Division of Kinesiology, Laval University, Ste-Foy, Québec, Canada

Correspondence to: A Tremblay, Division of Kinesiology, PEPS, Laval University, Ste-Foy, Québec, Canada G1K 7P4. E-mail: angelo.tremblay@kin.msp.ulaval.ca

OBJECTIVE: Sibutramine favors a negative energy balance and also has the potential to increase heart rate and blood pressure. We investigated if a progressive supervised sibutramine-diet-exercise clinical intervention could increase the body weight loss previously reported while minimizing the potential cardiostimulatory effects of this drug.

DESIGN AND SUBJECTS: The tri-therapy intervention was divided into two phases of 6 weeks each in which sibutramine (10 mg) was taken once daily by eight obese men (body mass index (BMI) between 30 and 40 kg/m²). Part A consisted of a dietary follow-up with an energy restriction, whereas in part B an aerobic exercise program combined with a low-fat diet was introduced. Systolic (SBP) and diastolic (DBP) blood pressure, resting heart rate (RHR) and body weight were measured every 2 weeks while body density, resting metabolic rate (RMR) and respiratory quotient (RQ) were determined before and after the intervention.

RESULTS: This clinical intervention produced a substantial body weight loss (-10.7 kg, P<0.01) which was about twice as much as other 12-week studies. In part A, both RHR (+4 beats/min) and DBP (+5 mmHg, P<0.01) were increased. However, after part B, RHR (-8 beats/min, P=0.02) and DBP (-3 mmHg, P<0.01) were significantly decreased. RMR was decreased at the end of the program but this effect did not persist after adjustments for fat-free mass. RQ was also reduced (-0.05, P<0.01) following the clinical tri-therapy.

CONCLUSION: In conclusion, these observations suggest that this clinical tri-therapy favored a satisfactory benefit-risk profile since it enhanced weight loss without inducing increases in heart rate and blood pressure or detrimental changes in RMR and substrate oxidation.

International Journal of Obesity (2001) 25, 1144-1153

sibutramine; body weight; energy expenditure; heart rate; blood pressure

Introduction

Sibutramine has been accepted in many countries as a pharmacological agent to treat obesity. Several studies of up to 1 y have shown that sibutramine compared with placebo induces clinically significant weight losses in obese individuals in a dose-dependent manner (5-30 mg/day).^1,2,3,4,5 In rodents, this drug has been reported to increase energy expenditure^6,7 whereas human studies did not convincingly reproduce this finding.^4,8 Recent experimental data suggest that the negative energy balance resulting from sibutramine consumption in humans is mainly related to a decrease in energy intake^9,10 and the prevention of the decline in energy expenditure that follows weight loss.¹⁰ As a noradrenaline re-uptake inhibitor,^11,12 sibutramine has the potential to induce negative cardiostimulatory side effects. Indeed, at the end point of studies (weight loss»5 kg), Hanotin et al² and Bray et al³ noted significant increases in heart rate (HR) of about 4 and 6 beats/min for subjects who received 10 or 15 mg/day sibutramine compared with placebo. In addition, systolic (SBP) and diastolic blood pressure (DBP) were increased by up to 2.8 and 4.2 mmHg, respectively with 10 mg sibutramine once daily.³ In another study,¹ the change in DBP from baseline was significantly different with 10 mg sibutramine daily (+1.5 mmHg) compared to placebo (-1.9 mmHg) despite a more pronounced weight loss in the sibutramine group. Since many candidates for treatment with sibutramine are characterized with high blood pressure and/or are at risk of developing coronary heart disease, it would be recommended to minimize the increase in blood pressure (BP) and HR caused by a sibutramine treatment. It is important to mention that in most studies, sibutramine was used in conjunction with a dietary prescription for weight loss.^2,3,4,13 However, after an initial diet prescription, further dietary counseling was usually not given during the course of these studies. Therefore, even if subjects were briefly encouraged to follow the dietary plan, there were no regular follow-ups and dietary compliance was not always rigorously supervised. Subjects were also encouraged to become more physically active but there was no supervision to verify activity compliance or to motivate the participants. Under these circumstances, the potential of a supervised sibutramine-diet-exercise strategy to promote and improve weight loss has not yet been established. Moreover, the result of such a clinical tri-therapy intervention in regards to the cardiostimulatory effects of sibutramine is unknown. Therefore, the primary aim of this study was to determine if it is possible to accentuate the weight-reducing effect of a sibutramine intervention by performing a progressive personalized tri-therapy (dietary restriction, exercise program with regular follow-up visits combined with sibutramine) clinical intervention without inducing increases in heart rate and blood pressure.

