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@GarveyEtAl_2025_CoadministeredCagrilintideSemaglutide

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Reference

Garvey, W. T., Blüher, M., Osorto Contreras, C. K., Davies, M. J., Winning Lehmann, E., Pietiläinen, K. H., Rubino, D., Sbraccia, P., Wadden, T., Zeuthen, N., & Wilding, J. P. H. (2025). Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity. New England Journal of Medicine, NEJMoa2502081. https://doi.org/10.1056/NEJMoa2502081

Blue: Important conclusions

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Cagrilintide affects appetite regulation through direct effects in the brain.

Yellow: Interesting

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adults without diabetes who had a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of 30 or higher or a BMI of 27 or higher with at least one obesity-related complication

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semaglutide

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howed clinically significant bodyweight reductions of 9.6 to 17.4% in persons with overweight or obesity with or without diabetes, as well as reductions in cardiometabolic risk factors and in cardiovascular events

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Amylin is a satiety hormone involved in the central regulation of food intake, body weight, and glycemia.10 Cagrilintide is a long-acting, human amylin analogue, with affinity for three amylin receptors (AMY1R, AMY2R, and AMY3R) and a calcitonin receptor.

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Investigators were permitted to delay dose escalation or reduce the dose if the current dose was associated with adverse effects or if the participant reached a BMI in the lower normal range and had a health concern. Although the goal was to escalate to the maximum dose, participants were allowed to continue in the trial while receiving a submaximum dose on the basis of clinical judgment.

  • como de importante es esto? conseguimos un 20 % de perdida de peso aun cuando un gran % de pacientes no llega a la dosis máxima?

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The coprimary end points were the percent change in body weight and a body-weight reduction of 5% or more with cagrilintide–semaglutide as compared with placebo. Confirmatory secondary end points were a reduction in body weight of 20% or more, 25% or more, and 30% or more; the changes with cagrilintide–semaglutide as compared with placebo in waist circumference, systolic blood pressure, the Impact of Weight on Quality of Life–Lite Clinical Trials Version (IWQOL-Lite-CT) Physical Function score, the 36-Item Short-Form Health Survey (SF-36), version 2, the Physical Functioning score, and the IWQOL-Lite-CT and SF-36 scores in participants with poor physical functioning at baseline; and the percent change in body weight with cagrilintide–semaglutide as compared with semaglutide alone and cagrilintide alone.

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We calculated that a sample size of 3400 would provide an effective power of 99% for the coprimary and confirmatory secondary end points, which were tested in a prespecified hierarchical order

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A majority of the participants were women (67.6%) and White (72.0%); the mean age was 47.0 years

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Dyslipidemia and hypertension were the most common obesity-related complications, and 32.1% of the population had prediabetes.21

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The percentage of participants still receiving the drug or placebo at week 68 was 88.2% in the cagrilintide–semaglutide group, 91.4% in the semaglutide group, 87.7% in the cagrilintide group, and 75.9% in the placebo group.

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At week 68, the percentage of participants receiving the maximum dose of the drug or placebo was 57.4% in the cagrilintide–semaglutide group, 70.9% in the semaglutide group, 82.5% in the cagrilintide group, and 70.6% in the placebo group, and the percentage who received the maximum dose at any point after randomization was 74.7%, 86.1%, 95.4%, and 91.6%, respectively (Table S3; dose levels over time are shown in Fig. S3).

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most common reasons for permanent discontinuation of the trial product were adverse events

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mean percent body-weight reduction at week 68 was −20.4% with cagrilintide–semaglutide and −3.0% with placebo

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estimated mean change in absolute body weight of −21.6 kg

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The percentages of participants reaching the weight-reduction targets of 25% or more and 30% or more were 34.7% and 19.3%, respectively, in the cagrilintide–semaglutide group

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change in BMI was −6.6

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Changes in BMI categories also favored cagrilintide–semaglutide (Fig. S6), with 54.0% of the participants with obesity at baseline in the cagrilintide–semaglutide group reaching the threshold for nonobesity at week 68

