The Long-term Outcomes of Sibutramine Effectiveness on Weight (LOSE Weight) Study: Evaluating the Role of Drug Therapy Within a Weight Management Program in a Group-Model Health Maintenance Organizati

Objective: To assess the benefit of sibutramine hydrochloride monohydrate within a weight management program.

Study Design: Prospective randomized controlled trial in a health maintenance organization.

Patients and Methods: Obese patients (n = 588) starting a weight management program were enrolled. Patients were randomly assigned to participate in the program alone or to participate in the program and receive sibutramine for 12 months. Outcome measures were change in weight, body mass index (BMI), percentage body fat, serum lipids, serum glucose, and blood pressure.

Results: At baseline, there was a younger age and higher weight, BMI, and waist circumference in the drug group. There was more degenerative joint disease in the nondrug group. The mean weight loss at 6 months was 6.8 kg (95% confidence interval [CI], &#8722;7.4 to &#8722;6.1 kg) in the drug group vs 3.1 kg (95% CI, &#8722;3.8 to &#8722;2.4 kg) (P < .001) in the nondrug group. Weight loss was maintained at 12 months. Significant reductions in BMI, body fat, and waist circumference occurred in the drug group. There were no significant changes in laboratory values or blood pressure. Patients taking sibutramine experienced a significant increase in heart rate (1.7 beats/min [95% CI, 0.5–2.9 beats/min] vs &#8722;0.4 beats/min [95% CI, &#8722;1.5 to 0.8 beats/min]; P <.004).

Conclusion: In this managed care setting, the effectiveness and safety of sibutramine were similar to those observed in randomized, double–blind clinical efficacy trials.

(Am J Manag Care. 2004;10:369–376)

The prevalence of overweight (body mass index [BMI], calculated as weight in kilograms divided by the square of height in meters, &#8805;25) and obese (BMI, &#8805;30) adults in the United States continues to increase. The most recent data from the continuous National Health and Nutrition Examination Survey show a significant increase in the age—adjusted prevalence of obesity (22.9% in National Health and Nutrition Examination Survey III [1988—1994], increasing to 30.5% in 1999—2000). This surveillance also showed a significant increase in the prevalence of overweight (55.9% in National Health and Nutrition Examination Survey III, compared with 64.5% in 1999—2000).¹

Obesity is associated with significant costs and comorbidities.^2,3 In 1995, the total costs of obesity were estimated at $95 billion.² Obesity is a major risk factor for comorbidities, including hypertension, hypercholesterolemia, type 2 diabetes mellitus, coronary artery disease, stroke, gallbladder disease, musculoskeletal disorders, certain cancers, as well as all—cause mortality.⁴ In managed care, health plan members are similar to the general population with regard to obesity and its attendant comorbidities. For example, unpublished data from Kaiser Permanente of Colorado suggest that about 22% of the adult health plan members are obese (J.A.M.).

Sibutramine hydrochloride monohydrate (Meridia, Abbott Laboratories, Inc) inhibits norepinephrine and serotonin reuptake, resulting in enhanced satiety and weight loss. In animals, the drug also increases thermogenesis through central activation of efferent sympathetic activity.⁵ The efficacy of sibutramine in inducing and maintaining weight loss has been established for up to 2 years in randomized, double—blind, placebo—controlled studies.^6—9

The US Preventive Services Task Force¹⁰ (USPSTF) has recently published evidence—based recommendations for screening and interventions for obesity in adults. These recommendations state that obese individuals should be offered a program that includes intensive counseling and behavior interventions to promote sustained weight loss. The USPSTF also recommends that pharmacologic agents should be used in conjunction with a program that includes significant lifestyle modification. The principal objective of our study was to determine the clinical effectiveness of sibutramine in the setting of a weight management program in a managed care environment.

METHODS

Patients

This prospective, randomized, controlled trial involved obese patients enrolled in the Kaiser Permanente Weight Management Program (KPWMP). Enrollment occurred from January 1999 through June 2000. Eligible patients were 18 years of age or older, willing to enroll in the KPWMP, willing and able to give informed consent, and had a BMI of 30 or higher. Patients with a BMI of 27 to 29.9 were eligible for enrollment only if they had 1 or more of the following comorbidities: diabetes mellitus with or without drug therapy, hypertension treated with drug therapy, or hyperlipidemia treated with drug therapy.

