Continued CagriSema treatment preserves weight loss by reducing energy intake and maintaining energy expenditure in rats.
CagriSema can induce weight loss in rats by reducing energy intake, but weight regain occurs rapidly after treatment stops, suggesting ongoing therapy may be necessary.
Where it sits
this study against the rest of the cagrilintide (am833) corpusSummary and findings
This study measured the effects of CagriSema (CS) on energy balance in male diet-induced obese rats over a treatment period of 6 weeks and a follow-up of 4 weeks after discontinuation. The study found that CS induced rapid weight loss primarily through reduced energy intake while maintaining energy expenditure. After discontinuation, rats exhibited hyperphagia and rapid weight regain.
Abstract
<h4>Purpose</h4>CagriSema (CS), combining the amylin receptor agonist cagrilintide with the glucagon-like peptide 1 receptor agonist semaglutide, is being developed for obesity and type 2 diabetes. We quantified CS effects on energy balance during initial treatment, weight maintenance, and after discontinuation.<h4>Methods</h4>Male diet-induced obese rats underwent indirect calorimetry during 6 weeks of treatment and for 4 weeks after discontinuation. Treatments were a) vehicle, b) CS, c) calorie-restriction to match CS body weight loss (weight matched, WM), and d) calorie-restriction to match CS food intake (pair-feeding, PF).<h4>Results</h4>CS effects occurred in four phases. During days 1-10 (Phase I), CS induced rapid weight loss mainly through reduced energy intake (EI), while energy expenditure (EE) was relatively preserved. EE was significantly lower in WM rats, consistent with metabolic adaptation. During days 11-42 (Phase II), reduced body weight was maintained in the CS, WM, and PF groups, and respiratory exchange ratio converged across groups, indicating metabolic steady state had been reached. Reduced EI and preserved total EE respectively explained 86% and 14% of CS weight loss efficacy. Maintained resting/sleeping EE contributed to the total EE preservation. Treatment discontinuation (days 43-52, Phase III) caused hyperphagia and rapid weight regain. During days 53-68 (Phase IV), all groups reached metabolic steady state and weight gain returned to pretreatment rates. Body weight plateaued in approximately half the time needed to reach metabolic steady state, and metabolic adaptation reversed within ∼7 days after discontinuation.<h4>Conclusions</h4>By persistently lowering EI and attenuating metabolic adaptation, CS enables sustained weight loss in rats; however, the reversal after treatment cessation suggests that chronic pharmacological therapy may be required to maintain weight loss.
Background
This study investigates the effects of CagriSema, a combination of cagrilintide and semaglutide, on energy balance in obese rats. Prior research has indicated that both components can influence weight management, but the specific mechanisms and long-term effects remain unclear. Understanding these effects is crucial for developing effective obesity treatments.
Methods
The study utilized male diet-induced obese rats, with a total duration of 10 weeks, including 6 weeks of treatment and 4 weeks post-treatment. The treatments included vehicle, CagriSema, calorie-restriction to match body weight loss, and calorie-restriction to match food intake. Primary outcomes measured included energy intake and energy expenditure.
Results
During days 1-10, CS induced rapid weight loss mainly through reduced energy intake. The study reported that reduced energy intake and preserved total energy expenditure explained 86% and 14% of CS weight loss efficacy, respectively. After treatment discontinuation, hyperphagia and rapid weight regain were observed during days 43-52.
Interpretation
The findings suggest that while CagriSema can effectively reduce energy intake and maintain energy expenditure, the rapid weight regain after treatment cessation highlights a potential limitation in long-term efficacy. The effect sizes, while statistically significant, may not be clinically meaningful in humans without further evidence. Confounding factors include the use of a rodent model and the short duration of follow-up.
Key findings
- CS induced rapid weight loss mainly through reduced energy intake during days 1-10.
- Reduced energy intake and preserved total energy expenditure explained 86% and 14% of CS weight loss efficacy, respectively.
- Treatment discontinuation caused hyperphagia and rapid weight regain during days 43-52.
- Body weight plateaued in approximately half the time needed to reach metabolic steady state after treatment cessation.
- Metabolic adaptation reversed within approximately 7 days after discontinuation.
Limitations
- Conducted in rats, which may not fully translate to human physiology.
- Small sample size limits generalizability.
- Short duration of treatment and follow-up may not capture long-term effects.
- No human data provided.