Sibutramine: A Novel New Agent for Obesity Treatment

Sibutramine is a novel new pharmacologic agent which is a specific reuptake inhibitor for norepinephrine and serotonin. Preclinical data show that sibutramine and its two metabolites reduce food intake of animals eating either high or low carbohydrate diets and of obese Zucker rats. An 8-week clinical trial showed a dose-dependent decrease on body weight. Sibutramine, 5 and 20 mg/day, produced a dose-related weight loss in obese subjects compared to placebo in an 8-week trial. In doses varying from 1 to 30 mg, sibutramine also produced a dose-dependent decrease in weight in the healthy obese population when used in 6-,8-,12–24- and 52-week trials. Although the majority of the weight loss occurred during the first 12 weeks of treatment, weight loss had not plateaued in by 24 weeks in the higher doses. Side effects were mild. This drug shows promise as an antiobesity drug.     

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.     

A Double-Blind Randomized Placebo-Controlled Trial of Sibutramine

Sibutramine is a β-phenethylamine which blocks reuptake of norepinephrine and serotonin. In this clinical study, a group of 173 patients were randomized to treatment with sibutramine at doses of 1, 5, 10, 15, 20 or 30 mg/d and were compared with placebo in a 24-week double-blind trial. There was a dose-dependent reduction in body weight, with doses of 10, 15, 20 and 30 mg being significantly greater than placebo. Weight loss was still continuing in the highest three doses at the end of the study. When drugs were discontinued patients regained weight, as expected. Side effects were generally mild and were most evident in the group treated with the highest dose. These studies suggest that sibutramine may be a valuable new drug for treatment of 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.     

The acyclic CB1R inverse agonist taranabant mediates weight loss by increasing energy expenditure and decreasing caloric intake

Cannabinoid 1 receptor (CB1R) inverse agonists are emerging as a potential obesity therapy. However, the physiological mechanisms by which these agents modulate human energy balance are incompletely elucidated. Here, we describe a comprehensive clinical research study of taranabant, a structurally novel acyclic CB1R inverse agonist. Positron emission tomography imaging using the selective CB1R tracer [(18)F]MK-9470 confirmed central nervous system receptor occupancy levels ( approximately 10%-40%) associated with energy balance/weight-loss effects in animals. In a 12-week weight-loss study, taranabant induced statistically significant weight loss compared to placebo in obese subjects over the entire range of evaluated doses (0.5, 2, 4, and 6 mg once per day) (p < 0.001). Taranabant treatment was associated with dose-related increased incidence of clinical adverse events, including mild to moderate gastrointestinal and psychiatric effects. Mechanism-of-action studies suggest that engagement of the CB1R by taranabant leads to weight loss by reducing food intake and increasing energy expenditure and fat oxidation.     

Sibutramine use in pregnancy: report of two cases

BACKGROUND: Sibutramine is a drug used for the medical treatment of obesity. No data are available on sibutramine use in pregnancy. We report the fetal outcomes of two pregnant women exposed to sibutramine. CASES: The first woman was exposed to 10 mg/day of sibutramine during gestational weeks 4-6. The second woman was exposed to 10 mg/day of sibutramine during gestational weeks 5-8. At weeks 37 and 39, they delivered healthy infants. CONCLUSIONS: To our knowledge, this is the first report of sibutramine exposure in pregnancy. These cases may contribute to the knowledge about sibutramine use during pregnancy.     

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.     

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.     

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.     