Patients were excluded from the study if they had taken a prescription weight loss agent within 6 months; had a history of coronary artery disease, congestive heart failure, cardiac arrhythmia, or stroke; had uncontrolled hypertension (mean blood pressure [BP] >145/95 mm Hg, or isolated mean systolic BP [SBP] >160 mm Hg with diastolic BP [DBP] <95 mm Hg, or isolated mean DBP >95 mm Hg with SBP <145 mm Hg); a mean resting heart rate of greater than 100 beats/min (bpm); or 1 of the contraindications to sibutramine listed in the product labeling. Other exclusions included narrow—angle glaucoma, severe renal impairment (creatinine clearance, &#8804;30 mL/min [&#8804;0.50 mL/s]), severe hepatic dysfunction (liver function test results, &#8805;3 times the upper limit of normal), obesity of organic origin (eg, untreated or uncontrolled hypothyroidism), seizures, other medical conditions that placed them at increased medical risk by participating in the study (as determined by the study physician), previous participation in this study, participation in KPWMP or any of the required American Heart Association (AHA) classes within the past 6 months, and inability to read English. Patients were excluded if they were pregnant, planning a pregnancy during the study, or breast—feeding. Finally, patients were also excluded if they were taking any of the following medications: selective serotonin reuptake inhibitors, St John's wort, sumatriptan succinate or related agents, ergotamine tartrate, lithium, fentanyl citrate, pentazocine, meperidine hydrochloride, dextromethorphan, tryptophan, and cisapride.

The study was reviewed and approved by the Kaiser Foundation Research Institute Institutional Review Board. All patients provided written informed consent before study enrollment.

Design

On enrollment in the KPWMP, patients were invited to participate in the study. Patients were randomized to receive sibutramine or no drug therapy, but all patients participated in the KPWMP. The KPWMP is a physiciansupervised, multidisciplinary program. Patients paid $100 for the program consisting of 5 monitored-care visits with a prevention specialist (served as study coordinators) and 2 weight management seminars chosen from a menu of 20 seminars. Study data collection was coordinated with the monitored care visits. All study patients also participated in 20 weeks of educational programs offered by the AHA. The Point of Change disease management program (program name is now Meridia Milestones, Abbott Laboratories, Inc) was available to patients taking sibutramine.

Patients had financial commitments to participate in the study. Participants paid for the AHA classes ($140) and the KPWMP ($100). Participants who completed 6 months of the study received a $50 gift check. Those patients who completed 12 months of the study received an additional $100 gift check. Patients randomized to sibutramine paid retail price for the drug and were later reimbursed for 75% of the cost on presentation of the receipt.

Randomization to drug or nondrug treatment arms was completed using a computer—generated random numbers table. Study assignments were placed in envelopes that were opened at the end of the baseline visit by the study coordinator. Patients and investigators were aware of study group assignment.

Study visits for all patients occurred at baseline and at 3, 6, 9, and 12 months. At study visits, demographics, weight, height, body fat, BP, heart rate, and waist and hip circumference were collected. Weight was measured (and BMI calculated) using the Tanita TBF—305 (Tanita Corporation of America, Inc, Arlington Heights, Ill) bioelectrical impedance technology body fat analyzer. Percentage body fat was measured by the FUTREX—5000 (FUTREX, Inc, Gaithersburg, Md), which uses near infrared light technology. Vital signs were measured after the patient had been sitting for 5 minutes. Blood pressure and heart rate were measured twice at 2—minute intervals and averaged. Baseline laboratories included fasting glucose and fasting lipid profile. Hemoglobin A_1c levels were obtained in patients with diabetes mellitus. Laboratory evaluations were repeated at 6 and 12 months. As part of standard care, the Zung Self—Rating Depression Scale was used to screen patients for depression.¹¹

