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Long-term use of diethylpropion in obesity
Abstract
Diethylpropion (‘Tenuate Dospan’) was found to be an acceptable therapy when given on a long-term basis to 20 very overweight patients who had failed to lose weight on diet alone. There were remarkably few untoward side-effects and no indication of the development of tolerance to the drug. An interesting feature of the trial was a correlation between fall in blood pressure with loss of weight.
... Table 1 highlights the limitations of these older antiobesity agents along with their regulatory status. [9][10][11][12] Thus, there is an obvious need for an effective antiobesity agent that causes substantial weight loss thereby reducing the risk of cardiovascular disease (CVD). This article is an attempt to highlight the new molecules that have been recently approved for obesity by the US FDA and the emerging molecules that are in clinical development for obesity. ...
... Demerits of Older Antiobesity Agents in Clinical Practice.[9][10][11][12] Abbreviations: FDA, Food and Drug Administration; SR, sustained release. ...
Obesity has become a growing pandemic of alarming proportions in the developed and developing countries over the last few decades. The most perturbing fact regarding obesity is the increased predisposition for coronary artery disease, congestive heart failure and sudden cardiac death. The modest efficacy of current anti-obesity agents such as orlistat and the increasing withdrawals of several anti-obesity agents such as sibutramine, rimonabant have led to huge gaps in the pharmacotherapy of obesity. Lorcaserin and Phentermine-topiramate combination (phen-top) are two drugs approved by US FDA in 2012. Lorcaserin, a 5HT2C agonist has moderate efficacy with an acceptable safety profile. Clinical trials with Phen-top have shown a reasonable efficacy but at the cost of risks such as teratogenicity and psychiatric disturbances. Cetilistat, a lipase inhibitor is claimed to have superior safety profile to orlistat and is in phase 3 clinical trials. Other promising anti-obesity molecules acting on the gut which are in clinical trials include exenatide and liraglutide. Drugs which act on the monoaminergic and opioid systems include bupropion-naltrexone and bupropion-zonisamide. Other novel first-in-class drugs which have been explored and have limited success in early clinical development include velneperit, tesofensine, and beloranib. Tesofensine is a triple monoamine re-uptake inhibitor, velneperit acts as a neuropeptide Y5 receptor antagonist and beloranib is a methionine amino peptidase 2 inhibitor. Novel targets such as histamine H3 receptor, VEGF, matrix-metalloproteinase, sirtuin receptors are also being investigated. This review is an attempt to describe the new and emerging molecules that are in clinical development for obesity.
... Diethylpropion (amfepramone) . another amphetamine-like analogue has been available for weight loss since the early 1960s; however there are few if any RCTs of its long-term use especially with large sample sizes [30, 31]. Diethylpropion (75 mg daily) demonstrated significantly greater weight loss in a small 24-week study of 20 patients than placebo (11.6 kg versus 2.5 kg, P < .01) ...
... ther amphetamine-like analogue has been available for weight loss since the early 1960s; however there are few if any RCTs of its long-term use especially with large sample sizes [30, 31]. Diethylpropion (75 mg daily) demonstrated significantly greater weight loss in a small 24-week study of 20 patients than placebo (11.6 kg versus 2.5 kg, P < .01) [31]. Recently, diethylpropion (50 mg twice a day) was shown to be more effective than placebo in a small 6-month RCT with 69 obese adult patients (9.3 kg [ [32]. Greater than 5% weight loss was achieved in 67.6% of diethylpropion patients and 25.0% of those receiving placebo (P = .0005). After further 6 months during an open label period of ...
Past therapies for the treatment of obesity have typically involved pharmacological agents usually in combination with a calorie-controlled diet. This paper reviews the efficacy and safety of pharmacotherapies for obesity focusing on drugs approved for long-term therapy (orlistat), drugs approved for short-term use (amfepramone [diethylpropion], phentermine), recently withdrawn therapies (rimonabant, sibutamine) and drugs evaluated in Phase III studies (taranabant, pramlintide, lorcaserin and tesofensine and combination therapies of topiramate plus phentermine, bupropion plus naltrexone, and bupropion plus zonisamide). No current pharmacotherapy possesses the efficacy needed to produce substantial weight loss in morbidly obese patients. Meta-analyses support a significant though modest loss in bodyweight with a mean weight difference of 4.7 kg (95% CI 4.1 to 5.3 kg) for rimonabant, 4.2 kg (95% CI 3.6 to 4.8 kg) for sibutramine and 2.9 kg (95% CI 2.5 to 3.2 kg) for orlistat compared to placebo at ≥12 months. Of the Phase III pharmacotherapies, lorcaserin, taranabant, topiramate and bupropion with naltrexone have demonstrated significant weight loss compared to placebo at ≥12 months. Some pharmacotherapies have also demonstrated clinical benefits. Further studies are required in some populations such as younger and older people whilst the long term safety continues to be a major consideration and has led to the withdrawal of several drugs.
... 9 Few studies have evaluated the long-term use of diethylpropion. [10][11][12] Obesity is a lifelong condition and the great majority of individuals who lose weight will eventually regain it. A long-standing treatment can be justified to prevent weight regain but more data on the efficacy and safety of this drug are needed. ...
... 8 Few studies with longer duration had been published. [10][11][12] The fact that these medications are no longer under patent and have a low cost may explain the limited interest from the pharmaceutical industry in carrying out long-duration clinical trials, at least to some extent. A randomized double-blind placebo-controlled study of diethylpropion C Cercato et al ...
To evaluate the efficacy of diethylpropion on a long-term basis, with emphasis in cardiovascular and psychiatric safety aspects.
Randomized, double-blind, placebo-controlled trial.
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.
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.
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.
... Nausea and diarrhea were also noted. Nonetheless, rimonabant is approved in 42 countries [126][127][128][129][130][131][132]. (Figure 5). ...
In recent decades, obesity has become a pandemic disease and appears to be an ultimate medical and social problem. Existing antiobesity drugs show low efficiency and a wide variety of side effects. In this review, we discuss possible mechanisms underlying brain–gut–adipose tissue axis, as well as molecular biochemical characteristics of various neurochemical regulators of body weight and appetite. Multiple brain regions are responsible for eating behavior, hedonic eating and food addiction. The existing pharmacological targets for treatment of obesity were reviewed as well.
