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Aim: This article provides the first comprehensive meta-analysis of randomized clinical trials of medications for obesity., Method: Based on stringent inclusionary criteria, a total of 108 studies were included in the final database. Outcomes are presented for comparisons of single and combination drugs to placebo and for comparisons of medications to one another., Result: Overall, the medications studied produced medium effect sizes. Four drugs produced large effect sizes (ie d>0.80; amphetamine, benzphetamine, fenfluramine and sibutramine). The placebo-subtracted weight losses for single drugs vs placebo included in the meta-analysis never exceeded 4.0 kg. No drug, or class of drugs, demonstrated clear superiority as an obesity medication. Effects of methodological factors are also presented along with suggestions for future research.

Objective: The aim of the present study was to determine the impact of weight loss on appetite as measured by visual analog scale (VAS)., Methods: Seventeen subjects (10 men and seven women) took part in a 15 week weight loss program which consisted of drug therapy (fenfluramine 60 mg/day) or placebo coupled to an energy restriction (-2930 kJ/day; phase 1) followed by an 18 week low-fat diet-exercise follow-up (phase 2). Subjects were given a standardized breakfast before and after phase 1 as well as after phase 2. Individuals were asked to fill out VAS before and at 0, 10, 20, 30, 40, 50 and 60 min after this test meal. Blood samples were drawn before the meal and at 0, 30 and 60 min postprandially and analyzed for glucose and insulin. Fasting plasma cortisol and leptin were also determined., Results: An increase in the fasting desire to eat, hunger and prospective food consumption (PFC) was observed after phase 1 and to an even greater extent after phase 2 in both men and women. In the fasting state, positive correlations were observed between changes in the desire to eat (r=0.76; P<0.05) as well as changes of PFC (r=0. 82; P<0.05) and changes in cortisol at the end of phase 1 for women. In response to phase 1, statistically significant correlations were found between changes of hunger (r=0.64; P<0.05) and desire to eat (r=0.67; P<0.05) as measured by AUC in response to the meal and changes of fasting plasma cortisol in men. The most consistent predictor of changes of baseline desire to eat (r=0.68 P<0.05), fullness (r=-0.78, P<0.05) and PFC (r=0.91, P<0.01) during phase 2 was the change in fasting cortisol in men. Changes of fullness were also associated with changes of fasting leptin in men (r=0.68; P<0. 05) during phase 2., Conclusion: These results suggest that weight loss is accompanied by an increase of baseline appetite in both men and women and that the most consistent predictor of these changes in appetite seems to be changes in fasting plasma cortisol.

Background: Initial weight loss has been used as a predictor of long-term response to obesity drugs. Discontinuation of drugs has been recommended if weight loss is not > or =1.81 kg (4 lb) in the first month of treatment., Objective: We compared the weight loss response at 6 months of patients losing > or =1.81 kg (responders) vs. < 1.81 kg (non-responders) in the first month of treatment with the combination of fenfluramine and phentermine., Design: Outcomes at 6 months in 975 patients treated in a comprehensive program of phentermine (15-30 mg/d) d,l-fenfluramine (20-60 mg/d), were compared for responders vs. non-responders., Results: In the total population, first month weight loss highly correlated with % reduction in body mass index (BMI) after 6 months of treatment (P<0.001). The reduction in baseline BMI after 6 months treatment was greater for the responders (15.9% vs. 10%, P<0.02). However, the North American Association for the Study of Obesity (NAASO) guidelines for drug treatment of obesity state that a 5% weight loss produces significant health benefits, and may be used as a criteria for success. At 6 months, 76%, 37% and 14% of the non-respondents had lost > or = 5%, > or = 10% and > or = 15% of baseline BMI, respectively. After 6 months treatment the reductions in serum cholesterol, triglycerides and LDL-cholesterol were 0.55, 0.31 and 0.42 mmol/L, respectively, (P< or =0.006), for the non-responders. Adverse effects after 6 months of treatment and the dropout rates after 1 y of treatment were not significantly different for the two groups., Conclusions: Although, the first month weight loss predicted the long-term response to phen-fen treatment, it was inadequate in identifying the non-responders and may unnecessarily preclude potential beneficiaries of the treatment.

