International Journal of Obesity (2015) 39, 849–857

© 2015 Macmillan Publishers Limited All rights reserved 0307-0565/15

www.nature.com/ijo

ORIGINAL ARTICLE
Changes in body weight and pulse: outcome events in
overweight and obese subjects with cardiovascular disease in
the SCOUT trial
RV Seimon1, D Espinoza2, N Finer3, WPT James4, UF Legler5, W Coutinho6, AM Sharma7, L Van Gaal8, AP Maggioni9, A Sweeting1,
C Torp-Pedersen10, V Gebski2 and ID Caterson1

BACKGROUND/OBJECTIVES: The Sibutramine Cardiovascular OUTcomes (SCOUT) trial showed a significantly increased relative risk
of nonfatal cardiovascular events, but not mortality, in overweight and obese subjects receiving long-term sibutramine treatment
with diet and exercise. We examined the relationship between early changes (both increases and decreases) in pulse rate, and the
impact of these changes on subsequent cardiovascular outcome events in both the placebo and sibutramine groups.
SUBJECTS/METHODS: 9804 males and females, aged ⩾ 55 years, with a body mass index of 27–45 kg m−2 were included in this
current subanalysis of the SCOUT trial. Subjects were required to have a history of cardiovascular disease and/or type 2 diabetes
mellitus with at least one cardiovascular risk factor, to assess cardiovascular outcomes. The primary outcome event (POE) was a
composite of nonfatal myocardial infarction, nonfatal stroke, resuscitated cardiac arrest or cardiovascular death. Time-to-event
analyses of the POE were performed using Cox regression models.
RESULTS: During the initial 6-week sibutramine treatment period, the induced pulse rate increase was related to weight change
(1.9 ± 7.7 beats per minute (bpm) with weight increase; 1.4 ± 7.3 bpm, 0–5 kg weight loss; 0.6 ± 7.4 bpm, ⩾ 5 kg weight loss).
Throughout the subsequent treatment period, those continuing on sibutramine showed a consistently higher mean pulse rate than
the placebo group. There was no difference in POE rates with either an increase or decrease in pulse rate over the lead-in period, or
during lead-in baseline to 12 months post randomization. There was also no relationship between pulse rate at lead-in baseline and
subsequent cardiovascular events in subjects with or without a cardiac arrhythmia.
CONCLUSION: Baseline pulse rate and changes in pulse rate may not be an important modifier nor a clinically useful predictor of
outcome in an individual elderly cardiovascular obese subject exposed to weight management.
International Journal of Obesity (2015) 39, 849–857; doi:10.1038/ijo.2014.211

INTRODUCTION
Heart rate (pulse rate) has become an accepted modifiable risk
factor for cardiovascular disease (CVD).1 Previous studies have
demonstrated a relationship between elevated resting heart rate
and the risk for CVD in the overall population,2 and in patients
with coronary artery disease with or without comorbidities,
including hypertension and/or type 2 diabetes mellitus.3–5 This
relationship is strong, graded and independent of other cardio-
vascular risk factors. However, the threshold above which risk
increases and the relationship between alterations in heart rate
and CVD outcome are still disputed.4 Analysis of the BEAUTIFUL
(morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in
patients with coronary disease and left ventricULar dysfunction)
and INVEST (International Verapamil-Trandolapril Study) study,
identified ⩾ 70 beats per minute (bpm)5 and ⩾ 75 bpm,4
respectively, as a threshold for adverse cardiovascular outcomes.
However, the unexpected and controversial results of SIGNIFY6
and SHIFT7,8 have caused doubt that heart rate control is always
beneficial in a stable cardiovascular population. Little is known
regarding this risk relationship in a contemporary elderly, obese
population with several comorbidities, and an activated sympa-
thetic nervous system displayed as elevated resting heart rate
within the framework of recent guidelines both for the primary
and secondary prevention of CVD.9–11
Sibutramine hydrochloride monohydrate (sibutramine) is a
norepinephrine and serotonin reuptake inhibitor that induces
satiety, resulting in reduced food intake and increased energy
expenditure.12,13 In some individuals, sibutramine also increases
blood pressure and/or pulse, in part, due to its sympathomimetic
effects.14,15 The Sibutramine Cardiovascular OUTcomes (SCOUT)
trial assessed the morbidity and mortality benefits of weight
management in over 10 000 overweight and obese subjects with
and without established CVD, hypertension and type 2 diabetes
mellitus, all of whom were already on medication for their