... However, there are few if any RCTs of its longterm use especially with large sample sizes (25). Diethylpropion (75mg daily) demonstrated significantly greater weight loss in a small 24-week study of 20 patients than placebo (26). Diethylpropion (50mg twice a day) was shown to be more effective than placebo in a small 6-month RCT with 69 obese adult patients (9.3 kg versus 3.1 kg, respectively) (27) . ...
Obesity is a chronic disease associated with serious health problems such as metabolic syndrome, diabetes, hypertension, and cardiovascular diseases. Due to the growing trend of returning to nature and the fear of adverse reactions from conventional medicines, people are increasingly resorting to the use of herbal preparations. Adulterated herbal weight loss products containing undeclared synthetic drugs are common and responsible for many serious health damages. Because of long-term use and natural origin, these preparations give a sense of security. But herbal weight loss formulations also possess undesirable effects and, among other dangers, present a risk connected with deliberate addition of synthetic compounds, deliberate or unintentional replacement of the plant species or simply a risk of mislabeling. The most undeclared ingredients, which were illegally added include sibutramine, phenolphthalein, bumetanide, and phenytoin in the herbal called products, weight reducing and fat loss supplements. Caffeine, pseudoephedrine, theobromine and amfepramone were also found in these supplements. In this review article, the safety issues related to adulterated or mislabeled herbal products and the most common analytical methods for the detection of adulterated in the herbal weight loss products were reported.
... However, there are few if any RCTs of its longterm use especially with large sample sizes (25). Diethylpropion (75mg daily) demonstrated significantly greater weight loss in a small 24-week study of 20 patients than placebo (26). Diethylpropion (50mg twice a day) was shown to be more effective than placebo in a small 6-month RCT with 69 obese adult patients (9.3 kg versus 3.1 kg, respectively) (27) . ...
Obesity is a chronic disease associated with serious health problems such as metabolic syndrome, diabetes, hypertension, and cardiovascular diseases. Due to the growing trend of returning to nature and the fear of adverse reactions from conventional medicines, people are increasingly resorting to the use of herbal preparations. Adulterated herbal weight loss products containing undeclared synthetic drugs are common and responsible for many serious health damages. Because of long-term use and natural origin, these preparations give a sense of security. But herbal weight loss formulations also possess undesirable effects and, among other dangers, present a risk connected with deliberate addition of synthetic compounds, deliberate or unintentional replacement of the plant species or simply a risk of mislabeling. The most undeclared ingredients, which were illegally added include sibutramine, phenolphthalein, bumetanide, and phenytoin in the herbal called products, weight reducing and fat loss supplements. Caffeine, pseudoephedrine, theobromine and amfepramone were also found in these supplements. In this review article, the safety issues related to adulterated or mislabeled herbal products and the most common analytical methods for the detection of adulterated in the herbal weight loss products were reported.
... Tabela 4 -Estudos com medicamentos β-fenetilamínicos; SA = substância ativa; t = tempo de estudo; sem = semanas; N = número de pacientes no estudo; P = placebo; PC = prega cutânea; TEF = efeito térmico do alimento; VLCD = dieta de muito baixo valor calórico; NS = não significativo; SS = estatisticamente significativo A excelente revisão de Bray e Greenway (8) apresenta uma análise detalhada de alguns desses estudos. Apresentamos na Tabela 4, 41 estudos duplocegos com pelo menos dez semanas de duração, com derivados fenetilamínicos ou tricíclicos (dietilpropiona, (76)(77)(78)(79)(80)(81)(82)(83) mazindol (84)(85)(86)(87)(88)(89)(90)(91)(92)(93)(94)(95) , fentermina (96)(97)(98) , fenfluramina (99)(100) , dexfenfluramina (101)(102)(103)(104)(105)(106)(107)(108)(109)(110)(111)(112)(113)(114)(115) . Essas medicações cumprem os critérios atualmente usados para aprovação de medicamentos anti-obesidade (13)(14) exceto em relação à fenfluramina e à dexfenfluramina. ...
Pharmacological treatment of obesity is an area of sudden changes,development of new drugs and treatment propositions. This articlepresents information on physiological agents that are currentlybeing used as well as drugs that were widely used but are nomore available.
... A excelente revisão de Bray & Greenway (8) apresenta uma revisão detalhada de alguns desses estudos. Apresentamos na tabela 3, 41 estudos duplocegos com pelo menos dez semanas de duração, com derivados fenetilamínicos ou tricíclicos (dietilpropiona [76][77][78][79][80][81][82][83], mazindol [84,95], fentermina [96][97][98]), fenfluramina [99,100], dexfenfluramina [64,[101][102][103][104][105][106][107][108][109][110][111][112][113][114][115]). ...
A informação apresentada nesta revisão oferece uma visão da terapêutica corrente, bem como de medicamentos que já foram extensamente utilizados e que não mais estão disponíveis ou não são considerados classicamente agentes anti-obesidade. Os autores realizam uma extensa revisão sobre os critérios de avaliação de eficácia de tratamentos anti-obesidade, sobre agentes farmacológicos derivados beta-fenetilamínicos (anfepramona, fenfluramina, dexfenfluramina, fentermina e sibutramina), derivados tricíclicos (mazindol), derivados fenilpropanolamínicos (efedrina, fenilpropanolamina), derivado oxitrifluorfenil da fenilpropanolamina (fluoxetina), derivado naftilamínico (sertralina) e derivado da lipstatina (orlistat). É apresentada uma análise de todos os estudos clínicos de mais de dez semanas de duração com medicamentos usados no tratamento da obesidade.
... A variety of pharmacological compounds has been used as antiobesity agents in obese patients, including sibutramine, orlistat, rimonabant, fenfluramine, phentermine, mazindol, ephedrine, diethylpropion, amphetamine, fluoxetine and phenylpropanolamine [14][15][16][17][18][19][20][21]. However, less evidence exists regarding pharmacotherapy of obesity in obese individuals with type 2 diabetes. ...
