Sibutramine Plus Meal Replacement Therapy for Body Weight Loss and Maintenance in Obese Patients James L. Early,* Caroline M. Apovian,† Louis J. Aronne,‡ Madelyn H. Fernstrom,§ Arthur Frank,¶ Frank L. Greenway,储 David Heber,** Robert F. Kushner,†† Kristine M. Cwik,‡‡ Julia K. Walch,‡‡ Ann C. Hewkin,‡‡ and Vicky Blakesley‡‡

Abstract EARLY JAMES L., CAROLINE M. APOVIAN, LOUIS J. ARONNE, MADELYN H. FERNSTROM, ARTHUR FRANK, FRANK L. GREENWAY, DAVID HEBER, ROBERT F. KUSHNER, KRISTINE M. CWIK, JULIA K. WALCH, ANN C. HEWKIN, AND VICKY BLAKESLEY. Sibutramine plus meal replacement therapy for body weight loss and maintenance in obese patients. Obesity. 2007;15:1464 –1472. Objective: Our objective was to assess the efficacy and safety of sibutramine with a low-calorie diet (LCD) and commercial meal-replacement product in achieving weight loss and weight-loss maintenance in obese patients. Research Methods and Procedures: Eight U.S. centers recruited 148 obese patients for a 3-month comprehensive weight-loss therapy (Phase I) comprising daily sibutramine 10 mg ⫹ LCD (two Slim-Fast meal-replacement shakes, one low-calorie meal; total kcal/d ⫽ 1200 –1500). Patients (N ⫽ 113) who lost ⱖ5% of initial body weight during Phase I were randomized for a 9-month period (Phase II) to daily sibutramine 15 mg ⫹ LCD (one meal-replacement

shake; two low-calorie meals: total kcal/d ⬃1200 –1500) or daily placebo ⫹ three low-calorie meals (total kcal/d ⬃1200 –1500). Both phases included behavior modification. Efficacy was assessed by body weight change during each phase and by the number of patients at endpoint maintaining ⱖ80% of the weight they had lost by the end of Phase I. Other outcomes included changes in cardiovascular and metabolic risk factors, adverse events, and vital signs. Results: Mean body weight change during Phase I was ⫺8.3 kg (p ⬍ 0.001). Patients randomized to sibutramine in Phase II had an additional ⫺2.5 kg mean weight loss vs. a 2.8-kg increase in the placebo group (p ⬍ 0.001). More sibutramine patients maintained ⱖ80% of their Phase I weight loss at the end of Phase II (85.5% vs. placebo 36.7%, p ⬍ 0.001). Most adverse events were mild or moderate in severity, and all serious adverse events were unrelated to sibutramine. Discussion: Sibutramine plus LCD with meal replacements and behavior modification is a safe and effective strategy for achieving and sustaining weight loss in obese patients.

Received for review March 24, 2006. Accepted in final form December 11, 2006. The costs of publication of this article were defrayed, in part, by the payment of page charges. This article must, therefore, be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. *Department of Preventive Medicine and Public Health, University of Kansas School of Medicine, Wichita, Kansas; †Department of Medicine, Boston University School of Medicine, Boston, Massachusetts; ‡Department of Medicine, Weill Medical College of Cornell University, New York, New York; §Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania; ¶George Washington University Medical Center, Washington, DC; 储Outpatient Clinic Unit, Pennington Biomedical Research Center of the Louisiana State University System, Baton Rouge, Louisiana; **Center for Human Nutrition, University of California, Los Angeles, Los Angeles, California; ††Department of Medicine, Northwestern University, Chicago, Illinois; and ‡‡Abbott, Abbott Park, Illinois. Address correspondence to James Early, Department of Preventive Medicine and Public Health, University of Kansas School of Medicine, 1010 N. Kansas Rd., Wichita, KS 67214-3199. E-mail: [email protected] Copyright © 2007 NAASO

Key words: clinical management, pharmacotherapy, behavior modification, risk factor, meal replacement

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Introduction Clinical studies have suggested that moderate, sustained weight loss can reduce or eliminate surrogate markers of obesity-related disorders (such as type 2 diabetes, hypertension, and dyslipidemia) (1– 8). Unfortunately, long-term data show that most patients who lose weight regain their lost weight within 5 years and that these disease-associated risk factors are re-established in patients with abnormal biomarkers [for example, increased fasting glucose, triglyc-

