Orforglipron, a novel oral nonpeptide GLP-1 receptor agonist (RA), led to a greater reduction in A1c and more significant weight loss compared to oral semaglutide in patients with type 2 diabetes (T2D) inadequately controlled by metformin, a phase 3 randomized controlled trial showed.
“The primary objective of non-inferiority was met, and both orforglipron doses showed superiority to both semaglutide doses,” lead author Julio Rosenstock, MD, director, Dallas Diabetes Research Center at Medical City and clinical professor of medicine, University of Texas Southwestern Medical Center, Dallas, and colleagues reported in the study, which was published online in The Lancet.
“ACHIEVE-3 is the first study to directly compare the efficacy and safety of two oral GLP-1 receptor agonists in a randomized controlled trial,” they noted.
As previously reported by Medscape Medical News, a prior phase 3 study (ACHIEVE-1) of people with early T2D inadequately controlled with diet and exercise found that at 40 weeks, orforglipron monotherapy reduced A1c from baseline compared to placebo.
Oral Formulations
Most GLP-1 RAs are peptide-based, with a large molecular weight that necessitates administration via subcutaneous injection to allow absorption, avoid proteolytic degradation in the gastrointestinal tract, and minimize the effect of first-pass metabolism, the authors explained. However, some patients are reluctant to use injectable agents, which can “delay timely treatment initiation and intensification.”
Oral semaglutide, a peptide-based GLP-1 RA and the only currently available oral formulation, is co-formulated with an absorption enhancer, leading to low bioavailability; it must be administered under fasting conditions to achieve therapeutic concentrations.
Orforglipron, on the other hand, is a nonpeptide (small molecule) partial GLP-1 RA with pharmacokinetic characteristics that allow for once-daily administration without dietary restrictions.
The current 52-week ACHIEVE-3 trial was a head-to-head comparison of the efficacy and safety of the two oral GLP-1 agents.
The researchers compared orforglipron to semaglutide in 1698 patients with T2D inadequately controlled by metformin. The mean age of participants was 53.9 years, mean BMI was 35.1, and mean A1c was 8.3%.
Participants were randomly assigned to receive orforglipron 12 mg or 36 mg (n = 424 and 423, respectively) or semaglutide 7 mg or 14 mg (n = 426 and 425, respectively). The primary objective was to assess the noninferiority of orforglipron by comparing the two higher-dose regimens to each other and the two lower-dose regimens to each other.
New Therapeutic Option?
The researchers found that both doses of orforglipron outperformed both doses of semaglutide, with mean A1c changes from baseline in orforglipron 12 mg vs semaglutide 7 mg of -1.71% vs -1.23%, respectively. There was also a larger magnitude of change with orforglipron 36 mg vs semaglutide 14 mg (-1.91% vs -1.47%, respectively).
Estimated treatment differences were -0.48% (95% CI, -0.65 to -0.31) for the comparison of the two lower-dose regimens and -0.44% (95% CI, -0.62 to -0.26) for orforglipron for the two higher-dose regimens (P < .0001 for all).
Participants in both orforglipron groups showed significant weight reductions from baseline, beginning with week 4 and continuing to week 52. Orforglipron treatment was superior to semaglutide for weight loss, with estimated treatment differences of -2·3% (-3.2 to -1.3) for orforglipron 12 mg vs semaglutide 7 mg; -4.3% (-5.3 to -3.3) for orforglipron 36 mg vs semaglutide 7 mg; and -2.8% (-3.9 to -1.9) for orforglipron 36 mg vs semaglutide 14 mg (P < .0001 for all).
The most frequent adverse events were gastrointestinal, affecting 59% and 58% of participants receiving 12-mg and 36-mg orforglipron, respectively, vs 37% and 45% of those receiving 7-mg and 14-mg semaglutide, respectively. Most events were “mild to moderate in severity,” but 9%-10% of participants in the orforglipron groups discontinued study treatment due to adverse events, compared to 4%-5% in the semaglutide groups.
Limitations noted by the authors include the open-label design and the possibility that self-reported gastrointestinal adverse events represent a “potential source of bias.”
Nevertheless, they concluded, orforglipron represents a “potential new therapeutic option” for individuals with T2D considering initiation of GLP-1 RA therapy who might “prefer an alternative to the subcutaneous route of administration.”
Efficacy vs Tolerability
Commenting for Medscape Medical News, Michael Nauck, MD, head of clinical research, Diabetes Division, Medical Department I, Josef-Hospital, Ruhr University Bochum, Germany, called the study “important” because it allows comparison of “competing GLP-1 RAs designed for oral administration, with respect to efficacy and tolerability.”
Nauck, coauthor of an accompanying editorial, believes the differences between orforglipron and semaglutide — that is, better efficacy but greater risk for gastrointestinal adverse events — “suggest differential use for those needing substantial improvements in glycemic control, vs giving priority to good tolerability.”
Also commenting for Medscape Medical News, Daniel Drucker, MD, senior investigator at the Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada, said, “There’s growing interest in orforglipron, an investigational medicine for T2D and obesity, that may become the first small molecule approved in the class of GLP-1 medicines.”
Drucker, a professor in the Department of Medicine’s Division of Endocrinology, the Banting and Best Diabetes Centre-Novo Nordisk Chair in Incretin Biology, University of Toronto, said he looks forward to the “totality of phase 3 data from the ACHIEVE and ATTAIN programs studying orforglipron. Hopefully, this will become a new affordable and convenient option for people living with T2D and/or obesity.”
The study was funded by Eli Lilly. Rosenstock has served on scientific advisory boards and received honoraria or consulting fees from Amgen, Applied Therapeutics, Biomea Fusion, Boehringer Ingelheim, Corcept, Eccogene, Eli Lilly, Novo Nordisk, Oramed Pharmaceuticals, Regeneron, Regor, Sanofi, Scholar Rock, Structure Therapeutics, and Terns Pharmaceuticals and has received grants and research support from Amgen, Applied Therapeutics, Biomea Fusion, Boehringer Ingelheim, Corcept, Eli Lilly, Hanmi Pharmaceutical, Merck, Novo Nordisk, Oramed Pharmaceuticals, Pfizer, Regeneron, Regor, Sanofi, Structure Therapeutics, and Terns Pharmaceuticals. The other authors’ disclosures are listed on the original paper.
Nauck has been member on advisory boards or has consulted with Boehringer Ingelheim, Eli Lilly, Medtronic, Merck Sharp & Dohme, Novo Nordisk, Pfizer, Regor, Sun Pharma, and Structure Therapeutics (Gasherbrum); has served on the speakers bureau of AstraZeneca, Eli Lilly, Medscape, Medical Learning Institute, and Novo Nordisk, Sanofi, and Sun Pharma; has received support for attending meetings and/or travel from Eli Lilly and Novo Nordisk; and is on a Data Monitoring and Safety Board for Inventiva. His coauthor’s disclosures are listed on the original paper.
Drucker has received consulting fees from Amgen, Alnylam, AstraZeneca Inc, Crinetics, Eli Lilly, General Medicines Inc, Kallyope, Metsera, Pfizer Inc, Protagonist Therapeutics Inc, and Sanofi and speaking fees from Novo Nordisk Inc and Eli Lilly within the past 12 months. Mount Sinai Hospital has received investigator-initiated grant support from Amgen, Eli Lilly Inc, and Zealand Pharmaceuticals Inc to support preclinical studies in the Drucker lab.
Batya Swift Yasgur, MA, LSW, is a freelance writer with a counseling practice in Teaneck, New Jersey. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom(the memoir of two brave Afghan sisters who told her their story).
