Weight-loss medications (WLMs) may offset the physiological adaptations in appetite and energy expenditure that promote weight regain in patients with obesity after initial weight loss (WL) with lifestyle modification (LSM). 1,2 In essentially all randomised clinical trials (RCTs) of WLMs, the addition of these drugs consistently results in a greater weight reduction than LSM alone. According to clinical guidelines, WLMs should be considered in patients with a BMI ≥30 kg/m 2 or ≥27 kg/m 2 with a weight-related comorbidity when a WL of at least 5% has not been reached after 3-6 months of an LSM programme. 3-5 Until a few years ago, the lipase inhibitor orlistat was the only WLM available in Europe for long-term clinical use.The European Medicines Agency (EMA) approved in 2015 two new drugs: liraglutide 3.0 mg, a glucagon-like peptide-1 (GLP-1) receptor agonist and the combination of the antidepressant bupropion, a dopamine and norepinephrine reuptake inhibitor, with the opioid antagonist naltrexone. In the USA, two other drugs were approved by Summary Aims: To evaluate in a real-world setting the effectiveness of two drugs, orlistat and liraglutide, in patients with overweight or obesity and insufficient weight loss (WL) after a lifestyle modification programme. Methods:Retrospective, observational cohort study comparing clinical outcomes of orlistat 120 mg three times a day and liraglutide (up to 3 mg daily) in adult patients with BMI ≥30 kg/m 2 or ≥27 kg/m 2 with at least a weight-related comorbidity who had failed to lose at least 5% of their weight after 6 months of lifestyle modification.The co-primary end-points, assessed at 3-6 months and at the end of the follow-up, were weight change from baseline, proportion of patients who lost at least 5% of their baseline weight and adjusted differences in WL between both drugs.Results: Five hundred patients, 400 in the group of orlistat (age 47.0, weight 107.8 kg) and 100 in the group of liraglutide (age 51.9 years, weight 105.1 kg), were included.Treatment with both drugs significantly reduced weight, fasting plasma glucose, systolic BP, low-density lipoprotein-cholesterol and alanine transaminase over a median follow-up period of 7 months. WL with liraglutide (−7.7 kg) was significantly greater than that observed with orlistat (−3.3 kg), and more individuals lost at least 5% of their baseline weight with liraglutide (64.7%) than with orlistat (27.4%). Rates of prediabetes significantly decreased with liraglutide in comparison to orlistat. Conclusions:In this real-world study, liraglutide showed a greater effectiveness in WL compared with orlistat and improved several obesity-associated metabolic and cardiovascular risk factors.

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