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Dexfenfluramine

An Updated Review of its Therapeutic Use in the Management of Obesity

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Abstract

Synopsis

Dexfenfluramine increases serotonergic activity by stimulating serotonin (5-hydroxytryptamine; 5-HT) release into brain synapses, inhibiting its reuptake into presynaptic neurons and by directly stimulating postsynaptic serotonin receptors. On the basis of the serotonin hypothesis of appetite control, these actions would be expected to reduce appetite and, consequently, bodyweight. Studies conducted in animals and in overweight patients with and without associated disorders have confirmed the weight-reducing efficacy and good tolerability of dexfenfluramine.

In 3-month clinical studies in obese patients, weight reductions with dexfenfluramine 15mg twice daily combined with dietary support were significantly higher than those achieved with placebo and similar to those with ephedrine/caffeine 20/200mg 3 times daily, sibutramine 10mg once daily and fluoxetine 60 mg/day. Furthermore, dexfenfluramine recipients with non-insulin-dependent diabetes mellitus, hyperlipidaemia or hypertension consistently show improvements in glycaemic control, blood lipid profiles and blood pressure. 12-month trial results indicate that most weight loss occurs in the initial 6 months and appears to be maintained for a further 6 months. Weight regain after withdrawal of treatment in 12-month studies demonstrates that dexfenfluramine is effective in maintaining a stable bodyweight at a lower level than placebo and in limiting food intake over this time period.

Commonly reported adverse events with dexfenfluramine include diarrhoea, tiredness, dry mouth and somnolence; these symptoms are generally mild and transient. Approximately 7 and 10% of dexfenfluramine recipients in short and long term studies withdrew because of adverse events. Dexfenfluramine was better tolerated than ephedrine/caffeine and fluoxetine in short term studies.

Obesity is a chronic condition that is accompanied by a number of metabolic complications. It is a significant health problem in developed countries; and as a major risk factor for many chronic diseases, including diabetes and cardiovascular disease, the economic burden of this condition is considerable. As with other chronic conditions, there is a role for pharmacological intervention in patients with severe obesity. However, drugs should be considered as only one component of a weight-control programme, since additional lifestyle modification is required to maintain weight loss.

The promising data on the long term efficacy and tolerability of dexfenfluramine as well as its favourable effects on risk factors associated with obesity requires confirmation in long term studies. In the meantime, dexfenfluramine should be considered a valuable adjunct to a reduced-calorie diet in the management of severe obesity, particularly in patients with associated disorders and those unsuccessful with conventional weight loss measures. Available data support the use of the drug for up to 1 year to maintain weight loss and thus dexfenfluramine should be considered for long term administration.

Pharmacodynamic Properties

Dexfenfluramine, the therapeutically active dextro-rotatory stereoisomer of fenfluramine, is a serotonin (5-hydroxytryptamine; 5-HT) agonist. The drug inhibits serotonin reuptake into presynaptic nerve endings and stimulates serotonin release directly into the synaptic cleft. These effects, in accordance with the serotonin hypothesis of appetite control, reduce food intake and thus bodyweight. Dexfenfluramine is more potent than its active metabolite dexnorfenfluramine with respect to inhibition of serotonin reuptake, but less potent with respect to stimulation of serotonin release. Studies evaluating the serotonin receptor subtypes suggest that the hypophagic effects of dexfenfluramine are mediated by actions on 5-HT1B and/or 5-HT2C (formerly termed 5-HT1C) receptors.

Recent studies of dexfenfluramine have shown no neurotoxicity in humans as assessed by positron emission tomography or in animals as assessed by measures of serotonin messenger RNA expression, axonal retrograde transport, glial fibrillary acid protein or growth-associated phosphoprotein 43. Pathological changes in serotonergic axons following high dose dexfenfluramine administration have been reported in squirrel monkeys and rodents; however, these findings are the subject of much debate over the relevance of the doses used in humans and the criteria used to determine neurotoxicity.

It is well established that dexfenfluramine reduces total food intake in a number of feeding models. Recent results from studies in humans which did not artificially restrict food selection (i. e. offering patients limited choices of carbohydrate- or protein-rich food) consistently show that dexfenfluramine reduces overall caloric intake with reductions in caloric intake from both carbohydrate and fat.

Results of studies assessing the effect of dexfenfluramine on thermogenesis are equivocal. Resting metabolic rate and glucose-induced thermogenesis, when expressed per kilogram of bodyweight or fat-free mass, were significantly increased with dexfenfluramine 15mg twice daily compared with placebo in a 3-month study in obese postmenopausal women.