It is well documented that a modest body weight loss is generally associated with a reduced risk of developing diabetes and cardiac diseases.^14,15 On the other hand, an important body weight loss is also associated with a decrease in resting metabolic rate (RMR) and fat oxidation^16,17,18 and recent experimental data have suggested other potential negative side effects of body weight loss such as an altered immune function, eg lower counts and functional capacity of lymphocytes and neutrophils,^19,20,21 which could lead to health complications such as increased risks of infections, infection related-mortality and certain types of cancer.²² The latter observations offer a new perspective for the health professional as the outcome of his/her intervention to treat obesity should be assessed in relation to the beneficial and the less desirable effects of body weight loss.²³ In this context, the secondary aim of this study was to determine where the outcome of a progressive clinical tri-therapy intervention stands on the benefit-risk continuum of obesity treatment.

Methods

Participants

Healthy, non-smoking, sedentary, obese Caucasian men (n=8), from 28 to 52 y of age, and with a body mass index (BMI) between 30 and 40 kg/m² were selected to participate in this study. Participants with diabetes, cardiac problems, high blood pressure (seated systolic/diastolic blood pressure£140/90 mmHg), or any other medical complications known to interfere with the outcome of this clinical intervention, were excluded. In addition, all eight participants had a stable weight (±3 kg) for at least 3 months before the protocol. They gave their written consent to participate in this study which received approval of the Laval University Medical Ethics Committee.

Clinical tri-therapy intervention

Before this clinical intervention, anthropometric measurements, RMR, resting blood pressure (RBP), resting heart rate (RHR), ambulatory blood pressure as well as heart rate monitoring were performed. The participants were then submitted to a 3 month clinical intervention which consisted of a sibutramine treatment in conjunction with energy restriction and an exercise program, according to the sequence described in Figure 1. Participants were advised to take one 10 mg sibutramine capsule per day in the morning for 12 weeks. Medication was provided by Knoll Pharma Canada. In order to gradually improve lifestyle habits, sibutramine was combined with a non-macronutrient-specific energy restriction alone for the first 6 weeks of the clinical intervention (part A). The exercise program was then progressively introduced in part B of this program with an energy restriction focussing on low fat intake. In addition, four of the eight participants were available for a 12-week facultative clinical follow-up (healthy food habits combined with exercise) once the first 12 weeks of the clinical intervention with sibutramine were completed.

Dietary counseling: prescription and follow-up visits

The energy content of the diet prescription was determined in part with an RMR measurement to which an activity factor of 1.4²⁴ was multiplied to estimate daily energy expenditure (DEE) of the subjects who were sedentary at the beginning of the intervention. Calculation of DEE was as follows: DEE=RMR (kcal/min)´1440 min/day´1.4. To determine prescribed energy intake, 700 kcal were subtracted from DEE. The calculated energy intake (2470±342 kcal/ day) was then fixed throughout the entire clinical intervention (part A and part B).

