established in 1812
`
`July 2, 2015
`
`vol. 373 no. 1
`
`A Randomized, Controlled Trial of 3.0 mg of Liraglutide
`in Weight Management
`Xavier Pi-Sunyer, M.D., Arne Astrup, M.D., D.M.Sc., Ken Fujioka, M.D., Frank Greenway, M.D.,
`Alfredo Halpern, M.D., Michel Krempf, M.D., Ph.D., David C.W. Lau, M.D., Ph.D., Carel W. le Roux, F.R.C.P., Ph.D.,
`Rafael Violante Ortiz, M.D., Christine Bjørn Jensen, M.D., Ph.D., and John P.H. Wilding, D.M.,
`for the SCALE Obesity and Prediabetes NN8022-1839 Study Group*
`
`a bs tr ac t
`
`BACKGROUND
`Obesity is a chronic disease with serious health consequences, but weight loss is
`difficult to maintain through lifestyle intervention alone. Liraglutide, a glucagon-
`like peptide-1 analogue, has been shown to have potential benefit for weight
`management at a once-daily dose of 3.0 mg, injected subcutaneously.
`
`METHODS
`We conducted a 56-week, double-blind trial involving 3731 patients who did not
`have type 2 diabetes and who had a body-mass index (BMI; the weight in kilo-
`grams divided by the square of the height in meters) of at least 30 or a BMI of at
`least 27 if they had treated or untreated dyslipidemia or hypertension. We ran-
`domly assigned patients in a 2:1 ratio to receive once-daily subcutaneous injections
`of liraglutide at a dose of 3.0 mg (2487 patients) or placebo (1244 patients); both
`groups received counseling on lifestyle modification. The coprimary end points were
`the change in body weight and the proportions of patients losing at least 5% and
`more than 10% of their initial body weight.
`
`RESULTS
`At baseline, the mean (±SD) age of the patients was 45.1±12.0 years, the mean
`weight was 106.2±21.4 kg, and the mean BMI was 38.3±6.4; a total of 78.5% of
`the patients were women and 61.2% had prediabetes. At week 56, patients in the
`liraglutide group had lost a mean of 8.4±7.3 kg of body weight, and those in the
`placebo group had lost a mean of 2.8±6.5 kg (a difference of −5.6 kg; 95% confi-
`dence interval, −6.0 to −5.1; P<0.001, with last-observation-carried-forward impu-
`tation). A total of 63.2% of the patients in the liraglutide group as compared with
`27.1% in the placebo group lost at least 5% of their body weight (P<0.001), and
`33.1% and 10.6%, respectively, lost more than 10% of their body weight (P<0.001).
`The most frequently reported adverse events with liraglutide were mild or moder-
`ate nausea and diarrhea. Serious events occurred in 6.2% of the patients in the
`liraglutide group and in 5.0% of the patients in the placebo group.
`
`CONCLUSIONS
`In this study, 3.0 mg of liraglutide, as an adjunct to diet and exercise, was associ-
`ated with reduced body weight and improved metabolic control. (Funded by Novo
`Nordisk; SCALE Obesity and Prediabetes NN8022-1839 ClinicalTrials.gov number,
`NCT01272219.)
`
`n engl j med 373;1 nejm.org
`
`July 2, 2015
`
`From the Division of Endocrinology and
`Obesity Research Center, Columbia Uni-
`versity, New York (X.P.-S.); Department
`of Nutrition, Exercise and Sports, Univer-
`sity of Copenhagen, Frederiksberg (A.A.),
`and Novo Nordisk, Søborg (C.B.J.) —
`both in Denmark; Department of Nutri-
`tion and Metabolic Research, Division of
`Endocrinology, Scripps Clinic, La Jolla,
`CA (K.F.); Pennington Biomedical Re-
`search Center, Louisiana State University
`System, Baton Rouge (F.G.); Obesity and
`Metabolic Syndrome Unit, Division of En-
`docrinology and Metabolism, Hospital das
`Clínicas, University of São Paulo Medical
`School, São Paulo (A.H.); Clinique d’Endo-
`crinologie et Nutrition, Centre Hospitalier
`Universitaire, Nantes, France (M.K.); De-
`partments of Medicine and Biochemistry
`and Molecular Biology, University of Cal-
`gary, Calgary, AB, Canada (D.C.W.L.); Di-
`abetes Complications Research Centre,
`Conway Institute, University College Dub-
`lin, Dublin (C.W.R.); Departamento Endo-
`crinología, Instituto Mexicano del Seguro
`Social, Cuidad Madero, Mexico (R.V.O.);
`and Department of Obesity and Endocri-
`nology, University of Liverpool, Liverpool,
`United Kingdom (J.P.H.W.). Address re-
`print requests to Dr. Pi-Sunyer at the
`Obesity Research Center, Columbia Uni-
`versity Medical Center, Berrie Bldg., 1150
`St. Nicholas Ave., New York, NY 10032,
`or at fxp1@ cumc . columbia . edu.
