CagriSema, a dual-agonist medication combining cagrilintide and semaglutide, is emerging as a promising therapeutic option for weight management and glycemic control in individuals with obesity, overweight, and type 2 diabetes. Clinical trials, such as REDEFINE 1 and 2, have demonstrated its superior efficacy in promoting weight loss compared to its individual components and placebo, while also exhibiting a favorable safety profile.
Understanding CagriSema: A Dual-Agonist Approach
CagriSema is a combination of amylin (cagrilintide) and glucagon-like peptide-1 (semaglutide) analogues being developed for weight management. It uniquely targets two key pathways involved in weight regulation and glucose metabolism:
- Cagrilintide: A long-acting amylin analogue that primarily reduces energy intake.
- Semaglutide: A long-acting glucagon-like peptide-1 (GLP-1) analogue that enhances glucose regulation and also contributes to appetite control.
By acting on both pathways simultaneously, CagriSema offers a synergistic effect, leading to greater weight loss and improved metabolic outcomes compared to either agent alone.
REDEFINE Clinical Trials: Evidence of Efficacy
The REDEFINE (Researching Effects of Dual Incretin and Amylin Full Agonism on Weight) clinical trial program has been instrumental in evaluating the safety and efficacy of CagriSema in diverse populations.
REDEFINE 1: Weight Loss in Adults without Type 2 Diabetes
The randomized, phase 3 REDEFINE 1 study (ClinicalTrials.gov Identifier: NCT05567796) assessed CagriSema's effectiveness in 3417 adults with obesity or overweight and at least one comorbidity, but without type 2 diabetes. Participants were randomly assigned to receive subcutaneous CagriSema 2.4mg/2.4mg, cagrilintide 2.4mg, semaglutide 2.4mg, or placebo once weekly for 68 weeks.
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The results demonstrated that CagriSema-treated patients achieved significantly greater weight loss compared to the other treatment groups. When evaluating under the trial product estimand, findings showed CagriSema-treated patients achieved a superior weight loss of 22.7% compared with 11.8% with cagrilintide 2.4mg, 16.1% with semaglutide 2.4mg and 2.3% with placebo after 68 weeks. Similarly, when evaluating under the treatment policy estimand, CagriSema-treated patients achieved a superior weight loss of 20.4% vs 11.5% with cagrilintide 2.4mg, 14.9% with semaglutide 2.4mg and 3.0% with placebo. Notably, 40.4% of participants achieved at least 25% weight loss with CagriSema when adhering to full treatment.
REDEFINE 2: Weight Loss and Glycemic Control in Adults with Type 2 Diabetes
REDEFINE 2, a phase 3a, double-blind, randomized, placebo-controlled trial, involved 1206 adults with a body-mass index of 27 or more, a glycated hemoglobin level of 7 to 10%, and type 2 diabetes. Participants were assigned in a 3:1 ratio to receive once-weekly cagrilintide-semaglutide (2.4 mg each) or placebo, along with lifestyle intervention, for 68 weeks.
The study revealed that CagriSema significantly reduced body weight and improved glycemic control compared to placebo. The estimated mean change in body weight from baseline to week 68 was −13.7% in the cagrilintide-semaglutide group and −3.4% in the placebo group (estimated difference, −10.4 percentage points; 95% confidence interval, −11.2 to −9.5; P<0.001). More patients in the cagrilintide-semaglutide group than in the placebo group had a weight reduction of 5% or more (P<0.001); the same was true of reductions of at least 10%, 15%, and 20% (P<0.001 for the last comparison). The percentage of patients who had a glycated hemoglobin level of 6.5% or less was 73.5% in the cagrilintide-semaglutide group and 15.9% in the placebo group.
These findings highlight CagriSema's potential to address both weight management and glucose control in individuals with type 2 diabetes and obesity. When considering the results of all study participants adhered to treatment, weight loss with CagriSema rose to 15.7%, compared to 3.1% with placebo.
Safety and Tolerability
In both REDEFINE 1 and 2, CagriSema was generally well-tolerated, with adverse events being mostly mild to moderate and similar to the GLP-1RA class. The most common side effects were gastrointestinal issues, which were typically transient and mild or moderate in severity.
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CagriSema's Impact on Metabolic Adaptation
Weight loss achieved through calorie restriction is often accompanied by metabolic adaptation, where the body reduces its metabolic rate to conserve energy. This adaptation can hinder long-term weight maintenance. Research suggests that CagriSema may help mitigate metabolic adaptation, making it a more effective weight-loss therapy.
Studies in diet-induced obese (DIO) male rats have shown that CagriSema treatment leads to a smaller reduction in total energy expenditure (TEE) compared to calorie restriction alone. This suggests that CagriSema helps preserve energy expenditure, potentially preventing the metabolic slowdown that often accompanies weight loss.
Rat Study Details
Diet-induced obese (DIO) male rats were treated with (1) vehicle with ad libitum feeding (V), (2) CagriSema with ad libitum feeding (CS), (3) vehicle with pair-feeding matched to the caloric intake of the CS rats (PF) or (4) vehicle with caloric restriction to match the weight of the CS rats [weight matched (WM)]. After 21 days, BW increased by 2.6% ± 0.71% in V rats and was reduced in the other cohorts by 8.7% ± 0.91% (CS), 5.6% ± 0.50% (PF) or 9.0% ± 0.42% (WM) (all P < 0.0001 compared with V; P < 0.01 between CS or WM and PF, one-way analysis of variation (ANOVA) with Tukey multiple comparison). Thus, the vehicle-adjusted weight loss was ~12% in the CS and WM rats, but only ~8% in the PF animals.
CS treatment reduced cumulative EI by 39%, but the WM rats required a 51% reduction (P = 0.03 CS versus WM) to reach same weight loss. The cumulative total energy expenditure (TEE) during treatment was similar in the V and CS cohorts, but was reduced by 17% in the WM rats (P = 0.008). Initially, CS treatment drastically reduced EI, which attenuated during treatment to a 25% reduction (P = 0.001). For the WM group, the required EI restriction plateaued at 40% below baseline. Thus, the WM group tended to require a greater reduction in EI than the CS cohort (P = 0.0288), suggesting differences in TEE. Indeed, TEE in CS-treated rats was higher than in WM rats at all points and was statistically different from V at days 7-9, but not at days 1-3 or 18-20.
Mechanisms of Action on Metabolic Adaptation
Researchers examined possible mechanisms for this effect. Plasma leptin levels were similarly reduced in the CS and WM cohorts. Triiodothyronine (T3) and thyroxine (T4) levels did not change. Informative changes were also not detected for plasma glucagon, glucose, free fatty acids (FFA), glycerol, triglyceride, cholesterol, high-density lipoprotein (HDL), alanine aminotransferase or aspartate aminotransferase concentrations. As expected, insulin levels were reduced in the CS and WM cohorts, and β-hydroxybutyrate levels were elevated in the WM cohort. Transcriptome analysis showed many changes in the WM rats, more in liver than muscle. By contrast, the CS rats had far fewer changes, closely matching the V profile.
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Future Directions and Clinical Implications
CagriSema represents a significant advancement in the treatment of obesity and type 2 diabetes. Its dual-agonist mechanism, targeting both appetite regulation and glucose metabolism, offers a more comprehensive approach to weight management and metabolic control.
While CagriSema cannot yet be prescribed by doctors, it is currently under development by Novo Nordisk. The ongoing REDEFINE program continues to evaluate CagriSema's effectiveness across different populations, with the goal of informing future regulatory submissions.