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Early Weight Loss with Liraglutide 3.0 mg Predicts
1-Year Weight Loss and is Associated with Improvements
in Clinical Markers
Ken Fujioka
1
, Patrick M. O’Neil
2
, Melanie Davies
3
, Frank Greenway
4
, David C.W. Lau
5
, Birgitte Claudius
6
,
Trine Vang Skjøth
6
, Christine Bjørn Jensen
6
, and John P.H. Wilding
7
Objective: To identify an early response criterion for predicting 5% weight loss with liraglutide 3.0 mg
at week 56 and to compare efficacy outcomes in early responders (ERs) and early nonresponders
(ENRs).
Methods: Using pooled data from the SCALE Obesity and Prediabetes and SCALE Diabetes trials,
weight loss of 4% at 16 weeks best predicted 5% weight loss after 56 weeks. Weight loss and
changes in cardiometabolic risk factors and health-related quality of life were evaluated in ERs (4%
weight loss at week 16) and ENRs (<4% weight loss at week 16) completing 56 weeks’ treatment.
Results: Proportions of ERs/ENRs to liraglutide 3.0 mg were 77.3%/22.7% (individuals without type 2
diabetes, T2D) and 62.7%/37.3% (those with T2D). Greater mean weight loss was observed in ERs ver-
sus ENRs: 10.8% versus 3.0% (without T2D) and 8.5% versus 3.1% (T2D). In both trials, greater propor-
tions of ERs versus ENRs achieved 5%, >10%, and >15% weight loss at week 56 with liraglutide
1
Scripps Clinic, La Jolla, California, USA. Correspondence: Ken Fujioka (fujioka.ken@scrippshealth.org)
2
Department of Psychiatry and Behavioral
Sciences, Weight Management Center, Medical University of South Carolina, Charleston, South Carolina, USA
3
Department of Health Sciences, Diabetes
Research Centre, University of Leicester, Leicester, UK
4
Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
5
Departments of
Medicine, Biochemistry and Molecular Biology, University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada
6
Novo Nordisk A/S,
Søborg, Denmark
7
Department of Obesity and Endocrinology, University of Liverpool, Liverpool, UK.
Funding agencies: The preparation of this article was supported by Novo Nordisk A/S, which sponsored the trials on which this article is based.
Disclosure: KF received research grants from Orexigen Therapeutics; received research grants, acted as consultant, and attended speakers’ bureaus for Novo Nordisk;
received research grants and acted as consultant for Enteromedics; received research grants and attended speakers’ bureaus for Shire; attended speakers’ bureaus for
Abbott; acted as consultant and attended speakers’ bureaus for Takeda; received research grants, acted as consultant, and attended speakers’ bureaus for Eisai; and
acted as consultant for Gelesis, Nazura, and Zafgen. PMO received research grants from Orexigen Therapeutics; received research grants from and attended speakers’
bureaus for Weight Watchers International; received research grants from and attended speakers’ bureaus for Novo Nordisk; attended advisory panels for Fleishman-
Hillard; attended speakers’ bureaus for Vindico CME, Practicing Clinicians Exchange, and Eisai; and attended advisory panels for Medscape CME. MD attended advisory
boards, acted as consultant, and attended speakers’ bureaus for Sanofi-Aventis, Eli Lilly and Company, Merck, Boerhinger Ingelheim, AstraZeneca, Janssen, and Novo
Nordisk and attended speakers’ bureaus for Mitsubishi Tanabe Pharma Corp. FG reviewed a proposal for American Pistachio; attended medical advisory boards for
Curves; had travel reimbursement for meeting attendance from Diabetes Technology Society; attended editorial board meetings for Diabetic Living; attended scientific
advisory boards, acted as consultant for, and holds stock options in MicroBiome Therapeutics; acted as consultant for and holds stock options in Neothetics, Inc.;
attended scientific advisory boards for Neurium, GNC, and Pamlab, Inc.; holds stock options in and patent licenses with NeuroQuest, Inc.; attended advisory boards for
Novo Nordisk; attended board meetings for Obesity Medicine Society (OMA); attended advisory boards and acted as consultant for Orexigen Therapeutics; acted as
medical expert for PlenSat, Inc.; acted as consultant for Synergy Medical Education, AlphaSights, ClearView Healthcare Partners, Eisai, and Embera; attended medical
scientific boards for Takeda Pharmaceuticals; attended a GRAS panel for Techenterprises, LLC; acted as faculty consultant for Vindico Medical Education; was a witness
for Wilson, Sonsini, Goodrich & Rosati Professional Corp; attended scientific advisory boards for and acted as consulta nt for Zafgen; is in receipt of research grants from
NIH (NIDDK), Novo Nordisk, Hanmi Pharmaceuticals, NIH, and Tufts University; has been in receipt of research grants from American Egg Board, Biologene, Pennington
Biomedical Research Foundation, MannKind Corporation, Wright Group, NuMe Health, Orexigen Therapeutics, OmniActive, and PepsiCo; and has two patents pending
(WO 2016/033063 A1; PCT/US16/15395). DCWL attended advisory boards and speakers’ bureaus for Amgen, Janssen, and Valeant; attended advisory boards for
Roche; attended advisory boards for Shire; is President of the Canadian Association of Bariatric Physicians and Surgeons; is President of Obesity Canada; and received
research grants from and attended advisory boards and speakers’ bureaus for AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly and Company, Merck,
and Novo Nordisk. BC, TVS, and CBJ are employees and shareholders of Novo Nordisk. JPHW received research grants from and attended advisory boards and
speakers’ bureaus for AstraZeneca, Bristol-Myers Squibb, and Novo Nordisk; attended advisory panels and speakers’ bureaus for Boehringer Ingelheim, Janssen, and
Astellas; attended speakers’ bureaus for Eli Lilly and Company; attended advisory panels for Merck, Sanofi, and Orexigen Therapeutics; and acted as consultant for Pfizer.
Author contributions: The decision to examine the outcomes in early responders and early nonresponders was a joint one by all the authors, based on trials in which all
the academic authors were investigators. The statistical analyses were performed by Novo Nordisk. All authors were involved in discussing the results of the analyses,
writing the article, and approving the submitted version. The final version of the manuscript was reviewed and approved by the authors.
Clinical trial registration: ClinicalTrials.gov identifiers NCT01272219 and NCT01272232.
Additional Supporting Information may be found in the online version of this article.
Received: 26 May 2016; Accepted: 18 July 2016; Published online 2 November 2016. doi:10.10 02/oby.21629
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium,
provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
2278 Obesity |VOLUME 24 | NUMBER 11 | NOVEMBER 2016 www.obesityjournal.org
Obesity Symposium
CLINICAL TRIALS AND INVESTIGATIONS
Obesity
3.0 mg. Greater improvements in cardiometabolic risk factors and health-related quality of life scores
were observed in ERs versus ENRs.
Conclusions: The early response criterion was clinically useful to identify individuals who would achieve
clinically meaningful weight loss at 56 weeks.