The dietary counseling was done in a personalized manner in order to take into account specific characteristics of each individual. In addition, in order to gradually modify food habits of the participants, part A of the clinical intervention (week 1 to week 6) was a non-macronutrient-specific energy-restricted diet prescription. At the beginning (week 0), the mean daily energy and macronutrient intakes were assessed by means of a 3 day dietary record (2 week days and 1 weekend day). Initial macronutrient composition was maintained in part A in order to facilitate diet modifications. A nutritionist explained to the participants how to complete their records and to measure quantities of ingested foods. Upon collection day, the 3 day dietary record was reviewed by the nutritionist and then analyzed with a computerized version of the Canadian Nutrient File²⁵ in order to maintain the initial macronutrient composition of the diet throughout part A of the clinical intervention. The contribution of macronutrients to energy intake in part A was 34±2%, 49±2% and 14±1% from fat, carbohydrates and proteins, respectively. It was also suggested to minimize the contribution of alcohol to energy intake. Participants were given a diet-exchange-type nutrition plan in order to best follow the prescription. In other words, the participants had to record the amount of servings consumed in each of the six groups (bread and starch foods, vegetables, fruit, milk products, protein foods (meats and substitutes) and fats and oils) every day. In order to create a supportive and motivating environment, participants came for follow-up visits every 2 weeks. During those visits, a 24 h dietary recall was performed by the nutritionist and was then analyzed with the computerized version of the Canadian Nutrient File.²⁵ The nutritionist also verified the diet-exchange-type nutrition plan. These two clinical nutrition tools were very useful for the nutritionist as she was able to guide the participants in their food choices and verify if the subjects were compliant with the dietary prescription. Table 1 presents a summary of the daily energy and macronutrient intakes of participants during the clinical intervention (parts A and B). According to the mean of three 24 h dietary recalls (weeks 2, 4 and 6), the participants appeared to be compliant with the dietary prescription of part A (Table 1).

For part B of the clinical intervention (week 7 to week 12), a low-fat nutrition plan was prescribed. The fraction of energy intake in part B was 30±1%, 50±3%, 20±3% from fat, carbohydrates and proteins, respectively. Once again, it was suggested to minimize the contribution of alcohol to energy intake. Specific recommendations were also made in order to improve the quality of fat consumed. Hence, participants were encouraged to consume lipids from vegetable sources (grains), poultry, fish and lean meats to maximize unsaturated fatty acid consumption. Furthermore, participants were encouraged to choose sources of carbohydrates with a high fiber content (>3 g of fiber per serving) and to limit the intake of refined foods with a high simple sugar content. Participants were then again given a new diet-exchange-type nutrition plan in order to follow the dietary prescription and guidelines of part B. As for part A, they came for regular follow-up visits every 2 weeks during which a 24 h dietary recall and the verification of the nutrition plan were also performed as described above. The mean of the three 24 h dietary recalls (weeks 8, 10 and 12) in Table 1 suggests that the participants were eating less fat (in Part B) and appeared to be compliant with the diet prescription of part B (Table 1).

Exercise program: prescription and follow-up visits

At the beginning of the clinical intervention (week 0) the participants were sedentary. They were asked to remain physically inactive for the duration of part A (week 1 to week 6) in order to permit gradual changes in their lifestyle. For part B of the clinical intervention (week 7 to week 12), an aerobic exercise program was prescribed. The physical activity prescription was established on the basis of a submaximal exercise treadmill test that was performed to ensure that the planned exercise prescription represented a safe exercise stimulus and to get an indication of subjects' aerobic fitness. Briefly, the participants had to perform an incremental exercise test on a treadmill up to a maximum of eight levels of 10 min/level. During the test, the rate was steady at 2.7 miles per hour with an increasing slope from 0 to 9%, until 75% of predicted maximal heart rate of the subjects was reached. The intensity of the exercise program was fixed between 65 and 72% (116±2 to 129±2 beats/min) of the estimated maximal heart rate (220-age=179±3 beats/min) at a frequency of three sessions/week for a duration of 20-50 min/session. The intensity and duration of the exercise prescription were planned to be increased progressively over the 6-week period. As planned, exercise duration increased over the course of part B. However, even if it was also intended to increase exercise intensity, it remained rather stable during part B, as reflected by the absence of elevation in exercise heart rate (see Appendix 1). The participants were asked to use our laboratory training facilities under supervision for two sessions/week. For the third session, they were encouraged to walk or bike at home while adhering to the intensity and duration of the prescription. In order to increase the motivation of some participants, it was possible to exercise in groups. To ensure proper monitoring of exercise intensity and duration, the subjects had to wear a heart rate monitor (Polar Vantage XLÔ HRM, Stamford, CT) during all the sessions (home and supervised). Further information about the exercise prescription is presented in Appendix 1.