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erides or hemoglobin A1c or low high-density lipoprotein (HDL)1-cholesterol] at the beginning of weight loss (9). There is evidence to suggest that adherence to a lowcalorie diet can be facilitated by using commercially produced meal-replacement products (10 –14). The addition of pharmacotherapy to these diets may enhance compliance and increase efficacy. Sibutramine, a serotonin and norepinephrine re-uptake inhibitor, has effects on satiety and is indicated for the long-term management of obesity (15–18). It seems reasonable, therefore, to hypothesize that a combination therapy of sibutramine plus a low-calorie diet and commercially available meal-replacement products would be useful for the management of obesity. The present study was designed to evaluate the efficacy and safety of this combination for weight loss and weight-loss maintenance as well as its effect on cardiovascular risk factors.

Research Methods and Procedures Patients Patients were recruited at eight sites in the United States. Eligible patients were men and premenopausal women 18 to 45 years of age in good general health, who had a BMI of 30 to 40 kg/m2 and who had maintained a stable body weight (⫾ 2 kg) for 3 months before screening. All patients were required to have mean systolic blood pressure (SBP) ⱕ140 mm Hg, mean diastolic blood pressure (DBP) ⱕ90 mm Hg, and mean pulse rate ⱕ95 bpm at the screening and baseline visits. Study Design and Treatment The trial design included a 3-month, open-label weightloss phase (Phase I) followed by a 9-month, randomized, placebo-controlled, parallel-group, single-blind, weightmaintenance phase (Phase II). In Phase I (baseline to end of 3 months), all patients received comprehensive weight-loss therapy that included: ● ●

●

Sibutramine 10 mg once daily A low-calorie diet (LCD) consisting of two Slim-Fast (Unilever N.V., Rotterdam, Netherlands) milk-based, ready-to-drink, meal-replacement shakes (⬃440 kcal/d) and one low-calorie meal plus healthy snacks (⬃800 kcal/d; total kcal/d 1200 –1500) Behavioral modification strategies

In Phase II (end of 3 months through 12 months), patients who had lost ⱖ5% of their initial body weight in Phase I were randomized in a 1:1, single-blind fashion to receive

1

Nonstandard abbreviations: HDL, high-density lipoprotein; SBP, systolic blood pressure; DBP, diastolic blood pressure; LCD, low-calorie diet; ECG, electrocardiogram; OR, odds ratio; CI, confidence interval; SE, standard error; STORM, Sibutramine Trial of Obesity Reduction and Maintenance.

behavioral modification and either sibutramine 15 mg once daily and an LCD [⬃1500 total kcal/d consisting of one meal-replacement (Slim-Fast) shake and two low-calorie meals] or placebo once daily and an LCD (⬃1500 total kcal/d consisting of three low-calorie meals). Titration of the sibutramine dose to 15 mg in Phase II mirrors the physician practice of optimizing therapy to achieve maximum weight-loss benefit. The behavioral modification strategies included selfmonitoring of eating habits and physical activity, problem solving, contingency management, and social support. Patients were encouraged to exercise, and counseling was provided to enhance incorporation of increased physical activity into daily activities. Exercise was to be initiated slowly and the intensity increased gradually. Nutritional counseling was provided with a goal of having patients develop healthful eating habits and of encouraging the patients to favor fruit and vegetable intake to maximize the food volume of their daily allotted calories. Study medications were provided by Knoll Pharmaceuticals (Abbott Laboratories, Abbott Park, IL). Patients were given coupons to be exchanged for Slim-Fast (Unilever) shakes. Study Assessments At the screening visit, all patients had a complete medical and obesity history recorded, a physical examination, and laboratory assessments. Screening laboratory results were used as baseline values. Efficacy was assessed by measurement of body weight, BMI, waist circumference, serum lipids, and glycemic parameters. Adverse events, laboratory parameters, vital signs (blood pressure and heart rate), electrocardiogram (ECG), physical examination, concurrent medications, and pregnancy tests (for women of childbearing potential) were monitored throughout the study at scheduled visits. Body weight and height were measured on a calibrated scale to the nearest 0.1 kg and 0.5 cm, respectively, with patients wearing a standard gown and without shoes. Waist circumference was measured and recorded to the nearest 0.5 cm at the level of the umbilicus over light clothing with the patient supine and under normal minimal respiration. Laboratory assessments were conducted at screening and at months 3, 6, 9, and 12. Compliance was assessed by pill count, and study-drug concentrations were not measured. Measurements scheduled for the 12-month visit were completed for all randomized patients who left the study prematurely. The overall enrollment goal was 100 to 140 obese adults at eight study centers. Statistics According to the intention-to-treat principle, the efficacy analyses included all patients who received at least one dose of study drug and provided at least one follow-up assessOBESITY Vol. 15 No. 6 June 2007

