AGA Clinical Practice Guideline on Pharmacological Interventions for Adults With Obesity.

BACKGROUND & AIMS: Pharmacological management of obesity improves outcomes and decreases the risk of obesity-related complications. This American Gastroenterological Association guideline is intended to support practitioners in decisions about pharmacological interventions for overweight and obesity. METHODS: A multidisciplinary panel of content experts and guideline methodologists used the Grading of Recommendations Assessment, Development and Evaluation framework to prioritize clinical questions, identify patient-centered outcomes, and conduct an evidence synthesis of the following agents: semaglutide 2.4 mg, liraglutide 3.0 mg, phentermine-topiramate extended-release (ER), naltrexone-bupropion ER, orlistat, phentermine, diethylpropion, and Gelesis100 oral superabsorbent hydrogel. The guideline panel used the evidence-to-decision framework to develop recommendations for the pharmacological management of obesity and provided implementation considerations for clinical practice. RESULTS: The guideline panel made 9 recommendations. The panel strongly recommended the use of pharmacotherapy in addition to lifestyle intervention in adults with overweight and obesity (body mass index ≥30 kg/m2, or ≥27 kg/m2 with weight-related complications) who have an inadequate response to lifestyle interventions. The panel suggested the use of semaglutide 2.4 mg, liraglutide 3.0 mg, phentermine-topiramate ER, and naltrexone-bupropion ER (based on moderate certainty evidence), and phentermine and diethylpropion (based on low certainty evidence), for long-term management of overweight and obesity. The guideline panel suggested against the use of orlistat. The panel identified the use of Gelesis100 oral superabsorbent hydrogel as a knowledge gap. CONCLUSIONS: In adults with overweight and obesity who have an inadequate response to lifestyle interventions alone, long-term pharmacological therapy is recommended, with multiple effective and safe treatment options.

Systematic review and meta-analysis of the efficacy and safety of amfepramone and mazindol as a monotherapy for the treatment of obese or overweight patients.

The aim of this study was to evaluate efficacy and safety of amfepramone, fenproporex and mazindol as a monotherapy for the treatment of obese or overweight patients. A systematic review of primary studies was conducted, followed by a direct meta-analysis (random effect) and mixed treatment comparison. Medline and other databases were searched. Heterogeneity was explored through I2 associated with a p-value. Of 739 identified publications, 25 were included in the meta-analysis. The global evaluation of Cochrane resulted in 19 studies with a high level of bias and six with unclear risk. Due to the lack of information in primary studies, direct meta-analyses were conducted only for amfepramone and mazindol. Compared to placebo, amfepramone resulted in higher weight loss in the short-term (<180 days; mean difference (MD) -1.281 kg; p<0.05; I2: 0.0%; p=0.379) and long-term (≥180 days; MD -6.518 kg; p<0.05; I2: 0.0%; p=0.719). Only studies with long-term follow up reported efficacy in terms of abdominal circumference and 5-10% weight reduction. These results corroborated the finding that the efficacy of amfepramone is greater than that of placebo. Treatment with mazindol showed greater short-term weight loss than that with placebo (MD -1.721 kg; p<0.05; I2: 0.9%; p=0.388). However, metabolic outcomes were poorly described, preventing a meta-analysis. A mixed treatment comparison corroborated the direct meta-analysis. Considering the high level of risk of bias and the absence of important published outcomes for anti-obesity therapy assessments, this study found that the evaluated drugs showed poor evidence of efficacy in the treatment of overweight and obese patients. Robust safety data were not identified to suggest changes in their regulatory status.

Diethylpropion and mazindol: An end to the discussion?

Antiobesity pharmacotherapy remains the main point of disagreement among both scientists and regulators. This is probably due to small sample sizes, high levels of heterogeneity, and low methodological quality. For many years, Brazil was one of the largest consumers of appetite suppressants worldwide, with evidence of irrational use of this drug class. Therefore, the country was the scene of a debate that divided the Brazilian Health Surveillance Agency (Anvisa - Agência Nacional de Vigilância Sanitária) and medical societies over the maintenance record of diethylpropion, mazindol and fenproporex. In this context, this commentary presents new arguments to contribute to the discussion, as well as recommendations for future studies.

