International Journal of Obesity (2014), 1–7 © 2014 Macmillan Publishers Limited All rights reserved 0307-0565/14 www.nature.com/ijo

ORIGINAL ARTICLE

Changes in body weight and blood pressure: paradoxical outcome events in overweight and obese subjects with cardiovascular disease RV Seimon1, D Espinoza2, L Ivers2, V Gebski2, N Finer3, UF Legler4, AM Sharma5, WPT James6, W Coutinho7 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 body weight and blood pressure, and the impact of these changes on subsequent cardiovascular outcome events. SUBJECTS/METHODS: A total of 9804 male and female subjects, aged 55 years or older, 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 (hypertension, dyslipidemia, current smoking or diabetic nephropathy) to assess cardiovascular outcomes. Post hoc subgroup analyses of weight change (categories) and blood pressure were performed overall and by treatment group (6-week sibutramine followed by randomized placebo or continued sibutramine). 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 with factors for treatment, subgroups and interactions. RESULTS: During the initial 6-week sibutramine treatment period, systolic blood pressure decreased progressively with increasing weight loss in hypertensive subjects (−8.1 ± 10.5 mm Hg with o 5 kg weight loss to −10.8 ± 11.0 mm Hg with ⩾5 kg weight loss). The highest POE incidence occurred mainly in groups with increases in both weight and blood pressure. However, with long-term sibutramine treatment, a markedly lower blood pressure tended to increase POEs. CONCLUSION: Modest weight loss and modest lower blood pressure each reduced the incidence of cardiovascular events, as expected. However, the combination of early marked weight loss and rapid blood pressure reduction seems to be harmful in this obese elderly cardiovascular diseased population. International Journal of Obesity advance online publication, 11 February 2014; doi:10.1038/ijo.2014.2 Keywords: sibutramine; weight loss; outcome events; myocardial infarction

INTRODUCTION Obesity is a well-recognized risk factor for cardiovascular disease (CVD).1,2 Prevention of weight gain and reduction of excess weight are recommended in the current guidelines both for the primary and secondary preventions of CVD.3–5 Long-term data on intentional weight loss in individuals at high risk for CVD events are scarcely reported, and until the recent analysis of the Sibutramine Cardiovascular OUTcomes (SCOUT) trial,6 only surgically induced weight loss had been shown to reduce cardiovascular morbidity and mortality in severely obese individuals.7,8 Sibutramine hydrochloride monohydrate (sibutramine) is a norepinephrine and serotonin reuptake inhibitor that induces satiety, thereby reducing food intake, and limits the decrease in energy expenditure caused by weight loss.9,10 In some individuals, sibutramine also increases blood pressure and/or pulse due, in part, to its sympathomimetic effects.11,12 The SCOUT trial evaluated the long-term effects of sibutramine treatment with

diet and exercise on cardiovascular morbidity and mortality in over 10 000 subjects at high cardiovascular risk.13 The primary results reported a 16% relative risk increase in the composite primary outcome event (POE, which included: nonfatal myocardial infarction (MI), nonfatal stroke, resuscitated cardiac arrest and CVD death), with no increase in all-cause mortality in the sibutramine group; these findings subsequently led to the drug’s withdrawal in many countries. The initial analysis did not account for the variable responses in body weight and blood pressure seen in the trial participants. The aim of the current paper is to examine the relationship between early changes (both increases and decreases) in body weight and blood pressure, and the impact of these changes on subsequent cardiovascular outcome events. We acknowledge that pulse may also have an effect on cardiovascular outcome events and this will be addressed in subsequent papers together with the combined effects of blood pressure and pulse on cardiovascular outcome events.

