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Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide

Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1... International Journal of Obesity (2012) 36, 843–854 & 2012 Macmillan Publishers Limited All rights reserved 0307-0565/12 www.nature.com/ijo ORIGINAL ARTICLE Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide This article has been corrected since Advance Online Publication and a corrigendum is also printed in this issue 1 2 3 4 5 6 7 8 A Astrup , R Carraro , N Finer , A Harper , M Kunesova , MEJ Lean , L Niskanen , MF Rasmussen , 9 10 11 12 A Rissanen ,SRo ¨ ssner , MJ Savolainen and L Van Gaal on behalf of the NN8022-1807 Investigators 1 2 Department of Human Nutrition, Faculty of Life Sciences, University of Copenhagen, Frederiksberg, Denmark; Department of Endocrinology, University Hospital La Princesa, Instituto de Investigacion Sanitaria Princesa, Madrid, Spain; Department of 4 5 Medicine, University College London, London, UK; Clinical Reporting, Novo Nordisk A/S, Soeborg, Denmark; Obesity Management Centre, Institute of Endocrinology, Prague, Czech Republic; Department of Human Nutrition, University of Glasgow, Glasgow Royal Infirmary, Glasgow, UK; Department of Medicine, Central Hospital of Central Finland, Jyva¨skyla¨ and University of Eastern Finland, Kuopio, Finland; Medical and Science Department, Novo Nordisk Inc., Princeton, NJ, USA; 9 10 Obesity Research Unit, Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland; Obesity Unit, Karolinska University Hospital, Huddinge, Sweden; University of Oulu, Institute of Clinical Medicine, Oulu, Finland and Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, Antwerp, Belgium Objective: Having demonstrated short-term weight loss with liraglutide in this group of obese adults, we now evaluate safety/tolerability (primary outcome) and long-term efficacy for sustaining weight loss (secondary outcome) over 2 years. Design: A randomized, double-blind, placebo-controlled 20-week study with 2-year extension (sponsor unblinded at 20 weeks, participants/investigators at 1 year) in 19 European clinical research centers. Subjects: A total of 564 adults (n¼ 90–98 per group; body mass index 30–40 kg m ) enrolled, 398 entered the extension and 268 completed the 2-year trial. Participants received diet (500 kcal deficit per day) and exercise counseling during 2-week run-in, before being randomly assigned (with a telephone or web-based system) to once-daily subcutaneous liraglutide (1.2, 1.8, 2.4 or 3.0 mg, n¼ 90–95), placebo (n¼ 98) or open-label orlistat (120 mg 3, n¼ 95). After 1 year, liraglutide/placebo recipients switched to liraglutide 2.4 mg, then 3.0 mg (based on 20-week and 1-year results, respectively). The trial ran from January 2007–April 2009 and is registered with Clinicaltrials.gov, number NCT00480909. Results: From randomization to year 1, liraglutide 3.0 mg recipients lost 5.8 kg (95% confidence interval 3.7–8.0) more weight than those on placebo and 3.8 kg (1.6–6.0) more than those on orlistat (Pp0.0001; intention-to-treat, last-observation-carried- forward). At year 2, participants on liraglutide 2.4/3.0 mg for the full 2 years (pooled group, n¼ 184) lost 3.0 kg (1.3–4.7) more weight than those on orlistat (n¼ 95; Po0.001). Completers on liraglutide 2.4/3.0 mg (n¼ 92) maintained a 2-year weight loss of 7.8 kg from screening. With liraglutide 3.0 mg, 20-week body fat decreased by 15.4% and lean tissue by 2.0%. The most frequent drug-related side effects were mild to moderate, transient nausea and vomiting. With liraglutide 2.4/3.0 mg, the 2-year prevalence of prediabetes and metabolic syndrome decreased by 52 and 59%, with improvements in blood pressure and lipids. Conclusion: Liraglutide is well tolerated, sustains weight loss over 2 years and improves cardiovascular risk factors. International Journal of Obesity (2012) 36, 843–854; doi:10.1038/ijo.2011.158; published online 16 August 2011 Keywords: liraglutide; GLP-1 analog; weight loss Introduction Correspondence: Professor A Astrup, Department of Human Nutrition, Faculty of Life Sciences, University of Copenhagen, Rolighedsvej 30, DK-1958, Frederiksberg C, Denmark. Obesity increases risk of developing type 2 diabetes mellitus E-mail: [email protected] and cardiovascular disease, the leading cause of death. Listed in the Appendix. Reduction of 5–10% body weight improves obesity-related Received 4 April 2011; revised 5 July 2011; accepted 5 July 2011; published 3–5 online 16 August 2011 cardiovascular and metabolic abnormalities, but achieving Safety and weight loss with diet and liraglutide A Astrup et al 6–8 this target through diet and exercise is challenging. increasing weekly (dose escalation). The open-label com- Pharmacological treatment is recommended in addition to parator group (n¼ 95) was randomized to receive orlistat 4,7–9 diet and exercise when lifestyle intervention fails. capsules (3 120 mg) with each main meal for the full 2-year Liraglutide, an analog of the incretin hormone glucagon- period. After 20 weeks, participants could consent to enroll like peptide-1 (GLP-1), is currently licensed for treatment of in the extension, continuing on randomized treatment for type 2 diabetes at doses up to 1.8 mg, after demonstrating 1 year, after which liraglutide or placebo-treated individuals improvements in glycemic control and weight loss in more switched to liraglutide 2.4 mg, considered the most favorable than 4000 individuals of the Liraglutide Effect and Action in dose based on 20-week data analysis. However, when 1-year 10,11 Diabetes (LEAD) program, with satisfactory tolerability. results became available, the 3.0 mg dose was deemed more In obese non-diabetic adults, liraglutide at doses up to 3.0 mg favorable and participants switched to this dose between was more effective than orlistat, or diet and exercise alone, weeks 70–96, as sites obtained ethics committee approval. at reducing weight (primary outcome) over 20 weeks. In the main 20-week trial, eligible participants, sponsor Liraglutide also improved obesity-related risk factors, redu- and all study personnel were blinded to the random cing waist circumference, blood pressure (BP) and the injection treatment assignment, performed using a sponsor- prevalence of prediabetes. generated central telephone or web-based system, generated We now report 2-year results from the extension of the by the sponsor and concealed from trial investigators. A 20-week trial, as well as data after 1 year, the required balanced (1:1) treatment allocation was specified, stratified duration for demonstrating weight loss/maintenance in by gender. We instructed participants receiving liraglutide or confirmatory phase 3 trials. The primary outcome at 1 year placebo to administer daily injections (liraglutide was weight loss. In the extension at 2 years, we aimed to 6.0 mg ml or vehicle in identical 3 ml cartridges) in the evaluate the long-term safety/tolerability of liraglutide abdomen or thigh each evening, using a pen injector. Four (primary outcome) and efficacy for sustaining weight loss different placebo injection volumes corresponded to the (secondary) of liraglutide, with dietary therapy and exercise, different liraglutide doses, thereby masking treatment and also to examine the effects on cardiovascular risk factors. (active/placebo). From 20 to 52 weeks, participants/investigators remained blinded to liraglutide/placebo treatment but the sponsor/ Materials and methods statistician was unblinded; after 1 year, all were unblinded. Throughout run-in and treatment, participants were advised Participants on diet (about 30% of energy from fat, 20% from protein and We performed a randomized, double-blind, placebo- 50% from carbohydrates), providing an energy deficit of controlled 20-week trial (RCT) with a 2-year extension. The B500 kcal per day, and encouraged to maintain or increase data from the 20-week RCT has already been published. We physical activity. To encourage adherence, pedometers were recruited men and women aged 18–65 years, of stable distributed, and a 3-day food diary was dispensed for weight, with body mass index 30–40 kg m and fasting completion 4 times during the trial, and reviewed by a 1 1 plasma glucose (FPG) o7 mmol l (126 mg dl ) at run-in, dietician. from 19 research sites in 8 European countries. Participants The trial ran from January 2007 to April 2009 and is were recruited by local advertisement or were existing registered with Clinicaltrials.gov, number NCT00480909. patients at an obesity clinic or research center. Key exclusion criteria were type 1 or 2 diabetes mellitus, drug-induced obesity, use of weight-lowering pharmacotherapy or partici- Clinical outcomes pation in a weight-control study within the preceding 3 Efficacy endpoints included weight change from randomiza- months, surgical obesity treatment and major medical tion to years 1 and 2 in the intention-to-treat population, the conditions. There was no exclusion criterion based on proportion losing 45or 410% of randomization weight, psychiatric illness. Participants gave written informed con- and changes in waist circumference, BP, prevalence of sent. The protocol was approved by local ethics committees 14 15,16 prediabetes and metabolic syndrome, glycemic para- and the trial performed according to the Declaration of meters, fasting lipids and cardiovascular biomarkers, and Helsinki and Good Clinical Practice Guidelines. 17 14 quality of life. Prediabetes was defined as either impaired ) or impaired glucose tolerance FPG (5.6–6.9 mmol l Study design and treatments (7.8–11.0 mmol l ) after 2-hour oral glucose tolerance test Study design is shown in Figure 1. The 20-week RCT (75 g glucose). The diagnosis of metabolic syndrome was consisted of a 2-week placebo run-in period one week after made according to updated National Cholesterol Education screening, then randomization to a 4-week dose-escalation Program-Adult Treatment Panel III (NCEP-ATP III) criter- 15,16 period, and a 16-week constant-dose period. We randomly ia. Body composition in a subgroup of participants was assigned individuals to once-daily liraglutide 1.2, 1.8, 2.4 or measured at randomization and week 20 only by dual-energy 3.0 mg (n¼ 95, 90, 93 and 93) or placebo (n¼ 98) by evening X-ray absorptiometry and single-slice abdominal computer- subcutaneous injection, starting at 0.6 mg per day and ized axial tomography. Fully blinded specialists at SYNARC International Journal of Obesity Safety and weight loss with diet and liraglutide A Astrup et al Inclusion criteria: BMI ≥30 and ≤40 kg/m Liraglutide 3.0 mg s.c. Liraglutide 3.0 mg Age 18–65 years Stable body weight Liraglutide 2.4 mg s.c. FPG <7.0 mmol/L at Wk -2 Liraglutide 1.8 mg s.c. Liraglutide 2.4 mg Liraglutide 1.2 mg s.c. Switch was when approved locally Screening: Placebo Placebo s.c. (between 70–96 weeks) Wk -3 run-in: Orlistat 120 mg x3 Wk -2 Double blind Extension* n=398 Randomization 20 weeks year 1 year 2 n=564 472 completed 356 completed 268 completed Lifestyle intervention: -500 kcal/day deficit diet + increased physical activity Figure 1 Study design. *From 20–52 weeks, participants/investigators remained blinded to liraglutide/placebo treatment but the sponsor was unblinded; after 1 year, all were unblinded. in Portland, USA (dual-energy X-ray absorptiometry) and Statistical analysis Paris, France (computerized axial tomography) analyzed the Sample size estimation for the 20-week trial was based on scans. We measured weight and BP from screening, so effects the primary outcome weight. It was assumed that the s.d. for on total weight-loss maintenance could be determined post weight change at week 20 would be 5.6 kg; 547 randomized hoc. All other efficacy parameters were measured from individuals (91 per group) provided X85% confidence to randomization, so that effects of liraglutide treatment versus detect a clinically relevant 3 kg difference (P¼ 0.05, two- placebo and orlistat could be assessed. sided) in mean weight between people dosed with liraglutide Safety assessments included adverse events, recorded at and placebo, based on Dunnett’s test. A drop-out rate every visit, standard laboratory tests and serum liraglutide of 30% after 20 weeks was assumed. The objective of antibodies. Antibody-positive samples were further assessed the extension was to evaluate safety and weight-loss for neutralizing effect (against liraglutide) and crossreactivity durability. Data were analyzed according to a pre-established (to