Oral Small-Molecule Elecoglipron Tackles Obesity and Diabetes

NEW ORLEANS — Treatment with investigational elecoglipron led to weight loss in people with obesity and improved glucose control in those with type 2 diabetes, a pair of global phase II randomized trials showed.

In the dose-ranging VISTA study of adults with obesity or overweight without diabetes, mean body weight loss by week 26 ranged from 2.6% in the 5 mg elecoglipron group to 10.5% in the 75 mg group with weekly titration steps, compared with 0.6% weight loss with placebo.

In an extension phase that spanned to week 36, weight loss reached up to 11.8% with the 75 mg weekly titration dose compared with a 0.3% loss with placebo, reported Melanie Davies, MD, of the University of Leicester in England.

The weight loss had not yet plateaued, Davies said at the American Diabetes Association (ADA) annual meeting. The findings were simultaneously published in The Lancet.

Elecoglipron is an oral, small-molecule GLP-1 receptor agonist, similar to the recently approved once-daily weight-loss pill orforglipron (Foundayo). Both carry no food or fluid dosing restrictions, setting them apart from oral semaglutide (Wegovy), which needs to be taken with water in the morning on an empty stomach.

Development of oral, non-peptide GLP-1 receptor agonists has accelerated, with trials showing they deliver clinically meaningful weight loss, Davies’ group wrote. However, the authors emphasized that patient tolerability and high discontinuation rates at peak doses remain significant challenges.

About 5% of participants (12 of 229) discontinued elecoglipron due to side effects (five due to GI issues). Most GI events were mild, transient, and occurred during titration. Peak GI event rates for elecoglipron compared with placebo were: nausea (56% vs 20%), constipation (42% vs 6%), diarrhea (35% vs 25%), and vomiting (29% vs 5%).

In this parallel-group trial, 310 participants were randomly assigned in a 2:3:3:3:3:5 ratio to receive 5 mg, 15 mg, 50 mg, 75 mg (weekly titration), or 75 mg (every-2-week titration) of elecoglipron or matching placebo.

All participants had obesity or overweight with a weight-related condition. The average age was 48.4 years; most were female (73%) and white (72%). The mean body weight was 235.7 lb (106.9 kg) and BMI was 38.2.

The 5 mg and 15 mg groups received the drug once daily without titration, while higher-dose cohorts used three different escalation regimens. The 50 mg dose was increased every 4 weeks, while the 75 mg dose was escalated either weekly or every 2 weeks.

The authors noted that patients still achieved significant weight loss despite a slower ramp-up to the higher doses, suggesting that gradual titration can successfully balance drug effectiveness with patient tolerability.

Dose-dependent reductions in systolic blood pressure (up to -9.3 mm Hg) and high-sensitivity C-reactive protein (up to -44.4%) were also reported with elecoglipron.

“We know just how important it is to mitigate cardiovascular risk in people living with obesity. Our study shows us how this small-molecule oral GLP-1 receptor agonist can help address not only weight reduction, but broader obesity-related health risks,” Davies said in a statement. “By addressing blood pressure and C-reactive protein, we can help reduce the risk of type 2 diabetes, heart disease, and stroke.”

Type 2 Diabetes Benefit, Too

Elecoglipron also improved glycemic control in adults with type 2 diabetes, according to findings from the phase IIb SOLSTICE trial presented at ADA and published in The Lancet.

Among 406 participants, the mean HbA1c reduction by week 26 ranged from 0.91% with 5 mg elecoglipron to 1.88% with 75 mg elecoglipron (using an every-2-week dose-escalation step), compared with a 0.15% reduction with placebo.

An arm treated with oral semaglutide up to 14 mg was also included as “an exploratory benchmark,” noted Vanita Aroda, MD, of Brigham and Women’s Hospital in Boston. The reduction in HbA1c was 1.28% in this group.

“These findings suggest small-molecule GLP-1 receptor agonist therapies could provide an important new option for people living with type 2 diabetes and related metabolic conditions,” Aroda said in a statement. “Elecoglipron has the potential to offer people more treatment options that can meet their preferences and support their care goals.”

Superior improvements in fasting glucose and body weight also were reported among those taking elecoglipron.

Adverse events occurred in up to 87% of patients in the elecoglipron group versus 63% of those taking placebo, with discontinuation rates ranging from 2% to 17%. Dropouts peaked in the 25 mg fixed-dose group due to its high starting dose, Aroda noted. Only 8% of the placebo group and 6% of the oral semaglutide group discontinued.

Although elecoglipron’s success and safety match other oral GLP-1 drugs, its phase II outcomes shouldn’t be directly compared to phase III data for orforglipron or oral semaglutide, argued accompanying commentary author Matthias Blüher, MD, of the University of Leipzig Medical Center in Germany.

Blüher explained that because the studies used an efficacy estimand rather than a treatment-regimen estimand, direct comparisons to other trials are difficult, and results may not mirror real-world outcomes.

“Notably, both trials provide the basis for advancing the elecoglipron study program to phase III trials with a longer duration, inclusion of a larger number of participants of varied ethnicities, relevant cardiometabolic outcomes, and the selection of optimal doses and dose-escalation regimens,” he wrote.

The SOLSTICE trial enrolled adults with a BMI ≥23 and an HbA1c of 6.5% to 10.5% on diet/exercise alone or metformin/SGLT2 inhibitor monotherapy. Participants had a mean age of 58.4 years, HbA1c of 7.9%, weight of 220 lb (99.8 kg), and BMI of 34.9; 58% were male and 69% were white.

Drugmaker AstraZeneca said it is advancing elecoglipron into a phase III program in obesity and type 2 diabetes, which will include cardiovascular and kidney outcome trials.

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