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Table 1. Baseline characteristics of patients entering the weight-loss and weight-maintenance phases Phase II (weight maintenance) Variable Sex Women Men Race White Black/African-American Hispanic/Mexican-American Asian Other Age (yrs) 关mean (SD)兴 Weight (kg) 关mean (SD)兴 BMI (kg/m2) 关mean (SD)兴

Phase I (weight loss) (n ⴝ 148)

Sibutramine (n ⴝ 58)

Placebo (n ⴝ 55)

126 (85.1%) 22 (14.9%)

51 (87.9%) 7 (12.1%)

42 (76.4%) 13 (23.6%)

63 (42.6%) 66 (44.6%) 15 (10.1%) 2 (1.4%) 2 (1.4%) 34.2 (7.5) 97.7 (12.7) 35.1 (3.5)

28 (48.3%) 21 (36.2%) 6 (10.3%) 2 (3.4%) 1 (1.7%) 35.6 (6.4) 97.8 (10.4) 35.2 (3.0)

26 (47.3%) 24 (43.6%) 4 (7.3%) 0 (0%) 1 (1.8%) 34.2 (7.3) 97.8 (13.8) 34.6 (3.6)

SD, standard deviation.

ment during the study phase being analyzed. The safety analyses included all patients who received at least one dose of study drug during the phase of the study being analyzed. All statistical analyses were performed using the statistical analysis system (SAS Institute, Inc.) (19), release 6.12 software, and carried out by the Global Statistics and Data Management Department of Global Pharmaceutical Research and Development, Abbott. The primary outcome measures for efficacy were the absolute change in body weight from baseline to 3 months, the absolute change in body weight from randomization to endpoint (12 months or premature discontinuation), and the percentage of weight lost between baseline and randomization (3 months) maintained at endpoint (12 months or premature discontinuation). Successful weight maintenance was defined as maintaining 80% of total weight loss recorded at 3 months. Secondary efficacy measures included the percentage change in body weight during Phase II, weight maintenance during Phase II, and absolute change in BMI, waist circumference, serum lipids, and glycemic variables during Phase II. Safety variables included adverse events, vital signs, and ECG parameters. A 5% level of significance was used. We used a t test for analyses of change from baseline to 3 months in body weight and in vital sign variables and analysis of covariance with terms for baseline value, change during Phase I, treatment group, and center for analyses of changes from randomization to endpoint in efficacy and vital sign variables. To evaluate the robustness of the analyses of body size variable changes from randomization to endpoint, these 1466

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analyses were repeated for patients who completed the study, analyzing the changes from randomization to 12 months. We used logistic regression with terms as for the analysis of covariance models for analysis of weight maintenance. Fisher’s Exact Test was used for incidence of adverse events. Approval was obtained from individual institutional review boards. All patients gave written informed consent.

Results Patients Patients entering Phase I were predominately female (126 of 148; 85.1%) and represented a diverse racial mix. Age ranged from 18 to 50 years (although the entry criteria were between 18 and 45 years, 3 patients who were between 46 and 50 years were included anyway); mean age was 34.2 years, mean body weight was 97.7 kg, and mean BMI was 35.1 kg/m2. Patients who did not meet the criteria for randomization were generally similar to those patients who were randomized in terms of demographics, including gender, age, height, body weight, and BMI. In terms of race, a greater proportion of Black/African-American patients failed to meet the randomization criteria. Whites were the most frequent race randomized, followed by Black/African Americans. Table 1 summarizes the demographic characteristics of patients included in both study phases.

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Figure 1: Disposition of patients.

