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Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity
Sean Wharton1, Thomas Blevins1, Lisa Connery1
1From McMaster University, York University, and Wharton Weight Management Clinic - all in Toronto (S.W.); Texas Diabetes and Endocrinology, Austin (T.B.), and Velocity Clinical Research at Medical City, Dallas (J.R.) - both in Texas; Alliance for Multispecialty Research, Norman, OK (L.C.); and Eli Lilly, Indianapolis (S.R., R.L., X.M., K.J.M., A.H., D.R., E.P., C.K., M.K.).
Background:
Obesity is a major risk factor for many leading causes of illness and death worldwide. Data are needed regarding the efficacy and safety of the nonpeptide glucagon-like peptide-1 (GLP-1) receptor agonist orforglipron as a once-daily oral therapy for weight reduction in adults with obesity.
Methods:
In this phase 2, randomized, double-blind trial, we enrolled adults with obesity, or with overweight plus at least one weight-related coexisting condition, and without diabetes. Participants were randomly assigned to receive orforglipron at one of four doses (12, 24, 36, or 45 mg) or placebo once daily for 36 weeks. The percentage change from baseline in body weight was assessed at week 26 (primary end point) and at week 36 (secondary end point).
Results:
A total of 272 participants underwent randomization. At baseline, the mean body weight was 108.7 kg, and the mean body-mass index (the weight in kilograms divided by the square of the height in meters) was 37.9. At week 26, the mean change from baseline in body weight ranged from -8.6% to -12.6% across the orforglipron dose cohorts and was -2.0% in the placebo group. At week 36, the mean change ranged from -9.4% to -14.7% with orforglipron and was -2.3% with placebo. A weight reduction of at least 10% by week 36 occurred in 46 to 75% of the participants who received orforglipron, as compared with 9% who received placebo. The use of orforglipron led to improvement in all prespecified weight-related and cardiometabolic measures. The most common adverse events reported with orforglipron were gastrointestinal events, which were mild to moderate, occurred primarily during dose escalation, and led to discontinuation of orforglipron in 10 to 17% of participants across dose cohorts. The safety profile of orforglipron was consistent with that of the GLP-1 receptor agonist class.
Conclusions:
Daily oral orforglipron, a nonpeptide GLP-1 receptor agonist, was associated with weight reduction. Adverse events reported with orforglipron were similar to those with injectable GLP-1 receptor agonists. (Funded by Eli Lilly; GZGI ClinicalTrials.gov number, NCT05051579.).
Insights
Oral orforglipron, a nonpeptide GLP-1 receptor agonist, significantly reduced weight in adults with obesity. Gastrointestinal events were the most common side effects, similar to injectable GLP-1 agonists.
Area of Science:
- Pharmacology
- Endocrinology
- Obesity Research
Background:
- Obesity is a significant global health concern, increasing the risk of numerous diseases.
- Glucagon-like peptide-1 (GLP-1) receptor agonists are established treatments for weight management.
- There is a need for effective oral GLP-1 receptor agonist therapies for obesity.
Purpose of the Study:
- To evaluate the efficacy and safety of orforglipron, an oral nonpeptide GLP-1 receptor agonist, for weight reduction in adults with obesity.
- To determine the optimal dosage of orforglipron for weight loss.
- To assess the impact of orforglipron on weight-related and cardiometabolic parameters.
Main Methods:
- A phase 2, randomized, double-blind trial involving 272 adults with obesity or overweight with comorbidities (excluding diabetes).
- Participants received daily oral doses of orforglipron (12, 24, 36, or 45 mg) or placebo for 36 weeks.
- Primary endpoint was percentage change in body weight at week 26; secondary endpoint was at week 36.
Main Results:
- Orforglipron treatment resulted in mean weight reduction ranging from -8.6% to -14.7% at weeks 26 and 36, compared to -2.0% to -2.3% with placebo.
- Weight loss of at least 10% was achieved by 46-75% of participants on orforglipron versus 9% on placebo.
- Improvements were observed in weight-related and cardiometabolic measures; common adverse events were mild-to-moderate gastrointestinal issues.
Conclusions:
- Daily oral orforglipron demonstrated significant weight reduction in adults with obesity.
- The safety profile of orforglipron was comparable to injectable GLP-1 receptor agonists, with gastrointestinal events being the most frequent adverse events.
- Orforglipron represents a promising new oral therapeutic option for obesity management.
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