Novel GLP-1 Agonist Promotes Safe and Effective Weight Loss

Medscape

6 hours ago

Ecnoglutide, a novel glucagon-like peptide-1 (GLP-1) receptor agonist, was significantly more effective than placebo for inducing weight loss in adults with overweight or obesity, based on data from more than 600 individuals, results of the SLIMMER trial showed.
In addition, ecnoglutide significantly improved other key cardiometabolic risk factors including waist circumference, blood pressure, lipid profile, A1c, fasting glucose, insulin level, and uric acid, while concurrently reducing liver fat content, said study author Linong Ji, MD, of Peking University People's Hospital, Beijing, China.
"These benefits position ecnoglutide as a compelling therapeutic strategy for managing clinical obesity, especially in the context of metabolic dysfunction and associated steatotic liver disease (MASLD)," he noted.
The results of the phase 3 randomized trial were presented here at the American Diabetes Association (ADA) 85th Scientific Sessions and simultaneously published in The Lancet Diabetes & Endocrinology .
The new drug is distinct from other GLP-1 receptor agonists in its ability to selectively induce production of cyclic adenosine monophosphate (cAMP). Unlike unbiased GLP-1 therapies, ecnoglutide selectively activates cAMP signaling pathways while minimizing β-arrestin recruitment, which may explain its enhanced effectiveness for body weight reduction and sustained metabolic effects, Ji said in an interview.
Weight Loss at All Doses
The researchers randomized 664 overweight and obese Chinese adults to a weekly dose of 1.2 mg, 1.8 mg, or 2.4 mg of ecnoglutide or to placebo. The coprimary endpoints were percentage change in body weight and proportion of individuals with a reduction of 5% or more in body weight after 40 weeks.
The study population included adults aged 18-75 years with overweight or obesity, defined as a BMI of 28 kg/m² or higher, or 24 kg/m² or higher with at least one weight-related comorbidity (prediabetes, hypertension, hyperlipidemia, MASLD, obstructive sleep apnea syndrome, or weight-bearing joint pain), but without type 1 or 2 diabetes. The mean age of participants was 34.2 years, and half were female.
Individuals in the ecnoglutide group had an average body weight loss of 9.1%, 10.9%, and 13.2% from baseline at 40 weeks at doses of 1.2 mg, 1.8 mg, and 2.4 mg, respectively, which was significantly greater at all dose levels than placebo (0.1%) ( P < 0.0001 vs placebo for all doses).
In addition, significantly more patients in the ecnoglutide groups lost at least 5% of their body weight at week 40 compared to the placebo group (77%, 84%, 87%, and 16% in the 1.2-mg, 1.8-mg, 2.4-mg, and placebo groups, respectively).
A key secondary efficacy endpoint was the percentage of individuals who achieved a body weight loss of at least 5% after 48 weeks; 78% to 93% of participants across the ecnoglutide groups achieved this endpoint, with the greatest changes at the higher doses.
Ten individuals across the ecnoglutide groups discontinued the medication because of adverse events, the most common of which were mild-to-moderate gastrointestinal events. Treatment-emergent adverse events occurred in 93% of participants in each of the ecnoglutide groups and in 84% of the placebo group.
Clinical Takeaways and Next Steps
"Ecnoglutide not only represents a viable competitor in the GLP-1 analog market but also stands out with its potential to address the nonresponse limitations in obesity treatment while providing holistic metabolic benefits," Ji told Medscape Medical News .
At least 10% of weight-loss patients fail to achieve clinically significant weight loss of at least 5%, he explained. Possible reasons for the lack of success include genetic polymorphisms, metabolic heterogeneity, treatment compliance, or differential receptor sensitivity, he noted.
"Providing alternative treatment options with a high response rate is crucial for individuals nonresponsive to existing therapies," he said. The trial results mark a milestone in obesity therapeutics and are a significant achievement in weight management.
"After 48 weeks of treatment, ecnoglutide achieved a 15.4% weight reduction, with 92.8% of patients attaining clinically meaningful weight loss," he emphasized.
"Considering the high potency of ecnoglutide" and the safety data, "it might serve as a viable option for individuals who do not achieve sufficient weight reduction with existing GLP-1 receptor agonists at their approved doses or need to achieve a better reduction in body weight," he added. "I am confident and optimistic that we'll see more personalized treatment regimens for obesity."
Looking ahead, patients in the ecnoglutide 1.8-mg and 2.4-mg groups continued to have weight loss at week 48 without reaching a plateau, indicating that even greater weight loss might be possible with extended ecnoglutide treatment in studies of longer duration, Ji told Medscape Medical News .
"To confer the added clinical advantage, a study comparing the clinical effects of a biased GLP-1 analog with those of a pharmacokinetically-matched but balanced GLP-1 analog would be needed," he said.
In an accompanying editorial, Tricia M-M Tan, PhD, of Imperial College, London, UK, wrote: "The development of biased GLP-1 receptor agonists has been met with enthusiasm from the pharmaceutical industry, but does this design feature really confer any added clinical advantage?"
She agreed with Ji that a comparative study of "a biased GLP-1 analog with those of a pharmacokinetically-matched but balanced GLP-1 analog" is needed. "Only then will the clinical role of this design feature be clear," she said.
However, "the clinical results from ecnoglutide are likely to be generalizable to other populations," given that the effects of GLP-1 analogs are similar when tested in patients of various ethnicities, she said, adding this may increase the global availability of GLP-1 treatments.
Refining Molecules to Enhance Efficacy, Reduce Side Effects
Although current therapies represent potent, effective options for obesity-modifying treatment, they have limitations, with heterogeneity of responses in terms of potency and tolerability, said Andrew Kraftson, MD, a specialist in endocrinology and internal medicine at the University of Michigan, Ann Arbor, in an interview.
"Ecnoglutide continues the trend to refine these molecules to enhance efficacy and reduce side effects," he said. "When these types of peptides interact with cells, they activate certain receptors and generate a signal cascade that promotes the desired effects. However, the less specific the 'message', the less potent the signal. Additionally, side effects can be a result of the less-controlled message," he noted.
As with tirzepatide, ecnoglutide was developed to produce a "biased" signal with the intent to provide greater control of the signal/message to increase the odds of weight control and reduce the odds of side effects, he explained.
Although the current study was not a head-to-head comparison with other incretin mimetics, the similarity in weight loss efficacy to tirzepatide, a dual GLP-1/glucagon insulinotropic peptide agonist (GIP), was interesting and supports the biasing effect of the molecular manipulation as an effective strategy to refine incretin therapy, Kraftson told Medscape Medical News .
From a clinical standpoint, the trend towards refining weight management therapy will benefit patients by expanding their options, said Kraftson. "It may also help us address the observed heterogeneity in clinical response we see in our patients and bring us closer to personalized medicine," he said.
The current study's limitations, as acknowledged by the researchers, include the relatively short time period, small sample size, and lack of head-to-head comparison, said Kraftson. Additionally, the study differs from clinical practice in its dose escalation, he said.
In practice, "we are not trying to get patients to a certain dose, we are trying to find the lowest, most tolerable, and sufficiently effective dose to achieve health goals; therefore, we may determine that dose titration needs to happen more slowly and/or that a low(er) dose may be sufficiently effective," he told Medscape Medical News .
"The adverse event data for common gastrointestinal issues could potentially be better in clinical practice if mitigation strategies are employed," he said. "I would like to see future studies that go beyond finding the relative efficacy of doses to reporting on effective strategies for patient-dose matching."