BACKGROUND: Orforglipron is a small-molecule, nonpeptide glucagon-like peptide-1 (GLP-1) receptor agonist in clinical development for type 2 diabetes and weight management. Additional data on the efficacy and safety of orforglipron are needed.
METHODS: In this phase 3, double-blind, placebo-controlled trial, we randomly assigned participants in a 1:1:1:1 ratio to receive orforglipron at one of three doses (3 mg, 12 mg, or 36 mg) or placebo once daily for 40 weeks. Participants had type 2 diabetes treated only with diet and exercise, a glycated hemoglobin level of at least 7.0% but no more than 9.5%, and a body-mass index (the weight in kilograms divided by the square of the height in meters) of at least 23.0. The primary end point was the change from baseline to week 40 in the glycated hemoglobin level. A key secondary end point was the percent change in body weight from baseline to week 40.
RESULTS: A total of 559 participants underwent randomization. The mean glycated hemoglobin level at baseline was 8.0%. At week 40, the estimated mean change from baseline in the glycated hemoglobin level was -1.24 percentage points with the 3-mg dose, -1.47 percentage points with the 12-mg dose, -1.48 percentage points with the 36-mg dose, and -0.41 percentage points with placebo. All three doses of orforglipron were superior to placebo with respect to the primary end point; the estimated mean difference from placebo was -0.83 percentage points (95% confidence interval [CI], -1.10 to -0.56) with the 3-mg dose, -1.06 percentage points (95% CI, -1.33 to -0.79) with the 12-mg dose, and -1.07 percentage points (95% CI, -1.33 to -0.81) with the 36-mg dose (P<0.001 for all comparisons). The mean glycated hemoglobin level at week 40 was 6.5 to 6.7% with orforglipron. The percent change in body weight from baseline to week 40 was -4.5% with the 3-mg dose, -5.8% with the 12-mg dose, -7.6% with the 36-mg dose, and -1.7% with placebo. The most common adverse events were mild-to-moderate gastrointestinal events, most of which occurred during dose escalation. No episodes of severe hypoglycemia were reported. Permanent discontinuation of orforglipron or placebo due to adverse events occurred in 4.4 to 7.8% of participants receiving orforglipron and 1.4% of participants receiving placebo.
CONCLUSIONS: In adults with early type 2 diabetes, orforglipron significantly reduced the glycated hemoglobin level over a period of 40 weeks. (Supported by Eli Lilly; ACHIEVE-1 ClinicalTrials.gov number, NCT05971940.).
| Discipline Area | Score |
|---|---|
| Family Medicine (FM)/General Practice (GP) |  |
| General Internal Medicine-Primary Care(US) | |
| Internal Medicine | |
| Endocrine | |
Everyone wanted an oral GLP1 RA and here it is.
An oral GLP 1 that is very effective for weight loss and DM is welcome.
This large, well-conducted phase 3 trial of orforglipron, a novel oral small-molecule GLP-1 receptor agonist, reports clinically meaningful benefits. In 559 adults with early type 2 diabetes inadequately controlled with diet and exercise, orforglipron led to HbA1c reductions up to 1.5%, weight loss up to 7.6% from baseline, and an acceptable gastrointestinal side-effect profile over 40 weeks. Prior trials in obesity similarly showed 9–14% weight loss from baseline and improvements in cardio-metabolic parameters. From an internal medicine perspective, this study is highly clinically relevant, given the global burden of diabetes and obesity and the need for accessible, non-injectable therapies. Longer-term data on durability, cardiovascular outcomes, and safety are needed to guide practice. Orforglipron is not FDA-approved and is not available in Canada outside trials, but it holds promise as a more acceptable alternative for patients reluctant to use injectable GLP-1 receptor agonists.
