Orforglipron Lowers A1c, Weight in Early Type 2 Diabetes

CHICAGO — The investigational non-peptide small-molecule oral GLP-1 agonist orforglipron significantly reduced A1c over 40 weeks in adults with early type 2 diabetes, according to the results of ACHIEVE-1 sponsored by Eli Lilly.
In the trial, orforglipron reduced A1c to the 6.5% range and produced clinically meaningful weight loss with a safety profile similar to that of other GLP-1 drugs. ACHIEVE-1 is the first of seven phase 3 studies of the safety and efficacy of the drug in over 6000 patients with type 2 diabetes and obesity,
Orforglipron and other similar non-peptide small molecules "have the potential to be widely accepted as a much earlier therapy for type 2 diabetes," Julio Rosenstock, MD, senior scientific advisor for Velocity Clinical Research and clinical professor of medicine at the University of Texas Southwestern Medical Center, Dallas, said at a press briefing here at the American Diabetes Association (ADA) 85th Scientific Sessions. The findings were simultaneously published in the New England Journal of Medicine .
Orforglipron is a once-daily non-peptide small molecule that can be taken any time of day without restrictions on meals or water intake. This contrasts with the currently approved oral GLP-1 receptor agonist semaglutide (Rybelsus, Novo Nordisk), a peptide that ideally should be taken while fasting and with no food or water for at least 30 minutes after ingestion to prevent degradation.
Lilly is the farthest along in the development of a small-molecule non-peptide GLP-1 agonist, but at least two others are in phase 3 trials, including CX11 (also known as VCT220) from Corxel Pharmaceuticals and HRS-7535 from Jiangsu Hengrui Pharmaceuticals and Kailera Therapeutics. Several more are in phase 2 trials.
As a class, the oral non-peptide small-molecule GLP-1 receptor agonists "have the potential to open the access for more people because they're easier to take, they're simpler to produce, and in theory, they should be less expensive. So you can see the potential for these drugs," Rosenstock said.
However, Amy E. Rothberg, MD, clinical professor of internal medicine and of nutritional sciences at the University of Michigan, Ann Arbor, told Medscape Medical News that she's concerned because, unlike injectable GLP-1 receptor agonists, "most oral medications are metabolized by the liver. The enzymes that metabolize them may be affected by people's weight. Therefore, if you have obesity, the distribution and the kinetics of the drug may be different than someone who is normal weight. Also, if someone loses weight from having a higher BMI to a lower weight, that may affect the drug distribution and the drug bioavailability."
She believes that "the companies need to look at drug exposure before and after weight loss because efficacy and safety could be affected by weight change."
First Phase 3 Orforglipron Data Meets Endpoints
In ACHEIVE-1, 559 participants with early (duration range, 4.0-5.1 years) type 2 diabetes with A1c levels of 7.0%-9.5% (mean 8.0%) using only diet and exercise and a BMI 23.0 kg/m2 or greater, were randomized equally to receive orforglipron 3 mg, 12 mg, or 36 mg, or placebo once daily for 40 weeks.
The primary endpoint, percentage-point change in A1c from baseline to week 40, showed reductions of 1.24, 1.47, 1.48 for the 3-mg, 12-mg, and 36-mg doses, respectively, compared with a 0.41 percentage-point reduction with placebo. All three orforglipron doses produced significant A1c reductions compared with placebo ( P < .001 for all comparisons). At week 40, the mean A1c level ranged from 6.5% to 6.7% with orforglipron, Rosenstock reported.
Percentage of body weight losses from baseline to week 40 were 4.5%, 5.8%, and 7.6% for the 3-mg, 12-mg, and 36-mg doses, respectively, versus 1.7% with placebo.
The most common adverse events were mild-to-moderate gastrointestinal events, most of which occurred during dose escalation. Gastrointestinal events leading to drug discontinuation occurred in 2.8%, 2.2%, and 5.7% of patients, respectively, for the three orforglipron doses, versus none with placebo.
This was similar to what has been observed with other oral and injected GLP-1 agonists, Rosenstock said. "We did not see any surprises. You're going to see the same ranges of nausea and vomiting as with semaglutide and tirzepatide."
There were no episodes of severe hypoglycemia. The overall proportions discontinuing permanently due to adverse events ranged from 4% to 8% with orforglipron versus 1% with placebo.
"A Remarkable Scientific Achievement"
Asked to comment, Simeon Taylor, MD, PhD, professor of medicine and director of the Institutional Research Training Program in Diabetes & Obesity at the University of Maryland School of Medicine, Baltimore, told Medscape Medical News : "This landmark scientific achievement ushers in a new chapter in the development of GLP-1 agonists."
Taylor pointed out that "orforglipron's glycemic efficacy is only slightly less than monotherapy with Ozempic" and that it "has somewhat more placebo-subtracted weight loss efficacy in people with type 2 diabetes" than Ozempic.
Overall, he said, "It is a remarkable scientific achievement to have developed a first-in-class orally bioavailable organic chemical entity with efficacy comparable to a third-generation injectable peptide drug. It is likely that many people with type 2 diabetes will be attracted to the option of an orally bioavailable drug."
The other four ACHIEVE trials, to be reported later in 2025, will examine orforglipron in combination with metformin versus dapagliflozin (ACHIEVE-2), in combination with metformin compared to oral semaglutide (ACHIEVE-3), combined with multiple therapies versus insulin glargine (ACHIEVE-4), and in combination with insulin versus placebo (ACHIEVE-5).
Another Lilly phase 3 trial, ATTAIN, is evaluating orforglipron for weight management. Results from ATTAIN-1 and ATTAIN-2 will also be presented later in 2025.
"Lilly remains on track to submit orforglipron for weight management to global regulatory agencies by the end of this year and for the treatment of type 2 diabetes in 2026," according to a company statement.
Rosenstock has reported receiving research/grant support from, serving on advisory boards for, and/or receiving consulting fees/honoraria from Applied Therapeutics, AstraZeneca, Biomea Fusion, Boehringer Ingelheim, Corcept, Eli Lilly, Hanmi, Merck, Novartis, Novo Nordisk, Oramed, Pfizer, Regeneron, Regor, Roche, Sanofi, Structure Therapeutics, and Terns. Taylor has reported receiving payments from the National Institute of Diabetes and Digestive and Kidney Diseases for an inventor's share of a patent covering metreleptin as a treatment for generalized lipodystrophy. He was employed by Eli Lilly in 2000-2002 and Bristol Myers Squibb in 2002-2013.

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