An important international trial shows that combining cagrilintide and semaglutide helps adults with obesity achieve more dramatic weight loss and better metabolic health than current single-drug therapies.
Trial: Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity. Image Credit: Alones / Shutterstock
In a recent study published in the New England Journal of Medicine, a group of researchers evaluated the effectiveness of a combined regimen of cagrilintide and semaglutide in reducing body weight and its safety for adults with obesity but without diabetes.
Background
Almost half of adults worldwide now live with excess body fat, a figure projected to climb to 54% by 2035, and it drives type 2 diabetes, hypertension, dyslipidemia, osteoarthritis, and mood disorders. Long-term weight-management medications work best when paired with healthier eating habits and regular physical activity.
Semaglutide mimics glucagon-like peptide 1 (GLP-1), whereas cagrilintide mimics the satiety hormone amylin, so each curbs appetite through a distinct pathway. Their combined effect in non-diabetic adults has not been tested in a phase 3 trial; hence, further research is needed.
About the study
The phase 3a, multicenter, randomized, double-blind, placebo- and active-controlled REDEFINE 1 trial enrolled 3,417 adults across 22 countries. Eligibility required a body mass index (BMI) of 30 kg/m² or higher, or for those with at least one obesity-related comorbidity and no diabetes, a BMI of 27 kg/m² or higher.
Participants were allocated in a 21:3:3:7 ratio to weekly injections of one of four regimens: fixed-dose cagrilintide 2.4 mg plus semaglutide 2.4 mg, semaglutide alone, cagrilintide alone, or placebo. All volunteers also received standardized lifestyle coaching on diet and exercise.
Dosing began at 0.25 mg of each active drug and escalated every four weeks until the full 2.4 mg dose was reached by week 16. That dose was then maintained for 52 weeks, followed by seven weeks of observation. Investigators tapered or paused doses if intolerance developed (57.4% maintained maximum dose at week 68; 74.7% reached it at some point).
DXA scans in a subgroup (7.4% of participants) were used to track changes in fat and lean tissue. The primary outcomes were the percentage weight change and the proportion of participants losing at least 5% of their baseline weight, using treatment-policy estimand analysis (intention-to-treat principle).
Confirmatory secondary endpoints included ≥20%, ≥25%, and ≥30% weight loss, with all analyses performed on an intention-to-treat basis and reported with 95% confidence intervals. Investigators also collected serial blood samples to track shifts in lipids, C-reactive protein, and liver enzymes, providing a broader picture of metabolic health. Retention strategies like coaching calls, injection reminders, and motivational interviews kept dropout rates low.
Safety signals of special interest, including pancreatitis, gallbladder events, neoplasms, and suicidal ideation, were adjudicated by blinded expert committees. An extension phase (NCT06780449) will assess longer-term outcomes. Heart rate changes were monitored as part of the cardiovascular safety assessment.
Study results
Of the 3,417 randomized adults, 2,108 received the drug combination, 302 received semaglutide, 302 received cagrilintide, and 705 received a placebo. The mean age was 47 years; women comprised 67.6%, and most had dyslipidemia or hypertension at baseline. By week 68, 88.2% of those assigned to combination therapy remained on treatment.
The combination produced a mean weight reduction of 20.4% under the treatment-policy estimand, versus 3.0% with placebo (-17.3% difference; P<0.001). In the trial-product estimand analysis (accounting for treatment adherence), reductions reached 22.7% and 2.3%, respectively, corresponding to an absolute weight loss of -21.6 kg with combination therapy.
Notably, 91.9% of the combination group lost at least 5% of baseline weight, while 53.6% lost ≥20%. Further, 34.7% achieved ≥25% loss, and 19.3% achieved ≥30% loss. By contrast, semaglutide alone yielded 14.8% of patients achieving ≥25% weight loss, and cagrilintide alone yielded 6.5%.
BMI, waist circumference, and waist-to-height ratio improved significantly with combination therapy. Remarkably, 54% of those initially classified with obesity moved into the non-obese BMI range by study end vs. 11.1% with placebo.
In the DXA subgroup (n = 252), the data showed that 67% of the weight reduction originated from fat mass and 33% from lean soft tissue. This ratio of fat-to-lean mass reduction is consistent with established obesity therapies and suggests that metabolic function is preserved during weight loss. Fat mass decreased by 17.0 kg with the combination, compared to 3.4 kg with the placebo, whereas lean mass decreased by 8.4 kg, compared to 2.6 kg.
Cardiometabolic markers also shifted favorably. Systolic blood pressure declined by 9.9 mm Hg with the combination and 3.2 mm Hg with placebo (-6.7 mm Hg difference; P<0.001). Among prediabetic participants, 87.7% reverted to normoglycemia with the combination, compared with 32.2% on placebo.
Quality of life and physical function, gauged by the Impact of Weight on Quality of Life-Lite Clinical Trials (IWQOL-Lite-CT) and the 36-Item Short-Form Health Survey (SF-36), improved more with the combination therapy. Mean heart rate increased slightly by 0.94 beats per minute with combination therapy versus decreases in other groups.
Most adverse events were gastrointestinal, such as nausea, diarrhea, or constipation, and occurred in 79.6% of the combination arm versus 39.9% of placebo recipients. These events were usually mild or moderate. Serious adverse events appeared in 9.8% of the combination group, including two deaths (one suicide, one cancer).
Discontinuation because of adverse events remained low at 5.9%. Limitations included the predominantly White and female participants, as well as normal baseline metabolic values, which may have attenuated the improvements.
Conclusions
To summarize, the 68-week treatment with coadministered cagrilintide and semaglutide resulted in substantial and clinically meaningful weight loss in adults with overweight or obesity, significantly outperforming monotherapies and placebo (- 5.5% vs. semaglutide;- 8.9% vs. cagrilintide).
combination also improved several cardiometabolic parameters, including blood pressure and glucose levels, and enhanced physical functioning. Body composition data should be interpreted cautiously due to the small subgroup analysis; however, the fat-to-lean mass ratio aligns with metabolic preservation goals.
While gastrointestinal side effects were common, they were mostly not acute. Minimal changes in heart rate indicate cardiovascular safety. This trial highlights the potential of combining agents with complementary mechanisms to tackle obesity more effectively than single-drug therapies.