Introduction
Orforglipron is Eli Lilly’s GLP-1 pill that, in Phase III, reduced weight and blood sugar more than placebo.
The obesity drug race is shifting toward oral therapies: orforglipron, a once-daily GLP-1 pill from Eli Lilly, met endpoints in the Phase III ATTAIN-2 study, showing superior weight loss and glycemic control versus placebo. With two positive Phase III trials, the company plans to file for regulatory approvals, with a U.S. FDA decision expected next year. The pill format promises convenience over weekly injections and could ease manufacturing constraints that have strained supply for injectable GLP-1s.
- Format: once-daily oral GLP-1 therapy
- Outcomes: greater weight loss and glycemic reduction than placebo
- Timeline: filings imminent, FDA decision expected next year
Orforglipron: study context and status
ATTAIN-2 enrolled 1,600+ people across 10 countries with overweight/obesity and type 2 diabetes over 72 weeks.
In ATTAIN-2, participants were randomized to placebo or three doses of orforglipron, titrated to a maximum once-daily dose. Over 72 weeks, all doses outperformed placebo on weight and blood sugar. These results follow ATTAIN-1 in people with overweight/obesity without type 2 diabetes, a group that generally sees greater weight loss with GLP-1 therapy than those with diabetes. Armed with two Phase III wins, Eli Lilly is moving toward global submissions, with an FDA decision anticipated next year.
Key results and safety
Core finding: more weight loss than placebo at every dose, with superior glycemic improvements.
In ATTAIN-2, treatment groups consistently lost more weight than placebo. At the highest dose, average loss was about 10% of baseline body weight, versus 2.5% with placebo. Secondary endpoints also favored the drug, including a higher share achieving at least 15% weight loss (roughly one third at the top dose). Tolerability looked comparable to existing GLP-1s: common adverse events were diarrhea, vomiting, and constipation, more frequent at the highest dose. About 10% discontinued at the top dose due to adverse events, versus 5% on placebo.
"With these positive data in hand, we are moving with urgency toward global regulatory submissions to potentially meet the needs of patients who are waiting."
Kenneth Custer, Executive Vice President and President, Lilly Cardiometabolic Health
Comparisons and limitations
Orforglipron is promising but may not surpass the latest GLP-1 competitors.
Its best showing so far (ATTAIN-1) delivered a 12.4% average weight loss, below the roughly 14% seen in similar trials of injectable Wegovy (semaglutide) and under typical results with tirzepatide, a dual GLP-1/GIP drug from Eli Lilly. Novo Nordisk’s higher-dose oral semaglutide pill for obesity may arrive by late 2025, potentially absorbing demand. Not everyone will be an ideal candidate: some participants discontinued due to side effects, and preferences between a daily pill and a weekly injection vary.
Practical implications
A daily GLP-1 pill could boost convenience and availability.
Many users may prefer a once-daily tablet over weekly subcutaneous injections, even if slightly less effective. Oral manufacturing could be simpler than injectables, helping prevent or limit shortages that have affected semaglutide and tirzepatide. Some people who were unresponsive to existing options may also benefit from trying this therapy. Overall, expect intensifying competition across obesity treatments, with ongoing trade-offs among efficacy, safety, cost, and access.
Conclusion
Orforglipron is progressing toward approval with strong weight and glycemic outcomes amid stiff competition.
Barring unforeseen issues, Eli Lilly’s oral GLP-1 could be the next major approval for weight management. It won’t be the last: with more pills and injectables coming, the race for the best obesity drug will keep heating up, expanding choice and access for patients.
FAQ
- What is orforglipron in the context of obesity drugs?
An oral GLP-1 therapy from Eli Lilly with positive Phase III data on weight and glycemic control.
- How much weight loss did orforglipron show in ATTAIN?
About 10% average loss at the highest dose in ATTAIN-2; ATTAIN-1 reported a 12.4% average.
- Is orforglipron more effective than Wegovy or tirzepatide?
Data show average losses below Wegovy (~14%) and under typical tirzepatide results.
- What side effects are common with orforglipron?
Diarrhea, vomiting, and constipation; about 10% discontinued at the top dose vs 5% placebo.
- When could orforglipron receive FDA approval?
The company expects a decision next year after global regulatory submissions.
- Can an oral GLP-1 reduce shortages seen with injectables?
Oral formulations may be easier to mass-produce, potentially limiting widespread shortages.