Influence of Short‐Term Consumption of the Caffeine‐Free,Epigallocatechin‐3‐Gallate Supplement,Teavigo, on Resting Metabolism and the Thermic Effect of Feeding

Green tea is purported to promote weight loss. Resting metabolic rate (RMR) and the thermic effect of feeding (TEF) are significant components of total daily energy expenditure and are partially determined by the sympathetic nervous system via catecholamine‐mediated stimulation of β‐adrenergic receptors. Epigallocatechin‐3‐gallate (EGCG: the most bioactive catechin in green tea) inhibits catechol‐O‐methyltransferase, an enzyme contributing to the degradation of catecholamines. Accordingly, we hypothesized that short‐term consumption of a commercially available EGCG supplement (Teavigo) augments RMR and TEF. On two separate occasions, seven placebo or seven EGCG capsules (135 mg/capsule) were administered to 16 adults (9 males, 7 females, age 25 ± 2 years, BMI 24.6 ± 1.2 kg/m² (mean ± s.e.)). Capsules (three/day) were consumed over 48 h; the final capsule was consumed 2 h prior to visiting the laboratory. Energy expenditure (ventilated hood technique) was determined at rest and for 5 h following ingestion of a liquid meal (caloric content: 40% RMR). Contrary to our hypothesis, RMR was not greater (P = 0.10) following consumption of EGCG (6,740 ± 373 kJ/day) compared with placebo (6,971 ± 352). Similarly, the area under the TEF response curve (Δ energy expenditure) was also unaffected by EGCG (246,808 ± 23,748 vs. 243,270 ± 22,177 kJ; P = 0.88). EGCG had no effect on respiratory exchange ratio at rest (P = 0.29) or throughout the TEF measurement (P = 0.56). In summary, together RMR and TEF may account for up to 85% of total daily energy expenditure; we report that short‐term consumption of a commercially available EGCG supplement did not increase RMR or TEF.     

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.     

Metformin Decreases Food Consumption and Induces Weight Loss in Subjects with Obesity with Type II Non-Insulin-Dependent Diabetes

Metformin often promotes weight loss in patients with obesity with non-insulin-dependent diabetes mellitus (NIDDM). The mechanism may be attributed to decreased food intake. This study has tested the effect of metformin on satiety and its efficacy in inducing weight loss. Twelve diet-treated NIDDM women with obesity were randomly given two dose levels (850 mg or 1700 mg) of metformin or placebo at 0800 for three consecutive days followed by a meal test on the third day on three occasions using a 3times3 Latin square design. The number of sandwich canapes eaten in three consecutive 10-minute periods beginning at 1400 hours was used to quantitate food intake, and the level of subjective hunger was rated just before the sandwich meal with a linear analogue hunger rating scale at 1400 after a 6-hour fast. The prior administration of metformin produced a reduction in calorie intake after each of the two doses of metformin treatment. The 1700-mg metformin dose had the most marked appetite suppressant action. Similarly, hunger ratings were significantly lowered after metformin, and the effect was most pronounced after the administration of 1700 mg of metformin. To assess the efficacy of metformin in reducing bodyweight, 48 diet-treated NIDDM women with obesity who had failed to lose weight by diet therapy were first placed on a 1200-kcal ADA (American Diabetes Association) diet before being randomized to receive either metformin (850 mg) or placebo twice daily in a double-blind fashion for 24 weeks. A 4-week single-blind placebo lead-in period preceded and a 6-week single-blind placebo period followed the 24-week double-blind treatment period. Subjects treated with metformin continued to lose weight throughout 24 weeks of treatment; their mean maximum weight loss was 8 kg greater than that of the placebo group, with corresponding lower HbA1C and fasting blood glucose levels at the end of the active treatment period. These results indicate that metformin decreases calorie intake in a dose-dependent manner and leads to a reduction in bodyweight in NIDDM patients with obesity.     

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.     

Physical Activity and Low-Fat Diet: Is it Enough to Maintain Weight Stability in the Reduced-Obese Individual Following Weight Loss by Drug Therapy and Energy Restriction?