Objective: The aim of this study was to investigate the relationship between energy expenditure (EE) and fat mass (FM) by using a cross-sectional approach to study the linear relationship between body composition variables and EE phenotypes as well as an intervention design to investigate the effect of body weight loss on energy metabolism in both genders., Methods: The correlations and linear relationships between body weight, FM, fat-free mass (FFM) and abdominal fat vs 24 h EE (EE 24) and sleeping metabolic rate (SMR) were compared between 65 men and 35 women, and before and after weight loss in 10 men and 10 women., Results: Our results showed that for a given FM, men displayed a higher EE than women, independently of FFM. Furthermore, regression analysis revealed that after body weight loss, men displayed a lower SMR for a given FM or FM adjusted for FFM compared to before the treatment, but this was not so in women. However, when FM was adjusted for abdominal fat deposition, the difference between the conditions was no longer observed., Conclusions: FM has a significant impact on EE only in men. We suggest that abdominal adipose tissue may exert a potent regulatory effect on energy metabolism which would be more detectable in men who generally store more fat in this compartment than women.

Objective: To validate a variation of a well-established magnetic resonance imaging (MRI) technique to detect liver fat and use it to monitor liver fat changes after treatment with dexfenfluramine in men with non-insulin dependent diabetes mellitus (NIDDM)., Design: (a) Simple correlation study of MRI Liver Fat Index with liver biopsy results; (b) Open Study of 10 men with NIDDM treated with dexfenfluramine for 12 weeks in addition to their 'usual' therapy., Subjects: (a) 19 patients (3F; 16M) with abnormal liver function tests undergoing liver biopsy; (b) 10 men, Body Mass Index (BMI) < 30, Waist to hip ratio (WHR) > 0.90 with poorly controlled NIDDM despite oral sulphonylurea therapy., Measurements: (a) MRI liver fat; standard liver biopsy; (b) MRI visceral fat, MRI liver fat, euglycaemic clamp, plasma lipids, fasting glucose and c-peptide levels., Results: In the validation group, there was a strong relationship between the MRI Liver Fat Index and histopathological assessment of the liver biopsies (r = 0.87, < 0.0001). During treatment with dexfenfluramine the mean Liver Fat Index reduced from 10.6 +/- 3.4 to 6.6 +/- 2.8 (P = 0.05). The reduction in Liver Fat Index correlated with the reduction in visceral fat (r = 0.84, P = 0.001) as well as with the improvement in insulin sensitivity (r = 0.62, P = 0.05). Using partial correlation analysis, the relationship between the change in visceral adipose tissue and the improvement in insulin sensitivity was weaker if the Liver Fat Index was kept constant (r = 0.76 decreased to r = 0.56)., Conclusions: In this group of subjects MRI Liver Fat Index correlated well with liver fat as seen on biopsy. The Liver Fat Index reduced after 12 weeks therapy with dexfenfluramine suggesting a role for hepatic steatosis in the complex interaction between visceral adipose tissue and insulin sensitivity.

Obesity is a major health concern which must be treated. The classical treatment strategies of diet, behavioural modification and exercise have been found to be ineffective for maintaining long-term weight loss. Drugs have been used to try and improve long-term maintenance of weight loss. Such drugs act centrally, peripherally, or via a combination of these effects. The aim has generally been to increase satiety, thermogenesis, or both. For a drug to be an effective anti-obesity agent, it must meet a number of criteria. The drug should reduce weight and weight dependent diseases, and have no addictive properties. In addition, any side-effects should be tolerable and/or transient, and the mechanism of action of the drug should be known. Studies have shown that pharmacotherapy, combined with classical treatment strategies, has improved the long-term maintenance of weight loss.

