Lilly's oral GLP-1 orforglipron cut A1C up to 1.6 points in Phase 3 diabetes trial
A pill form of GLP-1 therapy moved a step closer to regulators with full Phase 3 diabetes data, though it is not approved and has not been compared with other diabetes drugs in this trial.
Eli Lilly's investigational once-daily pill orforglipron lowered A1C by 1.3% to 1.6% across three doses over 40 weeks in adults with type 2 diabetes, according to complete Phase 3 results published June 21 in The New England Journal of Medicine and presented at the American Diabetes Association's 85th Scientific Sessions [1].
ACHIEVE-1 randomized 559 people across the U.S., China, India, Japan and Mexico. Participants had not taken diabetes medication for at least 90 days before the study and had never used insulin. They started with an average A1C of 8.0% and received orforglipron 3 mg, 12 mg, 36 mg, or placebo for 40 weeks [1].
A1C fell by 1.3 points at 3 mg, 1.6 points at 12 mg and 1.5 points at 36 mg, compared with 0.1 points for placebo. Under a second analysis that counts people who stopped treatment or added another diabetes drug, the reductions were 1.2, 1.5 and 1.5 points, versus 0.4 with placebo. Lilly said improvements appeared as early as four weeks [1].
On weight, the 36 mg dose produced an average loss of 16.0 pounds (7.9%) from a starting average of 198.9 pounds. The 12 mg dose produced 12.2 pounds (6.1%) and the 3 mg dose 9.7 pounds (4.7%), compared with 2.9 pounds (1.6%) for placebo. Participants on the highest dose had not appeared to reach a weight plateau by week 40, and Lilly said the longer ATTAIN trials in obesity will assess that more fully [1].
For A1C targets, 72.9%, 76.2% and 74.9% of participants on the three doses reached the ADA goal of below 7%, compared with 28.0% on placebo. Between 61.5% and 66.0% reached 6.5% or lower, versus 13.5% on placebo. Between 17.7% and 25.8% reached a normal A1C below 5.7%, versus 3.8% on placebo, a measure Lilly noted was not controlled for statistical error [1].
The most common side effects were gastrointestinal. Diarrhea was reported by 19%, 21% and 26% of participants on the three doses, versus 9% on placebo; nausea by 13%, 18% and 16%, versus 2%; dyspepsia by 11%, 20% and 15%, versus 7%; constipation by 8%, 17% and 14%, versus 4%; and vomiting by 5%, 7% and 14%, versus 1%. These events were generally mild to moderate and occurred mainly during dose escalation. Treatment discontinuation because of side effects was 6% at 3 mg, 4% at 12 mg and 8% at 36 mg, versus 1% on placebo. Lilly reported that no hepatic safety signal was observed [1].
"The early onset of glycemic improvement, observed as soon as four weeks, reinforces the therapeutic potential of orforglipron as an effective, oral GLP-1 therapy for early type 2 diabetes treatment," said Dr. Julio Rosenstock, the lead trial investigator, in the announcement [1].
Why it matters for patients
Every GLP-1 medicine now used for type 2 diabetes or weight management in the U.S. is given by injection except oral semaglutide. Orforglipron is designed as a once-daily pill that can be taken at any time of day without restrictions on food or water, which Lilly says could suit people who prefer oral medicine over injections [1]. Lilly described it as the first oral small-molecule (non-peptide) GLP-1 to complete a Phase 3 trial [1].
Orforglipron is still investigational and is not approved by the FDA for any use [1]. ACHIEVE-1 tested it against placebo only, so how it compares with existing diabetes medicines is not established by these results. That comparison is the subject of two ongoing trials [1]. Pricing has not been disclosed.
What happens next
Lilly expects topline results later in 2025 from ACHIEVE-2, which compares orforglipron with dapagliflozin, and ACHIEVE-3, which compares it with oral semaglutide, both in adults with type 2 diabetes not controlled on metformin [1].
Results from ATTAIN-1 and ATTAIN-2, which test orforglipron for weight management, are expected in the third quarter of 2025. Lilly says it remains on track to submit the drug for weight management to global regulators by the end of 2025 and for type 2 diabetes in 2026 [1]. The company is also studying orforglipron in obstructive sleep apnea and hypertension in adults with obesity [1].
Sources
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