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.
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.
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.
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.
Providing alternative treatment options with a high response rate is crucial for individuals nonresponsive to existing therapies.
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