he increase in the rate of obesity, a chronic disease with serious health con- sequences, largely explains the recent tri- pling in the prevalence of type 2 diabetes.1,2 Weight loss of 5 to 10% has been shown to re- duce complications related to obesity and im- prove quality of life3-7; however, weight loss is difficult to maintain with lifestyle intervention alone.8Liraglutide, a glucagon-like peptide-1 analogue with 97% homology to human glucagon-like peptide-1, is approved for the treatment of type 2 diabetes at doses up to 1.8 mg once daily.9 Weight loss with liraglutide is dose-dependent up to 3.0 mg once daily10,11 and is mediated by reduced appe- tite and energy intake rather than by increased energy expenditure.12This 56-week, randomized, placebo-controlled trial aimed to evaluate the efficacy and safety of 3.0 mg of liraglutide, injected subcutaneously once daily, as an adjunct to a reduced-calorie diet and increased physical activity, for weight management in overweight or obese adults who did not have diabetes at baseline.MethodsStudy OverviewWe conducted the study from June 1, 2011, through March 18, 2013, at 191 sites in 27 coun- tries in Europe, North America, South America, Asia, Africa, and Australia. The trial protocol was approved by local ethics committees or in- stitutional review boards and is available with the full text of this article at NEJM.org. The trial was conducted in accordance with the principles of the Declaration of Helsinki13 and Good Clinical Practice guidelines.14 A 2-year exten- sion of the trial involving patients with predia- betes that was designed to evaluate whether lira- glutide is associated with delayed onset of type 2 diabetes was recently completed. All the au- thors were involved in the design or conduct of the study and the preparation of the manu- script, including the decision to submit it for publication, and all attest to the accuracy and completeness of data and the data analyses. The sponsor, Novo Nordisk, planned and per- formed the statistical analyses, provided editorial and writing assistance, and provided the trial drugs.PatientsThe trial enrolled patients 18 years of age or older who had stable body weight and a body- mass index (BMI; the weight in kilograms di- vided by the square of the height in meters) of 30 or higher, or 27 or higher if the patient had treated or untreated dyslipidemia or hyperten- sion (Table S1 in the Supplementary Appendix, available at NEJM.org). All the patients provided written informed consent before participation. Key exclusion criteria were type 1 or 2 diabetes, the use of medications that cause clinically sig- nificant weight gain or loss, previous bariatric surgery, a history of pancreatitis, a history of major depressive or other severe psychiatric dis- orders, and a family or personal history of mul- tiple endocrine neoplasia type 2 or familial medullary thyroid carcinoma. Details of the eli- gibility and exclusion criteria are provided in the Supplementary Appendix.Study Design and TreatmentsRandomization was performed with the use of a telephone or Web-based system provided by the sponsor. Eligible patients were randomly as- signed, in a 2:1 ratio, to receive once-daily sub- cutaneous injections of liraglutide, starting at a dose of 0.6 mg with weekly 0.6-mg increments to 3.0 mg, or placebo; both groups received counseling on lifestyle modification (Fig. S1 in the Supplementary Appendix). Patients were stratified according to prediabetes status at screening15 and according to BMI (≥30 vs. <30). Patients, investigators, and the sponsor were unaware of the study-group assignments. Lira- glutide and placebo were provided in FlexPen devices (Novo Nordisk). After 56 weeks, patients in the liraglutide group who did not have pre- diabetes at screening were randomly assigned in a 1:1 ratio to continue receiving liraglutide or to switch to placebo for 12 weeks to assess whether efficacy was maintained after discontin- uation of liraglutide treatment and whether there were safety issues related to discontinuation. Pa- tients in the placebo group continued to receive placebo.Study Procedures and End PointsPatients were evaluated every 2 weeks until week 8; thereafter, patients were evaluated every 4 weeks until week 44 and were evaluated again
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