GLP-1) in vitro. We measured serum calcitonin as thyroid analysis plan. All analyses were performed on a modified C-cell tumors have been detected in liraglutide-treated intention-to-treat population, comprising all randomized rodents. MDS Pharma Services (Hamburg, Germany) individuals who received at least one treatment dose and had performed the standard laboratory analyses, and Ligand at least one post-randomization assessment of body weight, Binding Services, MDS Pharma Services (Fehraltorf, Switzerland) with the last-observation-carried-forward for efficacy end- analyzed the liraglutide antibody concentration. A safety points (unless stated). Analysis of completers (those in the committee for data surveillance was established. intention-to-treat population who completed the trial Clinic visits over the 2-year trial period were weekly during period) from screening was also performed post hoc. All dose escalation, otherwise, every 4 weeks. Weight was analyses were two-sided, with 5% significance. The numbers measured at every visit from screening. Standardized waist of values that were imputed at year 1 and year 2 for the circumference assessments were made at randomization, parameters weight, waist circumference, BP, fasting lipids, then every 4 weeks. BP, glycemic parameters and lipids were prediabetes and metabolic syndrome are shown in Supple- measured at randomization, every 4 weeks to week 24, then mentary Table 1. at weeks 32, 44, 52, 64, 76, 88, 100 and 104; BP was also We analyzed 1-year weight, waist, BP and 20-week body measured at screening. Metabolic syndrome status, predia- composition (also glycemic parameters, fasting lipids, cardi- betes status, cardiovascular biomarkers and glycated hemo- ovascular biomarkers and pulse post hoc) by analysis of globin (HbA ) and quality of life were assessed at covariance (ANCOVA), investigating the superiority of each 1c randomization, week 20, week 52 and week 104. Participants of the four doses of liraglutide over placebo (primary underwent physical examination and electrocardiogram at objective) and orlistat (secondary objective). At year 2, the screening, week 20, week 52 and week 104. Pulse rate and superiority of liraglutide (in a pooled group of participants laboratory parameters were measured at screening, run-in who were on 2.4/3.0 mg for 2 years) versus orlistat was (laboratory parameters only), randomization, every 4 weeks assessed. Treatment, country and sex were fixed effects; the to week 24, then at weeks 32, 44, 52 and 104. Calcitonin value of the respective parameter at randomization was a concentration was categorized by one of four categories: covariate. The primary null hypothesis was that there was no olower level of quantification (LLOQ); XLLOQ and oupper difference between treatments. We adjusted for multiplicity normal range (UNR); XUNR and o2 UNR; and X2 UNR. using Dunnett’s method. International Journal of Obesity Safety and weight loss with diet and liraglutide A Astrup et al In support of the ANCOVA analyses for weight, waist and BP, was 5.8 kg (95% confidence interval 3.7–8.0) with liraglutide repeated measures analyses were performed using the long- 3.0 mg. Mean change in waist circumference was signifi- itudinal measurements available for the modified intention-to- cantly greater with liraglutide 2.4–3.0 mg versus placebo. treat population. These analyses were planned at year 1 and Weight loss for those on liraglutide 2.4/3.0 mg for 2 years was were performed post hoc at year 2. The repeated measures model significantly greater than with orlistat. No gender differences included the same effects as the ANCOVA model described in weight loss were observed (data not shown). Body above. Interactions between treatment and visit, country and composition results in subgroup participants showed that visit, and sex and visit were also included, with the restriction 20-week weight loss with liraglutide was primarily from fat that, for visits in the dose-escalation period (weeks 1– 4), means tissue (Table 1). for treatment groups having received the same treatment up to Significantly more individuals on liraglutide 1.8–3.0 mg the given visit were assumed to be equal. Evaluations of achieved weight losses 45 and 410% of randomization superiority of each liraglutide dose to placebo (primary weight versus placebo at year 1 (Figure 2b). At year 2, objective) and to orlistat (secondary objective) were carried significantly more on liraglutide 2.4/3.0 mg than on orlistat out using the Bonferroni adjustment for multiple testing. lost 45 and 410% weight. Of the 64% who achieved 45% The proportions of individuals losing 45 and 410% weight loss with liraglutide 2.4/3.0 mg at year 1, 485% weight were analyzed by logistic regression, using the same maintained this at year 2. model parameters (without country), with multiplicity adjustment using Bonferroni correction. As ‘country’ showed no significant effect it was removed from the model, to allow Blood pressure and pulse from randomization inclusion of a greater number of variables and to increase the Mean systolic and diastolic BP decreased in all groups over 1 accuracy of the estimates. Prediabetes and calcitonin were year, and systolic BP remained significantly lower with also analyzed by logistic regression, as were metabolic liraglutide 2.4/3.0 mg than orlistat at 2 years, while pulse syndrome status and nausea/vomiting incidence post hoc. rate was 3.5 beats min greater (Figure 2c). The logistic regression analysis for calcitonin noted if a trial participant moved up one category from randomization to year 2. Randomization means for treatment groups in all the Maintenance from screening: weight loss, BP reduction and pulse above analyses were assumed to be equal. We used the Mean weight reduction between screening and randomiza- Statistical Analysis System software package (version 9.1; SAS tion was 1.3 1.4 kg across groups. Figure 3a shows that Institute, Cary, NC, USA) for all analyses. participants randomized to liraglutide 3.0 mg for 1 year (and then maintained on 2.4/3.0 mg for the second year) main- tained a mean weight loss of 10.3 7.1 kg from screening over 2 years. Weight loss for the pooled group on liraglutide Results 2.4/3.0 mg for 2 years was estimated to be 7.8 kg by adjusted Trial population ANCOVA (Supplementary Figure 2a). Almost 70% of liraglu- tide 2.4/3.0 mg recipients maintained weight loss 45% of Of 616 individuals entering the 2-week run-in, 135 men and screening weight at year 2, 43% maintained 410% loss and 429 women (n¼ 564) were randomized to treatment, 398 25% maintained 415% loss (Supplementary Figure 2b). entered the extension and 268/398 (67%) completed 2 years Between screening and randomization, across all groups, (see Supplementary Figure 1). Included in the trial were 21 individuals (o4% overall) classified as having a rando- mean systolic BP decreased by 5.7 11.0 mm Hg, diastolic BP ± ± by 3.7 8.1 mm Hg and pulse rate fell by 0.9 10.1 mization glucose concentration in the range of type 2 beats min . For completers on liraglutide 2.4/3.0 mg, mean diabetes mellitus; this had developed since screening. Three systolic BP had decreased from screening levels by liraglutide-treated participants were excluded from the 12.5 mm Hg at year 2 (Figure 3b). With liraglutide, mean intention-to-treat population owing to missing post-rando- mization weight data. Major protocol deviations are pulse rate rose slightly from randomization in the first 30 weeks of the trial (Figure 3c), but subsequently fell, described in the Supplementary Information. approximately to screening levels (Figures 3b and c). Participant characteristics were comparable across groups at randomization (Supplementary Table 2) and entering the extension (not shown). Repeated measures analyses of weight, waist and BP At years 1 and 2, the repeated measures analyses, performed Weight and waist circumference from randomization in support of the primary ANCOVA analyses, in general gave For the intention-to-treat population (with last-observation- slightly greater estimates for weight and waist change, carried-forward), estimated mean weight loss from randomi- slightly lower estimates for systolic BP and similar estimates zation to year 1 was significantly greater with liraglutide for diastolic BP (Supplementary Tables 3 and 4). In terms of 1.8–3.0 mg compared with placebo, and was dose-dependent superiority, results of the repeated measures analyses were in (Figure 2a, ANCOVA). Placebo-subtracted mean weight loss general comparable to those of the ANCOVA analyses. International Journal of Obesity Safety and weight loss with diet and liraglutide A Astrup et al WEIGHT (kg) WAIST (cm) Placebo Year 1 Year 2 Year 1 Year 2 Orlistat 0.0 Liraglutide 1.2 mg -1.0 Liraglutide 1.8 mg Liraglutide 2.4 mg -2.0 -2.0 -2.3 Liraglutide 3.0 mg -3.0 -3.0 Liraglutide 2.4/3.0 mg -4.0 -3.8 -3.9 pooled group -4.5 -4.5 -5.0 -5.2 -5.3 -5.4 -5.6 -6.0 -6.1 -6.2 P < 0.001 -6.5 ** -7.0 -7.8 -7.8 -8.0 *P < 0.001 vs. placebo †P < 0.05 vs. orlistat ** ** **P ≤ 0.0001 ‡P ≤ 0.0001 *P ≤ 0.001 vs. placebo †P < 0.001 vs. orlistat **P = 0.02 ‡P = 0.03 #P < 0.01 P < 0.001 ** 44 † * P = 0.04 40 37 # 29 27 26 20 17 16 >5% >10% >5% >10% YEAR 1 YEAR 2 SYSTOLIC BP (mmHg) DIASTOLIC BP (mmHg) PULSE RATE (beats/minute) Year 1 Year 2 *P < 0.005 vs. placebo †P < 0.002 vs. orlistat 6.0 ‡P = 0.01 † P<0.001 † * 4.4 * ‡ 3.9 4.0 3.5 3.1 2.8 2.0 Year 1 Year 2 Year 1 Year 2 0.0 -0.2 -0.4 -0.6 -1.0 -1.2 -1.5 -1.5 -1.7 -1.5 -1.6 -2.0 -2.1 -2.0 -2.3 -2.8 -4.0 -4.0 -4.2 -4.6 -4.9 -6.0 P = 0.02 -7.0 -8.0 Figure 2 (a) Mean changes in body weight and waist circumference from randomization to years 1 and 2. (b) Participants with 45 and 410% randomization weight loss at years 1 and 2. (c) Mean changes in BP and pulse rate from randomization to years 1 and 2. Estimated mean changes in weight, waist, BP and pulse rate (by ANCOVA), and in weight-loss responders (by logistic regression) are shown for the intention-to-treat population with the last observation carried forward. Safety and tolerability and quality of life 40% of those randomized to placebo or orlistat. Adverse Over the 2-year period, 222 (39%) individuals withdrew from events include data previously reported for the 20-week the trial: 34–43% of those randomized to liraglutide, and trial. Summary data for year 1 are shown in Table 2, and in International Journal of Obesity Estimated mean change Proportion of individuals (%) Estimated mean change Safety and weight loss with diet and liraglutide A Astrup et al Table 1 Body composition assessed by dual-energy X-ray absorptiometry and computerized axial tomography in a subgroup of participants at 20 weeks Placebo Liraglutide Orlistat n¼ 14 n¼ 12 1.2 mg 1.8 mg 2.4 mg 3.0 mg n¼ 15 n¼ 13 n¼ 15 n¼ 15 Dual-energy X-ray absorptiometry measurements: body composition at randomization (kg) Fat tissue 45.8 (10.5) 43.5 (7.6) 45.0 (8.8) 42.6 (6.1) 43.9 (8.4) 41.3 (6.7) Lean tissue 51.0 (11.0) 55.0 (8.9) 51.7 (11.3) 50.6 (11.9) 53.1 (10.3) 47.4 (6.4) Relative change at week 20 (%) Fat tissue 11.9 (2.5) 13.9 (2.7) 13.0 (2.6) 16.5 (2.5) 15.4 (2.6) 13.3 (2.9) Change vs placebo F 2.0 (8.9 to 4.9); 1.1 (8.0 to 5.9); 4.6 (11.2 to 2.1); 3.5 (10.3 to 3.4); F P¼ 0.57 P¼ 0.76 P¼ 0.18 P¼ 0.32 Lean tissue 1.3 (1.0) 0.9 (1.1) 2.9 (1.1) 2.6 (1.0) 2.0 (1.1) 0.9 (1.2) Change vs placebo F 0.4 (2.4 to 3.3); 1.6 (4.4 to 1.3); 1.3 (4.1 to 1.4); 0.7 (3.6 to 2.1); F P¼ 0.77 P¼ 0.28 P¼ 0.33 P¼ 0.61 2 a Computerized axial tomography measurements: body composition at randomization (cm ) Visceral fat 136 (38) 172 (77) 121 (39) 149 (76) 145 (69) 101 (40) Subcutaneous fat 474 (107) 453 (68) 476 (71) 426 (75) 434 (116) 459 (113) Relative change at week 20 (%) Visceral fat 13.8 (5.7) 19.0 (6.3) 19.4 (6.0) 23.0 (5.7) 20.3 (6.0) 20.2 (6.7) Change vs placebo F 5.1 (21.2 to 11.0); 5.6 (21.8 to 10.6); 9.2 (24.7 to 6.4); 6.4 (22.1 to 9.2); F P¼ 0.53 P¼ 0.49 P¼ 0.25 P¼ 0.42 Subcutaneous fat 12.1 (3.0) 15.6 (3.3) 15.9 (3.6) 19.3 (3.0) 15.3 (3.3) 17.9 (3.6) Change vs placebo F 3.5 (11.8 to 4.9); 3.8 (12.6 to 5.1); 7.1 (15.2 to 1.0); 3.1 (11.5 to 5.2); F P¼ 0.41 P¼ 0.40 P¼ 0.09 P¼ 0.45 a b c Mean (s.d.). Estimated mean (s.e.). Estimated mean (95% CI); P-value. Values are for participants who completed the substudy according to the protocol (PP completers). Supplementary Table 5 for year 2. The most frequent female and randomized to liraglutide treatment, were with- liraglutide-associated side effects were gastrointestinal drawn owing to serious adverse events. One withdrew