1 The Boden Institute of Obesity, Nutrition Exercise & Eating Disorders, University of Sydney, Sydney, New South Wales, Australia; 2NHMRC 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; 4Special Vocational College for Handicapped Persons, Mainz, Germany; 5Department of Medicine, University of Alberta, Edmonton, Alberta, Canada; 6London School of Hygiene and Tropical Medicine, London, UK and 7Catholic University of Rio de Janeiro and State Institute of Diabetes and Endocrinology, Rio de Janeiro, Brazil. Correspondence: Dr RV Seimon, The Boden Institute of Obesity, Nutrition Exercise & Eating Disorders, University of Sydney, Camperdown, New South Wales 2050, Australia. E-mail: [email protected] Received 23 August 2013; revised 2 December 2013; accepted 1 January 2014; accepted article preview online 10 January 2014

Sibutramine, weight loss, blood pressure and cardiovascular outcomes RV Seimon et al

2 MATERIALS AND METHODS The SCOUT trial was a prospective, randomized, double-blind, multinational study conducted according to the principles of the International Conference on Harmonisation and the Declaration of Helsinki. Local ethics committees approved the protocol, and written informed consent was obtained from all subjects. The design and trial protocol, including power and sample size, has been described elsewhere.13–15 The trial included male and female subjects, aged 55 years or older, with a body mass index of 27–45 kg m − 2. Subjects were required to have a history of CVD and/or type 2 diabetes mellitus with at least one cardiovascular risk factor (hypertension, dyslipidemia, current smoking or diabetic nephropathy) to assess cardiovascular outcomes.13 The primary outcome of the trial was the time from randomization, to the first occurrence of a POE, which included nonfatal MI, nonfatal stroke, resuscitated cardiac arrest or cardiovascular death. Standard care nonpharmacological and pharmacological treatment recommendations, based on the respective national and international guidelines for the management of comorbidities and for primary and secondary preventions of CVD, were applied.3–5 As described previously, all subjects underwent an initial 6-week singleblind lead-in period during which they received 10 mg per day sibutramine with unchanged co-medication, as well as advice regarding diet and exercise, so that subjects with early and persistent increases in blood pressure or pulse rate could be identified and excluded from randomization. Eligible subjects were then randomized, in a double-blind manner, to receive 10- to 15-mg per day sibutramine or matching placebo. All subjects participated in individualized diet and exercise programs that were designed to result in a reduction in calories of 600 kcal per day.13 Systolic and diastolic blood pressures were measured in a seated position and after at least 5 min of rest as described previously.16 All changes in vital signs during the 6-week lead-in sibutramine treatment period were attributed to study interventions and not to changes in any co-medication. From the overall cohort of 10 744 subjects, 940 subjects either withdrew from the 6-week sibutramine lead-in period or were not randomized by the investigators because of marked increases in blood pressure or pulse during this initial treatment with sibutramine. This resulted in 9804 subjects having data for this current subanalysis of the SCOUT trial.

Statistical analysis Demographic and baseline characteristics at lead-in period baseline were summarized for the intention-to-treat (ITT) population, by treatment group (randomized sibutramine, randomized placebo), hypertension category (hypertension defined as a systolic blood pressure (SBP) ⩾140 mm Hg or diastolic blood pressure (DBP) ⩾90 mm Hg with or without co-existing antihypertensive therapy). Changes in weight, SBP and DBP for individual subjects were computed from the lead-in period baseline (Week-6) to the randomization phase baseline (that is, end of 6-week sibutramine lead-in period) and to Month 12 post randomization. Data were summarized within each categorization of interest as the mean and s.d. for continuous variables and as the number of subjects and percentage (%) for categorical variables. The mean changes in vital sign measurements from lead-in baseline to randomization phase baseline and to Month 12 were evaluated using paired t-tests. The mean blood pressure changes from the lead-in period baseline to each scheduled study visit were evaluated longitudinally with the use of a mixed-effects model for repeated measures, including factors for treatment-by-weight loss categorization (gained weight (>0 kg), lost 0 to less than 5 kg (0 to o−5 kg), lost 5 kg or more (⩾ −5 kg)); country; sex; age; baseline values for blood pressure; visit; interaction between treatment and visit; and interaction between baseline values and visit. The following covariance structures were considered: unstructured, compound symmetric, first-order autoregressive and Toeplitz. The covariance structure that provided the best fit according to Akaike’s information criterion was used in the analysis. Time-to-event analyses of POE rates for the intent-to-treat population were performed using Cox models, with factors for treatment (that is, 6-week sibutramine treatment followed by either placebo (lifestyle + sibutramine followed by placebo; placebo group) or continued sibutramine (lifestyle+sibutramine followed by sibutramine; long-term sibutramine group)), country, sex and age as covariates. Models were stratified by blood pressure change (>5, >0 to 5, > −5 to 0, > − 10 to −5, > − 15 to −10, ⩾ −15 mm Hg) for individual subjects over (a) the lead-in period baseline (Week-6) to the randomization phase baseline (that is, end of 6-week sibutramine lead-in period) and (b) the lead-in period baseline International Journal of Obesity (2014) 1 – 7

