Article

Blood Pressure and Heart Rate Effects, Weight Loss and Maintenance During Long-Term Phentermine Pharmacotherapy for Obesity

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Abstract

There is a perception that phentermine pharmacotherapy for obesity increases blood pressure and heart rate (HR), exposing treated patients to increased cardiovascular risk. We collected data from phentermine-treated (PT) and phentermine-untreated (P0) patients at a private weight management practice, to examine blood pressure, HR, and weight changes. Records of 300 sequential returning patients were selected who had been treated with a low-carbohydrate ketogenic diet if their records included complete weight, blood pressure, and HR data from seven office examinations during the first 12 weeks of therapy. The mean time in therapy, time range, and mode was 92 (97.0), 12-624, and 52 weeks. 14% were normotensive, 52% were prehypertensive, and 34% were hypertensive at their first visit or had a previous diagnosis of hypertension. PT subjects systolic blood pressure/diastolic blood pressure (SBP/DBP) declined from baseline at all data points (SBP/DBP -6.9/-5.0 mm Hg at 26, and -7.3/-5.4 at 52 weeks). P0 subjects' declines of SBP/DBP at both 26 and 52 weeks were -8.9/-6.3 but the difference from the treated cohort was not significant. HR changes in treated/untreated subjects at weeks 26 (-0.9/-3.5) and 52 (+1.2/-3.6) were not significant. Weight loss was significantly greater in the PT cohort for week 1 through 104 (P = 0.0144). These data suggest phentermine treatment for obesity does not result in increased SBP, DBP, or HR, and that weight loss assisted with phentermine treatment is associated with favorable shifts in categorical blood pressure and retardation of progression to hypertension in obese patients.

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... Studies on the effect of phentermine alone on weight reduction have shown a mean weight loss of 5% over a short-term period (no studies of safety or efficacy beyond 1 year have been done) (9)(10)(11)(12). While increased heart rate and blood pressure are often cited as potential adverse effects (13,14), a number of studies have shown decreases in blood pressure (12,15,16), likely related to weight loss (although the decrease is generally less than that achieved by patients who achieve similar weight loss on placebo) (17). A South Korean group performed post-marketing surveillance research on phentermine, finding that while adverse events due to phentermine were very common (30%), in most cases they were mild (insomnia and dry mouth), (18). ...
... As phentermine is thought to cause weight loss through suppression of hunger, it could be hypothesized that those individuals who eat excessively due to hunger (as opposed to emotional stress, boredom, etc.) might have a better weight loss response. However, only one study has made any mention of decreased hunger in phentermine-treated patients (15), and this was anecdotal. ...
... This suggests effects of treatment outside of the expected effects on hunger. One other study has suggested similar effects of phentermine treatment, through anecdotal reports of patients describing "stronger control of eating, diminution or absence of food cravings, or improved ability to follow their eating plan" (15). These effects on eating behavior are likely reflected in part by our findings of reduced disinhibition and increased CR with phentermine treatment. ...
Article
Objective: Phentermine is thought to cause weight loss through a reduction in hunger. It was hypothesized that higher hunger ratings would predict greater weight loss with phentermine. Methods: This is an observational pilot study in which all subjects were treated with phentermine for 8 weeks and appetite and eating behaviors were measured at baseline and week 8. Outcomes were compared in subjects with ≥5% vs. <5% weight loss, and linear regression was used to identify predictors of percent weight loss. Results: Twenty-seven subjects (37 ± 4.5 years, 93.8 ± 12.1 kg, BMI 33.8 ± 3.1 kg m(-2) ) completed the study, with mean weight loss of -5.4 ± 3.3 kg (-5.7% ± 3.2%). Subjects with ≥5% weight loss had higher baseline pre-breakfast hunger (P = 0.017), desire to eat (P =0.003), and prospective food consumption (0.006) and lower baseline cognitive restraint (P = 0.01). In addition, higher baseline home prospective food consumption (P = 0.002) and lower baseline cognitive restraint (P < 0.001) were found to be predictors of weight loss. Conclusions: These results suggest that individuals reporting greater hunger and less restraint are more likely to achieve significant weight loss with phentermine. This information can be used clinically to determine who might benefit most from phentermine treatment.
... Phenterminewas the most extensively used weight-loss pharmacotherapy in the United States (21) before the approval of new therapies and probably still is. It is available in two formulations: phentermine HCl: 1) an immediate release formulation with fast dissolution and absorption in the gastrointestinal tract that is approved for use at a dose of 15.0-37.5 mg/day for up to 12 weeks, and 2) phentermine resin-a slow release formulation drug that is also approved for short-term treatment of obesity (64). Both have been evaluated as a monotherapy in several studies for up to 36 weeks. ...
... One concern of chronic use of phentermine for obesity treatment is its sympathomimetic effects that can increase BP and HR (64,66,67). It is also a central nervous system stimulant and the risk of addiction due to its similarity to amphetamine is another concern (68). ...
... Similar findings were observed in clinical studies with phentermine monotherapy with either reductions in HR and BP or no significant changes in BP (64,65). ...
Article
Introduction: Few studies on combination therapies for the treatment of obesity had been conducted until recently, when two fixed-dose combinations, bupropion-naltrexone ER fixed-dose combination and phentermine-topiramate ER titrated-dose combinations were evaluated in clinical studies that ultimately led to FDA approval. Areas covered: In this review, we discuss safety concerns about both combinations, the rationale and history of combination therapies for obesity (including phentermine plus fenfluramine), and possible future new combinations. Expert commentary: Combination therapies are a promising new area in obesity treatment, similar to what occurs with diabetes and hypertension. Safety assessment is highly important due to the high number of potential users on a chronic basis.
... While phentermine is in the class of amphetamines, no adverse changes in either systolic or diastolic BP have been observed in studies of adults, including adults with pre-existing hypertension (44)(45)(46)(47), nor in adolescents (48). Most studies show a decrease in blood pressure with phentermine, including in patients with pre-existing hypertension, and patients on high doses of phentermine (including 37.5 mg BID) (45,47). ...
... While phentermine is in the class of amphetamines, no adverse changes in either systolic or diastolic BP have been observed in studies of adults, including adults with pre-existing hypertension (44)(45)(46)(47), nor in adolescents (48). Most studies show a decrease in blood pressure with phentermine, including in patients with pre-existing hypertension, and patients on high doses of phentermine (including 37.5 mg BID) (45,47). It is unknown whether the decreased blood pressure would occur in the absence of weight loss, but decreased blood pressure with phentermine has been observed at 1 week, and with as little as 4% weight loss at 1 year (45,47). ...
... Most studies show a decrease in blood pressure with phentermine, including in patients with pre-existing hypertension, and patients on high doses of phentermine (including 37.5 mg BID) (45,47). It is unknown whether the decreased blood pressure would occur in the absence of weight loss, but decreased blood pressure with phentermine has been observed at 1 week, and with as little as 4% weight loss at 1 year (45,47). Decreased blood pressure has remained in phentermine-treated patients at 2 years followup despite some weight regain (45). ...
Article
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Obesity is a complex disease influenced by many neurohormonal pathways which regulate body weight toward homeostasis. Presently, the disease of obesity effects over a billion individuals worldwide with scalable treatment options in dire need. Pharmacologic interventions for obesity have been developed to help promote weight loss in individuals with obesity. This area is rapidly developing and will only exponentially increase to serve the demand for persons with obesity seeking biologically orientated solutions to treat their disease. Therefore, understanding the cardiovascular risks and benefits of these weight loss medications is of particularly importance due to obesities strong association with cardiovascular (CV) disease risk. Moreover, past experiences with pharmacotherapy agents with weight loss properties have demonstrated an association with adverse CV outcomes, leading to market removal, in most cases and concerns over using similar medications. To better understand the CV risks and benefits pharmacotherapy agents used for weight loss, this review will discuss medications which are FDA-approved for weight loss, as well as medications commonly used off-label for this indication. The goal is to provide an overview of the risks and benefits many of these medications can offer to help guide clinical decision making and patient education.
... [2][3][4] There is also observational evidence that phentermine treatment induces changes in eating behavior, 5 and that some phentermineinduced eating behavioral changes persist with long-term therapy. 6 These observations suggest that short-and longterm obesity pharmacotherapy may be an essential adjunct to behavior modification therapy. Additional research in this arena is needed. ...
... Whatever the theoretical explanation, doses higher than 37.5 mg/day have been found effective and safe in a number of observational studies. 6,14,15,[19][20][21][22][23] Physicians treating attention deficit use dose-to-effect titration with methamphetamine up to 1 mg/kg/day and methylphenidates up to 2 or 3 mg/kg/day. 24 Attention deficit medicines have considerably greater potentials for abuse than sympathomimetic anorectics. ...
... The phentermine-treated patients had an average weight loss of 17.6%, and the phentermine untreated patients had an average weight loss of 12.8%, a significant difference. 6 The same study also found that patients on long-term phentermine were more successful with weight loss maintenance. 3) After several years of experience with the new drugs, some US physicians are concluding that phentermine is still the first choice drug, and that it must be used as long-term off-label for the best outcome for their patients. ...
Article
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The global pandemic of obesity and overweight now affects between 2.8 and 3.5 billion of the world population and shows no signs of abatement. Treatment for what is now recognized as a chronic disease includes pharmacotherapy, considered an essential component of comprehensive therapy. New drug discovery is robust, but the pace of the US Food and Drug Administration approval for obesity drugs has been glacial, and only a handful of approved drugs are available for treating obesity. In the last 20 years, the US Food and Drug Administration has and 223 endocrinologic drugs, but only 6 for obesity, 2 of which have been taken off market. Currently, there are only 9 drugs approved by the FDA for obesity treatment. US physicians have turned to off-label drug use in their effort to care for increasing numbers of patients with excess adiposity. Phentermine is the most commonly used drug for treating obesity. Although approved only for short-term use, US physicians have used it successfully for long-term since its initial approval in 1959. This drug, used off-label for long-term, has proven to be safe and effective, far safer than the disease it is used to treat. Phentermine and diethylpropion, an equally safe but somewhat less effective drug, are both generic and therefore inexpensive. These drugs have been maligned inappropriately because their two-dimensional structure diagrams resemble amphetamine and also because of unproven presumptions about their potential adverse effects. In the face of an increasing epidemic, worldwide obese and overweight patients deserve effective treatment that prescribing these drugs could provide, if rehabilitated and used more frequently. US physicians will likely continue to use any drug proven useful off-label for this illness until such time as more effective drugs are approved.
... Moreover, there were no cases of arterial hypertension reported. Although the evidence of 30 mg phentermine on other variables like blood pressure, lipid profile, or glycaemia is limited, our results are consistent with the improvement of glycemic parameters reported in previous studies, whereas the impact on blood pressure and lipids are inconsistent and smaller [19][20][21]. ...
... Even though no patients were withdrawn from the study due to adverse events, we could not determine if patients who withdrew voluntarily did it due to occurrence of AEs. The adverse event profile shown by 30 mg phentermine in this work was similar to those reported in other studies with high phentermine doses [19,20]. Interestingly, the disparity between the frequency of adverse events and development of tolerance suggests that the latter phenomenon may not be exclusively pharmacological in nature. ...
Article
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The efficacy of anti-obesity drugs usually does not consider the high degree of interindividual variability in responses to the drug which could affect the decision to withdraw the drug early due to ineffectiveness or to continue therapy according to specific expectations of success. The aim of this study was to analyze body weight loss in kilograms during the first month (1 mo-BWLkg) of treatment with 30 mg phentermine and development of tolerance to phentermine, on its 6-month efficacy. One hundred sixty-six subjects with obesity were individually or jointly analyzed in the study. Subjects with 1 mo-BWLkg of <1 kg, 1–3 kg, 3–5 kg, and ≥5 kg reached 6-month mean percentage body weight reductions (BWR%) of approximately 3%, 5%, 10%, and 15%, respectively. Development of late tolerance (4–6 months) to phentermine had a lower impact than early tolerance (2–3 months). Subjects with 1 mo-BWLkg <3 kg who developed early tolerance did not achieve relevant BWR% (≥5%) at month 6, while the rest of the subgroups achieved increasing and progressive BWR%, according to their 1 mo-BWLkg range and time of onset of tolerance. The 1 mo-BWLkg and development of tolerance to phentermine could be useful to predict the expected 6-month efficacy trends in obese patients treated with 30 mg phentermine.
