Eli Lilly’s Oral GLP Beats Oral Wegovy in Head-to-Head Trial

A new head-to-head clinical trial published in The Lancet suggests that an investigational once-daily pill, orforglipron, may offer stronger blood sugar and weight loss benefits than oral semaglutide for adults with Type 2 diabetes who are not adequately controlled on metformin.

The 52-week Phase 3 trial, called ACHIEVE-3, enrolled 1,698 adults across multiple countries. Participants were randomly assigned to receive one of two doses of orforglipron (12 milligrams or 36 milligrams) or one of two doses of oral semaglutide (7 milligrams or 14 milligrams). Both medications are GLP-1 receptor agonists, a class of drugs that help lower blood sugar, reduce appetite and promote weight loss.

Greater A1c Reductions

The main goal of the study was to compare changes in A1c (a measure of average blood sugar) over about three months. Participants started with an average A1c of 8.3%.

After 52 weeks:

• Orforglipron 36 milligrams lowered A1c by 2.2%.
• Oral semaglutide 14 milligrams lowered A1c by 1.4%.

This difference was statistically significant. A higher percentage of people taking orforglipron also reached common treatment goals:

• 85.4% of participants on orforglipron 36 milligrams achieved an A1c below 7%, compared with 66.1% on oral semaglutide 14 milligrams.
• 76.8% reached an A1c of 6.5% or lower on orforglipron 36 milligrams, compared with 50.9% on oral semaglutide 14 milligrams.

Notably, 37.1% of people on the higher dose of orforglipron achieved an A1c below 5.7% (a level considered in the nondiabetes range) compared with 12.5% on oral semaglutide 14 milligrams.

More Weight Loss

Weight loss was a key secondary outcome. Participants started at an average weight of about 213.9 pounds (97 kilograms).

At one year:

• Those taking orforglipron 36 milligrams lost 19.7 pounds (9.2% of body weight).
• Those taking oral semaglutide 14 milligrams lost 11.0 pounds (5.3%).

This represents about 73.6% greater relative weight loss with orforglipron at the higher dose. Even the lower 12-milligram dose of orforglipron produced more weight loss than the 14-milligram dose of oral semaglutide.

Cardiovascular Risk Factors

Beyond blood sugar and weight, orforglipron also showed improvements in several cardiovascular risk markers, including total cholesterol, non-HDL cholesterol, triglycerides and systolic blood pressure. Since heart disease is a major concern for people with Type 2 diabetes, these additional effects may be clinically meaningful.

Safety and Side Effects

The safety profile of orforglipron was similar to other GLP-1 medications. The most common side effects were gastrointestinal and included nausea, diarrhea, vomiting, indigestion and decreased appetite.

Discontinuation rates due to side effects were somewhat higher with orforglipron (8.7% for 12 milligrams and 9.7% for 36 milligrams) compared with oral semaglutide (4.5% for 7 milligrams and 4.9% for 14 milligrams).

As with many GLP-1 medications, doses were gradually increased over several weeks to help improve tolerability.

“The results of ACHIEVE-3 highlight the potential advantages of orforglipron over oral semaglutide for Type 2 diabetes: greater A1c reduction, more weight loss and the ability to take it without food or water timing restrictions — that’s a combination that could matter significantly to people managing their disease day in and day out,” said Kenneth Custer, Ph.D., executive vice president and president of Lilly Cardiometabolic Health.

What Makes Orforglipron Different?

Orforglipron is a small-molecule (nonpeptide) GLP-1 receptor agonist. Unlike current oral semaglutide, it can be taken at any time of day without food or water restrictions. That flexibility may be important for patients who find strict dosing instructions difficult to follow.

The drug is still investigational. Eli Lilly has submitted orforglipron to regulators in more than 40 countries, and U.S. regulatory action for obesity may occur in the second quarter of 2026. A submission for Type 2 diabetes in the U.S. is also planned.

“We’re focused on making this option available as quickly as possible,” Custer noted.

What This Means for Patients

If approved, orforglipron could become another oral option for people with Type 2 diabetes seeking meaningful A1c reductions and weight loss without injections. While more data from additional Phase 3 trials are expected later this year, ACHIEVE-3 provides encouraging evidence that a once-daily pill may deliver results comparable to (and in some measures greater than) existing oral GLP-1 therapy.