`* A complete list of investigators in the
`Satiety and Clinical Adiposity — Lira-
`glutide Evidence in Nondiabetic and
`Diabetic Individuals (SCALE) Obesity
`and Prediabetes NN8022-1839 Study
`Group is provided in the Supplementary
`Appendix, available at NEJM.org.
`N Engl J Med 2015;373:11-22.
`DOI: 10.1056/NEJMoa1411892
`Copyright © 2015 Massachusetts Medical Society.
`11
`
`The new england
`journal of medicine
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`

`A Quick Take
`summary is
` available at
`NEJM.org
`
`T h e ne w e ngl a nd jou r na l o f m e dic i ne
`
`The increase in the rate of obesity,
`
`a chronic disease with serious health con-
`sequences, largely explains the recent tri-
`pling in the prevalence of type 2 diabetes.1,2
`Weight loss of 5 to 10% has been shown to re-
`duce complications related to obesity and im-
`prove quality of life3-7; however, weight loss is
`difficult to maintain with lifestyle intervention
`alone.8
`Liraglutide, a glucagon-like peptide-1 analogue
`with 97% homology to human glucagon-like
`peptide-1, is approved for the treatment of type 2
`diabetes at doses up to 1.8 mg once daily.9 Weight
`loss with liraglutide is dose-dependent up to 3.0 mg
`once daily10,11 and is mediated by reduced appe-
`tite and energy intake rather than by increased
`energy expenditure.12
`This 56-week, randomized, placebo-controlled
`trial aimed to evaluate the efficacy and safety of
`3.0 mg of liraglutide, injected subcutaneously
`once daily, as an adjunct to a reduced-calorie
`diet and increased physical activity, for weight
`management in overweight or obese adults who
`did not have diabetes at baseline.
`
`Me thods
`
`Study Overview
`We conducted the study from June 1, 2011,
`through March 18, 2013, at 191 sites in 27 coun-
`tries in Europe, North America, South America,
`Asia, Africa, and Australia. The trial protocol
`was approved by local ethics committees or in-
`stitutional review boards and is available with
`the full text of this article at NEJM.org. The trial
`was conducted in accordance with the principles
`of the Declaration of Helsinki13 and Good
`Clinical Practice guidelines.14 A 2-year exten-
`sion of the trial involving patients with predia-
`betes that was designed to evaluate whether lira-
`glutide is associated with delayed onset of type 2
`diabetes was recently completed. All the au-
`thors were involved in the design or conduct of
`the study and the preparation of the manu-
`script, including the decision to submit it for
`publication, and all attest to the accuracy and
`completeness of data and the data analyses.
`The sponsor, Novo Nordisk, planned and per-
`formed the statistical analyses, provided editorial
`and writing assistance, and provided the trial
`drugs.
`
`Patients
`The trial enrolled patients 18 years of age or
`older who had stable body weight and a body-
`mass index (BMI; the weight in kilograms di-
`vided by the square of the height in meters) of
`30 or higher, or 27 or higher if the patient had
`treated or untreated dyslipidemia or hyperten-
`sion (Table S1 in the Supplementary Appendix,
`available at NEJM.org). All the patients provided
`written informed consent before participation.
`Key exclusion criteria were type 1 or 2 diabetes,
`the use of medications that cause clinically sig-
`nificant weight gain or loss, previous bariatric
`surgery, a history of pancreatitis, a history of
`major depressive or other severe psychiatric dis-
`orders, and a family or personal history of mul-
`tiple endocrine neoplasia type 2 or familial
`medullary thyroid carcinoma. Details of the eli-
`gibility and exclusion criteria are provided in the
`Supplementary Appendix.
`
`Study Design and Treatments
`Randomization was performed with the use of
`a telephone or Web-based system provided by
`the sponsor. Eligible patients were randomly as-
`signed, in a 2:1 ratio, to receive once-daily sub-
`cutaneous injections of liraglutide, starting at a
`dose of 0.6 mg with weekly 0.6-mg increments
`to 3.0 mg, or placebo; both groups received
`counseling on lifestyle modification (Fig. S1 in
`the Supplementary Appendix). Patients were
`stratified according to prediabetes status at
`screening15 and according to BMI (≥30 vs. <30).
`Patients, investigators, and the sponsor were
`unaware of the study-group assignments. Lira-
`glutide and placebo were provided in FlexPen
`devices (Novo Nordisk). After 56 weeks, patients
`in the liraglutide group who did not have pre-
`diabetes at screening were randomly assigned
`in a 1:1 ratio to continue receiving liraglutide or
`to switch to placebo for 12 weeks to assess
`whether efficacy was maintained after discontin-
`uation of liraglutide treatment and whether there
`were safety issues related to discontinuation. Pa-
`tients in the placebo group continued to receive
`placebo.