... Given the high prevalence rates of obesity and its harmful effects on health, it is crucial to explore treatment options for this disease. Pharmacotherapy and the use of meal replacements (in conjunction with a lifestyle intervention) have consistently demonstrated the ability to treat obesity (3)(4)(5)(6)(7). ...
... Phentermine in conjunction with a lifestyle intervention has been shown to have a modest effect on weight loss with an average of 3.6 kg weight loss compared with placebo (13). Long-term phentermine use has been associated with reduced blood pressure and diminished progression of hypertension in participants with obesity (6). Furthermore, Li et al. using a meta-analysis revealed no systematic reports of serious adverse events with phentermine monotherapy (14). ...
Article
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Objective: To examine the effects of phentermine combined with a meal replacement program on weight loss and food cravings and to investigate the relationship between food cravings and weight loss. Methods: In a 12-week randomized, double-blind, placebo-controlled clinical trial, 77 adults with obesity received either phentermine or placebo. All participants were provided Medifast(®) meal replacements, were instructed to follow the Take Shape for Life(®) Optimal Weight 5&1 Plan for weight loss, and received lifestyle coaching in the Habits of Health program. The Food Craving Inventory and the General Food Cravings State and Trait Questionnaires were used to measure food cravings. Results: The phentermine group lost 12.1% of baseline body weight compared with 8.8% in the placebo group. Cravings for all food groups decreased in both groups; however, there was a greater reduction in cravings for fats and sweets in the phentermine group compared with the placebo group. Percent weight loss correlated significantly with reduced total food cravings (r = 0.332, P = 0.009), cravings for sweets (r = 0.412, P < 0.000), and state food cravings (r = 0.320, P = 0.007). Conclusions: Both phentermine combined with a meal replacement program and meal replacements alone significantly reduced body weight and food cravings; however, the addition of phentermine enhanced these effects.
... As a noradrenergic agent, the concern has been for a risk of increased heart rate and blood pressure, but there is some evidence that treated patients with and without hypertension have a reduction in blood pressure and heart rate, presumably from the weight loss. 26 The usual dose is 15 to 37.5 mg daily. Common side effects include dry mouth, insomnia, tremors, anxiety, and gastrointestinal (GI) disturbances. ...
Article
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Obesity has reached epidemic proportions, accounting for increased morbidity, disability, health care expenditures, and mortality. Certain metabolic and comorbid conditions disproportionately affect women. Unfortunately, nonsurgical options for treatment are limited. Knowledge accrued over the past 2 decades regarding physiological and hormonal determinants of weight regulation has contributed to growing evidence regarding efficacious behavioral, dietary, and pharmacologic treatments. In this review, the biology of excess adiposity is summarized in the context of a shifting paradigm, approaching obesity as a chronic metabolic disease. Relevant updates are discussed regarding long-term lifestyle approaches and novel drug therapies, with attention to some issues specific to women.
... However, phentermine should not be administered to patients with pulmonary arterial hypertension, severe arterial hypertension, past or present cardiovascular disease, or cerebrovascular disease [28], long-term safety has not been confirmed [29]. Based on the studies included in the metaanalysis, the most frequent adverse drug reaction of phentermine was dry mouth and insomnia, and the incidence of the adverse reactions showed a significant increase in phentermine compared with placebo [22,[30][31][32][33][34]. In addition, cardiovascular and neurological symptoms, such as hypertension, nervousness, depression, and palpitation, were reported [22,30,[35][36][37]. ...
... Moreover, numerous dietary and exercise interventions have struggled in achieving positive long-term success, highlighting the difficulty in maintaining weight loss [29,30]. Studies have already shown that continuation of anti-obesity drugs can meaningfully improve longterm weight maintenance [31][32][33]. ...
Article
Despite the growing market for obesity care, the US Food and Drug Administration (FDA) has approved only two new pharmaceutical agents—lorcaserin and combination phentermine/topiramate—for weight reduction since 2000, while removing three agents from the market in the same time period. This article explores the FDA’s history and role in the approval of anti-obesity medications within the context of a public health model of obesity. Through the review of obesity literature and FDA approval documents, we identified two major barriers preventing fair evaluation of anti-obesity agents including: (1) methodological pitfalls in clinical trials and (2) misaligned values in the assessment of anti-obesity agents. Specific recommendations include the use of adaptive (Bayesian) design protocols, value-based analyses of risks and benefits, and regulatory guidance based on a comprehensive, multi-platform obesity disease model. Positively addressing barriers in the FDA approval process of anti-obesity agents may have many beneficial effects within an obesity disease model.
... 22 Phentermine is approved for use only in United States and not in Europe. 23 Pharmacotherapies for chronic weight management in adults that are available, including orlistat and two pharmaceuticals recently approved by the US FDA, lorcaserin and phentermine/topiramate extended released preparation (PHEN/TPM ER). 23 ...
Chapter
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Obesity is perhaps the most common clinical problem in today’s society associated with significant morbidity and mortality apart from adversely impacting the quality of life.1 The major health risks associated with obesity include diabetes, cardiovascular disease (CVD), hypertension, dys- lipidemia, sleep apnea, some cancers, musculoskeletal disease, infertility, disability, dementia, and mortality.1–3 Moderate weight loss of 5–10% has been associated with significantly improved clinical outcomes in obesity.4 Obe- sity is becoming a problem of epidemic proportions in our country with the advent of western lifestyles and food habits. The burden of obesity in India has been elaborated in Table 100.1. Lifestyle modification, pharmacotherapy,and bariatric surgery are the three main treatment options in managing obesity. This article intends to summarize the diagnostic and treatment issues associated with managing an individual with obesity.
... People with overweight or obesity and comorbid diabetes who are treated with phentermine may require reductions in concomitant antihyperglycaemic medication [45]. Phentermine monotherapy should be used with caution in those with hypertension because of the risk of an increase in blood pressure [45], although statistically significant increases have not been universally observed [48]. Phentermine is contraindicated in those with a history of cardiovascular disease and in pregnancy (category X) [45]. ...
Article
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Recently, the recognition of obesity as a complex disease that requires chronic management has broadened. There has also been a movement away from a focus on body mass index alone, and toward the management of obesity-related comorbidities as well as excess weight. This article examines the current and emerging pharmacologic options for weight management in people with overweight or obesity who have, or are at a high risk of, weight-related comorbidities. In the US, the current options for pharmacologic weight management are phentermine (indicated for short-term use only), orlistat, combined phentermine/topiramate extended release, lorcaserin, naltrexone/bupropion and liraglutide 3.0 mg. Currently, orlistat, naltrexone/bupropion and liraglutide 3.0 mg are approved in Europe. All of the above mentioned medications have demonstrated weight-loss efficacy versus placebo. Those approved for long-term weight management have also been associated with improvements in weight-related comorbidities, such as hypertension, prediabetes, diabetes, or dyslipidaemia, or related biomarkers. As with all drugs, the safety and tolerability profiles of medications for weight management should be considered alongside their efficacy, to ensure correct use. Additional medications for weight management that are in clinical development include bupropion/zonisamide and beloranib. The field of obesity treatment is advancing with a number of medications being recently approved, and other pharmacologic options emerging. This article is protected by copyright. All rights reserved.
... Several studies have reported higher weight loss (up to 10%) with varying dosages of phentermine for 12 weeks without intense dietary modifications [32,33]. Since phentermine is 220 given only in the short term, the medication tends to be well tolerated and does not appear to have residual effects on heart rate or BP [34][35][36]. The most commonly reported adverse effects are dry mouth, constipation, insomnia, and fatigue [31]. ...
Introduction: Obesity is a major health concern for several countries. The United States (U.S.) has arguably led the world in the percentage of overweight and/or obese per capita for several decades. As a result, numerous FDA-approved pharmacotherapeutic options are available for the long-term treatment of obesity. Although most of these medications have been on the U.S. market for a few years and have demonstrated efficacy for long-term weight loss in clinical trials, the impact of these medications on obesity in the U.S. has yet to be realized. Areas covered: We will review and evaluate why pharmacotherapy for obesity has not produced a meaningful reduction in the number of overweight and obese adults in the U.S. Expert Commentary: Several obstacles, such as adverse drug effects, poor insurance coverage, not treating obesity as a chronic disease, and availability of other weight loss alternatives, has resulted in poor performance of pharmacotherapy for obesity in the U.S. market.
... Our findings of no adverse changes in either systolic or diastolic blood pressure are in agreement with studies of adults. 9, 10 Hendricks and colleagues, in 269 adults with obesity taking phentermine (15 -37.5 mg/d) in addition to lifestyle modification therapy, observed significant decreases in systolic and diastolic blood pressure at 26 and 52 weeks along with significant weight loss. Interestingly, heart rate was not appreciably different across time points which is in contrast to our data showing an elevation at all time-points, although only statistically significant at 3 months. ...
Article
Phentermine is the most widely prescribed obesity medication in adults, yet studies of its use in the pediatric population are limited. We conducted a retrospective chart review of adolescents with obesity treated in a pediatric weight management clinic to examine the weight loss effectiveness of phentermine added to standard of care lifestyle modification therapy (SOC) versus SOC alone. All patients receiving phentermine plus SOC (n=25) were matched with a comparison group receiving only SOC (n=274). Differences at 1, 3, and 6 months were evaluated using generalized estimated equations adjusting for age, sex, and baseline body mass index (BMI) and robust variance standard error estimates for confidence intervals and P-values. Phentermine use was associated with a greater percent change in BMI at 1 month (-1.6% [95% CI (-2.6%, -0.6%); P=0.001), 3 months (-2.9% [95% CI (-4.5%, -1.4%); P<0.001]) and 6 months (-4.1% [95% CI (-7.1%, -1.0%); P=0.009]) compared to SOC alone, with no differences in systolic or diastolic blood pressure between groups. Heart rate was higher at all time-points in the phentermine plus SOC compared to SOC only group. These data suggest that short-term use of phentermine added to SOC may enhance weight loss in adolescents with obesity in the clinical setting.International Journal of Obesity accepted article preview online, 24 October 2016. doi:10.1038/ijo.2016.185.
... A meta-analysis [52] suggests that monotherapy phentermine produces modest weight loss for up to 6 months. However, despite the absence of addictive potential, due to its status as an amphetamine derivative, phentermine is presumed to increase blood pressure and heart rate (although there is evidence to contrary see Hendricks et al. [53]) and thus is approved for short-term treatment only. Topiramate is a sulphamate-substituted monosaccharide that is widely available as an anti-convulsant, with weight loss properties. ...
Article
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Pharmacotherapy provides an adjunct to behaviour modification in the management of obesity. There are a number of new drug therapies purportedly targeting appetite; liraglutide, and bupropion/naltrexone, which are European Medicines Agency and US Food and Drug Administration (FDA) approved, and lorcaserin and phentermine/topiramate, which have FDA approval only. Each of the six drugs, used singly or in combination, has distinct pharmacological, and presumably distinct behavioural, mechanisms of action, thus the potential to provide defined therapeutic options to personalise the management of obesity. Yet, with regard to pharmacotherapy for obesity, we are far from true personalised medicine. We review the limited mechanistic data with four mono and combination pharmacotherapies, to assess the potential for tailoring their use to target specific obesogenic behaviours. Potential treatment options are considered, but in the absence of adequate research in respect to effects of these drugs on eating behaviour, neural activity and psychological substrates that underlie poorly controlled eating, we are far from definitive therapeutic recommendations. Specific mechanistic studies and broader behavioural phenotyping, possibly in conjunction with pharmacogenetic research, are required to characterise responders for distinct pharmacotherapeutic options.
... Phentermine is the most widely used weight-loss drug in the USA; "phentermine HCl, an immediate release formulation that undergoes rapid dissolution and absorption in the gastrointestinal tract, is currently approved at a dose of 15.0-37.5 mg/day for the short-term (up to 12 weeks) treatment of obesity" [164]. "A phentermine resin that slowly releases active drug into the gastrointestinal system is also approved in the USA for the short-term treatment of obesity". ...
... These findings of no increase in blood pressure with phentermine are consistent with what has been found in adults. In adults, phentermine is not associated with increase in heart rate either (10). Further, phentermine abuse, psychological dependence, and withdrawal do not occur in adult patients treated with phentermine for obesity, even after years of treatment (11). ...