Obesity is considered as a major health problem, as its prevalence continuously rises worldwide. One of the common health consequences of obesity is type 2 diabetes mellitus. Therefore, antiobesity management is a prerequisite in treating diabetic patients. Lifestyle modifications combined with pharmacological agents appear to be an effective approach. Sibutramine is a serotonin-noradrenaline reuptake inhibitor, which acts centrally by promoting the feeling of satiety and decreasing caloric intake, thus resulting in weight loss. A potential association with cardiovascular side effects has been noted. Orlistat, a gastric and pancreatic lipase inhibitor, also achieves significant weight loss and improves glycaemic status, but it has gastrointestinal side effects. Rimonabant, the first endocannabinoid CB1 antagonist, is associated with weight reduction and it improves diabetic parameters; nevertheless, it is associated with psychiatric disorders; indeed, a recently conducted safety review led to the temporal suspension of its commercialization. The above-mentioned medications seem to be currently useful agents for treating obesity in patients with type 2 diabetes mellitus. Other medications used for diabetes management, such as exenatide, liraglutide and pramlintide, have also shown body weight reduction. Ongoing research is needed to scrutinize the precise impact of these agents in the daily clinical practice of management of obesity in patients with type 2 diabetes mellitus.
... Both groups were placed on a "strict diet." 16 The second trial (32 people with mean weight 13 kg above ideal body weight) found no significant difference in weight loss between diethylproprion (75 mg/day) and placebo after treatment for 12 months ( − 8.9 kg with diethylproprion v − 10.5 kg with placebo; mean difference + 1.6 kg, 95% CI not reported). Both groups were placed on a "low carbohydrate diet." 17 Fluoxetine: We found three systematic reviews (search dates 1995, 1996, 1998), which identified two RCTs of at least one year's duration evaluating fluoxetine, a selective serotonin reuptake inhibitor. ...
Definition Obesity is a chronic condition characterised by an excess of body fat. It is most often defined by the body mass index, a mathematical formula that is highly correlated with body fat. Body mass index is weight in kilograms divided by height in metres squared (kg/m 2 ). In the United States and the United Kingdom, people with a body mass index between 25 and 30 are categorised as overweight, and those with an index above 30 are categorised as obese. 1 Incidence/prevalence The prevalence of obesity has increased steadily in many countries since 1900. In England, in 1994, it was estimated that 13% of men and 16% of women were obese. 1,2 In the past decade alone, the prevalence of obesity in the United States has increased from 12.0% in 1991 to 17.9% in 1998. 3 Aetiology The aetiology of obesity includes both genetic and environmental factors. Obesity may also be induced by drugs (high dose glucocorticoids, for example) or be secondary to a variety of neuroendocrine disorders such as Cushing's syndrome and polycystic ovary syndrome. 4 Prognosis Obesity is a risk factor for several chronic diseases, including hypertension, dyslipidaemia, diabetes, cardiovascular disease, sleep apnoea, osteoarthritis, and some cancers. 1 The relation between increasing body weight and mortality is curvilinear, with mortality increasing in people with low body weight. Whether this is caused by increased mortality risk at low body weights or by unintentional weight loss is not clear. 3 Results from five prospective cohort studies and national statistics for 1991 show that in US adults about 280 000 deaths a year are attributable to obesity. 6 Aims To achieve realistic gradual weight loss and prevent the morbidity and mortality associated with obesity, without undue adverse effects. Outcomes We found no studies that used the primary outcomes of functional morbidity or mortality. Proxy measures include mean weight loss (kg), number of people losing 5% or more of baseline body weight, and maintenance of weight loss.
... 28 Such studies show a consistent but moderate difference in weight loss (a difference of 2 to 10 kg) in comparisons with placebo. [32][33][34][35][36][37] Side effects of noradrenergic medications include insomnia, dry mouth, constipation, euphoria, palpitations, and hypertension. 7 Although the most widely used of these compounds, phentermine, was used in combination with fenfluramine, it has not been independently associated with valvular heart disease. ...
Overweight and obesity are the most common nutritional disorders in the United States, affecting the majority of adults in the country. The prevalence of obesity has increased by more than 75 percent since the 1980's. Health care professionals should be concerned about overweight and obesity because of the well-established relations between excess body weight and such medical conditions as type 2 diabetes, hypertension, and osteoarthritis. Medications for the treatment of obesity are currently approved for the use in adults who have a body mass index of 27 or higher plus obesity-related medical conditions or a body-mass index of 30 or higher in the absence of such conditions. In this review, we briefly examine nonpharmacologic approaches to promoting weight loss and give greater consideration to the use of medications such as adjunctive therapy in the management of obesity. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
... Bray & Greenway's excellent review (8) includes a detailed analysis of some of those studies. Table 3 reports 41 studies which were at least 10 weeks long, on phenethylaminics or tricyclics such as diethylpropion (81)(82)(83)(84)(85)(86)(87)(88), mazindol (89-100), phentermine (101-103), fenfluramine (104,105) and dexfenfluramine (38,43,44,72,(106)(107)(108)(109)(110)(111)(112)(113)(114)(115)(116)(117). These medications comply with criteria currently used for anti-obesity medications (13,14), except for fenfluramine and dexfenfluramine. ...
The information presented in this article provides an overview of physiological agents, therapeutics in current use, and medications that have been extensively used in the past but are no longer available, or are not classically considered as anti-obesity drugs. The authors present an extensive review on the criteria for anti-obesity management efficacy, on physiological mechanisms that regulate central and/or peripheral action energetic homeostasis (nutrients, monoamines and peptides), and on beta-phenethylamine pharmacological-derivative agents (fenfluramine, dexfenfluramine, phentermine, diethylpropion, fenproporex and sibutramine), tricyclic derivatives (mazindol), phenylpropanolamine derivatives (ephedrine, phenylpropanolamine), a phenylpropanolamine oxy-tri-fluor-phenyl derivative (fluoxetine), a naftilamine derivative (sertraline) and a lipstatine derivative (orlistat). An analysis of all clinical trials longer than 10 weeks in duration is also presented for medications used in the management of obesity.