No clinically significant differences were observed among the groups with respect to SBP, DBP, pulse rate, or ECG findings at baseline. Furthermore, the proportion of patients with hypertension (SBP ⱖ130 mm Hg or DBP ⱖ85 mm Hg or ongoing medical history of hypertension or ongoing hypertension medication at baseline) was similar among the non-randomized, sibutramine, and placebo groups (17.1%, 22.4%, and 21.8%, respectively). Figure 1 summarizes patient disposition through the trial. During Phase II, mean compliance by pill count was high (91.1% sibutramine and 89.8% placebo). Weight Loss There was a mean absolute change in body weight of ⫺8.3 kg from baseline (97.9 kg) to the end of Phase I (3 months), which was statistically significant (p ⬍ 0.001). Overall in Phase I, 85.1% of patients achieved ⱖ5% body weight loss, 29.8% lost ⱖ10%, and 5.7% lost ⱖ15%. Only 2.1% of patients failed to lose weight, or gained weight, in this phase. Therefore, 85.1% of patients met the criteria for randomization into Phase II. The pattern of weight loss from baseline to the end of the trial is shown for all randomized patients in Figure 2.

Patients randomized to the Phase II sibutramine treatment group showed additional mean weight loss from randomization to endpoint (⫺2.5 kg), while patients in the placebo treatment group showed mean weight increase (2.8 kg). The absolute difference (5.3 kg) in mean weight change between the two groups from randomization to endpoint was statistically significant (p ⬍ 0.001). In those patients who completed the study, the mean change in body weight from randomization to 12 months in the sibutramine treatment group was ⫺3.5 kg compared with a mean increase of 2.6 kg for patients in the placebo group. The absolute difference in mean weight change was 6.2 kg (p ⬍ 0.001). In Phase II, 30.9% of patients randomized to sibutramine lost an additional ⱖ5% of their randomized weight at endpoint compared with only 2% of placebo patients. Table 2 summarizes the results of the efficacy parameters in Phase II. The proportion of patients who maintained 80% or more of their Phase I weight loss at endpoint in Phase II was statistically significantly higher among those randomized to sibutramine compared with those randomized to placebo [85.5% vs. 36.7%, odds ratio (OR) ⫽ 21.1; 95% confidence interval (CI) 6.1, 72.6; p ⬍ 0.001]. In the comOBESITY Vol. 15 No. 6 June 2007

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Figure 2: Weight loss (mean ⫾ SE) from baseline for all randomized patients by treatment group (observed data) through the weight-loss and weight-maintenance phases. SIB, sibutramine; LCD, low-calorie diet; MR, meal replacement; PLA, placebo; R, randomization.

pleters set, 83.3% in the sibutramine group vs. 40.9% in the placebo group maintained ⱖ80% of their Phase I weight at 12 months (OR ⫽ 24.67; 95% CI, 3.09, 197.22; p ⫽ 0.003). Changes in mean percentage change of body weight and BMI mirrored mean changes in absolute body weight in both study phases. Weight loss was associated with decreases in waist circumference. In Phase II, the difference of ⫺4.5 cm between the sibutramine and placebo treatment groups in mean waist circumference change from randomization to endpoint was statistically significant (p ⬍ 0.001). The changes in the body size variables for patients who completed the study were consistent with those reported for the last observation carried forward/endpoint analyses. Metabolic Changes In the whole population, i.e., those patients who received sibutramine 10 mg plus LCD including meal replacement, the mean absolute body weight loss of 8.3 kg from baseline to 3 months was associated with the following changes: 1468

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BMI, ⫺3.3 kg/m2, waist circumference, ⫺9.8 cm; triglycerides, ⫺34.0 mg/dL; HDL cholesterol, ⫺1.6 mg/dL; glucose, ⫺2.3 mg/dL; insulin, ⫺3.0 ␮U/mL; and insulin sensitivity as determined by homeostasis model assessment, ⫺5.1. Table 3 summarizes the changes in lipid and glycemic variables from randomization to endpoint. No clinically significant changes were observed for the lipid or glycemic parameters from randomization to endpoint, and the differences between treatment groups in this period were not statistically significant. A separate post hoc analysis of changes in circulating lipids from baseline to endpoint in patients receiving sibutramine and meal replacement throughout the study (n ⫽ 55) showed statistically significant improvements in mean triglycerides (⫺25.3 mg/dL, p ⬍ 0.001) and HDL cholesterol (8.9 mg/dL, p ⬍ 0.001). There were also small but statistically significant improvements in fasting glucose, insulin, and homeostasis model assessment score.