Measurements

Anthropometric measurements

Body weight was measured with a standard beam scale every 2 weeks during the clinical tri-therapy. Waist and hip circumferences were taken according to Lohman et al²⁶ before (week 0) and after every 2 weeks of the clinical intervention. Body density was determined by the underwater weighing technique²⁷ at the beginning (week 0) and at week 12 of the tri-therapy. The closed circuit helium dilution method was used²⁸ to assess residual lung volume. The Siri formula was used²⁹ to estimate the percentage of body fat from body density. Fat-free mass (FFM) and fat mass (FM) were estimated from the derived percent body fat and body weight.

Resting metabolic rate measurement

RMR was measured by indirect calorimetry in the morning, after 12 h overnight fast. Participants had to abstain from physical activity and alcohol consumption on the day prior to measurement. After a 15 min resting period, expired gas collection was performed through a mouthpiece while the nose was clipped for a 15 min period. Oxygen and carbon dioxide concentrations were determined by non-disperse infrared analysis (Uras 10 E, Hartmann & Braun, Germany) whereas pulmonary ventilation determination was assessed with a S-430A measurement system (KL Engineering, Ventura, CA). The Weir formula³⁰ was used to determine the energy equivalent of oxygen volume. As previously reported,³¹ RMR measurements as performed in our facilities provide a reliability coefficient of 0.9 and a coefficient of variation of less than 6%. RMR measurement was performed before treatment (week 0) and at week 12 of the clinical intervention.

Resting heart rate and blood pressure measurements

RHR and RBP measurements were performed before (week 0) and after every 2 weeks over the 12-week clinical intervention. At the beginning of each testing session, subjects were asked to sit quietly for a 5 min period. After the resting period, heart rate was measured by palpation of the radial artery on the right arm whereas blood pressure was taken with an appropriate size cuff (regular or large depending on arm circumference). Resting systolic (RSBP) and diastolic blood pressure (RDBP) were determined by the first and fifth Korotkoff's sounds, respectively. For week 0 and week 12, the measures were repeated three times at 2 min intervals and the mean of these three measures were calculated and used in the analysis. Moreover, RHR and RBP were always performed by the same investigator to maximize the consistency of these measurements.

Ambulatory blood pressure and heart rate monitoring

In order to determine the 24 h means (overnight+daily) for SBP, DBP and HR, participants were asked to wear an ambulatory blood pressure monitor at home, on a normal day for a 24 h period at 0 and 12 weeks of the clinical intervention. The participants were asked to refrain from exercise the day before as well as the day of the monitoring. The ambulatory blood pressure device (Space Labs Medical, USA, model no. 90207) that was installed by the investigator consisted of a programmed console that was worn on the belt with an appropriate size cuff (depending on arm circumference) worn on the non-dominant arm and a cable connecting the console to the cuff. Data were recorded at frequent intervals throughout the day (every 30 min) and at night (every hour) and was then analyzed with a computerized system (FT1000A). Ambulatory blood pressure measurements were performed in six of the eight participants.

Plasma glucose, lipids, lipoproteins and hematology

Blood samples were obtained in the morning after a 12 h overnight fast from an antecubital vein, before (week 0) and at week 12 of the clinical tri-therapy intervention. Plasma glucose was measured enzymatically.³² Plasma cholesterol (Chol) and triglyceride (TG) levels and lipoprotein fractions were measured enzymatically on an RA-100 automated analyzer (Technician, Instruments Corporation, Tarrytown, NY, USA). The high-density lipoprotein (HDL) fraction was obtained after precipitation of low-density lipoproteins (LDL) in the infranatant (d>1.006 g/ml) with heparin and MnCl₂.³³ The Coulter VCS Automated Differential Analyzer (Miami, Florida, USA) was used to measure hematological parameters. A combination of conductivity (DF 2) and light scatter (DF 1) integrated in this system permitted the identification of the white blood cells, including lymphocytes and neutrophils. It is important to note that plasma glucose, lipid and lipoprotein determinations were performed in six of the eight subjects whereas hematological parameters were measured in the eight subjects. In addition, beyond the fact that participants were fasted for at least 12 h, they also had to refrain from exercise and to eliminate alcohol consumption the day before blood sampling.