1
The Boden Institute of Obesity, Nutrition Exercise & Eating Disorders, University of Sydney, Sydney, New South Wales, Australia; 2National Health and Medical Research Council
Clinical Trials Centre, University of Sydney, Sydney, New South Wales, Australia; 3National Centre for Cardiovascular Prevention and Outcomes, University College London,
Institute for Cardiovascular Science, London, UK; 4London School of Hygiene and Tropical Medicine, London, UK; 5Special Vocational College for Handicapped Persons, Mainz,
Germany; 6Catholic University of Rio de Janeiro and State Institute of Diabetes and Endocrinology, Rio de Janeiro, Brazil; 7Department of Medicine, University of Alberta,
Edmonton, Alberta, Canada; 8Department of Diabetology, Metabolism and Clinical Nutrition, Antwerp University Hospital, Antwerp, Belgium; 9Associazione Nazionale Medici
Cardiologi Ospedalieri Research Center, Florence, Italy and 10Department of Cardiology, Gentofte University Hospital, Hellerup, Denmark. Correspondence: Dr R Seimon, The
Boden Institute of Obesity, Nutrition Exercise & Eating Disorders, The University Of Sydney, 92-94 Parramatta Road, Exercise & Eating Disorders, Camperdown, New South Wales
2050, Australia.
E-mail: radhika.seimon@sydney.edu.au
Received 29 August 2014; revised 25 November 2014; accepted 5 December 2014; accepted article preview online 18 December 2014; advance online publication, 3 February 2015
 Sibutramine, weight loss, pulse rate and cardiovascular outcomes
RV Seimon et al
850
comorbidities, which could be adjusted once the run-in period
Table 1. Demographics and clinical characteristics of the subjects at
had been completed.16 The primary results of SCOUT reported a
the randomized phase baseline
16% relative risk increase in primary outcome events for long-term
sibutramine therapy and denying therefore the study hypothesis; Variable Placebo Sibutramine
this analysis, however, included the full intention-to-treat (ITT)
population and did not take into account the variable responses in Gender, % male 2843/4898 (58%) 2807/4906 (57.2%)
Age (years) 63.3 ± 6.1 63.2 ± 6.1
body weight and pulse rate seen in this overweight and obese Weight (kg) 96.2 ± 15.5 (4897) 96.3 ± 15.4 (4905)
population.16 BMI (kg m − 2) 34.4 ± 4.5 (4897) 34.5 ± 4.6 (4905)
We recently demonstrated a complex interaction between the SBP (mm Hg) 138.2 ± 12.6 (4897) 138.2 ± 12.9 (4905)
effects of sibutramine on both blood pressure and weight loss and DBP (mm Hg) 77.9 ± 8.4 (4897) 77.8 ± 8.4 (4905)
Pulse (bpm) 71.1 ± 10.1 (4897) 71.1 ± 10.2 (4904)
subsequent cardiovascular events: modest weight loss and lower
blood pressure each reduced the incidence of cardiovascular Medical history
events but the combination of early marked weight loss and rapid Overall cardiovascular disease 3977/4884 (81.4%) 3971/4889 (81.2%)
blood pressure reduction seemed to be particularly harmful in an Revascularization procedure 1828/4898 (37.3%) 1786/4906 (36.4%)
Type 2 diabetes mellitus 4139/4884 (84.7%) 4167/4889 (85.2%)
obese elderly population with CVDs.17 The aim of the retro- Cardiac arrhythmia 662/4898 (13.5%) 610/4906 (12.4%)
spective analysis presented here is to characterize and compare
the relationship between early changes (both increases and Concomitant medication
Angiotensin receptor blockers 3792/4898 (77.4%) 3826/4906 (78.0%)
decreases) in body weight and pulse rate, and their impact on β-blockers 3034/4898 (61.9%) 2983/4906 (60.8%)
subsequent cardiovascular outcome events in the SCOUT Calcium channel blocker 1796/4898 (36.7%) 1861/4906 (37.9%)
population. Diuretics 2360/4898 (48.2%) 2310/4906 (47.1%)
Aspirin 3877/4898 (79.2%) 3832/4906 (78.1%)
Statins 3235/4898 (66.0%) 3288/4906 (67.0%)
PATIENTS AND METHODS Abbreviations: BMI, body mass index; bpm, beats per minute; DBP, diastolic
The design and the primary results of SCOUT, a multinational, prospective, blood pressure; SBP, systolic blood pressure. ± values are mean ± s.d. All
randomized, double-blind study conducted according to the principles of subjects received sibutramine during the 6-week lead-in period.
the International Conference on Harmonization and the Declaration of
Helsinki, have been described in detail previously.16,18 Locally appointed
ethics committees approved the protocol, and informed consent was
obtained from all subjects. Changes in weight and pulse rate for individual subjects were computed
The trial included males and females aged 55 years and older, with a from the lead-in baseline (week − 6) to randomization (that is, end of
body mass index of 27–45 kg m − 2. Subjects were required to have a 6-week sibutramine lead-in period) and to 12 months post randomization.
history of a clinically stable CVD (defined as coronary artery disease, stroke Data were summarized within each category of interest as mean and s.d.
or peripheral arterial occlusive disease) and/or type 2 diabetes mellitus for continuous variables and as the number of subjects and percentage (%)
with at least one other cardiovascular risk factor (hypertension, dyslipide- for categorical variables. Mean changes in vital sign measurements from
mia, current smoking or diabetic nephropathy).16 As described previously, lead-in baseline to randomization and to 12 months post randomization
all the subjects underwent an initial 6-week single-blind lead-in period were evaluated using paired t-tests.
during which they received 10 mg sibutramine per day as well as advice Time-to-event analyses were conducted looking at the effect of pulse
regarding diet and exercise, in addition to their usual pharmacotherapy, change (no change (±1 bpm), increase or decrease) on POE rates for the ITT
(dosage of which also remained unchanged) so that subjects with marked population using Cox models, with factors for treatment (that is, 6-week
increases in blood pressure or pulse rate due to sibutramine could be sibutramine treatment followed by either placebo (lifestyle+sibutramine
identified and excluded from the prolonged post-randomization period of followed by placebo; placebo group) or continued sibutramine (lifestyle+
observation.16 Eligible subjects were then randomized, in a double-blind sibutramine followed by sibutramine; long-term sibutramine group)),
manner, to receive 10–15 mg of sibutramine or a matching placebo country, sex and age as covariates. Pulse change (no change (±1 bpm),
per day. All subjects continued to participate in individualized diet and increase or decrease) for individual subjects calculated over (a) the lead-in
exercise programs designed to result in an energy deficit of 600 kcal per baseline to randomization and (b) the lead-in baseline to 12 months post
day.16 Heart rate was measured after the subject had been sitting, resting randomization in subjects with and without cardiac arrhythmia was
for at least 5 min. Sitting pulse rate was measured twice at least 1 min apart assessed. In each case the reference group, when comparing categories,
by palpation of the radial or brachial artery for 1 min. The mean value was was the no pulse change (±1 bpm) group. Estimates of hazard ratios (HR),
used for assessment. All changes in vital signs during the 6-week lead-in 95% confidence intervals (CI) and log-rank P-values were calculated within
sibutramine treatment period were attributed to study interventions as the Cox model framework. Analyses were conducted for (a) all POEs
pre-existing pharmacotherapy for comorbidities remained unchanged. reported during the randomization to a 5-year period and (b) all POEs that
The primary outcome event (POE) was the time from randomization, to occurred after 12 months post randomization (subjects who had a POE or
the first occurrence of nonfatal myocardial infarction, nonfatal stroke, were censored in the first 12 months were not included in this analysis).
resuscitation after cardiac arrest or cardiovascular death. Standard-of-care Further stratified analysis looking at the effect of treatment within pulse
non-pharmacological and pharmacological treatment recommendations change categories was conducted for pulse change categorized by
based on the respective national and international guidelines for the 2.5 bpm change increments for individual subjects over (a) the lead-in
management of comorbidities and for primary and secondary prevention baseline to randomization and (b) the lead-in baseline to 12 months post
of CVD were applied throughout the randomized period.1,9,11,19–22 randomization in subjects with and without cardiac arrhythmia.
From the overall cohort of 10 744 subjects, 940 subjects either withdrew All statistical analyses were performed using SAS, version 9.2 (SAS
from the 6-week sibutramine lead-in period or, according to protocol, were Institute, Cary, NC, USA). All statistical tests were conducted at the (two tail)
not randomized by the investigators because of marked increases in blood 0.05 level of significance. Body weight and vital sign changes were
pressure or pulse rate during this initial treatment with sibutramine. Out of imputed using a last observation carried forward approach if measure-
the remaining 9804 subjects, 1272 had a cardiac arrhythmia (for example, ments were not recorded at the indicated time points after lead-in
atrial fibrillation/flutter) or a pacemaker or implantable cardioverter- baseline.
defibrillator (Table 1).