`
`Study Procedures and End Points
`Patients were evaluated every 2 weeks until
`week 8; thereafter, patients were evaluated every
`4 weeks until week 44 and were evaluated again
`
`12
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`Liraglutide for Weight Management
`
`at weeks 50, 56, 58, 60, 64, 68, and 70. All pa-
`tients received standardized counseling on life-
`style modification approximately monthly (see
`the Supplementary Appendix).11 Patients who with-
`drew early were asked to return at week 56 for
`measurement of their weight and recording of
`adverse events.
`The three prespecified coprimary end points,
`assessed at week 56, were weight change from
`baseline, the proportion of patients who lost at
`least 5% of their baseline body weight, and the
`proportion of patients who lost more than 10%
`of their baseline body weight. Secondary end
`points included changes from baseline in BMI,
`waist circumference, glycemic control variables,
`cardiometabolic biomarkers, and health-related
`quality of life. The timing of assessments is de-
`scribed in the Methods section in the Supple-
`mentary Appendix. Health-related quality of life
`was assessed with the use of the Medical Out-
`comes Study 36-Item Short-Form Health Survey
`(SF-36; in which higher scores indicate better
`quality of life)16 and the Impact of Weight on
`Quality of Life–Lite17 (in which higher scores
`indicate better quality of life) and Treatment Re-
`lated Impact Measure–Weight18 (in which higher
`scores indicate better quality of life) question-
`naires. The proportion of patients who modified
`their use of lipid-lowering or antihypertensive
`medications was also assessed. Additional meth-
`ods are described in the Supplementary Appendix.
`Specific attention was given to types of ad-
`verse events that have an increased prevalence
`among obese persons or that were relevant to
`the drug class of liraglutide: of 17 types of ad-
`verse events, 9 were prospectively assessed by
`independent medical experts who were unaware
`of the study-group assignments (Table S2 in the
`Supplementary Appendix). We report adverse
`events that occurred during the main 56-week
`trial period, with onset on or after the first day
`of treatment and no later than 14 days after the
`last day of treatment, unless otherwise stated.
`
`Statistical Analysis
`We estimated that with a sample size of 2400
`patients assigned to receive liraglutide and 1200
`assigned to receive placebo, the study would
`have more than 99% power to detect a between-
`group difference in the three coprimary efficacy
`end points of the main 56-week trial and in the
`
`primary end point of the 2-year extension. The
`power for the first coprimary end point, weight
`change, was calculated with the use of a two-
`sided Student’s t-test at a 5% significance level.
`The power for the two categorical coprimary end
`points was calculated with the use of a two-
`sided chi-square test, also at a 5% significance
`level (see the Supplementary Appendix).
`The prespecified efficacy analyses used data
`from the full-analysis set, which included all
`patients who underwent randomization and re-
`ceived at least one dose of a study drug and had
`at least one assessment after baseline. The safety-
`analysis set included all patients who were ran-
`domly assigned to a study group and had exposure
`to a study drug. Missing values were imputed with
`the use of the last-observation-carried-forward
`method for measurements made after baseline.
`For weight, only fasting measurements were
`used. The three coprimary end points were ana-
`lyzed in hierarchical order. An analysis of covari-
`ance model was used to analyze mean changes
`in continuous end points. The model included
`treatment, country, sex, BMI stratification, status
`with respect to prediabetes at screening, and
`interaction between BMI strata and prediabetes
`status as fixed effects, with the baseline value of
`the relevant variable as a covariate. Categorical
`changes for dichotomous end points were ana-
`lyzed with the use of logistic regression with the
`same fixed effects and covariates as the respective
`analysis of covariance. Sensitivity analyses, per-
`formed to assess the robustness of the primary
`analyses, included repeated-measures and multi-
`ple-imputation analyses, which used a model-
`based approach for missing data (see the Supple-
`mentary Appendix). A total of 63 prespecified
`subgroup analyses were performed to investigate
`whether prediabetes status had any effect on
`the primary and secondary end points and wheth-
`er baseline BMI (in four categories) had any
`effect on weight or glycated hemoglobin level
`(see the Methods in the Supplementary Appen-
`dix). Results are presented only if an effect was
`shown.
`
`R esults
`
`Trial Population
`A total of 3731 patients underwent randomiza-
`tion: 2487 to lifestyle intervention plus liraglu-
`
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`T h e ne w e ngl a nd jou r na l o f m e dic i ne
`
`tide, at a dose of 3.0 mg once daily, and 1244 to
`lifestyle intervention plus placebo. The baseline
`characteristics were similar in the two groups
`(Table 1, and Tables S3 and S4 in the Supple-
`mentary Appendix). A total of 1789 patients
`(71.9%) in the liraglutide group, as compared
`with 801 patients (64.4%) in the placebo group,
`completed 56 weeks of treatment (Fig. S2 in the
`Supplementary Appendix). A larger percentage
`of patients in the liraglutide group than in the
`placebo group withdrew from the trial owing to
`adverse events (9.9% [246 of 2487 patients] vs.
