Abstract
Being obese goes beyond moral failure or a character flaw. Obesity has the defining characteristics of a chronic disease for which there is no cure. Treatment may require lifelong treatment which may include pharmacotherapy. Experience with long term use of obesity drugs is limited but evidence suggests that pharmacotherapy can improve patient outcomes and patient outlook. With current obesity drugs, weight loss is usually modest but clinically significant satisfying the FDA threshold for drug effectiveness. This weight loss is associated with clinically significant improvements in many obesity co morbidities and risk factors and could eliminate some risk factors with continued use. When used in conjunction with a comprehensive program for weight management, obesity drugs can reduce appetite or hunger, increase satiety, provide improved control over aberrant eating behaviors and modify food seeking behaviors. Pharmacotherapy can enhance weight loss and compliance during the periods of weight loss and in maintaining that weight loss, increasing physical activity and may enhance a focus on making life long changes.
This article will discuss mechanisms of action of obesity drugs, theories of altered body defense of body weight, Food and Drug Administration (FDA) approved obesity drugs, and off-label use of FDA approved drugs. The value of over-the counter (OTC) medications and diet supplements, as well as fat substitutes in the treatment of obesity drugs will be explored. Obesity drugs awaiting FDA approval and compounds under development will be reviewed. The section on approaches to drug management will include clinical considerations for; who should receive pharmacotherapy and when, length of treatment and drug discontinuation, weight regain and the role of pharmacotherapy.
‘Each component of obesity management claims its effectiveness; however, successful treatment often requires more than a single approach.’
Background
Obesity: A Serious Condition
According to the National Health and Nutrition Examination Survey 2009-2010, 37.5% of American adults were reported to be obese, together with16.9% of American children and adolescents. The percentage is higher for adolescents compared with preschool children. There are more obese boys (18.6%) compared with girls (15%). There has been no change in obesity prevalence in recent years. However, over the past decade, there has been a significant increase in obesity prevalence among men and boys but not among women and girls overall (US Department of Health and Human Services, Final review, Healthy People 2010 Final Review -www.cdc.gov/nchs/data/hpdata2010/hp2010_final_review.pdf
There are data to suggest that this significantly high rate has abated overall except for the boys in the 97th or higher percentile. Overweight and obesity may be having a greater effect on black and Hispanic populations (National Health and Nutrition Examination Survey 2007-2008, http://www.cdc.gov/nchs/nhanes.htm). The Healthy People 2010 goals of lowering the obesity percentage to 15% among adults and 5% among children were not met. The World Health Organization (WHO) estimates that more than 1 billion people are overweight globally and that if current trends continue, this number will increase to 1.5 billion by 2015 (http://www.who.int/mediacentre/news/releases/2005/pr44/en/). It is estimated that there are more than 475 million obese people worldwide (International Obesity Task Force, http://www.iaso.org/iotf/obesity/obesitytheglobalepidemic). Obesity promotes numerous medically significant comorbidities such as diabetes mellitus, hypertension, dyslipidemia, sleep apnea, several cancers, and gall bladder disease, all of which contribute to the increase in morbidity and mortality, particularly in younger individuals.1-4 It has been estimated that more than 300 000 people die each year from obesity-related diseases in the United States.5,6 Therefore, better measures to prevent and treat obesity are urgently needed.
Obesity Treatment
Historically, research and clinical practice treatment of obesity has focused on calories, macronutrient intake, lifestyle modification, and physical activity. Randomized obesity clinical trials that included behavior modification interventions have been shown to be effective in promoting weight loss. In the nonresearch, general medical practice clinical setting, however, there are significant barriers to providing these techniques. Barriers include limited physician and medical personnel training in obesity management, current structure and duration of a typical office visit, and the limited to no reimbursement from health insurers (private and government).
Obesity management has evolved to now include drug therapy and a bariatric surgery arm. Each component of obesity management claims its effectiveness; however, successful treatment often requires more than a single approach. Combinations of some of these components are recommended for maximum weight loss and successful weight maintenance.
There are some physicians and other health care professionals who seem to believe that all obesity is self-imposed. There are many more people in the general population who feel the same way. This attitude helps create further bias against the obese population and may have an effect on the degree of their overall medical care. A similarly expressed feeling is that it is both simple and easy to change attitudes and personal behaviors surrounding the food that obese people eat. Changes in attitudes and behaviors are needed, but they are neither easy nor simple to accomplish. For the majority of the obese population, successful weight management will be both difficult and a lifelong project.
Research over the past several decades has demonstrated not only the value of lifestyle modification as a treatment for obesity but that drug therapy as an adjunct to behavior changes is underutilized. Recent discoveries related to the genetic and chemical basis for obesity7-11 have encouraged further drug development. FDA drugs approved for short-time use can be effective and those approved for long-term use achieve medically effective weight loss in the long run.
The majority of obese adults will have already tried some variation of self-help behavioral approaches before consulting with their physicians for advice about their weight. Self-help advice is readily found on Internet sites, through social media, on TV and the radio, and in print media. Advice is given by friends and family members. The appropriateness and effectiveness of some advice obtained in this manner is of questionable value, and results obtained by following nonmedical advice may even discourage as many people as it attempts to help and inform. Nevertheless, it is utilized by the overweight public looking for weight loss answers.
There is an increase in the public awareness of the health and lifestyle consequences of being obese, but there are patients who feel that their doctors are both too busy and lack the expertise and perhaps the compassion to help them. 12 There is no obvious cure in sight. Behavior modification and pharmacotherapy have been inadequate to bring about needed changes at the community level or to stop the global obesity epidemic. The medical profession needs to be at the forefront to treat patients with obesity. This article will discuss mechanisms of action of obesity drugs, theories of altered body defense of body weight, Food and Drug Administration (FDA)-approved drugs, off-label use, over-the-counter (OTC) medications and diet supplements, fat substitutes, drugs awaiting FDA approval, compounds under development, and approaches to drug management.
Mechanisms of Action and Categories for Obesity Drugs
In obesity, the body stores excess energy in the form of fat. A period of negative energy balance is required to reduce this excess body fat. This can be accomplished either by a reduction in food intake or an increase in energy expenditure. Pharmacological agents act by various mechanisms on this energy balance equation but mainly focus on reducing energy intake. Maintenance of energy balance in the body is so critical to survival that there are many redundant mechanisms that influence food intake and energy expenditure. 13 Numerous areas of the brain participate in the regulation of energy balance, and they respond to different neurotransmitters. Most of the drugs currently approved for the treatment of obesity in the United States act on 2 of the more important neurotransmitter systems to regulate energy balance: the centrally acting serotonergic and adrenergic systems. Some other drugs reduce energy intake by reducing the digestibility and absorption of macronutrients.
Reduction of Energy Intake
Energy intake may be reduced in several ways. All obesity drugs currently approved by the FDA, except Orlistat, are thought to reduce appetite or hunger, increase satiety, and modify food seeking behavior.14-16 There is some evidence that obesity drugs may alter dietary preference for fat or carbohydrates, but this evidence is limited. By using obesity drugs selectively, patients may be better equipped to regain control over eating behaviors and possibly be more compliant with behavior and lifestyle changes that are needed for a long-term change in body weight.