Statistical analysis RESULTS

Demographic and baseline characteristics at lead-in period baseline were The demographics and clinical characteristics at the 6-week lead-
summarized for those who on randomization constituted the ITT in baseline for the overall study cohort (N = 9804) and the two
population, by treatment group (randomized sibutramine, randomized randomized treatment groups (6-week sibutramine followed by
placebo). placebo (N = 4898); 6-week sibutramine followed by sibutramine

International Journal of Obesity (2015) 849 – 857 © 2015 Macmillan Publishers Limited

(N = 4906)) have been described previously14,18 and are summar-
ized in Table 1. Two thousand one hundred and twenty-two out of
4898 in the placebo and 2034/4906 in the sibutramine group
completed the whole treatment period. The most common
primary reason for subjects prematurely discontinuing the study
therapy during the treatment period was withdrawal of consent
(which in practice is usually related to the individual's discontent
with the amount of weight lost). Treatment groups were well
balanced with the exception that subjects in the long-term
sibutramine treatment arm were more likely already to have
peripheral artery occlusive disease. At lead-in baseline, mean body
weight was 96 kg, body mass index was 34.5 kg m − 2, mean
systolic blood pressure was 138 mm Hg and diastolic blood
pressure 78 mm Hg and pulse rate was 71 bpm, in both the
subsequently randomized treatment groups.
Changes in weight and pulse rate during the entire trial period
As described previously,17 during the 6-week lead-in period, from
lead-in baseline (week-6) to randomization, when all subjects
received sibutramine and comorbidity related pharmacotherapy
remained unaltered, there was a mean weight loss of 2.5 kg.
Following randomization, there was further weight loss in the
sibutramine group (maximum mean additional weight loss 1.8 kg
at 12 months) and a small average increase in weight in the
placebo group (0.6 kg at 12 months). After the 12-month period,
both the groups showed only a small increase in mean weight.
During the 6-week lead-in period, the mean pulse rate
increased by 1.4 bpm (Figure 1). Following randomization, mean
pulse rate increased further in the sibutramine group, but
decreased in those randomized to placebo. Throughout the entire
treatment period, those who continued on sibutramine showed a
consistently higher mean pulse rate than the placebo group;
mean differences between the groups ranged from 2.2–3.7 bpm
(Figure 1).
Figure 1. The average pulse rate at each visit from the time of the
lead-in period (Wk-6) to the final visit (60 months) for all the
randomized subjects. All subjects underwent an initial 6-week (Wk-6
to randomization), single-blind lead-in period during which they
received 10 mg of sibutramine per day; subjects considered eligible
were then randomized to sibutramine or placebo. Analyses were
performed on the data obtained from the ITT population using
t-test. Pulse rate, P = 0.05 at months 30, 36 and 39, P = 0.01 at
months 12, 18–24, 45 and 54, Po 0.0001 at months 1–9, 15, 27 and
33 for the comparison between sibutramine and placebo. Wk, week;
R, randomization; M, month.
© 2015 Macmillan Publishers Limited
Sibutramine, weight loss, pulse rate and cardiovascular outcomes
RV Seimon et al
851
Interactions between pulse rate and weight
The relationship between categorical weight change (subjects
who gained weight, lost 0 to o5 kg, lost 5 kg or more) during the
sibutramine treatment lead-in period and subsequent pulse rate
change from randomization throughout the trial is shown for both
the randomized ITT (Figure 2a) and completer (Figure 2b)
populations. Similarly, categorical weight change during lead-in
baseline to 12 months and subsequent pulse rate change from
randomization is shown for the randomized ITT (Figure 2c) and
completer (Figure 2d) populations. Regardless of weight change,
in all analyses, those on sibutramine showed a significantly higher
pulse rate when compared with those on placebo, throughout
the trial.
In both the ITT and the completer populations, those
subsequently maintained on sibutramine who lost weight during
lead-in baseline to randomization period (Figures 2a and b),
showed a graded and smaller increase in pulse rate with greater
weight loss over the first 12 months. This was also observed in
those who lost weight from lead-in baseline to 12 months post
randomization (Figures 2c and d); they also showed a graded and
smaller increase in pulse rate with greater weight loss over the
24 months. However, in the placebo group there was almost no
effect of weight loss on pulse rate. In contrast, in both the placebo
and sibutramine groups who gained weight during lead-in
baseline to randomization, there was a consistent subsequent fall
in the pulse rate.
Relationship between pulse rate at lead-in baseline (−6 weeks)
and incidence of POE
Subjects without a cardiac arrhythmia showed no relationship
between pulse rate at lead-in baseline and subsequent cardio-
vascular events (Figure 3a). In those with a pre-existing cardiac
arrhythmia, the relationship was much less consistent; patients on
long-term sibutramine who had had a pulse rate of 465 to ⩽ 70
bpm at lead-in baseline showed an increased risk of POE (HR: 2.17
CI: 1.18–3.99, P = 0.01), when compared with placebo, but such an
effect could not be seen in subjects within any other lead-in
baseline pulse category (Figure 3b). However, in neither case, was
there an interaction effect between the different lead-in baseline
pulse change categories and sibutramine (subjects with cardiac
arrhythmia: P = 0.59 and without cardiac arrhythmia P = 0.47).
When adjusted for treatment, country, age and sex, in subjects
without cardiac arrhythmia there was an increased risk of POE
with a pulse rate of 470 bpm (HR: 1.18 CI: 1.03–1.35, P = 0.02),
475 (HR: 1.19 CI: 1.03–1.38, P = 0.02) and 485 (HR: 1.26 CI: 1.01–
1.58, P = 0.04) at lead-in baseline, when each of those with a
higher pulse rate value (⩽70, ⩽ 75 and ⩽ 85 bpm) was compared
with all those below this pulse rate. For subjects with a pre-
existing cardiac arrhythmia, pulse rate of 470 bpm (HR: 1.42
CI: 1.08–1.86, P = 0.01) and 475 (HR: 1.44 CI: 1.09–1.90, P = 0.01) at
lead-in baseline, also showed an increased risk of POE when
compared with a lead-in baseline pulse rate of ⩽ 70 and ⩽ 75 bpm,
respectively.
Detailed analysis showing participants in different pulse rate
categories at lead-in baseline and changes in pulse rate
categories during the lead-in period by various comorbidities
(age, β-blockade, baseline cardiac arrhythmias, gender and
treatment) are presented in Supplementary Tables S1 and S2.
Relationship between changes in pulse rate and the incidence of
POE
There were no differences in POE rates in subjects who either
increased or decreased pulse rate over the lead-in period, or
during lead-in baseline to 12 months post randomization
(Table 2). There was also no difference in various POE components
by pulse rate categories at lead-in baseline or 12 months
International Journal of Obesity (2015) 849 – 857
 Sibutramine, weight loss, pulse rate and cardiovascular outcomes
RV Seimon et al
852