Obesity (2016) 24, 2278–2288. doi:10.1002/oby.21629
Introduction
Managing obesity with pharmacotherapy plus lifestyle intervention
can help increase the proportion of people reaching 5% weight
loss, the regulatory benchmark for clinically meaningful weight loss
(1,2), but use of pharmacotherapy must be balanced against potential
adverse effects of treatment and costs. One strategy to increase ben-
efit versus risk in obesity pharmacotherapy is through identification
of long-term weight loss predictors. By stopping drug therapy early
in patients unlikely to achieve clinical benefit, clinicians can mini-
mize drug exposure, improve the benefit:risk ratio for the patient
(3), and use health resources more effectively. Early weight loss,
whether through lifestyle (4-7) or pharmacotherapy (8-11), is a good
predictor of long-term weight loss. Indeed, all recently approved
weight loss medication labels include “stopping rules” stating when
pharmacotherapy should be discontinued if clinically relevant weight
loss is not, or is unlikely to be, achieved. However, current labels
provide little information on outcomes in those individuals eligible
for continued treatment beyond the early milestone; reported results
are for all randomized individuals.
Liraglutide is a glucagon-like peptide-1 analog with 97% homology
to human glucagon-like peptide-1, a physiological regulator of appe-
tite (12,13). Liraglutide at doses up to 1.8 mg once daily (Victoza
V
R
,
Novo Nordisk, Bagsvaerd, Denmark) has been licensed for glycemic
control in type 2 diabetes (T2D) since 2009. More recently, liraglu-
tide 3.0 mg (Saxenda
V
R
; Novo Nordisk), as an adjunct to a reduced-
calorie diet and increased physical activity, has been approved for
weight management in the USA, EU, and elsewhere.
This article describes how the early treatment criterion that best pre-
dicts 5% weight loss with liraglutide 3.0 mg at week 56 was iden-
tified, based on data from the two largest trials in the SCALE pro-
gram of phase 3a trials of liraglutide 3.0 mg for weight
management. Post hoc analyses are presented of the efficacy and
safety results from these trials by early responder status, using this
early response criterion.
Methods
Trial design
The design, methods, patient populations, and results of the SCALE
Obesity and Prediabetes (NCT01272219) and SCALE Diabetes
(NCT01272232) trials were previously published (14,15). Briefly, in
SCALE Obesity and Prediabetes, 3,731 individuals with overweight
or obesity and without diabetes (body mass index [BMI] 30 kg/m
2
or 27 kg/m
2
with 1 obesity-related comorbidity) were random-
ized 2:1 to liraglutide 3.0 mg or placebo for 56 weeks (14). In
SCALE Diabetes, 846 individuals with BMI 27 kg/m
2
and T2D
were randomized 2:1:1 to liraglutide 3.0 mg, liraglutide 1.8 mg, or
placebo for 56 weeks (15). Both trials were double-blind, placebo-
controlled, multicenter trials, and trial drug was given as adjunct to
lifestyle intervention (500 kcal/day deficit diet and physical activity
150 min/week). Here, only results for liraglutide 3.0 mg and pla-
cebo are reported, referred to as “liraglutide 3.0 mg” or “placebo”
hereafter. Liraglutide was initiated at a dose of 0.6 mg and dose-
escalated by 0.6 mg increments weekly to the 3.0 mg treatment
dose. This was a forced dose escalation, with the dose at 3.0 mg for
all individuals by week 4; investigators could delay dose escalation
by 7 days in total.
Determination of early response criterion
We used pooled data from SCALE Obesity and Prediabetes and
SCALE Diabetes to determine the optimal treatment time point and
weight loss threshold for identifying subjects likely to achieve 5%
loss of initial body weight after 56 weeks’ treatment. Given the objec-
tive of the analysis (predictive value for 1-year weight loss), only tri-
als of minimum 1-year duration were eligible. Two of the four phase
3a trials were excluded: SCALE Sleep Apnea because it was a 32-
week trial and SCALE Maintenance because it required individuals to
lose 5% weight through diet and exercise before randomization;
thus their initial weight loss after randomization would not have rep-
resented general practice. The pooled analysis was predefined with
the FDA before individual trial data became available. For mean
weight loss in Table 1, only subjects with body weight measurements
at baseline and the specific time point being analyzed (8, 12, 16
weeks) and week 56 contributed to the analysis. For identifying indi-
viduals with 5% weight loss at week 56, missing data were imputed
using last observation carried forward (LOCF). Reasons for choosing
these time points are in the Supporting Information.
The ability to predict response status after 56 weeks was evaluated
by the positive predictive value (PPV; i.e., proportion of subjects
with an early response who had 5% weight loss after 56 weeks)
and the negative predictive value (NPV; i.e., proportion of subjects
with an early nonresponse who had <5% weight loss after 56
weeks) for 3%, 4%, and 5% weight loss at 8, 12, and 16 weeks.
The proportions of “correctly predicted overall” were calculated
from PPV and NPV (Table 1). The sensitivity and specificity of
these criteria were also evaluated (Supporting Information).
The pooled analysis was repeated for male and female subjects, and
the results were also analyzed separately by trial, to ensure that the
identified cut point for defining early response would be valid for
both sexes and for subjects with or without T2D. A sensitivity anal-
ysis was also performed in which missing week 56 responses were
imputed as nonresponse, rather than using LOCF.
Post hoc analysis of end points by early
response status
Once the optimal early response criterion was identified, subjects
were classified as early responders (ERs) or early nonresponders
Obesity Symposium Obesity
CLINICAL TRIALS AND INVESTIGATIONS
www.obesityjournal.org Obesity |VOLUME 24 | NUMBER 11 | NOVEMBER 2016 2279
(ENRs). We then assessed efficacy outcomes at week 56 for ERs
and ENRs, based on individuals who completed 56 weeks’ treat-
ment. Weight end points were mean change in body weight from
baseline and the proportion of patients with a weight loss of 5%,
>10%, and >15% at week 56. Secondary efficacy outcomes were
the changes from baseline to week 56 in HbA
1c
, fasting plasma glu-
cose, systolic (SBP) and diastolic blood pressure (DBP), BMI, waist
circumference, heart rate, fasting lipid profile, and various additional
cardiometabolic biomarkers. Changes in the following health-related
quality of life (HRQoL) scores were also evaluated: Impact of
Weight on Quality of Life-Lite (IWQOL-Lite) total score and physi-
cal function score (16) (both trials); and Short Form-36 (SF-36)
physical component summary score (17) (SCALE Obesity and Pre-
diabetes only).
Efficacy outcomes are reported for ERs and ENRs who completed
56 weeks’ treatment. Safety is reported based on the safety analysis
set for ERs and ENRs (i.e., all subjects with data at week 16,
regardless of whether they completed 56 weeks’ treatment) (Figure
1). The results are reported by trial for ERs and ENRs to liraglutide
3.0 mg or placebo so that any potential differences in clinical out-
comes in patients with T2D would not be masked due to the rela-
tively small size of this study population.