`3.8% [47 of 1244]); a smaller percentage of pa-
`tients in the liraglutide group withdrew from
`the trial owing to ineffective therapy (0.9% [23
`of 2487] vs. 2.9% [36 of 1244]) or withdrew
`their consent (10.6% [264 of 2487] vs. 20.0%
`[249 of 1244]).
`
`Body Weight
`After 56 weeks, patients in the liraglutide group
`had lost a mean (±SD) of 8.0±6.7% (8.4±7.3 kg)
`of their body weight, whereas patients in the
`placebo group had lost a mean of 2.6±5.7%
`(2.8±6.5 kg) of their body weight (Table 2).
`Weight loss with liraglutide was maintained over
`56 weeks and was similar regardless of pre-
`diabetes status (Fig. 1A). A greater proportion
`of patients in the liraglutide group than in the
`placebo group lost at least 5% of their body
`weight (63.2% vs. 27.1%), more than 10% of
`their body weight (33.1% vs. 10.6%), and more
`than 15% of their body weight (14.4% vs. 3.5%)
`(Fig. 1B). Overall, approximately 92% of the
`patients in the liraglutide group and approxi-
`mately 65% of the patients in the placebo
`group lost weight (Fig. 1C). The liraglutide group
`also had a greater reduction than the placebo
`group in mean waist circumference and BMI
`(Table 2).
`Several sensitivity analyses confirmed the su-
`periority of liraglutide over placebo with respect
`to the coprimary end points (Table S6 in the
`Supplementary Appendix). Liraglutide appeared
`to be less effective in patients with a mean BMI
`of 40 or higher than in patients with a lower
`BMI (Fig. S4 in the Supplementary Appendix).
`Estimated mean changes in body weight and
`secondary end points are presented in Tables S6
`and S8 in the Supplementary Appendix.
`
`Glycemic Control
`There was a greater reduction in glycated hemo-
`globin, fasting glucose, and fasting insulin levels
`in the liraglutide group than in the placebo
`group (Table 2). Liraglutide was also associated
`with a lowering of plasma glucose levels (Fig. 2A)
`and higher insulin and C-peptide levels relative
`to placebo during an oral glucose-tolerance test
`(Fig. S3 in the Supplementary Appendix). The
`effects of liraglutide on glycated hemoglobin,
`fasting glucose, and glucose levels during the
`oral glucose-tolerance test were greater in pa-
`tients with prediabetes than in those without
`(P<0.001) (Table S9 in the Supplementary Ap-
`pendix). Measures of insulin resistance and beta-
`cell function also showed improvement with
`liraglutide as compared with placebo (Table S10
`in the Supplementary Appendix).
`The prevalence of prediabetes was signifi-
`cantly lower in the liraglutide group than in the
`placebo group at week 56 (Fig. 2B), a finding
`that was consistent with the improvement in
`glycemic control with liraglutide. Type 2 diabe-
`tes developed in more patients in the placebo
`group than in the liraglutide group during the
`course of treatment.
`
`Cardiometabolic Variables
`Systolic and diastolic blood pressure decreased
`more in the liraglutide group than in the placebo
`group by week 56 (Table 2). All measures of fast-
`ing lipid levels (Table 2), as well as levels of high-
`sensitivity C-reactive protein, plasminogen acti-
`vator inhibitor-1, and adiponectin (Table S8 in
`the Supplementary Appendix), showed greater
`improvement in the liraglutide group than in the
`placebo group.