owing (Table 2; Supplementary Table 6). In year 1, more partici- to a serious event of cholelithiasis, occurring simultaneously pants reported nausea and/or vomiting with liraglutide with acute pancreatitis, after 299 days on liraglutide 3.0 mg; 3.0 mg (49/93; 53%) than with lower doses, placebo (8/98; the individual recovered without sequelae. Breast cancer 8%) (Po0.0001) or orlistat (7/95; 7%)(Po0.0001). Most occurred in an individual randomized to liraglutide 1.8 mg nausea/vomiting episodes started in weeks 1–6, were tran- and treated with 2.4 mg at the time of the event, which was sient and 490% were of mild or moderate intensity. Few reported after 465 days of treatment. The individual subse- episodes were serious (2 vomiting). Nausea incidence over 2 quently withdrew from the trial. A serious intestinal adeno- years was similar for males and females (P¼ 0.49). carcinoma was reported by a female participant after 410 days Mean 1-year weight loss from randomization with liraglu- on liraglutide 2.4 mg, after a screening program for lung tide 3.0 mg was 10.0 kg for those with nausea and/or cancer during the trial revealed metastases in the liver. The vomiting (n¼ 49) and 7.1 kg for those without individual withdrew from the trial and was not expected to (n¼ 43)(difference 2.9 kg (95% confidence interval 0.5–5.3); recover. A serious anaphylactic reaction was reported by one P¼ 0.02). Weight loss without nausea and/or vomiting was individual after 692 days of treatment with liraglutide 3.0 mg. still 4.2 kg greater than placebo (P¼ 0.0001) and 2.3 kg The event was due, according to the hospital to which the greater than orlistat (P¼ 0.04). individual was admitted, to administration of diclofenac/ No participant discontinued treatment owing to aversion misoprostol on the day of the reaction. The individual to injections or injection-site disorders during run-in recovered but later withdrew from the trial. A further three (Supplementary Figure 1). A total of 51 individuals (9%) serious adverse events of special interest and in the liraglutide withdrew from the trial over 2 years owing to adverse events. group were events of atrial fibrillation, uterine leiomyoma These were mostly gastrointestinal. Over 2 years, 15/371 and prostate cancer. A serious cardiovascular episode (atrial (4%) liraglutide-treated individuals discontinued owing to fibrillation) was reported in a male individual randomized to nausea and/or vomiting; none on placebo (in year 1) or placebo but on liraglutide 3.0 mg at the time of the event, orlistat did so. Four on liraglutide 2.4 mg discontinued which occurred after 707 days. Treatment was temporarily because of injection-site disorders (pain/extravasation; discontinued; the participant recovered and completed the hematoma; irritation; and discomfort). Four individuals, all trial without further events. The uterine leiomyoma occurred International Journal of Obesity Safety and weight loss with diet and liraglutide A Astrup et al Liraglutide 1.2 mg Placebo Liraglutide 1.8 mg Orlistat Liraglutide 2.4 mg n=561 Liraglutide 3.0 mg n=472 n=356 n=268 -2 All on liraglutide/placebo switched Below symbol to liraglutide 2.4 mg at week 52, represents ITT then between 70–96 weeks (shaded) -4 (LOCF) data: to 3.0 mg -6 -8 -10 n=561 -12 -14 -3 0 8 20 32 40 48 52 56 68 80 92 104 Weeks SYSTOLIC BP (mmHg) DIASTOLIC BP (mmHg) PULSE RATE (beats/minute) 2.0 0.8 n=91 0.0 -2.0 n=45 -4.0 -3.9 -6.0 n=45 n=92 P = 0.002 -6.9 -6.9 -8.0 n=45 -10.0 P = 0.98 -9.9 n=92 -12.0 Orlistat -12.5 Liraglutide 2.4/3.0 mg -14.0 pooled group P =0.17 3.0 Liraglutide 2.4/3.0 mg pooled group Orlistat 2.0 1.0 0.0 -1.0 -2.0 -3.0 -4.0 -5.0 Weeks Figure 3 (a) Change in body weight from screening over 2 years, presented as observed data for individuals completing each scheduled visit. (b) Estimated (ANCOVA) changes in BP and pulse rate from screening to year 2 for the completer population. (c) Mean change in pulse rate over 2 years, presented as observed data for the intention-to-treat population (with no imputation). in a participant on 2.4 mg liraglutide for 219 days, who was Trial drug continued unchanged throughout the event, the diagnosed with single fungal fibroid, underwent hysterec- individual completed the trial and was reported as recovering. tomy, but later recovered. Prostate cancer was detected in an A psychiatric medical history was present in 96/564 (17%) individual on liraglutide 1.8 mg after 94 days of treatment. participants. In year 1, the most frequently reported disorder International Journal of Obesity Screening Randomization -3 Randomization Mean change in pulse Estimated mean change (beats/minute) Screening Mean weight change (kg) Safety and weight loss with diet and liraglutide A Astrup et al Table 2 Summary of safety data, gastrointestinal disorders with an incidence of X5% in any group and all psychiatric disorders in year 1 Placebo n¼ 98 Liraglutide Orlistat n¼ 95 1.2 mg n¼ 95 1.8 mg n¼ 90 2.4 mg n¼ 93 3.0 mg n¼ 93 N (%) E N (%) E N (%) E N (%) E N (%) E N (%) E Summary of safety data Overall withdrawal rate 24 (25) 17 (18) 20 (22) 27 (29) 18 (19) 28 (30) Participants with AEs 87 (88.8) 374 88 (92.6) 362 84 (93.3) 430 88 (94.6) 485 89 (95.7) 492 89 (93.7) 372 Participants with any SAE 3 (3.1) 3 2 (2.1) 2 7 (7.8) 7 4 (4.3) 5 7 (7.5) 10 2 (2.1) 2 Withdrawals due to AEs 3 (3.1) 7 5 (5.3) 12 6 (6.7) 10 12 (12.9) 20 7 (7.5) 12 3 (3.2) 3 Gastrointestinal disorders 37 (37.8) 62 55 (57.9) 101 58 (64.4) 121 66 (71.0) 157 72 (77.4) 167 60 (63.2) 110 Abdominal pain 4 (4.1) 4 2 (2.1) 2 3 (3.3) 3 1 (1.1) 1 5 (5.4) 5 4 (4.2) 5 Abdominal pain upper 1 (1.0) 1 5 (5.3) 6 2 (2.2) 3 5 (5.4) 5 5 (5.4) 7 7 (7.4) 8 Constipation 12 (12.2) 14 15 (15.8) 17 11 (12.2) 12 21 (22.6) 24 17 (18.3) 18 7 (7.4) 8 Diarrhea 10 (10.2) 11 8 (8.4) 13 9 (10.0) 12 12 (12.9) 13 14 (15.1) 15 28 (29.5) 40 Dyspepsia 3 (3.1) 3 6 (6.3) 7 7 (7.8) 7 9 (9.7) 13 8 (8.6) 8 3 (3.2) 4 Flatulence 1 (1.0) 1 F 4 (4.4) 4 4 (4.3) 4 3 (3.2) 3 10 (10.5) 10 Nausea 7 (7.1) 8 23 (24.2) 27 29 (32.2) 33 35 (37.6) 48 45 (48.4) 68 7 (7.4) 7 Steatorrhea F FFFF 5 (5.3) 5 Toothache 1 (1.0) 1 1 (1.1) 1 5 (5.6) 7 1 (1.1) 1 F 1 (1.1) 1 Vomiting 2 (2.0) 2 5 (5.3) 6 9 (10.0) 18 14 (15.1) 17 12 (12.9) 16 2 (2.1) 4 Psychiatric disorders 5 (5.1) 5 3 (3.2) 3 4 (4.4) 4 11 (11.8) 14 12 (12.9) 14 5 (5.3) 8 Acute stress disorder FF F 1 (1.1) 1 FF Affect lability F FFFF 1 (1.1) 1 Alcohol abuse F FFFF 1 (1.1) 1 Anxiety 1 (1.0) 1 FF 2 (2.2) 2 2 (2.2) 2 F Burnout syndrome F FFF 1 (1.1) 1 F Depressed mood F 1 (1.1) 1 F 3 (3.2) 3 1 (1.1) 1 F Depression FF 2 (2.2) 2 2 (2.2) 2 1 (1.1) 1 2 (2.1) 3 Eating disorder FF F 1 (1.1) 1 FF Food aversion F 1 (1.1) 1 FFF F Insomnia 2 (2.0) 2 FF 2 (2.2) 2 5 (5.4) 6 2 (2.1) 3 Mood altered FF F 1 (1.1) 1 1 (1.1) 1 F Nervousness FF F 2 (2.2) 2 FF Restlessness FF 1 (1.1) 1 FF F Stress 2 (2.0) 2 1 (1.1) 1 1 (1.1) 1 F 2 (2.2) 2 F Abbreviations: AE, adverse event; E, number of adverse event; N (%), number and proportion of participants with an adverse event; SAE, serious adverse event. Does not include individuals who chose not to enroll in the extension period. coded as ‘psychiatric’ was insomnia (Table 2). Other 2.4/3.0 mg and orlistat by logistic regression (estimated odds frequently reported disorders included stress, depression, ratio for liraglutide 2.4/3.0 mg versus orlistat was 0.5 (95% depressed mood and anxiety. All were non-serious and of confidence interval 0.17–1.6); P¼ 0.26). mild or moderate severity. Overall, there were more Seven individuals developed antibodies to liraglutide over psychiatric disorders in general reported by participants on the 2-year trial period (6 on liraglutide and 1 on orlistat). 2.4 and 3.0 mg liraglutide than those on placebo, but there One subject randomized to liraglutide 1.2 mg had antibodies did not seem to be any pattern to the disorders reported, that crossreacted to GLP-1 in vitro at the end of the trial with specific events (other than insomnia) being reported by (the subject was exposed to both liraglutide 2.4 and 3.0 mg p3 participants in any group. Two participants withdrew during the extension period). because of anxiety (placebo) and food aversion (liraglutide Quality of life improved in all groups at year 1 (Supple- 1.2 mg). mentary Table 7) and year 2 (not shown). Over 2 years, 13 self-reported events of symptomatic hypoglycemia (unconfirmed by blood glucose measurement, non-serious) were reported by 9 individuals: 1 event in Other secondary endpoints from randomization placebo and 12 in liraglutide-treated participants. No At randomization, 176/564 (31%) individuals had predia- changes in calcitonin concentration were noted at 2 years. betes, and 229/564 (41%) met criteria for metabolic Most calcitonin assessments were below the upper normal syndrome. Prediabetes prevalence was significantly reduced limit during the 2-year trial period, and no differences in with liraglutide 1.8–3.0 mg versus both placebo and orlistat mean concentrations were observed between liraglutide at year 1, and with liraglutide 2.4/3.0 mg versus orlistat at International Journal of Obesity Safety and weight loss with diet and liraglutide A Astrup et al Placebo PREDIABETES METABOLIC SYNDROME Orlistat Liraglutide 1.2 mg *P ≤ 0.0001 vs. placebo †P ≤ 0.0002 vs. orlistat **P = 0.005 Liraglutide 1.8 mg #P = 0.01 50 Liraglutide 2.4 mg 42 Liraglutide 3.0 mg P < 0.001 40 37 36 37 36 36 Liraglutide 2.4/3.0 mg 32 32 pooled group # 20 ** # 17 * 16 16 † 14 † 11 Randomization Year 1 Year 2 Randomization Year 1 Year 2 TRIGLYCERIDES LDL-CHOLESTEROL HDL-CHOLESTEROL Year 1 Year 2 Year 1 Year 2 Year 1 Year 2 P = 0.03 0.10 †P = 0.03 vs. orlistat 0.07 0.06 0.06 0.06 0.05 0.05 0.03 0.03 ‡P = 0.007 0.01 0.01 0.00 0.01 -0.01 -0.04 -0.10 -0.10 -0.11 -0.14 -0.20 P = 0.053 -0.21 -0.24 ‡ † -0.27 -0.30 -0.28 † -0.28 -0.34 -0.40 -0.43 -0.46 -0.50 Figure 4 (a) The prevalence of prediabetes and the metabolic syndrome at randomization and after 1 and 2 years of treatment. Metabolic syndrome is defined by updated NCEP-ATP III criteria. (b) Mean changes in lipids from randomization to years 1 and 2. Estimated (ANCOVA) changes are shown for the intention-to-treat population with the last observation carried forward. year 2 (Figure 4a). Between 52–62% of liraglutide-treated Plasminogen activator inhibitor-1 significantly decreased individuals with prediabetes at randomization achieved with liraglutide 3.0 mg versus placebo (Supplementary normal glucose tolerance at year 2, compared with 26% of Table 8); otherwise, no significant liraglutide effects those on orlistat. At year 1, the prevalence of metabolic on cardiovascular biomarkers were observed at year 1. syndrome decreased significantly with liraglutide 1.8–3.0 mg Fibrinogen concentrations decreased across groups, while compared with placebo, and was reduced with both liraglu- adiponectin levels increased. tide 2.4/3.0 mg and orlistat at year 2. Fasting lipids, glycemic parameters and cardiovascular risk factors were first measured at randomization, so changes associated with weight loss between screening Discussion and randomization are not accounted for. No effects of liraglutide versus placebo on fasting lipids were apparent Over 2 years, liraglutide with a diet and exercise program was after 1 year (Figure 4b). At year 2, high-density lipoprotein well tolerated, produced sustained weight loss and reduced cholesterol significantly increased with liraglutide 2.4/ important cardiovascular risk factors in obese non-diabetic 3.0 mg versus orlistat (treatment difference 0.07 mmol l , adults. Estimated weight loss of 7.8 kg and systolic BP P¼ 0.03), and both low-density lipoprotein cholesterol decrease of 12.5 mm Hg was sustained with liraglutide and triglycerides decreased from randomization with liraglu- 2.4/3.0 mg in completers from screening. In obesity trials, tide 2.4/3.0 mg (treatment difference 0.12 mmol l for the intervention includes weight loss achieved during run- triglycerides, P¼ 0.053 versus orlistat). Mean FPG and in, before drug exposure, during which lifestyle changes are glycated hemoglobin (HbA ) decreased significantly with initiated, and, from a patient perspective, represents the 1c all liraglutide doses versus placebo at year 1 and with total effect on weight loss. Furthermore, biochemical and liraglutide 2.4/3.0 mg versus orlistat at year 2 (Supplemen- other parameters change during this weight-loss period: for tary Figure 3). example, the initial weight loss of 1.3 kg seen in the current International Journal of Obesity Estimated mean change (mmol/L) Proportion