... A excelente revisão de Bray & Greenway (8) apresenta uma revisão detalhada de alguns desses estudos. Apresentamos na tabela 3, 41 estudos duplocegos com pelo menos dez semanas de duração, com derivados fenetilamínicos ou tricíclicos (dietilpropiona [76][77][78][79][80][81][82][83], mazindol [84,95], fentermina [96][97][98]), fenfluramina [99,100], dexfenfluramina [64,[101][102][103][104][105][106][107][108][109][110][111][112][113][114][115]). ...
This review offers an overview of physiological agents, current therapeutics, as well as medications, which have been extensively used and those agents not currently available or non-classically considered anti-obesity drugs. As obesity - particularly that of central distribution - represents an important triggering factor for insulin resistance, its pharmacological treatment is relevant in the context of metabolic syndrome control. The authors present an extensive review on the criteria for anti-obesity management efficacy, on physiological mechanisms that regulate central and/or peripheral energy homeostasis (nutrients, monoamines, and peptides), on beta-phenethylamine pharmacological derivative agents (fenfluramine, dexfenfluramine, phentermine and sibutramine), tricyclic derivatives (mazindol), phenylpropanolamine derivatives (ephedrin, phenylpropanolamine), phenylpropanolamine oxytrifluorphenyl derivative (fluoxetine), a naftilamine derivative (sertraline) and a lipstatine derivative (orlistat). An analysis of all clinical trials - over ten-week long - is also presented for medications used in the management of obesity, as well as data about future medications, such as a the inverse cannabinoid agonist, rimonabant.
As obesity prevalence increases, more and more drugs that assist with weight loss have been developed. Numerous weight loss drugs had been approved, but many have also been withdrawn based on their lack of efficacy as well as safety concerns. Initial approaches in developing weight loss drugs was by increasing physiological energy expenditure and suppressing the appetite. Subsequently, as more physiological mechanisms for weight gain has been unearthed, drugs targeting newly discovered receptors and/or enzymes have been introduced with improved safety profiles and fewer psychological adverse events. Additionally, drugs targeting hunger or satiety signaling have been actively studied, and have shown increased adoption by physicians. Studies have also evaluated drugs that target metabolic tissues—such as adipose tissue or muscle—to promote weight loss, however to-date nothing has carried on into clinical practice. Starting with a brief history of early obesity treatments, this review evaluates current weight loss pharmaceutical options based on their duration of therapy status.
Purpose:
Obesity is a chronic clinical condition that is considered one of the most serious health problems in the world because it can cause other chronic metabolic disorders. A meta-analysis was conducted to evaluate the safety and efficacy of 4 central-acting drugs, all approved in Brazil's market for weight loss.
Methods:
PubMed, EMBASE, and Cochrane library databases were searched from inception until January 2018 to retrieve randomized controlled trials comparing sibutramine, diethylpropion, mazindol, and fenproporex versus placebo in overweight or obese patients. Language was not a restriction for the database searches. We extracted and combined data from studies that reported adverse drug events and weight change. A random effects meta-analytic model was applied in all calculations. The Cochrane Collaboration tool was used to assess the quality and bias of all included studies. Quality of evidence was assessed by using the Grading of Recommendations, Assessment, Development, and Evaluation criteria.
Findings:
Fifty-three studies were included, with a total of 16,903 patients with a median follow-up of 12 weeks (2-260 weeks). The appetite suppressants showed a significant weight loss compared with placebo (mean difference [MD], -4.70 kg; 95% CI, -5.25 to -4.15; I2 = 100%; 43 studies). There was an increased total number of adverse events, dry mouth, constipation, insomnia, dizziness, and tachycardia reported in the intervention group (risk ratio [RR], 1.06; 95% CI, 1.01 to 1.10; I2 = 20% [22 studies]; RR, 2.08; 95% CI, 1.76 to 2.47; I2 = 34% [25 studies]; RR, 2.31; 95% CI, 1.88 to 2.84; I2 = 0% [25 studies]; RR, 1.84; 95% CI, 1.40 to 2.39; I2 = 0% [17 studies]; RR, 1.78; 95% CI, 1.24 to 2.58; I2 = 0% [13 studies]; and RR, 2.01; 95% CI, 1.42 to 2.86; I2 = 0% [10 studies], respectively). Sibutramine showed a significant increase in heart rate and mean diastolic pressure compared with placebo (MD, 4.17 beats/min [95% CI, 3.60 to 4.74; I2 = 99%; 23 studies]; MD, 1.68 mm Hg [95% CI, 1.29 to 2.07; I2 = 98%; 22 studies]).
Implications:
These drugs are effective for weight loss in overweight and obese patients; however, they increase the risk of adverse events. In fact, the evidence is of low quality, the data availability of studied agents (especially for cardiovascular outcomes) are limited, and the studies are of short duration. PROSPERO identifier: CRD42018091083.
Obesity is the leading form of malnutrition in our affluent nations. In the United States, for example, between 40 to 80 million individuals are considered obese. Obesity is defined in terms of an excess of body fat, although there is little agreement as to the precise technique for determining who is obese.
Amphetamine and related central stimulant drugs are derivatives of β-phenylethylamine (Table 1) and are thus relatively simple organic bases. The general β-phenylethylamine skeleton is one which amphetamine shares with the neurotransmitters noradrenaline, adrenaline, and dopamine. Phenylethylamine itself has central stimulant properties, but has an extremely short half-life in the body due to rapid metabolism by monoamine oxidase (MAO). Amphetamine has, due to steric hindrance by the α-methyl group, much less affinity for MAO and therefore has a longer half-life.