Patients randomized to receive sibutramine received a physical examination by a KPWMP physician at baseline and then received a prescription for 10 mg of sibutramine to be taken once daily. These patients had a safety visit at 4 weeks to check vital signs and weight. If 4 pounds (1.8 kg) were not lost in the first 4 weeks, the dosage was increased to 15 mg daily. The dosage was not increased if the patient lost more than 10 pounds (4.5 kg) by the 4—week visit. The dosage was decreased by 5 mg daily if significant changes in BP (BP >150/100 mm Hg, SBP >160 mm Hg with a DBP <100 mm Hg, &#8805;20 mm Hg increase from baseline in SBP, or &#8805;15 mm Hg increase from baseline in DBP) or heart rate (>100 bpm or an increase of &#8805;15 bpm from baseline) occurred or if intolerable adverse events (AEs) were experienced. The higher dosage could be resumed after 2 weeks if the AE resolved or if changes in vital signs normalized. The dosage of sibutramine could be increased to 15 mg daily at 3 or 6 months, but not after 6 months. The KPWMP physician, study coordinators, and investigators were responsible for study—related examinations, prescribing of sibutramine if applicable, and monitoring study-related variables (ie, BP and heart rate). Drug treatment and control of concomitant medical conditions continued under the patients' primary care and other providers.

At each visit, patients in both study groups were asked whether they had an AE to report. The study coordinator and investigators evaluated the severity and potential relation of the AE to sibutramine use. If the AE was emergent or serious, the institutional review board and the study sponsor were notified.

Outcomes

The primary outcome measure was change in weight. Secondary outcomes included changes in the following: (1) BMI; (2) percentage body fat; (3) serum high—density lipoprotein cholesterol, low—density lipoprotein cholesterol, and triglycerides; (4) serum glucose; and (5) BP.

Statistical Analysis

t

A sample size of 285 in each group was determined as adequate to detect a 10% difference in change in weight between groups (2—tailed test), with &#945; = .05 and a power of 75%. To accommodate dropouts, the target enrollment was 700 patients to obtain 570 evaluable subjects. Evaluable subjects were defined as subjects who retained membership with Kaiser Permanente of Colorado for the 6— and 12—month follow—ups, received at least 1 dose of sibutramine (if randomized to drug), and had a body weight recorded at least 4 weeks after randomization. To assess differences between treatment groups at baseline, tests, Mann—Whitney tests, and &#967;² tests were used.

All data were analyzed using an intention—to—treat approach. Missing data from any period were replaced by data from the last available recorded visit. Inferential analyses on continuous variables were performed using general linear model techniques in SAS ¹² with 2 groups: sibutramine plus KPWMP and KPWMP alone. Adjustments were made for age, sex, and significant baseline differences between the 2 groups. Differences between the 2 groups for categorical variables were analyzed using &#967;² tests. Pharmacy compliance with sibutramine was determined from pharmacy medication dispensing or refill records. Compliance was calculated using the amount of medication obtained, date of dispensing, and enrollment or disenrollment dates. Compliance was calculated as 1 minus the number of days without medication.

Coding Symbols for Thesaurus of Adverse Reaction Terms

Adverse events experienced during the 12—month study and within 30 days following the last study visit were recorded. Adverse events were recorded in patients who may not have been included in the intention—to—treat efficacy analyses. Events were coded and analyzed using terminology.¹³ Significance was determined by comparing groups using a &#967;² test, with a Fisher exact test for small expected cell size if applicable.

RESULTS

Enrollment

Patients (n = 1564) were invited to participate in the study; 976 patients did not participate, primarily because of lack of interest. The second most frequent reason for not participating was that patients were taking selective serotonin reuptake inhibitor medication (an exclusion criteria). Randomization occurred at baseline for the entire study sample (ie, evaluable and nonevaluable patients). Five hundred eighty—eight patients were enrolled and randomized (296 in the drug group and 292 in the nondrug group). Further information about patients not included in the analysis is available from the authors.

