes and chronic kidney disease.” Postgraduate medicine, vol. 131,1 31-42.
Cherney, David, et al. “135-LB: Efficacy and Safety of Sotagliflozin (SOTA) in Patients with Type 2 Diabetes (T2D) and Severe Renal Impairment.” Diabetes, vol. 69, no. Supplement 1, 2020
Lawand Kamal, PharmD Candidate 2021, Skaggs School of Pharmacy and Pharmaceutical Sciences