Statistical analysis
For the pooled analysis to assess the optimal response criterion, no
covariate adjustments were made. Missing response status after 56
weeks was imputed using LOCF. The observed mean weight loss
was plotted during the course of the trial (Figure 2).
Analyses of outcomes at week 56 were performed in trial completers
split by ER and ENR status. The analyses of outcomes used the same
model as in the individual trials (14,15). The model included treatment,
country, sex, and interaction between BMI strata and prediabetes status
as fixed effects, with baseline body weight as covariate. In the SCALE
Diabetes ANCOVA model, BMI stratification and prediabetes status
was replaced by baseline HbA
1c
stratification and background medica-
tion. Continuous variables were estimated using ANCOVA, as
described above; categorical variables were estimated using a logistic
regression model with the same fixed effects and covariates as the rele-
vant ANCOVA. Efficacy data are estimated means or estimated pro-
portions; safety data are observed proportions or observed means.
Statistical analyses were conducted using SAS version 9.3 (SAS Insti-
tute Inc., Cary, NC). As ERs and ENRs are not randomized populations,
differences between them were not quantified or analyzed statistically.
Results
Subject disposition by trial for the individuals covered in these anal-
yses (i.e., those with body weight measurement at baseline and
weeks 16 and 56) is shown in Figure 1.
Optimal early response criterion for 5% weight
loss after 56 weeks
The proportion of subjects treated with liraglutide 3.0 mg who lost
3%, 4%, or 5% weight at 8, 12, and 16 weeks in the pooled
analysis of SCALE Obesity and Prediabetes and SCALE Diabetes
and associated PPVs and NPVs are shown in Table 1. The sensitiv-
ity and specificity of each criterion were also calculated (Supporting
Information Table S1).
The analyses showed that 4% weight loss at 16 weeks yielded the
highest correctly predicted value (80.1%), consistent with high val-
ues for both PPV (81.4%) and NPV (76.0%) (Table 1). The criteria
based on the 8-week time point were associated with lower overall
TABLE 1 Positive and negative predictive values for achieving 5% weight loss with liraglutide 3.0 mg at 56 weeks using
different early response criteria: pooled analysis of the SCALE Obesity and Prediabetes and SCALE Diabetes trials
Week
Early
response
criterion
(%) N
Early
response,
n(%)
Mean
week 56 weight
change (%)
in early
responders
Positive
predictive
value,
n(%)
a
Early
nonresponse,
n(%)
Mean
week 56 weight
change (%)
in early
nonresponders
Negative
predictive
value,
n(%)
b
Correctly
predicted,
n(%)
c
83 2,653 2,035 (76.7) 210.09 1,544 (75.9) 618 (23.3) 23.69 439 (71.0) 1,983 (74.7)
4 1,644 (62.0) 211.00 1,373 (83.5) 1,009 (38.0) 24.53 659 (65.3) 2,032 (76.6)
5 1,245 (46.9) 212.10 1,096 (88.0) 1,408 (53.1) 25.46 781 (55.5) 1,877 (70.8)
12 3 2,578 2,084 (80.8) 29.98 1,601 (76.8) 494 (19.2) 22.79 389 (78.7) 1,990 (77.2)
4 1,821 (70.6) 210.68 1,485 (81.5) 757 (29.4) 23.56 536 (70.8) 2,021 (78.4)
5 1,515 (58.8) 211.55 1,312 (86.6) 1,063 (41.2) 24.37 669 (62.9) 1,981 (76.8)
16 3 2,519 2,099 (83.3) 29.95 1,609 (76.7) 420 (16.7) 22.29 338 (80.5) 1,947 (77.3)
4 1,893 (75.1) 210.46 1,541 (81.4) 626 (24.9) 23.02 476 (76.0) 2,017 (80.1)
5 1,637 (65.0) 211.21 1,411 (86.2) 882 (35.0) 23.78 602 (68.3) 2,013 (79.9)
Week 56 response is defined as at least a 5% reduction in body weight. If data were missing for week 56, the last available body weight measurement was used (i.e.,
missing data were imputed using last observation carried forward). Mean weight loss is based on observed data only.
a
Positive predictive value is defined as the percentage of early responders who were week 56 responders.
b
Negative predictive value is defined as the percentage of early nonresponde rs who were week 56 nonresponders.
c
Correctly predicted proportion 5(number of correctly predicted week 56 responders 1number of correctly predicted week 56 nonresponders)/(total number of subjects).
Obesity Liraglutide 3.0 mg: Early Response, 1-Year Outcomes Fujioka et al.
2280 Obesity |VOLUME 24 | NUMBER 11 | NOVEMBER 2016 www.obesityjournal.org
correctly predicted values and, in particular, low NPVs, meaning that
treatment would have been incorrectly discontinued in a notable num-
ber of individuals who would have gone on to achieve 5% weight
loss after 56 weeks. For example, using NPV for 4% weight loss at 8
weeks, 34.7% (350 of 1,009 subjects identified as ENRs) would have
been incorrectly discontinued, versus 24% (150 of 626 subjects) using
the 16-week value (Table 1). The 12-week time point criteria had
PPVs similar to those at the 16-week time point but comparatively
lower NPVs (Table 1). Thus, using NPV for 4% weight loss at 12
weeks, 29.2% (221 of 757 subjects identified as ENRs) would have
been incorrectly discontinued, versus 24% (150 of 626 subjects) using
the 16-week value (Table 1). Furthermore, the choice of week 16
meant that individuals would have received treatment-dose liraglutide
3.0 mg for 12 weeks, consistent with the exposure period generally
recommended for other antiobesity medications.
Consistent results and conclusions were reached when the pooled
analysis was conducted separately for males and females, or for
each trial, and from a sensitivity analysis with missing week 56
responses imputed as nonresponse (Supporting Information Tables
S2-S4).
A separate analysis showed that 4% weight loss at 16 weeks was also a
good criterion for predicting weight loss with placebo, yielding a high
overall correctly predicted value (80.0%), consistent with a reasonably
high PPV (66.1%) and NPV (85.8%) (Supporting Information Table S5).
Early responder populations
Among individuals on liraglutide 3.0 mg with a week 16 measure-
ment, 77.3% without T2D and 62.7% with T2D were ERs, and
Figure 1 Sub ject disposition for results of post hoc analyses. Early responders (ERs), individuals who achieved 4%
weight loss from baseline at 16 weeks; early nonresponders (ENRs), individuals who achieved <4% weight loss from
baseline at 16 weeks. Full analysis set (FAS): in order to be defined as ER/ENR at week 16, individuals had to have a
fasting body weight measurement at baseline and the week 16 visit. Completers at week 56 were individuals with a
body weight measurement at week 56. Only individuals satisfying the respective criteria are shown. [Color figure can
be viewed at wileyonlinelibrary.com]
Obesity Symposium Obesity
CLINICAL TRIALS AND INVESTIGATIONS
www.obesityjournal.org Obesity |VOLUME 24 | NUMBER 11 | NOVEMBER 2016 2281
22.7% and 37.3% were ENRs. The proportions of individuals who
were ERs to placebo were much lower than with liraglutide 3.0 mg:
30.5% of individuals without T2D and 20.5% with T2D.