P

P

P

Demographics, clinical characteristics, and comorbidities of evaluable patients at baseline are given in Table 1. There was a significant difference in age between the 2 evaluable groups at baseline. Weight, BMI, and waist circumference were significantly higher in the drug group. These differences did not exist when all randomized (evaluable and nonevaluable) patients were included, attesting to the effectiveness of our randomization procedure. The incidence of degenerative joint disease was significantly higher in the nondrug group. The mean (SD) weight in the drug group was 108.2 (22.7) kg (range, 69.5—188.2 kg) compared with 103.5 (18.5) kg (range, 68.2—172.3 kg) in the nondrug group ( = .05). The mean (SD) BMI in the drug group was 38.6 (7.0) (range, 30.0—68.6) compared with 36.8 (5.6) (range, 27.9—56.8) in the nondrug group ( = .01). The mean (SD) waist circumference in the drug group was 109.7 (17.3) cm (range, 71.1—167.6 cm) compared with 106.4 (14.0) cm (range, 73.7—154.9 cm) in the nondrug group ( = .03). There were larger percentages of patients in the BMI categories of 35 to 39.9 and 40 or higher enrolled in the drug group (Table 2).

Although patients identified with known depression through selective serotonin reuptake inhibitor prescriptions were excluded from study participation, large numbers of patients were mildly to moderately depressed on study entry. Notably, 39.4% and 37.0% of patients in the nondrug and drug groups, respectively, had significant symptoms of depression (Self—Rating Depression Scale score, &#8805;50). Mean Self—Rating Depression Scale scores between the 2 study groups were not different.

Efficacy

P

The mean weight loss from baseline to 6 months was significantly greater in the drug group (6.8 kg [95% confidence interval {CI}, &#8722;7.4 to &#8722;6.1 kg] vs 3.1 kg [95% CI, &#8722;3.8 to &#8722;2.4 kg] for the nondrug group; <.001). Significantly greater decreases in percentage weight loss, BMI, percentage body fat, and waist circumference were seen in the drug group compared with the nondrug group at 6 months (Table 3). The percentage change in weight in the drug group was greater than in the nondrug group for all BMI categories. For the BMI category of less than 35, the mean (SD) percentage change in weight for the drug group was &#8722;6.7% (6.8%) vs &#8722;1.5% (4.4%) for the nondrug group (BMI of 35—39.9, &#8722;6.2% [6.4%] for the drug group vs &#8722;2.3% [4.8%] for the nondrug group; and BMI of &#8805;40, &#8722;5.2% [6.7%] for the drug group vs &#8722;3.1% [7.6%] for the nondrug group).

P

P

P

P

Most weight loss occurred during the first 6 months of study participation for both groups. The mean change in weight from 6 to 12 months was 0.50 kg (95% CI, &#8722;0.01 to 0.90 kg) (range, &#8722;23.60 to 13.20 kg) for the drug group vs 0.6 kg (95% CI, 0.1—1.1 kg) (range, &#8722;20.5 to 17.3 kg) for the nondrug group ( = .51). The net effect on weight from baseline to 12 months was a mean weight loss of 6.2 kg (95% CI, &#8722;7.1 to &#8722;5.4 kg) (range, &#8722;38.6 to 8.9 kg) for the drug group vs 2.3 kg (95% CI, &#8722;3.1 to &#8722;1.5 kg) (range, &#8722;35.9 to 9.1 kg) for the nondrug group ( < .001). Body mass index and percentage body fat did not significantly change between 6 and 12 months (mean change in BMI, 0.20 [95% CI, &#8722;0.01 to 0.30] for the drug group and 0.20 [95% CI, &#8722;0.03 to 0.40] for the nondrug group; = .73; and mean change in percentage body fat, &#8722;0.1% [95% CI, &#8722;0.5% to 0.3%] for the drug group and 0.2% [95% CI, &#8722;0.4% to 0.7%] for the nondrug group; = .46).

P

Significantly more patients in the drug group experienced a 5% or greater weight loss at 12 months (47.3% vs 19.1%, <.001; Figure). Patients who completed 6 months of the study showed similar results to the intention—to—treat analyses (ie, significantly greater decreases in weight, BMI, percentage body fat, and waist circumference for patients in the drug group).