Centrally Active Serotonergic Agents
The agents currently approved for obesity treatment are Drug Enforcement Agency (DEA) class-IV drugs that prevent the reuptake of serotonin in the neural clefts. Studies suggested 17 that serotonin may reduce cravings for carbohydrates. Lorcaserin (Belviq) is a selective serotonin 2C receptor agonist FDA approved for obesity treatment on July 17, 2012. There are FDA-approved serotonin reuptake inhibitors that have some potential to produce weight loss, 18 but these drugs are not FDA approved for obesity management. They are the antidepressant drugs fluoxetine (Prozac) and sertraline (Zoloft).
Centrally Active Adrenergic Agents
These are DEA schedule IV class drugs: phentermine and diethylpropion. These schedule IV obesity drugs have minimal addiction or abuse potential and are the most prescribed adrenergic drugs for obesity in America. 19 These adrenergic agents stimulate the secretion of norepinephrine from the central nerve terminals leading to actions on food intake and energy expenditure.
The schedule II drugs dexamphetimine, methamphetamine, and phenmetrazine are only used in extremely rare circumstances because of their significant abuse potential. They do not produce more weight loss than do the schedule IV agents and should be used only with extreme caution.
Schedule III drugs include benzephetamine (Didrex) and phendimetrazine (Bontril). They are rarely used by most physicians to treat obesity because their abuse potential is higher than that of the more-favored and lower-risk schedule IV agents.
Enzyme Inhibitors
As a class, they act by reducing the intestinal absorption of nutrients. Prescription orlistat (Xenical) and OTC orlistat (Allie) are the only FDA-approved drugs for obesity management in this class.
Increase in Energy Expenditure
Animal and human studies suggest that some obesity drugs may act by increasing energy consumption, by increasing the resting metabolic rate, or through increased thermogenesis induced by diet, cold, or exercise. Stimulation of physical activity through tremors or spontaneous physical activity is reported, but this literature is controversial.15,20 Anecdotally, patients on obesity drugs report an increase in willingness to exercise and are comfortable when active, but there have been no studies to clearly document this phenomenon or to attribute it to drug action. Phentermine and diethylpropion fall in this category. The drug combination of ephedrine and caffeine with or without aspirin increases resting metabolic rate probably by stimulating β-adrenergic receptors.21,22 The independent contribution of medications on the increasing energy expenditure component is difficult to determine in trials with a behavior and activity component.
Most obesity drug clinical trials discussed here include a behavioral therapy component with a focus on increasing activity, calorie, and food management and long-term changes in personal habits.
Drug Combinations
The newly approved phentermine/topiramate combination (Qysmia) and lorcaserin (Belviq) will be discussed. As with any new FDA-approved drug, long-term clinical practice experience is not yet available for these antiobesity drugs.
Set Point/Settling Points Theories and Obesity
Body weight control in the short term involves internal and external signals that initiate and terminate feeding. Body weight stability in the long term is more complex and complicated. It reflects genetic effects (DNA), heritable traits that do not involve changes in DNA, and the environment. 19 It involves changes in energy balance and energy stores. Both the set point and settling points theories are theories on long-term body weight control.
The set point theory proposes an active proportional homeostatic feedback control to regulate body weight to a constant.19-26 The central nervous system and peripheral systems regulate energy and nutrient balance by biological and behavioral mechanisms. A recent review suggests that many but certainly not all individuals appear to have a relatively constant body weight throughout life, and the set point may be fixed within a wide range with an upper and lower limit. 23 According to this theory, a body that is at a weight different from its set point is returned to that set point by mechanisms that adjust food intake or energy expenditure or both.23,25 Weight regain appears to be caused by additional factors besides variations in metabolic rate. 27
The settling points theory proposes that multiple set points could be established, and a new weight can be maintained for some time when it reaches a new zero energy balance. This new energy balance is influenced by calorie and macronutrient intake or through a control system that responds to negative energy food balance. 23 The set point and settling points may be interrelated.
In the chronically obese individual, control mechanisms such as set and settling points are probably altered or dismantled or overcome by external factors such as the typical Western diet, lifestyle, and environment. 23 Changes in lifestyles and eating habits and increased physical activity promoted in obesity research studies may be the triggers of reestablishing metabolic controls leading to a stable body weight.
Obesity drugs may reduce the level at which body weight is defended. 23 The reduction in body weight with obesity drugs may be maintained despite the lower metabolic rate. 15
The FDA-Approved Obesity Drugs
Drugs Approved for Long-term Use
Orlistat (Xenical)
This is a gastrointestinal (GI) lipase inhibitor that works by inactivating intestinal enzymes and partially inhibiting the digestion of fat. It is approved for long-term treatment of adult obesity. With orlistat, there is a decrease in fat absorption and energy intake.28-31 Less than 1% of this peripherally acting drug is absorbed. Fat absorption can be reduced by approximately a third in those taking orlistat while eating a recommended meal containing 30% fat.
The recommended dose of orlistat is a 120 mg capsule taken 3 times a day with each main meal that contains fat. The capsule can be taken right before a meal, during a meal, or up to 1 hour after a meal (http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=5bbdc95b-82a1-4ba5-8185-6504ff68cc06). If any meal during the day contains no fat, there is no advantage in taking that orlistat dose. For the same reason, orlistat need not be taken if a meal is skipped. Patients taking supplemental vitamins need to be advised to take their vitamin(s) on a schedule that is at least 2 hours before or after an orlistat dose. Bedtime may be the most convenient supplement time choice.
GI side effects may include diarrhea, fecal incontinence, urgency, oily stool, anal leakage, bloating, abdominal pain, and gas. Such side effects can occur in up to 40% of patients. Higher dietary fat content increases the likelihood of GI events. 32 Some nutrients and some medications might have decreased absorption,32-34 and there may be the need for fat-soluble vitamin replacement. GI side effects can be avoided by providing appropriate patient education. To help ensure continuing drug compliance, patients should also be advised that the voluntary ingestion of a meal containing higher than normal fat or eating a higher-fat meal by mistake may lead to an accidental GI event. The type of GI event may not have previously been experienced, or it may manifest as a more acute bout of previously experienced diarrhea. Such patient education and its reemphasis at subsequent medical visits may not only help avoid GI accidents but may prevent patients from discontinuing drug treatment unnecessarily. Patient avoidance of GI side effects may promote extended use of orlistat in both active weight loss and with weight maintenance.
Orlistat has been extensively studied.28-38 Multiple-year clinical trials, testing participants with type 2 diabetes34-36 and those without type 2 diabetes,28-33,38 have been performed and reported. In a 2-year study, drug-treated participants lost nearly 10% body weight in the first year (5% to 6% placebo) with a sustained weight reduction at the end of year 2, with only a 1.8-kg weight regain (3.6 kg in the placebo group). 32 Improvement in lipid and insulin levels were seen, and in obese individuals with or without type 2 diabetes, orlistat demonstrated an improvement in glucose metabolism and a reduction in high blood pressure.35,36 Metabolic syndrome has been studied in multiyear clinical trials with orlistat. In a 3-year study, orlistat was found to be a useful adjunct to conventional dietary and lifestyle treatment of high-risk obese individuals with abdominal obesity, dyslipidemia, impaired fasting glucose, and diet-treated type 2 diabetes. 38 Multiyear trials of orlistat treatment for obesity maintenance have been reported. In a 3-year weight maintenance study, a subgroup selectively decreased their intake of fatty foods and had a greater degree of weight maintained. 37 Continuing patient education on lowering dietary fat consumption is needed for maximizing weight loss.