of individuals (%) Safety and weight loss with diet and liraglutide A Astrup et al trial was associated with an immediate reduction in systolic and/or vomiting was associated with greater weight loss with BP of 5.7 mm Hg (in completers), so where screening data liraglutide 3.0 mg, but even those who did not experience exist we have additionally reported these. From randomiza- these events lost more weight than those on placebo or tion, reductions in FPG, HbA , and in the prevalence of orlistat. The injection regimen did not impair adherence or 1c prediabetes and metabolic syndrome, were observed during cause significant withdrawal during treatment or run-in. the trial. The main study limitations are the complex study design At year 1, superior weight loss with liraglutide (7.8 kg) over and the open-label nature of the orlistat treatment arm, both placebo (2.0 kg) and orlistat (3.9 kg) was demonstrated. although this represents existing best pharmacological Mean placebo-subtracted weight loss of 5.8 kg from rando- practice and provides a comparison for the long-term safety mization with liraglutide 3.0 mg was 1.5 kg more than with data of liraglutide over the 2-year period. The lack of the sibutramine in similar 1-year trials. Weight loss stabilized placebo comparison at 2 years is also a limitation, but it did by about 36 weeks, similar to trials with other weight-loss not seem feasible in terms of participant retention to 22,23 agents, was maintained over 2 years and was signifi- maintain the placebo arm. The presence of a diet and cantly greater with liraglutide 2.4/3.0 mg than with orlistat. exercise run-in period in the study design complicates Importantly, almost 70% of participants on liraglutide analyses, and limits the capacity of the trial to anticipate 2.4/3.0 mg over 2 years maintained a 45% weight loss from the total maintained effects of treatment. Most secondary screening, associated with improvements in several cardio- endpoints were not measured at screening, therefore several 4,5 vascular risk factors and metabolic abnormalities. biochemical changes brought about by weight loss during Liraglutide-associated weight loss, in this population not run-in cannot be evaluated. Lipids are likely to have selected for hypertension, was accompanied by decreased improved; a 6% decrease in low-density lipoprotein and systolic BP and unchanged pulse rate at 2 years from total cholesterol concentrations was previously observed screening. Compared with orlistat, BP was lower and pulse during 2-week run-in in a trial of orlistat versus placebo rate higher. The clinical significance of the initial pulse treatment. Analyses from randomization should be inter- increase with liraglutide, as has been reported previously, preted in this light. The initial choice of 2.4 mg as a long- in the context of decreased systolic BP, remains unknown. term maintenance dose after 1 year was based on 20-week At year 2, the prevalence of prediabetes was reduced with data. However, when the 12-month data were analyzed, and liraglutide 2.4/3.0 mg by over 50%. Mean FPG and HbA the decision taken to move up to 3.0 mg, the non-uniform 1c concentrations were also reduced, as in previous studies with time for dose-switch from liraglutide 2.4 to 3.0 mg during 10,11 liraglutide in type 2 diabetes. A significant increase in year 2 (as a result of differences in local ethical committee high-density lipoprotein cholesterol, and marked (nonsig- efficiency) is also a limitation. No participants had the nificant) decrease in triglycerides, was noted with liraglutide benefit of the 3.0 mg dose for the full 2 years, and some for as 2.4/3.0 mg versus orlistat. Changes in low-density lipopro- little as 8 weeks. tein cholesterol were comparable to those observed with In conclusion, results of this study indicate the ability of orlistat, whose mode of action includes reduced dietary fat liraglutide, with diet and exercise, to provide sustained absorption. weight loss over 2 years, greater efficacy compared to orlistat Obesity is associated with altered expression of adipocy- and improvements in many of the important obesity- 24,25 tokines and risk factors for cardiovascular disease. In associated metabolic and cardiovascular risk factors. There agreement with previous studies, weight loss in all groups were no major safety issues, confirming data from the LEAD increased concentrations of adiponectin and reduced fibri- trials in people with type 2 diabetes at liraglutide doses up to 26 10,11 nogen levels. Concentrations of plasminogen activator 1.8 mg. However, it will be necessary to confirm these inhibitor-1, which inhibits endogenous fibrinolysis, are results in a larger phase 3 program in obese adults, both in reduced by diet and exercise, as observed here for all terms of efficacy and (particularly) safety and tolerability. groups except orlistat; liraglutide 3.0 mg produced signifi- cantly greater reduction than diet and exercise alone at year 1. These data concur with effects demonstrated with Conflict of interest liraglutide in patients with type 2 diabetes. Reductions in highly sensitive C-reactive protein were also observed with In the light of Liraglutide is a Novo Nordisk proprietary compound under liraglutide and orlistat, as noted previously. the current focus on cardiovascular safety of weight-loss development for the treatment of obesity. AA has done 28,29 drugs, the favorable effect on cardiovascular risk factors commercially sponsored research for Novo Nordisk, is in the current trial seems promising. an advisory board member for Novo Nordisk, 7TM, Liraglutide was generally well tolerated and improved Neuro-Search, Amylin/Takeda, Pathway Genomics, Jenny quality of life. Adverse events were mostly mild or moderate. Craig, and has been a consultant to the following companies Gastrointestinal events (particularly nausea and vomiting), within the last 3 years: Orexigen, Vivus, Arena, GSK, Novo consistent with the known physiological effects of GLP-1, Nordisk, 7TM, Pharma, Neurosearch, and Johnson and were more frequent than with placebo. At year 1, nausea Johnson. SR has done paid lecturing and commercially International Journal of Obesity Safety and weight loss with diet and liraglutide A Astrup et al sponsored research for Novo Nordisk. LVG was an advisory and management of overweight and obesity in adults and children. NICE clinical guideline 43, 2006. board member for Novo Nordisk and Eli Lilly, and has done 9 EMEA, Committee for Medicinal Products for Human Use commercially sponsored research for Novo Nordisk. AR has (CHMP). Guideline on clinical evaluation of medicinal products done commercially sponsored research and/or been an used in weight control, 15 November 2007. advisory board member for Novo Nordisk, Novartis, Johnson 10 Garber A, Henry R, Ratner R, Garcia-Hernandez PA, Rodriguez- Pattzi H, Olvera-Alvarez I et al. Liraglutide versus glimepiride and Johnson, Boeringer Ingelheim and Eli Lilly. LN has done monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, paid lecturing and commercially sponsored research for Eli 52-week, phase III, double-blind, parallel-treatment trial. Lancet Lily, Merck, Novo Nordisk, Boehringer Ingelheim, Astra 2009; 373: 473–481. Zeneca, Sanofi Aventis, Bristol-Myers Squibb and Pfizer, 11 Vilsboll T, Zdravkovic M, Le-Thi T, Krarup T, Schmitz O, Courre `ges JP et al. Liraglutide, a long-acting human glucagon- and is an advisory board member for Novo Nordisk and like peptide-1 analog, given as monotherapy significantly Astra Zeneca. NF was an advisory board member and has improves glycemic control and lowers body weight without risk done paid lecturing and commercially sponsored research for of hypoglycemia in patients with type 2 diabetes. Diabetes Care Novo Nordisk, Abbott laboratories and Sanofi Aventis, and is 2007; 30: 1608–1610. an advisory board member for Pfizer, Allergan and Takeda. 12 Astrup A, Rossner S, Van Gaal L, Rissanen A, Niskanen L, Al Hakim M et al. Effects of liraglutide in the treatment of obesity: a MEJL and MJS have done commercially sponsored research randomised, double-blind, placebo-controlled study. Lancet 2009; for Novo Nordisk, and MEJL has done paid lecturing for 374: 1606–1616. Novo Nordisk. RC has done paid lecturing and commercially 13 World Medical Association Declaration of Helsinki. Ethical sponsored research for Astra Zeneca, Novo Nordisk, Novartis principles for medical research involving human subjects. JAMA 2000; 284: 3043–3045. and Sanofi Aventis. MK has done commercially sponsored 14 Genuth S, Alberti KG, Bennett P, Buse J, Defronzo R, Kahn R et al. research for Novo Nordisk and Boehringer Ingelheim. AH Follow-up report on the diagnosis of diabetes mellitus. Diabetes and MFR are employees of Novo Nordisk and own stock in Care 2003; 26: 3160–3167. Novo Nordisk. The work was funded by Novo Nordisk A/S, 15 National Cholesterol Education Program. Third report of the national cholesterol education program (NCEP) expert panel on Denmark. detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) final report. Circulation 2002; 106: 3143–3421. 16 Grundy SM, Brewer Jr HB, Cleeman JI, Smith Jr SC, Lenfant C. Acknowledgements Definition of metabolic syndrome: report of the national heart, lung, and blood institute/American heart association conference We thank the study participants and acknowledge the on scientific issues related to definition. Circulation 2004; 109: 433–438. members of the NN8022-1807 study group, their staff and 17 Kolotkin RL, Crosby RD, Kosloski KD, Williams GR. Development clinical trial personnel, without whom this trial would not of a brief measure to assess quality of life in obesity. Obes Res have been possible. We also thank Helle Hartvig (Novo 2001; 9: 102–111. Nordisk), who performed the statistical analyses. 18 Knudsen LB, Madsen LW, Andersen S, Almholt K, de Boer AS, Drucker DJ et al. Glucagon-like peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C- cell proliferation. Endocrinology 2010; 151: 1473–1486. References 19 Li Z, Maglione M, Tu W, Mojica W, Arterburn D, Shugarman LR et al. Meta-analysis: pharmacologic treatment of obesity. Ann Intern Med 2005; 142: 532–546. 1 Willett WC, Dietz WH, Colditz GA. Guidelines for healthy 20 Dunnett CW. A multiple comparisons procedure for comparing weight. N Engl J Med 1999; 341: 427–434. several treatments with a control. J Am Stat Assoc 1955; 50: 2 Van Gaal LF, Mertens IL, De Block CE. Mechanisms 1096–1121. linking obesity with cardiovascular disease. Nature 2006; 444: 21 Padwal R, Li SK, Lau DC. Long-term pharmacotherapy for obesity 875–880. and overweight. Cochrane Database Syst Rev 2004; 3: CD004094. 3 Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin 22 Toplak H, Ziegler O, Keller U, Hamann A, Godin C, Wittert G JM, Walker EA et al. Reduction in the incidence of type 2 diabetes et al. X-PERT: weight reduction with orlistat in obese subjects with lifestyle intervention or metformin. N Engl J Med 2002; 346: receiving a mildly or moderately reduced-energy diet. Early 393–403. response to treatment predicts weight maintenance. Diabetes 4 National Institutes of Health. Clinical Guidelines on the Obes Metab 2005; 7: 699–708. Identification, Evaluation, and Treatment of Overweight and 23 McMahon FG, Fujioka K, Singh BN, Mendel CM, Rowe E, Obesity in AdultsFThe Evidence Report. Obes Res 1998; 6(Suppl Rolston K et al. Efficacy and safety of sibutramine in obese white 2): 51S–209S. 5 Mertens IL, Van Gaal LF. Overweight, obesity, and blood pressure: and African American patients with hypertension - a 1-year, the effects of modest weight reduction. Obes Res 2000; 8: double-blind, placebo-controlled, multicenter trial. Arch Intern 270–278. Med 2000; 160: 2185–2191. 6 Avenell A, Broom J, Brown TJ, Poobalan A, Aucott L, Stearns SC 24 Nguyen XM, Lane J, Smith BR, Nguyen NT. Changes in et al. Systematic review of the long-term effects and economic inflammatory biomarkers across weight classes in a representative consequences of treatments for obesity and implications for US population: a link between obesity and inflammation. health improvement. Health Technol Assess 2004; 8: iii–iv, 1. J Gastrointest Surg 2009; 13: 1205–1212. 7 Food and Drug Administration. FDA Guidance for Industry: 25 Pi-Sunyer FX. The relation of adipose tissue to cardiometabolic developing products for weight management, 2007. risk. Clin Cornerstone 2006; 8(Suppl 4): S14–S23. 8 NHS, National Institute for Health and Clinical Excellence. 