Demographic and other baseline characteristics of all randomized
subjects, as well as ERs and ENRs in each trial, are shown in
Tables 2 and 3. The “all-randomized” group included individuals
who discontinued the trial before week 16, while the ER/ENR groups
did not (by definition they could not be classified as ER or ENR).
In general, baseline characteristics in the ER and ENR groups
appeared similar across treatment groups within each trial. In both
liraglutide 3.0 mg and placebo groups, individuals of White origin
appeared more prevalent in the ER versus ENR groups, and female
sex appeared consistently associated with early response to
liraglutide 3.0 mg (see percentages, Supporting Information Table
S3) but not to placebo in individuals with and without T2D.
Weight loss at week 56 in ERs and ENRs
In SCALE Obesity and Prediabetes, weight loss in ERs to liraglutide
3.0 mg was 10.8% (11.2 kg) versus 3.0% (3.2 kg) for ENRs (Figure
2A). Similarly, in SCALE Diabetes, ERs had a greater mean weight
loss than ENRs (8.5% [9.0 kg] vs. 3.1% [3.2 kg]) at 56 weeks (Fig-
ure 2B). ERs to placebo also achieved greater weight loss than
ENRs to placebo (Figure 2).
The proportions of ERs and ENRs achieving 5%, >10%, and
>15% weight loss at week 56 in both trials were always greater for
ERs versus ENRs to liraglutide 3.0 mg (Figure 3). The same pattern
Figure 2 Fasting body weight loss by early responder status. Line graphs are observed means (6SE) for ERs/ENRs
who completed 56 weeks. Fasting visit data only. ERs, early responders (individuals who achieved 4% weight loss
from baseline at 16 weeks); ENRs, early nonresponders (individuals who achieved <4% weight loss from baseline at
16 weeks); SE, standard error. Note that ENRs continued on treatment until week 56; in clinical practice, treatment
would cease for ENRs in line with the stopping rule.
Obesity Liraglutide 3.0 mg: Early Response, 1-Year Outcomes Fujioka et al.
2282 Obesity |VOLUME 24 | NUMBER 11 | NOVEMBER 2016 www.obesityjournal.org
TABLE 2 Demographics and baseline characteristics of patients by early responder status (SCALE Obesity and Prediabetes trial)
Liraglutide 3.0 mg Placebo
All
randomized
(N52,487)
Early
responders
(N51,433)
Early
nonresponders
(N5355)
All
randomized
(N51,244)
Early
responders
(N5265)
Early
nonresponders
(N5535)
Female sex, n(%) 1957 (78.7) 1151 (80.3) 251 (70.7) 971 (78.1) 205 (77.4) 415 (77.6)
Mean age, years [SD] 45.2 [12.1] 46.4 [11.6] 45.4 [11.8] 45.0 [12.0] 47.0 [11.7] 45.6 [12.1]
Race, n(%)
White 2107 (84.7) 1238 (86.4) 289 (81.4) 1061 (85.3) 240 (90.6) 455 (85.0)
Black/African-American 242 (9.7) 126 (8.8) 41 (11.5) 114 (9.2) 15 (5.7) 51 (9.5)
Other 138 (5.5) 69 (4.8) 25 (7.0) 69 (5.5) 10 (3.8) 29 (5.4)
Ethnicity, n(%)
Hispanic/Latino 259 (10.4) 126 (8.8) 31 (8.7) 134 (10.8) 31 (11.7) 46 (8.6)
Non-Hispanic/Latino 2228 (89.6) 1307 (91.2) 324 (91.3) 1110 (89.2) 234 (88.3) 489 (91.4)
Mean weight, kg [SD] 106.2 [21.2] 105.3 [20.4] 109.8 [23.7] 106.2 [21.7] 107.4 [23.6] 106.7 [22.3]
Mean BMI, kg/m
2
[SD] 38.3 [6.4] 38.1 [6.3] 38.9 [6.8] 38.3 [6.3] 38.7 [7.1] 38.3 [6.4]
Glycemic status, n(%)
Normoglycemic 959 (38.6) 528 (36.8) 151 (42.5) 487 (39.1) 100 (37.7) 196 (36.6)
With prediabetes 1528 (61.4) 905 (63.2) 204 (57.5) 757 (60.9) 165 (62.3) 339 (63.4)
Mean HbA
1c
, % points [SD] 5.6 [0.4] 5.6 [0.4] 5.6 [0.4] 5.6 [0.4] 5.6 [0.4] 5.6 [0.4]
Mean FPG, mg/dL [SD] 95.9 [10.6] 96.1 [10.4] 97.2 [11.3] 95.5 [9.8] 95.7 [9.2] 95.9 [9.9]
Early responders, individuals who achieved 4% weight loss from baseline at 16 weeks; early nonresponders, individuals who achieved <4% weight loss from baseline at
16 weeks. Based on individuals with a fasting body weight measurement at baseline and week 16 and who completed 56 weeks of treatment. “All randomized” refers to
all randomized patients in the overall trial.
BMI, body mass index; FPG, fasting plasma glucose; SD, standard deviation.
TABLE 3 Demographics and baseline characteristics of patients by early responder status (SCALE Diabetes trial)
Liraglutide 3.0 mg Placebo
All
randomized
(N5423)
Early
responders
(N5214)
Early
nonresponders
(N5110)
All
randomized
(N5212)
Early
responders
(N531)
Early
nonresponders
(N5101)
Female sex, n(%) 203 (48.0) 112 (52.3) 43 (39.1) 115 (54.2) 15 (48.4) 61 (60.4)
Mean age, years [SD] 55.0 [10.8] 55.5 [10.1] 54.1 [9.8] 54.7 [9.8] 57.9 [9.4] 55.7 [8.8]
Race, n(%)
White 353 (83.5) 184 (86.0) 86 (78.2) 175 (82.5) 27 (87.1) 83 (82.2)
Black/African-American 44 (10.4) 16 (7.5) 14 (12.7) 27 (12.7) 3 (9.7) 13 (12.9)
Other 26 (6.1) 14 (6.5) 10 (9.1) 10 (4.7) 1 (3.2) 5 (5.0)
Ethnicity, n(%)
Hispanic/Latino 46 (10.9) 19 (8.9) 15 (13.6) 24 (11.3) 3 (9.7) 9 (8.9)
Non-Hispanic/Latino 375 (88.7) 193 (90.2) 95 (86.4) 187 (88.2) 28 (90.3) 92 (91.1)
Mean weight, kg [SD] 105.7 [21.9] 106.8 [21.3] 102.8 [19.5] 106.5 [21.3] 109.3 [18.6] 104.7 [22.1]
Mean BMI, kg/m
2
[SD] 37.1 [6.5] 37.7 [6.5] 36.1 [6.3] 37.4 [7.1] 37.7 [5.7] 37.4 [7.6]
Mean HbA
1c
, % points [SD] 7.9 [0.8] 7.9 [0.8] 8.0 [0.8] 7.9 [0.8] 7.6 [0.5] 7.8 [0.7]
Mean FPG, mg/dL [SD]
a
158.4 [32.8] 158.5 [34.8] 157.7 [27.9] 155.5 [33.0] 151.4 [33.0] 149.6 [30.0]
a
Overall values are based on the full analysis set (N5407 and 211, respectively).
