ATLANTA — Eli Lilly’s investigational weekly amylin receptor agonist eloralintide produced significant weight loss over 48 weeks and was generally well tolerated, particularly with incremental dose escalation, new phase 2 data showed. 

Amylin is a peptide co-secreted with insulin in response to food intake. It controls gastric emptying, inhibits glucagon secretion, and promotes satiety. Several amylin receptor agonists are in development, both as monotherapy and in combination formulations. Novo Nordisk’s cagrilintide and cagrisema are in phase 3 trials. 

At the Obesity Society’s Obesity Week 2025 meeting, investigators presented results from the 48 week, phase 2, multicenter, double-blind randomized, placebo-controlled trial of eloralintide, in 263 adults from 46 US research centers. The findings were simultaneously published in the Lancet. 

“Eloralintide may expand weight loss treatment options for patients unable to achieve adequate benefit from or tolerate existing obesity treatments,” said study investigator Harold Bays, MD, medical director of the Louisville Metabolic and Atherosclerosis Research Center, and clinical associate professor at the University of Louisville School of Medicine, Kentucky.

Significant Weight Loss, Other Positive Findings Seen 

Efficacy data were presented by study investigator Liana K Billings, MD, director of the Diabetes and Obesity Research Program and the Personalized Medicine in Diabetes Program, NorthShore University HealthSystem, Skokie, Illinois. Study participants all had a BMI of ≥ 30 or 27 plus at least one weight-related comorbidity (but not diabetes). They had a mean baseline age of 49 years, mean BMI of 39.1, and 78% were female. 

They were randomized to 1 of 7 groups: placebo; 1 mg; 3 mg; 6 mg; or 9 mg once-weekly subcutaneous eloralintide for the entire 48 weeks; or dose escalations of 6-9 mg at week 20; or 3-6 mg at 4 weeks, then 6-9 mg at 8 weeks (ie, “3-9 mg” group) — all up to 48 weeks. 

At 48 weeks, mean percent body weight reduction from baseline at week 48 was greater in all the eloralintide groups compared with placebo. The efficacy estimand ranged from 9.4% with 1 mg to 20.9% with the 9 mg dose, with reductions of 19.9% and 16.4% for the 6-9 mg and 3-9 mg dose escalation groups, respectively, compared with a 0.4% drop with placebo. Weight loss of 10% or more was achieved in 92% of the 6-9 mg dose escalation group and in 81% of the 9 mg group. 

Waist circumference was reduced by up to 17.1 cm in the 6-9 mg dose escalation group, or about 6-7 inches. “We know waist circumference has important metabolic implications, but it’s also where we start to get the patient’s experience of this weight loss. Six or 7 inches is six belt holes on a belt. This is where patients start to say…I have to buy new clothes. You really start to see the impact of this weight loss on the way they feel,” Billings commented. 

BMI reductions ranged from 3.7 with 1 mg up to 7.8 in the 6-9 mg escalation group, vs 0.2 with placebo. In the three treatment groups that received 9 mg of eloralintide, between 78% and 80% shifted to a lower clinically defined BMI category, vs just 21% with placebo. 

By 48 weeks, the proportions achieving BMIs of 25 or less were 20%, 15%, and 11% of the 6 mg, 9 mg, and 6-9 mg groups, respectively, vs none of the lower dose or placebo groups.

Among a subset of patients who received DEXA scanning, more of the weight loss came from loss of body fat than lean mass, Billings said. 

Other secondary endpoints included a drop of up to 0.38 percentage point A1c drop (in the 6 mg group), which was similar across treatment groups and greater than the 0.13 drop in the placebo group. Reductions in total cholesterol, LDL cholesterol, and non-HDL cholesterol were also greater for all eloralintide treatment groups than for placebo, while HDL cholesterol increased with eloralintide but was unchanged with placebo. 

High-sensitivity C-reactive protein was reduced by up to 64% from elevated baseline levels. Except for the 1mg eloralintide group, the others all had improvements in physical functioning assessed by the SF-36v2 after 48 weeks. 

Adverse Events Were Lower When the Dose Was Titrated up

Bays presented the safety data, which included follow-up for 10 weeks beyond the 48-week treatment period. Overall, 81% on eloralintide reported one or more adverse events, compared with 71% on placebo. Serious adverse event rates didn’t differ, 5% and 6%, respectively. Adverse events leading to discontinuations occurred in 10% in the eloralintide groups — 21% with 6 mg — vs 8% with placebo. 

