Changes in Symptoms of Depression With Weight Loss: Results of a Randomized Trial

Recent studies of rimonabant have re‐awakened interest in the possible adverse psychiatric effects of weight loss, as well as of weight loss medications. This study examined changes in symptoms of depression in 194 obese participants (age = 43.7 ± 10.2 years; BMI = 37.6 ± 4.1 kg/m²) in a 1‐year randomized trial of lifestyle modification and medication. Participants were assigned to (i) sibutramine alone; (ii) lifestyle modification alone; (iii) sibutramine plus lifestyle modification (i.e., combined therapy); or (iv) sibutramine plus brief therapy. Participants completed the Beck Depression Inventory‐II (BDI‐II) at baseline and weeks 6, 10, 18, 26, 40, and 52. At 1 year, participants in combined therapy lost the most weight and those in sibutramine alone the least (12.1 ± 8.8% vs. 5.5 ± 6.5%; P < 0.01). Mean BDI‐II scores across all participants declined from 8.1 ± 6.9 to 6.2 ± 7.7 at 1 year (P < 0.001), with no significant differences among groups. Despite this favorable change, 13.9% of participants (across the four groups) reported potentially discernible increases (≥ 5 points on the BDI‐II) in symptoms of depression at week 52. They lost significantly less weight than participants in the rest of the sample (5.4 ± 7.8% vs. 9.0 ± 7.8%, respectively; P < 0.03). The baseline prevalence of suicidal ideation was 3.6%. Seven new cases of suicidal ideation were observed during the year, with three in lifestyle modification alone. Further research is needed to identify characteristics of obese patients at risk of negative mood changes (and suicidal ideation) in response to behavioral and pharmacologic therapies.     

Sibutramine plus meal replacement therapy for body weight loss and maintenance in obese patients

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 ≥5% 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 ≥80% 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 ≥80% 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.     

NPY5R antagonism does not augment the weight loss efficacy of orlistat or sibutramine

Objective: Central counter‐regulatory mechanisms, including those related to the orexigenic hormone neuropeptide Y (NPY), may limit the weight loss observed with conventional pharmacological monotherapy. This study evaluated whether blockade of the NPY Y5 receptor (NPY5R) with the selective antagonist MK‐0557 potentiates sibutramine and orlistat weight loss effects. Research Methods and Procedures: Obese patients (497, BMI 30 to 43 kg/m²) were randomized to 1 of 5 treatment arms [placebo, n = 101; sibutramine 10 mg/d, n = 100; MK‐0557 1 mg/d plus sibutramine 10 mg/d, n = 98; orlistat 120 mg TID, n = 99; MK‐0557 1 mg/d plus orlistat 120 mg TID, n = 99] in conjunction with a hypocaloric diet for 24 weeks. The all‐patients‐treated population, imputing missing data using last observation carried forward, was used to assess weight loss from baseline. Results: The study was completed by 71% of patients in placebo, 76% in sibutramine alone, 79% in MK‐0557 + sibutramine, 69% in orlistat alone, and 76% in MK‐0557 + orlistat groups. Least squares (LS) mean difference [95% confidence interval (CI)] in weight change from baseline between MK‐0557 + sibutramine and sibutramine alone was ?0.1 (?1.6, 1.4) kg (p = 0.892) and between MK‐0557 + orlistat and orlistat alone was ?0.9 (?2.4, 0.6) kg (p = 0.250). Sibutramine alone induced a LS mean weight loss of ?5.9 (?6.9, ?4.9) kg vs. ?4.6 (?5.7, ?3.6) kg for orlistat (p = 0.097). There were no serious drug‐related adverse events and MK‐0557 was well tolerated. Discussion: Blockade of the NPY5R with the potent antagonist MK‐0557 did not significantly increase the weight loss efficacy of either orlistat or sibutramine monotherapy.     