Obesity-induced insulin resistance plays an important role in several metabolic abnormalities (metabolic syndrome or syndrome X) which increase the risk of cardiovascular disease, stroke and non-insulin-dependent diabetes mellitus (NIDDM). Dexfenfluramine 1 to 5 mg/kg decreased food intake, bodyweight and adipose tissue mass, as well as blood levels of glucose, triglycerides, insulin, free cholesterol and phospholipids in JCR:LA-corpulent rats, an animal model that mimics syndrome X in humans. These results have been confirmed in placebo-controlled studies in obese patients with and without NIDDM. In addition, dexfenfluramine 30 mg/day for 3 months selectively and significantly reduced abdominal visceral fat as assessed by magnetic resonance imaging and significantly improved metabolic indices in mildly obese males with NIDDM; these results are important because abdominal visceral fat is a risk factor for obesity-related complications.

Significant reductions in systolic and diastolic blood pressure have been reported following dexfenfluramine therapy in obese patients and in obese patients with hypertension or dyslipidaemia. These findings were accompanied by a decrease in noradrenergic activity independent of the anorectic effect of dexfenfluramine.

Pharmacokinetic Properties

The bioavailability of dexfenfluramine is 69 and 61% in normal-weight and obese volunteers, respectively, with about 20% of the drug undergoing first-pass hepatic metabolism. Peak plasma dexfenfluramine concentrations are achieved 3 to 4.8 hours after oral administration in obese and normal-weight volunteers; those of an active metabolite dexnorfenfluramine are achieved after approximately 8 hours. Distribution of the drug is extensive and is greater in obese than in normal-weight individuals.

The approximate terminal elimination half-lives of dexfenfluramine and dexnorfenfluramine are 14 to 18 hours and 30 hours, respectively. Nearly 100% of the drug is eliminated in the urine: 7 to 19% as unchanged dexfenfluramine, 4 to 11% as dexnorfenfluramine and the remainder as inactive metabolites. Total and renal clearance of dexfenfluramine are reduced approximately 2-fold in individuals considered to be poor metabolisers compared with healthy volunteers.

After administration of dexfenfluramine 15mg twice daily or 30mg twice daily for 3 months, mean plasma dexfenfluramine concentrations were approximately 24 and 58 μg/L, respectively. Steady-state plasma drug concentrations are achieved in 4 days in most patients. There are no significant differences in the steady-state pharmacokinetic parameters for dexfenfluramine between obese and nonobese volunteers.

Therapeutic Efficacy

In short term clinical trials (≤3 months), dexfenfluramine 15mg twice daily was significantly more effective than placebo and was as effective as ephedrine/caffeine 20mg/200mg 3 times daily, sibutramine 10mg once daily and fluoxetine 20mg 3 times daily in reducing body weight in severely obese patients. Weight loss ranged from 3.1 to 6.6kg with dexfenfluramine and from 3kg to a gain of 0.4kg with placebo. Dexfenfluramine appeared to reduce overall caloric intake from meals and especially between-meal snacks; assessments of macronutrient selection mostly showed a reduced caloric intake from fat rather than carbohydrate.

In addition to significantly reducing bodyweight relative to placebo in obese patients with NIDDM, hyperlipidaemia or hypertension, dexfenfluramine appeared to produce improvements in a number of associated risk factors. These include improved glycaemic control, reduced cholesterol and triglyceride levels and reduced systolic and diastolic blood pressure.

In a 1-year multicentre European trial in 822 patients, dexfenfluramine recipients who completed the study (63% of the initial cohort) lost an average of 9.8kg compared with an average weight loss of 7.2kg in placebo recipients (55% of the initial cohort). Approximately twice as many patients in the dexfenfluramine as in the placebo group lost >10% of initial bodyweight, >30% of initial excess bodyweight or >10kg. Most study withdrawals were attributed to dissatisfaction with weight loss (20 and 12% for placebo and dexfenfluramine, respectively). Virtually all weight loss was attained in the first 6 months of dexfenfluramine treatment with a slight weight gain (approximately 1 to 2kg) in the second 6 months of treatment. Weight loss ≥1.8kg at 1 month and dexfenfluramine treatment were significant predictors of treatment success at 1 year; patients who achieved a weight loss ≥10% of initial bodyweight at 4 months were very likely to achieve a lasting weight loss at 1 year. These results were generally confirmed in more recent but smaller trials (n ≤ 75) of 6 or 12 months’ duration.