The 12-week facultative clinical follow-up

As indicated above, participants were encouraged to maintain the healthy food-activity habits that were taught in part B of the protocol. Four participants thus continued to eat a low-fat-high fiber-diet without recording servings in a nutrition plan. Once again, in order to create a supportive and motivating environment, participants came for personalized follow-up visits every 2 weeks. During one of these visits, the nutritionist gave a tour of a grocery store in order to explain which foods constitute healthier choices. In addition, participants continued the aerobic exercise program in combination with a muscular fitness program to their request. Participants used our training facilities under supervision alone or by group, for two sessions/week in order to increase their motivation. Body weight, waist and hip circumferences, resting HR, DBP, SBP, body composition (FM, FFM) and RMR measurements were performed at the end of the 12-week clinical facultative follow-up according to the same procedures as described above.

Statistical analysis

All statistical analyses were performed with the Jump version 3.2.2 program (SAS Institute, Cary, NC). Paired t-tests were performed on body composition (FM and FFM), ambulatory BP and HR, RMR, respiratory quotient (RQ) and on plasma variables (lipids, lipoproteins, glucose, hematology) in order to verify the response of these variables to the 12-week clinical intervention compared to the beginning. Tests were considered significant at P<0.05 when there was only one comparison (end of part B vs before clinical intervention). In addition, an analysis of variance (ANOVA) for repeated measures was performed on the means of anthropometric measurements (hip and waist circumferences, body weight), RHR, RSBP and RDBP variables to assess the response to both parts A and B of the clinical tri-therapy. When ANOVA tests were significant, paired t-tests were performed on all of these variables in order to identify the nature of the differences. When three comparisons (part A vs before clinical intervention; part B vs part A; part B vs before clinical intervention) were analyzed, a Bonferonni correction was performed and tests were then considered significant at P£0.02. For the four participants who continued in the 12 week facultative clinical follow-up, paired t-tests were done to compare values of week 24 with those collected on week 12 (end of the tri-therapy intervention).

Results

Body weight and other anthropometric measurements

Table 2 shows that the participants lost a significant amount of body weight after parts A and B of the clinical intervention (-6.1 and -4.6 kg, respectively, P<0.02). At the end of the intervention participants lost a total of 10.5% (-10.7 kg, P<0.01) of their initial body weight. FM and FFM were significantly lower at week 12 than before the clinical tri-therapy (P<0.01). Waist and hip circumferences were also significantly reduced at the end of the clinical intervention (-9.6 and-5.7 cm, respectively, P<0.01).

Resting metabolic rate and resting respiratory quotient

RMR (kcal/24 h) tended to be decreased at the end of the 12 week clinical intervention (-331 kcal/24 h, P=0.06). However this effect was no longer observed when RMR was adjusted for FFM. In addition, there was a significant decrease in RQ on week 12 (0.85 vs 0.80, P<0.05) compared to the beginning of the tri-therapy (Table 2).

Resting heart rate, systolic and diastolic blood pressure

Table 2 presents the effects of the clinical intervention on RHR, RSBP and RDBP. In response to part A, there was a mean increase in RHR of 4 beats/min that was not significantly different from the value measured before the intervention. After part B, there was a significant decrease in RHR compared to part A (-8 beats/min, P=0.02) so that RHR tended to be lower although not significantly compared to that observed at the beginning of the clinical intervention (week 0). In response to part A, there was a non significant decrease (-3 mmHg) in RSBP which was accentuated after part B to reach a value that was 7 mmHg (P=0.02) below the initial measurement (week 0). Regarding RDBP, there was a significant increase after part A (+5 mmHg, P<0.01). However, RDBP decreased (-3 mmHg, P=0.06) after part B of the clinical intervention so that RDBP was not significantly different from that measured before the beginning of the tri-therapy intervention.

Twenty-four-hour heart rate, systolic and diastolic blood pressure

Table 3 presents the results of the 24 h ambulatory heart rate and blood pressure monitoring. The 24 h mean of SBP tended to be lower at the end of the clinical tri-therapy compared to before the beginning of the intervention (P=0.09). Moreover, the 24 h mean of DBP was significantly decreased at the end of the clinical intervention compared to the beginning (P<0.05).