Article
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There is a gap in treatment modalities for pediatric patients with obesity for whom lifestyle modification therapy, on the one hand, may be insufficient to meaningfully reduce BMI, and bariatric surgery, which on the other hand, may not be indicated, available or desired. Although pharmacotherapy may help fill this treatment void, there is a paucity of FDA-approved medications indicated for pediatric obesity and further, most are single agents with only modest mean treatment effects. In contrast, combination pharmacotherapy, such as phentermine/topiramate, appears to offer greater weight loss efficacy in adults and may prove to be superior to monotherapy for pediatric patients as well. This case report describes the clinical management of severe obesity in a 10 year old girl with lifestyle modification therapy and subsequent addition of first topiramate and later phentermine. Using the case as a platform, the current state of pharmacotherapy for pediatric obesity will be described thereby highlighting the limited efficacy of single agents. Additionally, the biological rationale for combination pharmacotherapy, including potential mechanisms which may account for the poor response to single agents, will be discussed.
... 22 Phentermine is approved for use only in United States and not in Europe. 23 Pharmacotherapies for chronic weight management in adults that are available, including orlistat and two pharmaceuticals recently approved by the US FDA, lorcaserin and phentermine/topiramate extended released preparation (PHEN/TPM ER). 23 ...
... Providers should consider a 5-year, 5% weight loss maintenance threshold for therapies, akin to the definition of durable cancer remission (3). Despite phentermine and phentermine-topiramate's availability since 1959 and 2012, respectively, phentermine's 5-year efficacy remains unknown, and this study falls short of bridging the evidence gap (4,5). ...
... However, both medications demonstrate efficacy and increasing use within the medical community. 5,14,15 Phentermine is the most commonly prescribed pharmacotherapy for weightloss in the United States, despite FDA-approval for only short-term use (90 days) and a lack of large, long-term clinical trials. [15][16][17] In a randomized, placebo-controlled trial, individuals with overweight or obesity lost an average of 9.3% of baseline body weight after 14 weeks. ...
Article
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Background: The Food and Drug Administration has approved several pharmacotherapies for the treatment of obesity. This study assesses the cost-effectiveness of six pharmacotherapies and lifestyle intervention for people with mild obesity (body mass indices [BMIs] 30 to 35). Methods: A microsimulation model was constructed to compare seven weight loss strategies plus no treatment: intensive lifestyle intervention, orlistat, phentermine, phentermine/topiramate, lorcaserin, liraglutide, and semaglutide. Weight loss, quality-of-life scores, and costs were estimated using clinical trials and other published literature. Endpoints included costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) with a willingness-to-pay (WTP) threshold of $100 000/QALY. Results were analysed at 1-, 3-, and 5-year time horizons. Results: At each of the three follow-up periods, phentermine was the cost-effective strategy, with ICERs of $46 258/QALY, $20 157/QALY, and $17 880/QALY after 1, 3, and 5 years, respectively. Semaglutide was the most effective strategy in the 3- and 5-year time horizons, with total QALYs of 2.224 and 3.711, respectively. However, the ICERs were prohibitively high at $1 437 340/QALY after 3 years and $576 931/QALY after 5 years. Deterministic and probabilistic sensitivity analyses indicated these results were robust. Conclusions: Phentermine is the cost-effective pharmacologic weight-loss strategy. Although semaglutide is the most effective, it is not cost-effective because of its high price.
... For this reason, prescribing phentermine to patients with a history of CVD (e.g., coronary artery disease, stroke, arrythmias, congestive heart failure, uncontrolled hypertension) is cautioned [30,31]. Despite this concern, older studies have shown neutral changes to decreases in blood pressure and heart rate within the first few weeks of treatment while weight loss was still occurring [32][33][34]. However, it is difficult to separate these effects on cardiovascular parameters from weight loss with phentermine as these studies did not include patients with CVD [25,31]. ...
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Purpose of Review To summarize research from the last 5 years on the effects of weight loss treatments, including lifestyle changes, anti-obesity medications, and bariatric procedures on cardiovascular disease (CVD) risk factors and CVD outcomes in adults. Recent Findings This narrative review includes and summarizes the contemporary evidence of the effects of these different weight loss approaches individually. A literature search was performed using the key words obesity, weight loss, CVD, cardiometabolic, and risk factors and included key clinical trials from the past 5 years. Obesity management through weight loss is associated with improvements in CVD risk factors, such as improved blood pressure, lipid profiles, and glycemic control, with greater weight loss leading to greater improvements in CVD risk factors. Bariatric surgery is associated with greater weight loss than the other procedures and treatments for obesity, and for this, and possibly for other reasons, it is associated with greater reductions in CVD outcomes and mortality. Summary Obesity is an independent risk factor and modulator of other CVD risk factors, and thus, treatment of obesity should be an integral part of management strategies to reduce CVD risk. Future trials and real-world studies of longer duration are needed to inform providers and patients on how to individualize the approach to modifying risks of cardiometabolic disorders through obesity management.
... However, small increases in HR from baseline were reported in phentermine-treated patients, although this did not reach statistical significance. 36,40 Two studies reported on the effect of PHEN/TPM on cardiometabolic risk factors, with few changes in blood pressure, lipids, or glycemia observed (Table 5). 33,42 ...
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Anti‐obesity medications (AOMs) are efficacious and well tolerated in randomized controlled trials, but findings may not be generalizable to routine clinical practice. This systematic literature review aimed to identify real‐world (RW) evidence for AOMs to treat adults ( ≥ 18 years) with obesity or overweight (BMI ≥ 27 kg/m2). Searches conducted in MEDLINE, Embase, Health Technology Assessment (HTA) Database, National Health Service (NHS) Economic Evaluation Database, and Cochrane Central Register of Controlled Trials for studies of relevant FDA‐approved AOMs yielded 41 publications. Weight loss (WL) was consistently observed, with 14% to 58.6% of patients achieving ≥ 5% WL on orlistat, phentermine/topiramate, naltrexone/bupropion, phentermine, or liraglutide in studies of 3–6 months' duration where this was measured. When cardiometabolic risk factors were assessed, AOMs reduced or had no impact on blood pressure, lipids, or glycemia. RW data on the impact of AOMs on existing obesity‐related comorbidities and mortality were generally lacking. AOMs were associated with various adverse events, but these were of mild to moderate severity and no unexpected safety signals were reported. A pattern of poor adherence and persistence with AOMs was observed across studies. Overall, the review confirmed the effectiveness of AOMs in RW settings but demonstrated large gaps in the evidence base.
... inTrODUCTiOn One common treatment of the obesity epidemic involves the use of drugs (Hampp et al., 2013;Valsamakis et al., 2017;Srivastava and Apovian, 2018). One of the most widely prescribed of these drugs for humans in the USA is Phentermine (Phen), which is an appetite suppressant currently approved for the short-term treatment of obesity (Hendricks et al., 2009;Hendricks et al., 2011;Hendricks et al., 2014;Yanovski and Yanovski, 2014). Studies in rodents have also shown that repeated administration of Phen induces body weight loss, decreases food intake, and several psychomotor side effects such as locomotion and stereotypy (Kalyanasundar et al., 2015). ...
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Obesity has become a serious public health problem. Although diet, surgery, and exercise are the primary treatments for obesity, these activities are often supplemented using appetite suppressants. A previous study reported that obesity specialists frequently prescribed a new drug combination for its treatment that includes phentermine (Phen; dopaminergic appetite suppressant), a serotonin (5-HT) precursor 5-hydroxytryptophan (5-HTP; an appetite suppressant that increases the 5-HT concentration), and carbidopa (CB; peripheral blocker of conversion of 5-HTP to 5-HT). Despite its widespread use, there is neither a preclinical study confirming the drug efficacy nor studies of its effects on the brain. To fill this gap, in rats for seven consecutive days, we administered Phen intraperitoneally at different doses either alone or in combination with a fixed dose of 5-HTP/CB. In a different group, we infused drugs via an intraperitoneal catheter while extracellular-recordings were performed in the nucleus accumbens shell (NAcSh), a brain region with dopamine-releasing effects that is involved in the action of appetite suppressants. We found that the triple-drug combination leads to greater weight-loss than each drug alone. Moreover, and as the treatment progresses, the triple drug combination partially reversed psychomotor side-effects induced by Phen. Electrophysiological results revealed that Phen alone evoked a net inhibitory imbalance in NAcSh population activity that correlated with the onset of psychomotor effects. In addition, and unlike the greater weight loss, the addition of 5-HTP/CB did not alter the Phen-evoked inhibitory imbalance in NAcSh responses. Subsequent experiments shed light on the underlying mechanism. That is the majority of NAcSh neurons modulated by 5-HTP/CB were suppressed by Phen. Notably, and despite acting via a different mechanism of action (DA for Phen vs. 5-HT for 5-HTP/CB), both drugs recruited largely overlapping NAcSh neuronal ensembles. These data suggest that the neural correlates of the greater weight loss could be located outside the NAcSh, in other brain circuits. Furthermore, we conclude that Phen + 5-HTP/CB is a potential treatment for overweight and obesity.
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Obesity is a chronic, progressive, and relapsing disease state the management of which includes a comprehensive, long-term management plan. Comprehensive management of obesity includes 4 key components of care: nutrition, behavioral intervention, physical activity, and clinical management. This article reviews current evidence-based treatment of obesity and key components for all clinicians to have knowledge of.
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More than 40% of adults in the United States suffer from obesity. Obesity is inextricably linked to many chronic illnesses like type‐2 diabetes mellitus, hypertension, hyperlipidemia, heart disease, sleep apnea, stroke, and cancers. When used in combination with lifestyle modifications, pharmacotherapy has a vital role in treating obesity and improves short‐term and long‐term outcomes. A growing number of physicians are now interested in obesity medicine, and many of them are seeking guidance on how to treat complex patients with co‐morbidities. This review provides a practical guide to the use of anti‐obesity medications across various obesity‐related comorbidities. It provides a general review of the currently approved anti‐obesity medications and effective combinations. It discusses the highlights of the major trials and recent studies assessing the benefits of anti‐obesity medications in comorbid conditions such as type‐2 diabetes mellitus , psychiatric disorders, cardiovascular diseases, hypertension, renal diseases, and liver diseases. This review briefly examines the aspects of recognizing and addressing iatrogenic weight gain; discusses the precautions and prescribing considerations of anti‐obesity medications, including side effects and possible dose adjustments in various comorbid conditions; and provides an expert opinion on an individualized choice of the best anti‐obesity medication.
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Worldwide obesity prevalence has nearly doubled since 1980. Due to numerous co-morbidities, obesity represents a serious health and socioeconomic problem worldwide. Pharmacotherapy should be an integral part of comprehensive obesity management. Drug therapy can assist in weight loss and its maintenance in those individuals who do not achieve appropriate weight loss through lifestyle interventions alone. After the withdrawal of sibutramine from the market in 2010, orlistat, a lipase inhibitor, was the only remaining prescription drug approved for the long-term treatment of obesity. In 2012, phentermine/topiramate extended-release (PHEN/TPM ER) combination and lorcaserin were approved by the US FDA as novel medications for long-term weight management. Three major phase III trials conducted with each drug confirmed their efficacy in terms of weight loss/maintenance and improvement of cardiometabolic risks. No head-to-head studies between the two new anti-obesity drugs have been carried out. However, in the existing studies PHEN/TPM ER had a superior weight loss profile to lorcaserin but the incidence of adverse effects was lower with lorcaserin. Both drugs were well-tolerated, and adverse events were modest in intensity, dose dependent, rather rare, and tended to decrease with the duration of treatment. Major safety concerns regarding PHEN/TPM ER include elevations in resting pulse rate, teratogenicity, mild metabolic acidosis, and psychiatric and cognitive adverse events. Valvulopathy, cognitive impairment, psychiatric disorders, and hypoglycemia represent major safety concerns for lorcaserin. Although existing trials have not demonstrated any significant issues with PHEN/TPM ER-induced heart rate elevation and lorcaserin-induced valvulopathy, all safety concerns should be seriously taken into account in patients treated with either of these novel anti-obesity medications.