Nausea was reported by 32.7% overall with eloralintide vs 13.5% with placebo, with 64.3% in the 6 mg dose group vs just 25% for the 3-9 mg titration group. Vomiting was much less common, just 8.2% with eloralintide overall and zero in the placebo, 1 mg, and 3 mg treatment groups. 

Constipation and diarrhea were each reported by about 15% of the eloralintide groups, with slightly lower rates — 5.8% and 9.6%, respectively — with placebo. 

Fatigue was reported by 26.9% in the pooled eloralintide groups vs 11.5% with placebo. The highest proportion reporting fatigue was in the 6-9 mg group, 45.8%. 

Most of these events were mild to moderate in severity. There were no deaths, Bays reported. 

‘The More Targets We Have, the Better’

Asked to comment, W. Timothy Garvey, MD, professor in the Department of Nutrition Sciences, School of Health Professions, University of Alabama at Birmingham, told Medscape Medical News he was “excited” by the results. “The gastrointestinal side effects seem to be at least somewhat reduced compared with the GLP-1 receptor agonists and the efficacy was very impressive.” 

However, Garvey noted, “there was a very high proportion of females in the trial, and we know females tend to lose more weight than males with any intervention. So I’m wondering if they had a sub-analysis looking at the males.”

He also pointed out that “the drug discontinuation rate was much higher than what I’m used to seeing in clinical trials of this type…I think we need to better understand that.” 

Asked whether amylin agonists generally might replace GLP-1s, Garvey said, “I think it could be an alternative, but when you lose the GLP-1 component, you lose secondary cardio protection, potential benefits on congestive heart failure and [metabolic associated steatohepatitis] and sleep apnea and other complications.” 

On the other hand, Garvey noted, “many patients with obesity have not had a heart attack and don't have [metabolic dysfunction-associated steatohepatitis] and don't have congestive heart failure, so in those patients, this would be a very attractive first line medication.”

David White, FNP-C, a primary care nurse practitioner at Henry Ford Health System, Detroit, Michigan, who specializes in obesity and diabetes and follows drug development pipelines, told Medscape Medical News, “the fatigue concerns me a bit, but maybe it can be managed with slow titration. The weight loss is great.”

In general, White said, “I think the more targets we have the better. It’s like with blood pressure medicines…they all work a little differently, and if that’s where we’re going with obesity medicine, I think that’s a good thing. And the more choice, the more competition, hopefully. I don’t want to say prices will go down, but maybe.” 

Billings has received consulting fees from Amgen, Bayer, Eli Lilly, and Novo Nordisk; and served on advisory panels for Amgen, Bayer, Eli Lilly, and Novo Nordisk. Bays has received research support from Alon Medtech/Epitomee, Altimmune, Amgen, AstraZeneca, Bioage, Boehringer Ingelheim, Carmot, Chorus/Bioage, Eli Lilly, Graviton, Kallyope, Merck, Novartis, Novo Nordisk, Pfizer, Regeneron, Satsuma, Shionogi, Skye/Birdrock, Veru, Viking, Vivus, and Zomagen; received consulting fees from Altimmune, Amgen, Boehringer Ingelheim, Kiniksa, Eli Lilly, Nestle, Novo Nordisk, Regeneron, Rivus, Veru, Zomagen, and Zyversa; and has received honoraria from the Obesity Medicine Association, National Lipid Association, The Obesity Society, Harvard Blackburn review course, and the Radcliffe cardiovascular disease symposia, and has a leadership role with the Obesity Medicine Association and Obesity Pillars. 

Garvey has served as a consultant on advisory boards for Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Pfizer, Fractyl Health, Alnylam Pharmaceuticals, Inogen, Zealand, Allurion, Carmot/Roche, Terns Pharmaceuticals, Neurocrine, Keros Therapeutics, Gan & Lee, and Regeneron. He is a site principal investigator for multi-centred clinical trials sponsored by his university and funded by Novo Nordisk, Eli Lilly, Epitomee, Neurovalens, Zealand, Carmot/Roche, and Pfizer. He is a member of a Data Monitoring Committee for phase 3 clinical trials conducted by Boehringer-Ingelheim and Eli Lilly. 

White has no disclosures. 

Miriam E. Tucker is a freelance journalist based in the Washington DC area. She is a regular contributor to Medscape, with other work appearing in the Washington Post, NPR’s Shots blog, and Diatribe. She is on X (formerly Twitter) @MiriamETucker and BlueSky @miriametucker.bsky.social