Background <p>Obesity is a global health challenge associated with substantial cardiometabolic morbidity. Cagrilintide, a long-acting amylin analogue, alone or in combination with semaglutide (CagriSema), has emerged as a novel pharmacologic strategy for weight management. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of cagrilintide-based therapies in adults with overweight or obesity.</p> Methods <p>A systematic review and meta-analysis of randomized controlled trials was conducted according to PRISMA 2020 and AMSTAR 2. Eligible studies enrolled adults with overweight or obesity randomized to cagrilintide or CagriSema versus placebo and reported at least one efficacy or safety outcome. The primary outcome was percent change in body weight. Secondary outcomes included absolute weight change, waist circumference, blood pressure, glycated hemoglobin (HbA1c), and safety outcomes. Random-effects meta-analyses were conducted, and risk of bias was assessed using the Cochrane RoB 2 tool.</p> Results <p>Four trials including 5,023 participants were pooled. Cagrilintide significantly reduced percent body weight versus placebo (mean difference − 6.08%, 95% CI − 8.02 to − 4.14), as did CagriSema (− 5.98%, 95% CI − 10.64 to − 1.32). Both interventions significantly reduced absolute body weight. CagriSema produced a significant reduction in waist circumference and HbA1c, whereas cagrilintide alone showed modest blood pressure improvements without significant glycemic effects. Overall adverse events were more frequent with active treatment, but discontinuation rates were comparable to placebo.</p> Conclusions <p>Cagrilintide and CagriSema achieved clinically meaningful weight loss with favorable cardiometabolic effects and acceptable tolerability, supporting their role as emerging options in obesity pharmacotherapy.</p>