Tolerability

Dexfenfluramine 15mg twice daily has been well tolerated in clinical trials of up to 12 months’ duration. In a review of 3-month trials, diarrhoea (17.5 vs 7.3%) and dry mouth (12.5 vs 5%) were reported in ≥5% of patients and were at least twice as frequent with dexfenfluramine (n = 1159) compared with placebo (n = 1138); 6.6 and 5.2% of dexfenfluramine and placebo recipients, respectively, withdrew because of adverse events. Insomnia, headache, tiredness and depression accounted for 56% of the 77 withdrawals in the dexfenfluramine group.

Dry mouth, dizziness and thinking abnormality were reported significantly more frequently in patients receiving dexfenfluramine 30mg twice daily than in those receiving 15mg twice daily; approximately twice as many patients in the 60 mg/day group as in the 30 mg/day group withdrew because of adverse events (16 vs 9%).

Dexfenfluramine was better tolerated than ephedrine/caffeine in a 3-month study. The incidence of CNS adverse events (e. g. insomnia, twitching/tremor and palpitations) [46 vs 26%] and overall patient withdrawals (12 vs 3.7%) because of adverse events was higher in ephedrine/caffeine than dexfenfluramine recipients; the incidence of gastrointestinal events was higher with dexfenfluramine (17 vs 4%). Tolerability of dexfenfluramine and sibutramine was rated excellent or good by >90% of patients and investigators. A significantly higher percentage of fluoxetine 60 mg/day recipients withdrew because of adverse events compared with dexfenfluramine 30 mg/day recipients (23 vs 4%).

Tiredness, diarrhoea, dry mouth, polyuria and drowsiness were reported in significantly more dexfenfluramine 15mg twice daily than placebo recipients in a large 12-month study (n = 822). Adverse events were generally mild or moderate and usually resolved with continued treatment.

An increased risk of primary pulmonary hypertension (PPH) has been attributed to anorectic drugs, particularly with increased duration of use; however, obesity and systemic hypertension are also risk factors for PPH. Because of the rarity of PPH, anorectic drug use is associated with a low absolute risk.

Dosage and Administration

The recommended dosage of dexfenfluramine is 15mg twice daily with meals in conjunction with dietary restriction in obese patients with an initial body mass index (BMI) ≥30 kg/m2 following failure of appropriate weight-loss measures. The European Committee for Proprietary Medicinal Products has recently approved dexfenfluramine treatment beyond 3 months in patients who have responded to therapy as indicated by a weight loss ≥10% of initial bodyweight within 3 months of the start of treatment.

In the US, dexfenfluramine is indicated for the management of obesity including weight loss and maintenance of weight loss in patients with an initial BMI ≥30 kg/m2, or ≥27 kg/m2 in the presence of other risk factors (e. g. hypertension, diabetes, hyperlipidaemia). Re-evaluation of treatment is warranted if weight loss is not at least 1.8kg in the first 4 weeks of treatment. The efficacy and tolerability of dexfenfluramine beyond 1 year have not been determined.

Administration of dexfenfluramine is not advised in patients with pulmonary hypertension, during or within 2 weeks after therapy with monoamine oxidase inhibitors and in those taking other serotonergic drugs. The drug should be used with caution in patients with glaucoma. No specific administration guidelines are available for patients with hepatic or renal impairment.

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Various sections of the manuscript reviewed by: B. Andersson, Department of Medicine, Sahlgren’s Hospital, Gothenburg, Sweden; P.L. Beales, Department of Medical and Molecular Genetics, Guy’s Hospital, London, England; D.N. Brindley, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada; J.E. Blundell, Department of Psychiatry, University of Leeds, Leeds, England; G. Cheymol, Service of Pharmacology, Saint-Antoine Hospital, Paris, France; G. Curzon, Department of Neurochemistry, Institute of Neurology, London, England; H.H. Ditschuneit, Department of Medicine, University of Ulm, Ulm, Germany; M.L. Drent, Department of Endocrinology, Free University Hospital, Amsterdam, The Netherlands; N. Finer, Centre for Obesity Research, The Luton and Dunstable Hospital, Luton, England; B.J.P. Guy-Grand, Department of Medicine and Nutrition, University of Paris, Paris, France; E.M.H. Mathus-Vliegen, Department of Gastroenterology, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; H. O’Connor, Metabolism and Obesity Services, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia; M. Pfohl, Department of Internal Medicine, University of Tübingen, Tübingen, Germany; R.S. Scott, Lipid and Diabetes Research Group, Christchurch Hospital, Christchurch, New Zealand; T.B. VanItallie, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA; C. Wall, Massey University at Albany, Auckland, New Zealand; G.C. Weir, Joslin Diabetes Center, Boston, Massachusetts, USA.

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Davis, R., Faulds, D. Dexfenfluramine. Drugs 52, 696–724 (1996). https://doi.org/10.2165/00003495-199652050-00007

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