In 2007, FDA approved orlistat (Alli) as an OTC obesity drug for adults. The dose is 60 mg 3 times a day and should be taken in conjunction with a reduced calorie and low-fat diet. Exercise and a multivitamin are also recommended. Side effects of the OTC orlistat are similar to those of prescription orlistat. The FDA has received reports of rare cases of severe liver injury with the use of orlistat, both by prescription and in the OTC form. In response, the FDA has added a drug label (NIH Publication No. 07–4191November 2004, Updated December 2010) notice.
Newly Approved Drugs for Long-term Use
Lorcaserin (Belviq)
This drug was FDA approved on July 17, 2012, as an appetite suppressant to be used together with a reduced-calorie diet and exercise for long-term obesity treatment. It is a central nervous system selective serotonin 2C receptor agonist that influences hunger. 39 The FDA-approved labeling recommends dosing lorcaserin 10 mg orally twice daily, taken with or without food (www.belviq.com). Lorcaserin labeling recommends discontinuing patients who fail to lose 5% of their body weight after 12 weeks of treatment because these patients are unlikely to achieve clinically meaningful weight loss with continued treatment.
Short-term multiple-year and maintenance studies of patients on lorcaserin have demonstrated clinically significant weight loss.39-41 In a 2-year clinical study, at the end of the first year, 47.5% of patients who received lorcaserin lost 5% or more of their baseline body weight compared with 20.3% of those who received placebo, and at the end of the second year, 22.6% of the lorcaserin group lost 10% or more body weight compared with 7.7% of those on placebo. 39 Maintenance of weight loss at the end of year 2 was seen in almost 70% of Lorcaserin-treated patients and in 50% of the placebo group. 39 In a recently published 1-year lorcaserin obese type 2 diabetes study, lorcaserin-treated patients with diabetes lost 4.5% to 5.0% of their initial bodyweight compared with a loss of 1.5% in the placebo group. The treated group showed greater improvement in glucose control. 42 Common side effects included headache, dizziness, and nausea.39-41
The structure of lorcaserin is similar to that of dexfenfluramine, but lorcaserin is more selective for the serotonin 2C receptor, and no increase in valvulopathy was seen in serial echocardiograms.39,41 As a highly selective subtype of 5-HT receptors, lorcaserin has a low affinity for other 5-HT-receptor subtypes. When activated, it is these other 5-HT-receptor subtypes that are thought to underlie serious cardiovascular adverse effects, such as those that have been seen with nonselective serotonergic weight loss agents such as dexfenfluramine. 43
Phentermine/Topiramate (Qysmia)
This is an extended-release capsule. It is the only drug combination approved for chronic weight management by the FDA. It is to be used as an adjunct to a reduced-calorie diet plus exercise. It was approved on June 27, 2012. This time-release capsule combines the appetite suppressant adrenergic agonist drug phentermine (immediate release) with a delayed-release form of the anticonvulsant and migraine prevention drug topiramate. 44 Weight loss in humans taking topiramate may mostly be a result of appetite suppression. 44
It is administered once a day and is available in 4 dose strengths. FDA-approved labeling recommends a stepwise up-titrated dose schedule based on weight loss response. The first 2 dose schedules are only for titration. The initial dose of phentermine/topiramate is 3.75 mg/23 mg in the morning. Two weeks later the dose is up-titrated to 7.5 mg/46 mg and is to be continued for a total of 3 months. After 3 months of treatment, there are clinical options to be addressed and decisions to be made. If the patient has lost at least 3% of baseline weight, the dose should be increased to phentermine/topiramate 11.25 mg/69 mg. If the patient has not lost at least 3% body weight, it is unlikely that further weight loss will occur at a higher dose, and a choice to discontinue the drug should be considered. Two weeks later, the final dose titration of phentermine/topiramate 15 mg/92 mg daily in the morning is reached. After an additional 3 months on this final dose, there are again clinical decisions to be made. If weight loss of 5% or more has occurred, the drug should be continued at this final dose. If it has not occurred, the drug should be discontinued because further clinically meaningful weight loss is unlikely. This stepwise titration to the highest daily dose is designed to maximize clinical weight loss and minimize adverse events. For patients titrated up to the highest dose, there is an FDA-approved protocol to be followed when discontinuing this drug as a precaution against precipitating a seizure. The phentermine/topiramate 15 mg/92 mg dose is to be decreased to every other day for at least a week before stopping (http://www.fda.gov/downloads/Drugs/DrugSafety/UCM312590.pdf). 44
The most common side effects include paresthesia, dizziness, dysgeusia, insomnia, constipation, and dry mouth. Psychiatric and cognitive adverse effects can occur, including behavior and mood changes, depression, and suicidal thoughts (http://www.fda.gov/downloads/Drugs/DrugSafety/UCM312590.pdf). There are contraindications, warnings, and precautions that need to be reviewed, including preexisting hypertension and glaucoma and avoiding pregnancy during treatment because of related fetal toxicity. The risk evaluation and mitigation strategy recommended by the FDA mandates that this drug be dispensed only by mail order with 1 month’s supply at a time and a maximum of 5 refills. Specially certified pharmacies will be used.
This drug combination has been studied in healthy overweight and obese individuals as well as in those with 2 or more components of the metabolic syndrome.45,46 Data from 2 obesity studies, each of 56 weeks’ duration, done in sequence, were linked together to evaluate the long-term efficacy and safety in those with cardiometabolic disease.45,46 The total uninterrupted treatment time was 108 weeks. Weight loss and improvement in parameters of cardiometabolic disease (triglyceride and high-density lipoprotein [HDL] values, fasting blood sugar, insulin levels, and blood pressure) occurred over the first 56 weeks and were sustained at 108 weeks. At 108 weeks, the highest study drug doses produced the most weight loss. Weight loss from baseline was as much as 20% compared with placebo. Many patients on placebo who were being treated for cardiometabolic problems prior to and during the 108-week study required increases in their nonobesity medications.
When prescribing antiobesity medication, an echocardiogram may be indicated if a heart murmur or symptoms of dyspnea on exertion, easy fatigue, and fainting or chest pain are present, especially if a patient has previously been on the combination of phentermine and fenfluramine.
Drugs Approved for Short-term Use
Phentermine
This is the most commonly prescribed obesity drug in the United States. The popularity of phentermine is most likely a result of it being available with FDA approval since 1959 as a short-term treatment for obesity together with the subsequent clinical experience gathered using the drug combination of phentermine and fenfluramine.47-50 The combined use of phentermine with fenfluramine was prohibited when fenfluramine was withdrawn from the market by the FDA in 1997 because of its possible association with valvular heart disease. Phentermine alone was not shown to contribute to valvular heart disease and has not been withdrawn by the FDA. Long-term study criteria that are now required by the FDA did not exist in 1959. Currently, the efficacy criteria set forth by the FDA for a drug to be approved for the treatment of obesity require that it induce a placebo-adjusted weight loss of 5% or more at 1 year or that 35% or more of patients on the drug should achieve a 5% or more weight loss, with at least twice as many patients losing 5% or more relative to those treated with placebo.
It is a centrally active adrenergic, sympathomimetic amine that stimulates norepinephrine release in synaptic terminals. With phentermine use, patients can experience increased satiety and less hunger, craving, binging, and nighttime eating. Phentermine is available as Phentermine HC in both tablet form (some generic phentermine tablets are scored) and as a capsule. Both the tablet and the capsule contain 37.5 mg, which is equal to 30 mg of phentermine base. Phentermine HC is also available as an orally disintegrating tablet containing 15, 30, or 37.5 mg (equivalent to 12-, 24-, or 30-mg phentermine base, respectively). Doses of phentermine higher than 37.5 mg are not FDA approved. Phentermine resin is available as capsule of 30 mg. Phentermine resin capsules contain a cationic resin complex equivalent to 30 mg phentermine base. Doses higher than 30 mg of phentermine resin are not FDA approved and should not be prescribed. As with other generic prescription drugs, phentermine can also be purchased online.