(Week-6) to Month 12 post randomization. In each case the reference group, when comparing categories, was the >0–5 mm Hg group. Estimates of hazard ratios, 95% confidence intervals (CI), and log-rank P-values were calculated within the Cox model framework. Analyses were conducted for (1) all POEs reported during the randomization phase and (2) for all POEs that occurred on or after Month 12 of the randomization phase. All statistical analyses were performed using SAS, version 9.2 (SAS Institute, Cary, NC, USA). All statistical tests were conducted at the (twotailed) 0.05 level of significance.

RESULTS Subject characteristics at the lead-in period baseline for the overall study cohort (N = 9804) and the two randomized treatment groups (6-week sibutramine followed by placebo (N = 4898); 6-week sibutramine followed by sibutramine (N = 4906)) have been described previously11,15 and are summarized in Table 1. The 10-year risk of fatal CVD was 10% or greater in the majority of subjects according to the European Heart Score.4 Treatment groups were well balanced with the exception that subjects in the long-term sibutramine treatment arm were more likely to have had prior peripheral artery occlusive disorder. At lead-in period baseline, the mean body weight was 96 kg and mean SBP was 138 mm Hg in both randomized groups. Changes in weight and blood pressure during the trial period During the 6-week lead-in period (Week-6) to the randomization baseline (BL), during which all subjects received sibutramine and any co-medication was kept unchanged, there was a mean weight loss of 2.5 kg. After randomization, there was a further reduction in weight in the sibutramine group (maximum mean additional weight loss; 1.8 kg at 12 months) and a mean increase in weight in the placebo group (0.6 kg at 12 months). Thereafter, both groups had a limited increase in the mean weight. During the 6-week lead-in period to the randomization baseline, there was a significant decrease in both SBP (reduction of 4.7 mm Hg; P o 0.001) and DBP (reduction of 1.5 mm Hg; P o 0.001; Figure 1). The mean blood pressure remained below initial values in both groups throughout the treatment period but was consistently higher in the sibutramine group when compared with the placebo group. The mean differences between the groups ranged from -0.3 to 1.9 mm Hg systolic and from -0.7 to 1.4 mm Hg diastolic pressure (Figure 1). There were peaks in SBP and DBP at 12-, 24-, 36-, 48- and 60-month visits as subjects were Table 1. Demographics and clinical characteristics of the subjects at the randomized phase baseline Variables Gender, % male Age (years) Weight (kg) BMI (kg m − 2) Medical history Overall cardiovascular disease Revascularization procedure Type 2 diabetes mellitus SBP (mm Hg) DBP (mm Hg) 1o 130/80 mm Hg 2⩾ 130 to o 140/ ⩾ 80 to o 90 mm Hg 3⩾ 140/ ⩾ 90 mm Hg Pulse (b.p.m.)

Placebo 2843/4898 (58%) 63.3 ±6.1 96.2 ± 15.5 (4897) 34.4 ± 4.5 (4897) 3977/4884 1828/4898 4139/4884 138.2 ± 12.6 77.9 ± 8.4 964/4897 1474/4897

Sibutramine 2807/4906 (57.2%) 63.2 ± 6.1 96.3 ± 15.4 (4905) 34.5 ± 4.6 (4905)

(81.4%) 3971/4889 (37.3%) 1786/4906 (84.7%) 4167/4889 (4897) 138.2 ± 12.9 (4897) 77.8 ± 8.4 (19.7%) 989/4905 (30.1%) 1488/4905

(81.2%) (36.4%) (85.2%) (4905) (4905) (20.2%) (30.3%)

2459/4897 (50.2%) 2428/4905 (49.5%) 71.1 ± 10.1 (4897) 71.1 ± 10.2 (4904)

Abbreviations: BMI, body mass index; b.p.m., beats per minute; DBP, diastolic blood pressure; SBP, systolic blood pressure. Plus–minus values are mean ± s.d. All subjects received sibutramine during the 6-week lead-in period.