26 Belza A, Toubro S, Stender S, Astrup A. Effect of diet-induced Obesity - guidance on the prevention, identification, assessment energy deficit and body fat reduction on high-sensitive CRP and International Journal of Obesity Safety and weight loss with diet and liraglutide A Astrup et al other inflammatory markers in obese subjects. Int J Obes 2009; 33: 30 Muls E, Kolanowski J, Scheen A, Van GL. The effects of orlistat 456–464. on weight and on serum lipids in obese patients with hyperch- 27 Courreges JP, Vilsbøll T, Zdravkovic M, Le-Thi T, Krarup T, olesterolemia: a randomized, double-blind, placebo-controlled, Schmitz O et al. Beneficial effects of once-daily liraglutide, a multicentre study. Int J Obes Relat Metab Disord 2001; 25: human glucagon-like peptide-1 analogue, on cardiovascular risk 1713–1721. biomarkers in patients with type 2 diabetes. Diabet Med 2008; 25: 1125–1131. This work is licensed under the Creative 28 Astrup A. Is cardiometabolic risk improved by weight-loss drugs? Lancet 2010; 376: 595–605. Commons Attribution-NonCommercial-No 29 James WPT, Caterson ID, Coutinho W, Finer N, Van Gaal LF, Derivative Works 3.0 Unported License. To view a copy Maggioni AP et al. Effect of sibutramine on cardiovascular of this license, visit http://creativecommons.org/ outcomes in overweight and obese subjects. N Engl J Med 2010; licenses/by-nc-nd/3.0/ 363: 905–917. Supplementary Information accompanies the paper on International Journal of Obesity website (http://www.nature.com/ijo) Appendix Leo Niskanen, Markku Savolainen. Netherlands: Mazin Al NN8022-1807 Investigators Hakim. Spain: Guillem Cuatrecasas Cambra, Bele ´nSa ´daba, Belgium: Luc Van Gaal. Czech Republic: Stepan Svacina, Raffaele Carraro, Basilio Moreno. Sweden: Stephan Ro ¨ ssner, Marie Kunesova. Denmark: Arne Astrup, Bjørn Richelsen, Martin Ridderstra ˚ le. United Kingdom: Michael Lean, Nick Finer, Mike Sampson. Kjeld Hermansen, Steen Madsbad. Finland: Aila Rissanen, International Journal of Obesity http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png International Journal of Obesity Springer Journals

Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide

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Springer Journals
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Copyright © 2012 by The Author(s)
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Medicine & Public Health; Medicine/Public Health, general; Public Health; Epidemiology; Internal Medicine; Metabolic Diseases; Health Promotion and Disease Prevention
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10.1038/ijo.2011.158
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International Journal of Obesity (2012) 36, 843–854 & 2012 Macmillan Publishers Limited All rights reserved 0307-0565/12 www.nature.com/ijo ORIGINAL ARTICLE Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide This article has been corrected since Advance Online Publication and a corrigendum is also printed in this issue 1 2 3 4 5 6 7 8 A Astrup , R Carraro , N Finer , A Harper , M Kunesova , MEJ Lean , L Niskanen , MF Rasmussen , 9 10 11 12 A Rissanen ,SRo ¨ ssner , MJ Savolainen and L Van Gaal on behalf of the NN8022-1807 Investigators 1 2 Department of Human Nutrition, Faculty of Life Sciences, University of Copenhagen, Frederiksberg, Denmark; Department of Endocrinology, University Hospital La Princesa, Instituto de Investigacion Sanitaria Princesa, Madrid, Spain; Department of 4 5 Medicine, University College London, London, UK; Clinical Reporting, Novo Nordisk A/S, Soeborg, Denmark; Obesity Management Centre, Institute of Endocrinology, Prague, Czech Republic; Department of Human Nutrition, University of Glasgow, Glasgow Royal Infirmary, Glasgow, UK; Department of Medicine, Central Hospital of Central Finland, Jyva¨skyla¨ and University of Eastern Finland, Kuopio, Finland; Medical and Science Department, Novo Nordisk Inc., Princeton, NJ, USA; 9 10 Obesity Research Unit, Department of Psychiatry, Helsinki University Central Hospital, Helsinki, Finland; Obesity Unit, Karolinska University Hospital, Huddinge, Sweden; University of Oulu, Institute of Clinical Medicine, Oulu, Finland and Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, Antwerp, Belgium Objective: Having demonstrated short-term weight loss with liraglutide in this group of obese adults, we now evaluate safety/tolerability (primary outcome) and long-term efficacy for sustaining weight loss (secondary outcome) over 2 years. Design: A randomized, double-blind, placebo-controlled 20-week study with 2-year extension (sponsor unblinded at 20 weeks, participants/investigators at 1 year) in 19 European clinical research centers. Subjects: A total of 564 adults (n¼ 90–98 per group; body mass index 30–40 kg m ) enrolled, 398 entered the extension and 268 completed the 2-year trial. Participants received diet (500 kcal deficit per day) and exercise counseling during 2-week run-in, before being randomly assigned (with a telephone or web-based system) to once-daily subcutaneous liraglutide (1.2, 1.8, 2.4 or 3.0 mg, n¼ 90–95), placebo (n¼ 98) or open-label orlistat (120 mg 3, n¼ 95). After 1 year, liraglutide/placebo recipients switched to liraglutide 2.4 mg, then 3.0 mg (based on 20-week and 1-year results, respectively). The trial ran from January 2007–April 2009 and is registered with Clinicaltrials.gov, number NCT00480909. Results: From randomization to year 1, liraglutide 3.0 mg recipients lost 5.8 kg (95% confidence interval 3.7–8.0) more weight than those on placebo and 3.8 kg (1.6–6.0) more than those on orlistat (Pp0.0001; intention-to-treat, last-observation-carried- forward). At year 2, participants on liraglutide 2.4/3.0 mg for the full 2 years (pooled group, n¼ 184) lost 3.0 kg (1.3–4.7) more weight than those on orlistat (n¼ 95; Po0.001). Completers on liraglutide 2.4/3.0 mg (n¼ 92) maintained a 2-year weight loss of 7.8 kg from screening. With liraglutide 3.0 mg, 20-week body fat decreased by 15.4% and lean tissue by 2.0%. The most frequent drug-related side effects were mild to moderate, transient nausea and vomiting. With liraglutide 2.4/3.0 mg, the 2-year prevalence of prediabetes and metabolic syndrome decreased by 52 and 59%, with improvements in blood pressure and lipids. Conclusion: Liraglutide is well tolerated, sustains weight loss over 2 years and improves cardiovascular risk factors. International Journal of Obesity (2012) 36, 843–854; doi:10.1038/ijo.2011.158; published online 16 August 2011 Keywords: liraglutide; GLP-1 analog; weight loss Introduction Correspondence: Professor A Astrup, Department of Human Nutrition, Faculty of Life Sciences, University of Copenhagen, Rolighedsvej 30, DK-1958, Frederiksberg C, Denmark. Obesity increases risk of developing type 2 diabetes mellitus E-mail: [email protected] and cardiovascular disease, the leading cause of death. Listed in the Appendix. Reduction of 5–10% body weight improves obesity-related Received 4 April 2011; revised 5 July 2011; accepted 5 July 2011; published 3–5 online 16 August 2011 cardiovascular and metabolic abnormalities, but achieving Safety and weight loss with diet and liraglutide A Astrup et al 6–8 this target through diet and exercise is challenging. increasing weekly (dose escalation). The open-label com- Pharmacological treatment is recommended in addition to parator group (n¼ 95) was randomized to receive orlistat 4,7–9 diet and exercise when lifestyle intervention fails. capsules (3 120 mg) with each main meal for the full 2-year Liraglutide, an analog of the incretin hormone glucagon- period. After 20 weeks, participants could consent to enroll like peptide-1 (GLP-1), is currently licensed for treatment of in the extension, continuing on randomized treatment for type 2 diabetes at doses up to 1.8 mg, after demonstrating 1 year, after which liraglutide or placebo-treated individuals improvements in glycemic control and weight loss in more switched to liraglutide 2.4 mg, considered the most favorable than 4000 individuals of the Liraglutide Effect and Action in dose based on 20-week data analysis. However, when 1-year 10,11 Diabetes (LEAD) program, with satisfactory tolerability. results became available, the 3.0 mg dose was deemed more In obese non-diabetic adults, liraglutide at doses up to 3.0 mg favorable and participants switched to this dose between was more effective than orlistat, or diet and exercise alone, weeks 70–96, as sites obtained ethics committee approval. at reducing weight (primary outcome) over 20 weeks. In the main 20-week trial, eligible participants, sponsor Liraglutide also improved obesity-related risk factors, redu- and all study personnel were blinded to the random cing waist circumference, blood pressure (BP) and the injection treatment assignment, performed using a sponsor- prevalence of prediabetes. generated central telephone or web-based system, generated We now report 2-year results from the extension of the by the sponsor and concealed from trial investigators. A 20-week trial, as well as data after 1 year, the required balanced (1:1) treatment allocation was specified, stratified duration for demonstrating weight loss/maintenance in by gender. We instructed participants receiving liraglutide or confirmatory phase 3 trials. The primary outcome at 1 year placebo to administer daily injections (liraglutide was weight loss. In the extension at 2 years, we aimed to 6.0 mg ml or vehicle in identical 3 ml cartridges) in the evaluate the long-term safety/tolerability of liraglutide abdomen or thigh each evening, using a pen injector. Four (primary outcome) and efficacy for sustaining weight loss different placebo injection volumes corresponded to the (secondary) of liraglutide, with dietary therapy and exercise, different liraglutide doses, thereby masking treatment and also to examine the effects on cardiovascular risk factors. (active/placebo). From 20 to 52 weeks, participants/investigators remained blinded to liraglutide/placebo treatment but the sponsor/ Materials and methods statistician was unblinded; after 1 year, all were unblinded. Throughout run-in and treatment, participants were advised Participants on diet (about 30% of energy from fat, 20% from protein and We performed a randomized, double-blind, placebo- 50% from carbohydrates), providing an energy deficit of controlled 20-week trial (RCT) with a 2-year extension. The B500 kcal per day, and encouraged to maintain or increase data from the 20-week RCT has already been published. We physical activity. To encourage adherence, pedometers were recruited men and women aged 18–65 years, of stable distributed, and a 3-day food diary was dispensed for weight, with body mass index 30–40 kg m and fasting completion 4 times during the trial, and reviewed by a 1 1 plasma glucose (FPG) o7 mmol l (126 mg dl ) at run-in, dietician. from 19 research sites in 8 European countries. Participants The trial ran from January 2007 to April 2009 and is were recruited by local advertisement or were existing registered with Clinicaltrials.gov, number NCT00480909. patients at an obesity clinic or research center. Key exclusion criteria were type 1 or 2 diabetes mellitus, drug-induced obesity, use of weight-lowering pharmacotherapy or partici- Clinical outcomes pation in a weight-control study within the preceding 3 Efficacy endpoints included weight change from randomiza- months, surgical obesity treatment and major medical tion to years 1 and 2 in the intention-to-treat population, the conditions. There was no exclusion criterion based on proportion losing 45or 410% of randomization weight, psychiatric illness. Participants gave written informed con- and changes in waist circumference, BP, prevalence of sent. The protocol was approved by local ethics committees 14 15,16 prediabetes and metabolic syndrome, glycemic para- and the trial performed according to the Declaration of meters, fasting lipids and cardiovascular biomarkers, and Helsinki and Good Clinical Practice Guidelines. 