Orforglipron and Titrated Insulin Glargine in Type 2 Diabetes

Key Takeaways

• Greater HbA1c reductions were observed with each orforglipron dose than with placebo by week 40.
• Weight loss and smaller insulin dose increases were observed with orforglipron than with placebo by week 40.
• Clinically significant hypoglycemia was not increased, while gastrointestinal adverse events were most common and usually mild to moderate.

Added to titrated insulin glargine, oral orforglipron lowered HbA1c by 0.78 to 1.08 percentage points more than placebo by week 40 in adults with inadequately controlled type 2 diabetes. The ACHIEVE-5 JAMA randomized clinical trial tested three once-daily doses against placebo during basal insulin titration.

ACHIEVE-5 was a 40-week, phase 3, multicenter, randomized, parallel-group, double-blind, placebo-controlled trial at 72 sites in the US, Brazil, China, Japan, and Romania. A total of 546 adults were assigned to 3 mg, 12 mg, 36 mg, or placebo, all added to titrated insulin glargine. Group sizes were 137, 132, 136, and 141; after a 4-week stabilization period, insulin was self-adjusted weekly toward fasting glucose below 100 mg/dL. Baseline HbA1c ranged from 7.0% to 10.5%; mean age was 61.0 years, mean HbA1c 8.50%, mean BMI 30.8, and median diabetes duration 14.6 years. After a 4-week lead-in, orforglipron started at 1 mg and escalated every 4 weeks, with the main assessment at week 40.

At week 40, HbA1c changed by -1.58%, -1.88%, -1.82%, and -0.79% with 3 mg, 12 mg, 36 mg, and placebo, respectively. The treatment differences versus placebo were -0.78, -1.08, and -1.03 percentage points. HbA1c fell below 7.0% in 57.1%, 70.5%, 65.4%, and 24.7%, and reached 6.5% or lower in 42.8%, 59.7%, 54.9%, and 11.7%. Body weight changed by -2.6%, -4.8%, -5.4%, and 0.2%, corresponding to -2.3 kg, -4.3 kg, -4.6 kg, and -0.04 kg. Weight-loss thresholds were reached more often with orforglipron, and all key secondary outcomes favored active treatment.

Mean daily insulin dose rose by 8.6, 11.5, 9.2, and 21.0 IU, with week 40 doses of 0.54, 0.58, 0.58, and 0.67 IU/kg. Clinically significant hypoglycemia in the orforglipron groups remained below 1 event per patient-year and was generally similar to or lower than placebo, while severe episodes occurred in two 12-mg participants and one 36-mg participant. Gastrointestinal events were most common, were mostly mild to moderate, and occurred mainly during dose escalation; discontinuations due to adverse events were 3.6% to 9.6% with orforglipron versus 3.6% with placebo. There were no adjudicated confirmed cases of pancreatitis or any reported cases of medullary thyroid cancer. Serious adverse events ranged from 5.1% to 7.4% across orforglipron groups and were 4.3% with placebo.