© 2014 Macmillan Publishers Limited

Sibutramine, weight loss, blood pressure and cardiovascular outcomes RV Seimon et al

3 Systolic Blood Pressure

Diastolic Blood Pressure 79

75 74 73

130 0

Placebo Sibutramine

Time

Wk-6

M60

M48

M36

M24

BL M1 M2 M3 M6 M12

Wk-6

72 0

M60

132

76

M48

134

77

M36

136

78

M24

138

BL M1 M2 M3 M6 M12

Placebo Sibutramine

Pressure (mmHg)

Pressure (mmHg)

140

Time

Figure 1. Blood pressure from lead-in period (−6 weeks) to the final visit (60 months). All subjects underwent an initial 6-week (−6 weeks to BL), single-blind lead-in period, during which they received 10 mg per day sibutramine, eligible subjects were then randomized (at BL) to the sibutramine or the placebo group. Analyses were performed on data from the intention-to-treat population using t-test. Systolic blood pressure, P = 0.05 at months 3, 15 and 24, P = 0.01 at months 6, 30, 33, 54 and 60, and P = 0.001 at months 27, from months 36 to 48 and 57. Diastolic blood pressure, P = 0.01 at month 60, and P = 0.001 from months 1 to 57. Wk, week; BL, randomization; M, month.

fasted for blood tests and probably did not take their medication until after the test visit. Interaction between blood pressure and weight The relationship between the categories of weight loss and fall in blood pressure persisted post randomization and was evident in both treatment groups (that is, both those who randomized to placebo treatment and those who continued on long-term sibutramine after the 6-week lead-in period). The long-term sibutramine group tended to have slightly higher mean SBP compared with the randomized placebo group (Figures 2a and c). Even subjects who gained weight during the sibutramine lead-in period experienced mean falls in SBP, which was sustained over the whole treatment period (Figure 2a). Sibutramine-treated subjects who lost more than 5 kg of their lead-in weight showed the largest increase in blood pressure but started as a group with the lowest SBP (Figure 2b). In subjects who gained weight during the lead-in to 12-month period, those on placebo had a lower SBP than those on sibutramine throughout the study (Figure 2c). Placebo-treated subjects who lost more than 5 kg of their weight during the time from lead-in baseline to 12-month post randomization showed the largest decrease in blood pressure (Figure 2d). Relationship between incidence of POE with SBP and weight changes during the 6-week sibutramine lead-in period to randomization and through 12 months post randomization Both increases and marked decreases in SBP were associated with higher POE rates. An increase in SBP of greater than 5 mm Hg during the lead-in period up to randomization was associated with a significant increased risk of POE when compared with an increase in SBP between 0 and 5 mm Hg (P o 0.01; N = 1420; Table 2). A decrease in SBP of greater than or equal to 15 mmHg during lead-in to 12-month change trended to be associated with an increased risk of POE when compared with an increase in SBP between 0 and 5 mm Hg (P = 0.08; N = 1521; Table 2). When an interaction term for SBP change (over lead-in or during lead-in to 12 months) and treatment allocation was added to the Cox model, no association was present between POE and the interaction term, and it was thus removed from the model; the effect of SBP change was found to be independent of treatment allocation. Weight change had an important impact on the incidence of POE. The greater the weight loss during the 6-week sibutramine lead-in period, the lower the subsequent POE rate. MI was lowest with greatest weight loss for both the sibutramine and placebo groups (Table 3). Subjects on sibutramine, who lost greater than 5 kg during lead-in, had the greatest increase in SBP (Figure 2) but a © 2014 Macmillan Publishers Limited

reduced POE when compared with subjects who lost 0–5 kg or who gained weight. MI was also reduced in this group of subjects. When the analysis of the increases in weight during the initial 12-month post randomization is taken into account, there is almost no suggestion of an enhanced risk for subjects with weight gain compared with those with weight loss (Table 3). There was no interaction for treatment and weight change categories during the first 6-week lead-in period or through the subsequent 12-month post randomization for POE or MI (P>0.35 for all), suggesting that the effect of sibutramine is not modified by weight loss with respect to the POE or MI (Table 3). In addition, the effect of weight change on CV events was found to be independent of treatment allocation. Finally, it is also important to note that the number of subjects who achieved more than 5 kg weight loss after 12 months of long-term sibutramine therapy was almost double that for the randomized placebo subjects, that is, 1617 versus 815 subjects.