17 14 quality of life. Prediabetes was defined as either impaired ) or impaired glucose tolerance FPG (5.6–6.9 mmol l Study design and treatments (7.8–11.0 mmol l ) after 2-hour oral glucose tolerance test Study design is shown in Figure 1. The 20-week RCT (75 g glucose). The diagnosis of metabolic syndrome was consisted of a 2-week placebo run-in period one week after made according to updated National Cholesterol Education screening, then randomization to a 4-week dose-escalation Program-Adult Treatment Panel III (NCEP-ATP III) criter- 15,16 period, and a 16-week constant-dose period. We randomly ia. Body composition in a subgroup of participants was assigned individuals to once-daily liraglutide 1.2, 1.8, 2.4 or measured at randomization and week 20 only by dual-energy 3.0 mg (n¼ 95, 90, 93 and 93) or placebo (n¼ 98) by evening X-ray absorptiometry and single-slice abdominal computer- subcutaneous injection, starting at 0.6 mg per day and ized axial tomography. Fully blinded specialists at SYNARC International Journal of Obesity Safety and weight loss with diet and liraglutide A Astrup et al Inclusion criteria: BMI ≥30 and ≤40 kg/m Liraglutide 3.0 mg s.c. Liraglutide 3.0 mg Age 18–65 years Stable body weight Liraglutide 2.4 mg s.c. FPG <7.0 mmol/L at Wk -2 Liraglutide 1.8 mg s.c. Liraglutide 2.4 mg Liraglutide 1.2 mg s.c. Switch was when approved locally Screening: Placebo Placebo s.c. (between 70–96 weeks) Wk -3 run-in: Orlistat 120 mg x3 Wk -2 Double blind Extension* n=398 Randomization 20 weeks year 1 year 2 n=564 472 completed 356 completed 268 completed Lifestyle intervention: -500 kcal/day deficit diet + increased physical activity Figure 1 Study design. *From 20–52 weeks, participants/investigators remained blinded to liraglutide/placebo treatment but the sponsor was unblinded; after 1 year, all were unblinded. in Portland, USA (dual-energy X-ray absorptiometry) and Statistical analysis Paris, France (computerized axial tomography) analyzed the Sample size estimation for the 20-week trial was based on scans. We measured weight and BP from screening, so effects the primary outcome weight. It was assumed that the s.d. for on total weight-loss maintenance could be determined post weight change at week 20 would be 5.6 kg; 547 randomized hoc. All other efficacy parameters were measured from individuals (91 per group) provided X85% confidence to randomization, so that effects of liraglutide treatment versus detect a clinically relevant 3 kg difference (P¼ 0.05, two- placebo and orlistat could be assessed. sided) in mean weight between people dosed with liraglutide Safety assessments included adverse events, recorded at and placebo, based on Dunnett’s test. A drop-out rate every visit, standard laboratory tests and serum liraglutide of 30% after 20 weeks was assumed. The objective of antibodies. Antibody-positive samples were further assessed the extension was to evaluate safety and weight-loss for neutralizing effect (against liraglutide) and crossreactivity durability. Data were analyzed according to a pre-established (to GLP-1) in vitro. We measured serum calcitonin as thyroid analysis plan. All analyses were performed on a modified C-cell tumors have been detected in liraglutide-treated intention-to-treat population, comprising all randomized rodents. MDS Pharma Services (Hamburg, Germany) individuals who received at least one treatment dose and had performed the standard laboratory analyses, and Ligand at least one post-randomization assessment of body weight, Binding Services, MDS Pharma Services (Fehraltorf, Switzerland) with the last-observation-carried-forward for efficacy end- analyzed the liraglutide antibody concentration. A safety points (unless stated). Analysis of completers (those in the committee for data surveillance was established. intention-to-treat population who completed the trial Clinic visits over the 2-year trial period were weekly during period) from screening was also performed post hoc. All dose escalation, otherwise, every 4 weeks. Weight was analyses were two-sided, with 5% significance. The numbers measured at every visit from screening. Standardized waist of values that were imputed at year 1 and year 2 for the circumference assessments were made at randomization, parameters weight, waist circumference, BP, fasting lipids, then every 4 weeks. BP, glycemic parameters and lipids were prediabetes and metabolic syndrome are shown in Supple- measured at randomization, every 4 weeks to week 24, then mentary Table 1. at weeks 32, 44, 52, 64, 76, 88, 100 and 104; BP was also We analyzed 1-year weight, waist, BP and 20-week body measured at screening. Metabolic syndrome status, predia- composition (also glycemic parameters, fasting lipids, cardi- betes status, cardiovascular biomarkers and glycated hemo- ovascular biomarkers and pulse post hoc) by analysis of globin (HbA ) and quality of life were assessed at covariance (ANCOVA), investigating the superiority of each 1c randomization, week 20, week 52 and week 104. Participants of the four doses of liraglutide over placebo (primary underwent physical examination and electrocardiogram at objective) and orlistat (secondary objective). At year 2, the screening, week 20, week 52 and week 104. Pulse rate and superiority of liraglutide (in a pooled group of participants laboratory parameters were measured at screening, run-in who were on 2.4/3.0 mg for 2 years) versus orlistat was (laboratory parameters only), randomization, every 4 weeks assessed. Treatment, country and sex were fixed effects; the to week 24, then at weeks 32, 44, 52 and 104. Calcitonin value of the respective parameter at randomization was a concentration was categorized by one of four categories: covariate. The primary null hypothesis was that there was no olower level of quantification (LLOQ); XLLOQ and oupper difference between treatments. We adjusted for multiplicity normal range (UNR); XUNR and o2 UNR; and X2 UNR. using Dunnett’s method. International Journal of Obesity Safety and weight loss with diet and liraglutide A Astrup et al In support of the ANCOVA analyses for weight, waist and BP, was 5.8 kg (95% confidence interval 3.7–8.0) with liraglutide repeated measures analyses were performed using the long- 3.0 mg. Mean change in waist circumference was signifi- itudinal measurements available for the modified intention-to- cantly greater with liraglutide 2.4–3.0 mg versus placebo. treat population. These analyses were planned at year 1 and Weight loss for those on liraglutide 2.4/3.0 mg for 2 years was were performed post hoc at year 2. The repeated measures model significantly greater than with orlistat. No gender differences included the same effects as the ANCOVA model described in weight loss were observed (data not shown). Body above. Interactions between treatment and visit, country and composition results in subgroup participants showed that visit, and sex and visit were also included, with the restriction 20-week weight loss with liraglutide was primarily from fat that, for visits in the dose-escalation period (weeks 1– 4), means tissue (Table 1). for treatment groups having received the same treatment up to Significantly more individuals on liraglutide 1.8–3.0 mg the given visit were assumed to be equal. Evaluations of achieved weight losses 45 and 410% of randomization superiority of each liraglutide dose to placebo (primary weight versus placebo at year 1 (Figure 2b). At year 2, objective) and to orlistat (secondary objective) were carried significantly more on liraglutide 2.4/3.0 mg than on orlistat out using the Bonferroni adjustment for multiple testing. lost 45 and 410% weight. Of the 64% who achieved 45% The proportions of individuals losing 45 and 410% weight loss with liraglutide 2.4/3.0 mg at year 1, 485% weight were analyzed by logistic regression, using the same maintained this at year 2. model parameters (without country), with multiplicity adjustment using Bonferroni correction. As ‘country’ showed no significant effect it was removed from the model, to allow Blood pressure and pulse from randomization inclusion of a greater number of variables and to increase the Mean systolic and diastolic BP decreased in all groups over 1 accuracy of the estimates. Prediabetes and calcitonin were year, and systolic BP remained significantly lower with also analyzed by logistic regression, as were metabolic liraglutide 2.4/3.0 mg than orlistat at 2 years, while pulse syndrome status and nausea/vomiting incidence post hoc. rate was 3.5 beats min greater (Figure 2c). The logistic regression analysis for calcitonin noted if a trial participant moved up one category from randomization to year 2. Randomization means for treatment groups in all the Maintenance from screening: weight loss, BP reduction and pulse above analyses were assumed to be equal. We used the Mean weight reduction between screening and randomiza- Statistical Analysis System software package (version 9.1; SAS tion was 1.3 1.4 kg across groups. Figure 3a shows that Institute, Cary, NC, USA) for all analyses. participants randomized to liraglutide 3.0 mg for 1 year (and then maintained on 2.4/3.0 mg for the second year) main- tained a mean weight loss of 10.3 7.1 kg from screening over 2 years. Weight loss for the pooled group on liraglutide Results 2.4/3.0 mg for 2 years was estimated to be 7.8 kg by adjusted Trial population ANCOVA (Supplementary Figure 2a). Almost 70% of liraglu- tide 2.4/3.0 mg recipients maintained weight loss 45% of Of 616 individuals entering the 2-week run-in, 135 men and screening weight at year 2, 43% maintained 410% loss and 429 women (n¼ 564) were randomized to treatment, 398 25% maintained 415% loss (Supplementary Figure 2b). entered the extension and 268/398 (67%) completed 2 years Between screening and randomization, across all groups, (see Supplementary Figure 1). Included in the trial were 21 individuals (o4% overall) classified as having a rando- mean systolic BP decreased by 5.7 11.0 mm Hg, diastolic BP ± ± by 3.7 8.1 mm Hg and pulse rate fell by 0.9 10.1 mization glucose concentration in the range of type 2 beats min . For completers on liraglutide 2.4/3.0 mg, mean diabetes mellitus; this had developed since screening. Three systolic BP had decreased from screening levels by liraglutide-treated participants were excluded from the 12.5 mm Hg at year 2 (Figure 3b). With liraglutide, mean intention-to-treat population owing to missing post-rando- mization weight data. Major protocol deviations are pulse rate rose slightly from randomization in the first 30 weeks of the trial (Figure 3c), but subsequently fell, described in the Supplementary Information. approximately to screening levels (Figures 3b and c). Participant characteristics were comparable across groups at randomization (Supplementary Table 2) and entering the extension (not shown). Repeated measures analyses of weight, waist and BP At years 1 and 2, the repeated measures analyses, performed Weight and waist circumference from randomization in support of the primary ANCOVA analyses, in general gave For the intention-to-treat population (with last-observation- slightly greater estimates for weight and waist change, carried-forward), estimated mean weight loss from randomi- slightly lower estimates for systolic BP and similar estimates zation to year 1 was significantly greater with liraglutide for diastolic BP (Supplementary Tables 3 and 4). In terms of 1.8–3.0 mg compared with placebo, and was dose-dependent superiority, results of the repeated measures analyses were in (Figure 2a, ANCOVA). Placebo-subtracted mean weight loss general comparable to those of the ANCOVA analyses. International Journal of Obesity Safety and weight loss with diet and liraglutide A Astrup et al WEIGHT (kg) WAIST (cm) Placebo Year 1 Year 2 Year 1 Year 2 Orlistat 0.0 Liraglutide 1.2 mg -1.0 Liraglutide 1.8 mg Liraglutide 2.4 mg -2.0 -2.0 -2.3 Liraglutide 3.0 mg -3.0 -3.0 Liraglutide 2.4/3.0 mg -4.0 -3.8 -3.9 pooled group -4.5 -4.5 -5.0 -5.2 -5.3 -5.4 -5.6 -6.0 -6.1 -6.2 P < 0.001 -6.5 ** -7.0 -7.8 -7.8 -8.0 *P < 0.001 vs. placebo †P < 0.05 vs. orlistat ** ** **P ≤ 0.0001 ‡P ≤ 0.0001 *P ≤ 0.001 vs. placebo †P < 0.001 vs. orlistat **P = 0.02 ‡P = 0.03 #P < 0.01 P < 0.001 ** 44 † * P = 0.04 40 37 # 29 27 26 20 17 16 >5% >10% >5% >10% YEAR 1 YEAR 2 SYSTOLIC BP (mmHg) DIASTOLIC BP (mmHg) PULSE RATE (beats/minute) Year 1 Year 2 *P < 0.005 vs. placebo †P < 0.002 vs. orlistat 6.0 ‡P = 0.01 † P<0.001 † * 4.4 * ‡ 3.9 4.0 3.5 3.1 2.8 2.0 Year 1 Year 2 Year 1 Year 2 0.0 -0.2 -0.4 -0.6 -1.0 -1.2 -1.5 -1.5 -1.7 -1.5 -1.6 -2.0 -2.1 -2.0 -2.3 -2.8 -4.0 -4.0 -4.2 -4.6 -4.9 -6.0 P = 0.02 -7.0 -8.0 Figure 2 (a) Mean changes in body weight and waist circumference from randomization to years 1 and 2. (b) Participants with 45 and 410% randomization weight loss at years 1 and 2. (c) Mean changes in BP and pulse rate from randomization to years 1 and 2. Estimated mean changes in weight, waist, BP and pulse rate (by ANCOVA), and in weight-loss responders (by logistic regression) are shown for the intention-to-treat population with the last observation carried forward. Safety