Real-World Effectiveness and Safety of Tirzepatide, Semaglutide, and Liraglutide in Adults with Overweight or Obesity without Diabetes: A Comparative Study

Background: Obesity is a chronic metabolic disease associated with substantial cardiometabolic risk and long-term morbidity. Although randomized controlled trials have demonstrated the efficacy of incretin-based therapies, real-world comparative data in adults with overweight or obesity without diabetes remain limited. Real-world studies provide complementary evidence by capturing treatment effectiveness, tolerability, dose escalation, and adherence in routine clinical practice. Methods: This single-center, retrospective, real-world observational study was conducted at a private internal medicine clinic in Istanbul, Turkey, using electronic medical records of consecutively treated patients between September 2023 and September 2024. Adults aged 18– 75 years with overweight or obesity without diabetes who received liraglutide, semaglutide, or tirzepatide for at least 36 weeks were included. Treatment allocation was based on routine clinical decision-making. Insulin resistance was assessed using the homeostasis model assessment of insulin resistance (HOMA-IR). The primary outcome was percent change in body weight from baseline to week 36. Secondary outcomes included changes in waist circumference, lipid profile, liver enzymes, pancreatic enzymes, HbA1c, insulin resistance, and adverse events. Between-group comparisons were performed using appropriate parametric or non-parametric tests and multivariable models. Baseline hepatic steatosis was assessed by ultrasonography. Lipid-lowering therapies were recorded and considered in analyses. Adverse events were systematically collected during follow-up; mild elevations in amylase and lipase were defined as ≤ 3 times the upper limit of normal. Results: All three treatments were associated with significant reductions in body weight and waist circumference at week 36 (p < 0.01). Weight loss was greater in the tirzepatide group compared with the liraglutide and semaglutide groups. Improvements in lipid parameters were observed across all groups, with greater triglyceride reduction in the tirzepatide group. Liver enzyme levels improved similarly between groups. Gastrointestinal adverse events were common, particularly with liraglutide, and no clinically confirmed pancreatitis was observed. Conclusion: In this real-world cohort, liraglutide, semaglutide, and tirzepatide were effective and generally well tolerated in adults with overweight or obesity without diabetes. Tirzepatide was associated with greater weight loss; however, these findings are observational and hypothesis-generating, supporting the need for prospective or randomized comparative studies. Keywords: tirzepatide, semaglutide, liraglutide, obesity, real-world study, GLP-1 receptor agonist