The starting dose of phentermine will be determined by which phentermine form (HC or resin) a physician chooses to prescribe. Phentermine HC gives the physician greater options if a stepwise dosing approach is preferred. In a stepwise approach, a scored 37.5 mg tablet can be halved to a starting dose of 18.75 mg or even lower with an oral disintegrating tablet of 15 mg6,41 and up-titrated. Should side effects be an issue at 37.5 mg of the HC form of phentermine, the dose can be reduced. The highest final dose form can be either phentermine HC 37.5 mg or phentermine resin 30 mg.
There are no recent studies with phentermine, but earlier studies with phentermine alone show effectiveness and safety.51,52 Phentermine is associated with a rapid onset of appetite control. Improvement in patient attitude and weight management program adherence is seen.47-50,53,54 After about 6 months, lost weight usually reaches a plateau regardless of the form used.47,51,53
The most common side effects of phentermine include decreased appetite, dry mouth, headache, insomnia, irritability, nervousness, euphoria, palpitations, tachycardia, and an elevated blood pressure. Phentermine should be avoided in patients with active cardiovascular disease, moderate to severe hypertension, hyperthyroidism, agitated states, glaucoma, and a history of drug abuse. Drug abuse potential and addiction is reported as minimal. 55 There have been a few case reports of primary pulmonary hypertension in patients taking phentermine alone. 56
Diethylproprion
This is a centrally active adrenergic sympathomimetic agent with an action similar to phentermine and structurally similar to the FDA-approved antidepressant drug bupropion. Bupropion has been studied for its weight loss effect. 57 The recommended dose is 75 mg/d.
Short-term studies 58 showed that treated patients lost 12.3% of initial body weight (2.8% loss with placebo), and continuous treatment was more successful than intermittent drug treatment. Blood pressure reduction occurred in proportion to the weight lost. Adverse effects included dry mouth, euphoria, asthenia, nervousness, decreased appetite, insomnia, and sleeplessness with frequent awakening. This drug is not recommended for patients with heart disease, high blood pressure, hyperthyroidism, or glaucoma. 52
Off-Label Drug Use
The off-label clinical and investigational use of marketed drugs is defined by the FDA as follows:
Good medical practice and the best interests of the patient require that physicians use legally available drugs, biologics and devices according to their best knowledge and judgment. If physicians use a product for an indication not in the approved labeling, they have the responsibility to be well informed about the product, to base its use on firm scientific rationale and on sound medical evidence, and to maintain records of the product’s use and effects. Use of a marketed product in this manner when the intent is the “practice of medicine” does not require the submission of an Investigational New Drug Application (IND), Investigational Device Exemption (IDE) or review by an Institutional Review Board (IRB). However, the institution at which the product will be used may, under its own authority, require IRB review or other institutional oversight. (“Off-Label” and Investigational Use Of Marketed Drugs, Biologics, and Medical Devices—Information Sheet Guidance for Institutional Review Boards and Clinical Investigators; http://www.fda.gov/RegulatoryInformation/Guidances/ucm126486.htm)
There is no FDA restriction on physicians using an FDA-approved medicine for a condition or a dose or duration that is different from that approved by the FDA. The National Institutes of Health document titled, “Prescription Medications for the treatment of Obesity” reminds prescribers that for off-label determinations, there needs to be a balance between a drug’s known and unknown side effects and the potential added benefit of off-label use (Prescription medications for the treatment of obesity, NIDDK, Weight Control Information Network, US Department Of Health and Human Services, National Institutes of Health NIH Publication No. 07-4191; November 2004; Updated December 2010). It is recommended that a careful and detailed review of the rationale for using an off-label drug be documented in patient records. Each patient should be informed and educated as to why this drug is being prescribed, and patient agreement to the treatment should be documented. It is recommended that such a document be signed and maintained in the patient record. Clinical evidence for the off-label use for obesity treatment is reported for the following medications.
Antidepressants
Fluoxetine (Prozac)
This is a highly selective serotonin reuptake inhibitor approved by the FDA as an antidepressant. It has been investigated for its weight loss effect. The weight loss mechanism for fluoxetine is not well understood. The most common side effects include anxiety, nervousness, weakness, asthenia, decreased sexual desire or ability, loss of appetite, nausea, diarrhea, dizziness, drowsiness, dry mouth, flu-like symptoms, increased sweating, or trouble sleeping.
Weight loss has not been consistent in all clinical trials, and patients who lost weight in the initial 6 months tend to regain weight despite the ongoing fluoxetine therapy.59,60 Fluoxetine dosage for obesity treatment varied from 20 to 80 mg in clinical trials.18,59-61 In trials that contained a behavior modification component, weight loss at 1 year in both fluoxetine and placebo groups may reflect the addition of a behavior program.59,60 A 1-year study that included behavior modification using fluoxetine 60 mg showed a maximum fluoxetine group weight loss of 12.4 kg (4.5 kg placebo) at 29 weeks. 61 The fluoxetine-treated group regained a mean weight of 4.2 kg from its lowest weight at study end, and the placebo group had no weight regain. Both groups lost a significant amount of weight compared with baseline; however, this difference was not statistically significant.59,61 In some studies, there were site to site differences in the use of nutritional counseling or behavior modification. 61 This variance may have been reflected in improved efficiency at certain sites. Various combinations of behavior modification, nutrition advice, and pharmacotherapy as part of a protocol reinforce the role of a comprehensive therapy approach even in an off-label format.59-61 In a 1-year study of fluoxetine 20 mg daily for depression (meeting Diagnostic and Statistical Manual of Mental Disorders, 3rd edition [DSM-III]-R criteria with a modified 17-item Hamilton Depression Rating Scale), patients on fluoxetine whose depression resolved after 12 weeks lost about 0.5 kg compared with placebo-treated depressed patients. 62 At the end of the 12 weeks, patients on fluoxetine whose depression was resolved were randomized to continued fluoxetine or switched to placebo. Weight gain during the contiuation phase of this study was observed in both the placebo- and fluoxetine-treated groups with slower weight gain for periods up to 26 total weeks in the fluoxetine group. 62 The authors of this study commented on data showing that recovery from depression is often associated with improved appetite and social functioning, which could lead to greater food intake and potential weight gain.
In most obesity studies with fluoxetine, the observed weight regain at 6 months may suggest that there is no clinical place for fluoxetine in the comprehensive management armamentarium of obesity therapy. However, depression and depressive symptoms may have deleterious effects on successful obesity management. An obese patient with depressive symptoms as a confounding factor may respond to a short course of fluoxetine therapy (3-6 months) with resolution of depressive symptoms and an improvement in body weight.59-62 The resolution of depression may then allow a longer-term obesity management plan to be better effective.