Enhanced Weight Loss Following Coadministration of Pramlintide With Sibutramine or Phentermine in a Multicenter Trial

Preclinical evidence suggests that pharmacotherapy for obesity using combinations of agents targeted at distinct regulatory pathways may produce robust additive or synergistic effects on weight loss. This randomized placebo‐controlled trial examined the safety and efficacy of the amylin analogue pramlintide alone or in combination with either phentermine or sibutramine. All patients also received lifestyle intervention. Following a 1‐week placebo lead‐in, 244 obese or overweight, nondiabetic subjects (88% female; 41 ± 11 years; BMI 37.7 ± 5.4 kg/m²; weight 103 ± 19 kg; mean ± s.d.) received placebo subcutaneously (sc) t.i.d., pramlintide sc (120 µg t.i.d.), pramlintide sc (120 µg t.i.d.) + oral sibutramine (10 mg q.a.m.), or pramlintide sc (120 µg t.i.d.) + oral phentermine (37.5 mg q.a.m.) for 24 weeks. Treatment was single‐blind for subjects receiving subcutaneous medication only and open‐label for subjects in the combination arms. Weight loss achieved at week 24 with either combination treatment was greater than with pramlintide alone or placebo (P < 0.001; 11.1 ± 1.1% with pramlintide + sibutramine, 11.3 ± 0.9% with pramlintide + phentermine, ?3.7 ± 0.7% with pramlintide; ?2.2 ± 0.7% with placebo; mean ± s.e.). Elevations from baseline in heart rate and diastolic blood pressure were demonstrated with both pramlintide + sibutramine (3.1 ± 1.2 beats/min, P < 0.05; 2.7 ± 0.9 mm Hg, P < 0.01) and pramlintide + phentermine (4.5 ± 1.3 beats/min, P < 0.01; 3.5 ± 1.2 mm Hg, P < 0.001) using 24‐h ambulatory monitoring. However, the majority of subjects receiving these treatments remained within normal blood pressure ranges. These results support the potential of pramlintide‐containing combination treatments for obesity.     

Sibutramine Treatment in Obesity: Predictors of Weight Loss Including Rorschach Personality Data

Objective: To study personality and clinical factors in weight loss by sibutramine (Meridia and Reductil), an anti‐obesity drug enhancing satiety. Research Methods and Procedures: The subjects were 30 obese patients [43 ± 12 years (mean ± SD), BMI 40 ± 4 kg/m²]. The treatment comprised 15 mg of sibutramine administered daily and monthly dietary advice. Weight loss after 6 months of treatment was evaluated. For psychological assessment, the Rorschach method (Comprehensive System) and the Beck Depression Inventory were used. Results: A multiple linear regression model including the Rorschach predictors’ physical demand states (animal movement, designated as FM) being intrusive or difficult to hold and a dependency orientation (food contents) could explain 47% of 6 months of weight loss. A model including initial weight loss in addition to the Rorschach predictors explained 58% of the 6‐month weight loss. Discussion: The personality factors predicted greater weight loss. In particular, patients with difficulties concerning physical demand states, which would include hunger, could have reduced their eating behavior with enhanced satiety, resulting in greater weight loss. Enhanced satiety could also have helped patients with a dependent need for food to limit food intake. Being enrolled in a treatment program could also have provided essential support for patients with dependency needs. Furthermore, initial weight loss was a predictor of greater weight loss in sibutramine treatment, in accordance with prior research.     

A Comparison of Sibutramine and Dexfenfluramine in the Treatment of Obesity

Objective : Because long-term weight reduction is often unsuccessful with dietary restriction alone, pharmacological agents have been used to promote weight loss. We have compared the novel (multiple monoamine neurotransmitter reuptake inhibitor) antiobesity drug sibutramine (10 mg once daily) with the extensively studied serotonin-releasing antiobesity agent dexfenfluramine (15 mg twice daily). Research Methods and Procedures : 226 healthy outpatients (aged 18 to 65 years; body mass index ≥27 kg/m²) were included in a 12-week, randomized, double-blind, parallel group study. The main outcome measures were changes in weight, body mass index, waist and hip circumference and ratio, and safety profiles. Results : Mean (±SEM) absolute weight loss was 4.5 ± 0.4 kg in the sibutramine group (n = 112) and 3.2 ± 0.3 kg in the dexfenfluramine group (n=112) (endpoint analysis); 4.7 ± 0.4 kg in the sibutramine group (n=101); and 3.6 ± 0.3 kg in the dexfenfluramine group (n = 94) (completers analysis). Comparing the two treatments under the conventional null hypothesis of equality as a secondary analysis, weight loss at endpoint in patients receiving sibutramine was significantly greater than that achieved with dexfenfluramine (p<0.05). Both drugs had similar adverse events profiles: 174 patients (77%) experienced adverse events; 17 patients withdrew due to adverse events (sibutramine, n = 6; dexfenfluramine, n = 11). Pulse rate increased significantly in sibutramine-treated patients (3.6 bpm), but decreased in dexfenfluramine-treated patients (-0.9 bpm). Discussion : Sibutramine (10 mg once daily) is at least as effective as dexfenfluramine (15 mg twice daily) in achieving weight loss in patients with obesity.     

