Background Cellulite is a highly prevalent condition associated with alterations in adipose tissue architecture, microcirculation, and connective tissue integrity. Emerging evidence suggests that cellulite may represent a manifestation of both local structural changes and systemic metabolic dysfunction. This study aimed to evaluate the independent and combined effects of systemic metabolic therapy with tirzepatide and a multi-target topical formulation (G21) on cellulite severity and body composition. Methods This retrospective observational cohort study included 92 consecutively treated participants with grade II-III cellulite. Participants were categorized into three groups according to treatment received in routine clinical practice: combination therapy (tirzepatide + G21), tirzepatide alone, or topical G21 alone. The primary outcome was the change in cellulite severity assessed using the Nürnberger-Müller classification scale over 12 months. Secondary outcomes included changes in body weight, waist circumference, and body composition parameters measured by bioelectrical impedance analysis. Between-group differences were assessed using one-way ANOVA, while correlations and multivariable linear regression were performed to evaluate predictors of treatment response. Results Significant improvements in cellulite severity were observed across treatment groups (mean change: -1.63 ± 0.81; p < 0.001), with the greatest reductions observed in the combination and topical therapy groups compared with tirzepatide monotherapy (p = 0.001). Weight loss differed significantly between groups (p = 0.007), with the largest reductions observed in the combination and tirzepatide groups. Importantly, changes in cellulite severity were not significantly correlated with changes in body weight (r = 0.059, p = 0.587) or fat mass (r = -0.115, p = 0.575). In multivariable analysis, baseline body weight (β = 0.811, p < 0.001) and baseline cellulite severity (β = -0.440, p = 0.015) were independent predictors of improvement, whereas weight loss and fat mass reduction were not. Conclusions Improvement in cellulite severity was not significantly associated with weight loss in this cohort and is more strongly associated with baseline tissue characteristics and targeted local interventions. While tirzepatide effectively reduces body weight, topical therapy appeared to be associated with a greater improvement in modulating cellulite-specific structural changes. The combination approach provides the most comprehensive benefit, supporting a potential complementary effect between systemic metabolic and local tissue-targeted mechanisms. These findings reinforce the concept of cellulite as a metabolic-dermal interface and support the use of integrated therapeutic strategies.