A 6-month weight loss trial combining fluoxetine (from 20 to 60 mg/d) and phentermine HC (from 18.75 to 37.5 mg/d) produced significant weight loss of 9% compared with the combination of phentermine and the now-discontinued drug fenfluramine (15% weight loss). 63 There were no echocardiography cardiac valve lesions found in the fluoxetine- and phentermine-treated patients or in controls. 64
Bupropion (Welbutrin)
This is FDA approved and indicated for the treatment of depression and smoking cessation. It is a norepinephrine, serotonin, and dopamine uptake inhibitor. It has been shown to be effective in promoting weight loss in patients with or without depression.65,66 In a 48-week study of bupropion versus placebo for weight loss, all patients were counseled on energy-restricted diets, meal replacements, and exercise. 65 Net weight losses compared with placebo were 2.2% (bupropion SR 300) and 5.1% (bupropion 400 mg). Maintained mean loss of initial body weight in the bupropion groups were 7.5% and 8.6%. 65
In a 26-week weight loss study of those with depressive symptoms, bupropion-treated patients lost an average of 4.4 kg compared with 1.7 kg for those on placebo and also demonstrated improvement in depressive symptoms. Both groups received nutrition counseling. 66
Side effects were reported to be minimal. The most common side effects included agitation, weight loss, dry mouth, nausea, headache, constipation, dizziness, tremors, and tachycardia.
Antiseizure Drugs
Topiramate (Topamax)
This is an antiepilepsy drug that blocks sodium channels and enhances the neuroinhibition of γ-aminobutyric acid.
There have been observational reports of weight loss associated with topiramate treatment of bipolar disorders. A small group of patients with a DSM-IV diagnosis of bipolar disorder or schizoaffective disorder received topiramate treatment, and a chart review documented weight loss. 67 The average weight loss was 10 kg (range = 4-25 kg) with topiramate. The topiramate dose was slowly up-titrated starting with 25 or 50 mg daily into a twice-daily format. The mean split daily dose of topiramate was 195 mg/d (range = 100-375 mg/d). 67 Common side effects of topiramate include fatigue, sedation, concentration and focus issues, slow thinking, memory problems, psychomotor slowing, diplopia, nystagmus, dizziness, ataxia, paresthesia, anorexia, headache, and speech problems. 67 There were no dropouts as a result of side effects, and the authors suspected that the slow titration may have been responsible. In a 24-week weight loss study of topiramate, 68 weight loss was dose dependent, with the most weight lost (6.3% treated, 2.6% placebo) at the highest daily dose. The dose was slowly up-titrated to a daily divided dose of 384 mg/d. The drop-out rate for the drug group (21%) was double that of the placebo group (11%). This drop-out rate was attributed to the side effects of cognitive dysfunction and paresthesia. 68 A weight maintenance topiramate study of 60 weeks demonstrated a weight loss of 6% after weight lost on 8 weeks of a low-calorie diet. The study was discontinued at 44 weeks as a result of the sponsor’s decision to develop a new controlled-release formulation. 69 The drug was generally well tolerated. 69 In a 1-year study utilizing 3 different doses of topiramate, 70 weight loss occurred at all dose levels compared with placebo. Weight loss of 9.7% (1.7% placebo) occurred at the highest daily total dose of 256 mg. Improvements in glucose tolerance and in blood pressure were documented. Side effects mostly occurred during upward drug titration and included difficulty with concentration/attention, depression, difficulty with memory and concentration, language problems, nervousness, and psychomotor slowing and paraesthesia. 70 This was originally to be a 2-year study but also ended early in order for the sponsor to develop a controlled-release formulation.
Zonisamide (Zonegran)
Zonisamide was approved by the FDA in 2000 for the treatment of partial focal seizures in adults with epilepsy. Zonisamide has serotonergic and dopaminergic actions in addition to blockade of sodium and calcium channels. Weight loss was identified during clinical trials for epilepsy and has since been studied for weight loss. 71 In a 16-week study with a 16-week extension, zonisamide-treated individuals lost considerably more weight compared with placebo. 71 The study dose was titrated from 100 to 400 mg, and in those who lost less than 5% body weight at 12 weeks, it was titrated to 600 mg. At 32 weeks, drug-treated participants had a mean weight loss of 9.2 kg (1.5 kg placebo), with 57% of the drug-treated group and 10% of the placebo group losing at least 5% of body weight. There was also an associated improvement in mobility, occupational functioning, and activities of daily living. Fatigue was the only drug-related side effect reported. In antiepileptic clinical trials of zonisamide, cognitive impairment, dizziness, and somnolence were frequently noted. Zonisamide is a sulfonamide, and there is a potential for hypersensitivity reactions. 71 A combination of zonisamide and bupropion was compared with zonisamide alone in a 12-week weight loss study of 18 obese women. 72 The initial zonisamide dose was 100 mg/d, with a gradual increase to 400 mg/d in both groups given as a nighttime dose. Bupropion was titrated up from 100 to 200 mg/d and given as a morning dose. The combination produced more weight loss (8.1 kg) than zonisamide alone (3.0 kg). 72
Atomoxetine
This is FDA approved for treating attention-deficit hyperactivity disorder. It is a central norepinephrine uptake inhibitor. A 12-week study of atomoxetine for weight loss included 30 healthy but obese women. The study dose was titrated from 25 to 100 mg/d. Weight loss of 3.7% was seen with those on the study drug, with a 0.2% placebo weight gain. 73 ) The most common side effect reported was a decrease in appetite.
Antidiabetic Drugs
Metformin (Glucophage)
This is an FDA-approved antidiabetic drug. Studies with metformin have shown it to be either weight neutral or promoting weight loss when compared with sulfonylureas, thiazolidinediones, and insulin, which are more associated with weight gain. In a clinical trial to assess weight changes associated with antihyperglycemic agents in type 2 diabetes mellitus, the study authors concluded that a case can be made for the early use of metformin as a treatment of choice in the management of type 2 diabetes to prevent weight gain or to promote weight loss.74,75 In some metformin obesity trials, hunger and calorie intake were reduced.76,77 Metformin for weight loss has also been studied in obese children. 78 In a 1-year study of 100 severely obese insulin-resistant children (6-12 years old), metformin was part of a comprehensive weight-reduction lifestyle modification program promoting a reduced calorie diet, increased physical activity, and decreased inactivity. Metformin was titrated from 500 mg twice daily to a maximum dose of 1000 mg twice daily over a 3-week period. The weight loss difference for the metformin group compared with placebo was −3.38 kg. 79 This difference persisted during treatment. 79 Improved measures of body fatness were seen. During the initial placebo-controlled randomized phase, both groups had a significant reduction in BMI Z scores, with metformin-treated children having greater decreases in BMI Z scores compared with those on placebo (−0.070). The BMI difference was −1.09 kg. During the open-label phase, children who were switched to metformin from placebo significantly decreased their BMI Z scores, whereas those on continuous metformin had nonsignificant increases in BMI Z scores. Side effects included nausea, loose stools, and fatigue. There were no significant liver function abnormalities.
Acarbose (Precose)
Acarbose is FDA approved for the treatment of diabetes. It is an α-glucoside inhibitor that delays the digestion of disaccharide.80,81 Studies of acarbose for obesity treatment in diabetic patients and in polycystic ovary syndrome patients have demonstrated only small changes in body weight.80,81
Side effects are caused by the presence of undigested complex carbohydrates in the colon. They include increased intestinal gas, flatulence, diarrhea, and abdominal pain. In a National Institutes of Health publication, it was reported that there is not sufficient efficacy or safety evidence to consider prescribing acarbose in nondiabetics as an off-label treatment for obesity (Diabetes prescription medications for the treatment of obesity, NIDDK, Weight Control Information Network. US Department Of Health And Human Services National Institutes of Health NIH Publication No. 07–4191; November 2004; Updated December 2010).