Plasma lipids, lipoproteins, glucose (n=6) and hematology (n=8)

Plasma cholesterol (week 0, 4.80±0.41 mmol/l vs week 12, 4.33±0.35 mmol/l), HDL-cholesterol (week 0, 1.14± 0.10 mmol/l vs week 12, 1.07±0.08 mmol/l), LDL-cholesterol (week 0, 2.95±0.29 mmol/l vs week 12, 2.67± 0.29 mmol/l), triglyceride (week 0, 1.54±0.43 mmol/l vs week 12, 1.31±0.19 mmol/l) and fasting glucose (week 0, 5.51±0.30 mmol/l vs week 12, 5.39±0.24 mmol/l) concentrations were lower at the end of part B compared to before the clinical tri-therapy, but these changes did not reach standard statistical significance. Lymphocyte (week 0, 1.51±0.09´10⁹/l vs week 12, 1.46±0.13´10⁹/l) and neutrophil (week 0, 3.31±0.34´10⁹/l vs week 12, 2.93± 0.30´10⁹/l) counts were also not significantly reduced at the end of the clinical intervention.

Twelve week facultative clinical follow-up

Table 4 presents the characteristics of the participants who engaged in the 12 week facultative clinical diet-exercise follow-up (n=4). After this follow-up, body weight was further decreased (-4.7 kg, P=0.08) compared to the end of the tri-therapy clinical intervention (week 12). FM (-5.7 kg, P<0.05) and hip circumference (-4 cm, P<0.05) were decreased on week 24 compared to week 12. Moreover, RDBP and RHR were further reduced at the end of this facultative clinical follow-up.

Discussion

The first aim of this study was to determine if it was possible to increase the weight-reducing impact of a sibutramine treatment by performing careful dietary and exercise follow-up visits during the program without inducing increases in heart rate and blood pressure. Since it was not possible to use obese subjects being treated with sibutramine and initial diet-exercise recommendations only as a reference group, the outcome of our approach was evaluated by comparison to other studies in which sibutramine prescription was only combined with initial dietary and exercise guidelines. Our progressive supervised clinical tri-therapy intervention produced a substantial body weight loss (-10.7 kg) which was about twice as much (mean of about-5.0 kg) as other 12 week studies combining sibutramine with initial dietary and exercise recommendations only.^3,5,34 We are aware that the comparison of our results to those of others is potentially undermined by our small sample size. Even if the subjects tested in this intervention were recruited through the media from the general population and not selected from a group of especially motivated individuals, we cannot exclude the possibility that we were fortunate to recruit motivated men whose initial characteristics were responsible for the larger weight loss that we observed compared to other reported 12 week studies. In contrast, we believe that the motivation experienced by the subjects was probably mostly related to the personalized regular diet and exercise follow-ups which was one of the main preoccupations of this study. Although we did not measure the motivation with a specific tool, it was easy to notice that the patients were highly motivated. Accordingly, they frequently expressed their enthusiasm with the careful supervised intervention. Therefore, we believe that the context in which the study was realized generated a higher degree of motivation and it is this rather than individual characteristics of subjects that induced the greater than previously observed weight loss.

These observations are in accordance with those observed in the subgroup of four subjects who continued the regular diet and exercise follow-up visits during an additional 12 week-period once sibutramine treatment was terminated. Indeed, the results of these subjects showed that a healthy food habits-exercise program in this context may accentuate the body weight and fat losses induced by a tri-therapy based on pharmacology, diet and exercise. This provides support to another recent study³⁵ performed in our laboratory that demonstrated an accentuation of weight loss by a healthy dietary regimen and exercise following a first phase of treatment with fenfluramine and dietary supervision. However, it is important to again mention that the success of these four subjects may be due in part to an effect of self-selection for highly motivated patients.

