ADA 2011: Novel SGLT2 Inhibitor Improves Glycemic Control in Patients with Diabetes

Japanese trial of TS-071 shows promise in weight loss and HbA1c reduction.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a relatively new focus of treatment for type 2 diabetes mellitus (T2DM). They lower blood glucose levels by inhibiting reabsorption of glucose in the proximal renal tubule, thereby increasing urinary glucose secretion.

In a poster at the ADA 71st Annual Meeting in San Diego, results were presented from a phase IIA study of an SGLT2 inhibitor led by investigator Yutaka Seino from Kansai Electric Power Hospital, Osaka, Japan.

TS-071 is a novel, orally bioavailable, and highly selective SGLT2 inhibitor. In a 12-week randomized, double-blind, placebo-controlled parallel group study, 236 Japanese patients with T2DM were assigned to placebo or 0.5, 2.5, or 5 mg TS-071 once daily. The primary endpoint was mean HbA1c change from baseline, with secondary endpoints being fasting plasma glucose (FPG), postprandial plasma glucose (PPG), and body weight change from baseline. Adverse events, vitals, electrocardiogram, and clinical laboratory tests were monitored throughout the study.

Patients were approximately 55-58 years old on average across all four groups, with approximately two-thirds male. At baseline, mean weight in kg was 65.4-69.7 across groups, mean BMI was 24.5-25.5, and mean HbA1c was 7.91-8.17%. Baseline mean FPG was 152.0-159.9 mg/dL, and mean two-hour PPG was 235.3-254.9 mg/dL. There were no significant differences in baseline characteristics between treatment groups.

Results revealed significant and dose-dependent decreases in HbA1c, with -0.43%, -0.70%, and -0.82 % decreases compared to placebo in the 0.5, 2.5, and 5 mg TS-071 groups, respectively.

Significant decreases from baseline were also found in FPG, with -14.6, -25.9, and -27.9 mg/dL versus placebo in the 0.5, 2.5, and 5 mg groups, respectively. PPG decreased significantly by -36.1, -43.0, and -57.3 mg/dL compared to placebo, and significant differences in body weight were also observed, with -1.8 kg in both the 2.5 and 5 mg TS-071 groups compared to placebo. Modest reductions in systolic blood pressure were observed in the 2.5 and 5 mg groups compared to placebo without relevant change in pulse, but these were not statistically significant.

There were no serious adverse events, no hypoglycemia, and no clinically meaningful changes in serum creatinine, cystatin C, or electrolytes. The most common event was nasopharyngitis, which was mild and occurred in 18.3% of participants in the 0.5 mg group and 7.4% in the placebo group. However, this difference was not significant. Six pollakiuria or urine output increases were observed in 2.5 and 5 mg groups, but all were mild in severity.

Soichi Sakai, from Taisho Pharmaceutical Co., Ltd., Tokyo, Japan, and one of the investigators in the study, explained that TS-071’s potency is supported by its favorable pharmacokinetic profile.

In another study conducted by the same investigators, urinary glucose excretion was found to be dose-dependently and significantly affected by TS-071 in healthy male Japanese participants. Participants were randomly assigned to a single ascending dose of 1-25 mg (n=57) or multiple ascending doses of 5 or 10 mg TS-071 (n=24) daily for 7 days. After a single dose of 25 mg, mean UGE up to 24 hours was approximately 70 g. Similar results were observed for the multiple doses. “This compound shows substantial power in a small dose, compared to other SGLT2 inhibitors with doses up to 100 mg,” said Sakai.