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Table 2. Changes in body-size parameters in Phase II* Adjusted mean change (SE)

LOCF population Absolute change in weight (kg) Change in weight (%) Absolute change in BMI (kg/m2) Absolute change in waist circumference (cm)

Completers population Absolute change in weight (kg) Change in weight (%) Absolute change in BMI (kg/m2) Absolute change in waist circumference (cm)

Sibutramine (n ⴝ 55)

Placebo (n ⴝ 49)

⫺2.5 (0.6) ⫺2.9 (0.7) ⫺0.9 (0.2) ⫺3.0 (0.7)

2.8 (0.6) 3.3 (0.7) 1.0 (0.2) 1.5 (0.8)

Sibutramine (n ⴝ 30)

Placebo (n ⴝ 22)

⫺3.5 (0.9) ⫺4.2 (1.0) ⫺1.3 (0.3) ⫺2.7 (1.1)

2.6 (1.1) 3.1 (1.3) 0.9 (0.4) 1.0 (1.4)

Difference (SE) with 95% CI ⫺5.3 ⫺6.2 ⫺1.9 ⫺4.5

(0.8), (0.9), (0.3), (1.1),

⫺6.9, ⫺8.0, ⫺2.5, ⫺6.6,

⫺3.7 ⫺4.3 ⫺1.3 ⫺2.5

⫺6.2 ⫺7.3 ⫺2.2 ⫺3.7

(1.4), (1.6), (0.5), (1.7),

⫺8.9, ⫺3.5 ⫺10.4, ⫺4.2 ⫺3.2, ⫺1.2 ⫺7.0, ⫺0.3

p value for difference ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001

⬍0.001 ⬍0.001 ⬍0.001 0.037

SE, standard error; CI, confidence interval; LOCF, last observation carried forward; ANCOVA, analysis of covariance. Adjusted mean changes and p values from ANCOVA models with terms for baseline value, Phase I change, treatment group, and center. * LOCF population from randomization to endpoint; completers population from randomization to Month 12.

Safety Analysis In Phase I, 148 patients received at least one dose of sibutramine and were included in the safety analyses. A total of 113 patients (76%) reported an adverse event, and 85 of 148 (57%) reported an event to be possibly, probably, or definitely related to the study drug. Three patients withdrew due to an adverse event. In Phase II, 113 patients (sibutramine n ⫽ 58; placebo n ⫽ 55) received at least one dose of study drug and were included in the safety analyses. Forty-six patients (79%) in the sibutramine group vs. 35 (64%) in the placebo group reported an adverse event (p ⫽ 0.094). Twenty-three (40%) patients in the sibutramine group vs. 10 (18%) in the placebo group reported an adverse event considered to be possibly, probably, or definitely related to the study drug (p ⫽ 0.014). Most adverse events were considered mild or moderate in severity. Three patients in the sibutramine group (5%) withdrew prematurely due to adverse events. The most common (ⱖ11%) treatment-emergent adverse events reported during Phase I were dry mouth, headache, infection, constipation, and insomnia. During Phase II, the most common (ⱖ11%) treatment-emergent adverse events in the sibutramine group were infection, headache, and accidental injury, whereas those in the placebo group were asthenia, pain, infection, accidental injury, and increased appetite.