Controlled studies have shown that sibutramine produces dose-related weight loss when given in the range 5-30 mg per day, with optimal doses of 10 and 15 mg per day. Weight loss with sibutramine is 3-5 kg better than placebo at 24 weeks, and weight loss is maintained to 52 weeks at doses of 10 and 15 mg. By six months, 69% of patients treated with sibutramine 15 mg achieve a 5% or greater reduction in their baseline weight. The weight loss achieved with sibutramine was similar to that achieved with dexfenfluramine over 12 weeks (4.5 kg compared with 3.2 kg). Sibutramine-induced weight loss has been found to be accompanied by a significant reduction in waist/hip ratio, and decreases in plasma triglycerides, total cholesterol and low density lipoprotein (LDL) cholesterol. There were also increases in high density lipoprotein (HDL) cholesterol. In patients with type II diabetes, sibutramine-induced weight loss was accompanied by a shift towards improved glycaemic control. In controlled studies, 84% of sibutramine-treated patients reported adverse events, compared with 71% of patients receiving placebo. The most frequently reported adverse events are related to pharmacological actions of sibutramine, and include dry mouth, decreased appetite, constipation and insomnia.

Objective: To investigate the specific effects of dexfenfluramine (dF) as an adjunct to a reduced-fat, ad libitum diet., Design: Double-blind, randomized, placebo-controlled study. Subjects were stabilized on the dietary program during a 12 w run-in period, and then were randomized to receive dF (15 mg) or placebo bd for an additional 12 w. One follow-up was conducted 12 w after cessation of treatment., Subjects: 84 obese subjects (57 F; 27 M, mean body mass index = 34.7 +/- 3.2 kg/m2)., Measurements: Body composition (by DEXA), fat distribution (by circumferences and DEXA), nutrient intake (by 7 d food diaries), blood lipids, blood glucose and blood pressure., Results: Mild side effects were reported by 19 dF subjects, and in seven subjects lethargy or dry mouth persisted for the 12 w of treatment. Relative to placebo, treatment with dF was associated with significantly greater reductions in body weight (-3.8 kg, 95% confidence interval [CI] = -4.9, -2.7), fat mass (-2.5 kg, 95% CI = -3.6, -1.4) and fat-free mass (-1.2 kg, 95% CI = 1.8, -0.7). Waist and hip circumferences also decreased (P < 0.01) but the waist:hip ratio remained unchanged. The ratio of waist:hip fat mass as measured by DEXA decreased more in the dF group (P < 0.01). Lower total energy intake (-439 kJ/d, 95% CI = -932, 54) and fat intake (-5.1 g/d, 95% CI = -10.8, 0.6) were also seen but were of borderline statistical significance. After adjusting for changes in fat intake, dF treatment was associated with lower cholesterol and triglyceride concentrations (P < 0.01). Twelve weeks following cessation of treatment, the rate of weight gain was not significantly different between the dF and the placebo groups (1.7 kg and 0.7 kg respectively), but the dF group remained significantly lighter than the placebo group (P < 0.01)., Conclusions: Dexfenfluramine treatment augments weight and fat loss on a reduced-fat, ad libitum diet, with some evidence for preferential loss of waist fat compared with hip fat. The decreases in total energy and fat intake with dF seem insufficient to explain the significant decreases in body weight and fat mass.

Rationale: Serotoninergic neurotransmission, mainly in specific hypothalamic nuclei, plays an important role in the regulation of appetite. Dysfunction of this system has been postulated to result in the clinical picture of carbohydrate craving obesity. This subgroup of obese patients is characterized by a specific preference for high-carbohydrate and low-protein snacks. Centrally acting serotoninergic drugs, such as the serotonin re-uptake inhibitor d-fenfluramine, have been hypothesized to restore serotonin mediated control of food intake., Objective: To test the hypothesis that serotoninergic drugs would induce a greater weight loss in carbohydrate craving (CC) than in non-carbohydrate craving (NC) obese patients., Design: A three months open intervention study with d-fenfluramine 15 mg twice daily. In order to be able to study the effect of the drug alone, no dietary restrictions were imposed. Both the medical doctor and the patient were unaware of who was a carbohydrate craving obese patient and who was not., Subjects: 10 CC and 10 NC patients, matched for sex, age, body mass index and family history of obesity., Measurements: Height, body weight, food intake (energy intake and macronutrient selection) and patient compliance., Results: CC patients lost 4.8 +/- 3.9 kg body weight or 15.9 +/- 13.5% of their pretreatment overweight, whereas NC patients lost 4.5 +/- 2.9 kg or 16.4 +/- 11.6% of their overweight (t-test for paired samples, P = 0.82 and P = 0.93 respectively)., Conclusion: We conclude that CC patients do not constitute a subgroup of obese patients that should be treated with a serotoninergic drug preferentially.