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cagrilintide–semaglutide (such that 67% of total weight loss corresponded to fat mass and 33% to lean soft-tissue mass)

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mean reduction from baseline to week 68 in systolic blood pressure

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mean changes in glycated hemoglobin, glucose, insulin, lipid, and C-reactive protein levels were greater with cagrilintide–semaglutide than with placebo. Within the group of participants with prediabetes at baseline, 87.7% of those receiving cagrilintidesemaglutide and 32.2% of those receiving placebo attained normoglycemia

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The percentage of participants who reported any adverse event with cagrilintide–semaglutide was 92.3%, as compared with 89.7% with semaglutide,

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gastrointestinal events, which occurred more often with cagrilintide–semaglutide than with semaglutide, cagrilintide, or placebo (79.6% vs. 73.8%,

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Most gastrointestinal adverse events were mild to moderate in severity

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most common serious adverse events were hepatobiliary and gastrointestinal disorders in the cagrilintide–semaglutide

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The mean weight reduction observed with cagrilintide–semaglutide is in the highest range of that observed with existing weight-loss interventions

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In many persons with obesity, weight reductions of 20% or more lead to reductions in obesity-related complications

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Although 57.4% of the participants assigned to cagrilintide–semaglutide were receiving the

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maximum dose at 68 weeks, 74.7% had received the maximum dose at some point after randomization. This finding most likely reflects the ability of the investigators to follow protocol-specified dose-adjustment flexibility rules and to maintain submaximum doses according to their clinical judgment to balance efficacy and adverse events

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doses below the target might be highly effective for some patients and that dose reductions based on the clinical judgment of study site investigators may be appropriate

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Gastrointestinal adverse events occurred less frequently in the cagrilintide group than in the semaglutide and cagrilintide–semaglutide groups

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Green: Agree with the paper

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coprimary end points were the relative change in body weight and a reduction of 5% or more in body weight from baseline to week 68 with cagrilintide–semaglutide as compared with placebo

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Body-weight reductions of 20% or more, 25% or more, and 30% or more were assessed as confirmatory secondary end points.

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mean percent change in body weight from baseline to week 68 was –20.4% with cagrilintide–semaglutide as compared with –3.0% with placebo

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Participants receiving cagrilintide–semaglutide were more likely than those receiving placebo to reach weight-loss targets of 5% or more, 20% or more, 25% or more, and 30% or more

Red: Disagree with the paper

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Gastrointestinal adverse events (affecting 79.6% in the cagrilintide–semaglutide group and 39.9% in the placebo group), including nausea, vomiting, diarrhea, constipation, or abdominal pain, were mainly transient and mild-to-moderate in severity.

  • Lanzo reflexión al aire: parece que en la carrera por el mercado del sobrepeso y la diabetes, las farmas y el mercado buscan el fármaco que produzca la MAYOR pérdida de peso. ¿No es un -20% de peso suficiente? Deberían centrarse más en reducir los efectos secundarios (que no son pocos) que puedan llevar al paciente a dejar la terapia.

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Key exclusion criteria were diabetes, surgical treatment (exceptions are described in the Supplementary Appendix, available with the full text of this article at NEJM.org), and treatment with a glucose-lowering agent, GLP-1 receptor agonist, or antiobesity medication within 90 days before screening.

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Fatigue, dizziness, alopecia, gallbladderrelated disorders, and injection-site reactions (Table 3) also occurred more frequently

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prevalence of nausea, diarrhea, and vomiting peaked during dose escalation and decreased thereafter, whereas the prevalence of constipation remained relatively constant after dose escalation

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Serious adverse events were reported in 9.8% of the participants receiving cagrilintide–semaglutide, in 5.0% of those receiving semaglutide

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Two deaths were reported in the cagrilintide–semaglutide group; the causes of death, as established by the event adjudication committee, were suicide and cancer

Purple: To learn more

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Improvements in blood pressure generally occurred early in the trial, when maximum weight loss had not yet been achieved, and were sustained through week 68 in participants receiving cagrilintide–semaglutide; improvements of this magnitude may be considered to be similar to those achieved with antihypertensive medications in clinical trials

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