Figure 2. Mean change in pulse rate (bpm) from the randomization of patients into the sibutramine and placebo groups but categorized by
the extent of weight change from lead-in period to randomization (a and b) and from lead-in period to 12 months post randomization
(c and d), for ITT and completer population, in subjects who gained weight (40 kg), lost 0 to o5 kg, lost 5 kg or more (⩾ −5 kg).
R, randomization; M, month.

Figure 3. Subgroup analysis looking at the effect of treatment on primary outcome events stratified by pulse rate categories at lead-in
baseline (−6 weeks) in subjects without (a) and with (b) cardiac arrhythmias. Estimates of hazard ratios (95% CI) and log-rank P-values were
calculated using the Cox model, adjusted for various factors. Lead-in baseline pulse categories: ⩽ 65, 465– ⩽ 70, 470– ⩽ 75, 475– ⩽ 80,
480– ⩽ 85 and 485 bpm. HR, hazard ratios; CI, confidence intervals.

International Journal of Obesity (2015) 849 – 857 © 2015 Macmillan Publishers Limited
 Sibutramine, weight loss, pulse rate and cardiovascular outcomes
RV Seimon et al
853
Table 2. Primary outcome events by absolute change categories in pulse rate responsiveness during lead-in period (−6 weeks) to randomization and
over subsequent 12 months (note: subjects with cardiac arrhythmias were excluded from this analysis)

Pulse categories (bpm) N Placebo Event rate (%) Total Model 1a P-value Model 2a P-value Model 3a P-value
Sibutramine HR (95% CI) HR (95%CI) HR (95%CI)

Absolute change in pulse rate during lead-in to randomization change

Decrease 2956 141 (9.63%) 160 (10.72%) 301 (10.18%) 1.10 (0.88–1.38) 0.40 1.07 (0.85–1.34) 0.57 1.10 (0.88–1.38) 0.41
No change (±1) 1060 51 (9.51%) 47 (8.97%) 98 (9.25%) 1.00 0.26b 1.00 0.38b 1.00 0.26b
Increase 4513 196 (8.77%) 233 (10.23%) 429 (9.51%) 1.01 (0.81–1.26) 0.93 1.00 (0.80–1.25) 0.99 1.01 (0.81–1.26) 0.94

Absolute change in pulse rate from lead-in baseline to 12 months post randomization
Decrease 3191 128 (6.83%) 116 (8.81%) 244 (7.65%) 0.93 (0.70–1.23) 0.59 0.94 (0.71–1.25) 0.68 0.94 (0.70–1.24) 0.64
No change (±1) 721 32 (8.40%) 28 (8.24%) 60 (8.32%) 1.00 0.57b 1.00 0.44b 1.00 0.36b
Increase 3251 86 (6.86%) 153 (7.66%) 239 (7.35%) 0.88 (0.66–1.17) 0.37 0.88 (0.66–1.17) 0.37 0.86 (0.65–1.14) 0.29
Abbreviations: CI, confidence interval; HR, hazard ratio. Estimates of hazard ratios (95% CI) and log-rank P-values were calculated using the Cox model. aModel 1:
not adjusted for any factors; Model 2: adjusted for sibutramine or placebo treatment, country, sex and age; Model 3: adjusted for treatment only. Pulse
categories: no change (±1 bpm), increase or decrease. Data are absolute number (%). Reference group: no change (±1 bpm). P-values refer to the HR of each
pulse category compared with the reference group. bIndicated P-value for trend.