It has been estimated that well over 5 million prescriptions were written for the anti-obesity drugs in 1966 in the United Kingdom. Since then, the number of scripts issued has steadily fallen to ‘only’ slightly more than 3 million prescriptions in 1975. This figure would suggest that either the anti-obesity drugs are effective or that they are being extensively over-prescribed. At present, more than one-third of subjects enrolling in a slimming organization will have previously taken at least one anti-obesity agent, and more than three-quarters of subjects referred by general practitioners to a hospital obesity clinic will have previously received drug therapy. It follows that subjects with a weight problem of sufficient concern to make them seek medical attention may, at present, reasonably expect to be prescribed a weight-reducing drug. Certainly most general practitioners prescribe at least one anti-obesity agent, and the majority of patients say that they find such drugs are helpful. Indeed, in a recent survey undertaken by the Consumers’ Association, appetite-suppressant drugs were rated by women slimmers to be the best method of achieving rapid weight loss. However, only 16% of these women considered that dieting with the aid of appetite-reducing pills was a successful method of producing a long-term weight loss1.
This review presents information regarding current therapy and also about pharmacological treatments commonly used in the past, but not available anymore or not considered formally as anti-obesity agents. Authors made an extensive review about the criteria used by American and European agencies to evaluate efficacy and to approve anti-obesity drugs. They also consider pharmacological agents β-phenetilamine derivatives (dietylpropion, fenfluramine, dexfenfluramine, phentermine and sibutramine), tricyclic derivatives (mazindol), phenylpropanolamine derivatives (ephedrine, phenylpropanolamine), an oxi-tri-fluor-phenylpropanolamine derivative (fluoxetina), a naftilamine derivative (sertraline), a lipstatine derivative (orlistat) and a cannabinoid-1 receptor antagonist (rimonabant). An analysis of all clinical trials lasting more than ten weeks with drugs used in the treatment of obesity is presented.
I. Introduction II. Criteria for Evaluating the Efficacy of Antiobesity Treatment III. Physiological and Pharmacological Mechanisms to Reduce Food Intake A. Peripherally acting agents B. Centrally acting agents IV. Drugs That Alter Metabolism A. Preabsorptive agents B. Postabsorptive modifiers of nutrient metabolism V. Drugs That Increase Energy Expenditure A. Thyroid hormone B. Adrenergic thermogenic drugs VI. Conclusion
Anorectic drugs, as their name implies, are substances which, when given in adequate dosage, produce a state of anorexia, a condition defined as ‘being without appetite’; indeed, anorectic drugs are often called ‘appetite suppressants’. The term ‘appetite’ refers to an individual’s tendency to experience ‘hunger’, a state which, in turn, may be defined as ‘the desire to eat’; hunger being generally regarded as a more immediate sensation than appetite. Hunger can change from hour to hour whereas appetite, although also referring to the desire for food, is usually used in a context where change is less rapid.
The treatment of obesity is one of the major measures available today in the field of preventive medicine. In particular, the coronary epidemic of Western civilisation would be halted, and most cases of maturity-onset diabetes prevented, if obesity were to be treated effectively.
Anorectic drugs act mainly on the satiety centre in the hypothalamus to produce anorexia. They also have various metabolic effects involving fat and carbohydrate metabolism, but many of these may be secondary to loss of weight. Most of the drugs are related directly or indirectly to amphetamine and in addition act by increasing general physical activity. Anorectic drugs tend to lose their effect after some months, and part of this reduction in effect may be due to chemical alterations produced by the drugs in the brain. All the drugs, with the exception of fenfluramine, have a stimulant effect on the central nervous system in some individuals, resulting in restlessness and nervousness, irritability and insomnia. Fenfluramine commonly produces drowsiness in normal doses, but has stimulant effects with overdosage. Dexamphetamine, phenmetrazine and benzphetamine all tend to cause euphoria and the risk of addiction is therefore considerable. Euphoria occasionally occurs with diethylpropion, phentermine and chlorphentermine, but to a much lesser extent.
Side-effects also occur due to sympathetic stimulation and gastro-intestinal irritation. These side-effects may cause some individuals to stop taking the drug, but are never serious or dangerous. Drug interactions may occur with monoamine oxidase inhibitors and to a clinically unimportant extent, with antihypertensive drugs.
The anorectic drugs have a very definite part to play in the treatment of obesity, mainly for those individuals who have altered their eating habits but have come to a plateau of weight which they find difficult to get below. The drugs are best given in a long-acting form and can safely be continued as long as weight loss persists, provided that the clinician exercises careful supervision. Dexamphetamine, phenmetrazine and benzphetamine should rarely be used because of the danger of addiction, and chlorphentermine is potentially hazardous for long-term use. Diethylpropion emerges as the drug of first choice, as fenfluramine has a tendency to cause depression and has a higher incidence of side-effects. Fenfluramine is mainly useful for people who are especially tense and for obese maturity-onset diabetics who have been unable to lose weight with the biguanides. Mazindol and phentermine appear to be useful as alternative drugs.
Being obese goes beyond moral failure or a character flaw. Obesity has the defining characteristics of a chronic disease for which there is no cure. Treatment may require lifelong treatment which may include pharmacotherapy. Experience with long term use of obesity drugs is limited but evidence suggests that pharmacotherapy can improve patient outcomes and patient outlook. With current obesity drugs, weight loss is usually modest but clinically significant satisfying the FDA threshold for drug effectiveness. This weight loss is associated with clinically significant improvements in many obesity co morbidities and risk factors and could eliminate some risk factors with continued use. When used in conjunction with a comprehensive program for weight management, obesity drugs can reduce appetite or hunger, increase satiety, provide improved control over aberrant eating behaviors and modify food seeking behaviors. Pharmacotherapy can enhance weight loss and compliance during the periods of weight loss and in maintaining that weight loss, increasing physical activity and may enhance a focus on making life long changes.
This article will discuss mechanisms of action of obesity drugs, theories of altered body defense of body weight, Food and Drug Administration (FDA) approved obesity drugs, and off-label use of FDA approved drugs. The value of over-the counter (OTC) medications and diet supplements, as well as fat substitutes in the treatment of obesity drugs will be explored. Obesity drugs awaiting FDA approval and compounds under development will be reviewed. The section on approaches to drug management will include clinical considerations for; who should receive pharmacotherapy and when, length of treatment and drug discontinuation, weight regain and the role of pharmacotherapy.