Objective: To characterize differences in metabolic indices as well as body composition in two ethnic groups., Subjects: Eight black and eight white obese urban women were studied., Design: Eight black and eight white obse (BMI > 34) urban women (BW, WW) were matched for age, BMI, WHR, diet and physical activity and investigated before and after 12 weeks of Dexfenfluramine treatment., Measurements: Anthropometric measurements; Post 75 g OGTT, plasma glucose, insulin and C-peptide levels were done. FFA and lactate levels were done at onset. Skinfold thickness with Harpenden calipers, bio-impedance for analyses of body composition and CT scan for assessment of regional adiposity (at onset and after 3 months)., Results: In the postabsorptive state the WW had significantly higher plasma total cholesterol and triglyceride levels and an unfavourable HDL : total cholesterol ratio. Their FFA levels were significantly lower (324 +/- 51 vs 985 +/- 84 mumol/l; p < 0.0001) and their lactate levels were significantly higher (3045 +/- 245 vs 1938 +/- 358 mumol/l; p < 0.001) as compared with the BW. During a 75 g OGTT the BW had significantly higher glucose levels at 1 h (8.6 +/- 0.8 vs 5.1 +/- 0.4 mmol/l; p < 0.005) and 2 h (7.6 +/- 0.6 vs 4.4 +/- 0.3 mmol/l) but not at fasting. In contrast the BW had lower insulin concentrations (fasting: 77 +/- 9 vs 139 +/- 19 pmol/l; p < 0.04 and 1 h 318 +/- 56 vs 624 +/- 75 pmol/l; p < 0.005), and C-peptide concentrations (fasting: 400 +/- 99 vs 1600 +/- 99 pmol/l; p < 0.000 04, 1 h 1400 +/- 433 vs 5966 +/- 333 pmol/l; p < 0.0007 and 2 h 1266 +/- 333 vs 4066 +/- 366 pmol/l; p < 0.0005). CT scan measurements showed that the WW had significantly more visceral fat than the BW (148.5 +/- 2.0 vs 115.5 +/- 6.9 cm2; p < 0.05) but lost less weight during Dexfenfluramine treatment (-4 kg vs -9 kg). Despite this, the WW lost more visceral fat than the BW (-27.3 cm2/-18.5%; p < 0.03 vs -15.5 cm2/-13.2%; p < 0.04). In contrast the BW had a larger reduction in subcutaneous (SC) fat (-13.9% vs -1.7%; p < 0.01), with the greatest reduction in the SC gluteofemoral adipose tissue (widest hip circumference -20.8% vs -0.2%; p < 0.001) and mid-femur region (-13.1% vs -0.7%; p < 0.08)., Conclusion: Weight loss in obese black women is associated with a major reduction in SC fat mass with the most active mobilization of fat tissue occurring in the gluteofemoral area. In contrast the WW had more visceral fat that was more readily mobilized. The difference in adipose tissue distribution and pattern of mobilization was associated with lower plasma insulin, C-peptide and triglyceride concentrations in the BW despite increased FFA and glucose levels. These data suggest that plasma insulin concentrations are important in regulating differences in regional adipose tissue metabolism as well as the serum lipid profile.

In this study 25 patients, who had completed the INDEX trial (Guy-Grand et al. Lancet 1989; 2: 1142-1145) were reexamined 2 months after withdrawal of the study medication. The patients then in an open trial received dexfenfluramine (dF) for 6 months. The observed weight gain after withdrawal of study medication was higher in patients treated beforehand with dF (2.6 +/- 1.2 kg) than in patients who had received placebo (0.8 +/- 1.0 kg). In the open dF trial rate of weight loss was lower than it had initially been in the patients receiving dF from the outset of the INDEX trial (13.1 +/- 4.6 kg within 6 months). In the previous dF treated patients weight loss after re-introduction of dF was 3.7 +/- 2.7 kg. The previous placebo-treated patients, now receiving dF for the first time, lost 4.8 +/- 1.1 kg. Thus, after withdrawal of dF, patients experience weight gain, but after re-introduction of dF, renewed weight loss is achieved. However, the rate of weight loss declines with time.