`
`Health-Related Quality of Life
`Liraglutide treatment was associated with higher
`scores on the SF-36 for overall physical and men-
`tal health, a higher total score (indicating better
`quality of life) on the Impact of Weight on Qual-
`ity of Life–Lite questionnaire (Table S7 in the
`Supplementary Appendix), and more favorable
`individual domain scores on both instruments
`(Fig. S5 in the Supplementary Appendix) than
`was placebo. The total score and the scores for
`weight management and treatment burden on
`the Treatment Related Impact Measure–Weight
`
`14
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`Liraglutide for Weight Management
`
`Table 1. Baseline Characteristics of the Patients.*
`
`Characteristic
`Sex — no. (%)
`Female
`Male
`Age — yr
`Race or ethnic group — no. (%)†
`White
`Black
`Asian
`American Indian or Alaska Native
`Native Hawaiian or other Pacific Islander
`Other
`Hispanic or Latino ethnic group†
`Weight — kg
`Body-mass index‡
`Body-mass index categories — no. (%)‡
`27–29.9: overweight
`30–34.9: obese class I
`35–39.9: obese class II
`≥40: obese class III
`Waist circumference — cm
`Glycated hemoglobin — %
`Fasting glucose — mg/dl
`Fasting insulin — μIU/ml§
`Blood pressure — mm Hg
`Systolic
`Diastolic
`Cholesterol — mg/dl
`Total
`LDL
`HDL
`VLDL
`Free fatty acids — mmol/liter
`Triglycerides — mg/dl
`Prediabetes — no. (%)¶
`Dyslipidemia — no. (%)‖
`Hypertension — no. (%)‖
`
`Liraglutide (N = 2487)
`
`Placebo (N = 1244)
`
`1957 (78.7)
`530 (21.3)
`45.2±12.1
`
`2107 (84.7)
`242 (9.7)
`90 (3.6)
`5 (0.2)
`2 (<0.1)
`41 (1.6)
`259 (10.4)
`106.2±21.2
`38.3±6.4
`
`66 (2.7)
`806 (32.4)
`787 (31.6)
`828 (33.3)
`115.0±14.4
`5.6±0.4
`95.9±10.6
`16.3±79.8
`
`123.0±12.9
`78.7±8.6
`
`193.7±19.1
`111.6±27.9
`51.4±26.2
`25.1±49.6
`0.45±40.5
`126.2±56.9
`1528 (61.4)
`737 (29.6)
`850 (34.2)
`
`971 (78.1)
`273 (21.9)
`45.0±12.0
`
`1061 (85.3)
`114 (9.2)
`46 (3.7)
`4 (0.3)
`2 (0.2)
`17 (1.4)
`134 (10.8)
`106.2±21.7
`38.3±6.3
`
`44 (3.5)
`388 (31.2)
`398 (32.0)
`414 (33.3)
`114.5±14.3
`5.6±0.4
`95.5±9.8
`16.1±89.3
`
`123.2±12.8
`78.9±8.5
`
`194.3±18.8
`112.2±27.6
`51.0±26.4
`25.7±49.4
`0.46±39.7
`128.9±61.0
`757 (60.9)
`359 (28.9)
`446 (35.9)
`
`* Plus–minus values are observed means ±SD. For fasting insulin and lipid levels, plus–minus values are geometric means
`and coefficients of variation. There were no statistically significant differences between the two groups for any charac-
`teristic. To convert values for glucose to millimoles per liter, multiply by 0.05551. To convert values for cholesterol to
`millimoles per liter, multiply by 0.0259. HDL denotes high-density lipoprotein, LDL low-density lipoprotein, and VLDL
`very-low-density lipoprotein.
`† Race and ethnic group were self-reported. Patients from France did not report race or ethnic group.
`‡ The body-mass index is the weight in kilograms divided by the square of the height in meters.
`§ The reference range is 3.0 to 25.0 μIU/mL for both sexes and all ages.
`¶ Prediabetes was defined according to American Diabetes Association 2010 criteria.15
`‖ The diagnoses of dyslipidemia and hypertension were based on self-reported medical history.
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`T h e ne w e ngl a nd jou r na l o f m e dic i ne
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`Table 2. Changes in Coprimary End Points and Cardiometabolic Risk Factors between Baseline and Week 56.*
`
`End Point
`
`Coprimary end points
`
`Change in body weight
`
`% of body weight
`
`Kilograms of body weight
`
`Loss of ≥5% body weight (%)‡
`
`Loss of >10% body weight (%)‡
`
`Body weight-related end points
`
`Body-mass index
`
`Waist circumference (cm)
`
`Glycemic control variables
`
`Glycated hemoglobin (%)
`
`Fasting glucose (mg/dl)
`
`Fasting insulin (%)
`
`Liraglutide
`(N = 2437)
`
`Placebo
`(N = 1225)
`
`Estimated Treatment
`Difference, Liraglutide
`vs. Placebo (95% CI)†
`
`P Value
`
`−8.0±6.7
`
`−8.4±7.3
`
`63.2
`
`33.1
`
`−3.0±2.6
`
`−8.2±7.3
`
`−2.6±5.7
`
`−2.8±6.5
`
`27.1
`
`10.6
`
`−1.0±2.3
`
`−3.9±6.6
`
`−5.4 (−5.8 to −5.0)
`
`−5.6 (−6.0 to −5.1)
`
`4.8 (4.1 to 5.6)
`
`4.3 (3.5 to 5.3)
`
`−2.0 (−2.2 to −1.9)
`
`−4.2 (−4.7 to −3.7)
`
`−0.30±0.28
`
`−7.1±10.8
`
`−12.6
`
`−8.9
`
`−0.06±0.30
`
`−0.23 (−0.25 to −0.21)
`
`0.1±10.4
`
`−6.9 (−7.5 to −6.3)
`