Excess adiposity and obesity are the root cause of at least 27 diseases that cause considerable lifelong morbidity and, in many scenarios, eventual cardiovascular mortality. The human body has the ability to increase the number and size of its adipocytes by approximately 10-fold over the course of a lifetime. As fat mass increases, its blood supply, supporting cells, tissue structure, and local and systemic hormonal control also increase. This results in excess adiposity, leading to progressive obesity and the resistance to weight-loss attempts. There have been numerous trials of food diets combined with exercise that, in general, have a 50% dropout rate at 1 year and lead to very modest (∼ 5%) reductions in body weight. Thus, many with obesity require interventions beyond casual diet and exercise advice. Meal replacement diets and bariatric surgery offer considerably greater degrees of weight loss, but both can be plagued by weight regain. Because the ability to control food urges has been shown to be a key psychological factor for success, medicinal approaches that work in this domain are attractive adjuncts to diet, exercise, and weight-loss surgery. This article reviews the emerging role of medical therapy in the treatment of excess adiposity with the goal of reducing comorbidities and possibly improving cardiovascular survival.
Medicating for treatment of obesity can be a useful adjunct to diet and exercise and can help selected patients achieve and
maintain meaningful weight loss. A report from the Heart, Lung and Blood Institute of the National Institutes of Health entitled
Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults—The Evidence Report (1) emphasizes the need for physicians to address obesity in their patients. This report sanctions the clinical use of weight
loss drugs approved by the US Food and Drug Administration (FDA) for long-term use as part of a concomitant lifestyle-modification
program. Appropriate patients include those who have been unsuccessful in previous weight-loss attempts and whose BMI exceeds
27 kg/m2 who have associated conditions such as diabetes, hypertension, or dyslipidemia, or whose BMI exceeds 30 kg/m2. Still, for many physicians, treatment of obesity is not a routine part of their clinical practices, in part because of the
stigma associated with medication usage.
The treatment of obesity is one of the major measures available today in the field of preventive medicine. In particular, the coronary epidemic of Western civilisation would be halted, and most cases of maturity-onset diabetes prevented, if obesity were to be treated effectively. Anorectic drugs act mainly on the satiety centre in the hypothalamus to produce anorexia. They also have various metabolic effects involving fat and carbohydrate metabolism, but many of these may be secondary to loss of weight. Most of the drugs are related directly or indirectly to amphetamine and in addition act by increasing general physical activity. Anorectic drugs tend to lose their effect after some months, and part of this reduction in effect may be due to chemical alterations produced by the drugs in the brain. All the drugs, with the exception of fenfluramine, have a stimulant effect on the central nervous system in some individuals, resulting in restlessness and nervousness, irritability and insomnia. Fenfluramine commonly produces drowsiness in normal doses, but has stimulant effects with overdosage. Dexamphetamine, phenmetrazine and benzphetamine all tend to cause euphoria and the risk of addiction is therefore considerable. Euphoria occasionally occurs with diethylpropion, phentermine and chlorphentermine, but to a much lesser extent. Side-effects also occur due to sympathetic stimulation and gastro-intestinal irritation. These side-effects may cause some individuals to stop taking the drug, but are never serious or dangerous. Drug interactions may occur with monoamine oxidase inhibitors and to a clinically unimportant extent, with antihypertensive drugs. The anorectic drugs have a very definite part to play in the treatment of obesity, mainly for those individuals who have altered their eating habits but have come to a plateau of weight which they find difficult to get below. The drugs are best given in a long-acting form and can safely be continued as long as weight loss persists, provided that the clinician exercises careful supervision. Dexamphetamine, phenmetrazine and benzphetamine should rarely be used because of the danger of addiction, and chlorphentermine is potentially hazardous for long-term use. Diethylpropion emerges as the drug of first choice, as fenfluramine has a tendency to cause depression and has a higher incidence of side-effects. Fenfluramine is mainly useful for people who are especially tense and for obese maturity-onset diabetics who have been unable to lose weight with the biguanides. Mazindol and phentermine appear to be useful as alternative drugs.
Centrally acting appetite suppressant drugs used in the treatment of obesity fall into 2 broad pharmacological categories; those which act via brain catecholamine pathways and those which act via serotonin pathways. Of the former group, amphetamine and phenmetrazine are no longer recommended because of their stimulant properties and addictive potential. The remaining drugs in this class include amfepramone (diethylpropion), phentermine, mazindol and phenylpropanolamine. All have been shown to reduce appetite and lower food intake, thereby helping obese patients more easily keep to a low-calorie diet and lose weight. They all have some sympatho-mimetic and stimulant properties. Anorectic drugs which promote serotonin neurotransmission have no such stimulant or sympathomimetic properties. They are fenfluramine, together with its recently introduced dextrorotatory stereoisomer dexfenfluramine, and fluoxetine. They reduce appetite and food intake and are effective in the treatment of obesity.
Anorectic drugs should be reserved for those who are clinically at risk from being overweight, and then only as part of a comprehensive weight-reducing programme including regular dietary counselling. Although current licensing regulations only allow their use over a relatively short period (12 to 16 weeks), clinical trials have shown them to be effective over longer periods, particularly in preventing weight regain. Of the compounds currently indicated for use in obesity, dexfenfluramine appears to have the most suitable pharmacological profile, although it should not be given to patients with a history of depression.
When used appropriately, appetite suppressants can be of real therapeutic benefit, and pose little risk.
We reviewed 20 English-language weight-reduction studies, reported between 1967 and March 1993, of the effect of > or = 6 mo of pharmacologic therapy on weight loss and its maintenance to determine the clinical benefits of extended treatment, propose treatment guidelines, and identify future research needs. Pharmacologic agents included phentermine, mazindol, fenfluramine, dexfenfluramine, and fluoxetine. Study designs varied with respect to blinding, use of a single agent vs a combination, dosing, length of therapy, patient selection, adjunctive therapy, and visit frequency. At endpoint, weight loss varied from study to study but a plateauing of weight loss or weight regain was observed after approximately 6 mo. The benefits of extended treatment appear to outweigh the risks for those patients who are unable to lose sufficient weight without pharmacologic therapy but who maintain adequate weight loss with long-term pharmacologic therapy. Future studies should define and evaluate pharmacologically responsive and unresponsive subgroups.