Article
Objective: To investigate the safety, tolerability and efficacy of combination phentermine and topiramate therapy for maintenance of weight loss. Design, setting and patients: Retrospective audit of patients attending the Austin Health Weight Control Clinic who were dispensed phentermine-topiramate between 22 January 2010 and 16 July 2012 and after reaching a target weight by following a very low energy diet (VLED). Data collection continued until July 2013. Main outcome measures: Number of patients who ceased pharmacotherapy; duration of use of pharmacotherapy; types and numbers of adverse effects; and mean weight and blood pressure measurements at the initial visit, the end of the VLED and the last observation during pharmacotherapy. Results: Data were available for 103 patients who were dispensed phentermine-topiramate; 61 patients ceased combination pharmacotherapy before the end of the data collection period, 41 due to adverse effects (eg, paraesthesia, cognitive changes, dry mouth and depression). The mean duration of use of pharmacotherapy was 10 months. Mean weight decreased by 10% due to the VLED (from 135.5 kg to 122.5 kg) and this loss was maintained. For 30 patients who continued on phentermine-topiramate, the mean duration of pharmacotherapy was 22 months and the mean weight decreased by 6.7 kg between the end of the VLED and the last observation during pharmacotherapy. Conclusion: Phentermine-topiramate therapy was not well tolerated; more than half of the patients in our study stopped taking it because of adverse effects, and more than half of the adverse events reported were ascribed to topiramate. However, in those able to continue with pharmacotherapy, the combination was efficacious for both maintenance of weight loss and ongoing weight loss.
Article
Background: A survey of obesity medicine specialists was conducted before the approval of new obesity medications in 2012. Methods: An Internet survey was sent to obesity medicine specialists inquiring about their practice and prescribing habits. Results: Twenty-five percent of 1992 obesity medicine specialists responded. They used stimulant obesity medication for longer and at higher doses than recommended in the package insert. Medications for other indications were used off-label alone and in combination for obesity treatment. Only 15 % saw surgical patients. Conclusions: The survey is a baseline for when more obesity medications exist in 5 years. We hope discovering a lack of collaboration between obesity medical specialists and obesity surgeons will stimulate more team work that will benefit obese patients contemplating or undergoing obesity surgery.
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Objective/methods: The American Association of Clinical Endocrinologists/American College of Endocrinology "Consensus conference on obesity: building an evidence base for comprehensive action" convened March 23-25, 2014, in Washington, D.C. The premise of the conference was that by bringing together stakeholders in U.S. obesity care, representing the biomedical and public health models, new information would emerge to formulate actionable recommendations. Results: Key conference findings include 5 affirmed and 8 emergent concepts. These concepts include the need for a medically meaningful and actionable diagnosis of obesity, research that evaluates and refines a complications-centric clinical approach to obesity, the need for a better understanding of reimbursement mechanisms and the value associated with obesity prevention and management, increased nutrition and obesity education, and enhanced public awareness and health literacy. Conclusion: Next steps include deriving a more robust medical definition of obesity, translation of the affirmed and emergent concepts into actionable recommendations in the interests of patients with obesity, and developing logistics for effective implementation.
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Enormous progress has been made in the last half-century in the management of diseases closely integrated with excess body weight, such as hypertension, adult-onset diabetes and elevated cholesterol. However, the treatment of obesity itself has proven largely resistant to therapy, with anti-obesity medications (AOMs) often delivering insufficient efficacy and dubious safety. Here, we provide an overview of the history of AOM development, focusing on lessons learned and ongoing obstacles. Recent advances, including increased understanding of the molecular gut–brain communication, are inspiring the pursuit of next-generation AOMs that appear capable of safely achieving sizeable and sustained body weight loss.
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Effective treatment of obesity could reduce the burden of diseases primarily driven by excess body weight (e.g., Type 2 diabetes). At present, effective nonsurgical weight management tools are scarce. This paper reviews the investigational combination of phentermine, a weight-loss drug available for over half a century, and topiramate, an antiepileptic drug with known weight-loss effects, as a proposed anti-obesity intervention. The combination therapy achieves weight loss of a magnitude that meets the expectations of the US FDA along with improvement of some obesity-related risks. The safety profile is consistent with known adverse effects of individual constituents; cognitive and psychiatric adverse events were dose dependent. Other safety concerns include a small increase in heart rate and potential teratogenicity associated with topiramate.
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Obesity is associated with a number of co-morbidity including type 2 diabetes, hypertension, dyslipidemia and cardiovascular diseases. Current researches mainly focus on drug development to treat severely obese individuals with a body mass index(BMI)>30 kg/m2 or those with a BMI>27 kg/m2 who have additional co-morbidity. However, prolonged use of these drugs is limited by significant side effects and lack of long-term safety and efficacy data. This review commented on the anti-obesity drugs' pharmacological mechanisms, efficacy and their influences on cardiovascular risks.
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Losing ≥ 5% of initial weight improves quality of life and risk factors for cardiovascular disease (CVD) in obese individuals. Lifestyle modification, the cornerstone of weight reduction, may be complemented by pharmacotherapy. In 2012, the FDA approved the combination of phentermine and topiramate extended release (ER) for chronic weight management, as an adjunct to lifestyle modification. This review examines the safety and efficacy of phentermine-topiramate ER, as determined by randomized controlled trials (RCTs). A preliminary study confirmed the benefit of combining the two medications for improving weight loss and reducing adverse effects, as compared to using equivalent-dose monotherapy alone. Across RCTs, groups prescribed phentermine 15 mg/topiramate ER 92 mg lost an average of 10% of initial weight, ∼ 8% more than placebo and 2% more than phentermine 7.5 mg/topiramate 46 mg. Weight loss reduced the risk of developing type 2 diabetes and improved CVD risk factors. Phentermine-topiramate ER, however, was associated with increased heart rate, the clinical significance of which is being investigated in an FDA-required CVD outcomes study. The medication also must be used with caution in women of child-bearing age because of an increased risk to infants of oral cleft.
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The recognition of the complex counter-regulatory hormonal, metabolic and neurochemical mechanisms that promote weight regain following weight loss and the conceptualisation of obesity as a chronic disease requiring long-term management has led to increasing focus on the role of adjunctive therapies for obesity, particularly pharmacotherapy. Currently available pharmacotherapy achieves a weight loss intermediate between that commonly attained by lifestyle intervention and bariatric surgery, however its accessibility, compared to bariatric surgery increases its appeal. Despite the poor history of obesity pharmacotherapy, novel agents that are in development appear to have several advantages over predecessors. They are generally more selective in their mechanism of action, thereby potentially minimising adverse sequelae and improving the risk-benefit ratio of pharmacotherapy. Another approach has been to use combined pharmacotherapy to better counteract the multiple counter-regulatory neuroendocrine mechanisms which promote weight regain, as well as allowing lower constituent doses of the combined monotherapy agents, which improves the safety and tolerability of these agents that are usually required long-term for chronic weight maintenance. This review will provide an overview of past, present and future pharmacotherapy for obesity. The efficacy and safety profile of currently available pharmacotherapy will be discussed in the setting of stringent regulatory review processes now in place given the fraught history of pharmacological interventions for obesity. Potential novel therapies that seek to better target the multiple complex counter-regulatory mechanisms promoting weight regain while improving the efficacy/safety profile, will also be examined.
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In light of the increasing prevalence of obesity, a large proportion of patients are taking weight loss medications or undergoing weight loss procedures. The typical paradigm for treating obesity begins with lifestyle interventions and progresses to medical treatments, and when nonsurgical interventions have failed, procedural techniques are considered. The effect of these interventions on the skin and dermatologic conditions has not been reviewed in depth. Herein, we review the impact of weight loss on pre-existing dermatologic conditions, as well as the development of novel skin changes and consequences of redundant skin after these interventions.
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Current regulatory hurdles, the withdrawal of several drugs due to safety concerns, modest weight-loss efficacy using existing drugs and the lack of reimbursement in the US has resulted in limited investment in research and development of anti-obesity drugs by pharmaceutical companies. This has resulted in a limited range of treatment strategies for obese patients. The recent registration of lorcaserin (a 5-HT2C receptor agonist) and Qsymia (a combination of phentermine and topiramate), and the progression of the late-stage drugs liraglutide and NB32 may provide the backdrop for reinvestment to occur. Unlike many other therapeutic areas, preclinical models of obesity have a high degree of predictive validity for efficacy in the clinic and are of value in the discovery of novel compounds and their progression from research into the clinic. Although clinical trials for obesity drugs are of long duration with large patient cohorts required, recruitment is not an issue and end-points e.g. BMI are straightforward to measure. The emergence of new weight-loss agents that also treat diabetes, a co-morbidity associated with obesity, may provide improved treatment strategies. Importantly, even limited success of such drugs is likely to stimulate a marked increase in research and development as obesity is showing no sign of decline.
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Introduction: Obesity is a growing health problem that has numerous comorbidities, including cardiovascular disease (CVD). The multi-disciplinary treatment of obesity now includes the use of pharmacotherapy. When treating patients with obesity and CVD, certain medications may be more appropriate than others. Areas covered: Herein, the authors review the most commonly used FDA approved medications for the treatment of obesity, describing their mechanism of action, and the efficacy and safety of the medications as seen in recent studies, particularly in patients with CVD. Expert opinion: In the population of patients with obesity and CVD, the medications orlistat, lorcaserin and liraglutide are considered the most appropriate options for their treatment, in terms of safety. Sympathomimetic medications, such as phentermine, should be avoided in this group. The recent CAMELLIA-TIMI 61 trial supports the safety of lorcaserin in patients with CVD. Until there are more studies, it is reasonable to extrapolate the findings of the LEADER trial, which found improved CV outcomes in subjects with type 2 diabetes taking liraglutide, to the population of nondiabetic patients being treated for obesity. Further cardiovascular outcomes trials (CVOT) are needed to assess the safety of other pharmacotherapeutic options for weight loss.
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Many patients achieve desired weight loss by changing their lifestyle. However, if not successful, they have the secondary option of obesity pharmacotherapy. Currently there are three drugs approved by FDA for weight loss: phentermine, phentermine/topiramate and lorcaserin; with another three drugs in development (naltrexone/bupropion, zonisamide/bupropion and liraglutide). Five drugs have been used off label for the treatment of obesity in clinical practice. Recently, obesity pharmacotherapy is becoming more affordable and therefore popular as federal employees and some privately insured patients are now covered for these expenses. More research on cost-effectiveness, reduction in concomitant drug use, and long-term safety is needed to optimize access to obesity pharmacotherapy. © 2014 Springer Science+Business Media New York. All rights are reserved.
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Objective Development of these guidelines is mandated by the American Association of Clinical Endocrinologists (AACE) Board of Directors and the American College of Endocrinology (ACE) Board of Trustees and adheres to published AACE protocols for the standardized production of clinical practice guidelines (CPGs). Methods Recommendations are based on diligent review of clinical evidence with transparent incorporation of subjective factors. Results There are 9 broad clinical questions with 123 recommendation numbers that include 160 specific statements (85 [53.1%] strong [Grade A]; 48 [30.0%] intermediate [Grade B], and 11 [6.9%] weak [Grade C], with 16 [10.0%] based on expert opinion [Grade D]) that build a comprehensive medical care plan for obesity. There were 133 (83.1%) statements based on strong (best evidence level [BEL] 1 = 79 [49.4%]) or intermediate (BEL 2 = 54 [33.7%]) levels of scientific substantiation. There were 34 (23.6%) evidence-based recommendation grades (Grades A-C = 144) that were adjusted based on subjective factors. Among the 1,790 reference citations used in this CPG, 524 (29.3%) were based on strong (evidence level [EL] 1), 605 (33.8%) were based on intermediate (EL 2), and 308 (17.2%) were based on weak (EL 3) scientific studies, with 353 (19.7%) based on reviews and opinions (EL 4). Conclusion The final recommendations recognize that obesity is a complex, adiposity-based chronic disease, where management targets both weight-related complications and adiposity to improve overall health and quality of life. The detailed evidence-based recommendations allow for nuanced clinical decision-making that addresses real-world medical care of patients with obesity, including screening, diagnosis, evaluation, selection of therapy, treatment goals, and individualization of care. The goal is to facilitate high-quality care of patients with obesity and provide a rational, scientific approach to management that optimizes health outcomes and safety. (Endocr Pract. 2016;22:Supp3;1-205)
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This article, co-authored by a patient with obesity, diabetes, and hypertension, and an obesity medicine specialist, discusses the patient's experience with the onset of diabetes complicating obesity and with her frustration living with these diagnoses until finding an obesity medicine specialist physician who helped her lose weight and reverse her diabetes. The patient continues to maintain a significant weight loss and is diabetes free for 5.5 years after treatment initiation. The physician discusses the application of combination treatment that can be effective in diabetes reversal in such cases. He also discusses salient clinical lessons exemplified by this case.