No patient died during the study. No serious adverse events were reported during Phase I, but during Phase II of the study, 3 (5%) patients in the sibutramine group (ectopic pregnancy, accidental injury, and ovarian cyst) and 2 (4%) patients in the placebo group (removal of uterine fibroids and hysterectomy) reported serious adverse events. The difference in the reported incidence of serious adverse events was not statistically significant (p ⫽ 1.000). All of the serious adverse events were reported by investigators as being unlikely related or unrelated to the study drug. Mean changes in hematology and chemistry variables from baseline to end of Phase I and from randomization to endpoint (Phase II) were small and not clinically significant. There were no statistically significant changes in either SBP or DBP in Phase I: mean [standard error (SE)] absolute change from baseline to 3 months; SBP, ⫺0.9 mm Hg (0.7; p ⫽ 0.225); DBP, 1.2 mm Hg (0.7; p ⫽ 0.060). There was a statistically significant increase of 3.2 bpm (0.8; p ⬍ 0.001) in mean absolute pulse rate. When blood pressure data were analyzed for very high or very low values [SBP (mm Hg) ⱕ90 and a decrease of ⱖ20 or SBP ⱖ180 and an increase of ⱖ20; DBP (mm Hg) ⱕ50 and a decrease of ⱖ15 or DBP ⱖ105 and an increase of ⱖ15], only one patient met the criteria in Phase I (very low DBP). No patient met the very high blood pressure criteria. OBESITY Vol. 15 No. 6 June 2007

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Table 3. Change in metabolic variables in Phase II

Triglycerides (mg/dL) Sibutramine (n ⫽ 47) Placebo (n ⫽ 38) Cholesterol (mg/dL) Sibutramine (n ⫽ 47) Placebo (n ⫽ 38) LDL cholesterol (mg/dL) Sibutramine (n ⫽ 47) Placebo (n ⫽ 36) HDL cholesterol (mg/dL) Sibutramine (n ⫽ 47) Placebo (n ⫽ 38) Insulin (␮U/mL) Sibutramine (n ⫽ 47) Placebo (n ⫽ 38) Glucose (mg/dL) Sibutramine (n ⫽ 47) Placebo (n ⫽ 37) HOMA Sibutramine (n ⫽ 46) Placebo (n ⫽ 37)

Randomization 关mean (SE)兴

Endpoint 关mean (SE)兴

Change 关mean (SE)兴

Treatment difference 关mean (SE)兴, 95% CI 关p兴

113.9 (10.6) 113.7 (13.3)

104.2 (19.0) 125.5 (23.8)

⫺5.0 (5.7) 2.9 (7.1)

⫺7.9 (8.0), ⫺23.6, 7.8 关0.327兴

181.8 (5.7) 181.7 (7.1)

193.2 (5.9) 200.4 (7.4)

12.4 (3.5) 18.8 (4.4)

⫺6.4 (4.9), ⫺15.9, 3.2 关0.196兴

112.4 (4.6) 114.1 (5.8)

113.9 (5.3) 119.6 (6.7)

2.3 (3.4) 5.8 (4.3)

⫺3.5 (4.8), ⫺12.9, 5.9 关0.467兴

46.1 (1.6) 45.3 (2.0)

57.8 (2.4) 58.4 (3.0)

11.4 (1.4) 13.6 (1.7)

⫺2.2 (1.9), ⫺6.0, 1.5 关0.252兴

11.0 (0.6) 9.6 (0.8)

11.8 (0.9) 12.4 (1.1)

1.4 (0.8) 2.9 (1.0)

⫺1.6 (1.1), ⫺3.8, 0.6 关0.159兴

87.3 (1.3) 90.0 (1.6)

87.4 (1.4) 88.1 (1.8)

0.5 (1.3) ⫺0.4 (1.6)

0.9 (1.8), ⫺2.6, 4.4 关0.611兴

16.8 (1.1) 15.4 (1.3)

19.9 (1.8) 21.0 (2.3)

3.2 (1.7) 5.8 (2.0)

⫺2.5 (2.3), ⫺6.9, 1.9 关0.266兴

SE, standard error; CI, confidence interval; LDL, low-density lipoprotein; HDL, high-density lipoprotein; HOMA, homeostasis model of assessment; ANCOVA, analysis of covariance. Adjusted mean changes and p values from ANCOVA models with terms for baseline value, Phase I change, treatment group, and center.