`−4.4
`
`−7.9
`
`−8 (−12 to −5)
`
`−1 (−3 to 2)
`
`<0.001
`
`<0.001
`
`<0.001
`
`<0.001
`
`<0.001
`
`<0.001
`
`<0.001
`
`<0.001
`
`<0.001
`
`0.51
`
`Fasting C-peptide (%)
`
`Vital signs
`
`Systolic blood pressure (mm Hg)
`
`Diastolic blood pressure (mm Hg)
`
`Pulse (beats/min)
`
`Fasting lipid profile
`
`Cholesterol (%)
`
`Total
`
`LDL
`
`HDL
`
`VLDL
`
`Non-HDL
`
`Triglycerides
`
`Free fatty acids
`
`−4.2±12.2
`
`−2.6±8.7
`
`2.5±9.8
`
`−1.5±12.4
`
`−2.8 (−3.56 to −2.09)
`
`−1.9±8.7
`
`0.1±9.5
`
`−0.9 (−1.41 to −0.37)
`
`2.4 (1.9 to 3.0)
`
`<0.001
`
`<0.001
`
`<0.001
`
`−3.1
`
`−3.0
`
`2.3
`
`−13.1
`
`−5.1
`
`−13.3
`
`1.7
`
`−1.0
`
`−1.0
`
`0.7
`
`−5.5
`
`−1.8
`
`−5.5
`
`3.5
`
`−2.3 (−3.3 to −1.3)
`
`−2.4 (−4.0 to −0.9)
`
`1.9 (0.7 to 3.0)
`
`−9.1 (−11.4 to −6.8)
`
`−3.9 (−5.2 to −2.5)
`
`−9.3 (−11.5 to −7.0)
`
`−4.2 (−7.3 to −0.9)
`
`<0.001
`
`0.002
`
`0.001
`
`<0.001
`
`<0.001
`
`<0.001
`
`0.01
`
`* Plus–minus values are observed means ±SD. For fasting insulin, fasting C-peptide, and fasting lipids, the relative change
`from baseline is presented. Post hoc analysis was performed for non-HDL cholesterol.
`† Estimated treatment differences are from an analysis of covariance with data from the full-analysis set, with last-obser-
`vation-carried-forward (LOCF) imputation. The full-analysis set comprised patients who underwent randomization, were
`exposed to at least one treatment dose, and had at least one assessment after baseline (69 patients were excluded
`from the full-analysis set: 61 owing to lack of an assessment and 8 owing to no exposure). Data on pulse are based on
`the safety-analysis set, which included all patients who were randomly assigned to a study group and had exposure to a
`study drug. Data for fasting insulin, fasting C-peptide, and fasting lipids were log-transformed for analysis and are pre-
`sented as relative treatment differences.
`‡ Loss of at least 5% and more than 10% of body weight were analyzed by logistic regression with data from the full-analysis
`set, with LOCF imputation, and are presented as the proportions of patients (%) and odds ratios.
`
`questionnaire were also higher in the liraglutide
`group than in the placebo group, although the
`liraglutide group had a lower score for the expe-
`rience of side effects.
`
`Side Effects and Adverse Events
`Among patients in the safety-analysis set, the
`most common side effects in the liraglutide
`group were related to the gastrointestinal system
`
`16
`
`n engl j med 373;1 nejm.org
`
`July 2, 2015
`
`
`
`
`
`MPI EXHIBIT 1125 PAGE 6
`
`

`

`Liraglutide for Weight Management
`
`Normoglycemia
`Prediabetes
`
`Liraglutide
`Liraglutide
`
`Placebo
`Placebo
`
`LOCF
`
`LOCF
`
`0
`
`4
`
`8
`
`12 16 20 24 28 32 36 40 44 48 52 56
`Weeks
`
`Liraglutide
`
`Placebo
`
`0
`
`–2
`
`–4
`
`–6
`
`–8
`
`–10
`
`–12
`
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`
`100
`
`80
`
`60
`
`40
`
`ChangeinBodyWeight(%)
`
`Patients(%)
`
`Patients(%)
`
`A
`
`B
`
`C
`
`Figure 1. Liraglutide and Body Weight.
`Panel A shows the mean body weight for patients in
`the full-analysis set who completed each scheduled
`visit, according to presence or absence of prediabetes
`at screening. I bars indicate standard error, and the
`separate symbols above the curves represent the 56-
`week weight change using last-observation-carried-
`forward (LOCF) imputation. The full-analysis set com-
`prised patients who underwent randomization, were
`exposed to at least one treatment dose, and had at
`least one assessment after baseline (69 patients were
`excluded from the full-analysis set: 61 owing to lack of
`an assessment and 8 owing to no exposure). Panel B
`shows the proportions of patients who lost at least 5%,
`more than 10%, and more than 15% of their baseline
`body weight. Data shown are the observed means for
`the full-analysis set (with LOCF). Findings from logis-
`tic-regression analysis showed an odds ratio of 4.8
`(95% confidence interval [CI], 4.1 to 5.6) for at least
`5% weight loss and an odds ratio of 4.3 (95% CI, 3.5
`to 5.3) for more than 10% weight loss; the analysis of
`more than 15% weight loss was performed post hoc
`(odds ratio, 4.9 [95% CI, 3.5 to 6.7]). Panel C shows the
`cumulative percentage of patients with those changes
`in body weight after 56 weeks of treatment.
