Long-Term Clinical Outcomes and Real-World Effectiveness of Tirzepatide in Adults With Overweight or Obesity: A Systematic Review.

Obesity is a chronic, progressive, and relapsing disease associated with substantial morbidity, premature mortality, and increased healthcare utilisation. Although lifestyle modification remains the cornerstone of management, long-term weight-loss maintenance is challenging. Tirzepatide, a once-weekly dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, has demonstrated substantial weight-loss efficacy, but its long-term clinical outcomes have not been comprehensively synthesised. A systematic search of Ovid MEDLINE ALL, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), and Cumulative Index to Nursing and Allied Health Literature (CINAHL) was conducted from database inception to June 30, 2026. Eligible studies included Phase III randomised controlled trials, randomised withdrawal trials, long-term extension studies, prespecified secondary analyses reporting unique outcomes, and real-world observational studies. Two reviewers independently screened studies, extracted data, and assessed methodological quality using the Cochrane Risk of Bias 2 (RoB 2) and Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tools. Owing to substantial clinical and methodological heterogeneity, findings were synthesised narratively in accordance with the Synthesis Without Meta-analysis (SWiM) guidelines. Twenty-six publications representing 11 independent parent studies met the inclusion criteria, comprising eight Phase III randomised controlled trials, one long-term extension study, two real-world observational cohort studies, and 15 prespecified secondary analyses. Tirzepatide consistently produced substantial, dose-dependent, and durable weight reduction, with mean weight loss approaching 21% after 72 weeks. Continued therapy maintained weight loss, whereas treatment discontinuation resulted in progressive weight regain. Tirzepatide also improved cardiometabolic risk factors, body composition, physical functioning, and health-related quality of life. Gastrointestinal adverse events were the most common and were generally mild to moderate. Real-world studies demonstrated effectiveness and safety comparable to those observed in randomised clinical trials. Current evidence indicates that tirzepatide provides durable weight reduction and broad cardiometabolic benefits in adults with overweight or obesity. Sustained treatment is important for maintaining these benefits, while additional long-term studies are needed to evaluate treatment persistence, cardiovascular outcomes, comparative effectiveness, and long-term safety across diverse populations.