Influence of Sibutramine on Energy Expenditure in African American Women

Objective: African American women have a high prevalence of obesity, which partially may be explained by their lower rates of resting energy expenditure (REE). The aim of this study was to examine the influence of acute sibutramine administration on REE and post‐exercise energy expenditure in African American women. Research Methods and Procedures: A total of 15 premenopausal, African American women (age, 29 ± 5 years; body fat, 38 ± 7%) completed a randomized, double‐blind cross‐over design with a 30‐mg ingestion of sibutramine or a placebo. Each trial was completed a month apart in the follicular phase and included a 30‐minute measurement of REE 2.5 hours after sibutramine or placebo administration. This was followed by 40 minutes of cycling at ～70% of peak aerobic capacity and a subsequent 2‐hour measurement of post‐cycling energy expenditure. Results: There was no difference (p > 0.05) in REE (23.70 ± 2.81 vs. 23.69 ± 2.95 kcal/30 min), exercise oxygen consumption (1.22 ± 0.15 vs. 1.25 ± 0.15 liter/min), and post‐cycling energy expenditure (104.2 ± 12.7 vs. 104.9 ± 11.4 kcal/120 min) between the sibutramine and placebo trials, respectively. Cycling heart rate was significantly higher (p = 0.01) during the sibutramine (158 ± 14 beats/min) vs. placebo (150 ± 12 beats/min) trials. Discussion: These data demonstrate that acute sibutramine ingestion does not increase REE or post‐exercise energy expenditures but does increase exercising heart rate in overweight African American women. Sibutramine may, therefore, impact weight loss through energy intake and not energy expenditure mechanisms.     

Absence of Cardiac Valve Dysfunction in Obese Patients Treated with Sibutramine

BACH, DAVID S., AILA M. RISSANEN, CARL M. MENDEL, GILLIAN SHEPHERD, STEVEN R. WEINSTEIN, FINIAN KELLY, TIMOTHY B. SEATON, BABABHAI PATEL, TUULA A. PEKKARINEN, AND WILLIAM F. ARMSTRONG. Absence of cardiac valve dysfunction in obese patients treated with sibutramine. Obes Res. Objective: Serotonin-releasing agents prescribed as weight-loss medications have been implicated as a cause of acquired aortic and mitral valve abnormalities. Sibutramine hydrochloride (MERIDIA®) is a serotonin and norepi-nephrine reuptake inhibitor with proven efficacy of weight reduction. The purpose of this study was to determine the incidence of cardiac valve disease in sibutramine-treated patients. Research Methods and Procedures: Obese patients with type 2 diabetes mellitus enrolled in an ongoing double-blind, placebo-controlled, parallel-arm, 12-month study of sibutramine (followed by a 12-month open label extension) underwent transthoracic echocardiographic imaging and color Doppler interrogation for assessment of cardiac valve anatomy and function. Results: A total of 210 patients were evaluated. Of these, 133 were receiving sibutramine (72 in the double-blind period), and 77 were receiving placebo. The mean ± Standard Deviation age was 54±9 years, and the mean duration of treatment was 229±117 days (approximately 7. 6 months). The prevalence of left-sided cardiac valve dysfunction was low and similar for the two treatment groups (sibutramine 31133, or 2. 3%; placebo 2/77, or 2. 6%). All five cases were cases of aortic insufficiency; four were mild, one was severe (in a placebo patient). All three sibutramine cases were patients over age 50; two had a history of systemic hypertension. Conclusion: The prevalence of left-sided cardiac valve dysfunction was not higher than background in obese patients treated with sibutramine for an average of 7. 6 months.     