Early responders, individuals who achieved 4% weight loss from baseline at 16 weeks; early nonresponders, individuals who achieved <4% weight loss from baseline at
16 weeks. Based on individuals with a fasting body weight measurement at baseline and week 16 and who completed 56 weeks of treatment. “All randomized” refers to
all randomized patients in the overall trial.
BMI, body mass index; FPG, fasting plasma glucose; SD, standard deviation.
Obesity Symposium Obesity
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was observed for placebo, although proportions achieving each cate-
gory were smaller than for liraglutide 3.0 mg.
Secondary end points at week 56 in ERs and
ENRs
In SCALE Obesity and Prediabetes, changes in all cardiometabolic
biomarkers examined, except heart rate, appeared to be more favor-
able in ERs than ENRs to liraglutide 3.0 mg, consistent with greater
weight loss (Table 4, Supporting Information Table S6a). In particu-
lar, greater improvements were observed in ERs versus ENRs to lir-
aglutide 3.0 mg for SBP, HDL cholesterol, LDL cholesterol, total
cholesterol, and triglycerides. Most changes were also more favor-
able in ERs versus ENRs to placebo. With liraglutide 3.0 mg, pulse
rate increased by 2.7 beats per minute (bpm) in ERs and 2.6 bpm in
ENRs. With placebo, pulse rate changes were 21.2 and 10.2 bpm,
respectively. Improvements in the IWQOL-Lite total score and
physical function score and the SF-36 physical component summary
score were reported by all groups, but appeared greater in ERs ver-
sus ENRs to both liraglutide 3.0 mg and placebo (Table 4, Support-
ing Information Table S6a).
Similarly in SCALE Diabetes, changes in most cardiometabolic bio-
markers and HRQoL scores appeared more favorable in ERs than
ENRs (Table 5, Supporting Information Table S6b). Notably,
improvements in glycemic markers were observed in both ERs and
ENRs to liraglutide 3.0 mg.
Safety
Safety results for the randomized populations in both trials were
reported previously (14,15). The most common adverse events
(AEs), occurring more frequently with liraglutide 3.0 mg versus pla-
cebo, were gastrointestinal.
Figure 3 Categorical weight loss at week 56. Proportions of subjects are estimated proportions from a logistic regres-
sion model for ERs/ENRs who completed 56 weeks of treatment. ERs, early responders (individuals who achieved
4% weight loss from baseline at 16 weeks); ENR, early nonresponders (individuals who achieved <4% weight loss
from baseline at 16 weeks).
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2284 Obesity |VOLUME 24 | NUMBER 11 | NOVEMBER 2016 www.obesityjournal.org
TABLE 4 Changes from baseline in selected secondary end points (SCALE Obesity and Prediabetes trial)
Liraglutide 3.0 mg Placebo
Early responders
(N51,433)
Early nonresponders
(N5355)
Early responders
(N5265)
Early nonresponders
(N5535)
Baseline
Change at
56 weeks
[SE] Baseline
Change at
56 weeks
[SE] Baseline
Change at
56 weeks
[SE] Baseline
Change at
56 weeks
[SE]
HbA
1c
(% points) 5.6 20.36 [0.01] 5.6 20.23 [0.01] 5.6 20.17 [0.02] 5.6 20.06 [0.01]
FPG (mg/dL) 96.1 28.2 [0.2] 97.2 26.3 [0.5] 95.7 22.3 [0.5] 95.9 10.9 [0.4]
SBP (mm Hg) 123.4 25.1 [0.3] 123.8 22.0 [0.6] 123.0 22.3 [0.7] 124.0 21.8 [0.5]
DBP (mm Hg) 78.9 23.3 [0.2] 78.6 21.4 [0.4] 78.3 23.0 [0.5] 79.4 22.1 [0.3]
Pulse (bpm) 71.2 12.7 [0.2] 70.8 12.6 71.0 21.2 71.0 10.2
HDL cholesterol, mg/dL (%)
a
51.8 13.9 [0.4] 52.0 10.0 [0.8] 51.9 14.8 [0.9] 50.9 21.0 [0.6]
LDL cholesterol, mg/dL (%)
a
111.4 23.6 [0.5] 113.2 20.9 [1.1] 115.6 22.0 [1.3] 111.7 21.0 [0.9]
Total cholesterol, mg/dL (%)
a
193.0 23.2 [0.3] 196.7 21.7 [0.7] 198.6 21.7 [0.8] 193.9 20.9 [0.6]
Triglycerides, mg/dL (%)
a
125.2 215.3 [0.7] 129.4 27.1 [1.6] 128.3 212.8 [1.8] 130.3 22.5 [1.4]
IWQOL-Lite total score 73.0 112.7 70.7 18.2 72.7 113.0 73.9 16.3
a
Baseline value is in mg/dL, and change is presented as relative change.
Early responders, individuals who achieved 4% weight loss from baseline at 16 weeks; early nonresponders, individuals who achieved <4% weight loss from baseline at
16 weeks. Based on individuals with a fasting body weight measurement at baseline and week 16 and who complete d 56 weeks of treatment. Changes are estimated
mean changes from baseline to week 56 from an ANCOVA. Missing values post-baseline were imputed using last observation carried forward. Additional end points are
reported in Supporting Information Table S6a, b.
DBP, diastolic blood pressure; FPG, fasting plasma glucose; HDL, high-density lipoprotein; LDL, low-density lipoprotein; IWQOL-Lite, Impact of Weight on Qual ity of Life-
Lite; SBP, systolic blood pressure.
TABLE 5 Changes from baseline in selected secondary end points (SCALE Diabetes trial)
Liraglutide 3.0 mg Placebo
Early responders
(N5214)
Early nonresponders
(N5110)
Early responders
(N531)
Early nonresponders
(N5101)
Baseline
Change at
56 weeks
[SE] Baseline
Change at
56 weeks
[SE] Baseline
Change at
56 weeks
[SE] Baseline
Change at
56 weeks
[SE]
HbA
1c
(% points) 7.9 21.60 [0.05] 8.0 21.11 [0.08] 7.6 21.17 [0.14] 7.7 20.30 [0.09]
FPG (mg/dL) 158.5 244.2 [2.4] 157.7 230.1 [30.3] 151.4 230.4 [6.2] 151.4 21.9 [3.7]
SBP (mm Hg) 128.4 23.3 [0.8] 129.1 21.3 [1.1] 128.7 23.2 [2.1] 129.8 10.7 [1.2]
DBP (mm Hg) 78.5 20.6 [0.5] 79.9 21.8 [0.8] 78.5 22.1 [0.4] 79.3 21.0 [0.8]
Pulse (bpm) 74.0 11.7 [0.6] 72.1 13.1 [0.8] 74.3 23.8 [1.5] 73.4 21.4 [0.8]
HDL cholesterol, mg/dL (%)
a
45.3 17.2 [1.0] 46.2 10.7 [1.3] 43.7 17.7 [2.6] 45.6 10.6 [1.3]
LDL cholesterol, mg/dL (%)
a
85.1 11.6 [1.9] 91.7 20.3 [2.5] 76.7 12.5 [4.9] 79.8 14.1 [2.7]
Total cholesterol, mg/dL(%)
a
169.1 21.5 [1.0] 175.6 21.1 [1.5] 159.3 10.3 [2.8] 164.2 13.9 [1.6]
Triglycerides, mg/dL (%)
a
162.0 219.2 [2.1] 155.8 26.9 [3.3] 163.6 212.7 [5.9] 157.2 13.2 [3.8]
IWQOL-Lite total score 69.7 113.2 [0.8] 79.5 17.9 [1.1] 73.8 110.8 [2.1] 75.9 17.2 [1.2]
a
Baseline value is in mg/dL, and change is presented as relative change.