DISCUSSION In this paper, we report that modest weight loss and modest blood pressure reduction each reduced the incidence of cardiovascular events, as expected. However, the combination of early marked weight loss and rapid blood pressure reduction seems to be harmful in this obese, elderly, cardiovascular-diseased population. Of equal clinical relevance is the confirmation that, in general, increases in blood pressure and early weight gain, both resulted in increased risk of POE in obese and overweight subjects with pre-existing CVD. Hypertension (defined here as those on antihypertensive therapy and/or a SBP/DBP ⩾140/ ⩾ 90 mm Hg) was observed in 88% of the subjects who entered SCOUT, whereas 84% of the subjects had type 2 diabetes mellitus. The observed fall in blood pressure with weight loss in the placebo group and the small rise in blood pressure, despite weight loss in the sibutramine group (Figure 2), was anticipated as similar effects had been observed previously in the Trials of Hypertension Prevention.16,17 In SCOUT, a reduction in blood pressure following treatment with sibutramine during the initial 6-week, single-blind lead-in period was evident,18 despite its known peripheral sympathomimetic actions; however, when the fall in blood pressure was large, subjects who were subsequently randomized to long-term sibutramine therapy appeared to have been at increased risk of suffering harm (Tables 2 and 3). As a consequence, the overall 16% increase in POEs, without a corresponding increase in all-cause mortality, originally observed in the long-term sibutramine group13 may be ascribed to the unexpected higher risk seen in subjects whose International Journal of Obesity (2014) 1 – 7

Sibutramine, weight loss, blood pressure and cardiovascular outcomes RV Seimon et al

4 SBP vs lead-in to baseline weight change

SBP vs change in weight from lead-in to baseline 4

134 132

0 -2 -4

4

M60

M48

M36

M24

M12

M3 M6

BL M1

M60

M48

SBP vs lead-in to 12 month weight loss

140

2

-6 M36

BL M1

0

M24

Placebo >0kg Sibutramine >0kg Placebo 0 to 0–5 1703 83 (10.27%) 83 (9.27%) 166 (9.75%) 1.00 >5c 1420 90 (12.50%) 97 (13.86%) 187 (13.17%) 1.35 (1.10–1.66) >−5 to 0 2183 87 (8.03%) 134 (12.18%) 221 (10.12%) 1.04 (0.85–1.27) >−10 to −5 1627 80 (9.49%) 89 (11.35%) 169 (10.39%) 1.07 (0.86–1.32) >−15 to −10 1211 59 (9.97%) 75 (12.12%) 134 (11.07%) 1.16 (0.92–1.45) ⩾ −15 1658 91 (10.69%) 83 (10.29%) 174 (10.49%) 1.07 (0.86–1.32)

0.86b 0.005 0.701 0.562 0.209 0.544

SBP changes from lead-in baseline to 12 months after randomization >0–5 1159 39 (6.81%) 49 (8.36%) >5 2130 91 (9.09%) 93 (8.24%) >−5 to 0 1345 38 (5.64%) 58 (8.64%) >−10 to −5 1179 47 (7.68%) 54 (9.52%) >−15 to −10 894 36 (7.93%) 49 (11.14%) 1521 64 (8.56%) 83 (10.74%) ⩾ −15d

0.040b 0.372 0.618 0.409 0.129 0.078

(weight 12 months—weight baseline) 88 (7.59%) 1.00 184 (8.64%) 1.12 (0.87–1.45) 96 (7.14%) 0.93 (0.70–1.24) 101 (8.57%) 1.13 (0.85–1.50) 85 (9.51%) 1.26 (0.94–1.70) 147 (9.66%) 1.27 (0.97–1.65)

HR (95% CI)

P-value

1.36 1.08 1.08 1.14 1.08

1.00 (1.10–1.68) (0.88–1.32) (0.87–1.34) (0.91–1.43) (0.87–1.33)

0.82b 0.004 0.480 0.472 0.265 0.489

1.11 0.92 1.09 1.23 1.26

1.00 (0.86–1.43) (0.69–1.23) (0.82–1.46) (0.91–1.66) (0.97–1.65)