Most of the available appetite-suppressant drugs act on noradrenergic and possibly dopaminergic receptors to produce satiety. A smaller number increase excess neuronal serotonin levels by blocking serotonin reuptake or by increasing its release. All these drugs produce significantly greater weight loss than does placebo in most studies. Abuse is a problem with amphetamine, methamphetamine, and benzphetamine, whereas other drugs have minimal or no potential for abuse. Weight loss can be sustained for up to 36 months. Net weight loss, compared with placebo, ranges from 2 to 10 kg, and weight regain after terminating drug treatment proves that drugs do not work when not taken. The stigma of obesity, the public opprobrium toward obese persons, and regulatory rigidity have led to unjustified distrust in the potential of drug treatment for obesity.
Criteria for the evaluation of new drugs to treat obesity are important as guides for designing clinical trials to test these agents. These criteria must be developed in relation to the realities of obesity, which is a chronic disease associated with morbidity and mortality that is increased by visceral fat deposits. The observation that patients regain weight after stopping drug treatment for obesity argues for the proposition that drugs work only when taken and NOT that the drugs are ineffective. The analogy between the development of treatments for obesity to those for the treatment of hypertension is used to highlight potential areas for new developments. Several features of an ideal drug for the treatment of obesity are suggested. Criteria for evaluating new drugs include both primary and secondary endpoints. The primary endpoint for an anti-obesity drug should be weight loss, possibly by category of success. Losses of total body fat or visceral fat might be alternative primary endpoints. Secondary endpoints include reduction in risk factors for associated diseases and improvement in the quality of life. In trials where vigorous placebo designs including highly aggressive behavior modification or very-low-calorie diets were used, it may be difficult or impossible to detect a response to a drug.
This review evaluates the benefits and potential health risks of the currently used drugs that are approved for the pharmacological treatment of obesity. Analysis of several long term clinical trials indicates that all of these drugs are efficient in reducing excess bodyweight, and that the majority of them allow the maintenance of the reduced bodyweight for at least 1 year. However, the loss of body-weight attributable to these drugs is in general rather modest, approaching only 0.2kg per week during the first 6 months of treatment, and at least a partial regain of bodyweight occurs when these drugs are used for periods longer than 1 year.
All of these drugs induce several adverse effects. Although most of these adverse effects are mild and transient, the prolonged use of adrenergic or serotonergic anorectic drugs, or their use as combination treatment, may induce serious and potentially life-threatening complications, such as primary pulmonary hypertension or valvular heart disease. The adrenergic appetite-suppressing drugs are not recommended for the treatment of obesity, since their safety has never been evaluated in long term clinical trials, and because of their stimulatory effects on the cardiovascular and nervous systems. The serotonergic drugs, such as fenfluramine and dexfenfluramine, have been the most widely used during the past decade; however, both these compounds have recently been withdrawn from the market, since their use was associated with serious cardiovascular complications. The safety of the prolonged therapeutic use of newer compounds such as sibutramine and orlistat has not yet been demonstrated. Therefore, none of the currently available anti-obesity medications meets the criteria of an ‘ideal anti-obesity drug’ and, if prescribed, these medications should be used with caution and only under careful medical supervision.
Since obesity is recognised as a chronic health-threatening condition, and since classical behavioural therapeutic approaches lack long term efficacy, there is clearly a need for an efficient pharmacological treatment offering an acceptable safety profile. Such a treatment is not available at present. Development of new agents and a more careful assessment of the safety of currently available drugs are needed.
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.
This meta-analysis evaluated the types of lifestyle treatments used in published obesity drug studies and assessed their contribution to weight losses associated with pharmacological interventions.
Randomized, placebo-controlled, double-blind clinical trials of anti-obesity agents that are/were Food and Drug Administration-approved for the treatment of obesity (both prescription and over-the-counter), and drugs that are Food and Drug Administration-approved and are used off-label for obesity were included. Studies were located by computer searches of databases (e.g., Medline, PsychInfo) and reviewing tables of content/reference sections of journals, abstracts, previous reviews, past empirical studies, relevant book chapters, and recent issues of journals that regularly publish obesity research. In addition, a number of individuals who regularly publish in the obesity literature were asked to provide personal lists of obesity-drug studies. Based on the above criteria, a total of 108 randomized clinical trials were located.
Balanced-deficit diets, low-calorie diets, and self-monitoring were the most used lifestyle treatments in published obesity studies. They were incorporated into 40.7%, 25%, and 23.1% of pharmacotherapy studies, respectively. Physical activity and other behavioral or psychotherapeutic interventions rarely were used. A substantial portion of weight loss experienced by patients was attributable to both "placebo effects" and to the lifestyle treatments.
Obesity-pharmacotherapy trials do not use lifestyle treatments with the frequency expected based on the official positions of most professional organizations concerned with the comprehensive management of obesity.
At present only two drugs are approved for long-term treatment of obesity. Sibutramine inhibits the reuptake of serotonin and norepinephrine. In clinical trials it produces a dose-dependent 5-10% decrease in body weight. Its side effects include dry mouth, insomnia, asthenia, and constipation. In addition, sibutramine produces a small increase in blood pressure and pulse that is a contraindication to the use of this drug in some individuals with heart disease. Xenical is the other drug approved for long-term use in the treatment of obesity. It works by blocking lipase and thus increasing the fecal loss of triglyceride. One valuable consequence of this mechanism of action is the reduction of serum cholesterol that averages about 5% more than can be accounted for by weight loss alone. In clinical trials it produces a 5-10% loss of weight. Its side effects are entirely due to undigested fat in the intestine that can lead to increased frequency and change in the character of stools. It can also lower fat-soluble vitamins. The ingestion of a vitamin supplement before bedtime is a reasonable treatment strategy. The effect on weight loss during long-term trials with these two drugs is shown in Figs 7 and 8 above. Also in this figure is data on phentermine used in trials of six months or more. Although there were differences in mean weight losses with these drugs, when the placebo effect was taken into account they all had a surprisingly similar magnitude of weight loss.