Sibutramine Produces Dose-Related Weight Loss

BRAY, GEORGE A., GEORGE L. BLACKBURN, JAMES M. FERGUSON, FRANK L. GREENWAY, ADESH K. JAIN, CARL M. MENDEL, JOSEPH MEN-DELS, DONNA H. RYAN, SHERWYN L. SCHWARTZ, MONTE L. SCHEINBAUM, AND TIMOTHY B. SEATON. Sibutramine produces dose-related weight loss. Obes Res. Objective Sibutramine is a weight control drug that inhibits the reuptake of both serotonin and norepinephrine. In animals, it reduces food intake and increases thermogenesis and preliminary data in human beings showed weight loss. This paper reports a 24-week dose-ranging study to determine the effect of sibutramine on body weight of patients with obesity. Research Methods and Procedures Seven clinical centers screened 1463 patients with obesity and randomized 1047 to 24 weeks of treatment with 1 of 6 doses of sibutramine (1, 5, 10, 15, 20, or 30 mg) or placebo once daily. Six hundred eighty-three patients completed the study. A two-week placebo run-in period was used to initiate a standardized program of diet, physical activity, and lifestyle changes. Results Weight loss was dose-related and statistically significant vs. placebo (p <0.05) across all time-points for a 5 mglday to 30 mglday dosage of sibutramine. At week 24, percent weight loss from baseline for completers was: placebo, 1.2%; 1 mg, 2.7%; 5 mg, 3.9%; 10 mg, 6.1%; 15 mg, 7.4%; 20 mg, 8.8%; and 30 mg, 9.4%. Weight loss achieved at week 4 was predictive of weight loss achieved at week 24. Patients losing weight demonstrated an increase in serum high density lipoprotein cholesterol and reductions in serum triglycerides, total cholesterol, low density lipoprotein cholesterol, and uric acid. Small mean increases in blood pressure and pulse rate (with considerable individual variability) were observed in patients treated with sibutramine. The most frequent adverse events were dry mouth, anorexia, and insomnia. Discussion Sibutramine administered once daily for 24 weeks in the weight loss phase of treatment for uncomplicated obesity produced dose-related weight loss and was well tolerated. Improvements in serum lipids and uric acid accompany sibutramine-induced weight loss. Most of the adverse events observed on sibutramine are related to its pharmacology, including small mean increases in blood pressure and heart rate.     

Effects of Sibutramine on Binge Eating,Hunger, and Fullness in a Laboratory Human Feeding Paradigm

Objective : The purpose of this study was to evaluate the effects of sibutramine vs. placebo on binge‐eating behavior, hunger, and satiety in patients who had problems with binge eating. Research Methods and Procedures : Seven adult subjects who had problems with binge eating (mean age, 42 years) were randomly assigned to receive alternating sibutramine and placebo in a double‐blind placebo‐controlled crossover study. This involved two 4‐week dosing periods separated by a 2‐week washout. Results : Subjects lost weight on sibutramine but not on placebo. There was a significant difference in the number of kilocalories consumed between the sibutramine and placebo conditions, with a significant reduction of intake during binge‐eating episodes on sibutramine. Discussion : Sibutramine suppresses intake during binge‐eating episodes. This effect is demonstrable in a human feeding laboratory paradigm.     

Two-year internet-based randomized controlled trial for weight loss in African-American girls

