Subcutaneous injections of olatorepatide, an investigational dual glucagon-like peptide-1 (GLP-1)/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, are associated with up to a 19-percent decrease in body weight and favourable gastrointestinal (GI) tolerability in Chinese adults with overweight or obesity, as shown in the phase III LIGHTEN study.
Over 48 weeks, participants in all olatorepatide dose groups lost a significantly greater percentage of their body weight compared with those in the placebo group, with no weight-loss plateau observed, reported lead investigator Dr Linong Ji from the Peking University People’s Hospital in Beijing, China.
Using the efficacy estimand, mean body weight reductions from baseline to week 48 were 12.5 percent with olatorepatide 5 mg, 17.5 percent with 10 mg, and 19.3 percent with 15 mg groups vs 2.7 percent with placebo (p<0.0001 for all). [EASD 2026, abstract LBA27]
Compared with those who received placebo, significantly more olatorepatide-treated participants achieved a weight loss response of ≥5 percent (87.3 percent to 97.2 percent vs 28.6 percent), ≥10 percent (61.7 percent to 89.3 percent vs 14.6 percent), or ≥15 percent (32.6 percent to 71.7 percent vs 3.2 percent; p<0.001 for all).
Olatorepatide was also associated with more favourable improvements in waist circumference, blood pressure, lipids, HbA1c, and urine albumin-to-creatinine ratio.
In terms of safety, treatment-related adverse events (TRAEs) occurred in 46.4 percent, 57 percent, and 56.4 percent of participants treated with olatorepatide 5, 10, or 15 mg, respectively, vs 24.2 percent of those who received placebo. Rates of serious AEs ranged from 0.7 percent to 5.3 percent across the olatorepatide groups vs 3.3 percent in the placebo group.
“No TRAEs led to treatment discontinuation or early withdrawal from the study,” Ji noted. “We did not observe additional safety signals other than what has been described for GLP-1/GIP receptor agonist-related treatment.”
The rates of GI events with olatorepatide were low, which Ji described as a surprising finding. Diarrhoea occurred in 16.9 percent of participants in the pooled olatorepatide groups, nausea in 7.8 percent, constipation in 5.1 percent, and vomiting in 4.9 percent. In the placebo group, the rates were 7.8 percent, 2.6 percent, 1.3 percent, and 2 percent, respectively.
“Olatorepatide is a dual-biased GLP-1/GIP receptor agonist, designed to minimize GI side effects without compromising efficacy. We now have evidence suggesting that olatorepatide is well tolerated,” Ji said.
Taken together, these findings highlight olatorepatide’s potential as a novel therapy for weight management, Ji concluded.
Conducted at 33 sites in China, LIGHTEN included 604 nondiabetic adults (mean age 35 years, 69 percent female, mean BMI 32.4 kg/m2) with BMI of ≥28 kg/m2 or BMI ≥24 kg/m2 and at least one weight-related comorbidity (prediabetes, hypertension, dyslipidaemia, metabolic dysfunction-associated steatotic liver disease, dyspnoea, or obstructive sleep apnoea).
The participants were randomly assigned to receive treatment with olatorepatide 5 mg (n=151), 10 mg (n=151), or 15 mg (n=149) or placebo (n=153). Treatment was administered subcutaneously once weekly for 48 weeks. A total of 544 participants (90.1 percent) completed 48 weeks of treatment.
The co-primary endpoints were body weight change and proportion of participants achieving ≥5-percent weight loss.