Efficacy of lifestyle modification combined with GLP-1 receptor agonists on body weight and cardiometabolic biomarkers in individuals with overweight or obesity: a systematic review and meta-analysis.
This systematic review and meta-analysis pooled data from 33 randomized controlled trials (n = 12,028 adults with overweight or obesity) to evaluate whether combining lifestyle modifications with GLP-1 receptor agonists (GLP-1RAs) produces greater improvements in body weight and cardiometabolic markers than lifestyle modification plus placebo. Searches covered PubMed, Embase, and the Cochrane Library through May 2025, and the protocol was pre-registered on PROSPERO. The study found that the combination therapy was associated with a statistically significant mean weight reduction of 7.13 kg, along with improvements in waist circumference, fat mass, systolic blood pressure, fasting blood glucose, glycated hemoglobin, total cholesterol, triglycerides, and LDL cholesterol. HDL cholesterol did not show a significant change. Subgroup analyses suggested that longer treatment duration, use of semaglutide or tirzepatide, weekly dosing, and trials conducted in North America were associated with larger weight loss effects. No included trials were rated high risk of bias. GRADE certainty ranged from low to high across outcomes, with heterogeneity and potential publication bias limiting confidence in several findings. The authors conclude that results should be interpreted cautiously given this variability in evidence certainty.
Why this grade: Although the meta-analysis synthesizes 33 RCTs in humans, GRADE certainty is moderate-to-low for most primary outcomes due to significant heterogeneity and potential publication bias, preventing a strong-human rating.
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, P P P = 0.004), fat mass (MD: -2.93 kg, 95% CI: -4.70, -1.12, P = 0.001), systolic blood pressure (MD: -3.99 mmHg, 95% CI: -5.66, -2.33, P P = 0.002), glycated hemoglobin (MD: -0.31%, 95% CI: -0.47, -0.15, P P = 0.004), total cholesterol (MD: -5.85 mg/dL, 95% CI: -9.78, -1.91, P = 0.004), triglycerides (MD: -13.44 mg/dL, 95% CI: -20.38, -6.50, P P = 0.003), with the exception of high-density lipoprotein cholesterol (MD: -0.14 mg/dL, 95% CI: -1.05, 0.76, P = 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).
Educational summary of published research — not medical advice. License: cc by-nc-nd. Full text is shown only where licensing permits.