Oral GLP-1 Drug Shows Promise for Type 2 Diabetes Without Meal Timing Rules

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A once-daily pill in development for type 2 diabetes has shown promising results in a late-stage clinical trial and may offer a more convenient alternative to other medications in its class.

The drug, orforglipron, is being developed by Eli Lilly and Company and is a member of the GLP-1 receptor agonists class of medications. Unlike most GLP-1 drugs, which are injected, orforglipron is an oral tablet taken daily. An additional feature that distinguishes orforglipron from other oral GLP-1 therapies is its lack of food and water restrictions. Unlike oral semaglutide (Rybelsus), which must be taken on an empty stomach with limited water and a delay before eating, orforglipron can be taken without regard to meals or fluid intake, according to Lilly.

Orforglipron Improved A1C and Weight Loss in Phase 3 Trial

In the ACHIEVE-1 trial, orforglipron demonstrated significant reductions in blood sugar and body weight compared with placebo over 40 weeks.The phase 3 trial enrolled 559 adults with type 2 diabetes who were managing their condition with diet and exercise alone.

Participants were randomly assigned to receive orforglipron at one of three doses (3 mg, 12 mg, or 36 mg) or placebo for 40 weeks. The average starting A1C was 8.0%, and participants had lived with diabetes for an average of 4.4 years.

At the end of the study, those in the orforglipron 3 mg group reduced HbA1c by 1.24 percentage points, those in the 12 mg group had reduced their HbA1c by 1.47 percentage points, and the 36 mg group had reduced their HbA1c by 1.48 percentage points. The placebo group had a reduction of 0.41 percentage points.

All dose groups receiving orforglipron reached mean A1C levels between 6.5% and 6.7% by week 40.

Participants also lost weight during the trial, with the highest-dose group averaging a 7.6% reduction from baseline, compared with 1.7% in the placebo group. The study investigators also pointed to improvements were seen in fasting glucose, triglycerides and non-HDL cholesterol.

Side effects were similar to those seen with other GLP-1 therapies, with mild to moderate gastrointestinal issues being the most common. No episodes of severe hypoglycemia were reported, and discontinuation due to adverse events occurred in 4.4% to 7.8% of patients on orforglipron, compared to 1.4% in the placebo group.

“This convenient once-daily pill with no restrictions on food and water intake could be an option for millions of people with type 2 diabetes who prefer oral medications over injectables,” said Jeff Emmick, M.D., Ph.D.,senior vice president of product development at Eli Lilly and Company, in a press release. "The positive ACHIEVE-1 results position orforglipron as a potential treatment option with meaningful A1C and weight reduction, and a safety profile similar to injectable GLP-1 therapies."

Orforglipron is still investigational and not yet approved by the U.S. Food and Drug Administration (FDA). The results come amid growing interest in GLP-1 drugs for both diabetes and weight management. Injectable medications like tirzepatide (Mounjaro) and semaglutide (Ozempic) have become widely used, but oral alternatives remain limited. Eli Lilly and Company has not provided a specific timeline for submission of orforglipron for FDA review.