Table 3A. Primary outcome event components by pulse rate categories at lead-in period (−6 weeks) and at 12 months

⩽ 65 65–70 70–75 75–80 80–85 485 P-valuea

Pulse rate categories at lead-in baseline (−6 weeks)

POE
N 2634 (30.1%) 1621 (18.5%) 1680 (19.2%) 1203 (13.7%) 813 (9.3%) 799 (9.1%) 0.19
Y 294 (28.0%) 186 (17.7%) 195 (18.6%) 151 (14.4%) 107 (10.2%) 118 (11.2%)
CVD
N 2812 (30.1%) 1724 (18.4%) 1786 (19.1%) 1286 (13.8%) 874 (9.3%) 867 (9.3%) 0.39
Y 116 (25.7%) 83 (18.4%) 89 (19.7%) 68 (15.0%) 46 (10.2%) 50 (11.1%)
MI
N 2821 (29.9%) 1740 (18.4%) 1806 (19.1%) 1305 (13.8%) 891 (9.4%) 879 (9.3%) 0.93
Y 107 (29.8%) 67 (18.7%) 69 (19.2%) 49 (13.6%) 29 (8.1%) 38 (10.6%)
RCA
N 2923 (29.9%) 1806 (18.5%) 1873 (19.1%) 1350 (13.8%) 917 (9.4%) 914 (9.3%) 0.39
Y 5 (27.8%) 1 (5.6%) 2 (11.1%) 4 (22.2%) 3 (16.7%) 3 (16.7%)
STK
N 2862 (29.9%) 1772 (18.5%) 1840 (19.2%) 1324 (13.8%) 891 (9.3%) 890 (9.3%) 0.19
Y 66 (29.7%) 35 (15.8%) 35 (15.8%) 30 (13.5%) 29 (13.1%) 27 (12.2%)

Pulse rate categories at 12 months post randomization

POE
N 2281(30.3%) 1355 (18.0%) 1356 (18.0%) 1041 (13.8%) 670 (8.9%) 818 (10.9%) 0.13
Y 212 (30.2%) 132 (18.8%) 109 (15.5%) 84 (12.0%) 70 (10.0%) 94 (13.4%)
CVD
N 2400 (30.3%) 1425 (18.0%) 1423 (18.0%) 1084 (13.7%) 715 (9.0%) 876 (11.1%) 0.53
Y 93 (31.1%) 62 (20.7%) 42 (14.0%) 41 (13.7%) 25 (8.4%) 36 (12.0%)
MI
N 2416 (30.3%) 1447 (18.1%) 1433 (17.9%) 1097 (13.7%) 712 (8.9%) 881 (11.0%) 0.24
Y 77 (32.6%) 40 (16.9%) 32 (13.6%) 28 (11.9%) 28 (11.9%) 31 (13.1%)
RCA
N 2491 (30.4%) 1485 (18.1%) 1464 (17.8%) 1124 (13.7%) 735 (9.0%) 908 (11.1%) 0.006
Y 2 (13.3%) 2 (13.3%) 1 (6.7%) 1 (6.7%) 5 (33.3%) 4 (26.7%)
STK
N 2453 (30.4%) 1459 (18.1%) 1431 (17.7%) 1111 (13.8%) 728 (9.0%) 889 (11.0%) 0.19
Y 40 (26.5%) 28 (18.5%) 34 (22.5%) 14 (9.3%) 12 (7.9%) 23 (15.2%)
Abbreviations: CVDs, cardiovascular disease; MI, Myocardial infarction; N, no; POE, primary outcome event; RCA, resuscitated cardiac arrest; STK, stroke; Y, yes.
a
P-value from χ2-test for categorical variables. Event numbers for the component RCA are small 8 thus care is cautioned in interpreting the χ2-test for
homogeneity.

(Table 3A) or over the lead-in period or during lead-in baseline to
12 months post randomization (Table 3B).
More detailed analyses of the incremental changes showed that
in all the subjects without cardiac arrhythmia who had increased
their pulse rate by 47.5– ⩽ 10 bpm from lead-in baseline to
randomization (that is, when all subjects were receiving sibu-
tramine) the risk of POE was increased (HR: 1.77 CI: 1.07–2.91,
P = 0.03). However, this effect was not present when considering
pulse rate changes from lead-in baseline to 12 months post
randomization (Figure 4). There also appeared to be a trend for
those subjects with cardiac arrhythmia who had a decreased pulse
of 4 − 2.5 to ⩽ 0 bpm from lead-in baseline to randomization to
have an increased risk of POE (HR: 1.86 CI: 0.98–3.51, P = 0.06). For
subjects who decreased their pulse from lead-in baseline to

© 2015 Macmillan Publishers Limited International Journal of Obesity (2015) 849 – 857
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854
Table 3B. Primary outcome event components by change categories in pulse rate during lead-in baseline (-6 weeks) to randomization and during
lead-in baseline to 12 months

o − 10 − 10 to − 7.5 − 7.5 to − 5 − 5 to − 2.5 − 2.5 to 0 0–2.5 2.5–5 5–7.5 7.5–10 ⩾ 10 P-valuea