Early responders, individuals who achieved 4% weight loss from baseline at 16 weeks; early nonresponders, individuals who achieved <4% weight loss from baseline at
16 weeks. Based on individuals with a fasting body weight measurement at baseline and week 16 and who complete d 56 weeks of treatment. Changes are estimated
mean changes from baseline to week 56 from an ANCOVA. Missing values post-baseline were imputed using last observation carried forward. Additional end points are
reported in Supporting Information Table S6a, b.
DBP, diastolic blood pressure; FPG, fasting plasma glucose; HDL, high-density lipoprotein; LDL, low-density lipoprotein; IWQOL-Lite, Impact of Weight on Qual ity of Life-
Lite; SBP, systolic blood pressure.
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www.obesityjournal.org Obesity |VOLUME 24 | NUMBER 11 | NOVEMBER 2016 2285
An overview of safety results by early responder status is shown in
Tables 6 and 7. AEs occurring in 5% of individuals treated with
liraglutide 3.0 mg and more frequently with liraglutide 3.0 mg than
placebo are listed by preferred term in Supporting Information Table
S7. AE rates were generally comparable between ERs and ENRs to
liraglutide 3.0 mg, and comparable to the overall trial population,
except that in SCALE Diabetes, rates of gastrointestinal- or
appetite-related AEs were higher in ERs versus ENRs.
In SCALE Obesity and Prediabetes, pancreatitis was uncommon in
ERs (<0.1/100 patient-years’ exposure [PYE]) and ENRs (0.2/100
PYE) to liraglutide 3.0 mg. Gallbladder disorders were more fre-
quent in ERs (2.8% of individuals; 2.9/100 PYE) versus ENRs to
liraglutide 3.0 mg (1.4%; 1.9/100 PYE). Psychiatric AEs appeared
similar in ER and ENRs.
In SCALE Diabetes, no events of pancreatitis were reported, and
there were too few gallbladder-related and psychiatric AEs to allow
any conclusions to be drawn. Documented symptomatic hypoglyce-
mia, defined according to ADA criteria (18), was similar in ERs
versus ENRs to liraglutide 3.0 mg (event rates of 79.5/100 PYE and
93.3/100 PYE, respectively).
For ERs and ENRs to placebo, results were as follows: in SCALE
Obesity and Prediabetes, no pancreatitis was reported in either ERs
or ENRs; gallbladder disorders occurred in 1.6% of ERs (2.2/100
PYE) and 0.5% of ENRs (0.6/100 PYE); and psychiatric AEs
appeared similar in ER and ENRs. In SCALE Diabetes, documented
hypoglycemia occurred at event rates of 20.5/100 PYE (ERs to pla-
cebo) and 31.1/100 PYE (ENRs to placebo).
Discussion
It is well documented that early response to a weight loss interven-
tion can predict long-term weight loss (8-11); this is the basis for
the stopping rules for all recently approved weight loss medications
(19-21). Weight loss response after 1 to 4 months has been used to
predict weight loss at 1 year. Interestingly, in the Look AHEAD
study, 1- and 2-month weight loss was associated with weight loss
TABLE 6 Overview of adverse events in the overall trial and in early responders and early nonresponders (SCALE Obesity and
Prediabetes trial)
Liraglutide 3.0 mg Placebo
All randomized
(N52,481)
ERs
(N51,668)
ENRs
(N5491)
All randomized
(N51,242)
ERs
(N5322)
ENRs
(N5735)
Adverse events 2,285 (92.1) 1,559 (93.5) 453 (92.3) 1,043 (84.0) 285 (88.5) 651 (88.6)
Serious adverse events 154 (6.2) 106 (6.4) 24 (4.9) 62 (5.0) 21 (6.5) 33 (4.5)
Severe adverse events 304 (12.3) 190 (11.4) 51 (10.4) 113 (9.1) 36 (11.2) 66 (9.0)
Fatal 1 (0.0) 0 (0.0) 1 (0.2) 2 (0.2) 0 (0.0) 0 (0.0)
Leading to withdrawal
a
244 (9.8) 54 (3.2) 20 (4.1) 47 (3.8) 4 (1.2) 17 (2.3)
AE data given as n(% of patients). Safety analysis set (for ERs and ENRs, all subjects with data at week 16).
a
Withdrawal rates cover the entire trial period for “All randomized” and week 16 onwards for ERs and ENRs.
ERs, early responders (individuals who achieved 4% weight loss from baseline at 16 weeks); ENRs, early nonresponde rs (individuals who achieved <4% weight loss
from baseline at 16 weeks).
TABLE 7 Overview of adverse events in the overall trial and in early responders and early nonresponders (SCALE Diabetes
trial)
Liraglutide 3.0 mg Placebo
All randomized
(N5422)
b
ERs
(N5229)
ENRs
(N5136)
All randomized
(N5212)
ERs
(N534)
ENRs
(N5132)
Adverse events 392 (92.9) 222 (96.9) 124 (91.2) 182 (85.8) 32 (94.1) 120 (90.9)
Serious adverse events 37 (8.8) 17 (7.4) 15 (11.0) 13 (6.1) 1 (2.9) 10 (7.6)
Severe adverse events 52 (12.3) 30 (13.1) 14 (10.3) 21 (9.9) 1 (2.9) 17 (12.9)
Fatal 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Leading to withdrawal
a
39 (9.2) 7 (3.1) 6 (4.4) 7 (3.3) 0 (0.0) 3 (2.3)
AE data given as n(% of patients).
Safety analysis set (for ERs and ENRs, all subjects with data at week 16).
a
Withdrawal rates cover the entire trial period for “All randomized” and week 16 onwards for ERs and ENRs.
b
One subject did not receive treatment and was excluded from the safety analysis set for SCALE Diabetes.
ERs, early responders (individuals who achieved 4% weight loss from baseline at 16 weeks); ENRs, early nonresponde rs (individuals who achieved <4% weight loss
from baseline at 16 weeks).