0.046b 0.440 0.591 0.541 0.177 0.084

Abbreviations: CI, confidence intervals; HR, hazard ratios; SBP, systolic blood pressure. 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 treatment, country, sex and age. SBP categories: >5, >0 to 5, >−5 to 0, >−10 to -5, >−15 to −10, ⩾ −15 mm Hg. Data are absolute number (% number). Reference group: >0–5 mm Hg group. P-values refer to the HR of each SBP category compared with the reference group. bIndicates P-value for trend. cSignificant increased risk of POE from 0–5 mm Hg (Po 0.01; N = 1420). dTrend for increased risk of POE from 0–5 mm Hg (P = 0.08; N = 1521).

blood pressure was reduced excessively in conjunction with the use of sibutramine. These data from SCOUT allow the impact of modest intentional weight reduction on cardiovascular outcomes to be distinguished from the effect of concomitant blood pressure changes. Such early weight loss, amplified by either short-term or chronic pharmacotherapy with sibutramine, reduced outcome events to a clinically meaningful degree in proportion to the degree of weight International Journal of Obesity (2014) 1 – 7

loss in both randomized treatment groups, that is, 6-week sibutramine followed by long-term placebo or continued sibutramine (Table 3). The expected benefits of modest intentional weight loss on blood pressure were observed in both hypertensive and normotensive subjects but were more marked in hypertensive subjects. The unexpected clinical finding in the SCOUT population, however, was that progressive falls in blood pressure in conjunction with the use of sibutramine showed © 2014 Macmillan Publishers Limited

Sibutramine, weight loss, blood pressure and cardiovascular outcomes RV Seimon et al

5 Table 3. Primary outcome events (A) and myocardial infarction (B) event rates by treatment in relation to weight categories over the first 6 weeks lead-in period and from lead-in baseline through subsequent 12 months post-randomization Weight categories (kg)

Model 1a

Event rate (%) N

Placebo

Sibutramine

Total

Model 2a

HR (95% CI)

P-value

HR (95% CI)

P-value

1.00 0.87(0.70–1.07) 0.61(0.46–0.82)

o 0.001b

1.00 0.91 (0.73–1.13) 0.68 (0.51–0.91)

0.007b

1.00 0.88 (0.73–1.06) 0.84 (0.68–1.04)

0.130b

(A) Primary outcome events rates in relation to weight change categories Over the first 6 weeks lead-in period >0 731 0 to o−5 7898 ⩾ −5 1173

(weight randomization—weight baseline) 45 (13.04%) 47 (12.18%) 166 (9.75%) 399 (10.06%) 467 (11.87%) 187 (13.17%) 46 (7.84%) 47 (8.02%) 221 (10.12%)

From lead-in baseline through subsequent 12 months >0 1857 117 (9.17%) 0 to o−5 3832 138 (7.05%) ⩾ −5 2538 60 (7.25%)

post-randomization (weight 12 months—weight baseline) 49 (8.43%) 169 (10.39%) 1.00 0.360b 188 (10.03%) 134 (11.07%) 0.95 (0.79–1.15) 149 (8.71%) 174 (10.49%) 0.91 (0.74–1.12)

(B) Myocardial infarction rates in relation to weight change categories Over the first 6 weeks lead-in period >0 731 15 (4.35%) 0 to o−5 7898 127 (3.20%) ⩾ −5 1173 17 (2.90%)

26 (3.56%) 307 (3.89%) 26 (2.22%)

1.00 1.09 (0.73–1.62) 0.61 (0.35–1.04)

0.038b

1.00 1.13 (0.76–1.70) 0.66 (0.38–1.14)

0.090b

From lead-in baseline through subsequent 12 month post randomization >0 1859 31 (2.43%) 16 (2.75%) 47 (2.53%) 0 to o−5 3849 55 (2.81%) 71 (3.79%) 126 (3.29%) ⩾ −5 2546 12 (1.45%) 51 (2.98%) 63 (2.48%)

1.00 1.30 (0.93–1.82) 0.97 (0.67–1.42)

0.704b

1.00 1.21 (0.86–1.70) 0.89 (0.60–1.31)