Exenatide
This is FDA approved for type 2 diabetes. It is part of the incretin family of type 2 diabetes drugs, a glucagon-like peptide-1 (GLP-1) receptor agonist. It suppresses appetite and promotes weight loss in obese diabetic patients. 82 A 2-year glycemic control and body weight study in type 2 diabetes used 2 treatment groups of exenatide. This 2-stage protocol consisted of a randomized, open-label comparison of subcutaneous doses of exenatide. Dosage was once weekly (long-acting form) and twice daily for 30 weeks, followed by all patients receiving exenatide weekly (long acting) for the remainder of the 2 years. 82 In completers, 2-year results showed significant improvement in body weight (−3.64 to −1.58 kg) and glycosylated hemoglobin (HbA1c; −1.7%) with exenatide. The percentages of patients who achieved an HbA1c of less than7.0% and equal to or less than 6.5% at 2 years were 60% and 39%, respectively. 82
Amylin
This is a peptide hormone that is secreted from pancreatic ß cells in response to eating a meal and is part of a complex neurohormonal feedback system. It slows gastric emptying and stimulates satiety after a meal. 83 It acts within the brain to reduce food intake and body weight. 84 Studies are ongoing.
Pramlintide
This is a subcutaneous injectable synthetic analog of human amylin. It is FDA approved for type 1 diabetes and used for patients with type 1 or type 2 diabetes who are taking insulin and need further diabetes control. Pramlintide appears to have a therapeutic role in patients with type 2 diabetes with obesity. In studies of obese type 2 diabetic adults, pramlintide has produced sustained reductions in food intake, body weight, and total daily insulin use, 85 and the addition of pramlintide, to preexisting insulin treatment of type 2 diabetes results in reductions in HbA1c and body weight. 85 Weight loss also occurred in nonobese patients with diabetes. 86 In a study of men and women with or without type 2 diabetes, pramlintide-treated patients had increased weight loss that was accompanied by a reduction in waist circumference. Those completing 16 weeks of pramlintide treatment experienced placebo-corrected reductions in body weight of 3.6 ± 0.6 kg and waist circumference of 3.6 ± 1.1 cm. This study did not include lifestyle intervention.87,88
A combination of pramlintide and metreleptin (leptin) resulted in about 13% weight loss, significantly greater than pramlintide or metreleptin treatment alone. 89 Nausea was the main side effect.87,89
The safety and efficacy of pramlintide alone or in combination with either phentermine or sibutramine (no longer on the market) was tested in a 24-week study. 90 Weight loss achieved at week 24 with either combination was greater than with pramlintide alone or placebo. Weight loss with pramlintide and sibutramine was 11.1%, pramlintide and phentermine 11.3%, pramlintide alone 3.7%, and placebo 2.2%.
Ephedrine With Caffeine and/or Aspirin
The FDA has banned ephedrine from OTC products, but it remains available for medical use. 91 Ephedrine increases the synaptic release of norepinephrine, modulating food intake, heart rate, and blood pressure.
It enhances thermogenesis through its sympathomimetic effect. Caffeine appears to potentiate the effect of ephedrine. Aspirin inhibits the activity of prostaglandins.21,22,92,93 The combination possesses anorectic and thermogenic properties, resulting in a prolonged norepinephrine activity. Ephedrine alone and in combination with caffeine has been shown to increase thermogenesis in humans.94-96
Clinical trials with ephedrine in combination with caffeine and aspirin have demonstrated an increase in lean body mass and a decrease in fat mass. Side effects were mild and transient.21,22,92-94
A 50-week study evaluated the combination of ephedrine and caffeine with each alone. No aspirin was included in this study. The ephedrine dose was 20 mg 3 times a day (TID) with caffeine 200 mg TID, or ephedrine 20 mg TID alone, or caffeine 200 mg TID alone versus the placebo. A weight loss of about 16 kg was found in the ephedrine and caffeine group. 93 Other studies show that premeal doses vary for ephedrine (75-150 mg TID), caffeine (150 mg TID), and aspirin (330 mg TID). In a study using all 3 together, weight loss over 8 weeks was 2.2 versus 0.7 kg for placebo. 92 Here, 5 months poststudy, 8 of 13 participants on placebo returned and received ephedrine, caffeine, and aspirin in combination, and after 8 weeks, the mean weight loss was 3.2 versus 1.3 kg for placebo. Some studies have shown some weight regain by 7 months.92,97 Adverse effects in these studies were minimal and included tremor, insomnia, and dizziness and increase in heart rate and blood pressure. Side effects occurred early in treatment and resolved within 1 to 2 months. Elevated serum insulin levels and occasional worsening of glucose intolerance or diabetic control were observed and also resolved over time.21,22
Nonprescription Medications for Obesity Treatment
FDA-Approved Medications
Alli was introduced as an OTC drug in 2007 as a low-dose version of the FDA-approved obesity drug orlistat. This GI lipase inhibitor that partially blocks the absorption of dietary fat is the only FDA-approved OTC product for weight loss. In short- and long-term studies,32,98,99 GI events were more common in the orlistat-treated group. 98
In the first year of a 2-year study, orlistat dosage was 120 mg TID. 32 The second year focused on preventing weight regain. The dosage in year 2 was either decreased to 60 mg TID (equivalent to the OTC dose), or patients were switched to placebo. In year 2, the Orlistat group maintained their body weight within two-thirds of the maximum loss in year 1. Those who switched to placebo regained most of the lost weight. 32 A 3-month long pharmacy-based OTC study tested how consumers would use the dosing of orlistat in a nonsupervised environment. Most took 2 to 3 capsules per day with meals throughout the study. About 80% of users successfully made use of the educational materials and lost approximately 5% body weight. 99 The results of a 24-week weight loss study using orlistat versus placebo 100 was the first study to demonstrate that Orlistat 60 mg significantly reduces visceral adipose tissue (VAT) in addition to total body fat compared with placebo. Both orlistat- and placebo-treated patients significantly decreased their VAT at 24 weeks, with a significantly greater loss of VAT in orlistat-treated patients (−15.7% vs −9.4%). 100
Laxatives
These have been included in selective OTC weight loss products. There are no data to support their use in weight management.
Phenylpropanolamine (PPA)
The FDA has removed PPA from OTC weight loss and cold and sinus preparations. 91 The DEA as part of its implementation of the Combat Methamphetamine Epidemic Act of 2005 removed the OTC drug products containing PPA and also removed pseudoephedrine. This was done mostly to address the potential diversion of chemicals to narcotic raw materials. The DEA has classified these chemicals as List I chemicals. List 1 chemicals now also include ephedrine, pseudoephedrine, and PPA, which can be diverted to those narcotic raw materials. Their importation into the United States is prohibited. These chemicals are produced in limited amounts and remain available for medical, scientific, or other legitimate use. 91 In some states, nonprescription products containing PPA can be purchased with a personal ID card directly from the pharmacist.