and tolerability and quality of life 40% of those randomized to placebo or orlistat. Adverse Over the 2-year period, 222 (39%) individuals withdrew from events include data previously reported for the 20-week the trial: 34–43% of those randomized to liraglutide, and trial. Summary data for year 1 are shown in Table 2, and in International Journal of Obesity Estimated mean change Proportion of individuals (%) Estimated mean change Safety and weight loss with diet and liraglutide A Astrup et al Table 1 Body composition assessed by dual-energy X-ray absorptiometry and computerized axial tomography in a subgroup of participants at 20 weeks Placebo Liraglutide Orlistat n¼ 14 n¼ 12 1.2 mg 1.8 mg 2.4 mg 3.0 mg n¼ 15 n¼ 13 n¼ 15 n¼ 15 Dual-energy X-ray absorptiometry measurements: body composition at randomization (kg) Fat tissue 45.8 (10.5) 43.5 (7.6) 45.0 (8.8) 42.6 (6.1) 43.9 (8.4) 41.3 (6.7) Lean tissue 51.0 (11.0) 55.0 (8.9) 51.7 (11.3) 50.6 (11.9) 53.1 (10.3) 47.4 (6.4) Relative change at week 20 (%) Fat tissue 11.9 (2.5) 13.9 (2.7) 13.0 (2.6) 16.5 (2.5) 15.4 (2.6) 13.3 (2.9) Change vs placebo F 2.0 (8.9 to 4.9); 1.1 (8.0 to 5.9); 4.6 (11.2 to 2.1); 3.5 (10.3 to 3.4); F P¼ 0.57 P¼ 0.76 P¼ 0.18 P¼ 0.32 Lean tissue 1.3 (1.0) 0.9 (1.1) 2.9 (1.1) 2.6 (1.0) 2.0 (1.1) 0.9 (1.2) Change vs placebo F 0.4 (2.4 to 3.3); 1.6 (4.4 to 1.3); 1.3 (4.1 to 1.4); 0.7 (3.6 to 2.1); F P¼ 0.77 P¼ 0.28 P¼ 0.33 P¼ 0.61 2 a Computerized axial tomography measurements: body composition at randomization (cm ) Visceral fat 136 (38) 172 (77) 121 (39) 149 (76) 145 (69) 101 (40) Subcutaneous fat 474 (107) 453 (68) 476 (71) 426 (75) 434 (116) 459 (113) Relative change at week 20 (%) Visceral fat 13.8 (5.7) 19.0 (6.3) 19.4 (6.0) 23.0 (5.7) 20.3 (6.0) 20.2 (6.7) Change vs placebo F 5.1 (21.2 to 11.0); 5.6 (21.8 to 10.6); 9.2 (24.7 to 6.4); 6.4 (22.1 to 9.2); F P¼ 0.53 P¼ 0.49 P¼ 0.25 P¼ 0.42 Subcutaneous fat 12.1 (3.0) 15.6 (3.3) 15.9 (3.6) 19.3 (3.0) 15.3 (3.3) 17.9 (3.6) Change vs placebo F 3.5 (11.8 to 4.9); 3.8 (12.6 to 5.1); 7.1 (15.2 to 1.0); 3.1 (11.5 to 5.2); F P¼ 0.41 P¼ 0.40 P¼ 0.09 P¼ 0.45 a b c Mean (s.d.). Estimated mean (s.e.). Estimated mean (95% CI); P-value. Values are for participants who completed the substudy according to the protocol (PP completers). Supplementary Table 5 for year 2. The most frequent female and randomized to liraglutide treatment, were with- liraglutide-associated side effects were gastrointestinal drawn owing to serious adverse events. One withdrew owing (Table 2; Supplementary Table 6). In year 1, more partici- to a serious event of cholelithiasis, occurring simultaneously pants reported nausea and/or vomiting with liraglutide with acute pancreatitis, after 299 days on liraglutide 3.0 mg; 3.0 mg (49/93; 53%) than with lower doses, placebo (8/98; the individual recovered without sequelae. Breast cancer 8%) (Po0.0001) or orlistat (7/95; 7%)(Po0.0001). Most occurred in an individual randomized to liraglutide 1.8 mg nausea/vomiting episodes started in weeks 1–6, were tran- and treated with 2.4 mg at the time of the event, which was sient and 490% were of mild or moderate intensity. Few reported after 465 days of treatment. The individual subse- episodes were serious (2 vomiting). Nausea incidence over 2 quently withdrew from the trial. A serious intestinal adeno- years was similar for males and females (P¼ 0.49). carcinoma was reported by a female participant after 410 days Mean 1-year weight loss from randomization with liraglu- on liraglutide 2.4 mg, after a screening program for lung tide 3.0 mg was 10.0 kg for those with nausea and/or cancer during the trial revealed metastases in the liver. The vomiting (n¼ 49) and 7.1 kg for those without individual withdrew from the trial and was not expected to (n¼ 43)(difference 2.9 kg (95% confidence interval 0.5–5.3); recover. A serious anaphylactic reaction was reported by one P¼ 0.02). Weight loss without nausea and/or vomiting was individual after 692 days of treatment with liraglutide 3.0 mg. still 4.2 kg greater than placebo (P¼ 0.0001) and 2.3 kg The event was due, according to the hospital to which the greater than orlistat (P¼ 0.04). individual was admitted, to administration of diclofenac/ No participant discontinued treatment owing to aversion misoprostol on the day of the reaction. The individual to injections or injection-site disorders during run-in recovered but later withdrew from the trial. A further three (Supplementary Figure 1). A total of 51 individuals (9%) serious adverse events of special interest and in the liraglutide withdrew from the trial over 2 years owing to adverse events. group were events of atrial fibrillation, uterine leiomyoma These were mostly gastrointestinal. Over 2 years, 15/371 and prostate cancer. A serious cardiovascular episode (atrial (4%) liraglutide-treated individuals discontinued owing to fibrillation) was reported in a male individual randomized to nausea and/or vomiting; none on placebo (in year 1) or placebo but on liraglutide 3.0 mg at the time of the event, orlistat did so. Four on liraglutide 2.4 mg discontinued which occurred after 707 days. Treatment was temporarily because of injection-site disorders (pain/extravasation; discontinued; the participant recovered and completed the hematoma; irritation; and discomfort). Four individuals, all trial without further events. The uterine leiomyoma occurred International Journal of Obesity Safety and weight loss with diet and liraglutide A Astrup et al Liraglutide 1.2 mg Placebo Liraglutide 1.8 mg Orlistat Liraglutide 2.4 mg n=561 Liraglutide 3.0 mg n=472 n=356 n=268 -2 All on liraglutide/placebo switched Below symbol to liraglutide 2.4 mg at week 52, represents ITT then between 70–96 weeks (shaded) -4 (LOCF) data: to 3.0 mg -6 -8 -10 n=561 -12 -14 -3 0 8 20 32 40 48 52 56 68 80 92 104 Weeks SYSTOLIC BP (mmHg) DIASTOLIC BP (mmHg) PULSE RATE (beats/minute) 2.0 0.8 n=91 0.0 -2.0 n=45 -4.0 -3.9 -6.0 n=45 n=92 P = 0.002 -6.9 -6.9 -8.0 n=45 -10.0 P = 0.98 -9.9 n=92 -12.0 Orlistat -12.5 Liraglutide 2.4/3.0 mg -14.0 pooled group P =0.17 3.0 Liraglutide 2.4/3.0 mg pooled group Orlistat 2.0 1.0 0.0 -1.0 -2.0 -3.0 -4.0 -5.0 Weeks Figure 3 (a) Change in body weight from screening over 2 years, presented as observed data for individuals completing each scheduled visit. (b) Estimated (ANCOVA) changes in BP and pulse rate from screening to year 2 for the completer population. (c) Mean change in pulse rate over 2 years, presented as observed data for the intention-to-treat population (with no imputation). in a participant on 2.4 mg liraglutide for 219 days, who was Trial drug continued unchanged throughout the event, the diagnosed with single fungal fibroid, underwent hysterec- individual completed the trial and was reported as recovering. tomy, but later recovered. Prostate cancer was detected in an A psychiatric medical history was present in 96/564 (17%) individual on liraglutide 1.8 mg after 94 days of treatment. participants. In year 1, the most frequently reported disorder International Journal of Obesity Screening Randomization -3 Randomization Mean change in pulse Estimated mean change (beats/minute) Screening Mean weight change (kg) Safety and weight loss with diet and liraglutide A Astrup et al Table 2 Summary of safety data, gastrointestinal disorders with an incidence of X5% in any group and all psychiatric disorders in year 1 Placebo n¼ 98 Liraglutide Orlistat n¼ 95 1.2 mg n¼ 95 1.8 mg n¼ 90 2.4 mg n¼ 93 3.0 mg n¼ 93 N (%) E N (%) E N (%) E N (%) E N (%) E N (%) E Summary of safety data Overall withdrawal rate 24 (25) 17 (18) 20 (22) 27 (29) 18 (19) 28 (30) Participants with AEs 87 (88.8) 374 88 (92.6) 362 84 (93.3) 430 88 (94.6) 485 89 (95.7) 492 89 (93.7) 372 Participants with any SAE 3 (3.1) 3 2 (2.1) 2 7 (7.8) 7 4 (4.3) 5 7 (7.5) 10 2 (2.1) 2 Withdrawals due to AEs 3 (3.1) 7 5 (5.3) 12 6 (6.7) 10 12 (12.9) 20 7 (7.5) 12 3 (3.2) 3 Gastrointestinal disorders 37 (37.8) 62 55 (57.9) 101 58 (64.4) 121 66 (71.0) 157 72 (77.4) 167 60 (63.2) 110 Abdominal pain 4 (4.1) 4 2 (2.1) 2 3 (3.3) 3 1 (1.1) 1 5 (5.4) 5 4 (4.2) 5 Abdominal pain upper 1 (1.0) 1 5 (5.3) 6 2 (2.2) 3 5 (5.4) 5 5 (5.4) 7 7 (7.4) 8 Constipation 12 (12.2) 14 15 (15.8) 17 11 (12.2) 12 21 (22.6) 24 17 (18.3) 18 7 (7.4) 8 Diarrhea 10 (10.2) 11 8 (8.4) 13 9 (10.0) 12 12 (12.9) 13 14 (15.1) 15 28 (29.5) 40 Dyspepsia 3 (3.1) 3 6 (6.3) 7 7 (7.8) 7 9 (9.7) 13 8 (8.6) 8 3 (3.2) 4 Flatulence 1 (1.0) 1 F 4 (4.4) 4 4 (4.3) 4 3 (3.2) 3 10 (10.5) 10 Nausea 7 (7.1) 8 23 (24.2) 27 29 (32.2) 33 35 (37.6) 48 45 (48.4) 68 7 (7.4) 7 Steatorrhea F FFFF 5 (5.3) 5 Toothache 1 (1.0) 1 1 (1.1) 1 5 (5.6) 7 1 (1.1) 1 F 1 (1.1) 1 Vomiting 2 (2.0) 2 5 (5.3) 6 9 (10.0) 18 14 (15.1) 17 12 (12.9) 16 2 (2.1) 4 Psychiatric disorders 5 (5.1) 5 3 (3.2) 3 4 (4.4) 4 11 (11.8) 14 12 (12.9) 14 5 (5.3) 8 Acute stress disorder FF F 1 (1.1) 1 FF Affect lability F FFFF 1 (1.1) 1 Alcohol abuse F FFFF 1 (1.1) 1 Anxiety 1 (1.0) 1 FF 2 (2.2) 2 2 (2.2) 2 F Burnout syndrome F FFF 1 (1.1) 1 F Depressed mood F 1 (1.1) 1 F 3 (3.2) 3 1 (1.1) 1 F Depression FF 2 (2.2) 2 2 (2.2) 2 1 (1.1) 1 2 (2.1) 3 Eating disorder FF F 1 (1.1) 1 FF Food aversion F 1 (1.1) 1 FFF F Insomnia 2 (2.0) 2 FF 2 (2.2) 2 5 (5.4) 6 2 (2.1) 3 Mood altered FF F 1 (1.1) 1 1 (1.1) 1 F Nervousness FF F 2 (2.2) 2 FF Restlessness FF 1 (1.1) 1 FF F Stress 2 (2.0) 2 1 (1.1) 1 1 (1.1) 1 F 2 (2.2) 2 F Abbreviations: AE, adverse event; E, number of adverse event; N (%), number and proportion of participants with an adverse event; SAE, serious adverse event. Does not include individuals who chose not to enroll in the extension period. coded as ‘psychiatric’ was insomnia (Table 2). Other 2.4/3.0 mg and orlistat by logistic regression (estimated odds frequently reported disorders included stress, depression, ratio for liraglutide 2.4/3.0 mg versus orlistat was 0.5 (95% depressed mood and anxiety. All were non-serious and of confidence interval 0.17–1.6); P¼ 0.26). mild or moderate severity. Overall, there were more Seven individuals developed antibodies to liraglutide over psychiatric disorders in general reported by participants on the 2-year trial period (6 on liraglutide and 1 on orlistat). 2.4 and 3.0 mg liraglutide than those on placebo, but there One subject randomized to liraglutide 1.2 mg had antibodies did not seem to be any pattern to the disorders reported, that crossreacted to GLP-1 in vitro at the end of the trial with specific events (other than insomnia) being reported by (the subject was exposed to both liraglutide 2.4 and 3.0 mg p3 participants in any group. Two participants withdrew during the extension period). because of anxiety (placebo) and food aversion (liraglutide Quality of life improved in all groups at year 1 (Supple- 1.2 mg). mentary Table 7) and year 2 (not shown). Over 2 years, 13 self-reported events of symptomatic hypoglycemia (unconfirmed by blood glucose measurement, non-serious) were reported by 9 individuals: 1 event in Other secondary endpoints from randomization placebo and 12 in liraglutide-treated participants. No At randomization, 176/564 (31%) individuals had predia- changes in calcitonin concentration were noted at 2 years. betes, and 229/564 (41%) met criteria for metabolic Most calcitonin assessments were below the upper normal syndrome. Prediabetes prevalence was significantly reduced limit during the 2-year trial period, and no differences in with liraglutide 1.8–3.0 mg versus both placebo and orlistat mean concentrations were observed between liraglutide at year 1, and with liraglutide 2.4/3.0 mg versus orlistat at International Journal of Obesity Safety and weight loss with diet and liraglutide A Astrup et al Placebo PREDIABETES METABOLIC SYNDROME Orlistat Liraglutide 1.2 mg *P ≤ 0.0001 vs. placebo †P ≤ 0.0002 vs. orlistat **P = 0.005 Liraglutide 1.8 mg #P = 0.01 50 Liraglutide 2.4 mg 42 Liraglutide 3.0 mg P < 0.001 40 37 36 37 36 36 Liraglutide 2.4/3.0 mg 32 32 pooled group # 20 ** # 17 * 16 16 † 14 † 11 Randomization Year 1 Year 2 Randomization Year 1 Year 2 TRIGLYCERIDES LDL-CHOLESTEROL HDL-CHOLESTEROL Year 1 Year 2 Year 1 Year 2 Year 1 Year 2 P = 0.03 0.10 †P = 0.03 vs. orlistat 0.07 0.06 0.06 0.06 0.05 0.05 0.03 0.03 ‡P = 0.007 0.01 0.01 0.00 0.01 -0.01 -0.04 -0.10 -0.10 -0.11 -0.14 -0.20 P = 0.053 -0.21 -0.24 ‡ † -0.27 -0.30 -0.28 † -0.28 -0.34 -0.40 -0.43 -0.46 -0.50 Figure 4 (a) The prevalence of prediabetes and the metabolic syndrome at randomization and after 1 and 2 years of treatment. Metabolic syndrome is defined by updated NCEP-ATP III criteria. (b) Mean changes in lipids from randomization