DOUCET, ERIC, PASCAL IMBEAULT, NATALIE ALMÉRAS, AND ANGELO TREMBLAY. Physical activity and low-fat diet: Is it enough to maintain weight stability in the reduced-obese individual following weight loss by drug therapy and energy restriction? Obes Res. Objective: The anthropometric and physiological effects of a physical activity (PA) and a mildly energy-restricted low-fat diet (LFD) follow-up program after a long-term dietary restriction were studied in 12 men and 8 women. Research Methods and Procedures: The dietary restriction (?700 kcal/day) was accompanied by a fenfluramine (60 mg/day) or placebo treatment for 15 weeks, whereas the mean duration of the PA-LFD follow-up was 18 weeks. Results: The long-term dietary restriction reduced body weight (?11. 9 and ?7. 6 kg, p<. 001), fat mass (FM) (?10. 6 and ?5. 8 kg, p<0. 01), resting metabolic rate (RMR) (?304 kcal/day, p<0. 01 and ?148 kcal/day, NS) in men and women, respectively. A decrease in fat-free mass (FFM) was also observed in women (?1. 8 kg, p<0. 05). The PA-LFD follow-up preserved weight stability at a reduced body weight and caused an additional significant decrease in FM for men (?3. 4 kg, p<0. 05). This part of the intervention also caused an increase in daily RMR for men (134 kcal/day, NS) to the point where this value no longer differed from the pre-energy restriction value. In contrast, RMR was further reduced in women (?200 kcal/day) to the point where it Significantly differed from initial values (p<0. 01). Resting seated heart rate was reduced by the PA-LFD follow-up in men leading it to differ significantly from both pre- and post-energy restriction values (?8. 5 and ?5. 5 bpm, p<0. 01). Discussion: In conclusion, these results suggest that a PA-LFD follow-up has the potential to permit body weight stability and may even accentuate fat loss in the reduced-obese state. Moreover, resting energy expenditure is increased under such conditions in men. These stimulating effects seem to be specific to energy metabolism since seated heart rate was either further reduced or remained stable in response to the PA-LFD follow-up.     

The Novel Antiobesic HMR1426 Reduces Food Intake without Affecting Energy Expenditure in Rats

Objective: To determine the effect of acute and chronic administration of a new food intake‐reducing compound (HMR1426) with novel mode of action (retardation of gastric emptying) on body weight development, food intake, and energy metabolism in rats. Research Methods and Procedures: Adult male Shoe‐Wistar rats were implanted with transponders allowing registration of body temperature (T_b) and locomotor activity. HMR1426 (10 or 50 mg/kg) was given orally, and acute (8 hours) and chronic (15 days) effects were measured on food intake, T_b, activity, total energy expenditure (indirect calorimetry), and epididymal adipose tissue mass. The effect of chronic treatment was compared with the effect of sibutramine (10 mg/kg). Results: HMR1426 (50 mg/kg) caused an acute and chronic decrease of food intake. There was no effect on the level and daily pattern of total energy expenditure, T_b, and locomotor activity. Respiratory quotient was acutely decreased by HMR1426 due to reduced food intake. Chronic treatment with HMR1426 decreased weight gain by 31% and epididymal white fat by 24%. Sibutramine caused a respective reduction of 48% and 35%. Energy efficiency was not affected by HMR1426 in contrast to sibutramine, which reduced energy efficiency and transiently increased activity. Discussion: HMR1426 showed an anorectic potential in rats and decreased body weight and fat mass. This was achieved solely by reducing food intake without influencing overall energy expenditure or behavior suggesting a peripheral mode of action. Thus, HMR1426 can be considered a potential new drug for obesity treatment.     

Sibutramine alters the central mechanisms regulating the defended body weight in diet-induced obese rats