Systematic review and meta-analysis of the efficacy and safety of amfepramone and mazindol as a monotherapy for the treatment of obese or overweight patients

The aim of this study was to evaluate efficacy and safety of amfepramone, fenproporex and mazindol as a monotherapy for the treatment of obese or overweight patients. A systematic review of primary studies was conducted, followed by a direct meta-analysis (random effect) and mixed treatment comparison. Medline and other databases were searched. Heterogeneity was explored through I2 associated with a p-value. Of 739 identified publications, 25 were included in the meta-analysis. The global evaluation of Cochrane resulted in 19 studies with a high level of bias and six with unclear risk. Due to the lack of information in primary studies, direct meta-analyses were conducted only for amfepramone and mazindol. Compared to placebo, amfepramone resulted in higher weight loss in the short-term (<180 days; mean difference (MD) -1.281 kg; p<0.05; I2: 0.0%; p=0.379) and long-term (≥180 days; MD -6.518 kg; p<0.05; I2: 0.0%; p=0.719). Only studies with long-term follow up reported efficacy in terms of abdominal circumference and 5-10% weight reduction. These results corroborated the finding that the efficacy of amfepramone is greater than that of placebo. Treatment with mazindol showed greater short-term weight loss than that with placebo (MD -1.721 kg; p<0.05; I2: 0.9%; p=0.388). However, metabolic outcomes were poorly described, preventing a meta-analysis. A mixed treatment comparison corroborated the direct meta-analysis. Considering the high level of risk of bias and the absence of important published outcomes for anti-obesity therapy assessments, this study found that the evaluated drugs showed poor evidence of efficacy in the treatment of overweight and obese patients. Robust safety data were not identified to suggest changes in their regulatory status.

The efficacy of the appetite suppressant, diethylpropion, is dependent on both when it is given (day vs. night) and under conditions of high fat dietary restriction.

Obesity is a public health problem caused by excessive consumption of high caloric diets and/or lack of physical activity. Although treatments for obesity include low caloric diets and exercise programs, these activities frequently are supplemented with appetite suppressants. For the short-term treatment of weight loss, diethylpropion (DEP) is a commonly used appetite suppressant. However, little is known with regard to how to improve its weight loss efficacy. We therefore evaluated, in rats, two administration protocols where the animals received daily injections of DEP. First, when these nocturnal animals were normally active (at night) and when they were normally inactive (daytime), and second, with or without high fat dietary restriction (HFDR). We observed that DEP induced a greater weight-loss administered when the animals were in their active phase than in their inactive phase. Moreover, DEP's administration during the inactive phase (and to a lesser degree in the active phase) promotes the consumption of food during normal sleeping time. In addition, we found that DEP-induced weight loss under ad libitum access to a HF diet, but its efficacy significantly improved under conditions of HFDR. In summary, the efficacy of DEP, and presumably other like appetite suppressants, is enhanced by carefully controlling the time it is administered and under dietary restriction of HF diets.

Six-month efficacy and safety of amfepramone in obese Mexican patients: a double-blinded, randomized, controlled trial.

Amfepramone, also known as diethylpropion, is an anorectic drug used for the short-term treatment of obesity; however, its efficacy and safety during periods greater than 3 months has been scarcely studied. To evaluate the 6-month efficacy and safety of amfepramone treatment in obese adult Mexican patients resistant to diet and exercise, a double-blinded, randomized, and placebo-controlled clinical trial study was designed on 156 volunteers with a body mass index (BMI) greater than 30 kg/m2 and less than 45 kg/m2. Patients were randomized to receive a 75 mg tablet of amfepramone or placebo daily for 6 months. Primary outcome was the absolute body weight loss, whereas secondary outcomes were the percentage of patients who achieved at least 5% or 10% weight loss, as well as the improvement of anthropometric and metabolic parameters. Amfepramone treatment produced a superior efficacy to decrease body weight than placebo at 3 months (-4.9±0.25 kg vs. -0.7±0.32 kg) and 6 months (-7.7±0.52 kg vs. -1.1±0.7 kg). In addition, 64 and 34 patients achieved at least 5% or 10% weight loss, respectively, with amfepramone at 6 months, compared with 8 and 0 patients on placebo. Amfepramone also significantly improved BMI and waist circumference, but it only showed a favorable tendency in the waist-hip index (WHI), glucose, total cholesterol, low-density lipoproteins (LDL), high-density lipoproteins (HDL), triglycerides, heart rate, systolic blood pressure, and diastolic blood pressure at 3 and 6 months. Amfepramone produced only mild adverse events, and they were presented in a greater number than placebo only at 3 months, dry mouth being the the main adverse event. Data suggest that amfepramone is effective and well tolerated in obese Mexican patients during a 6-month regimen.