Obesity Liraglutide 3.0 mg: Early Response, 1-Year Outcomes Fujioka et al.
2286 Obesity |VOLUME 24 | NUMBER 11 | NOVEMBER 2016 www.obesityjournal.org
through year 8 among individuals with T2D who received an inten-
sive lifestyle intervention (7).
In order to identify an optimal early response criterion for liraglutide
3.0 mg, we examined weight loss of 3%, 4%, or 5% at 8, 12, or
16 weeks in a pooled analysis predefined with the US FDA before
trial data became available. Weight loss of 4% at week 16 was
shown to be the best predictor of 5% weight loss at 56 weeks and
to be appropriate for individuals with and without T2D and for both
genders (Table 1, Supporting Information Table S1). Earlier time
points would result in discontinuation of treatment in a significant
number of individuals who would indeed achieve 5% weight loss
after 56 weeks, while later time points would likely have achieved
even greater predictive accuracy but were not considered as they
would have entailed additional unnecessary exposure in nonrespond-
ers. Accordingly, the stopping rule in the USA specifies a weight
loss of 4% at 16 weeks (22). While health authorities across the
world focus on limiting treatment to those who will benefit, their
approaches differ slightly. The European Medicines Agency required
an early response criterion optimized to exclude individuals who
were unlikely to achieve 10% weight loss at 56 weeks; this was
best fulfilled by weight loss of 5% after 16 weeks (data not
shown). Accordingly, the European label requires 5% weight loss
after 12 weeks on the full 3.0 mg dose to qualify for continued
treatment (23).
In both trials, higher proportions of subjects were early responders
to liraglutide 3.0 mg than to placebo. Early responders to liraglutide
achieved greater mean weight loss than early nonresponders and
were more likely to achieve 5%, >10%, and >15% weight loss at
56 weeks. Greater responses were also seen among early responders
versus early nonresponders to placebo; but fewer subjects were early
responders to placebo compared with liraglutide 3.0 mg.
The greater weight loss in early responders was accompanied by a
trend toward greater improvements in cardiometabolic biomarkers.
Decreases in mean SBP and DBP and favorable changes in lipid
profile, in particular, are expected effects of weight loss, contribut-
ing to a decreased risk of developing cardiovascular disease (24). In
SCALE Diabetes, clinically meaningful reductions in HbA
1c
and
fasting plasma glucose were seen in both early responders and early
nonresponders to liraglutide, due to its direct glucose-lowering effect
(25); in early responders, this effect appeared further enhanced by
the greater weight loss versus early nonresponders. The combination
of direct effects of liraglutide on glycemia, as well as further
improvement likely mediated by enhanced weight loss in early
responders, may be particularly beneficial for slowing progression to
T2D and increasing regression to normoglycemia in individuals with
prediabetes, which further reduces the risk of conversion to T2D
(26).
It has been suggested that, in trials of antiobesity drugs, improve-
ments in feeling and functioning should be measured when validated
measures exist (27). Improvements in HRQoL were recorded as
assessed by IWQOL-Lite, a questionnaire developed specifically to
evaluate the impact of weight on quality of life (both trials), and
SF-36, a more general HRQoL questionnaire (SCALE Obesity and
Prediabetes only). For both liraglutide 3.0 mg and placebo, improve-
ments were greater in early responders than early nonresponders.
The changes recorded for early responders (to either intervention)
were clinically relevant. (Clinically relevant improvements for an
individual are increases of 7.7 to 12 points for IWQOL-Lite total
score, depending on baseline score (28), and 2 points for SF-36
physical component summary score (17).)
The greater improvements observed in early responders, compared
with early nonresponders, were generally not accompanied by an
increase in AEs: the safety profiles of early responders and early
nonresponders were similar within each trial, except that early
responders reported higher rates of gastrointestinal disorders in
SCALE Diabetes and higher rates of gallbladder disorders in
SCALE Obesity and Prediabetes. No new safety signals arose
among early responders or early nonresponders.
In pooled analyses of the SCALE trials, women had slightly greater
weight loss than men with liraglutide 3.0 mg (29); however, both
men and women experienced a clinically meaningful weight loss.
Consistent with this, there appeared to be more women than men
among early responders to liraglutide 3.0 mg in both trials. Greater
weight loss in women may in part be explained by higher plasma
liraglutide exposure in women versus men (30).
The comparisons between early responders and early nonresponders
must be interpreted with caution as they are not comparisons
between randomized groups and were therefore not subjected to sig-
nificance testing. In the case of the diabetes trial, conclusions are
further limited by the low number of individuals in the liraglutide
early nonresponder and placebo early responder groups. An addi-
tional limitation is the use of a forced dose escalation of liraglutide
from 0.6 mg daily to 3.0 mg daily in 0.6 mg increments over 4
weeks (with 1 additional week at investigator’s discretion) in the
original trials. Also, early nonresponders in these trials were contin-
ued on treatment for 56 weeks; in clinical practice their treatment
would be discontinued after 16 weeks, and improvements in end
points might therefore be smaller than those reported here.
From a clinical perspective, use of the stopping rules should help
optimize the use of liraglutide 3.0 mg for weight management.
Patients can be informed that, if they respond well during the first
16 weeks, it is likely they will continue to do so. It is reassuring
that most AEs were no more frequent in early responders compared
with early nonresponders, even with greater weight loss, with the
exception of gallbladder disorders, perhaps reinforcing the sugges-
tion that at least part of the increased risk of gallbladder disorders
seen in SCALE Obesity and Prediabetes was related to weight loss
(14).
Conclusion
Weight loss of 4% after 16 weeks of treatment is a strong predic-
tor of a clinically meaningful weight loss at 56 weeks. More individ-
uals without or with T2D were early responders to liraglutide
3.0 mg in combination with lifestyle intervention compared with
lifestyle intervention alone.
Among early responders to liraglutide 3.0 mg, greater mean weight
loss, greater proportions achieving weight loss thresholds, and
generally greater improvements in cardiometabolic risk factors
and HRQoL scores were observed compared with early
nonresponders.O
Obesity Symposium Obesity
CLINICAL TRIALS AND INVESTIGATIONS
www.obesityjournal.org Obesity |VOLUME 24 | NUMBER 11 | NOVEMBER 2016 2287
Acknowledgments
Medical writing assistance, supported by Novo Nordisk A/S, was
provided by Grace Townshend, MSc, of Watermeadow Medical, an
Ashfield Company, who wrote the first draft of the manuscript
under the guidance of the authors. Statistical analyses were per-
formed by Arne Haahr Andreasen of Novo Nordisk.
V
C2016 The Authors. Obesity published by Wiley Periodicals, Inc. on
behalf of The Obesity Society (TOS)
References
1. Golden J. FDA 2007 Draft Guidance for Industry: Developing Products for Weight
Management. Endocrinologic and Metabolic Drugs Advisory Committee Meeting.
March 28, 2012. http://www.fda.gov/downloads/AdvisoryCommittees/Committees
MeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/
UCM299133.pdf. Accessed 5 May 2016.