In Phase II, there were statistically significant differences between the treatment groups in both blood pressure and pulse rate. During the second phase, adjusted mean (SE) absolute changes in vital signs for sibutramine vs. placebo, respectively, were: ● ● ●

3.4 (1.0) vs. 0.3 [1.1; difference (SE) 3.2 (1.4), 95% CI, 0.4, 6.0, p ⫽ 0.028] for SBP (mm Hg) 0.8 (0.9) vs. ⫺3.2 [1.0; difference (SE) 4.1 (1.2), 95% CI, 1.6, 6.5, p ⫽ 0.002] for DBP (mm Hg) 0.2 (1.1) vs. ⫺4.2 [1.3; difference (SE) 4.4 (1.6), 95% CI, 1.1, 7.6, p ⫽ 0.009] for pulse rate (bpm)

Analysis of very high/very low blood pressure values in Phase II indicated that one sibutramine-treated patient met the DBP criterion of ⱖ105 mm Hg and increase of ⱖ15 (relative to their baseline and randomization values). Baseline and randomization values were 83 and 76 mm Hg, respectively; maximum DBP in Phase II was 107 mm Hg, and DBP at endpoint was 95 mm Hg. 1470

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The mean changes from baseline to endpoint in ECG intervals (PR, QRS, QT, QTc, and ventricular heart rate) were not clinically significant. ECG evaluations demonstrated no evidence of clinically significant QTc prolongation. ECG data were also analyzed for very high or very low values (PR interval ⬍120 or ⬎200 ms; QRS interval ⬍60 or ⬎100 ms; QTc interval ⬎450 or ⬎480 or ⬎500 ms or increase of ⱖ30 ms from baseline or increase of ⱖ60 ms from baseline; ventricular heart rate ⱕ50 bpm or ⱖ120 bpm or decrease of ⱖ15 bpm from baseline or increase of ⱖ15 bpm from baseline). These criteria were seen in one patient (of 35; 2.9%) who received sibutramine in Phase I, but was not randomized at 3 months, and in 13 of 58 (22.4%) patients who continued to receive sibutramine in Phase II and 20 of 55 (36.4%) patients in the placebo group. The most common ECG variable meeting these criteria in the sibutramine group was an increase in ventricular heart

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rate ⱖ15 bpm from baseline, occurring in 6 of 58 (10.3%) patients. In the placebo group, a decrease in ventricular heart rate ⱖ15 bpm from baseline was the most common criterion, occurring in 6 of 55 (10.9%) patients.

Discussion This study demonstrated that a combination therapy of sibutramine with LCD incorporating Slim-Fast meal replacements plus behavioral modification led to substantial weight loss over 3 months and facilitated maintenance of weight loss over an additional 9-month period when compared with treatment with placebo plus LCD plus behavioral modification. Those patients randomized to the sibutramine-based combination therapy achieved additional weight loss in Phase II, while patients in the placebo-based combination therapy showed a mean weight gain. The magnitude of weight loss observed in this study compares well to previous results from larger studies of sibutramine-assisted weight loss conducted at specialist hospital clinics and using complex lifestyle intervention (17,18). In the present study, with only a 3-month weight-loss phase, over 85% of patients were able to lose at least 5% of their initial body weight with sibutramine-based combination therapy. Among those who were randomized to continue receiving sibutramine and completed the weight-maintenance phase, 83% maintained 80% or more of their original weight loss to 12 months. These data compare favorably with the results from the longer Sibutramine Trial of Obesity Reduction and Maintenance (STORM) trial, where 77% of patients were able to lose at least 5% of their initial body weight with sibutramine and dietary intervention in the 6-month open-label phase. Of those who completed the 18-month weight-maintenance phase of the STORM trial, 43% maintained 80% or more of their original weight loss. The mode of action of sibutramine may explain how it is able to assist in both weight loss and weight maintenance. Sibutramine acts by inhibiting neuronal re-uptake of norepinephrine and serotonin in the hypothalamus. The predominant effect is to enhance satiety or a feeling of fullness, leading to early termination of eating behavior during a meal and prolonged satiation (15). A subsidiary effect is the prevention of the decline in energy expenditure that accompanies weight loss (16). As in STORM, the weight loss observed in this study was accompanied by clinically significant improvements in BMI and waist circumference and, therefore, a probable decrease in metabolically harmful abdominal adipose tissue. Previous studies conducted with sibutramine have reported marked improvements in HDL-cholesterol levels (17,18,20), particularly during weight maintenance once the mobilization of lipids from fat stores into the circulation during the period of acute weight loss has passed. Thus, in this study, the beneficial effects of the substantial Phase I