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Objective: Mexico has the second largest prevalence of obesity among adults worldwide, a condition especially affecting the low-income population. There is a pressing need to improve therapeutic options for weight loss. Phentermine is an old and low-cost agent given as an adjuvant therapy for obesity for a 12-week period, at an initial dose of 15 mg or 30 mg. However, there are no precise guidelines on the suitability of both the starting dose and the continuation of treatment for 6 months. The aim of this study was to evaluate the 3- and 6-month efficacy and safety of phentermine in obese Mexican patients to elucidate the aforementioned. Materials and methods: In this prospective, multi-center, open-label study, 932 obese adults received 15 mg or 30 mg phentermine once daily for 6 months. Results: 30 mg phentermine was more effective than 15 mg phentermine in improving anthropometric variables in the 3-month follow-up, but not after completing the 6-month treatment period. Nearly 40% of 3-month non-responders reached a body weight reduction of at least 5% at 6 months. Conversely, ~ 65% and 25% of 3-month responders maintained or improved, respectively, their body weight reduction with long-term phentermine. Potential tolerance as weight regain was ~ 10% from 3 to 6 months. None of the doses increased cardiovascular risk, although mild-to-moderate adverse events were more frequent with 30 mg phentermine. Conclusion: 30 mg phentermine was more effective than 15 mg phentermine after 3 months, but not at 6 months of treatment. An important number of subjects could benefit following the therapy from 3 to 6 months.
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Obesity is one of the biggest public health concerns identified by an increase in adipose tissue mass as a result of adipocyte hypertrophy and hyperplasia. Pertaining to the importance of adipose tissue in various biological processes, any alteration in its function results in impaired metabolic health. In this review, we discuss how adipose tissue maintains the metabolic health through secretion of various adipokines and inflammatory mediators and how its dysfunction leads to the development of severe metabolic disorders and influences cancer progression. Impairment in the adipocyte function occurs due to individuals’ genetics and/or environmental factor(s) that largely affect the epigenetic profile leading to altered gene expression and onset of obesity in adults. Moreover, several crucial aspects of adipose biology, including the regulation of different transcription factors, are controlled by epigenetic events. Therefore, understanding the intricacies of adipogenesis is crucial for recognizing its relevance in underlying disease conditions and identifying the therapeutic interventions for obesity and metabolic syndrome.
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Background This “Anti-Obesity Medications and Investigational Agents: An Obesity Medicine Association Clinical Practice Statement 2022” is intended to provide clinicians an overview of Food and Drug Administration (FDA) approved anti-obesity medications and investigational anti-obesity agents in development. Methods The scientific information for this Clinical Practice Statement (CPS) is based upon published scientific citations, clinical perspectives of OMA authors, and peer review by the Obesity Medicine Association leadership. Results This CPS describes pharmacokinetic principles applicable to those with obesity, and discusses the efficacy and safety of anti-obesity medications [e.g., phentermine, semaglutide, liraglutide, phentermine/topiramate, naltrexone/bupropion, and orlistat, as well as non-systemic superabsorbent oral hydrogel particles (which is technically classified as a medical device)]. Other medications discussed include setmelanotide, metreleptin, and lisdexamfetamine dimesylate. Data regarding the use of combination anti-obesity pharmacotherapy, as well as use of anti-obesity pharmacotherapy after bariatric surgery are limited; however, published data support such approaches. Finally, this CPS discusses investigational anti-obesity medications, with an emphasis on the mechanisms of action and summary of available clinical trial data regarding tirzepatide. Conclusion This “Anti-Obesity Medications and Investigational Agents: An Obesity Medicine Association Clinical Practice Statement 2022” is one of a series of OMA CPSs designed to assist clinicians in the care of patients with pre-obesity/obesity.
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Excess body fatness is the major environmental cause of type 2 diabetes, and even a minor weight loss can prevent its development in high-risk subjects. Weight loss and exercise programs can also improve quality of life, glycemic control, and comorbid conditions in type 2 diabetics, but do not reduce total or cardiovascular mortality. A weight loss of 5–10% can be induced in almost all simple and diabetic obese patients by a professional management program. Whereas the diet can be individualized, a higher protein, lower carbohydrate diet, with focus on low glycemic index carbohydrates, seems to be superior to a traditional low-fat diet for producing weight control and cardiometabolic risk improvement. Physical activity and regular exercise does not significantly affect rate of weight loss in the induction phase but plays an important role in the weight maintenance phase due to an important impact on daily energy expenditure and to direct enhancement of insulin sensitivity. Weight loss drugs have a role in patients in whom lifestyle treatment fails to produce the required weight control, and in obese subjects drugs may produce both weight loss and reduce the risk of complications, such as type 2 diabetes.
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Arthroplasty in patients with elevated body mass index results in increased rates of reoperation, instability, revision, and infection. Preoperative weight loss may reduce the complication rate associated with orthopaedic surgery. In addition to lifestyle modification, anti-obesity medications are available to help patients to reduce their preoperative weight. Currently, there are 6 U.S. Food and Drug Administration (FDA)-approved anti-obesity medications in the United States: phentermine, orlistat, phentermine with topiramate extended release (ER), lorcaserin, sustained release (SR) naltrexone with bupropion, and liraglutide. Anti-obesity medications potentially provide a new way to optimize patients before surgery and to ensure successful recovery postoperatively.
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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.
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An FDA advisory panel voted against approval of the appetite-suppressing, anti-obesity drug lorcaserin in September this year. Do the findings of a recent, randomized trial of lorcaserin provide clues to the decision?
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Previous studies comparing low-carbohydrate and low-fat diets have not included a comprehensive behavioral treatment, resulting in suboptimal weight loss. To evaluate the effects of 2-year treatment with a low-carbohydrate or low-fat diet, each of which was combined with a comprehensive lifestyle modification program. Randomized parallel-group trial. (ClinicalTrials.gov registration number: NCT00143936) 3 academic medical centers. 307 participants with a mean age of 45.5 years (SD, 9.7 years) and mean body mass index of 36.1 kg/m(2) (SD, 3.5 kg/m(2)). A low-carbohydrate diet, which consisted of limited carbohydrate intake (20 g/d for 3 months) in the form of low-glycemic index vegetables with unrestricted consumption of fat and protein. After 3 months, participants in the low-carbohydrate diet group increased their carbohydrate intake (5 g/d per wk) until a stable and desired weight was achieved. A low-fat diet consisted of limited energy intake (1200 to 1800 kcal/d; <or=30% calories from fat). Both diets were combined with comprehensive behavioral treatment. Weight at 2 years was the primary outcome. Secondary measures included weight at 3, 6, and 12 months and serum lipid concentrations, blood pressure, urinary ketones, symptoms, bone mineral density, and body composition throughout the study. Weight loss was approximately 11 kg (11%) at 1 year and 7 kg (7%) at 2 years. There were no differences in weight, body composition, or bone mineral density between the groups at any time point. During the first 6 months, the low-carbohydrate diet group had greater reductions in diastolic blood pressure, triglyceride levels, and very-low-density lipoprotein cholesterol levels, lesser reductions in low-density lipoprotein cholesterol levels, and more adverse symptoms than did the low-fat diet group. The low-carbohydrate diet group had greater increases in high-density lipoprotein cholesterol levels at all time points, approximating a 23% increase at 2 years. Intensive behavioral treatment was provided, patients with dyslipidemia and diabetes were excluded, and attrition at 2 years was high. Successful weight loss can be achieved with either a low-fat or low-carbohydrate diet when coupled with behavioral treatment. A low-carbohydrate diet is associated with favorable changes in cardiovascular disease risk factors at 2 years. National Institutes of Health.
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Preclinical evidence suggests that pharmacotherapy for obesity using combinations of agents targeted at distinct regulatory pathways may produce robust additive or synergistic effects on weight loss. This randomized placebo-controlled trial examined the safety and efficacy of the amylin analogue pramlintide alone or in combination with either phentermine or sibutramine. All patients also received lifestyle intervention. Following a 1-week placebo lead-in, 244 obese or overweight, nondiabetic subjects (88% female; 41 +/- 11 years; BMI 37.7 +/- 5.4 kg/m(2); weight 103 +/- 19 kg; mean +/- s.d.) received placebo subcutaneously (sc) t.i.d., pramlintide sc (120 microg t.i.d.), pramlintide sc (120 microg t.i.d.) + oral sibutramine (10 mg q.a.m.), or pramlintide sc (120 microg t.i.d.) + oral phentermine (37.5 mg q.a.m.) for 24 weeks. Treatment was single-blind for subjects receiving subcutaneous medication only and open-label for subjects in the combination arms. Weight loss achieved at week 24 with either combination treatment was greater than with pramlintide alone or placebo (P < 0.001; 11.1 +/- 1.1% with pramlintide + sibutramine, 11.3 +/- 0.9% with pramlintide + phentermine, -3.7 +/- 0.7% with pramlintide; -2.2 +/- 0.7% with placebo; mean +/- s.e.). Elevations from baseline in heart rate and diastolic blood pressure were demonstrated with both pramlintide + sibutramine (3.1 +/- 1.2 beats/min, P < 0.05; 2.7 +/- 0.9 mm Hg, P < 0.01) and pramlintide + phentermine (4.5 +/- 1.3 beats/min, P < 0.01; 3.5 +/- 1.2 mm Hg, P < 0.001) using 24-h ambulatory monitoring. However, the majority of subjects receiving these treatments remained within normal blood pressure ranges. These results support the potential of pramlintide-containing combination treatments for obesity.
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The use of medications to treat obesity remains controversial. Our goal was to assess national trends in antiobesity medication use with a focus on patterns surrounding the 1997 removal of antiobesity drugs from the market. Using a serial cross-sectional study design, we analyzed a nationally representative sample of US office-based physician visits from 1991 to 2002. Data come from the IMS HEALTH National Disease and Therapeutic Index. These data include a sample of 13 452 patient visits for which a diagnosis of clinical obesity was made, with annual visits ranging from 666 in 1994 to 1854 in 1996. The unit of analysis is the patient visit, while the primary outcome measures are the annual and quarterly number of antiobesity drug mentions for clinically obese patients. At its peak in the second quarter of 1997, 2.5 million Americans were taking antiobesity medications, a 4-fold increase over the prior 2 years. Although antiobesity medication use diminished following the market exit of fenfluramine hydrochloride and dexfenfluramine hydrochloride, current levels of use remain above those in the early 1990s. Phentermine has consistently been the most common antiobesity medication. In 2002, an annualized 1.2 million mentions of phentermine use were noted (31% of drug-treated obese patients). Newly released medications, orlistat (0.6 million) and sibutramine hydrochloride (0.4 million), were used less often. Most antiobesity medication use occurs in patients without other reported medical conditions. Use of antiobesity medications increased rapidly with public and professional interest in fenfluramine-phentermine (fen-phen) combination therapy. Despite reports of adverse outcomes associated with fenfluramine agents (fen-phen and dexfenfluramine), the use of these medication therapies did not diminish until soon before their removal from the market in 1997.
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The National High Blood Pressure Education Program presents the complete Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Like its predecessors, the purpose is to provide an evidence-based approach to the prevention and management of hypertension. The key messages of this report are these: in those older than age 50, systolic blood pressure (BP) of greater than 140 mm Hg is a more important cardiovascular disease (CVD) risk factor than diastolic BP; beginning at 115/75 mm Hg, CVD risk doubles for each increment of 20/10 mm Hg; those who are normotensive at 55 years of age will have a 90% lifetime risk of developing hypertension; prehypertensive individuals (systolic BP 120-139 mm Hg or diastolic BP 80-89 mm Hg) require health-promoting lifestyle modifications to prevent the progressive rise in blood pressure and CVD; for uncomplicated hypertension, thiazide diuretic should be used in drug treatment for most, either alone or combined with drugs from other classes; this report delineates specific high-risk conditions that are compelling indications for the use of other antihypertensive drug classes (angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, beta-blockers, calcium channel blockers); two or more antihypertensive medications will be required to achieve goal BP (<140/90 mm Hg, or <130/80 mm Hg) for patients with diabetes and chronic kidney disease; for patients whose BP is more than 20 mm Hg above the systolic BP goal or more than 10 mm Hg above the diastolic BP goal, initiation of therapy using two agents, one of which usually will be a thiazide diuretic, should be considered; regardless of therapy or care, hypertension will be controlled only if patients are motivated to stay on their treatment plan. Positive experiences, trust in the clinician, and empathy improve patient motivation and satisfaction. This report serves as a guide, and the committee continues to recognize that the responsible physician's judgment remains paramount.