Objective: A randomized controlled trial tested the efficacy of an internet‐based lifestyle behavior modification program for African‐American girls over a 2‐year period of intervention. Research Methods and Procedures: Fifty‐seven overweight (mean BMI percentile, 98.3) African‐American girls (mean age, 13.2 years) were randomly assigned to an interactive behavioral internet program or an internet health education program, the control condition. Overweight parents were also participants in the study. Forty adolescent‐parent dyads (70%) completed the 2‐year trial. Outcome data including BMI, body weight, body composition, and weight loss behaviors were collected at baseline and at 6‐month intervals. A computer server tracked use of the web sites. Results: An intention‐to‐treat statistical approach was used, with the last observation carried forward. In comparison with the control condition, adolescents in the behavioral program lost more mean body fat (BF) (?1.12 ± 0.47% vs. 0.43 ± 0.47% BF, p < 0.05), and parents in the behavioral program lost significantly more mean body weight (?2.43 ± 0.66 vs. ?0.35 ± 0.64 kg, p < 0.05) during the first 6 months. This weight loss was regained over the next 18 months. After 2 years, differences in fat for adolescents (?0.08 ± 0.71% vs. 0.84 ± 0.72% BF) and weight for parents (?1.1 ± 0.91 vs. ?0.60 ± 0.89 kg) did not differ between the behavioral and control programs. Discussion: An internet‐based weight management program for African‐American adolescent girls and their parents resulted in weight loss during the first 6 months but did not yield long‐term loss due to reduced use of the web site over time.     

Use of lifestyle changes treatment plans and drug therapy in controlling cardiovascular and metabolic risk factors

Intervention in weight management should begin before the onset of the metabolic syndrome. Therapeutic lifestyle changes (e.g., diet and physical activity) comprise the cornerstone of care for overweight and obese patients. Behavior modification approaches are useful in facilitating adherence to specific dietary regimens. Pharmacotherapy is an option for patients with a BMI >30 kg/m(2) or for those with a BMI of 27 to 30 kg/m(2) and two or more risk factors, who have failed on diet and exercise alone. To date, the U.S. Food and Drug Administration has approved three weight loss agents: sibutramine, orlistat, and phentermine.     

Effect of Sibutramine on Weight Loss and Blood Pressure: A Meta‐analysis of Controlled Trials

Objective: Sibutramine causes weight loss by suppressing the appetite and by promoting energy expenditure, but it can also increase blood pressure through a norepinephrine effect. The aim of this study was to provide a comprehensive meta‐analysis of randomized, controlled trials on the effects of sibutramine on blood pressure and weight loss. Research Methods and Procedures: Twenty‐one placebo‐controlled, double‐blind, randomized trials of sibutramine were identified using MEDLINE, EMBASE, and a manual search. The effect sizes of sibutramine on weight and systolic (SBP) and diastolic (DBP) blood pressure changes were estimated. Subgroup analyses were undertaken to explore the relationship between effect sizes and the study characteristics. Results: The effect size of sibutramine on weight change was ?1.00 (?1.17 to ?0.84), whereas the effect sizes on SBP and DBP changes were 0.16 (0.08 to 0.24) and 0.26 (0.18 to 0.33), respectively. By subgroup analysis, the effect sizes on weight loss were significantly larger when the dosage was ≥15 mg. The effect sizes on increased SBP were significantly larger when the initial body weight was ≥92 kg and the age was <44 years; similarly, the effect sizes on increased DBP were significantly larger when the initial weight was ≥92 kg. Discussion: Sibutramine showed a large effect on weight loss. Because blood pressure was found to be increased slightly, but significantly, sibutramine should be used cautiously in patients with borderline or high blood pressure. Additional studies on its effect on blood pressure are needed.     

Lifestyle Modification in the Pharmacologic Treatment of Obesity: A Pilot Investigation of a Potential Primary Care Approach

This study examined a new method of providing brief, individual lifestyle modification to obese individuals treated by pharmacotherapy. Twenty-six women with a mean (±SD) age of 47.0 ± 7.2 years, weight of 97.6 ± 13.0 kg, and body mass index of 36.5 ± 5.0 kg/m² were prescribed 60 mg/d of fenfluramine and 15 mg/d of phentermine for one year. In addition, half of the women were randomly assigned to traditional group behavior modification, conducted by a nutritionist, which included 32 75-minute sessions during the year. The other half were provided lifestyle modification by a physician during 10 15–20 minute structured visits. All participants received identical treatment manuals and comparable assignments for behavior change. At the end of one year, patients in the physician group achieved the same highly successful weight losses as those treated by group behavior modification (13.9 ± 9.6 kg vs. 15.4 ± 7.9 kg, respectively). Treatment was associated with highly significant improvements in lipids and lipoproteins, as well as in mood and several measures of appetite. Weight loss the first four weeks, as well as patient completion of daily food records during the first 18 weeks, correlated positively with weight loss at weeks 18, 26, and 52. Results of this study await replication using larger samples but strongly suggest that effective lifestyle modification can be provided during brief, structured physician visits. The findings are discussed in terms of their implications for the treatment of obesity in primary care practice.     