P

P

P

P

P

There were no significant changes at 6 months in either group for total cholesterol, triglycerides, high—density lipoprotein cholesterol, low—density lipoprotein (LDL) cholesterol, glucose, or hemoglobin A_1c among patients with diabetes mellitus. The mean increase in total cholesterol was 0.4 mg/dL (0.01 mmol/L) (95% CI, &#8722; 2.5 to 3.3 mg/dL [&#8722;0.07 to 0.09 mmol/L]) in the drug group vs 1.8 mg/dL (0.05 mmol/L) (95% CI, &#8722;1.4 to 5.0 mg/dL [&#8722;0.04 to 0.13 mmol/L]) in the nondrug group ( = .38). The mean decrease in triglycerides was 13.1 mg/dL (0.15 mmol/L) (95% CI, &#8722;21.6 to &#8722;4.6 mg/dL [&#8722; 0.24 to &#8722;0.05 mmol/L]) in the drug group compared with 7.8 mg/dL (0.09 mmol/L) (95% CI, &#8722;16.3 to 0.7 mg/dL [&#8722;0.18 to 0.008 mmol/L]) in the nondrug group ( = .35). The mean increase in high—density lipoprotein cholesterol was 0.5 mg/dL (0.01 mmol/L) (95% CI, &#8722;0.4 to 1.3 mg/dL [&#8722;0.01 to 0.03 mmol/L]) in the drug group vs 0.4 mg/dL (0.01 mmol/L) (95% CI, &#8722;0.9 to 1.6 mg/dL [&#8722;0.02 to 0.04 mmol/L]) in the nondrug group ( = .87). The mean increase in LDL cholesterol was 0.9 mg/dL (0.02 mmol/L) (95% CI, &#8722;1.7 to 3.5 mg/dL [&#8722;0.04 to 0.09 mmol/L]) in the drug group vs 2.6 mg/dL (0.07 mmol/L) (95% CI, &#8722;0.2 to 5.4 mg/dL [&#8722;0.005 to 0.14 mmol/L]) in the nondrug group ( = .39). The mean decrease in glucose was 0.7 mg/dL (0.04 mmol/L) (95% CI, &#8722;3.7 to 2.2 mg/dL [&#8722;0.21 to 0.12 mmol/L]) in the drug group vs 2.5 mg/dL (0.1 mmol/L) (95% CI, &#8722;5.3 to 0.3 mg/dL [&#8722;0.3 to 0.02 mmol/L]) in the nondrug group ( = .30). No significant changes in blood chemistries were seen at 12 months.

P

P

P

P

No significant changes occurred in BP from baseline to 6 months in either group (SBP mean change, &#8722;1.4 mm Hg [95% CI, &#8722;2.7 to &#8722;0.1 mm Hg] for the drug group and &#8722;2.1 mm Hg [95% CI, &#8722;3.5 to &#8722;0.7 mm Hg] for the nondrug group; = .63; and DBP mean change, &#8722;0.9 mm Hg [95% CI, &#8722;1.9 to 0.2 mm Hg] for the drug group and &#8722;1.7 mm Hg [95% CI, &#8722;2.9 to &#8722;0.5 mm Hg] for the nondrug group; = .35). No significant changes were observed at 12 months. Patients in the drug group experienced a significant increase in heart rate from baseline to 6 months (1.7 bpm [95% CI, 0.5—2.9 bpm] for the drug group vs &#8722;0.4 bpm [95% CI, &#8722;1.5 to 0.8 bpm] for the nondrug group; = .004). This significant increase in heart rate continued at 12 months (1.1 bpm [95% CI, &#8722;0.1 to 2.4 bpm] for the drug group vs &#8722;1.1 bpm [95% CI, &#8722;2.2 to 0.1 bpm] for the nondrug group; = .01). Compliance for patients taking sibutramine averaged 76%. During the study, the percentage of patients in the drug group who had documented degenerative joint disease increased to a percentage similar to that seen at baseline in the nondrug group, resulting in no significant difference in the incidence of degenerative joint disease or any other comorbidity between the 2 groups at 12 months.

Safety

Adverse events (n = 552) were reported in 230 patients initially randomized to receive sibutramine. Adverse events were similar to those reported in sibutramine package labeling, including dry mouth, tachycardia, constipation, hypertension, insomnia, and headache.¹⁴ Table 4 gives the AEs that were significantly greater for patients receiving sibutramine therapy. Thirty—seven patients (12.5%) receiving sibutramine had treatment discontinued as a result of 43 reported AEs (6 [2.0%] with constipation, 6 [2.0%] with hypertension, 4 [1.4%] with tachycardia, 3 [1.0%] with headache, 3 [1.0%] with chest pain, 2 [0.7%] with insomnia, 2 [0.7%] with dizziness, 2 [0.7%] with hemorrhoidal or rectal events, 2 [0.7%] with rash, and 13 [4.4%] with miscellaneous events). Sibutramine dosage was reduced most commonly as a result of hypertension (n = 20), tachycardia (n = 16), appetite increase (n = 11), and headache (n = 6).