0.409b

11 (2.85%) 180 (4.58%) 9 (1.54%)

Abbreviations: CI, confidence intervals; HR, hazard rations; POE, primary outcome event. 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 treatment, country, sex and age. Weight change categories (gained weight (>0 kg), lost 0 to less than 5 kg (0 to o −5 kg), lost 5 kg or more ( ⩾ −5 kg)). Data are absolute number (% number). Reference group: >0 kg group. Landmark survival analysis from 12 month post randomization (n = 9566). P-values refer to the HR of each weight change category compared with the reference group. bIndicates P-value for trend. P-interaction for treatment and weight change categories during the first 6-week lead-in period or through subsequent 12 month post randomization for POE or MI was P>0.35 for all.

a progressive increase in POEs. Indeed, SBP falls in >10 mm Hg even in the placebo group stopped the improvement in risk and suggested even some increase in risk. The design of the SCOUT trial involved the exposure of older overweight or obese subjects to sibutramine whether or not they had overt CVD. However, by including subjects without known overt clinical CVD but with diabetes and at least one additional risk factor such as smoking, hypertension or dyslipidemia, the SCOUT population, in effect, was at much greater risk of adverse cardiovascular events than the general overweight and obese population. There is evidence of considerable genetic polymorphism in some of the enzymes that metabolise sibutramine, with higher concentrations of sibutramine metabolites and longer elimination times in some subgroups.19 This may have led to greater weight loss and possibly lower blood pressure due to the central effect of sibutramine. However, there were no specific Asian populations (who have a greater prevalence of polymorphisms) in this study nor were sibutramine metabolite levels measured; therefore, it cannot be determined whether this occurred or was a major contributor to the results found in this study. In addition, analysis of 32 body mass index and sibutramine single-nucleotide polymorphisms in a subset of 1682 SCOUT subjects initially revealed an association between a variant in the cytochrome P450 gene CYP2C19 and weight loss during the 6-week active sibutramine treatment run-in; however, this was not confirmed by subsequent Taqman assay of the whole SCOUT data set (Personal communication: Carss, K and Barroso I; Wellcome Trust Sanger Institute). The concern about weight loss in patients with CVD is that weight loss itself may be harmful—the so-called ‘obesity paradox’;20–22 however, this hypothesis has been based on © 2014 Macmillan Publishers Limited

reported outcomes of patients with pre-existing degrees of underweight, overweight or obesity who have substantial preexisting cardiovascular impairment and have survived an event, despite being overweight/obese and not from prospective clinical trials of weight status or weight change and their cardiovascular effects. SCOUT provides prospective data that show that even modest degrees of intentional weight loss achieved by the majority of subjects had a beneficial impact on cardiovascular outcome.6 However, further analysis suggests that this only remains true provided in these cardiovascularly vulnerable patients the blood pressure does not fall too far. Thus, the benefit of early weight loss seemed to be negated after 12 months; however, as demonstrated in Figure 1, in both the placebo and sibutramine group, there was a progressive fall in SBP in both groups with weight loss amplifying the fall in SBP. In addition, there was a very low all-cause mortality risk in these overweight subjects receiving multiple pharmacotherapy for their blood pressure, cardiac, diabetes or lipid problems in keeping with the recognised fall in mortality rates observed in many cardiovascular trials over the last decade. The deleterious effects of low blood pressure independent of weight change are in keeping with the observed greater rates of adverse cardiovascular events evident in patients with type 2 diabetes when SBP is reduced below 130 mm Hg.23–26 This adverse outcome signal in SCOUT induced by lowering SBP was amplified by the concomitant weight loss with sibutramine therapy (Table 2). Under these circumstances, the risk for POE was almost similar to that seen in subjects with large SBP increases accompanying weight gain. The paradoxical blood pressurelowering effect of sibutramine is a recognized effect, in part, induced by an alpha-adrenergic type blocking of central International Journal of Obesity (2014) 1 – 7

Sibutramine, weight loss, blood pressure and cardiovascular outcomes RV Seimon et al