Change in pulse rate categories during lead-in baseline to randomization

POE
N 561 (6.4%) 325 (3.7%) 553 (6.3%) 831 (9.5%) 1411 (16.1%) 1328 (15.2%) 1311 (15.0%) 971 (11.1%) 760 (8.7%) 698 (8.0%) 0.11
Y 74 (7.0%) 58 (5.5%) 70 (6.7%) 111 (10.6%) 153 (14.6%) 154 (14.7%) 158 (15.0%) 113 (10.8%) 74 (7.0%) 86 (8.2%)
CVDs
N 605 (6.5%) 351 (3.8%) 595 (6.4%) 899 (9.6%) 1489 (15.9%) 1424 (15.2%) 1397 (14.9%) 1043 (11.2%) 797 (8.5%) 748 (8.0%) 0.07
Y 30 (6.6%) 32 (7.1%) 28 (6.2%) 43 (9.5%) 75 (16.6%) 58 (12.8%) 72 (15.9%) 41 (9.1%) 37 (8.2%) 36 (8.0%)
MI
N 609 (6.5%) 366 (3.9%) 599 (6.3%) 903 (9.6%) 1514 (16.0%) 1423 (15.1%) 1413 (15.0%) 1045 (11.1%) 811 (8.6%) 758 (8.0%) 0.80
Y 26 (7.2%) 17 (4.7%) 24 (6.7%) 39 (10.9%) 50 (13.9%) 59 (16.4%) 56 (15.6%) 39 (10.9%) 23 (6.4%) 26 (7.2%)
RCA
N 634 (6.5%) 383 (3.9%) 622 (6.4%) 940 (9.6%) 1563 (16.0%) 1479 (15.1%) 1464 (15.0%) 1083 (11.1%) 833 (8.5%) 781 (8.0%) 0.70
Y 1 (5.6%) 0 (0.0%) 1 (5.6%) 2 (11.1%) 1 (5.6%) 3 (16.7%) 5 (27.8%) 1 (5.6%) 1 (5.6%) 3 (16.7%)
STK
N 618 (6.5%) 374 (3.9%) 606 (6.3%) 915 (9.6%) 1537 (16.0%) 1448 (15.1%) 1444 (15.1%) 1052 (11.0%) 821 (8.6%) 763 (8.0%) 0.24
Y 17 (7.7%) 9 (4.1%) 17 (7.7%) 27 (12.2%) 27 (12.2%) 34 (15.3%) 25 (11.3%) 32 (14.4%) 13 (5.9%) 21 (9.5%)

Change in pulse rate categories from lead-in baseline to 12 months post randomization
POE
N 941 (12.5%) 450 (6.0%) 672 (8.9%) 710 (9.4%) 1039 (13.8%) 867 (11.5%) 787 (10.5%) 617 (8.2%) 472 (6.3%) 966 (12.8%) 0.18
Y 92 (13.1%) 54 (7.7%) 68 (9.7%) 69 (9.8%) 92 (13.1%) 73 (10.4%) 59 (8.4%) 43 (6.1%) 50 (7.1%) 101 (14.4%)
CVDs
N 994 (12.5%) 482 (6.1%) 708 (8.9%) 748 (9.4%) 1088 (13.7%) 909 (11.5%) 823 (10.4%) 640 (8.1%) 501 (6.3%) 1030 (13.0%) 0.79
Y 39 (13.0%) 22 (7.4%) 32 (10.7%) 31 (10.4%) 43 (14.4%) 31 (10.4%) 23 (7.7%) 20 (6.7%) 21 (7.0%) 37 (12.4%)
MI
N 1006 (12.6%) 486 (6.1%) 719 (9.0%) 754 (9.4%) 1101 (13.8%) 920 (11.5%) 818 (10.2%) 646 (8.1%) 505 (6.3%) 1031 (12.9%) 0.67
Y 27 (11.4%) 18 (7.6%) 21 (8.9%) 25 (10.6%) 30 (12.7%) 20 (8.5%) 28 (11.9%) 14 (5.9%) 17 (7.2%) 36 (15.3%)
RCA
N 1032 (12.6%) 503 (6.1%) 738 (9.0%) 778 (9.5%) 1130 (13.8%) 938 (11.4%) 846 (10.3%) 659 (8.0%) 521 (6.3%) 1062 (12.9%) 0.55
Y 1 (6.7%) 1 (6.7%) 2 (13.3%) 1 (6.7%) 1 (6.7%) 2 (13.3%) 0 (0.0%) 1 (6.7%) 1 (6.7%) 5 (33.3%)
STK
N 1008 (12.5%) 491 (6.1%) 727 (9.0%) 767 (9.5%) 1113 (13.8%) 920 (11.4%) 838 (10.4%) 652 (8.1%) 511 (6.3%) 1044 (12.9%) 0.30
Y 25 (16.6%) 13 (8.6%) 13 (8.6%) 12 (7.9%) 18 (11.9%) 20 (13.2%) 8 (5.3%) 8 (5.3%) 11 (7.3%) 23 (15.2%)

Abbreviations: CVDs, cardiovascular disease; MI, Myocardial infarction; N, no; POE, primary outcome event; RCA, resuscitated cardiac arrest; STK, stroke; Y, yes.
a
P-value from chi square test for categorical variables. Event numbers for the component RCA are small thus care is cautioned in interpreting the χ2-test for
homogeneity.