Thirty—three serious AEs were reported in 30 patients in the drug group, and 21 serious AEs were reported in 18 patients in the nondrug group. Five patients (1.7%) experienced serious AEs indicated as possibly or probably related to sibutramine. One patient received a cholecystectomy for cholelithiasis. Another patient was evaluated for chest pain that was determined to be noncardiac. One patient in the drug group was admitted to an inpatient psychiatric facility for suicidal depression. Two patients were evaluated in the emergency department, 1 for hypertension and 1 for hemorrhoidal pain.

DISCUSSION

Obesity is a devastating medical condition.⁴ The clinical and economic burden of obesity has been estimated in the managed care environment. In a cost—of—illness model, healthcare costs due to obesity were estimated to be almost $350 million annually.¹⁵ A 5% to 10% weight loss can decrease the associated medical risks.¹⁶ Our study in this managed care environment demonstrated that patients enrolled in a weight management program who took sibutramine lost significantly more weight than participants in the same program who did not receive medication (6.8 vs 3.1 kg). The results in the drug group are similar to those obtained from previous studies ^6,7,17 with sibutramine, despite our unique managed care study environment. We believe this study setting is more comparable to a usual care environment compared with traditional clinical trial settings. The amount of weight loss observed in patients who were in the weight management program testifies to the effectiveness of the program, with increased benefit with the addition of drug therapy.

The methods and results from this trial are consistent with recent evidence—based recommendations from the USPSTF.¹⁰ These recommendations state that there is fair to good evidence that patients involved in intense (>1 person—to—person session per month for at least the first 3 months) counseling and behavioral interventions can achieve modest, sustained weight loss (3—5 kg for &#8805;1 year). In our trial, which included the KPWMP seminars, monitored care visits, and AHA classes, the USPSTF definition of high intensity was met. Weight loss was similar to that suggested by the USPSTF. These recommendations also state that pharmacologic treatment for obesity should be used as part of a program that includes lifestyle modification. This is an important consideration for managed care organizations considering the use of drug therapy for obesity or the development of a weight management program.

Similar to randomized, double—blind, placebo—controlled trials with sibutramine, most weight loss occurred during the first 6 months of therapy.^6,17,18 The role of the medication after 6 months was to maintain the weight previously lost and to prevent weight gain. There was a small amount of weight regain observed in both groups from 6 to 12 months. The minimal weight regain in the nondrug group again attests to the efficacy of the weight management program. The mean percentage weight loss in patients taking sibutramine exceeds the amount of weight loss thought to produce clinical improvements in obesity—related conditions.¹⁶ Almost 3 times as many patients who received sibutramine lost 5% or more of their body weight compared with patients who did not receive drug therapy. Whether this weight loss can be maintained with continuation or after discontinuation of the drug is not known. One trial demonstrated that patients who initially lost greater than 5% of their body weight after 6 months of sibutramine were able to maintain that weight loss for an additional 18 months with continued therapy.⁷

Obesity—related comorbidities were not reduced in this 1—year study. There were no significant changes in lipid variables or fasting glucose levels, despite weight loss. Most trials with sibutramine have not demonstrated clinically significant decreases in total or LDL cholesterol.^6,7,9 The number of patients with diabetes mellitus in our study population was too small to evaluate effect on diabetes mellitus control. Approximately 35% of patients in our study had hypertension. Small decreases in SBP and DBP were observed, but these were not significantly different between groups. The study sample size was determined on the basis of the primary outcome; therefore, our study could have lacked the power to detect changes in comorbid conditions or laboratory variables. In addition, ongoing treatment for concomitant medical conditions outside the study was not controlled for and could have precluded us from finding significant changes.