The second objective of this study was to determine where our clinical tri-therapy intervention stands on the benefit-risk continuum related to effects of body weight loss. When this issue is considered by health professionals attention is usually focused on the ability of weight loss to decrease the risk of diseases such as diabetes and cardiopathies.¹⁴ In the present study, the variables related to an increased risk of these diseases, ie plasma glucose, lipid and lipoprotein levels were slightly favorably influenced by the intervention. As indicated above, the metabolic profile of our obese participants was improved by the program but not to a statistically significant extent presumably because their initial metabolic profile did not present any marked deterioration and because of the small number of patients studied. On the other hand, a substantial body weight loss may promote some metabolic vulnerability at the other end of the benefit-risk continuum. This is reflected by a significant decrease in RMR and an increase in RQ^16,18 indicating a reduced contribution of lipid in the substrate mix oxidized. Since a reduced RMR and an increased RQ both have been suggested to represent a greater risk of body weight gain^36,37 particular attention was given to measuring these variables in the present clinical intervention. After 12 weeks of supervision, RMR was decreased. However, there was no change in this variable when it was expressed in kcal/kg FFM indicating that the body did not display an increased metabolic efficiency in response to weight loss that would be additive to the effect of body substance loss on RMR.³⁸ With respect to the substrate mix oxidized, RQ was actually reduced both after the first 12 weeks of intervention and after the additional 12 weeks of diet and exercise supervision. This indicates that the present protocol produced a beneficial effect on the fat oxidation profile of subjects. Moreover, this observation is consistent with the documented effected of exercise on the potential of skeletal muscle to use fat for energy production.³⁹

Recent studies have demonstrated that substantial body weight loss may promote some diminution of the immune function. Some indicators of this are decreases in counts of plasma neutrophils and lymphocytes^19,20 and in plasma concentration of natural killer cell activity^20,40,41 as well as a decline in delayed-type hypersensitivity response.⁴² As a first attempt to examine this issue in our clinical intervention, we measured a basic profile of immune function which revealed that there was no marked deterioration of the immune function resulting from our intervention. Taken together, our results pertaining to energy metabolism and immune function suggest that the clinical tri-therapy intervention did not favor vulnerability regarding these components of body homeostasis.

Beyond the potential side effects that may result from any weight-reducing strategy, there are some side effects which are specific to sibutramine use. Since obese individuals are at greater risk of developing cardiac problems, the potential of sibutramine to produce small increases in HR and BP is a particular matter of concern for health professionals. In the present clinical intervention, we verified whether a progressive tri-therapy intervention could increase the weight-reducing effect without inducing negative cardiostimulatory side effects. Since regular physical activity results in a decrease in resting HR and BP,^43,44 we hypothesized that when performed in the context of sibutramine therapy, adding regular exercise could be helpful to partly or even completely abolish the cardiostimulatory effects of the medication. Our results show that at the end of the clinical intervention RDBP and RHR were not significantly different from values measured before the beginning of the program even if subjects were still taking sibutramine once daily when these measurements were performed. The results also showed that the 24 h mean of SBP tended to be lower at the end of the intervention while the 24 h DBP was significantly reduced at the end of week 12 compared to the beginning of the program. Therefore, these results also indicate that combining sibutramine and physical activity prevents the occurrence of non-specific cardiostimulatory effects that are observed when the drug is prescribed alone. This effect might be explained by the exercise-induced decrease in heart rate -adrenoreceptors that was documented in animals.⁴⁵

Although this clinical intervention was of short term and based on a small number of participants, the results are very promising for health professionals who treat obesity. In fact, our results showed that a personalized progressive clinical tri-therapy intervention with regular follow-up visits can accentuate the weight-reducing impact of sibutramine without inducing increases in heart rate and blood pressure. The data also supported our previous finding³⁵ that regular physical activity and healthy food habits permit the maintenance of body weight loss or may even accentuate it when a drug therapy is interrupted. The weight loss achieved in this study was induced without detrimental changes in the immune function, RMR and substrate oxidation, suggesting that the supervised clinical tri-therapy intervention tested in this study promotes a favorable benefit-risk profile of a weight-reducing strategy.

Acknowledgements

This research was supported by a grant from Knoll Pharma Company. We wish to thank Yanick Angers and Patrick Dufour who were responsible for the prescription and supervision of the exercise program.

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Figure 1 Summary of the clinical tri-therapy intervention.

Table 1 Mean daily energy and macronutrient intakes of participants before and during the clinical intervention

Table 2 Participants' characteristics before and after the clinical tri-therapy intervention

Table 3 Twenty-four-hour ambulatory blood pressure (SBP and DBP) and heart rate before and after the clinical tri-therapy intervention

Table 4 Participants' characteristics after the clinical tri-therapy intervention and the facultative clinical follow-up

Appendix Description of exercise sessions from week 7 to week 12 (Part B)