Oral GLP-1 drug elecoglipron helps adults lose up to 11.8% body weight

A once-daily oral small-molecule GLP-1 receptor agonist delivered progressive, dose-dependent weight loss without food or fluid restrictions, supporting larger phase 3 trials for long-term weight management.

Study: Elecoglipron, an oral small molecule GLP-1 receptor agonist in adults with obesity or overweight (VISTA): a multicentre, phase 2, randomised, placebo-controlled clinical trial. Image Credit: grinny / Shuttertock

In a recent study published in The Lancet, a group of researchers evaluated the efficacy, safety, and tolerability of oral non-peptide small-molecule elecoglipron for weight management in adults with obesity or overweight and at least one weight-related health condition without diabetes.

Background

More than one billion people are living with obesity, a condition linked to cardiovascular disease, hypertension, sleep apnea, and reduced quality of life. Glucagon-like peptide-1 (GLP-1) receptor agonists provide an effective treatment option for obesity-related weight loss.

Currently available options can require injections or strict dosing conditions, which may discourage patients from continuing their use for the long term. Due to the continual rise in the number of people living with obesity, there is an increased demand for easily accessible medications that provide significant long-term weight loss while still fitting into patients' daily routines.

Oral medications that do not require fasting or special administration conditions may improve accessibility and patient acceptance. Further research is needed to identify effective and practical oral therapies that provide sustained weight reduction with acceptable safety profiles.

About the Study

Researchers conducted a multicenter, randomized, double-blind, placebo-controlled phase 2 clinical trial across Australia, Canada, Germany, Japan, Taiwan, the United Kingdom, and the United States.

Adults with obesity, defined as having a body mass index (BMI) of 30 kg/m² or higher, or overweight, defined as having a BMI of 27 kg/m² or greater with at least one weight-related condition, were eligible to participate. Patients with type 1 or type 2 diabetes, glycated hemoglobin A1c of 6.5% or higher at screening, recent diabetes medication use, or recent weight-loss medication use were excluded from the trial.

A total of 310 adult participants were randomly assigned to receive either active oral elecoglipron or oral placebo. The elecoglipron groups received once-daily tablets using the following regimens: 5 mg without titration; 15 mg without titration; 50 mg with every-4-week dose escalation; 75 mg with weekly dose escalation; or 75 mg with every-2-week dose escalation. All participants received treatment for 36 weeks after baseline assessments were completed.

All participants received counseling on dietary and exercise behaviors, including education on achieving a daily caloric deficit of 500-750 kcal. Researchers also assessed participants for body weight, waist circumference, blood pressure, laboratory values, adverse events, electrocardiograms, and suicidality and mood-related assessments throughout the study period.

The primary outcomes were the percentage change in body weight from baseline and the proportion of participants who lost at least 5% of their body weight at 26 weeks. Secondary outcomes included measurements of weight loss at 36 weeks and evaluations of participant safety.

Study Results

In the present study, a total of 472 individuals were screened, 310 met eligibility requirements, and were then randomly assigned to one of the treatment groups. Overall, 288 participants completed the trial; of those participants, 231 completed their assigned treatment. The average age of participants was 48.4 years, the average weight was 106.9 kg, and the average BMI was 38.2 kg/m². Approximately 73% of all participants were female.

Elecoglipron produced clear dose-dependent reductions in body weight. Estimated average weight loss ranged from 2.6% to 10.5% for the 5 mg and 75 mg once-daily weekly-titration groups, respectively, at week 26. Those on placebo lost an average of only 0.6% of their body weight. The estimated proportion of participants who achieved at least 5% weight loss was 40.4%-88.8% in the low- and high-dose groups, compared with 15.6% in the placebo group.

Weight loss continued throughout the study, suggesting that maximal weight loss might not yet have been achieved during the 36-week treatment period. At the end of treatment, average weight losses were 11.8% in the 75 mg once-daily weekly-titration group and 11.1% in the 75 mg once-daily every-2-week titration group. The placebo group's average weight loss was only 0.3%.

Higher doses of elecoglipron increased the likelihood that participants would lose significant weight. By week 36, across all elecoglipron groups, between 8.8% and 62.5% lost at least 10% of baseline body weight compared with 4.5% of placebo participants. The proportion achieving at least a 15% reduction in body weight ranged from 4.9% to 39.8% across the elecoglipron groups, whereas only 2.7% of placebo patients achieved a similar reduction.

The use of elecoglipron was associated with additional exploratory changes beyond weight loss; for example, participants taking elecoglipron experienced reductions in BMI, waist circumference, systolic blood pressure, and markers of inflammation such as high-sensitivity C-reactive protein. Improvements generally became greater as the dose increased. These findings should be interpreted as changes in cardiometabolic risk markers rather than evidence of reduced clinical events.

The safety profile was broadly consistent with the safety profile observed for other GLP-1 receptor agonists. The adverse events that occurred most frequently included nausea, constipation, diarrhea, headache, and vomiting.

Generally, gastrointestinal adverse events were mild to moderate, mostly occurred during dose titration, and often resolved over time. There were no deaths during the trial, and no clinically diagnosed cases of pancreatitis were reported.

Serious adverse events occurred in eight of 98 participants in the two 75 mg elecoglipron groups and two of 81 placebo participants, although the authors reported no meaningful difference in the distribution of event types.

A small number of participants experienced gallbladder-related events or temporary elevations in bilirubin, but most cases were manageable and did not require permanent discontinuation of treatment.

Conclusion

The study suggests that once-daily oral elecoglipron produced clinically meaningful and progressive weight loss in adults living with obesity or overweight without diabetes. Higher doses achieved substantial reductions in body weight, with benefits continuing through 36 weeks and no evidence of a weight loss plateau.

In addition to promoting weight loss, elecoglipron was associated with reductions in multiple exploratory cardiometabolic risk markers, including blood pressure, waist circumference, and high-sensitivity C-reactive protein. The overall safety profile observed in the trial was consistent with the safety profiles of GLP-1 receptor agonist medications, including predominantly manageable gastrointestinal adverse events.

As a phase 2 trial, the study was not designed to assess long-term durability, rare adverse events, or cardiovascular outcomes. Based on these data, further phase 3 trials evaluating elecoglipron as a potentially effective and convenient oral treatment for long-term weight management are warranted.

AstraZeneca funded the trial, and the funder contributed to the study design, conduct, data collection, analysis, interpretation, and report writing.

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• Davies, M. J., Aroda, V. R., Rosenstock, J., Capehorn, M., Pedersen, S. D., Morizzo, E., Malhotra, S., Johansson, P. A., Grice, D., Andersson, A., Rizi, E. P., & Sjöström, C. D. (2026). Elecoglipron, an oral small molecule GLP-1 receptor agonist in adults with obesity or overweight (VISTA): A multicentre, phase 2, randomised, placebo-controlled clinical trial. The Lancet. DOI: 10.1016/S0140-6736(26)00748-8. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(26)00748-8/fulltext