Adverse events with sibutramine were similar to those reported in the package labeling, but the incidence of several of these events in this study was higher.¹⁴ This could be because this study was not blinded and patients were asked at each visit to report any new symptoms. A significant increase in heart rate was noted in patients taking sibutramine, but this was less than the increase reported in other sibutramine trials.^7—9,19 The increase in heart rate is consistent with the sympathomimetic properties of sibutramine. Blood pressure decreases related to weight loss might not have been observed because of sibutramine's potential to raise BP. The incidence of patients discontinuing sibutramine because of increases in BP or heart rate was low.

Our study had several limitations. Most patients were white and female. Because of the clinical environment in which the study was conducted, the study was not blinded or placebo—controlled. Like other trials in obese populations, our study dropout rate was high. We anticipated that the dropout rate would be higher in the nondrug group because the study was not blinded. Many patients in the nondrug group left the study soon after randomization to pursue medication for obesity. This resulted in a greater number of nonevaluable patients in the nondrug group for the intention—to—treat efficacy analyses. The patients who enrolled in the trial were motivated to lose weight, as many had decided to join the weight management program before they were aware of the potential for study participation. Drug treatment and control of concomitant medical conditions were at the discretion of the patients' primary care providers (not the study physician). All patients participated in the KPWMP, but patients who were randomized to receive sibutramine were also given information regarding the manufacturer's patient education program. Patients' participation in this program, or any other educational opportunity provided in the study, was not monitored. It is unknown whether differences in participation in weight management—related education affected the observed effectiveness of the drug.

Several aspects of our study, however, strengthen the external validity and generalizability of the study results. The study was conducted in the clinical environment of a group—model health maintenance organization. Lifestyle modification was encouraged during KPWMP visits and AHA courses. Participants had financial responsibilities on study enrollment for program costs (and medication costs, if randomized to receive sibutramine). Clinical judgment rather than strict protocol guided dosing of sibutramine.

Our study demonstrated that the addition of sibutramine to a weight management program in a managed care environment was effective in achieving significantly greater weight loss and greater decreases in BMI, percentage weight loss, and waist circumference than a weight management program alone. Whether the addition of sibutramine to such a program helps to decrease obesity—related comorbidities and costs has not been determined and should be addressed. Areas for future study therefore include the effect of sibutramine on obesity—related comorbidities, the efficacy of sibutramine therapy beyond 2 years as part of a long—term strategy for managing weight, and the cost effectiveness of sibutramine for treatment of obesity.

Acknowledgments

The investigators worked closely with Knoll Pharmaceutical Company in protocol development and study initiation. Epi—Q (Oakbrook Terrace, Ill) performed the adverse event analyses. Abbott Laboratories participated in manuscript review but did not have the right to disapprove publication of this article. Dr Merenich has served on the speaker's bureau for Knoll Pharmaceutical Company.

The investigators thank the following individuals for their hard work and contributions to this study: Sally Butler, MSW; Anne Drobny, BS; Anita Huttenhower, PharmD; Maura Kopulos, BA; Deanna Kurz, BA; Lynn Liebert, BA; Daniel Malone, PhD; Deanna Mrkvicka, AA; Matthew Nguyen, PharmD; Elizabeth Nugent, MSPH; Marilyn Pearson, BS; Jared Rowe, PharmD; Alicia Shillington, BSN, MPH; Michele Singer, BS; G. Rhys Williams, ScD; and Kristi Yamasaki, PharmD.

From Aventis Pharmaceuticals, Inc, Bridgewater, NJ (JAP); and School of Pharmacy (JAP, MAR, FAL, EAV) and School of Medicine (JAM), University of Colorado, and Departments of Research and Development (MAR, DAC), Pharmacy (FAL, EAV), Prevention (ECG), and Endocrinology (JAM), Kaiser Permanente of Colorado, Denver. At the time of this work, Dr Porter was a clinical pharmacy specialist with Kaiser Permanente of Colorado.

Funding for this study was obtained from Knoll Pharmaceutical Company, now Abbott Laboratories (Abbott Park, Ill). Additional details on support provided is given in the acknowledgements at the end of the article.

Address correspondence to: Julie A. Porter, PharmD, Aventis Pharmaceuticals, Inc, 300 Somerset Corporate Boulevard, Mail Stop SC3-730A, Bridgewater, NJ 08807. E-mail: julie.porter@aventis.com.

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