A comparative study of five centrally acting drugs on the pharmacological treatment of obesity.

CONTEXT: No long-term studies have compared centrally acting drugs for treating obesity. OBJECTIVE: To compare the efficacy and safety of diethylpropion (DEP), fenproporex (FEN), mazindol (MZD), fluoxetine (FXT) and sibutramine (SIB) in promoting weight loss. DESIGN AND SETTING: A prospective, randomized, placebo (PCB)-controlled study conducted at a single academic institution. PATIENTS: A total of 174 obese premenopausal women. INTERVENTION: Participants randomly received DEP 75 mg (n=28), FEN 25 mg (n=29), MZD 2 mg (n=29), SIB 15 mg (n=30), FXT 20 mg (n=29) or PCB (n=29) daily over 52 weeks. Diet and physical activity were encouraged. MAIN OUTCOME MEASURES: The primary endpoints were changes in body weight and the proportion of women who achieved at least 5% weight loss by week 52 in the intent-to-treat population. Other measurements included anthropometry, safety, metabolic and cardiovascular parameters. RESULTS: Weight loss was greater than PCB (-3.1±4.3 kg) with DEP (-10.0±6.4 kg; P<0.001), SIB (-9.5±5.9 kg; P<0.001), FEN (-7.8±6.9 kg; P<0.01) and MZD (-7.4±4.9 kg; P<0.01) but not with FXT (-2.5±4.1 kg). Ten (33.3%) women lost⩾5% of their initial weight with PCB, compared with 20 (71.4%; P<0.001) with DEP, 20 (69%; P<0.02) with FEN, 21 (72.4%; P<0.01) with MZD, 22 (73.3%; P<0.001) with SIB and 10 (35.5%) with FXT. Each medically treated group experienced more adverse events compared with PCB (P<0.001). Compared with PCB, constipation was more prevalent with DEP, SIB and MZD (P<0.01); anxiety was more prevalent with DEP (P=0.01); and irritability occurred more frequently with DEP and FEN (P=0.02). Significant improvements in the depression and anxiety scores, binge-eating episodes and quality of life correlated with weight loss. CONCLUSION: The centrally acting drugs DEP, FEN, MZD and SIB were more effective than PCB in promoting weight loss in obese premenopausal women, with a satisfactory benefit-risk profile.

A randomized double-blind placebo-controlled study of the long-term efficacy and safety of diethylpropion in the treatment of obese subjects.

OBJECTIVE: To evaluate the efficacy of diethylpropion on a long-term basis, with emphasis in cardiovascular and psychiatric safety aspects. DESIGN: Randomized, double-blind, placebo-controlled trial. MEASUREMENTS: Following a 2-week screening period, 69 obese healthy adults received a hypocaloric diet and were randomized to diethylpropion 50 mg BID (n=37) or placebo (n=32) for 6 months. After this period, all participants received diethylpropion in an open-label extension for an additional 6 months. The primary outcome was percentage change in body weight. Electrocardiogram (ECG), echocardiography and clinical chemistry were performed at baseline and every 6 months. Psychiatric evaluation and application of Hamilton rating scales for depression and anxiety were also performed by experienced psychiatrists at baseline and every 3 months. RESULTS: After 6 months, the diethylpropion group lost an average of 9.8% (s.d. 6.9%) of initial body weight vs 3.2% (3.7%) in the placebo group (P<0.0001). From baseline to month 12, the mean weight loss produced by diethylpropion was 10.6% (8.3%). Participants in the placebo group who were switched to diethylpropion after 6 months lost an average of 7.0% (7.7%) of initial body weight. The difference between groups at month 12 was not significant (P=0.07). No differences in blood pressure, pulse rate, ECG and psychiatric evaluation were observed. Dry mouth and insomnia were the most frequent adverse events. CONCLUSION: Diethylpropion plus diet produced sustained and clinically significant weight loss over 1 year. It seems to be safe in relation to cardiovascular and psychiatric aspects in a well-selected population.