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The phentermine, an appetite suppressant, has been widely applied in Korea since 2004. However, there have been relatively few reports about the efficacy and the safety of phentermine in Korea. The aim of this study is to verify the effect of phentermine on weight reduction and the safety in Korean patients. This randomized, double-blind, placebo- controlled study had been performed between February and July, 2005, in Seoul on 68 relatively healthy obese adults whose body mass index was 25 kg/m2 or greater. They received phentermine-HCl 37.5 mg or placebo once daily with behavioral therapy for obesity. The primary endpoints were the changes of body weight and waist circumference from the baseline in the intention-to-treat population. Mean decrease of both body weight and waist circumference in phentermine-treated subjects were significantly greater than that of placebo group (weight: -6.7 +/- 2.5 kg, p < 0.001; waist circumference: -6.2 +/- 3.5 cm, p < 0.001). Significant number of subjects in phentermine group accomplished weight reduction of 5% or greater from the baseline and 10% or more (p < 0.001). There were no significant differences in systolic and diastolic blood pressure between the groups (p = 0.122 for systolic BP; p = 0.219 for diastolic BP). Dry mouth and insomnia were the only statistically significant adverse events that occurred more frequently in phentermine group. Most side effects of phentermine were mild to moderate in intensity. Short-term phentermine administration induced significant weight reduction and reduction of waist circumference without clinically problematic adverse events on relatively healthy Korean obese people.
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Intranasal methamphetamine abuse has increased dramatically in the past decade, yet only one published study has investigated its acute effects under controlled laboratory conditions. Thus, the current study examined the effects of single-dose intranasal methamphetamine administration on a broad range of behavioral and physiological measures. Eleven nontreatment-seeking methamphetamine abusers (two females, nine males) completed this four-session, in-patient, within-participant, double-blind study. During each session, one of four intranasal methamphetamine doses (0, 12, 25, and 50 mg/70 kg) was administered and methamphetamine plasma concentrations, cardiovascular, subjective, and psychomotor/cognitive performance effects were assessed before drug administration and repeatedly thereafter. Following drug administration, methamphetamine plasma concentrations systematically increased for 4 h postdrug administration then declined. Methamphetamine dose dependently increased cardiovascular measures and 'positive' subjective effects, with peaks occurring approximately 5-15 min after drug administration, when plasma levels were still ascending. In addition, cognitive performance on less complicated tasks was improved by all active methamphetamine doses, whereas performance on more complicated tasks was improved only by the intermediate doses (12 and 25 mg). These results show that intranasal methamphetamine produced predictable effects on multiple behavioral and physiological measures before peak plasma levels were observed. Of interest is the dissociation between methamphetamine plasma concentrations with cardiovascular measures and positive subjective effects, which might have important implications for potential toxicity after repeated doses.
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To evaluate the long-term impact of Medifast meal-replacement supplements (MMRS) combined with appetite suppressant medication (ASM) among participants who received 52 weeks of treatment. We conducted a systematic program evaluation of weight loss data from a medically-supervised weight control program combining the use of MMRS and ASM. Data were obtained and analyzed from 1,351 patient (BMI> or =25) medical charts who had participated for at least 12 weeks of treatment. Outcomes included weight loss (kg) and percent weight loss from baseline and at 12, 24, and 52 weeks. Both completers and intention-to-treat analyses were conducted. Completers' (i.e., those with complete data for 52 weeks) outcomes were evaluated after stratification for reported adherence to the MMRS and ASM. Participants who completed 52 weeks of treatment experienced substantial weight losses at 12 (-9.4+/-5.7 kg), 24 (-12.0+/-8.1 kg), and 52 weeks (-12.4+/-9.2 kg) and all measures were significantly different from baseline weight (p<0.001 for all contrasts) for both true completers (n=324) and for ITT analysis (n=1,351). Fifty percent of patients remained in the program at 24 weeks and nearly 25% were still participating at one year. This weight loss program using a combination of MMRS and ASM produced significant and sustained weight losses at 52 weeks. Results were better than those typically reported for obesity pharmacotherapy in both short- and long-term studies and also better than those reported for partial meal replacement programs. Program retention at one year was similar to that reported in many controlled drug trials and better than most commercial programs reported in the literature.
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Background: Previous studies comparing low-carbohydrate and low-fat diets have not included a comprehensive behavioral treatment, resulting in suboptimal weight loss. Objective: To evaluate the effects of 2-year treatment with a low-carbohydrate or low-fat diet, each of which was combined with a comprehensive lifestyle modification program. Design: Randomized parallel-group trial. (ClinicalTrials.gov registration number: NCT00143936) Setting: 3 academic medical centers. Patients: 307 participants with a mean age of 45.5 years (SD, 9.7 years) and mean body mass index of 36.1 kg/m(2) (SD, 3.5 kg/m(2)). Intervention: A low-carbohydrate diet, which consisted of limited carbohydrate intake (20 g/d for 3 months) in the form of low-glycemic index vegetables with unrestricted consumption of fat and protein. After 3 months, participants in the low-carbohydrate diet group increased their carbohydrate intake (5 g/d per wk) until a stable and desired weight was achieved. A low-fat diet consisted of limited energy intake (1200 to 1800 kcal/d; <or=30% calories from fat). Both diets were combined with comprehensive behavioral treatment. Measurements: Weight at 2 years was the primary outcome. Secondary measures included weight at 3, 6, and 12 months and serum lipid concentrations, blood pressure, urinary ketones, symptoms, bone mineral density, and body composition throughout the study. Results: Weight loss was approximately 11 kg (11%) at 1 year and 7 kg (7%) at 2 years. There were no differences in weight, body composition, or bone mineral density between the groups at any time point. During the first 6 months, the low-carbohydrate diet group had greater reductions in diastolic blood pressure, triglyceride levels, and very-low-density lipoprotein cholesterol levels, lesser reductions in low-density lipoprotein cholesterol levels, and more adverse symptoms than did the low-fat diet group. The low-carbohydrate diet group had greater increases in high-density lipoprotein cholesterol levels at all time points, approximating a 23% increase at 2 years. Limitation: Intensive behavioral treatment was provided, patients with dyslipidemia and diabetes were excluded, and attrition at 2 years was high. Conclusion: Successful weight loss can be achieved with either a low-fat or low-carbohydrate diet when coupled with behavioral treatment. A low-carbohydrate diet is associated with favorable changes in cardiovascular disease risk factors at 2 years. Primary funding source: National Institutes of Health.
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Obesity results from a prolonged small positive energy balance, and its treatment needs to reverse this imbalance. Citations retrieved from PubMed and The Handbook of Obesity 2008 were selected to illustrate the points. Many different diets have been tried to treat obesity, and weight loss occurs with all of them. There is currently no evidence that clearly supports a superiority of one macronutrient composition for diets used for weight loss. The principal effect seems to be the degree of adherence to the prescribed calorie reduction. Lifestyle strategies to modify eating behavior can be used in individual counseling sessions or in groups, both of which are important in helping patients modify their patterns of eating. Physical activity is particularly important in helping patients maintain a weight loss once achieved and is less valuable for weight loss itself. Food intake is controlled through many different mechanisms, but only a few drugs have been developed that tap these mechanisms. Orlistat, which blocks intestinal lipase, is one; sibutramine, a serotonin-norepinephrine reuptake inhibitor, is a second. Surgical approaches provide the most dramatic weight loss and have been demonstrated to reduce long-term mortality and reduce the incidence of diabetes. Weight loss can be achieved by many methods, but the surgical procedures appear to be the most durable.
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Recent reports indicate an increase in intranasal use of prescription oral stimulant medication. However, there do not appear to be any published clinical studies that have characterized the behavioral and cardiovascular effects of intranasally administered d-amphetamine, which is commonly prescribed for Attention Deficit Hyperactivity Disorder. In this study, a range of d-amphetamine doses (0, 16, 24, and 32 mg/70 kg) were administered as an intranasal solution delivered using a mucosal atomization device. Equal oral doses were included for comparison. Assessments were conducted before and at regular intervals for 3 hours following drug administration and included self-reported drug-effect questionnaires, cardiovascular indices, a performance task, and 2 measures of impulsivity. d-Amphetamine produced prototypical stimulant effects (eg, increased subject ratings of Stimulated and Like Drug, elevated heart rate and blood pressure, and improved rate and accuracy on the digit symbol substitution task) irrespective of dose, but the onset of these effects was generally earlier following intranasal administration, with significant effects emerging 15 to 30 minutes after intranasal dosing and 45 to 60 minutes after oral dosing. These results demonstrate that intranasal administration of d-amphetamine results in a more rapid onset compared to oral dosing, which could be associated with the popularity of intranasal prescription stimulant use and an enhanced potential for abuse.
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This article examines the transitions in pharmacological therapy for obesity. It reviews the current options approved by the Food and Drug Administration and several drugs approved for other indications that can be used to treat obesity as well. Because weight regulation is complex and redundant systems protect against perceived starvation, optimal treatment of obesity in individual patients will likely require different combinations of behavioral, nutritional, pharmacologic, endoscopic, and surgical therapies.
To evaluate the prevalence of prehypertension among middle-aged and elderly people in Taiwan and to explore the evolutionary changes of blood pressure in 5-year follow-up period. In 2000, people aged over 40 participating in annual health examinations at local health stations in I-Lan County were invited to join the study. Past medical histories were reviewed, physical examinations and serial laboratory tests were performed for participants. All participants were followed in 2005 by a medical record review, telephone survey or personal visit. Subjects with prehypertension were sorted for further analysis. Overall, 1053 people (mean age=64.4+/-11.4 years, 44.4% males) were enrolled in the primary cohort. The prevalence of hypertension and prehypertension was 40.4% and 35.8%, respectively. In 2005, 677 subjects (mean age: 68.8+/-10.4 years, 42.5% males) were successfully followed, which revealed a significant increase of systolic blood pressure (3.7+/-16.8 mmHg, p<0.001), but not diastolic blood pressure (0.3+/-11.5 mmHg, p=0.758) in prehypertensive subjects; however, both systolic blood pressure (14.3+/-17.4 mmHg, p<0.001) and diastolic blood pressure (7.7+/-13.3 mmHg, p<0.001) were significantly increased among normotensive subjects. The cumulative incidence of prehypertensive subjects becoming hypertensive was 31.3%, and those who became hypertensive were significantly older (65.3+/-8.6 vs. 62.2+/-12.3 years, p=0.024), having higher pulse pressure in 2000 (49.6+/-10.6 vs. 45.1+/-11.6 mmHg, p=0.001), serum total cholesterol (214.3+/-31.7 vs. 204.0+/-37.2 mg/dL, p=0.020) and low-density lipoprotein-cholesterol (141.7+/-29.2 vs. 132.7+/-34.7 mg/dL, p=0.042). The prevalence of prehypertension among older Taiwanese was 35.8% and the 5-year cumulative incidence of hypertension from prehypertension was 31.3%. Older prehypertensive subjects with higher pulse pressure, higher serum total cholesterol and higher low-density lipoprotein-cholesterol were more likely to become hypertensive within 5 years.
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Prehypertension (defined by the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure) frequently evolves to hypertension (HTN) and increases cardiovascular risk. It is unclear whether metabolic and/or cardiac characteristics favor development of HTN in prehypertensive subjects. We evaluated baseline anthropometric, laboratory, and echocardiographic characteristics of 625 untreated prehypertensive participants in the Strong Heart Study, without prevalent cardiovascular disease (63% women; 22% with diabetes mellitus; mean age: 59+/-7 years) to identify predictors of the 4-year incidence of HTN. Diabetes mellitus was assessed by American Diabetic Association criteria, and a diabetes-specific definition of HTN was used. Four-year incidence of HTN was 38%. Incident HTN was independently predicted by baseline systolic blood pressure (odds ratio [OR]: 1.60 per 10 mm Hg; 95% CI: 1.30 to 2.00; P<0.0001), waist circumference (OR: 1.10 per 10 cm; 95% CI: 1.01 to 1.30; P=0.04), and diabetes mellitus (OR: 2.73; 95% CI=1.77 to 4.21; P<0.0001), with no significant effect for age, sex, hemoglobin A1c, homeostatic model assessment index, C-reactive protein, fibrinogen, low-density lipoprotein and high-density lipoprotein cholesterol, triglycerides, plasma creatinine, or urine albumin:creatinine ratio. Higher left ventricular mass index (OR: 1.15 per 5 g/m(2.7); 95% CI: 1.01 to 1.25; P=0.03) or stroke volume index (OR: 1.25 per 5 mL/m(2.04); 95% CI: 1.10 to 1.50; P=0.03) was also identified, together with baseline systolic blood pressure and the presence of diabetes mellitus, as an independent predictor of incident HTN, without an additional predictive contribution from other anthropometric, metabolic, or echocardiographic parameters (all P>0.10). Thus, progression to HTN in 38% of Strong Heart Study prehypertensive participants could be predicted by higher left ventricular mass and stroke volume in addition to baseline systolic blood pressure and prevalent diabetes mellitus.