12 months post randomization by 4 − 5 to ⩽ − 2.5 bpm, there DISCUSSION

was a trend for increased risk (HR: 2.37 CI: 0.97–5.81, P = 0.06); for a
pulse decrease of 4 − 10 to ⩽ 7.5 bpm, risk of POE was
significantly elevated (HR: 4.08 CI: 1.02–16.32, P = 0.047;
Figure 4). It should be noted that investigation into the possible
effect modification showed that the effect of sibutramine on POEs
was consistent across the pulse rate change category subgroups
(no significant interaction effect was found between the pulse rate
change and sibutramine).
Detailed analysis showing participants in different pulse rate
categories at 12 months and changes in pulse rate categories from
lead-in baseline to 12 months by various comorbidities (age,
β-blockade, baseline cardiac arrhythmias, gender and treatment)
are presented in Supplementary Tables S3 and S4.
At lead-in baseline, approximately two thirds of the SCOUT
population were on β-blocker therapy (N = 6017). When adjusted
for treatment, country, age and sex, analyses of β-blocker users in
the overall subject population showed a significant influence on
POE (HR: 1.17, CI: 1.02–1.33, P = 0.02) and myocardial infarction
(HR: 1.36, CI: 1.08–1.72, P = 0.01), when compared with nonusers.
Further analyses showed that β-blocker use in subjects without
cardiac arrhythmias had no significant influence on POE (HR: 1.07,
CI: 0.8–1.45, P = 0.65), whereas in those with cardiac arrhythmias
β-blocker use had a trend to increase POE (HR: 1.16, CI: 1.00–1.34,
P = 0.06), when compared with nonusers.
At lead-in baseline, roughly, 17% of the SCOUT population was
⩾ 70 years of age (N = 1701); those with cardiac arrhythmia, had an
increased risk of POE, (HR: 1.35, CI: 1.02–1.79, P = 0.04) as had those
without arrhythmia (HR: 1.66, CI: 1.41–1.96, P o 0.0001) when
compared with subjects o 70 years of age.
We report the surprising observations that in the obese high
cardiovascular risk population recruited into the SCOUT trial,
intentional weight loss did not influence pulse rate, and that a
higher pulse rate during up to 5 years of weight management may
be beneficial, which adds new information to the complex issue of
heart rate control in cardiovascular subjects without clinical heart
failure.
Substantial evidence suggests that pulse rate is a key
determinant of cardiac ischemia23 and a strong and independent
predictor of cardiovascular events in healthy men and women,24
as well as those with established coronary artery disease or
previous myocardial infarction.3,25 Furthermore, low pulse rate
variability is also a risk for cardiovascular events in populations
with26 and without27 known CVDs. The relationship with obesity
has not specifically been evaluated, and is likely to be confounded
by other obesity-related cardiovascular risk factors28 such as
hypertension, heart failure, insulin resistance, diabetes, sleep
apnea, inflammation, activated sympathetic nervous system,
physical fitness and concomitant drug treatment such as
β-blockers. Neither have ‘optimal’ pulse rates for the obese been
established.
The interaction between obesity, pulse rate and hypertension
(a major risk factor for cardiovascular events) is complex. In the
Hypertension and Ambulatory Recording Venetia Study of
participants who were never treated, both baseline clinic pulse
rate (P = 0.007) and 24-h ambulatory pulse rate (P = 0.013), were
independent predictors of weight change at study end. In
addition, changes in HR during the follow-up either measured in
the clinic (P = 0.036) or with 24-h recording (P = 0.009) were

International Journal of Obesity (2015) 849 – 857 © 2015 Macmillan Publishers Limited
 Sibutramine, weight loss, pulse rate and cardiovascular outcomes
RV Seimon et al
855

Figure 4. Subgroup analysis looking at the effect of treatment on primary outcome events: stratified by changes in pulse rate during lead-in
baseline (−6 weeks) to randomization (a and b) and from lead-in baseline to 12 months (c and d), in subjects with (interaction P-value = 0.9)
and without (interaction P-value = 0.3) cardiac arrhythmias. Estimates of hazard ratios (95% CI) and log-rank P-values were calculated using the
Cox model, adjusted for various factors. Pulse categories: ⩽ − 10, 4 − 10 to ⩽ − 7.5, 4 − 7.5 to ⩽ − 5, 4 − 5.0 to ⩽ − 2.5, 4 − 2.5 to ⩽ 0, 40 to
⩽ 2.5, 42.5 to ⩽ 5, 45.0 to ⩽ 7.5, 47.5 to ⩽ 10 and 410 bpm. CA, cardiac arrhythmia.