weight loss on HDL levels observed in both treatment groups by 12 months, but not by 3 months, were expected. In both phases, changes in triglycerides mirrored weight changes. There was no difference between treatment groups in the prospective analysis of mean changes in HDL-cholesterol and triglyceride levels in Phase II. A post hoc analysis of changes in these two lipid variables in patients receiving sibutramine and meal replacement throughout the study showed clinically meaningful and statistically significant beneficial changes in mean HDL cholesterol and triglycerides. No unusual treatment-emergent adverse events or changes in vital signs were observed, indicating that the combination of sibutramine with a low-calorie diet incorporating Slim-Fast meal-replacement products is a safe strategy for achieving weight loss and maintenance. The design of this study does not permit identification of which component of the weight-management strategy, namely, pharmacotherapy with sibutramine or meal replacement, contributed the most to the continued weight loss after randomization. However, despite this limitation, it may be concluded that behavioral modification plus a low-calorie diet of 1200 to 1500 kcal/d when delivered with a meal replacement and sibutramine was more effective than behavioral modification plus a low-calorie diet alone. Sibutramine given with a diet that includes meal replacement helped 85% of obese patients lose 5% or more of their body weight and helped them to maintain that weight loss over 12 months. This amount of weight loss has the potential in these patients to reduce the chance of developing other obesity-related diseases. Waist circumference, a surrogate marker for abdominal fat and a major component of the metabolic syndrome (21), was also reduced. Diets that include meal-replacement products seem to have a high rate of compliance compared with diets based on self-selected food, possibly because using them reduces the number of food choices that patients are required to make, which may help to prevent dietary failures (22). Since the majority of the patients in this study followed the treatment plan, this study shows that combining sibutramine with a diet that includes an easy-to-use meal replacement is an added weight-loss treatment option for obese patients. There is a growing evidence base to support the use of meal-replacement products for use either alone or in combination in weight management strategies (12–14). More scientifically robust data are likely to be produced by the U.S. NIH-funded “Look AHEAD” study, which is using meal replacements as part of an intensive weight-loss program delivered over 4 years to achieve weight loss among 5000 overweight and obese patients with type 2 diabetes (23). However, with an 11-year follow-up period, this study is not expected to report for some years. OBESITY Vol. 15 No. 6 June 2007

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In summary, there is a clear need for a variety of strategies to help overweight and obese people lose weight and maintain weight loss. The results of the present study suggest that the combination therapy of sibutramine plus a low-calorie diet incorporating Slim-Fast meal-replacement products supported by brief behavior modification sessions is a safe and effective strategy for achieving sustained weight loss in overweight and obese patients. This strategy of using sibutramine and meal replacement with a behavior program is an easy paradigm to incorporate into a family medicine practice environment.

Acknowledgments This study was supported by Knoll Pharmaceutical Co. (BASF Pharma), now Abbott Laboratories, Abbott Park, IL. References 1. Tuomilehto J, Lindstrom J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344:1343–50. 2. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393– 403. 3. Pan XR, Li GW, Hu YH, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance: the Da Qing IGT and Diabetes Study. Diabetes Care. 1997;20:537– 44. 4. Stevens VJ, Corrigan SA, Obarzanek E, et al. Weight loss intervention in Phase 1 of the Trials of Hypertension Prevention: the TOHP Collaborative Research Group. Arch Intern Med. 1993;153:849 –58. 5. Stevens VJ, Obarzanek E, Cook NR, et al. Long-term weight loss and changes in blood pressure: results of the Trials of Hypertension Prevention, Phase II. Ann Intern Med. 2001; 134:1–11. 6. Avenell A, Broom J, Brown TJ, et al. Systematic review of the long-term effects and economic consequences of treatments for obesity and implications for health improvement. Health Technol Assess. 2004;8:1–182. 7. Wood PD, Stefanick ML, Williams PT, Haskell WL. The effects on plasma lipoproteins of a prudent weight-reducing diet, with or without exercise, in overweight men and women. N Engl J Med. 1991;325:461– 6. 8. Poobalan A, Aucott L, Smith WC, et al. Effects of weight loss in overweight/obese individuals and long-term lipid outcomes: a systematic review. Obes Rev. 2004;5:43–50. 9. Wadden TA, Sternberg JA, Letizia KA, Stunkard AJ, Foster GD. Treatment of obesity by very low calorie diet, behavior therapy, and their combination: a five-year perspective. Int J Obes. 1989;13(suppl):39 – 46.

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