2. European Medicines Agency. Guideline on Clinical Evaluation of Medicinal Products
used in Weight Control. http://www.ema.europa.eu/docs/en_GB/document_library/
Scientific_guideline/2014/07/WC500170278.pdf. Published 2014 June 26. Accessed 5
May 2016.
3. Apovian CM, Aronne LJ, Bessesen DH, et al. Pharmacological management of
obesity: an endocrine society clinical practice guideline. J Clin Endocrinol Metab
2015;100:342-362.
4. Wadden TA, Foster GD, Wang J, et al. Clinical correlates of short- and long-term
weight loss. Am J Clin Nutr 1992;56:271S-274S.
5. Stotland SC, Larocque M. Early treatment response as a predictor of ongoing
weight loss in obesity treatment. Br J Health Psychol 2005;10:601-614.
6. Handjieva-Darlenska T, Handjiev S, Larsen TM, et al. Initial weight loss on an
800-kcal diet as a predictor of weight loss success after 8 weeks: the Diogenes
study. Eur J Clin Nutr 2010;64:994-999.
7. Unick JL, Neiberg RH, Hogan PE, et al.; Look AHEAD Research Group. Weight
change in the first 2 months of a lifestyle intervention predicts weight changes 8
years later. Obesity (Silver Spring) 2015;23:1353-1356.
8. Rissanen A, Lean M, R€
ossner S, Segal KR, Sj€
ostr€
om L. Predictive value of early
weight loss in obesity management with orlistat: an evidence-based assessment of
prescribing guidelines. Int J Obes Relat Metab Disord 2003;27:103-109.
9. Fujioka K, Plodkowski R, O’Neil PM, Gilder K, Walsh B, Greenway FL. The
relationship between early weight loss and weight loss at 1 year with naltre xone
ER/bupropion ER combination therapy. Int J Obes (Lond) 2016;40:1369-1375.
10. Finer N, Ryan DH, Renz CL, Hewkin AC. Prediction of response to sibutramine therapy
in obese non-diabetic and diabetic patients. Diabetes Obes Metab 2006;8:206-213.
11. Smith SR, O’Neil PM, Astrup A, et al. Early weight loss while on lorcaserin, diet
and exercise as a predictor of week 52 weight-loss outcomes. Obesity (Silver
Spring) 2014;22:2137-2146.
12. Knudsen LB. Liraglutide: the therapeutic promise from animal models. Int J Clin
Pract 2010;64:4-11.
13. Van Can J, Sloth B, Jensen CB, Flint A, Blaak EE, Saris WH. Effects of the once-
daily GLP-1 analog liraglutide on gastric emptying, glycemic parameters, appetite
and energy metabolism in obese, non-diabetic adults. Int J Obes (Lond) 2014;38:
784-793.
14. Pi-Sunyer X, Astrup A, Fujioka K, et al. A Randomized, Controlled Trial of 3.0 mg
of Liraglutide in Weight Management. N Engl J Med 2015;373:11-22.
15. Davies MJ, Bergenstal R, Bode B, et al. Efficacy of liraglutide for weight loss
among patients with type 2 diabetes: the SCALE Diabetes randomized clinical trial.
JAMA 2015;314:687-699.
16. Kolotkin RL, Crosby RD, Kosloski KD, Williams GR. Development of a brief
measure to assess quality of life in obesity. Obes Res 2001;9:102-111.
17. Maruish ME. User’s Manual for the SF-36V2 Health Survey.3rded.Lincoln,RI:Quality
Metric; 2011.
18. American Diabetes Association. Defining and reporting hypoglycemia in diabetes: a
report from the American Diabetes Association Workgroup on Hypoglycemia.
Diabetes Care 2005;28:1245-1249.
19. Eisai Inc. Belviq (Lorcaserin Hydrochloride) Full Prescribing Information. http://
www.accessdata.fda.gov/drugsatfda_docs/label/2012/022529lbl.pdf. Revised June
2012. Accessed 5 May 2016.
20. Takeda Pharmaceuticals America, Inc. Contrave (Naltrexone HCl and Bupropion
HCl) Extended-Release Tablets Full Prescribing Information. http://ge neral.
takedapharm.com/content/file.aspx?filetypecode5CONTRAVEPI&cacheRandomizer5
eedcee06-8dad-4cf0-910b-06e13004a474. Revised September 2014. Accessed 5 May
2016.
21. Vivus Inc. QSYMIA (Phentermine and Topiramat e Extended-Release Capsules, for
Oral Use, CIV). Highlights of Prescribing Information. https://qsymia.com/patient/
include/media/pdf/prescribing-information.pdf. Revised October 2014. Accessed 5
May 2016.
22. Novo Nordisk Inc. SaxendaV
R(Liraglutide [rDNA Origin] Injection) Full
Prescribing Information. http://www.novo-pi.com/saxenda.pdf. Revised January
2015. Accessed 5 May 2016.
23. European Medicines Agency. Saxenda (Liraglutide 3.0 mg). Summary of Product
Characteristics. 2015. http://ec.europa.eu/health/documents/community-register/2015/
20150323131125/anx_131125_en.pdf. Accessed 5 May 2016.
24. Jensen MD, Ryan DH, Donato KA, et al. Guidelines (2013) for managing
overweight and obesity in adults. Obesity 2014;22(S2):S1-S410.
25. Bode B. An overview of the pharmacokinetics, efficacy and safety of liraglutide.
Diabetes Res Clin Pract 2012;97:27-42.
26. Perreault L, Pan Q, Mather KJ, Watson KE, Hamman RF, Kahn SE, Diabetes
Prevention Program Research Group. Effect of regression from prediabetes to
normal glucose regulation on long-term reduction in diabetes risk: results
from the Diabetes Prevention Program Outcomes Study. Lancet 2012;379:
2243-2251.
27. Ferguson C, David S, Divine L, et al., George Washington University. Obesity
Drug Outcome Measures. A Consensus Report of Considerations Regarding
Pharmacologic Intervention. Available from: http://publichealth.gwu.edu/pdf/
obesitydrugmeasures.pdf Published 2012. Accessed 5 May 2016.
28. Crosby RD, Kolotkin R, Williams GR. An integrated method to determine
meaningful changes in health-related quality of life. J Clin Epidemiol 2004;57:
1153-1160.
29. FDA. Liraglutide 3.0 mg for Weight Management, NDA 206-321. Briefing
Document. Endocrinologic and Metabolic Drugs Advisory Committee Meeting
http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/
endocrinologicandmetabolicdrugsadvisorycommittee/ucm413318.pdf. Published 11
September 2014. Accessed 5 May 2016.
30. Wilding JP, Overgaard RV, Jacobsen LV, Jensen CB, le Roux CW. Exposure-
response analyses of liraglutide 3.0 mg for weight management. Diabetes Obes
Metab 2016;18:491-499.
Obesity Liraglutide 3.0 mg: Early Response, 1-Year Outcomes Fujioka et al.
2288 Obesity |VOLUME 24 | NUMBER 11 | NOVEMBER 2016 www.obesityjournal.org