`
`(Table 3); 94% or more were of mild or moderate
`severity. Gastrointestinal events were also the
`most common reason that patients in the lira-
`glutide group withdrew from the trial (159 of
`2481 patients [6.4%], as compared with 9 of 1242
`patients [0.7%] in the placebo group) (Fig. S6 in
`the Supplementary Appendix). Nausea (Fig. S7 in
`the Supplementary Appendix) and vomiting oc-
`curred primarily within the first 4 to 8 weeks
`after initiation of liraglutide treatment. The inci-
`dence of serious adverse events was higher in the
`liraglutide group than in the placebo group
`(Table 3). Three patients died — 1 in the liraglu-
`tide group (with death due to cardiomegaly and
`hypertensive heart disease) and 2 in the placebo
`group (one death each from pulmonary fibrosis
`and cardiorespiratory arrest).
`Gallbladder-related events were more com-
`mon in the liraglutide group than in the pla-
`cebo group (occurring in 61 of 2481 patients
`[2.5%], 3.1 events per 100 patient-years of expo-
`sure; vs. 12 of 1242 patients [1.0%], 1.4 events
`per 100 patient-years of exposure), including more
`cases of cholelithiasis and cholecystitis in the
`liraglutide group. Most patients who reported
`cholelithiasis or cholecystitis underwent an elec-
`tive cholecystectomy (40 of 51 patients [78%] in
`
`P<0.001
`
`33.1
`
`10.6
`
`>10%
`
`WeightLoss
`
`P<0.001
`
`14.4
`
`3.5
`
`>15%
`
`Liraglutide
`
`Placebo
`
`Patients(%)
`
`100
`
`80
`
`60
`
`40
`
`20
`0
`
`65%
`
`27%
`11%
`4%
`
`0
`
`5
`
`10 15 20
`
`P<0.001
`
`63.2
`
`27.1
`
`≥5%
`
`92%
`
`63%
`
`33%
`14%
`
`20
`0
`–45 –40 –35 –30 –25 –20 –15 –10 –5
`WeightChange(%)
`
`the liraglutide group and 6 of 8 patients [75%]
`in the placebo group), and most recovered and
`continued their assigned course of treatment or
`had treatment reintroduced after surgery (43 of
`51 patients [84%] in the liraglutide group and
`6 of 8 patients [75%] in the placebo group). The
`weight loss among patients with gallbladder-
`related adverse events was greater than the mean
`weight loss in the total population (Fig. S8 in the
`Supplementary Appendix).
`
`n engl j med 373;1 nejm.org
`
`July 2, 2015
`
`17
`
`
`
`
`
`MPI EXHIBIT 1125 PAGE 7
`
`

`

`T h e ne w e ngl a nd jou r na l o f m e dic i ne
`
`Liraglutide
`
`Placebo
`
`P<0.001
`
`67.3
`
`P<0.001
`
`20.7
`
`30.8
`
`7.2
`7
`
`20
`
`29
`
`63
`
`Normoglycemia
`atScreening
`
`Prediabetes
`atScreening
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`B
`
`PatientswithPrediabetesatWk56(%)
`
`Screening
`
`After56WeeksofTreatment
`Liraglutide
`Placebo
`
`20
`
`40
`
`60
`Minutes
`
`80
`
`100 120
`
`180
`
`160
`
`140
`
`120
`
`100
`
`0
`
`0
`
`Prediabetes(mg/dl)
`
`PlasmaGlucoseinPersonswith
`
`180
`
`160
`
`140
`
`120
`
`100
`
`0
`
`0
`
`20
`
`80
`
`100 120
`
`Normoglycemia(mg/dl)
`
`PlasmaGlucoseinPersonswith
`
`A
`
`Liraglutide
`
`Placebo
`
`P<0.001
`
`8
`
`24
`
`Week
`
`10
`9
`
`14
`
`12
`
`13
`11
`
`32
`
`40
`
`48
`
`56
`
`3
`2
`
`1
`
`0
`
`8
`
`4
`
`2
`
`1
`
`5
`
`4
`
`3
`
`16
`
`40
`60
`Minutes
`
`3.0
`
`2.5
`
`2.0
`
`1.5
`
`1.0
`
`0.5
`
`0.0
`
`ofDiabetes(%)
`
`PatientsReceivingaDiagnosis
`
`C
`
`CumulativeNo.ofPatientsReceivingaDiagnosisofDiabetesover56Weeks(No.atRisk)
`Liraglutide
`1 (2219)
`2 (2210)
`3 (2137)
`4 (2130)
`Placebo
`1 (1225)
`2 (1210)
`3 (1204)
`4 (1096)
`
`10 (908)
`
` 11 (818)
`
`12(817)
`
`13 (816)
`
`14 (813)
`
`5 (1035)
`
`8 (984)
`
`9 (911)
`
`Figure 2. Liraglutide and Glucose Levels during Oral Glucose-Tolerance Test and Glycemic Status.
