Individuals with overweight or obesity in East Asia shed more weight following treatment with the fixed-dose combination of cagrilintide plus semaglutide than with semaglutide alone, as shown in the phase 3a REDEFINE 5 trial.
In a cohort of adults with a BMI of ≥27 kg/m² and at least two obesity-related complications (per the Japan Society for the Study of Obesity [JASSO] guidelines) or a BMI of ≥35 kg/m2 and at least one obesity-related complication, the primary endpoint of bodyweight after 68 weeks of treatment decreased by 18.4 percent in those who received cagrilintide–semaglutide and by 11.9 percent in those who received semaglutide (estimated treatment difference [ETD], −6.5 percentage points, 95 percent confidence interval [CI], −8.4 to −4.6; p<0.0001). [Lancet Diabetes Endocrinol 2026;doi:10.1016/S2213-8587(25)00402-4]
Results were similar regardless of the presence of type 2 diabetes (T2D), such that the change in bodyweight was consistently greater with cagrilintide–semaglutide among participants without T2D (ETD, –7 percentage points, 95 percent CI, –9.3 to –4.8; p<0.0001) and those with T2D (ETD, –4.6 percentage points, 95 percent CI, –8.3 to –0.9; p=0.015).
Significantly more participants in the cagrilintide–semaglutide vs the semaglutide arm achieved bodyweight reductions of ≥25 percent (22.4 percent vs 9.6 percent; p=0.0020), ≥20 percent (39.4 percent vs 18.6 percent; p<0.0001), ≥15 percent (60.2 percent vs 30 percent; p<0.0001), ≥10 percent (81.9 percent vs 48.5 percent; p<0.0001), and ≥5 percent (95.4 percent vs 78.7 percent; p<0.0001).
Treatment with cagrilintide–semaglutide vs semaglutide also resulted in greater reductions in waist circumference (–13.5 vs –9.7 cm; p<0.0001) and BMI (–6.2 vs –4 kg/m²; p<0.0001).
Results in perspective
These results have important clinical implications, given that bodyweight reductions of ≥5 percent and >10 percent “are recommended by JASSO to improve obesity-related complications (including but not restricted to impaired glucose tolerance, hypertension, and coronary artery disease) that contribute to morbidity in individuals with obesity,” said lead investigator Prof Toshimasa Yamauchi from the University of Tokyo, Japan. [Endocr J 2024;71:223-231]
“Most participants (82 percent) [in REDEFINE 5] had two to four of the 11 obesity-related complications described in the JASSO guidelines that can be prevented or alleviated by bodyweight reduction,” Yamauchi added. [Endocr J 2024;71:223-231]
The investigator also acknowledged that while the trial was not specifically powered to measure the impact of diabetes status, weight-loss outcomes with cagrilintide–semaglutide vs semaglutide were numerically lower among participants with T2D.
“Substantial bodyweight reduction is more challenging in individuals with diabetes than in those without, due to several factors, including the use of diabetes medications that can lead to weight gain,” Yamauchi explained. [Obes Pillars 2023;7:100076]
Regardless, mean bodyweight reductions among participants with T2D in the cagrilintide–semaglutide arm appeared consistent with those observed in REDEFINE 2, which exclusively included individuals with overweight or obesity and T2D, he continued. [N Engl J Med 2025;393:648-659]
“These findings support the efficacy of cagrilintide–semaglutide across the glycaemic spectrum … [and] are applicable to local practice, as lower cutoffs are used for obesity disease diagnosis and weight management in East Asian countries (including Japan) than the rest of the world.”
Improved cardiometabolic health
After 68 weeks of treatment, HbA1c was substantially reduced in the cagrilintide–semaglutide arm than the semaglutide arm (–12 vs –10.9 mmol/mol; p=0.017), although no significant between-group difference was observed in fasting plasma glucose (−1.4 vs −1.4 mmol/L; p=0.43).
More favourable improvements were also observed with cagrilintide–semaglutide vs semaglutide in fasting lipid profiles (very low-density lipoprotein cholesterol: p=0.0003; triglycerides: p=0.0003; high-density lipoprotein cholesterol: p<0.0001), systolic (ETD, –4.9 mm Hg; p=0.0008) and diastolic blood pressure (ETD, –3.8 mm Hg; p=0.0001), Homeostatic Model Assessment for Insulin Resistance score (ETD, –0.6; p=0.0035), and high-sensitivity C-reactive protein (p=0.0004).
Altogether, these data “indicate that cagrilintide–semaglutide might further improve cardiometabolic health in East Asian individuals living with obesity,” Yamauchi said.
He underscored the need to account for ethnicity when treating individuals with overweight or obesity and believed that REDEFINE 5 might help inform regional practice or global guideline updates in a bid to achieve holistic weight management care across populations.
Region-, population-relevant evidence
“REDEFINE 5 shows what becomes possible when regional expectations are treated as a scientific catalyst rather than a regulatory milestone: eligibility aligned with local thresholds, thoughtful phenotyping that captures relevant biology, and prespecified questions that can meaningfully inform care in certain populations,” wrote Drs Yu Mi Kang and Vanita Aroda from Harvard Medical School, Boston, Massachusetts, US. [Lancet Diabetes Endocrinol 2026;doi:10.1016/S2213-8587(26)00012-4]
Kang and Aroda emphasized the importance of region-relevant and population-relevant evidence, including appropriate BMI thresholds and careful characterization of baseline cardiometabolic risk phenotypes, “to avoid one-size-fits-all extrapolation and to enable equitable translation into practice and public health policy.”
“The next step is not additional region-limited programmes confined to a few jurisdictions, but sustained investment in trained, high-performing trial networks across the Asian subcontinent, including South and Southeast Asia, where representation in contemporary obesity and cardiometabolic trials remains poor and the knowledge gaps are often greatest,” they said.
“Treating Asian evidence as foundational, not jurisdictional, is how global programmes earn truly global inference, ensuring that clinical breakthroughs are scientifically representative of all populations,” Kang and Aroda concluded.
REDEFINE-5 population
The trial included 331 participants (mean age 51.1 years, 68 percent male, 24 percent had T2D, mean bodyweight 95.3 kg, mean BMI 34.1 kg/m²), enrolled across 21 sites in Japan and one in Taiwan. The most common obesity-related complications were dyslipidaemia (86 percent) and hypertension (77 percent).
The participants were randomly assigned to receive once-weekly subcutaneous injections of cagrilintide–semaglutide (n=164) or semaglutide (n=167) (both escalated to 2.4 mg), in addition to lifestyle intervention, for 68 weeks. Of the participants, 73 percent received the maximum dose of cagrilintide–semaglutide and 90 percent received the maximum dose of semaglutide.
“The safety and tolerability data for cagrilintide–semaglutide in this population were consistent with previous observations in non-Asian populations,” noted Yamauchi.
Adverse events occurred in 87 percent participants in the cagrilintide–semaglutide arm and in 84 percent of those in the semaglutide arm, with the most common being gastrointestinal disorders. One participant in the semaglutide arm died, with the cause of death not deemed to be related to treatment.