Weight loss medications--where do they fit in?

BACKGROUND: Obesity is a chronic disease requiring a similar long term approach to management as that of other chronic conditions. OBJECTIVE: This article discusses the role of medications in the overall management of obesity. DISCUSSION: Management needs to be multifaceted, aiming to alter the patient and family micro-environment to one favouring better weight control through sustainable behavioural changes to physical activity and diet. Weight loss medications may provide additional benefit. Currently we have only two medications suitable for long term therapy--orlistat and sibutramine. Sibutramine, which acts centrally to suppress appetite, has shown efficacy for up to 2 years. Orlistat, a lipase inhibitor, reduces fat absorption and has been shown to reduce and maintain weight for up to 4 years. The effect of these medications is modest, generally providing less than 5 kg weight loss when compared with placebo. Patients need to have realistic expectations and understand the benefits of sustained modest weight loss. It is important that weight loss medications are prescribed in combination with lifestyle modification.

[Drug treatment of obesity]. / Medikamentel behandling af fedme.

Acceptable adverse effects and a clinical relevant weight loss of 3 to 5 kilograms have been found in long-term randomized clinical trials for sibutramine (Reductil) and orlistat (Xenical); these drugs may be prescribed for treatment of obesity for a duration of one and four years, respectively. This also seems to be the case for rimonabant (Acomplia), which is expected to receive approval in 2005 or 2006. However, until data on morbidity and mortality are available from RCTs, there is no absolute indication for prescribing drugs for treatment of obesity.

Primary pulmonary hypertension after amfepramone (diethylpropion) with BMPR2 mutation.

Primary pulmonary hypertension (PPH) is characterised by sustained elevations of pulmonary arterial pressure without a demonstrable cause, leading to right ventricular failure and death. Hereditary mutations in the bone morphogenetic protein receptor type II (BMPR2) gene result in familial PPH transmitted as an autosomal dominant trait, albeit with low penetrance. The causes in cases without a BMPR2 mutation are unknown, but a syndrome of pulmonary arterial hypertension (PAH) similar to hereditary PPH is associated with systemic connective tissue disease, congenital heart disease, portal hypertension, and human immunodeficiency virus infection, or with the use of appetite-suppressant drugs. The authors identified a BMPR2 gene mutation in a 27-yr-old female who developed PAH after a short course of the appetite-suppressant drug amfepramone (diethylpropion). This allowed molecular genetic counselling and prevention of potentially harmful drug exposure in the patient's son treated for attention deficit disorder with methylphenidate, an amphetamine-related drug. No BMPR2 mutation was found in four additional, unrelated patients with appetite suppressant-related PPH. The findings provide strong evidence that amfepramone can trigger primary pulmonary hypertension in a bone morphogenetic protein receptor type II gene mutation carrier, and indicate that other genes are probably implicated in genetic susceptibility to appetite suppressants.

Clinical and oculographic response to Tenuate Dospan (diethylpropionate) in a patient with congenital nystagmus.