`Panel A shows the mean plasma glucose levels during a 75-g oral glucose-tolerance test (OGTT), according to prediabetes status at
`screening in the full-analysis set. The OGTT was performed at screening for the diagnosis of prediabetes and again after 56 weeks of
` assigned treatment (see the Methods section in the Supplementary Appendix). To convert the values for glucose to millimoles per liter,
`multiply by 0.05551. Panel B shows the prediabetes status after 56 weeks in patients who had normoglycemia and in those who had pre-
`diabetes at screening. Findings from logistic-regression analysis showed an odds ratio for prediabetes at week 56 of 3.3 (95% confidence
`interval [CI], 2.4 to 4.7) among patients with normoglycemia at screening and 4.9 (95% CI, 4.0 to 5.9) among patients with prediabetes
`at screening. In Panels A and B, data shown are the observed means for the full-analysis set (with last-observation-carried-forward imputa-
`tion). Panel C shows Kaplan-Meier estimates of the proportion of patients who received a diagnosis of type 2 diabetes during the course
`of the 56-week main trial period. Findings from logistic-regression analysis showed an odds ratio for development of diabetes of 8.1
`(95% CI, 2.6 to 25.3). The prediabetes definition includes patients with transient and confirmed type 2 diabetes. In Panel C, all patients
`in whom diabetes had developed had prediabetes at screening, except for one patient in the placebo group (indicated by a red circle),
`who had normoglycemia. The numbers along the graphs show the cumulative number of patients who received a diagnosis of diabetes
`over the course of 56 weeks. The numbers of patients at risk (i.e., remaining in the trial) are shown in the table beneath the x axis.
`
`The rates of adverse events of pancreatitis
`(Table S11 in the Supplementary Appendix) and
`neoplasms were calculated in terms of 100 patient-
`years at risk, covering the period from the start
`of treatment until the final contact with the
`patient (including events that occurred during
`
`the second randomized period after the end of
`the 56-week main study and those that occurred
`15 days or more after the last day the study drug
`was received). Overall, 11 cases of pancreatitis
`were confirmed by adjudication; these cases oc-
`curred in 10 of 2481 patients in the liraglutide
`
`18
`
`n engl j med 373;1 nejm.org
`
`July 2, 2015
`
`
`
`
`
`MPI EXHIBIT 1125 PAGE 8
`
`

`

`Liraglutide for Weight Management
`
`Table 3. Adverse Events and Serious Adverse Events.*
`
`Event
`
`Liraglutide (N = 2481)
`
`Placebo (N = 1242)
`
`No. of
`Patients (%) No. of Events
`
`Event Rate per
`100 Exposure-
`Years
`
`No. of
`Patients (%) No. of Events
`
`Event Rate per
`100 Exposure-
`Years
`
`Adverse events in ≥5% of patients
`
`1992 (80.3)
`
`Nausea
`
`Diarrhea
`
`Constipation
`
`Vomiting
`
`Dyspepsia
`
`Upper abdominal pain
`
`997 (40.2)
`
`518 (20.9)
`
`495 (20.0)
`
`404 (16.3)
`
`236 (9.5)
`
`141 (5.7)
`
`7191
`
`1429
`
`754
`
`593
`
`597
`
`282
`
`171
`
`163
`
`321.8
`
`63.9
`
`33.7
`
`26.5
`
`26.7
`
`12.6
`
`7.7
`
`7.3
`
`786 (63.3)
`
`183 (14.7)
`
`115 (9.3)
`
`108 (8.7)
`
`51 (4.1)
`
`39 (3.1)
`
`43 (3.5)
`
`43 (3.5)
`
`2068
`
`223
`
`142
`
`121
`
`62
`
`44
`
`49
`
`53
`
`193.7
`
`20.9
`
`13.3
`
`11.3
`
`5.8
`
`4.1
`
`4.6
`
`5.0
`
`Abdominal pain
`
`Nasopharyngitis
`
`Upper respiratory tract infection
`
`Sinusitis
`
`Influenza
`
`Headache
`
`Dizziness
`
`Decreased appetite
`
`Back pain
`
`130 (5.2)
`
`427 (17.2)
`
`213 (8.6)
`
`128 (5.2)
`
`144 (5.8)
`
`327 (13.2)
`
`167 (6.7)
`
`267 (10.8)
`
`171 (6.9)
`
`586
`
`247
`
`141
`
`170
`
`441
`
`203
`
`283
`
`210
`
`133
`
`26.2
`
`11.1
`
`6.3
`
`7.6
`
`19.7
`
`9.1
`
`12.7
`
`9.4
`
`6.0
`
`234 (18.8)
`
`122 (9.8)
`
`7