to years 1 and 2. Estimated (ANCOVA) changes are shown for the intention-to-treat population with the last observation carried forward. year 2 (Figure 4a). Between 52–62% of liraglutide-treated Plasminogen activator inhibitor-1 significantly decreased individuals with prediabetes at randomization achieved with liraglutide 3.0 mg versus placebo (Supplementary normal glucose tolerance at year 2, compared with 26% of Table 8); otherwise, no significant liraglutide effects those on orlistat. At year 1, the prevalence of metabolic on cardiovascular biomarkers were observed at year 1. syndrome decreased significantly with liraglutide 1.8–3.0 mg Fibrinogen concentrations decreased across groups, while compared with placebo, and was reduced with both liraglu- adiponectin levels increased. tide 2.4/3.0 mg and orlistat at year 2. Fasting lipids, glycemic parameters and cardiovascular risk factors were first measured at randomization, so changes associated with weight loss between screening Discussion and randomization are not accounted for. No effects of liraglutide versus placebo on fasting lipids were apparent Over 2 years, liraglutide with a diet and exercise program was after 1 year (Figure 4b). At year 2, high-density lipoprotein well tolerated, produced sustained weight loss and reduced cholesterol significantly increased with liraglutide 2.4/ important cardiovascular risk factors in obese non-diabetic 3.0 mg versus orlistat (treatment difference 0.07 mmol l , adults. Estimated weight loss of 7.8 kg and systolic BP P¼ 0.03), and both low-density lipoprotein cholesterol decrease of 12.5 mm Hg was sustained with liraglutide and triglycerides decreased from randomization with liraglu- 2.4/3.0 mg in completers from screening. In obesity trials, tide 2.4/3.0 mg (treatment difference 0.12 mmol l for the intervention includes weight loss achieved during run- triglycerides, P¼ 0.053 versus orlistat). Mean FPG and in, before drug exposure, during which lifestyle changes are glycated hemoglobin (HbA ) decreased significantly with initiated, and, from a patient perspective, represents the 1c all liraglutide doses versus placebo at year 1 and with total effect on weight loss. Furthermore, biochemical and liraglutide 2.4/3.0 mg versus orlistat at year 2 (Supplemen- other parameters change during this weight-loss period: for tary Figure 3). example, the initial weight loss of 1.3 kg seen in the current International Journal of Obesity Estimated mean change (mmol/L) Proportion of individuals (%) Safety and weight loss with diet and liraglutide A Astrup et al trial was associated with an immediate reduction in systolic and/or vomiting was associated with greater weight loss with BP of 5.7 mm Hg (in completers), so where screening data liraglutide 3.0 mg, but even those who did not experience exist we have additionally reported these. From randomiza- these events lost more weight than those on placebo or tion, reductions in FPG, HbA , and in the prevalence of orlistat. The injection regimen did not impair adherence or 1c prediabetes and metabolic syndrome, were observed during cause significant withdrawal during treatment or run-in. the trial. The main study limitations are the complex study design At year 1, superior weight loss with liraglutide (7.8 kg) over and the open-label nature of the orlistat treatment arm, both placebo (2.0 kg) and orlistat (3.9 kg) was demonstrated. although this represents existing best pharmacological Mean placebo-subtracted weight loss of 5.8 kg from rando- practice and provides a comparison for the long-term safety mization with liraglutide 3.0 mg was 1.5 kg more than with data of liraglutide over the 2-year period. The lack of the sibutramine in similar 1-year trials. Weight loss stabilized placebo comparison at 2 years is also a limitation, but it did by about 36 weeks, similar to trials with other weight-loss not seem feasible in terms of participant retention to 22,23 agents, was maintained over 2 years and was signifi- maintain the placebo arm. The presence of a diet and cantly greater with liraglutide 2.4/3.0 mg than with orlistat. exercise run-in period in the study design complicates Importantly, almost 70% of participants on liraglutide analyses, and limits the capacity of the trial to anticipate 2.4/3.0 mg over 2 years maintained a 45% weight loss from the total maintained effects of treatment. Most secondary screening, associated with improvements in several cardio- endpoints were not measured at screening, therefore several 4,5 vascular risk factors and metabolic abnormalities. biochemical changes brought about by weight loss during Liraglutide-associated weight loss, in this population not run-in cannot be evaluated. Lipids are likely to have selected for hypertension, was accompanied by decreased improved; a 6% decrease in low-density lipoprotein and systolic BP and unchanged pulse rate at 2 years from total cholesterol concentrations was previously observed screening. Compared with orlistat, BP was lower and pulse during 2-week run-in in a trial of orlistat versus placebo rate higher. The clinical significance of the initial pulse treatment. Analyses from randomization should be inter- increase with liraglutide, as has been reported previously, preted in this light. The initial choice of 2.4 mg as a long- in the context of decreased systolic BP, remains unknown. term maintenance dose after 1 year was based on 20-week At year 2, the prevalence of prediabetes was reduced with data. However, when the 12-month data were analyzed, and liraglutide 2.4/3.0 mg by over 50%. Mean FPG and HbA the decision taken to move up to 3.0 mg, the non-uniform 1c concentrations were also reduced, as in previous studies with time for dose-switch from liraglutide 2.4 to 3.0 mg during 10,11 liraglutide in type 2 diabetes. A significant increase in year 2 (as a result of differences in local ethical committee high-density lipoprotein cholesterol, and marked (nonsig- efficiency) is also a limitation. No participants had the nificant) decrease in triglycerides, was noted with liraglutide benefit of the 3.0 mg dose for the full 2 years, and some for as 2.4/3.0 mg versus orlistat. Changes in low-density lipopro- little as 8 weeks. tein cholesterol were comparable to those observed with In conclusion, results of this study indicate the ability of orlistat, whose mode of action includes reduced dietary fat liraglutide, with diet and exercise, to provide sustained absorption. weight loss over 2 years, greater efficacy compared to orlistat Obesity is associated with altered expression of adipocy- and improvements in many of the important obesity- 24,25 tokines and risk factors for cardiovascular disease. In associated metabolic and cardiovascular risk factors. There agreement with previous studies, weight loss in all groups were no major safety issues, confirming data from the LEAD increased concentrations of adiponectin and reduced fibri- trials in people with type 2 diabetes at liraglutide doses up to 26 10,11 nogen levels. Concentrations of plasminogen activator 1.8 mg. However, it will be necessary to confirm these inhibitor-1, which inhibits endogenous fibrinolysis, are results in a larger phase 3 program in obese adults, both in reduced by diet and exercise, as observed here for all terms of efficacy and (particularly) safety and tolerability. groups except orlistat; liraglutide 3.0 mg produced signifi- cantly greater reduction than diet and exercise alone at year 1. These data concur with effects demonstrated with Conflict of interest liraglutide in patients with type 2 diabetes. Reductions in highly sensitive C-reactive protein were also observed with In the light of Liraglutide is a Novo Nordisk proprietary compound under liraglutide and orlistat, as noted previously. the current focus on cardiovascular safety of weight-loss development for the treatment of obesity. AA has done 28,29 drugs, the favorable effect on cardiovascular risk factors commercially sponsored research for Novo Nordisk, is in the current trial seems promising. an advisory board member for Novo Nordisk, 7TM, Liraglutide was generally well tolerated and improved Neuro-Search, Amylin/Takeda, Pathway Genomics, Jenny quality of life. Adverse events were mostly mild or moderate. Craig, and has been a consultant to the following companies Gastrointestinal events (particularly nausea and vomiting), within the last 3 years: Orexigen, Vivus, Arena, GSK, Novo consistent with the known physiological effects of GLP-1, Nordisk, 7TM, Pharma, Neurosearch, and Johnson and were more frequent than with placebo. At year 1, nausea Johnson. SR has done paid lecturing and commercially International Journal of Obesity Safety and weight loss with diet and liraglutide A Astrup et al sponsored research for Novo Nordisk. LVG was an advisory and management of overweight and obesity in adults and children. NICE clinical guideline 43, 2006. board member for Novo Nordisk and Eli Lilly, and has done 9 EMEA, Committee for Medicinal Products for Human Use commercially sponsored research for Novo Nordisk. AR has (CHMP). Guideline on clinical evaluation of medicinal products done commercially sponsored research and/or been an used in weight control, 15 November 2007. advisory board member for Novo Nordisk, Novartis, Johnson 10 Garber A, Henry R, Ratner R, Garcia-Hernandez PA, Rodriguez- Pattzi H, Olvera-Alvarez I et al. Liraglutide versus glimepiride and Johnson, Boeringer Ingelheim and Eli Lilly. LN has done monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, paid lecturing and commercially sponsored research for Eli 52-week, phase III, double-blind, parallel-treatment trial. Lancet Lily, Merck, Novo Nordisk, Boehringer Ingelheim, Astra 2009; 373: 473–481. Zeneca, Sanofi Aventis, Bristol-Myers Squibb and Pfizer, 11 Vilsboll T, Zdravkovic M, Le-Thi T, Krarup T, Schmitz O, Courre `ges JP et al. Liraglutide, a long-acting human glucagon- and is an advisory board member for Novo Nordisk and like peptide-1 analog, given as monotherapy significantly Astra Zeneca. NF was an advisory board member and has improves glycemic control and lowers body weight without risk done paid lecturing and commercially sponsored research for of hypoglycemia in patients with type 2 diabetes. Diabetes Care Novo Nordisk, Abbott laboratories and Sanofi Aventis, and is 2007; 30: 1608–1610. an advisory board member for Pfizer, Allergan and Takeda. 12 Astrup A, Rossner S, Van Gaal L, Rissanen A, Niskanen L, Al Hakim M et al. Effects of liraglutide in the treatment of obesity: a MEJL and MJS have done commercially sponsored research randomised, double-blind, placebo-controlled study. Lancet 2009; for Novo Nordisk, and MEJL has done paid lecturing for 374: 1606–1616. Novo Nordisk. RC has done paid lecturing and commercially 13 World Medical Association Declaration of Helsinki. Ethical sponsored research for Astra Zeneca, Novo Nordisk, Novartis principles for medical research involving human subjects. JAMA 2000; 284: 3043–3045. and Sanofi Aventis. MK has done commercially sponsored 14 Genuth S, Alberti KG, Bennett P, Buse J, Defronzo R, Kahn R et al. research for Novo Nordisk and Boehringer Ingelheim. AH Follow-up report on the diagnosis of diabetes mellitus. Diabetes and MFR are employees of Novo Nordisk and own stock in Care 2003; 26: 3160–3167. Novo Nordisk. The work was funded by Novo Nordisk A/S, 15 National Cholesterol Education Program. Third report of the national cholesterol education program (NCEP) expert panel on Denmark. detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) final report. Circulation 2002; 106: 3143–3421. 16 Grundy SM, Brewer Jr HB, Cleeman JI, Smith Jr SC, Lenfant C. Acknowledgements Definition of metabolic syndrome: report of the national heart, lung, and blood institute/American heart association conference We thank the study participants and acknowledge the on scientific issues related to definition. 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Spain: Guillem Cuatrecasas Cambra, Bele ´nSa ´daba, Belgium: Luc Van Gaal. Czech Republic: Stepan Svacina, Raffaele Carraro, Basilio Moreno. Sweden: Stephan Ro ¨ ssner, Marie Kunesova. Denmark: Arne Astrup, Bjørn Richelsen, Martin Ridderstra ˚ le. United Kingdom: Michael Lean, Nick Finer, Mike Sampson. Kjeld Hermansen, Steen Madsbad. Finland: Aila Rissanen, International Journal of Obesity

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International Journal of Obesity – Springer Journals

Published: Aug 16, 2011

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