Chronic administration of sibutramine lowers body weight, presumably by altering brain monoamine metabolism. Here the effect of sibutramine on sympathoadrenal function (24-h urine norepinephrine and epinephrine levels) and arcuate nucleus (ARC) neuropeptide Y (NPY) and proopiomelanocortin (POMC) expression was assessed in diet-induced obese rats fed a low-fat diet. Chronic (10 wk) sibutramine [5 mg. kg(-1). day(-1) ip; rats fed ad libitum and injected with sibutramine (AS)] lowered body weight by 15% but only transiently (3-4 wk) reduced intake compared with vehicle-treated controls [rats fed chow ad libitum and injected with vehicle daily (AV)]. Other rats food restricted (RS) to 90% of the weight of AS rats and then given sibutramine restored their body weights to the level of AS rats when allowed libitum food intake. After reequilibration, RS rats were again energy restricted to reduce their weight to 90% of AS rats, and additional vehicle-treated rats (RV) were restricted to keep their body weights at the level of AS rats for 3 wk more. Terminally, total adipose depot weights and leptin levels paralleled body weights (AV > AS = RV > RS), although AS rats had heavier abdominal and lighter peripheral depots than RV rats of comparable body weights. Sibutramine treatment increased sympathetic activity, attenuated the increased ARC NPY, and decreased POMC mRNA levels induced by energy restriction in RV rats. Thus sibutramine lowered the defended body weight in association with compensatory changes in those central pathways involved in energy homeostasis.     

Six‐Month Treatment of Obesity with Sibutramine 15 mg; A Double‐Blind,Placebo‐Controlled Monocenter Clinical Trial in a Hispanic Population

Objective: To evaluate the safety and efficacy of sibutramine 15 mg by mouth once per day in obese patients over a period of 6 months. Research Methods and Procedures: A monocenter, double‐blind, placebo controlled, parallel, prospective clinical trial was carried out. Sixty‐nine male and female obese patients (body mass index [BMI] > 30 kg/m²) aged 16 to 65 years entered the trial. Results: 22 of 35 patients in the sibutramine group and 9 of 34 patients in the placebo group completed the trial. The high dropout rate in the sibutramine group was due to adverse events in 3 cases, lack of efficacy (as judged by patients) in 7, loss to follow‐up in 2, and an orthopedic device being worn in 1; in the placebo group the dropouts were ascribed to lack of efficacy (as judged by patients) in 17 cases and to loss to follow‐up in 8 cases. Using the method of last observation carried forward, the weight loss in the sibutramine group was 10.27 kg (95% confidence intervals [95% CI] 7.66; 13.07) and 1.26 kg (95% CI 0.3; 2.23) in the placebo group. The BMI loss was 4.17 kg/m² (95% CI 3.11; 5.22) in the sibutramine group and 0.53 kg/m² (95% CI 0.13; 0.92) in the placebo group. The waist circumference reduction was 12.51 cm (95% CI 9.25; 15.77) in the sibutramine group and 3.26 cm (95% CI 1.38; 5.14) in the control group (p < 0.05 by paired Student's t test for all the intragroup comparisons). Twenty‐three sibutramine patients had 34 adverse events, the most frequent adverse events in the sibutramine group were upper respiratory tract infections (n = 6) and constipation (n = 6); 16 placebo patients had 21 adverse events. Three sibutramine patients withdrew their informed consent when they had adverse events. Discussion: The results show that sibutramine induces significant loss of body weight and waist circumference. Cardiovascular function was not significantly affected by sibutramine. Sibutramine was well tolerated by most of the patients.     

Fluoxetine: A Randomized Clinical Trial in the Maintenance of Weight Loss

Because current weight-reduction treatments have considerable recidivism, a therapy that could help patients maintain weight loss would be of benefit. A six-center, randomized, double-blind trial compared the effects of the specific serotonin uptake inhibitor, fluoxetine hydrochloride, and placebo on maintenance of weight loss. Obese outpatients who had lost ≤3.6 kg after 8 weeks of single-blind fluoxetine 60 mg/day in the qualification phase (N=317 [70.4% of patients entered]; mean ± standard deviation [SD] weight loss, 6.8 ± 2.8 kg) were randomly assigned to fluoxetine 20 mg/day (N=104), fluoxetine 60 mg/day (N=106), or placebo (N=107) for 40 weeks (maintenance phase). Patients received minimal nutrition/dietary counseling. Qualification phase clinic visits were biweekly; maintenance phase visits were monthly for 4 months, then bimonthly for 6 months. Patients treated with fluoxetine 60 mg/day continued to lose weight for 8 additional weeks (16 weeks total; maximum mean ± SD weight loss, 7.2 ± 4.6 kg); those treated with fluoxetine 20 mg/day or placebo began to regain weight. Mean weights remained below baseline values at week 48 (all groups); treatment differences were not statistically significant. Study completion rates were comparable (fluoxetine 20 mg/day, 67.3%; fluoxetine 60 mg/day, 56.6%; placebo, 67.3%; p = 0.175). Among commonly reported adverse events (>10% incidence), only asthenia was reported statistically significantly (p< 0.050) more frequently with fluoxetine than with placebo. Few patients discontinued for any single adverse event. Fluoxetine 60 mg/day was effective for a longer period than fluoxetine 20 mg/day or placebo in maintaining weight loss. Overall, fluoxetine was safe and well tolerated.     