Long-Term,Sustained, Lifestyle-Induced Weight Loss in Severe Obesity: the Get-Real Program

Objective: To study the long-term effectiveness of a patient-centered, multidisciplinary lifestyle intervention treatment in patients medically eligible for bariatric surgery.Methods: Using a case-control study design, we compared treatment results for 98 adults (mean body mass index [BMI], 44.2 kg/m²) with the outcomes of 148 controls (mean BMI, 43.0 kg/m²) receiving standard care. The approach included a phased triage for inclusion, followed by 12 lifestyle intervention group sessions alternating with individual visits for behavior, diet, and exercise instructions.Results: At 2 years, weight loss averaged 15.3 ± 1.4 kg (P<.0010) (12 ± 1% of initial body weight [IBW], P<.001; 21 ± 2% of excess body weight [EBW], P<.001) in an intention-to-treat (ITT) analysis; in completers, weight loss was 18.8 ± 1.5 kg (P<.001) (15 ± 1% IBW, P<.001; 26 ± 3% EBW, P<.001). A total of 42 patients lost ≥10% IBW. Controls remained weight stable (P =.35); 3% lost ≥10% IBW. Patients achieving weight loss that would be considered satisfactory for bariatric surgery included 20% who achieved ≥35% EBW loss, 29% who achieved a BMI <35 kg/m² (if starting BMI <50 kg/m²) or BMI <40 kg/m² (if starting BMI ≥50 kg/m²), and 37% who achieved EBW loss ≤50%. These values for completers were 31, 39, and 48%, respectively. In the 55 patients starting the program ≥4 years ago, weight loss maintenance of 12 ± 1% IBW (ITT, 16 ± 1% in completers) was observed.Conclusion: Substantial nonsurgical weight loss, maintained at 2 to 4 years, is achievable in severely obese patients using comprehensive lifestyle approaches; the efficacy/safety trade-off in obesity treatment is an important consideration in interpreting these results.Abbreviations: BMI = body mass index EBW = excess body weight HbA_1c = glycated hemoglobin IBW = initial body weight LOCFA = last observation carried forward analysis     

Changes in body composition with weight loss: obese subjects randomized to surgical and medical programs

Objective: To assess changes in body composition with weight loss in obese subjects randomized to a laparoscopic adjustable gastric band surgical program or a medical program using a very‐low‐energy diet and orlistat. Research Methods and Procedures: Using body composition measurements by DXA, neutron activation for total body nitrogen, and whole body γ counting for total body potassium, we studied changes in fat mass, fat distribution, fat‐free mass, total bone mineral content, total body protein, and body cell mass at 6 (n = 61 paired) and 24 months (n = 53 paired) after randomization. Results: At 24 months, the surgical group had lost significantly more weight (surgical, 20.3 ± 6.5 kg; medical, 5.9 ± 8.0 kg). There was favorable fat‐free mass to fat mass loss ratios for both groups (surgical, 1:5.5; medical, 1:5.9). Changes in total body nitrogen or potassium were favorable in each group. A small reduction in mean bone mineral content occurred throughout the study but was not associated with extent of weight loss or treatment group. At 6 months, weight loss for both groups was similar (surgical, 14.1 ± 4.5 kg; medical, 13.3 ± 7.3 kg). The medical program subjects lost less fat‐free mass and skeletal muscle and had increased total body protein. The proportion of body fat to limb fat remained remarkably constant throughout the study. Discussion: Weight loss programs used in this study induced fat loss without significant deleterious effects on the components of fat‐free mass.     

