A Randomized Placebo-Controlled Trial of HTD1801 Monotherapy in Participants With Type 2 Diabetes.

OBJECTIVE: The safety and efficacy of HTD1801 versus placebo were evaluated in participants with type 2 diabetes inadequately controlled with diet and exercise. RESEARCH DESIGN AND METHODS: Key entry criteria of this phase 3, randomized, placebo-controlled trial included type 2 diabetes (per World Health Organization guidelines), HbA1c 7.0-10.5% (53-91 mmol/mol), fasting plasma glucose ≤13.9 mmol/L, and ≥8 weeks of diet and exercise. Participants were randomized and treated 2:1 to HTD1801 1,000 mg twice daily (BID) (n = 271) or placebo (n = 136). The primary end point was the change from baseline in HbA1c at week 24. After completion of a 24-week, double-blind trial, participants could enter a 28-week open-label extension during which everyone received HTD1801 1,000 mg BID. Safety was assessed for 56 weeks. RESULTS: Baseline HbA1c was 8.5% (69 mmol/mol) in both groups. The primary end point was achieved: HTD1801-treated participants achieved a change in HbA1c of -1.3% versus -0.6% with placebo (least squares mean difference -0.7%; 95% CI -0.8, -0.5; P < 0.0001). After 24 weeks of HTD1801 treatment, significant improvements were observed in key cardiometabolic and inflammatory markers. HbA1c reductions were durable through 52 weeks. The most common adverse events were mild to moderate diarrhea (HTD1801: n = 26 participants [9.6%]; placebo: n = 1 participant [0.7%]); most of which occurred at treatment initiation. Longer-term safety (56 weeks) was consistent with safety findings of the double-blind trial. CONCLUSIONS: HTD1801 treatment produced sustained improvements in glycemic, cardiometabolic, and inflammatory parameters, supporting further evaluation as a well-tolerated oral therapy for patients with type 2 diabetes.