In depressive disorders an association between basal pre-treatment plasma ratios of tryptophan (Trp) and tyrosine (Tyr) to other large neutral amino acids (LNAA) and the clinical efficacy of serotonergic acting drugs have been established. In order to clarify whether a similar relation exists in obesity and to elucidate the long-term effect of dexfenfluramine (dF) on plasma amino acid profiles and macronutrient selection, we examined 29 obese patients participating in a 12 months double-blind weight loss trial with either dexfenfluramine (dF) (30 mg/day) or placebo (PL) in conjunction with 4.2-5.0 MJ/d diet. Maximum weight loss was obtained after 6 months (dF 12.8 +/- 5.4 kg; PL 13.8 +/- 9.2 kg, x +/- s.d., ns). Plasma Trp/LNAA and Tyr/LNAA were found to be lower than in normal weight controls and were further reduced during treatment (p < 0.05), but without differences between dF and PL groups. Macronutrient selection was not affected by the dF treatment. In the placebo group weight loss was associated with a high pre-treatment energy intake and a high carbohydrate-protein ratio (p < 0.05). A decrease in dietary fat and increase in protein intake (%) and age was found to explain 82% of the variation in weight loss (p < 0.0005), whereas no correlation could be shown in the dF group. Pre-treatment plasma Trp/LNAA or Tyr/LNAA and weight loss were not correlated. In conclusion, neither food selection nor basal plasma amino acid profiles were predictors of weight loss during long-term treatment with dF as an adjuvant to energy restriction, and they were not affected by the drug treatment.

Objective: To investigate the effect of the serotonin receptor agonist dexfenfluramine on eating habits and weight loss in ambulatory, android type, moderately obese patients with an overconsumption of snacks., Design: 9 week, randomized, double-blind treatment with either dexfenfluramine (30 mg/day) or placebo, without dietary intervention., Setting: Outpatient clinics of four University Hospitals in The Netherlands., Subjects: 112 healthy obese subjects, body mass index 28-35 kg/m2, waist-to-hip ratio > or = 1.0 for men and > or = 0.8 for women, consuming more than five snacks containing in total more than 500 kcal/day and/or more than 25% of total calorie intake in the form of snacks., Main Outcome Measures: Changes in macronutrient composition of the diet, food intake (total, at principal meals and in between meals in the form of snacks) and weight loss., Results: 104 subjects were included for efficacy analysis. In both the dexfenfluramine group (n = 51) and the placebo group (n = 53) the total energy intake decreased. The decrease during main meals was significantly greater in the dexfenfluramine group for all parameters tested except for simple carbohydrates. In between meals the decrease in intake was significantly greater in the dexfenfluramine group for total energy intake (P < 0.05) and intake in unsaturated fat (P < 0.05). The reported reduction in total food intake in the dexfenfluramine group was similarly due to reductions in carbohydrate and fat intake. No weight loss was seen in the placebo group. The treated group lost 3.1 +/- 0.2 kg (P < 0.01)., Conclusion: Dexfenfluramine effectively reduces the intake of carbohydrates as well as fat in ambulatory, non diet restricted android obese subjects by reducing food intake during and in between main meals.