Regulation of Body Weight and Carcass Composition by Sibutramine in Rats

Objective: We examined the effectiveness of sibutramine to modulate food intake and body composition in rats with two levels of adiposity imposed by the duration of their maintenance on a moderate-fat diet. Research Methods and Procedures: Male Sprague–Dawley rats were fed a 32% fat diet from weaning until 2 or 4 months of age, at which point, body fat was either 15% or 25%, respectively, as measured by DXA. Sibutramine (0.6 or 2 mg/kg, orally) was then given daily for 2 weeks. Results: Food intake and body weight decreased acutely in a dose-related manner in both groups with sibutramine treatment. In all rats, food intake suppression was attenuated after multiple days of sibutramine. Both 15%- and 25%-fat rats had a persistent decrease in weight gain over the 2-week period in response to sibutramine. The older, 25%-fat rats were more sensitive to sibutramine than the younger, 15%-fat rats with regard to the magnitude of overall food intake inhibition, decrease in body weight gain, and caloric efficiency. Despite these differences, sibutramine produced the same relative reductions in fat mass and had no effect on lean mass in the two groups. Discussion: Thus, sibutramine produced equivalent efficacy on carcass fat loss in both groups, despite less inhibition of feeding and body weight gain in leaner rats. Whether these changes are a result of the leaner rats being younger and on a steeper growth curve compared with older, fatter rats or whether this is a direct function of their level of adiposity remains to be determined.     

The Fen-Phen Finale: A Study of Weight Loss and Valvular Heart Disease

Objective : To assess weight loss, as well as the prevalence of valvular heart disease, in 21 obese women who completed 2 years of treatment by fenfluramine and phentermine (fen-phen) in June 1997. Research Methods and Procedures : Patients were 21 of 22 women who had completed a 1-year, open-label trial of fen-phen combined with lifestyle modification. This study describes the results of a second year of treatment. The presence of valvular heart disease, defined as aortic regurgitation of mild or greater severity and/or mitral regurgitation of moderate or greater severity, was assessed using two-dimensional, color Doppler and pulsed- and continuouswave Doppler examinations. Results : At 2 years, the 21 patients had a mean reduction in initial weight of 13.9 ±10.1%, which was significantly (p<<0.001) smaller than their 1-year loss of 17.1 ±8.7%. Nine of 21 patients reported that they took fen-phen irregularly during the last 4 months of the study because of fears of developing health complications. These nine patients had a 2-year weight loss of 8.7 ± 7.5%, compared with a significantly (p<0.04) larger loss of 17.6 ± 10.5% for participants who reported taking medication regularly. Six of 20 (30%) patients met criteria for valvular heart disease. None of the six had signs or symptoms of this condition. Discussion : Fenfluramine was withdrawn from the market on September 15, 1997 because of concerns that it was associated with valvular heart disease. The present findings are discussed in terms of the potentially favorable long-term benefits of combining lifestyle modification with weight loss medications that are both safe and effective.     

Orlistat Inhibits Dietary Cholesterol Absorption

Objective: Orlistat decreases the absorption of dietary triglycerides by inhibiting intestinal lipases. Orlistat therapy is associated with a greater decline in plasma low‐density lipoprotein‐cholesterol concentrations than that expected from weight loss alone. Therefore, we evaluated the effect of orlistat treatment on dietary cholesterol absorption as a possible mechanism for the independent effect of orlistat on plasma cholesterol concentration. Research Methods and Procedures: Cholesterol absorption from a standardized meal, containing 72 mg of cholesterol, was determined in 18 subjects with class II abdominal obesity (BMI, 35.0 to 39.9 kg/m²) by simultaneous administration of intravenous ([²H₆] cholesterol) and oral ([²H₅] cholesterol) cholesterol tracers. In protocol 1 (n = 9), cholesterol absorption was determined on two different occasions, 10 to 20 days apart, to assess the reproducibility of the tracer method. In protocol 2 (n = 9), cholesterol absorption was determined with and without orlistat therapy in a prospective, randomized, crossover design to assess the effect of orlistat on cholesterol absorption. Results: In protocol 1, cholesterol absorption from the test meal was the same on both occasions (53 ± 5% and 51 ± 5%). In protocol 2, orlistat treatment caused a 25% reduction in cholesterol absorption, from 59 ± 6% to 44 ± 5% (p < 0.01). Discussion: These data demonstrate that orlistat inhibits dietary cholesterol absorption, which may have beneficial effects on lipoprotein metabolism in obese subjects that are independent of weight loss itself.