Novel GLP-1 analog utreglutide confers weight loss, improves leptin resistance
Click Here to Manage Email Alerts
Key takeaways:
- Utreglutide, in multiple ascending doses, caused sustained weight loss weeks after treatment discontinuation.
- The GLP-1 analog also improved leptin resistance, “a major biological contribution to obesity.”
SAN ANTONIO — Utreglutide, a novel GLP-1 analog, when administered in multiple ascending doses, demonstrated sustained weight loss for weeks after discontinuation among otherwise healthy men with overweight or obesity, a speaker reported.
At ObesityWeek, Rajamannar Thennati, PhD, a researcher in high impact innovation – sustainable health solutions for Sun Pharmaceutical Industries, presented the results of a randomized, double-blind, single-center, phase 1 trial that evaluated the safety and tolerability of multiple ascending doses of utreglutide (Sun Pharmaceutical Industries) among healthy men aged 18 to 40 years with a BMI of at least 28 kg/m2 and HbA1c of 7.5% or less.
“Worldwide, 43% of adults were overweight in 2022 and the number may escalate to 4 billion by 2035. Obesity increases all-cause mortality due to increased cardiovascular disease and diabetes in affected individuals,” Thennati said during the presentation. “Utreglutide is a novel analog with potent G-protein bias, long-acting agonist activity at the glucagon-like peptide-1 receptor. In the phase 1 study, we did observe that in one single dose that weight loss of about 3 kg persisted for about 3 more weeks [after treatment discontinuation]. That’s the something which was unique with this product.”
The trial was conducted in Belgium and enrolled 24 participants who were assigned to one of three groups: four standardized doses of utreglutide 640 g; four ascending doses of utreglutide 680 g, 900 g, 1,520 g and 2,000 g; and placebo.
The participants were all men with an average age ranging 30 to 33 years and an average BMI ranging from 32 kg/m2 to 33 kg/m2 across the three cohorts.
The researchers reported a significant reduction of glucose area under the curve during a 120-minute oral glucose tolerance test among participants assigned to utreglutide 640 g (mean at baseline, 289.2 mg h/dL; mean reduction, 58 mg h/dL) and multiple ascending doses of utreglutide (mean at baseline, 222.1 mg h/dL; mean reduction, 44.7 mg h/dL) compared with baseline. An increase in glucose AUC was reported in the placebo group.
The researchers also reported a significant reduction of insulin AUC during a 120-minute OGTT among participants assigned to utreglutide 640 g (mean at baseline, 1,803.6 pmol h/dL; mean reduction, 154.6 pmol h/dL) and multiple ascending doses of utreglutide (mean at baseline, 798.9 pmol h/dL; mean reduction, 221.2 pmol h/dL) compared with baseline. An increase in insulin AUC was reported in the placebo group.
Thennati and colleagues observed significant weight reduction by day 29 among participants assigned both utreglutide 640 g (mean reduction, 2.9 kg) and multiple ascending doses of utreglutide (mean reduction, 4.6 kg); however, weight loss sustained to day 43 was only achieved in the group assigned to multiple ascending doses (mean 43-day reduction, 3.7 kg).
The researchers estimated that utreglutide 640 g, with a total dose of 2.72 mg, was associated with 1 kg of weight loss for every 1 mg dose. Within the multiple ascending dose group, every 1 mg dose was associated with 0.9 kg of weight loss, with a total dose of 5.1 mg.
Significant reduction of triglyceride levels was reported in the ascending dose group (mean at baseline, 167.6 mg/d; mean reduction, 47.1; P < .05) but not among those assigned to utreglutide 640 g or placebo.
Significant reduction of total cholesterol was observed in both the utreglutide 640 g group (mean at baseline, 177.3 mg/dL; mean reduction, 21.3 mg/dL; P < .001) and the ascending dose groups (mean at baseline, 182.8 mg/dL; mean reduction, 20 mg/dL) but not in the placebo group.
LDL levels were also decreased, but only among participants assigned to utreglutide 640 g (mean baseline, 129.4 mg/dL; mean reduction, 17.4 mg/dL), according to the presentation.
Thennati reported that leptin levels were decreased by day 23 in both utreglutide 640 g (mean baseline, 19.8 ng/dL; mean reduction, 6 ng/dL) and the ascending dose groups (mean baseline, 17 ng/dL; mean reduction, 5.7 ng/dL) but not in the placebo group.
Moreover, HbA1c was also reduced by the end of the study in both utreglutide 640 g (mean at baseline, 5.5%; mean by end of study, 5.3%; P < .05) and the ascending dose groups (mean at baseline, 5.1%; mean by end of study, 4.9%; P < .05) but not in the placebo group.
The most common treatment-emergent adverse events were mild to moderate gastrointestinal (GI) events and were consistent with this class of drugs, according to the presentation.
One participant experienced a severe GI event requiring IV rehydration, but rapidly recovered, Thennati reported.
“[Utreglutide] was generally very tolerated. The reported GI events were consistent with the incretin class. Significant weight loss of 2.9 kg and 4.6 kg at a total dose of 2.72 mg and 5.1 mg, respectively. A reduction of body weight by 1 kg and 0.9 per mg dose at 4 weeks on day 29,” Thennati said during the presentation. “Reduction in leptin and lipid levels were observed at day 23 and some of which are with significance. Leptin resistance is a major biological contribution to obesity, [utreglutide] presented clinically meaningful weight loss with metabolic improvement and with a favorable tolerability profile. [Utreglutide], a selective GLP-1 receptor agonist, is likely to demonstrate improved therapeutic benefits and data warrant further clinical evaluation.”
Collapse
Thennati R. Oral-077. Presented at: ObesityWeek; Nov. 3-6, 2024; San Antonio.
Read more about
Click Here to Manage Email Alerts