Objective: As successful weight management demands a long term approach, a better understanding of weight changes during and for significant periods after cessation of dexfenfluramine therapy is essential to the evaluation of the drug's effectiveness in clinical practice. This study aimed to investigate additional benefits to weight loss during 6 months treatment with dexfenfluramine in 60 patients enrolled in a weight loss programme., Design: Sixty obese subjects (21 males; 39 females) were randomised to dexfenfluramine (15 mg twice daily) or placebo for six months. Fifty one (27 dexfenfluramine; 24 placebo) subjects completed the double blind, randomised, placebo controlled clinical trial., Results: After a one month 'run in' phase and six months treatment, weight loss in the dexfenfluramine group was significantly greater than placebo, 9.7 +/- 1.1 kg vs 4.9 +/- 0.9 kg (mean +/- s.e.m.); P = 0.002. Reduction in body fat, 5.0 +/- 0.7 kg vs 1.0 +/- 0.9 kg; P = 0.002 and waist circumference, 10.5 +/- 1.9 cm vs 5.7 +/- 1.1 cm; P = 0.04 was also greater in the dexfenfluramine group. Despite significant weight loss, waist to hip ratio (WHR) did not change in either group. The dexfenfluramine group reported a significantly greater incidence of nausea, dry mouth and dizziness which tended to decrease as treatment progressed. No subjects withdrew due to drug induced side effects. Reduction in serum triglyceride levels and an increase in HDL cholesterol (in female subjects) in conjunction with a reduction in fasting insulin, collectively support an improved cardiovascular risk profile in the dexfenfluramine group. Despite significant weight loss, these risk factor measurements worsened in the placebo group. After cessation of dexfenfluramine therapy, there was a significantly greater weight regain indicating a loss of treatment effect. By 5 months after cessation of dexfenfluramine, the treatment effect was negated with weight loss in the dexfenfluramine (6.0 +/- 1.6 kg) and placebo (6.2 +/- 1.3 kg) group, similar., Conclusion: The results of this study support the longer term use of dexfenfluramine therapy for patients with chronic obesity.

The aim of this work was to investigate the long-term changes of body weight and cardiovascular risk factors after weight reduction with dexfenfluramine (dF) compared to placebo (pI) and additional group therapy. There was a 3 year follow-up of obese patients after 1 year double-blind, randomized treatment with 30mg dF or pI and group therapy. The work was carried out at the outpatient clinic of University Hospital, Tübingen. Forty-eight (24 dF, 24 pI) patients were investigated with more than 120% of ideal body weight. Body weight, blood pressure, blood glucose, serum cholesterol and triglycerides were measured. During 1 year of treatment body weight fell by 11.2% (dF) and 9.1% (pI) (P < 0.001 for time, n.s. for dF/pI), systolic blood pressure by 7.3 and 9.9 mm Hg (P = 0.044/n.s.). There were no significant changes of serum cholesterol, triglycerides, and blood glucose. At the follow-up of 22 (11/11) patients 3 years later, the dF group had regained more than the lost weight; the placebo group had lost 2.4% of the initial body weight. Serum cholesterol (dF + 0.64/pI + 0.65 mmol/l, P = 0.010/n.s.), triglycerides (+0.74/+0.59 mmol/l, P = 0.002/n.s.), and blood glucose (+0.56/+0.81mmol/l, P < 0.001/n.s.) increased significantly. Systolic blood pressure increased slightly, diastolic blood pressure did not change significantly. Without appropriate prevention of weight regain even combined weight reduction therapy over a period of one year results in weight regain and deterioration of cardiovascular risk factors.

This study investigated the potential for dexfenfluramine to improve biochemical and clinical risk factors for cardiovascular disease, in obese dyslipidaemic individuals. Dexfenfluramine, the dextro isomer of fenfluramine, has been shown to aid weight reduction and lower blood lipids in normal subjects, and to improve glucose tolerance and insulin sensitivity in subjects with diabetes mellitus. Twenty-nine overweight (mean weight 83.3 +/- 11.3 kg), hyperlipidaemic (mean total cholesterol 7.3 +/- 1.2 mol/l) subjects participated in a 12-week randomized double-blind parallel study of dexfenfluramine versus placebo. After an eight-week dietary run-in phase, subjects were randomised to treatment with either dexfenfluramine or placebo for 12 weeks. During the run-in, energy intakes fell in both groups (5.5% for dexfenfluramine, 5% for placebo, no significant difference between groups). Dietary composition improved, fat as a percentage of energy decreased (14%, P < 0.001, for dexfenfluramine; 11.7%, P < 0.05, for placebo), and carbohydrate increased (8.5%, P < 0.05, for dexfenfluramine; 5.6%, not significant, for placebo). During the treatment period, energy intakes in the dexfenfluramine group were further reduced by 7.5%, whereas there was no change in the placebo group (P = 0.02 between dexfenfluramine and placebo groups); however, nutrient composition remained constant for both groups. Side-effects were formally reported by 40% of subjects during the initial four weeks' treatment with dexfenfluramine with three subjects withdrawing from the study. Side-effects were largely resolved by week 4. Both groups lost weight similarly during the run-in but there were no significant changes in any biochemical parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

