Cagrilintide in combination with Semaglutide Significantly Promotes Weight Loss in Overweight and Obese Adults--An Analysis of the Results of a 68-Week Multicenter Randomized Controlled Clinical Trial
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Cagrilintide in combination with Semaglutide Significantly Promotes Weight Loss in Overweight and Obese Adults--An Analysis of the Results of a 68-Week Multicenter Randomized Controlled Clinical Trial
Views: 1 创始人: Site Editor Publish Time: 2025-07-07 Origin: Site
A multicenter, double-blind, randomized, placebo-controlled and active-drug-controlled Phase 3 clinical trial published in the New England Journal of Medicine recently released the latest findings on the combination of Cagrilintide (a long-acting human insulin analogue) and Semaglutide (a GLP-1 receptor agonist) in the treatment of overweight or obese adults. The study, which covered 3,417 non-diabetic adults in 22 countries and lasted 68 weeks, showed that the combination of the two drugs was effective in weight management, with improvements in relevant cardiometabolic markers and quality of life.
The background of this study is that the current obesity prevalence continues to climb, and the associated complications are serious, the medical community is in urgent need of more effective interventions for weight reduction.Semaglutide alone is effective in weight reduction and cardiovascular risk benefit, while Cagrilintide is expected to be effective due to its unique mechanism of appetite regulation. Combining the two drugs with different mechanisms is expected to achieve synergistic effects.
Research background and existing challenges
Approximately 46% of adults worldwide are overweight or obese, and this is expected to rise to 54% by 2035. Obesity not only leads to metabolic diseases (type 2 diabetes, hypertension, dyslipidemia), but also mechanical problems such as obstructive sleep apnea and osteoarthritis, as well as psychological burdens such as depression and anxiety, which have a serious impact on life expectancy and quality of life.
Pharmacological treatment of obesity has become an important adjunct for patients who have difficulty with lifestyle interventions, and Semaglutide, a GLP-1 receptor agonist, has been approved by the FDA and the EMA, demonstrating its efficacy in obesity weight management and cardiovascular risk reduction. Nonetheless, there is a need to improve the efficacy and tolerance of the drug.
Amylin regulates appetite and body weight through the central nervous system, while Cagrilintide, a human amylin analog that acts on multiple amylin receptors, has shown potential for weight loss in initial clinical trials. The combination of the two may lead to better weight management through complementary mechanisms.
Therefore, the aim of this study was to critically evaluate the safety and weight loss efficacy of Cagrilintide in combination with Semaglutide in overweight and obese adults.
Study Design and Methods.
This study was a 68-week multicenter, double-blind, randomized, placebo- and active-controlled phase 3a clinical trial. Those with 1) BMI ≥30 kg/m^2 or 2) BMI ≥27 kg/m^2 with at least one obesity-related complication were included. Diabetics and those who had recently used related glucose-lowering or weight-loss medications were primarily excluded.
3417 adults without diabetes mellitus were randomized into four groups according to the 21:3:3:7 ratio and received:
All participants were given a uniform lifestyle intervention. The medication was administered via subcutaneous injection once a week in a gradual escalation from 0.25 mg to a target dose of 2.4 mg.
To accurately assess efficacy, two major primary endpoints were set:
Percentage of relative weight change
Proportion of patients with ≥5% weight loss (combination vs placebo)
Secondary endpoints included higher percentage weight loss attainment (20%, 25%, 30%), change in waist circumference and blood pressure, and quality of life scores. DXA scans were also performed on some patients to assess changes in body composition.
Statistical analyses were based on treatment-policy estimation, which included all randomized groups, and reflected real-world clinical efficacy, with a significance level of 5%.
Main findings
Basic Patient Characteristics
3417 participants were included, 67.6% female, 72.0% white, mean age 46-47 years.
Mean weight was about 107 kg, mean BMI 37.9 kg/m^2, and waist circumference about 115 cm.
Common comorbidities were hyperlipidemia and hypertension; 32.1% had prediabetic status.
Participants' baseline characteristics were more balanced across groups.
Weight Loss Effect
At the end of 68 weeks, the mean weight loss was 20.4% in the combination group and only 3.0% in placebo, a significant difference between the two groups (difference -17.3 percentage points, 95% CI -18.1 to -16.6, P<0.001) (see [Fig1]).
More than 90% of patients in the combination group lost ≥5% of their body weight, compared with only 31.5% in the placebo group.
The proportions of patients who lost ≥20%, ≥25%, and ≥30% of their body weight were 53.6%, 34.7%, and 19.3%, respectively, in the combination group, which was much higher than in the single-agent and placebo groups.
Fifty-four percent of patients with baseline obesity in the combination group had their BMI reduced to the non-obese range (BMI <30) after treatment, while only 11.1% in the placebo group achieved this goal.
Absolute weight loss was approximately 21.6 kg.
Changes in body composition
The DXA data showed that the combination treatment resulted in a reduction of approximately 17.0 kg of total fat mass and approximately 8.4 kg of lean body tissue.
Approximately 67% of the weight loss was fat loss and 33% was lean body tissue loss, showing good body composition improvement.
Metabolic and Cardiovascular Risk Indicators Improved
Systolic blood pressure decreased by 6.7 mmHg and diastolic blood pressure decreased by 3.2 mmHg in the combination group compared with placebo (both P<0.001).
There were significant improvements in blood glucose, insulin, lipid and C-reactive protein levels.
Of the prediabetic patients, 87.7% reversed to normoglycemia in the combination group and only 32.2% in the placebo group.
Quality of life-related physical function scores improved significantly.
Safety Assessment
The major adverse reactions focused on gastrointestinal reactions such as nausea, vomiting, and diarrhea, which were usually mild to moderate, occurring more often than not and abating after the dose-escalation period.
Both deaths were related to non-drug directly related causes (cancer and suicide).
There was a slight increase in heart rate and no significant mental health adverse effects.
Value and Significance of the Study
This study demonstrates the seminal efficacy of the combination of Cagrilintide and Semaglutide for weight management in overweight and obese adults - which has led to new heights of drug options available for clinical treatment of obesity. Approximately 53.6% of patients lost ≥20% of their body weight, and nearly 20% even lost more than 30% of their body weight, which not only far exceeds the efficacy of most existing medications, but also provides a solid rationale for mitigating obesity-related multisystem comorbidities.
The significant weight and fat loss accompanied by significant improvement in blood pressure and blood glucose indicators greatly enhances the overall cardio-metabolic benefit potential of this regimen, which has a wide clinical applicability and is expected to reduce the burden of diabetes mellitus and cardiovascular disease. In addition, the improvement in quality of life and physical function will provide tangible benefits to patients in their daily lives.
The safety assessment suggests that common gastrointestinal side effects, although high, are mild to moderate and well tolerated and can be mitigated by individualized dose adjustments. The flexible dose-escalation design is also clinically feasible.
The biological basis for the advantages of the combination is the synergistic regulation of appetite and energy metabolism through different neuroendocrine pathways, promoting the evolution of therapeutic strategies from single-target to multi-target.
This study provides an important scientific and clinical reference for the future treatment of obesity, and opens a new chapter of multi-mechanism combination for precise weight loss treatment.
Trends in body weight
Histogram of rate of achievement of different weight loss goals