6 sympathetic neuronal activity, which tends to counteract any peripheral stimulatory effect.12,27 The existence of a J-shaped curve for the relationship between blood pressure and cardiovascular outcomes has long been debated. Several reports have shown low blood pressure to be associated with an increased risk of cardiovascular events, including mortality, in patients aged >55–60 years and in those with pre-existing CVD,28–30 that is, in patients very similar to the SCOUT population. The J-shaped curve phenomenon for blood pressure was still apparent in the SCOUT trial even when other cardiovascular risk factors such as obesity, LDL cholesterol or diabetes were managed according to the treatment guidelines available at the time of the study. The long-term impact of very modest early weight loss during the 6-week, single-blind lead-in period on blood pressure and on the subsequent 5-year incidence of cardiovascular events is perhaps surprising. However, as noted in the primary publication,13 there was an unexpected, longer-term weight stability in those subjects who only received short-term sibutramine treatment (that is, randomized placebo group) with little evidence of the (mean) weight regain so frequently seen in other short-term weight loss trials. This may be related to the fact that subjects in SCOUT received continued dietary and physical activity counselling throughout the trial or to age differences comparing to other weight loss trials. The key finding from SCOUT is that early substantial weight loss with simultaneous substantial reduction in blood pressure appears to be harmful in a vulnerable population. This may have important implications for weight management in a population with high risks for cardiovascular events. Study limitations Assessment of the effects of weight loss and blood pressure management on adverse cardiovascular outcomes was preplanned; however, the current analyses are post hoc in terms of the detailed choice of categories. In this older, overweight/obese CVD population, the tight control of cardiovascular risk factors was emphasized, so there were multiple on-going interventions as in normal clinical care so SCOUT differs from one where a cohort is specifically enrolled for the standardized management of their blood pressure. We did not adjust for dosage (which was not collected) or class of antihypertensive agents received or for other potential confounders. The absence of a true placebo group (that is, all subjects had an initial 6-week treatment period with sibutramine) prevented the assessment of unequivocal sibutramine-related effects. The blood pressure changes reported may also in part reflect regression to the mean. Another potential explanation is the selective central alpha-adrenergic effects of sibutramine in blocking the central sympathetic nervous drive11 in obese subjects, and furthermore a large drop in blood pressure may also have reflected progression of the original cardiac disease process.

CONCLUSION Although modest early weight loss induces lower blood pressure with subsequent lower incidences of adverse cardiovascular events, early marked weight loss with simultaneously early rapid blood pressure reductions with sibutramine seems to be harmful in an older, overweight and obese cardiovascular impaired population. Continued long-term sibutramine treatment with substantial falls in blood pressure in these obese/overweight vulnerable subjects was more harmful compared with short-term sibutramine treatment. These findings may have important implications for weight loss treatment in populations with a high risk for adverse cardiovascular events. International Journal of Obesity (2014) 1 – 7

CONFLICT OF INTEREST NF: member of SCOUT 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. UFL was an employee of Abbott with equity interest in the Company. AMS is the member of the SCOUT ESC received payment from Abbott Laboratories, and is an advisor for Abbott, Merck, Arena, Novo-Nordisk, sanofi-aventis, GlaxoSmithKline, Boehringer Ingelheim and NeuroSearch, as a consultant for Vivus and Allegan, provided expert testimony for GlaxoSmithKline, received grants from Abbott and Covidian. WPTJ: Chair of the SCOUT ESC received payment from Abbott; the International Association for the Study of Obesity of which he is the President, he also received a grant from Novo Nordisk. WC is the 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 an advisor for Abbott, Ache Laboratorios Farmaceuticos S/A, GSK, Novo Nordisk, Takeda and Roche, and provided expert testimony for Abbott. IDC is a member of SCOUT Executive Steering Committee (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 sanofi-aventis, Pfizer (Australia), Weight Watchers, Allergan and the Korean Ministry of Agriculture. The remaining authors declare no conflict of interest.

ACKNOWLEDGEMENTS This work was supported and funded by Abbott Laboratories (Abbott Park, IL, USA). The Executive Steering Committee designed the study in co-operation with the Sponsor. The Sponsor obtained the data, which were assessed jointly by the authors and the Sponsor. The authors had full access to all data, determined the analyses, were responsible for its interpretation and wrote the manuscript. The final decision to submit the manuscript for publication was taken by the authors. The study was registered as a clinical trial on the Clinical Trial Registry, www.clinicaltrials.gov (Identifier: NCT00234832).

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