In previous separate studies, dexfenfluramine (DF) and ephedrine/caffeine (EC) have been shown to promote weight loss in obese patients as compared with placebo. In order to compare the efficacy and safety of these two anorectic drugs, 103 patients with 20-80% overweight were included in a 15-week double-blind study in general practice. Patients were randomized to either 15 mg DF twice daily (n = 53), or 20 mg/200 mg ephedrine/caffeine three times a day (n = 50), supplementary to a 5 MJ/day diet. Forty-three patients from the DF group and 38 from the EC group completed the study. After 15 weeks of treatment, the DF group (n = 43) had lost 6.9 +/- 4.3 kg and the EC group (n = 38) had lost 8.3 +/- 5.2 kg (mean +/- s.d., P = 0.12). In the subgroup of patients with BMI > or = 30 kg/m2 (n = 59), the mean weight loss was 7.0 +/- 4.2 kg in the DF group (n = 29) and 9.0 +/- 5.3 kg in the EC group (n = 30), P < 0.05. Both systolic and diastolic blood pressures were reduced similarly during both treatments. Twenty-three patients in the DF group (43%) and 27 in the EC group (54%) complained of side-effects. Central nervous system side-effects, especially agitation, were more pronounced in the EC group (P < 0.05), whereas gastro-intestinal symptoms were more frequent in the DF group (P < 0.05). The side-effects declined markedly during the first month of treatment in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

The purpose of this study was to determine the effects of dexfenfluramine on body weight and post-prandial thermogenesis in obese subjects. Thirty obese subjects, men and women, with an excess weight between 20 and 80% of the ideal weight and aged from 20 to 60 years, participated in this double-blind, placebo-controlled study. During the treatment period, the subjects were not submitted to caloric restriction. Basal metabolic rate and postprandial thermogenesis (following a 400 kcal test meal) measurements were made by indirect calorimetry. Metabolic parameters such as glucose, insulin, thyroid hormones, free fatty acids, beta-hydroxybutyrate, total cholesterol and triglycerides were also measured before the test meal. These measurements were done at baseline, after one week and after three months of treatment. Following the three month treatment period, the mean weight loss of the dexfenfluramine group was 4.6 +/- 1.6 kg (s.e.) (P < 0.01) whereas the placebo group maintained the initial weight. The mean weight loss in the dexfenfluramine group represented 15% of the initial overweight. There was no significant change in either group in basal metabolic rate and postprandial thermogenesis following one week and three months of treatment (P > 0.05). The caloric intake after the treatment period was significantly reduced in the dexfenfluramine group (from 1631 +/- 103 kcal (s.e.) to 1353 +/- 109 kcal (s.e.); P < 0.05); in the placebo group, the changes were not significant (P > 0.05). The plasma concentrations of tri-iodothyronine, total cholesterol and triglycerides were significantly reduced in the dexfenfluramine group (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