independent associates of weight gain.29 Furthermore, in this
study, clinic pulse rate and changes in the pulse rate during the
first 6 months of follow-up were independent predictors of
subsequent systolic blood pressure and diastolic blood pressure
regardless of initial blood pressure and other confounders (all
P o0.01).30
The impact of pulse rate on cardiovascular outcomes has
become of key importance in regulatory assessments of the risks
and benefits of pharmacological treatments of obesity. In 2010,
the US Food and Drugs Administration,31 and more recently, the
European CHMP (Committee on Human Medicinal Products)
rejected the approval of a combination of phentermine+topir-
amate in part because even though there was no overall signal of
an increased risk of cardiovascular events in the studies, the
consequences of an increased pulse rate in subjects with history
of, or with ongoing CVDs, are unknown,32 especially after the
recent results of SIGNIFY6 which showed that a lower heart rate is
not always better.
Glucagon-like peptide 1 (GLP-1) agonists such as exenatide and
liraglutide are extensively used for treating type 2 diabetes. A
recent systematic review confirms GLP-1 agonists are associated
with pulse rate increases of 1.86 bpm (95% CI 0.85–2.87) versus
placebo and 1.90 bpm (95% CI 1.30–2.50) versus active diabetes
pharmacotherapy control.33 Liraglutide at a higher dose than that
used for diabetes treatment (3.0 compared with 0.6–1.8 mg daily)
is currently under review by the European CHMP and has also
shown increases in pulse rate (mean increase from randomization
—after initial weight loss of 3.6+9.4 bpm compared with placebo
2.4+8.6 bpm)34 and in an earlier Phase 2 trial,35 3.5 bpm placebo-
subtracted. Clinical outcome trials underway, now effectively a
prerequisite for regulatory approval, will eventually determine
whether these pulse rate changes will offset the well-
demonstrated cardioprotective effects of GLP-1 agonists.36–38
Interestingly enough, the correlation between pulse rate and
mortality in the Heart Association Study was U-shaped—since
excess mortality was found also for pulse rate values o60 bpm.28
This was, in fact, until SIGNIFY, the only study where bradycardia
was associated with increased coronary mortality. In the current
study, those who had a pre-existing cardiac arrhythmia in whom
the pulse rate fell over the course of the study were at an
increased risk of POE (HR ranging from 1.86–4.08 with decreasing
pulse rate).
While in this study those in the sibutramine group had an
increase in pulse rate, the increase may in part have been driven
by the up-titration of sibutramine dose from 10 to 15 mg that
applied to 33% of subjects on sibutramine and 40% in the placebo
group during the early post-randomization period as dictated in
the protocol in an effort to achieve weight loss. The incidence of
POEs was generally lower in subjects who received 15 mg dose
than in those who did not across both the treatment groups.
Those subjects treated with sibutramine who lost weight showed
a graded decrease in pulse rate, compared with those who did not
lose weight.
In this elderly obese population pulse rate seems to be neither
an important modifier nor does it appear to be a clinically useful
predictor of the outcomes in an individual subject, at least not
compared with the impact of other known cardiovascular markers
(for example blood pressure, cholesterol and blood glucose). In
this population of obese individuals with CVD there is an
unexpected finding that a continuously lower pulse rate had no

© 2015 Macmillan Publishers Limited International Journal of Obesity (2015) 849 – 857
 Sibutramine, weight loss, pulse rate and cardiovascular outcomes
RV Seimon et al
856
beneficial effect compared with a significantly higher pulse rate,
even when the latter was drug induced.
Study limitations
Assessment of the effects of weight loss and blood pressure
management on adverse cardiovascular outcomes was pre-
planned; however, the detailed choice of categories in the current
analyses are post hoc. The SCOUT study population was not typical
of a more general population being treated for hypertension; it
comprised an older, overweight/obese CVD cohort receiving
intensive cardiovascular risk factor monitoring and optimization
with multiple adjustable concomitant pharmacotherapies/inter-
ventions. We did not adjust for dosage (because of the lack of
data) or class of anti-hypertensive agents received or for other
potential confounders, especially those which are predictors of
poor health, socioeconomic status, job stress or mental health.
SCOUT did not assess the presence or severity of possible
diabetic-related cardiac autonomic neuropathy, which could
modify heart rate responses to sibutramine.
The absence of a true placebo group during this initial
treatment period (that is, all subjects had an initial 6-week
treatment period with sibutramine) prevented the assessment of
unequivocal sibutramine-related effects. The changes reported,
specifically those relating to pulse rate, may also in part reflect a
regression to the mean and this should be taken into account
when interpreting the data.
CONFLICT OF INTEREST
NF: member of SCOUT Executive Steering Committee (ESC) received payments from
Abbott, as advisor for Novo Nordisk, Merck, sanofi-aventis, GlaxoSmithKline and
Shionogi, consultant for Ajinomoto, and provided expert testimony for sanofi-aventis,
Vivus, Arena and received a grant from GlaxoSmithKline. WPTJ: Chair of the SCOUT
ESC received payment from Abbott; the International Association for the Study of
Obesity when he was the President also received a grant from Novo Nordisk.
UFL: was an employee of Abbott with equity interest in the Company. WC: member
of the SCOUT ESC received payments from Abbott Laboratories, lecture fees and/or
travel reimbursement from Abbott, Ache Laboratorios Farmaceuticos S/A, Roche and
Novo Nordisk, as advisor for Abbott, Ache Laboratorios Farmaceuticos S/A, GSK, Novo
Nordisk, Takeda and Roche, and provided expert testimony for Abbott. AMS: member
of the SCOUT ESC received payment from Abbott Laboratories, and as advisor for
Abbott, Merck, Arena, Novo Nordisk, sanofi-aventis, GlaxoSmithKline, Boehringer
Ingelheim, and NeuroSearch, as consultant for Vivus and Allegan, provided expert
testimony for GlaxoSmithKline, received grants from Abbott and Covidian.
LVG: Received a research grant from National Research Funds, Belgium; served on
the speaker's bureaus of Sanofi-Aventis and Abbott; served as a consultant to Amylin
Pharmaceuticals, Sanofi-Aventis, Eli Lilly, and Abbott; member of SCOUT ESC
receiving payment from Abbott. IDC: member of SCOUT ESC received payment
from Abbott Laboratories, royalties from Wiley-Blackwell as co-editor of an obesity
textbook, and the Boden Institute of Obesity, Nutrition and Exercise received grants
from Novo Nordisk, sanofi-aventis, Pfizer (Australia), Weight Watchers, Allergan and
the Korean Ministry of Agriculture. The remaining authors declare no conflict of
interest.
ACKNOWLEDGEMENTS
The original trial was supported and funded by Abbott Laboratories (Abbott Park, IL,
USA). The Executive Steering Committee designed the study in cooperation with the
sponsor. RVS was supported by a National Health and Medical Research Council of
Australia Early Career Research Fellowship (no 1072771). We are also grateful to the
Endocrine Society of Australia for a Postdoctoral Award to RVS.
DISCLAIMER
The authors have full access to all data, determined the analyses, are solely
responsible for its interpretation and this manuscript without reference to the
original sponsor and took the final decision to submit the manuscript for publication.
International Journal of Obesity (2015) 849 – 857
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