Dietary Supplements
The US Congress defined the term dietary supplement in the Dietary Supplement Health and Education Act of 1994 as follows:
A dietary supplement is a product taken by mouth that contains a “dietary ingredient” intended to supplement the diet. The “dietary ingredients” in these products may include: vitamins, minerals, herbs or other botanicals, amino acids, and substances such as enzymes, organ tissues, glandulars, and metabolites. Dietary supplements can also be extracts or concentrates, and may be found in many forms such as tablets, capsules, softgels, gelcaps, liquids, or powders. They can also be in other forms, such as a bar, but information on their label must not represent the product as a conventional food or a sole item of a meal or diet. Whatever their form may be, DSHEA [Dietary Supplement Health and Education Act] places dietary supplements in a special category under the general umbrella of “foods,” not drugs, and requires that every supplement be labeled a dietary supplement. (http://www.cfsan.fda.gov)
The FDA does not analyze dietary supplements before they are sold to consumers. It is the manufacturer’s responsibility to ensure that a dietary supplement or ingredient is safe before it is placed on the market. Dietary supplements, therefore, can be manufactured and sold without FDA approval. The FDA responsibility for taking safety issue action occurs only when safety or efficacy issues are reported by the manufacturer or by the public. Manufacturers are not obligated to document to the FDA or to consumers any data on product safety or what claims they are making about their product. The FDA’s Center for Food Safety and Applied Nutrition is responsible for the agency’s oversight of these products (http://www.cfsan.fda.gov).
Dietary supplement use by the overweight population is common. It has been estimated that as many as 20.6% of women and 9.7% of men have at one time used a weight loss supplement, and many of these patients do not share information about their use of supplements with their doctor. 101 Most of the weight loss supplements contain stimulants, and the majority of users have no idea that the safety and efficacy of the product they are about to purchase is without FDA regulation. 102 Some physicians also misunderstand the dietary supplement regulations. 103 Many of the popular dietary supplements used for weight loss contain some of the following ingredients: chromium picolinate, guar gum, chitosan, citrus auantium, Camellia sinensis, conjugated linoleic acid, and calcium. 104
Use of supplements for weight loss should be identified and recorded in patient charts. Treating physicians have the responsibility to discuss common misconceptions about weight loss supplements and issues of safety and efficacy of some dietary supplements with their patients. This should be addressed if patients ask about dietary supplement use or if they are recommended as part of a weight loss program. 101
Fat Substitutes for Weight Loss
Fat substitutes are nonprescription food additives. They were developed by the commercial food industry to provide, among other benefits, a more pleasing taste, while providing a lower fat content for prepackaged grocery store foods.
Olestra (Olean) is a long-chain fatty acid sucrose polyester that is too big a molecule to be digested or absorbed. It is a food additive, a fat substitute developed to replace the fat content of prepackaged foods such as potato chips and crackers. 47 An early clinical study used a sucrose polymer as a substitute for dietary fat (30 g/d) in a hypocaloric diet and demonstrated a 3.7 kg mean weight loss and a 23% reduction in low-density lipoprotein (LDL) cholesterol in 5 patients with familial hypercholesterolemia. 105 In one study, healthy men and women participants were given olestra as a substitute for one-third of ingested dietary fat. The men’s study was 2 weeks long, and the women were treated for approximately10 weeks. 106 Both men and women in the study lost weight. A 9-month obesity study randomized men to eating a control fat (33% fat) diet, a low-fat diet (25%), and an olestra fat substitute (one-third fat substitute) diet to reach a final fat content of 25% in the diet. 107 At study end, there was an 18% reduction in body fat with olestra. Manufacturers are required to include vitamins A, D, and E in food products containing olestra substitutes. 108 In October 2003, the FDA removed a warning on GI side effects of olestra. The FDA concluded that “subjects eating olestra-containing chips were no more likely to report having had loose stools, abdominal cramps, or any other GI symptom compared to subjects eating an equivalent amount of [potato] chips” (Department of Health and Human Services Food and Drug Administration 21 CFR Part 172Food Additives Permitted for Direct Addition to Food for Human Consumption; Olestra; Final Rules).
Drugs Awaiting FDA Approval
Contrave
It is an off-label combination of the drugs bupropion and naltrexone. Both drugs have been approved by the FDA for almost 25 years. In the combined drug form, both drugs have been manufactured as a sustained-release formula. The sustained release naltrexone reduces the potential for nausea. The drug combination appears to decrease appetite. Bupropion is a dopamine and norepinephrine reuptake inhibitor approved for depression and smoking cessation. Naltrexone is an opioid receptor antagonist approved for alcohol and opioid dependence.
A 56-week study involving 1742 patients studied the drug combination for weight loss. 109 The 2 study doses included sustained-release bupropion 360 mg per day plus sustained-release naltrexone at either 16 or 32 mg. The third group received placebo. Weight losses were 6.1% and 5.0% at the higher and lower doses of study drug, respectively, whereas the placebo group lost 1.3% body weight. Side effects included a transient rise in systolic and diastolic blood pressures of 1.5 mm Hg, followed by a 1 mm Hg reduction below baseline. There was no increase in depression or suicidal events compared with placebo, whereas headache, constipation; dizziness, vomiting, and dry mouth were experienced more frequently in the drug groups. In December 2010, the FDA Advisory Committee approved Contrave, but on January 30, 2011, the FDA turned down their approval recommendation, stating that the side effect of hypertension was worrisome enough to the FDA to refuse approval. To further assess effectiveness and cardiac side effects, the FDA has required a cardiovascular safety study prior to approval. The cardiovascular safety end points include myocardial infarction, stroke, and death. The plan is in process.
Candidates for Developing Obesity Drugs
Cannabinoid (CB) Antagonists
The endocannabinoid system, through its CB-1 receptors, has energy homeostasis effects on food intake and body weight. These effects are both central and peripheral. 110 CB-1 receptor blockers decrease both central and peripheral effects of the endocannabinoid system and increase satiety and promote weight loss.111-115 A series of studies called RIO Europe, RIO North America, RIO Lipid, and RIO Diabetic111-115 evaluated the CB-1 receptor blocker drug Rimonabant. All studies used similar formats. RIO Europe 111 results demonstrated a reduction in body weight, weight circumference, and triglyceride levels. HDL cholesterol levels increased, and there was improvement in plasma glucose–insulin homeostasis. In the 2-year RIO North America 113 study, drug participants for the 2 years lost 7.4 kg of body weight and maintained it, compared with a loss of 2 kg in the placebo group. There was improvement in waist circumference and in cardiometabolic risk factors in these 3045 overweight and obese individuals. In RIO Lipid, 112 there was a reduction in body weight and waist circumference. RIO Lipid had a focus on improvement in metabolic risk factors in overweight dyslipidemic individuals. Improvements were seen in LDL particle size, adiponectin levels, glucose tolerance, fasting and post challenge insulin levels, and plasma C-reactive protein levels. RIO Diabetic 114 was a 1-year study of 692 obese individuals with uncontrolled diabetes despite treatment with metformin or a sulfonylurea. Greater weight loss occurred in the rimonabant-treated group (5.3 vs 1.4 kg). In a group of drug-naive patients with type 2 diabetes, 115 the baseline HbA1c (7%-10%) decreased to less than 7% in 51% of the treatment group and in only 35% of the placebo group. Adverse events that led to study drug discontinuation were mainly depressed mood, disorders, nausea, and dizziness. The study authors felt that rimonabant together with diet and exercise (used in these studies) may produce clinically meaningful weight loss and improvement in metabolic risk factors and diabetes. The FDA denied approval for rimonabant at the end of 2007 because of an increased risk for psychiatric and neurological adverse events. Rimonabant was initially approved for the European market then removed because of association with depression and suicidal ideation.