While very low calorie diets (VLCD) can lead to rapid weight loss, even in patients who have often failed with conventional diets, maintaining this loss remains a clinical challenge. Since dietary re-education or more formal behaviour modification techniques are not easily applicable to large numbers of patients and are not always successful, drugs to maintain and improve upon initial VLCD success would be of clinical benefit. Pharmacological treatment of obesity has evolved in recent years with the development and licensing of potent serotonin agonists, such as dexfenfluramine (D-F). VLCD followed by D-F has been shown to be effective. A double-blind trial randomized 45 patients who had successfully completed eight weeks' VLCD treatment, to either placebo or D-F 15 mg b.d. for 26 weeks. Patients continued on a diet giving 60-75% of daily energy needs. Patients treated with D-F had lost 14.9 +/- 0.9 kg on the Cambridge diet and a further 5.8 +/- 1.8 kg during the drug treatment. In contrast, patients who received placebo regained 2.9 +/- 1.3 kg of the 13.5 +/- 1.0 kg they had lost during VLCD. The total weight loss after 34 weeks in total was thus 21.3 +/- 2.6 versus 11.3 +/- 1.9 kg. Patients were offered the option of continuing on D-F, or switching from placebo, in an open continuation of the trial. Ten patients, regaining weight on placebo, stabilized their weight without further regain over the next 24 weeks when switched to D-F.(ABSTRACT TRUNCATED AT 250 WORDS)

The combined syndrome of android (upper body) obesity, diabetes, hyperlipidaemia and hypertension is discussed in terms of a deranged endocrine regulation of metabolism. The syndrome is characterized by insulin insensitivity and an increased control of metabolism by cortisol. The antagonism between the two hormones appears to be partly responsible for the hyperglycaemia, hypertriglyceridaemia and hypercholesterolaemia. The synergism between insulin and cortisol in stimulating energy deposition, associated with a decreased effect of corticotropin-releasing factor in stimulating energy expenditure, is likely to contribute to the development of obesity. The efficacy of D-fenfluramine in treating the obese-diabetic-hyperlipidaemic-hypertensive syndrome probably depends on its actions on the serotoninergic system in the hypothalamus which both decreases food consumption and tends to normalize hormonal balance through the hypothalamic-pituitary-adrenal axis.

Cigarette smoking suppresses body weight, discouraging many smokers from trying to quit. Behavioural therapies have so far proved unsuccessful in preventing post-cessation weight gain, and have in fact tended to undercut abstinence from smoking. The mental demands of implementing behavioural weight management strategies may compete with the concentration needed to maintain abstinence from smoking. Consequently, a pharmacological approach offers potential treatment advantages by minimizing the effort needed to achieve weight control. Of the agents found effective in minimizing weight gain, serotoninergic drugs, particularly dexfenfluramine, show special promise because they prevent an increase in caloric intake but do not decrease energy intake below pre-cessation levels.

A short review has been made of the experimental studies performed in man, in which the effect of dexfenfluramine (D-F) on resting energy expenditure has been explored. It appears that the extent to which D-F possesses thermogenic properties (in addition to its anorectic effect) still remains controversial. Some investigators found either no significant increase in energy expenditure in response to the drug or a moderate effect in post-absorptive and/or postprandial state. It may be reasonable to assume that the supplementary weight loss observed with D-F as compared to a placebo can be primarily attributed to its anorectic effect rather than to its putative thermogenic effect.

Dexfenfluramine (dF) was compared to placebo as adjuvant to a very energy-restricted diet (1.6-4.2 MJ/24 h). The diet was continued as long as possible or until a satisfactory weight loss had been achieved, and dietary efforts were continued throughout the study. Of the 37 females and five males included, 71 per cent could be followed up for 12 months. Initial BMI ranged from 28 to 54 kg/m2. The lowest body weight was reached 1 month earlier in the dF group (P = 0.037). Throughout the study, the reduction of excess weight (REW) was greater in dF patients (P less than 0.05 only at 4 and 6 months). At 6 months, excess weight had declined by 15 per cent more in the dF group than in the placebo group (95 per cent confidence limits of the median being 1-31 per cent). Between 6 and 12 months, both groups regained weight significantly, the rates of regain differing only insignificantly. At 12 months, excess weight showed a net decrease of only 8 per cent more in the dF group than in the placebo group (95 per cent confidence limits being -7 to +24 per cent). Therefore, REW showed no significant group difference after 12 months. Type of obesity (android or gynoid) as determined by waist to hip ratio had no significant impact on either weight loss, REW, reductions of waist and hip circumferences, or on waist to hip ratio changes. S-alkaline phosphatases and s-uric acid declined significantly in the dF group only. Side-effects were all mild and their prevalence showed no group difference.(ABSTRACT TRUNCATED AT 250 WORDS)