This article provides the first comprehensive meta-analysis of randomized clinical trials of medications for obesity.
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.
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.
Drugs to treat obesity can be divided into three groups: those which reduce food intake, those which alter metabolism and those which increase thermogenesis. Monoamines acting on noradrenergic receptors, serotonin receptors, dopamine receptors and histamine receptors can reduce food intake. A number of peptides also affect food intake. The noradrenergic drugs phentermine, diethylpropion, mazindol benzphetamine and phendimetrazine are approved only for short-term use. Sibutramine, a norepinephrine–serotonin re-uptake inhibitor, is approved for long-term use. Orlistat inhibits pancreatic lipase and can block 30% of triglyceride hydrolysis in subjects eating a 30% fat diet. The only thermogenic drug combination that has been tested is ephedrine and caffeine, but this treatment has not been approved by regulating agencies. Leptin is currently in clinical trials and other drugs that may modulate peptide-feeding systems are being developed.
Although a nutritionally balanced, energy-controlled diet and regular exercise form the cornerstone of weight management, supporting therapies may include antiobesity medications when a clinician determines that pharmacologic assistance could contribute to treatment success. The US Food and Drug Administration has approved certain medications for helping achieve weight loss in patients with obesity or overweight who have comorbidities. However, some clinicians prescribe medications not approved for weight loss for this purpose. Evidence from clinical trials indicates that weight loss resulting from the use of many of these off-label pharmaceutical agents is modest, but in a range that correlates with favorable modification of cardiovascular risk factors, and significant when compared with placebo plus diet and lifestyle modification. Clinical trials also demonstrate a slight but significant effect in the weight-maintenance phases following weight loss. Pharmacotherapy alone, without behavior modification, is not effective; patients who respond to medication typically regain weight when the drug is discontinued. The fact that many weight-loss medications are sold over the Internet without a prescription suggests that they are being used without medical supervision. The purpose of this review is to present evidence for and against the obesity medications currently used in clinical practice, and the possible role for these agents in a person's overall weight loss plan.
Pharmacotherapy for the management of obesity is primarily aimed at weight loss, weight loss maintenance and risk reduction, and has included thyroid hormone, amphetamines, phentermine, amfepramone (diethylpropion), phenylpropanolamine, mazindol, fenfluramines and, more recently, sibutramine and orlistat. These agents decrease appetite, reduce absorption of fat or increase energy expenditure.
Primary endpoints used to evaluate anti-obesity drugs most frequently include mean weight loss, percentage weight loss and proportion of patients losing ≥5% and ≥10% of initial body weight. Secondary endpoints may include reduction in body fat, risk factors for cardiovascular disease and the incidences of diseases such as diabetes mellitus.
Most pharmacotherapies have demonstrated significantly greater weight loss in patients on active treatment than those receiving placebo in short-term (≤1 year) randomised controlled trials of pharmacological treatment in conjunction with a calorie-controlled diet or lifestyle intervention. The evidence of long-term efficacy is limited to sibutramine (2 years) and orlistat (4 years). These are the only drugs currently approved for the long-term management of obesity in adults. Sibutramine recipients randomised following 6 months’ treatment to either sibutramine or placebo demonstrated significantly better weight maintenance at 2 years than those taking placebo (p < 0.001), with ≥10% loss of initial bodyweight in 46% of patients. For patients taking orlistat, weight loss was 2.2kg greater than those on placebo at 4 years (p < 0.001), with significantly more patients achieving ≥10% loss of initial bodyweight (26.2% and 15.6%, respectively; p < 0.001).
Other drugs that have been evaluated for weight loss include ephedrine, the antidepressants fluoxetine and bupropion, and the antiepileptics topiramate and zonisamide. Two clinical trials with fluoxetine both reported no significant difference in weight loss compared with placebo at 52 weeks. Clinical trials evaluating ephedrine, bupropion, topiramate and zonisamide have demonstrated significantly greater weight loss than placebo but have been limited to 16–26 weeks’ treatment.
A major obstacle to the evaluation of the clinical trials is the potential bias resulting from low study completion rates. Completion rates varied from 52.8% of phentermine recipients in a 9-month study, to 40% of fenfluramine recipients in a 24-week comparative study with phentermine and 18% of amfepramone recipients in a 24-week study. One-year completion rates range from 51% to 73% for sibutramine and from 66% to 85% for orlistat. Other potential sources of bias include run-in periods and subsequent patient selection based on compliance or initial weight loss.
Several potential new therapies targeting weight loss and obesity through the CNS pathways or peripheral adiposity signals are in early phase clinical trials. Over the next decade the drug treatment of obesity is likely to change significantly because of the availability of new pharmacotherapies to regulate eating behaviours, nutrient partitioning and/or energy expenditure.
Coronary artery disease is the leading cause of death and disability in our Society. Coronary artery bypass graft surgery can be associated with remarkable relief of symptoms secondary to myocardial ischemia, and in selected cohorts, with prolonged survival. However, many patients have recurrent disease and symptoms. This vicious cycle continues to deplete medical resources and to keep the morbidity associated with CAD at unacceptable levels. Secondary prevention strategies are essential in the battle against heart disease. We have outlined a comprehensive cardiac rehabilitation protocol designed for the post-CABG patient. It incorporates not only exercise, traditionally an essential part of rehabilitation, but also risk factor modification, psychosocial readjustment, weight management, and inpatient rehabilitation. With the standardized and consistent application of such protocols a significant decrease in the morbidity and even the mortality associated with coronary heart disease can be anticipated.7,16,27,47-51.
Desirable weights of adults, 40,712. 493 Curr Med Res Opin Downloaded from informahealthcare
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Statist. Bull. Metrop. Life Insur. Co., (1959). Desirable weights of adults, 40,712. 493 Curr Med Res Opin Downloaded from informahealthcare.com by ThULB Jena on 11/12/14 For personal use only.
Desirable weights of adults
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