Original Articles Sibutramine Reduces Food Intake in Non-Dieting Women with Obesity

Sibutramine (SIB), an inhibitor of serotonin and noradrenaline reuptake, has been shown in clinical trials to be associated with a dose-related decrease in bodyweight. This double-blind, placebo-controlled, Latin square crossover study examined whether the effect on bodyweight could be due in part to a reduction in daily food intake. Twelve non-dieting, women with obesity (body mass index of 30.5 to 41.9) received three treatments (0 [matching placebo], 10, or 30 mg SIB/day) for 14 days, with 14-day washout periods in between. On days 7 and 14, participants came to the laboratory to eat breakfast, lunch, and dinner so that daily energy and macronutrient intakes and ratings of hunger and satiety could be measured. Significant reductions occurred in food intake (both grams and energy) over the 14-day study period. On day 7, SIB 30 reduced intake significantly by 1762 kJ (23% reduction from placebo), and on day 14, both SIB 10 and SIB 30 significantly reduced intake compared with placebo (SIB 10, 19% reduction [1490 kJ]; SIB 30,26% reduction [2079 HI). On day 7, the percentage of energy consumed from carbohydrate increased significantly with the 30-mg dose (56.7 %) compared with that of placebo (51.4%), with a reciprocal decrease in energy from fat (27.8% to 24%). The results show that SIB reduced energy intake in women with obesity who were not attempting to lose weight.     

5‐HT1A Activation Counteracts Cardiovascular But Not Hypophagic Effects of Sibutramine in Rats

The noradrenaline (NA) and serotonin reuptake inhibitor, sibutramine, gives effective weight loss, but full efficacy cannot be attained at approved doses due to cardiovascular side effects. We assessed in rats the contributions of NA and serotonin transporters to sibutramine's hypophagic and cardiovascular effects, and whether selective 5‐hydroxytryptamine (5‐HT_1A) receptor activation could counteract the latter without affecting the former. Food intake was assessed in freely feeding rats and cardiovascular parameters in conscious telemetered rats. Ex vivo radioligand binding was used to estimate brain monoamine transporter occupancy. Sibutramine (1–10 mg/kg p.o.) dose‐dependently reduced food intake; however, 10 mg/kg p.o. markedly elevated blood pressure and heart rate. Sibutramine gave greater occupancy of NA than serotonin reuptake sites. Coadministration of the selective 5‐HT_1A agonist F‐11440 (2.5 mg/kg p.o.) attenuated sibutramine‐induced hypertension and tachycardia without altering its food intake effects. The selective NA reuptake inhibitors, nisoxetine or reboxetine, did not alter food intake alone, but each reduced food intake when combined with F‐11440. These results suggest that sibutramine‐induced hypophagic and cardiovascular effects are largely due to increased brain synaptic NA via NA reuptake inhibition, and that 5‐HT_1A activation can counter the undesirable cardiovascular effects resulting from increased sympathetic activity. Selective NA reuptake inhibitors did not reduce food intake alone but did when combined with 5‐HT_1A activation. Hence increased synaptic serotonin, via serotonin reuptake inhibition or 5‐HT_1A activation, together with increased NA, would appear to produce hypophagia. Thus weight loss with minimal cardiovascular risk could be achieved by 5‐HT_1A activation combined with NA transporter blockade.