Lilly's oral GLP-1 orforglipron yields 27.3 pounds average weight loss in phase 3 trial
Orforglipron is still experimental, but if approved it would add a once-daily pill option taken without food or water restrictions to a market now dominated by injections.
Eli Lilly reported on Aug. 7, 2025 that its investigational once-daily pill orforglipron helped adults with obesity lose an average of 27.3 pounds, or 12.4% of body weight, after 72 weeks in the phase 3 ATTAIN-1 trial [1]. That figure came from the highest dose tested, 36 milligrams, and compared with an average loss of 2.2 pounds (0.9%) among participants taking placebo [1].
The trial enrolled 3,127 adults with obesity, or with overweight plus at least one weight-related medical problem, who did not have diabetes [1]. Participants began at 1 milligram and increased their dose in steps every four weeks to a final dose of 6, 12 or 36 milligrams. Average starting weight was 227.5 pounds (103.2 kilograms), with an average body mass index of 37.0 [1].
Lower doses produced smaller average losses: 17.6 pounds (7.8%) at 6 milligrams and 20.7 pounds (9.3%) at 12 milligrams, versus 2.2 pounds (0.9%) for placebo, under what Lilly calls the efficacy estimand — an estimate of results if everyone had stayed on treatment for the full 72 weeks [1]. A second measure, the treatment-regimen estimand, which counts participants regardless of whether they remained on the drug, showed 25.0 pounds (11.2%) lost at 36 milligrams and 5.3 pounds (2.1%) for placebo [1].
By threshold, 59.6% of people on 36 milligrams lost at least 10% of body weight and 39.6% lost at least 15%, compared with 8.6% and 3.6% on placebo [1]. Lilly said pooled results across doses showed reductions in non-HDL cholesterol, triglycerides and systolic blood pressure, and that the 36-milligram dose lowered high-sensitivity C-reactive protein by 47.7% in a pre-specified exploratory analysis [1].
Side effects were mostly gastrointestinal and generally mild to moderate, and no liver safety signal was observed, Lilly said [1]. Nausea was reported by 28.9%, 35.9% and 33.7% of people on 6, 12 and 36 milligrams respectively, versus 10.4% on placebo. Constipation was reported by 21.7%, 29.8% and 25.4% versus 9.3%; diarrhea by 21.0%, 22.8% and 23.1% versus 9.6%; and vomiting by 13.0%, 21.4% and 24.0% versus 3.5% [1]. Discontinuation because of adverse events was 5.1%, 7.7% and 10.3% across the three doses, versus 2.6% on placebo. Overall discontinuation for any reason was 21.9%, 22.5% and 24.4% for orforglipron, versus 29.9% for placebo [1].
Lilly described the tolerability profile as consistent with injectable GLP-1 therapies, but ATTAIN-1 did not compare orforglipron directly against any injectable GLP-1 medicine, so head-to-head results have not been reported [1].
Why it matters for patients
Orforglipron is not approved. It is an investigational small-molecule oral GLP-1 that Lilly says can be taken once a day at any time, without restrictions on food or water intake [1]. That is a practical difference for people who would rather take a pill than an injection, though whether regulators will clear it, and for which patients, is not yet known.
The main trade-off visible in the data is tolerability. Gastrointestinal side effects were the most common complaints, and the share of participants who stopped treatment because of side effects rose with dose, from 5.1% at 6 milligrams to 10.3% at 36 milligrams, against 2.6% on placebo [1]. More than one in five participants in every orforglipron group discontinued for any reason, though that was still below the placebo group's 29.9% [1].
The results reported are averages for each dose group. How widely individual outcomes varied, and how orforglipron compares with injected options, has not been reported [1].
What happens next
Lilly said it plans to submit orforglipron to global regulatory agencies by the end of 2025 and is investing to meet anticipated demand at launch [1]. Detailed ATTAIN-1 results are scheduled for presentation next month at the European Association for the Study of Diabetes annual meeting and for publication in a peer-reviewed journal [1]. More ATTAIN results, and findings from the ACHIEVE program in adults with type 2 diabetes, are expected later in 2025 [1]. The ATTAIN program has enrolled more than 4,500 people across two global registration trials [1]. An approval date, a launch date and a price have not been disclosed.
Sources
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