SAT-682 - Breaking the Weight-Loss Plateau: Superior Efficacy of Cagrilintide-Semaglutide Polytherapy over Semaglutide Monotherapy

Introduction

Semaglutide, a GLP-1 receptor agonist, is highly effective for obesity management but is frequently limited by a weight-loss plateau due to adaptive neurohormonal responses. Cagrilintide, a long-acting amylin analogue, enhances satiety and delays gastric emptying via central appetite regulation pathways distinct from GLP-1 signaling. Combined cagrilintide–semaglutide (CagriSema) polytherapy targets complementary, non-overlapping mechanisms to overcome weight-loss resistance. This systematic review and meta-analysis evaluates whether dual amylin–GLP-1 receptor activation provides superior weight-loss and glycemic outcomes compared with semaglutide monotherapy, the current standard of care.

Method

We performed a PRISMA-compliant systematic review of PubMed, Embase, Web of Science, and Scopus databases from their inception through August 2025. Randomised Control Trials evaluating the effects of Semaglutide monotherapy and CagriSema polytherapy were included. Primary outcomes assessed included absolute change in body weight, percentage change in body weight, and percentage change in HbA1c. A random-effects model was used for data synthesis, and heterogeneity was evaluated using the I² statistic. All statistical analyses were performed using Review Manager (RevMan) version 5.4.

Result

CagriSema displayed statistically significant superiority over Semaglutide monotherapy across all primary endpoints. CagriSema resulted in additional absolute weight reduction of 9.11 kg (95% CI: –12.84 to –5.39; p < 0.00001), greater percentage weight loss by 11.45% (95% CI: –15.49 to –7.49; p < 0.00001) and an incremental reduction in HbA1c by an additional 0.61% ( 95% CI: –1.10 to –0.12; p = 0.02) compared to Semaglutide alone. While semaglutide monotherapy was also effective as compared to placebo, with an absolute body weight reduction of 6.08 kg (95% CI: –7.18 to –4.98; p  < 0.00001), a percentage decrease in body weight by 3.9% (95% CI: –5.7 to –2.11; p  < 0.0001), and HbA1c reduction by 10.48%(95% CI: –18.9 to –2.05; p = 0.01), CagriSema conferred a robust additive benefit.

Conclusion

CagriSema redefines the efficacy ceiling for medical weight management by providing 11.45% greater percentage weight loss compared to Semaglutide alone. By combining the synergistic neurohormonal effects of GLP-1 agonism and Amylin, CagriSema offers a potent strategy for patients facing weight loss plateau providing substantial weight reduction beyond what monotherapy can provide.

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