PURPOSE: We report a female adult with congenital nystagmus who responded with improved visual function and oculographic parameters after taking the anorexic diet drug Tenuate Dospan (diethylproprionate; Watson Laboratories, Inc., Corona, California). METHODS: Observational case report. Clinical ophthalmic examination and ocular motility recordings were performed before and after administration of the drug Tenuate Dospan. RESULTS: The binocular visual acuity of the patient improved from 20/70 to 20/50, her exotropic deviation decreased from 12 to 4 prism diopters, her stereopsis increased from none to 200 seconds/arc, and her ocular motility recordings showed increased foveation periods and a broadened null zone. CONCLUSION: For unexplained reasons, the anorexic stimulant Tenuate Dospan "paradoxically" improved the nystagmus and binocular function in this patient with congenital nystagmus. This observation may be the basis for investigation of a new pharmacological treatment approach to patients with congenital nystagmus or strabismus.

Long-term pharmacotherapy of obesity 2000: a review of efficacy and safety.

To clarify the efficacy of antiobesity drugs, this article reviews all long-term (> or =36 weeks), placebo-controlled trials of obesity pharmacotherapy published since 1960. Since fears of anorexiant-induced heart valve damage preclude many physicians and patients from even considering antiobesity drugs, this area is also reviewed in-depth. Electronic database and manual bibliography search was used to identify all relevant publications. While existing studies are too few and heterogeneous to warrant meta-analysis, their review does provide evidence highly relevant to the safety and efficacy of available anorexiants. Weight loss attributable to obesity pharmacotherapy (ie, in excess of placebo) in trials lasting 36 to 52 weeks was 8.1% or 7.9 kg for those receiving phentermine resin, 5.0 % or 4.3 kg for those receiving sibutramine hydrochloride, 3.4% or 3.4 kg for those receiving orlistat, and -1.5% or -1.5 kg for those receiving diethylpropion hydrochloride. Physiologic, pathologic, and epidemiological studies strongly support that anorexiant-induced valvulopathy is attributable to specific serotonergic properties of the fenfluramines that are not present with available weight loss drugs.

Challenges in obesity management.

CONTEXT: Obesity is increasing at an alarming rate. During the past decade, the overall prevalence of obesity in the United States increased over 30%, with more than one third of the adult population meeting the definition of being overweight. OBJECTIVE: We review current and emerging therapies, present outcome data from a large clinical practice, and discuss challenges for physicians and researchers involved in obesity treatment. SUMMARY: Because obesity is a risk factor for numerous medical disorders and excess mortality, it is imperative that effective treatments be developed. While the current conservative therapies produce short-term weight losses, they are ineffective in the long term. Some obesity treatments are controversial, most notably the increasing use of anorexiant medications. For example, the Food and Drug Administration (FDA) recently requested the withdrawal of two widely used medications because of concerns about side effects. Currently, therapies that combine psychosocial interventions, drugs, and extended maintenance appear to have the most promising long-term benefits. CONCLUSIONS: Long-term treatment, including extended pharmacotherapy, may be necessary for many obese patients. Broader definitions of treatment outcome and success, including improvements in comorbid conditions, physical activity, and quality of life are needed.

Pupillary changes associated with the development of stimulant-induced mania: a case report.

A 30-year-old cocaine-dependent man who was a subject in a study evaluating the anticraving efficacy of the stimulant medication diethylpropion (DEP) became manic during his second week on the study drug. Pupillometric changes while on DEP, especially changes in the total power of pupillary oscillation, were dramatically different than those observed in the eight other study subjects who did not become manic. The large changes in total power of pupillary oscillation occurred a few days before the patient became fully manic. Such medication-associated changes in the total power of pupillary oscillation might be of utility in identifying persons at risk for manic-like adverse effects during the medical use of psychomotor stimulants or sympathomimetic agents.

Lack of neurotoxic effect of diethylpropion in crack-cocaine abusers.

Dopamine agonists have been used with some success in treating cocaine addiction. However, both cocaine and psychostimulants have been reported to produce neurotoxic effects. We evaluated the effect of the stimulant diethylpropion on cognitive performance in a double-blind, placebo-controlled trial. Forty-six abstinent crack-cocaine users received either placebo, 25-mg, 50-mg, or 75-mg doses of diethylpropion. Patients were tested at baseline and again after 9-14 days of medication. There were no differences between placebo and medication groups on any test, indicating that, within the time frame studied, diethylpropion does not produce neurotoxic effects that can be detected with standardized neuropsychological tests.