Article
Weight gain may increase blood pressure. Weight loss may reduce this. Reviews have considered the long-term effects of weight loss but are related mainly to more obese participants often on obesity medication and/or undergoing obesity surgery. This systematic review, based on lifestyle interventions for adults (18 to 65 years) with mean baseline BMI of <35 kg/m(2), links weight change to blood pressure difference. A systematic review of studies reporting weight differences and blood pressure outcomes, published between 1990 and 2008 with follow-up of > or =2 years identified 8 clinical trials or controlled before and after studies (represented by 9 articles) and 8 cohort studies. Differences ranged from -11 to +4kg for weight, -7 to +2.2 mm Hg for diastolic blood pressure and -13 to +6.1 mm Hg for systolic blood pressure. For this population group, no quantifiable relationship between weight and diastolic blood pressure difference was found, possibly because of small weight losses, differing weight status responses, or because pharmacologically controlled hypertension masked weight loss influences. Systolic differences were in line with previous reviews of 1 kg:1 mm Hg relationship, but only for follow-up periods of 2 to 3 years, possibly reflecting the fact that regardless of maintained weight loss, blood pressure often reverts back to higher levels. Lifestyle interventions for weight and blood pressure are limited in this target group, and there has been no exploration of successful intervention components. An individual patient data analysis may uncover baseline and medication effects, explore differences between weight groups, and may identify successful components. Such an analysis would enable effective development of preventative interventions for both hypertension and obesity.
Article
The article in the current issue of Hypertension by Aucott et al1 raises some interesting questions. Does weight loss in the long term (ie, >3 years) result in a decrease in blood pressure (BP) levels? Is there difference in the effect of weight loss on decreased systolic BP (SBP) versus diastolic BP (DBP)? They combined 8 clinical trials and 8 cohort studies and tried to evaluate the linear relationship between change in BP and weight change. Overall, there was only a 2.8-kg weight loss, which resulted in a 1.9-mm decrease in DBP and 2.9 mm for SBP, neither of which were significant. Most important, the association between decrease in SBP with weight loss dissipated substantially over time (that is, >3 years from the onset of the study). The conclusion is that in long term, weight loss had little effect on change in BP levels. Weight loss has been a recommended nonpharmacological therapy for reducing BP levels for many years. Before the introduction of effective antihypertensive drug therapy, reduction of salt in the diet, weight loss, and mild sedation were recommended therapies for patients with nonmalignant hypertension.2 Previous meta-analyses of clinical trials on the effects of weight reduction on BP concluded that weight loss is important in both the prevention and treatment of hypertension.3 Most of the studies in the meta-analysis had relatively small sample sizes and short duration, usually <1 year. Is there really no health benefit of weight loss with decreased BP in the long term? To test such a hypothesis, participants would have to lose a substantial amount of weight (ie, >10 kg), have good BP measures before and after weight loss, a comparison group without substantial weight loss but having similar diet except for the differences in caloric intake or energy expenditure (ie, physical …
Article
To examine the effects of high doses of extended-release methylphenidate (OROS MPH) on cardiovascular variables in adolescents with attention deficit hyperactivity disorder (ADHD). ECG indices plus systolic blood pressure (SBP), diastolic BP (DBP) and heart rate (HR) were assessed during an open-label study of OROS MPH in 114 adolescents with ADHD (doses up to 1.5 mg/kg/d). Cardiovascular parameters were assessed at 6 weeks and 6 months. Small but statistically significant changes in DBP and HR were observed at 6 weeks, without further increases up to 6 months' follow-up. A small but statistically significant increase in SBP was observed over time. Twenty-nine percent of patients had isolated elevations in BP readings prior to study entry, and 14% had >3 consecutive visits at which elevated BP were observed during OROS MPH treatment. No clinically significant changes in ECG parameters were observed. No serious cardiovascular adverse events occurred. Treatment with relatively high doses of OROS MPH was associated with small but statistically significant mean increases in BP and HR, primarily during the first 6 weeks of treatment, without clinically meaningful changes in ECG. These observations are consistent with previous reports using lower doses.
Article
To evaluate the effect of anthropometric indices in the 5-year incidence of hypertension, in a sample of cardiovascular disease-free adults. 1514 men and 1528 women (>18 years) without any clinical evidence of cardiovascular disease, living in Attica area, Greece, were enrolled in the ATTICA study from May 2001 to December 2002. In 2006, the 5-year follow-up was performed. Hypertension was defined as systolic/diastolic blood pressure measurements >140/90 mmHg or use of antihypertensive treatment. Weight, height, waist and hip circumferences, as well as body mass index (BMI) and waist-to-height and waist-to-hip ratios were tested in relation to the development of hypertension. During 2001-2006, 86 men and 102 women were diagnosed as having hypertension. Thus, annual incidence rate is 2.86 per 100 men and 2.68 per 100 women. From the anthropometric indices, waist, and hip circumferences, BMI, weight and waist-to-height ratio were associated with the development of hypertension. Particularly, for every 1cm difference in baseline measurements of waist a 2% higher risk of hypertension was observed; while abnormal waist at baseline examination was associated with 1.92-times (95% CI, 1.35-2.77) higher risk of hypertension, in both genders. Moreover, presence of obesity at baseline examination was associated with a 2.4-fold (95% CI, 1.62-3.79) of the risk of hypertension. All the aforementioned relationships were independent from age, sex, and various other confounders, while the model that contained waist had the best diagnostic ability, followed by BMI, hip circumference and weight. Among various anthropometric measurements that showed a significant association with hypertension incidence, waist circumference was the best predictor. The latter finding may lead to new pathophysiological mechanisms for the development of hypertension.
Article
The increasing prevalence of obesity in the United States is widely recognized as a complex problem with significant public health implications, morbidity, mortality, and costs. Pharmacotherapy can contribute to the treatment of obesity. The regulation of appetite and body weight involves multiple parallel neuronal and bodily mechanisms. Not surprisingly, experience has shown that a medication that targets any one mechanism produces weight loss of 5%-10%. Although weight loss of this magnitude may produce significant reductions in risk factors associated with cardiovascular morbidity and mortality, patients expect cosmetically meaningful reductions in weight (~20%-25%). Combining 2 medications that work via different mechanisms, that is, "combination pharmacotherapy," is an approach to obtaining cosmetically relevant reductions in weight. The most effective example of this approach was the combination of phentermine and fenfluramine. This article will describe a novel combination pharmacotherapy developed in clinical practice: the combination of phentermine with the serotonin precursor L-5-hydroxytryptophan plus the peripheral decarboxylase inhibitor, carbidopa. Observational data on the efficacy and safety of this combination pharmacotherapy will be presented. In conclusion, combination pharmacotherapy can make important contributions to the treatment of obesity. Controlled clinical trials should be done before such combination treatments are widely adopted.
Article
Specialist physicians may have prescribing habits that are different from nonspecialist physicians. Little is known about the prescribing habits of physicians specializing in the treatment of obesity. An anonymous survey was given to the physician members of the American Society of Bariatric Physicians (ASBP). There was a 35% response rate (266 physicians) to the questionnaire that was represented nationally. Almost all prescribed medications and all of them recommended phentermine. The average maximal dose of phentermine was above that approved in the package insert, and these physicians disagreed with the National Institutes of Health (NIH) Obesity Treatment Guidelines. Phendimetrazine, metformin, and phentermine plus L-5-hydroxytryptophan (5-HTP) with carbidopa were all used more frequently than either orlistat or sibutramine. The combination of sibutramine and orlistat as well as 5-HTP/carbidopa were prescribed by 14 and 20%, respectively. As 5-HTP-carbidopa was a combination not previously reported for the treatment of obesity, a retrospective chart review was performed in a single obesity practice, which may not be representative. Twenty-two subjects had a 16% weight loss with phentermine over 6 months and an additional 1% weight loss with the addition of 5-HTP/carbidopa for an additional 6 months. One subject who started on 5-HTP/carbidopa alone lost 24.4% of initial body weight over 6 months. This questionnaire revealed that 20% of the obesity specialists responding to the survey used phentermine plus of 5-HTP/carbidopa, an unreported combination. A controlled, randomized, clinical trial to evaluate the safety and efficacy of this combination in treating obesity should be considered.
Article
Attention deficit hyperactivity disorder (ADHD) is a neurobehavioral disorder that affects approximately 2.9-4.7% of US adults. Studies have revealed high rates of ADHD (26-61%) in patients seeking weight loss treatment suggesting an association between ADHD and obesity. The objective of the present study was to test the association between ADHD and overweight and obesity in the US population. Cross-sectional data from the Collaborative Psychiatric Epidemiology Surveys were used. Participants were 6,735 US residents (63.9% white; 51.6% female) aged 18-44 years. A retrospective assessment of childhood ADHD and a self-report assessment of adult ADHD were administered. Diagnosis was defined by three categories: never met diagnostic criteria, met full childhood criteria with no current symptoms, and met full childhood criteria with current symptoms. The prevalence of overweight and obesity was 33.9 and 29.4%, respectively, among adults with ADHD, and 28.8 and 21.6%, respectively, among persons with no history of ADHD. Adult ADHD was associated with greater likelihood of overweight, (odds ratio (OR) = 1.58; 95% confidence interval (CI) = 1.05, 2.38) and obesity (OR = 1.81; 95% CI = 1.14, 2.64). Results were similar when adjusting for demographic characteristics and depression. Mediation analyses suggest that binge eating disorder (BED), but not depression, partially mediates the associations between ADHD and both overweight and obesity. Results suggest that adult ADHD is associated with overweight and obesity.
Article
To investigate the value of anorexiant medications as an adjunct to other forms of weight control therapy, we studied 121 people in a 34-week, double-blind clinical trial of 60 mg extended-release fenfluramine plus 15 mg phentermine resin versus placebo added to behavior modification, caloric restriction, and exercise. Participants weighed 130% to 180% (154% +/- 1.2%, mean +/- SEM) of ideal body weight (1983 Metropolitan Life tables) and were in good health. By week 34, participants receiving active medication lost an average of 14.2 +/- 0.9 kg, or 15.9% +/- 0.9% of initial weight (n = 58), versus a loss of 4.6 +/- 0.8 kg or 4.9% +/- 0.9% of initial weight by subjects taking placebo (n = 54; p less than 0.001). On visual analog scales, participants rated fenfluramine plus phentermine as more helpful than placebo (50.3 +/- 0.5 versus 20.3 +/- 0.3) and not bothersome (fenfluramine plus phentermine, 17.4 +/- 0.3 versus 13.5 +/- 0.2). Blood pressure decreased and pulse remained unchanged in both groups. Dry mouth was the most common adverse effect in subjects receiving fenfluramine plus phentermine; all adverse effects decreased after 4 weeks. Only nine participants left the study in the first 34 weeks. Two subjects from each group left the study as a result of adverse effects. Overall, fenfluramine plus phentermine used in conjunction with behavior modification, caloric restriction, and exercise aided weight loss and continued to be efficacious for 34 weeks.
Article
In a controlled therapeutic trial, 68 obese children were treated successively with (1) amphetamine resinate, (2) phentermine, and (3) diet with placebo capsules. Considerable weight reduction was achieved by all three regimes initially, but the effectiveness of all three tended to wane, especially that of diet. Long-acting amphetamine resinate was the most successful drug. Side-effects were very rare. The long-term prognosis of severe obesity in children still remains unsatisfactory.
