Comparative Effects of Diet, Exercise, and Pharmacotherapy on Metabolic Syndrome Severity in Overweight and Obese...

Background/Objectives: Lifestyle modification is a cornerstone of obesity and metabolic syndrome (MetS) management, yet pharmacological agents are increasingly prescribed in the treatment of these highly prevalent issues. This meta-analysis compared the effects of diet-only, exercise-only, combined diet + exercise, and pharmacological interventions on MetS severity (MetS z-score) and related cardiometabolic outcomes in adults with overweight or obesity. Methods: A systematic search of relevant databases identified eligible studies published up to October 2025. Random-effects meta-analyses were conducted for pooled pre-post changes within intervention types and, where available, intervention-versus-control and head-to-head comparisons. Results: Forty-six studies comprising 85 intervention arms and 12,128 participants were included. Significant reductions in pooled MetS z-scores were observed following diet-only (-0.72 units; 17 arms), exercise-only (-0.63 units; 40 arms), diet + exercise (-0.68 units; 23 arms), and pharmacological interventions (-0.30 units; 5 arms) (all p < 0.001). Compared with controls, exercise-only reduced MetS z-score by -0.68 units (21 arms), and diet + exercise by -0.45 units (6 arms) (both p < 0.001), whereas pharmacotherapy showed no significant effect (-0.07 units; 5 arms; p = 0.134). Direct comparisons demonstrated that combined diet + exercise achieved greater MetS z-score reductions than diet-only (-0.75 units; 10 arms, p < 0.001). Moreover, lifestyle interventions consistently improved fasting glucose, triglycerides, HDL cholesterol, waist circumference, and blood pressure. Subgroup analyses identified caloric restriction as a key dietary moderator for cardiometabolic improvements, and meta-regression revealed exercise volume as a predictor of MetS z-score decrease. Conclusions: All intervention types improved cardiometabolic risk, but lifestyle strategies-particularly diet + exercise-demonstrated the most consistent and robust effects. While contemporary pharmacological therapies are known to induce substantial weight loss, their effects on overall cardiometabolic risk assessed by composite measures such as the MetS z-score remain insufficiently characterized, as most medication trials report single outcomes and frequently include concurrent lifestyle interventions. Therefore, there is a need for further trials evaluating the impact of anti-obesity medications on overall cardiometabolic health.