A bold claim precedes the data: a once‑monthly peptide–antibody conjugate may drive meaningful weight reductions and several cardiometabolic benefits. That’s the central finding from a phase 2 study of maridebart cafraglutide (Amgen), which showed dose‑dependent weight loss in adults with obesity, with or without type 2 diabetes (T2D), as reported in The New England Journal of Medicine.
Maridebart cafraglutide combines glucagon‑like peptide‑1 (GLP‑1) receptor agonism with a glucose‑dependent insulinotropic polypeptide (GIP) receptor antagonism. The aim is to enable less frequent dosing while sustaining weight‑loss effects and metabolic improvements, a promising direction for chronic weight management.
Although these results are not yet definitive and require confirmation in larger, longer trials, the researchers note that starting at a lower dose with gradual escalation reduced gastrointestinal adverse events in a pharmacokinetic–dose‑intensity (PK‑LDI) framework, informing a phase 3 strategy to optimize tolerability.
One‑year weight loss outcomes
The study (NCT05669599) enrolled 592 adults and examined 11 dosing regimens across two cohorts, with the primary endpoint being the percent change in body weight from baseline to week 52. In the obesity‑only cohort (n = 465), participants were randomized to several maridebart cafraglutide regimens at 140, 280, or 420 mg every 4 weeks (with or without dose escalation), 420 mg every 8 weeks, or to placebo.
In the obesity with T2D cohort (n = 127), options included 140, 280, or 420 mg every 4 weeks without escalation or placebo. Across all obesity groups, intention‑to‑treat analysis showed weight reductions at 52 weeks ranging from 12.3% to 16.2% with maridebart cafraglutide, versus a 2.5% decrease with placebo. For participants with obesity plus T2D, mean losses were 8.4% to 12.3% with treatment, compared with 1.7% with placebo.
Under a best‑case adherence scenario (efficacy estimand), weight loss was even greater. Obese participants could achieve roughly 16.3% to just under 20% weight reduction with maridebart cafraglutide, versus about 2.6% with placebo. Those with obesity and T2D could see 12.1% to 17% weight loss, compared with 1.4% on placebo.
Notably, a typical pattern for nutrient‑stimulated hormone receptor modulators appears here: individuals with obesity and T2D tend to experience somewhat smaller weight losses than those without diabetes, though the exact mechanisms remain to be clarified.
Body composition and metabolic effects
Weight loss largely reflected reductions in fat mass. Across treated groups, fat loss ranged approximately from 26% to 37% of baseline fat in adults with obesity, and from 17% to 34% in those with obesity and T2D, relative to smaller declines in placebo groups. Lean mass did decline as well, but to a lesser extent: roughly 9%–12% in obesity-only and 7%–10% in obesity with T2D, versus about 2% with placebo.
Glycemic outcomes were clinically meaningful, particularly in the obesity plus T2D cohort. A1C fell by up to 1.6 percentage points on the treatment‑policy estimand and up to 2.2 points on the efficacy estimand, versus a 0.1‑point rise with placebo. By week 52, 81%–87% of treated participants reached an A1C of 6.5% or lower, compared with 9% on placebo. A notable share achieved normoglycemia (A1C < 5.7%), and no placebo recipients reached this threshold.
Prediabetes at baseline also showed favorable reversal with treatment: among those with baseline prediabetes and available week‑52 data, 70%–95% achieved normoglycemia on active therapy versus 17% with placebo.
Beyond glucose control, the treatment was associated with improvements in waist circumference, systolic and diastolic blood pressure, fasting glucose, insulin, and high‑sensitivity C‑reactive protein.
Safety and tolerability
In the obesity‑only group, 90%–99% of participants on maridebart cafraglutide experienced at least one adverse event, compared with 68% on placebo. In the obesity with T2D cohort, adverse events occurred at similar rates with treatment (91%–97%) but were more frequent on placebo (81%) than in the obesity‑only group, suggesting a tolerability advantage with active therapy in the whole population.
Gastrointestinal symptoms were the most common adverse events, mirroring what is seen with established GLP‑1 weight‑loss therapies. Discontinuations due to GI symptoms were higher in non‑escalating regimens (12%–27%) but notably lower with dose escalation (about 8%). No major safety alarms emerged.
Two deaths occurred during the trial—one from traumatic intracranial hemorrhage and one sudden cardiac death in a participant with multiple cardiovascular risk factors—but investigators judged these events unrelated to the study drug. Mild hypersensitivity reactions were reported, gallbladder events were somewhat more frequent with active treatment, and there were no reports of pancreatitis, diabetic retinopathy, or thyroid C‑cell hyperplasia.
Bottom line
Early results from this phase 2 program point to substantial and dose‑dependent weight loss with maridebart cafraglutide, along with favorable shifts in cardiometabolic risk factors. While confirmatory data from larger, longer‑term trials are essential, these findings open a conversation about how such therapies could reshape obesity and diabetes management, including potential shifts in dosing strategies to balance efficacy and tolerability.
References
1. Jastreboff AM, Ryan DH, Bays HE, et al. Once-monthly maridebart cafraglutide for the treatment of obesity—a phase 2 trial. N Engl J Med. 2025;393(9):843‑857. doi:10.1056/NEJMoa2504214
2. Klein HE. How effective and safe are GLP‑1s for weight loss? AJMC. November 18, 2025. Accessed December 4, 2025. https://www.ajmc.com/view/how-effective-and-safe-are-glp-1s-for-weight-loss-
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