BACKGROUND

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are established treatments for obesity. However, it remains inconclusive whether the combination of lifestyle modifications and GLP-1RA interventions can lead to greater weight loss and better control of cardiovascular biomarkers. We aimed to evaluate the efficacy of this combination therapy on weight loss and cardiometabolic markers in adults with overweight or obesity.

METHODS

We searched PubMed, Embase, and the Cochrane Library to identify randomized controlled trials published from inception until May 10, 2025 that assessed the effects of lifestyle modifications combined with GLP-1RAs in adults with overweight or obesity. The standard control group in these trials was set as lifestyle modifications combined with placebo. The efficacy outcomes were the changes of body weight, waist circumference, blood pressure, fasting blood glucose, glycated hemoglobin and lipids. Mean differences (MDs) were calculated using a random-effects model to assess the effects of lifestyle modifications combined with GLP-1RAs on weight loss and cardiometabolic markers. Risk of bias was assessed with the Cochrane risk-of-bias algorithm, with overall certainty of evidence evaluated by Grading of Recommendations Assessment, Development and Evaluation (GRADE) tool. This study is registered with PROSPERO (CRD42024600250).

FINDINGS

A total of 33 randomized controlled trials involving 12,028 participants were included. Lifestyle modification combined with GLP-1RAs results in a significant mean weight loss of 7.13 kg compared with control groups (MD: -7.13 kg, 95% CI: -9.02, -5.24, < 0.001). Significant improvements were also observed in other body composition parameters and cardiometabolic biomarkers, including waist circumference (MD: -5.74 cm, 95% CI: -7.17, -4.31, < 0.001), lean mass (MD: -1.29 kg, 95% CI: -2.17, -0.41, = 0.004), fat mass (MD: -2.93 kg, 95% CI: -4.70, -1.12, = 0.001), systolic blood pressure (MD: -3.99 mmHg, 95% CI: -5.66, -2.33, < 0.001), diastolic blood pressure (MD: -1.11 mmHg, 95% CI: -1.71, -0.42, = 0.002), glycated hemoglobin (MD: -0.31%, 95% CI: -0.47, -0.15, < 0.001), fasting blood glucose (MD: -6.51 mg/dL, 95% CI: -7.31, -4.71, = 0.004), total cholesterol (MD: -5.85 mg/dL, 95% CI: -9.78, -1.91, = 0.004), triglycerides (MD: -13.44 mg/dL, 95% CI: -20.38, -6.50, < 0.001), low-density lipoprotein cholesterol (MD: -4.78 mg/dL, 95% CI: -7.35, -2.22, = 0.003), with the exception of high-density lipoprotein cholesterol (MD: -0.14 mg/dL, 95% CI: -1.05, 0.76, = 0.750). Longer treatment duration, use of semaglutide or tirzepatide, weekly dosing, and studies conducted in North America showed more pronounced weight loss effects. Risk of bias assessment indicated no high-risk studies among the included trials. The GRADE assessment indicated a range of certainty from low to high across outcomes, with high certainty for changes in high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and body fat percentage, and moderate to low certainty for changes in body weight, blood pressure, glycemic outcomes, and other metabolic outcomes, largely influenced by heterogeneity and potential publication bias.

INTERPRETATION

Lifestyle interventions combined with GLP-1RAs may help reduce body weight and improve cardiometabolic biomarkers in adults with overweight or obesity. In light of the varying certainty of evidence across outcomes, these results should be interpreted cautiously. Treatment duration, drug type, dosage, and geographic region were key influencing factors of intervention effectiveness.

FUNDING

Startup Fund for Young Faculty at Shanghai Jiao Tong University (Grant No. KJ3-0214-24-0011).