Article
We performed a double-blind, controlled clinical trial comparing phentermine resin (30 mg in the morning), fenfluramine hydrochloride (20 mg three times a day), and a combination of phentermine resin (15 mg in the morning) and fenfluramine hydrochloride (30 mg before the evening meal), and placebo. We combined low doses of the two drugs to maintain efficacy while diminishing adverse effects. Eighty-one people with simple obesity (130% to 180% of ideal body weight) participated. Individualized diets were prescribed and discussed again during the 24-week study period. Weight loss in those receiving the combination (8.4 +/- 1.1 kg; mean +/- SEM) was significantly greater than in those receiving placebo (4.4 +/- 0.9 kg; Scheff é's test) and equivalent to that of those receiving fenfluramine (7.5 +/- 1.2 kg) or phentermine (10.0 +/- 1.2 kg) alone. Adverse effects were less frequent with the combination regimen than with other active treatments. Thirty-seven participants dropped out of the study, 18 for reasons related to drug treatment. Combining fenfluramine and phentermine capitalized on their pharmacodynamic differences, resulting in equivalent weight loss, fewer adverse effects, and better appetite control.
Article
Fifty women with refractory obesity received phentermine resinate. Seven were withdrawn because of side-effects: three developed severe headaches, one each hypertension, depressive symptoms, breathlessness and palpitations with irritability. The mean weight loss in the 34 who completed the 20-week study was 6.4 kg. Nine lost 10 kg or more. Sustained appetite suppression was related to weight loss. Plasma phentermine concentrations did not correlate with the severity of the obesity problem, the degree of subjective anorexia or with weight loss. Poor initial response to standard dosage of phentermine is unlikely to improve with higher dosage. The individual's response to phentermine is unpredictable and appears to relate to factors other than the plasma drug concentration.
Article
A study was carried out in general practice to compare the effectiveness and tolerance of phentermine and diethylpropion in helping patients more than 20% above their desirable weight to lose weight. Patients were allocated at random to receive either one 30 mg capsule of phentermine (50 patients) or one 75 mg tablet of diethylpropion (49 patients) daily over a period of 12 weeks. They were also asked to restrict their calorie intake to 1500 calories per day. The results showed that there was a significantly greater weight loss in patients treated with phentermine which was particularly marked during the last 4 weeks of the study. There were significant reductions in blood pressure and heart rate in the phentermine group and of heart rate in the diethylpropion group. These were almost certainly related to weight loss rather than to a direct effect of drug treatment. Side-effects were generally minor in nature and the incidence and nature of them were comparable in the two groups.
Article
ATKINSON, RICHARD L, ROY C BLANK, DONALD SCHUMACHER, NIKHIL V DHURANDHAR, DOUGLAS L RITCH. Long-term drug treatment of obesity in a private practice setting. This study evaluated the long-term efficacy and safety of the combination of phentermine and fenfluramine for the treatment of obesity in a private practice setting. A total of 1388 consecutive, qualified patients presenting to a private general internal medicine practice in Charlotte, NC, were enrolled with eligibility criteria including: age 18 years to 60 years, 20% over “desirable” bodyweight or body mass index <27, no serious medical or psychiatric disease, and no contraindications to drug therapy. Patients were instructed in diet, exercise, and behavior modification techniques and received phentermine (15 mg/day to 30 mg/day) and fenfluramine (20 mg/day to 60 mg/day) continuously for over 3 years. Average duration of treatment was 15. 9 months, and average weight loss at the last visit was 11. 6 kg, or 11. 7% of initial bodyweight. For patients completing 1 year of drug treatment, mean weight loss was 16. 5 kg, or 16% of initial weight. Weight loss persisted for 2 years, but partial regain was seen at 3 years. The dropout rates were 18% at 6 months, 39% at 1 year, 68% at 2 years, and 78% at 3 years. At 1 year, blood pressure of hypertensive patients fell from 151/95 mm Hg to 127/78 mm Hg, and serum cholesterol and triglycerides of hyperlipidemic patients fell by 0. 750 mmol/L (29 mg/dL) and 0. 937 mmol/L (83 mg/dL), respectively. Adverse events were modest. We conclude that, in a private practice setting, long-term treatment of obesity with the combination of phentermine, fenfluramine, and a weight maintenance program is generally safe and effective. More research is needed to determine efficacy and safety for longer than 3 years.
Article
To describe and evaluate relationships between body mass index (BMI) and blood pressure, cholesterol, high-density lipoprotein-cholesterol (HDL-C), and hypertension and dyslipidemia. A national survey of adults in the United States that included measurement of height, weight, blood pressure, and lipids (National Health and Nutrition Examination Survey III 1988-1994). Crude age-adjusted, age-specific means and proportions, and multivariate odds ratios that quantify the association between hypertension or dyslipidemia and BMI, controlling for race/ethnicity, education, and smoking habits are presented. More than one-half of the adult population is overweight (BMI of 25 to 29.9) or obese (BMI of > or =30). The prevalence of high blood pressure and mean levels of systolic and diastolic blood pressure increased as BMI increased at ages younger than 60 years. The prevalence of high blood cholesterol and mean levels of cholesterol were higher at BMI levels over 25 rather than below 25 but did not increase consistently with increasing BMI above 25. Rates of low HDL-C increased and mean levels of HDL-C decreased as levels of BMI increased. The associations of BMI with high blood pressure and abnormal lipids were statistically significant after controlling for age, race or ethnicity, education, and smoking; odds ratios were highest at ages 20 to 39 but most trends were apparent at older ages. Within BMI categories, hypertension was more prevalent and HDL-C levels were higher in black than white or Mexican American men and women. These data quantify the strong associations of BMI with hypertension and abnormal lipids. They are consistent with the national emphasis on prevention and control of overweight and obesity and indicate that blood pressure and cholesterol measurement and control are especially important for overweight and obese people.
Article
This paper aims to review the evidence for long-term effectiveness of weight loss on cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and triglycerides in overweight/obese people. Current evidence is mostly based on short-term studies. A systematic review of long-term lipid outcomes of weight loss in studies published between 1966 and 2001, was conducted. Inclusion criteria included all cohort studies and trials carried out on participants with body mass index of greater than or equal to 28 kg m(-2). Studies had at least two weight change measurements and follow-up of more than 2 years. Thirteen long-term studies with a follow-up of more than 2 years were included. Cholesterol has a significant positive linear relationship with weight change (r = 0.89) where change in weight explains about 80% of the cholesterol difference variation (Adj R2 = 0.80). For every 10 kg weight loss a drop of 0.23 mmol L(-1) in cholesterol may be expected for a person suffering from obesity or are grossly overweight. Weight loss has long-term beneficial effects especially on LDL and cholesterol. Weight loss in obese patients should be encouraged and sustained.
Article
Long-term, possibly lifetime, use of medications for the management of obesity may be thought to be similar to the use of pharmacotherapy for other chronic diseases such as hypertension or diabetes. Because there have been no systematic studies of this extended use, the experience of eight patients who have used obesity medications in a sustaining manner was studied. The clinical characteristics of eight adult patients, each of whom has experience with long-term (more than 10 years) use of medications for weight loss and weight maintenance, were studied. The clinical experience of these eight patients was analyzed. Each chose to sustain the use of weight management medications for more than 10 years because of perceived benefit, comfort, and the absence of significant side effects. There has been no evidence of the development of tolerance, addiction, or misuse and no adverse events related to the medication. The beneficial effects of the medication have not diminished with time. The clinical characteristics of eight patients, each of whom has used obesity pharmacotherapy for more than 10 years, are described. The experience of these eight individuals cannot be generalized to the entire population of overweight or obese patients. It does suggest, however, that some patients respond successfully to this form of therapy and that they will derive value from it for the management of this disease. Efforts should be made to identify these patients, and consideration should be given to the use of chronic medications for the continuing management of obesity.
Article
The safety of obesity drugs has historically been poor. This and the stigmatisation of obesity in society ensured that a higher standard of safety for obesity drugs must be met. The authors review the safety disasters of obesity drugs that were withdrawn. The authors then review the safety of presently available drugs--benzphetamine, phendimetrazine, diethylpropion, phentermine, sibutramine and orlistat. The safety of rimonabant, a drug with a pending new drug application that has an independent effect on metabolic syndrome, is also reviewed. The authors compare the stage of obesity drug development to that of hypertension in the 1950s. As new and safer drugs with more downstream mechanisms are developed that have independent effects on the cardiovascular risks associated with obesity, third party reimbursement for obesity medicine is likely to improve. This may lead to obesity being treated like hypertension and other chronic diseases with long-term medication. With improved technological tools, the authors believe this process will be more rapid for obesity than it was for hypertension.
Article
The names assigned to attention-deficit/hyperactive disorder (ADHD) have changed over the years. ADHD cannot be cured, and the patient with ADHD journeys through life with a burden. Although ADHD is most commonly studied in school-aged children, it is a syndrome that spans the life cycle, through adolescence and into adulthood. Improvements in patient adherence to pharmacologic treatment, attributable to the launch of new formulations, the availability of new non-schedule II drugs, and the development of novel drugs in late-stage clinical trials, are transforming the treatment of ADHD. For example, atomoxetine is a nonstimulant treatment, and lisdexamfetamine was developed with the goal of providing an extended duration of effect with a reduced potential for abuse, overdose toxicity, and drug tampering. Known adverse effects of stimulant treatment of ADHD include appetite suppression and sleep disturbance. Other adverse effects, such as growth suppression and substance use disorder, are controversial. The US Food and Drug Administration (FDA) recently issued a public health advisory for drugs approved for the treatment of ADHD to provide more information for patients about potential risks of ADHD medications. Additional research is needed on approaches for treating ADHD in adolescents transitioning into adulthood, as are studies on the relationships between ADHD and comorbidities such as substance use disorder.
Article
A randomized, within-subject, double-blind, inpatient study of the physiological and subjective effects of oral 3,4-methylenedioxymethamphetamine (MDMA) was conducted in human volunteers with previous MDMA experience. Placebo, low (1.0 mg/kg), and high (1.6 mg/kg) doses of oral MDMA were administered in a controlled inpatient setting at least 7 days apart to 6 African American (4 male, 2 female) and 2 white (both male) volunteers (mean [SE] age, 21.1 [0.8] years; weight, 77.2 [7.7] kg). 3,4-Methylenedioxymethamphetamine doses were 46 to 150 mg, in the range of typical recreational doses. Participants completed all sessions without clinically significant adverse events. 3,4-Methylenedioxymethamphetamine produced significant dose-dependent increases in heart rate (highest, 132 bpm), systolic (highest, 171 mm Hg) and diastolic (highest, 102 mm Hg) blood pressure, and subjective responses for energy level, closeness to others, mind racing, heightened senses, and high (evaluated by visual analog scales). Peak effects occurred 1 to 2 hours after dose, with no secondary peak. There were no significant effects on body temperature (measured at tympanic membrane), respiratory rate, or blood oxygen saturation (by pulse oximetry). Although most physiological and subjective parameters were significantly correlated with MDMA plasma concentrations, correlation coefficients were low and clinically insignificant, eliminating the ability to predict effects from single plasma concentrations. These findings suggest that oral MDMA in typical recreational doses produces short-term effects on cardiovascular function and subjective state but that temperature effects may result from interaction with environmental and subject factors.
QNEXA FDA Advisory Committee Briefing Document
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Vivus. QNEXA FDA Advisory Committee Briefing Document. 2010 (cited 8 August 2010);
Department of Health and Human Services
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Colman E, Roberts MD. FDA Clinical Briefing Document, EMDAC, QNEXA, NDA 22580. Department of Health and Human Services: Washington, D.C. <http://www.fda.gov/downloads/AdvisoryCommittees/ CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugs AdvisoryCommittee/UCM218824.pdf> Accessed 15 July 2010.
Long-term weight control study. I (weeks 0 to 34) The enhancement of behavior modification, caloric restriction, and exercise by fenfluramine plus phentermine versus placebo
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Weintraub M, Sundaresan PR, Madan M et al. Long-term weight control study. I (weeks 0 to 34). The enhancement of behavior modification, caloric restriction, and exercise by fenfluramine plus phentermine versus placebo. Clin Pharmacol Ther 1992;51:586–594.
NDA) 22–580, proposed tradename, QNEXA (phentermine/topiramate) Controlled Release Capsules, for the Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee
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Vivus. QNEXA FDA Advisory Committee Briefing Document. 2010 (cited 8 August 2010); VIVUS, Inc. Briefing Information, (NDA) 22–580, proposed tradename, QNEXA (phentermine/topiramate) Controlled Release Capsules, for the July 15, 2010 Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee. <http:// www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ EndocrinologicandMetabolicDrugsAdvisoryCommittee/ucm218819.htm>.
Long-term weight control study. I (weeks 0 to 34). The enhancement of behavior modification, caloric restriction, and exercise by fenfluramine plus phentermine versus placebo
  • Weintraub