Ciliary Neurotrophic Factor
This is a member of a cytokine family related in structure and action to other metabolically active proteins and peptides, including leukemia inhibitory factor, interleukin (IL)-6, IL-1, and oncostatin M that play some role in the regulation of energy expenditure. 116 In studies in humans, the side effects of anorexia, weight loss, and cough seemed to be dose related. 117 Further human studies were abandoned because of the development of neutralizing antibodies. In mice, ciliary neurotrophic factor suppressed food intake without triggering hunger signals, and when treatment was stopped, the expected overeating and immediate rebound weight gain did not occur. 118
Leptin
It was shown in the 1990s in a mouse model that the regulation of energy balance could be controlled through the interactions of an obesity gene and that a defect in this gene causes massive obesity in these mice.11,119-121 This gene product called leptin reinforced claims for a genetic basis for obesity. 122 Leptin is secreted by adipocytes and plays a role in the signaling pathway from adipose tissue to the brain in the regulation of food intake and energy expenditure. It plays a pivotal role in long-term body weight regulation.9-11,119 It can be detected in serum, and levels correlate with percentage body fat. 123 Obese individuals have higher serum leptin concentrations than normal-weight individuals, suggesting a decreased leptin sensitivity. 123 The adipocytes may provide signals to the brain as to body fat content. 123 A leptin receptor (OB-Rb) is active in the parts of the brain associated with food intake and energy expenditure.7,9,10,124 To date, attempts to use recombinant leptin and metreleptin (leptin modification) for the treatment of obesity have not been very successful.123,125 Researchers have been assessing the role leptin plays in homeostasis after weight loss and weight gain. With a loss of body fat, leptin levels fall, appetite increases, and energy expenditure decreases. With weight gain, leptin levels rise, and appetite is suppressed until body fat mass is restored.119-121,123 The role leptin plays as a central regulator of homeostasis of body fat mass in humans is under investigation.122,125-127 Globally, there are only a few known cases of congenitally leptin-deficient individuals.
Neuropeptide Y (NPY)
This is a neuropeptide neuromodulator found in the brain and whose receptor may be involved in the regulation of food intake and body weight in humans. 126 The NPY stimulatory effect is primarily on carbohydrate intake.128,129 In mice with diet-induced obesity, an NPY antagonist decreased body weight and body fat. 130 Human clinical trials have not yet shown NPY antagonists to have a significant effect on body weight or food intake. 131
Human Growth Hormone (GH)
Studies reported in men and women have been mostly of short-term duration and suggest that GH treatment in obese individuals with GH deficiency will mobilize fat, reduce body fat, stimulate oxygen consumption, and decrease protein loss.132-134 These effects disappeared shortly after GH withdrawal. 133 Insulin resistance increased during the GH therapy. A 6-month obesity study was done in obese men who had no GH deficiency. 135 These men were treated with supraphysiological doses of GH for 6 months followed by drug discontinuation. 135 In the GH treatment phase, there was an increase in body weight and in lean body mass (2.5 kg) with an 8.8% reduction in visceral adiposity compared with placebo. 135 The participants were then followed for 6 months off GH. In the drug-free 6 months of the study, lean body mass decreased together with a rapid increase in body fatness and visceral adiposity. Resting energy expenditure increased, but so did fasting insulin, glucose, and insulin resistance. The study authors concluded that the GH doses used were supraphysiological and not an effective treatment approach. 135
Dehydroepiandrosterone (DHEA)
The role of the hormone DHEA in the treatment of human obesity remains unclear. Many of the actions of DHEA in humans are thought to be mediated through its conversion to sex hormones, which are modulators of adiposity, muscularity, and insulin sensitivity. Short-term studies with small numbers of participants treated with DHEA have been reported, and results have been mixed.136-138 In one 29-week crossover study, during the treatment phase, 3 of 14 individuals had fat losses of 18%, 19%, and 25%. 136 There was no weight change during the crossover placebo phase, and no significant side effects were reported. 136 A 10-week study involving 13 morbidly obese adolescents documented an increase in DHEA and testosterone concentrations but no effects on body weight, sense of well-being, or any other measured variables. 137 In a 12-month study in 120 older men and women 60 to 88 years old, central adiposity was not reduced, nor was insulin action improved. Triglycerides and HDL cholesterol decreased. The study authors concluded that restoring of DHEA serum levels in older adults to that of a young adult does not appear to reduce central adiposity or improve insulin action. 139 A 2-year DHEA study of 144 elderly men and women showed no significant effect on body composition. Measured outcomes of physical performance and quality of life showed no improvement. No major side effects were reported. 140
DHEA has been used as a performance-enhancing drug for athletes. A 28-day study of the acute effects of DHEA on body composition and serum steroid hormones was performed on 20 young competitive soccer players aged 19 to 22 years. DHEA dose was 100 mg daily or placebo. The drug group had increased DHEA and testosterone levels, but no significant change in body fat, total muscle mass or body mass index, or waist to hip ratio was noted. 138 DHEA can be purchased OTC in drug stores or health food stores and online as a dietary supplement and can be labeled DHEA.
Testosterone/Dehydrotestosterone
Testosterone is the principal androgen product of the testis and is responsible for body masculinization. It is converted peripherally to dehydrotestosterone. Regional fat deposition pattern in men and women is a secondary sex characteristic involving sex steroids, including testosterone.141,142 Testosterone studies in humans have been done mostly in older men and women with significantly low testosterone levels and have documented that low testosterone is associated with increased body fat, fat distribution, and waist circumference. As the level of obesity increases, testosterone levels drop.143-146
Although studies have shown an overall increase in lean body mass, there was no significant impact of testosterone on body fat in either young or older study participants.147-149
Anabolic steroids are used and abused by some athletes, recreational body builders, and others wishing to increase muscle mass and/or to lose weight. Researchers feel that testosterone supplements, if used extensively, have potentially serious adverse effects on the cardiovascular system, prostate, lipid metabolism, and insulin sensitivity. 149
Gastrointestinal Pathway Drugs
The GI pathway is among the most active of endocrine organs. Food intake may be influenced by neural and hormonal actions of the GI tract. These peptides appear to have a function on eating behavior and the regulation of energy balance and body fat accumulation. 150 Meal anticipation and the presence of food in the upper GI tract stimulate the release of gut hormones and neurotransmitters, and signals are then relayed to the central nervous system. 151 Because gut hormones are thought to play a role in the sustained weight loss following gastric bypass surgery, there may be a potential role for selective GI hormones as a direct treatment for obesity. 151 The mechanisms involved in sustaining weight loss following bariatric surgery are being investigated.
Cholecystokinins (CCK)
CCK is a GI peptide produced in the stomach, gallbladder, and pancreas. It is secreted postprandially into the circulation and effects energy balance by decreasing food intake. Plasma CCK levels rise within 15 minutes after meals. 151 In response to a dietary fat load, CCK action results in a slowing of gastric emptying and satiety. 152 A study utilizing a selective CCK-A agonist for 24 weeks randomized 701 patients to double-blind treatment.153,154 The primary efficacy end point was absolute change in body weight. The study drug did not reduce body weight and had no effect on waist circumference or other cardiometabolic risk markers. The authors concluded that CCK-A by itself does not have a central role in long-term energy balance. These results led to the discontinuation of the study drug development program.153.154
Glucagon-Like Peptide
GLP-1 is a hormone produced in the distal ileum and colon. It inhibits glucagon secretion, stimulates insulin secretion following carbohydrate ingestion, delays gastric emptying, and increases satiety.151,153-156 It improves blood glucose levels in individuals with diabetes. In obese individuals, GLP-1 secretion is likely to be decreased and may contribute to the development of obesity. 157 GLP-1 is significantly elevated post–intestinal bypass surgery and may be a factor in influencing weight loss after bypass surgery by reducing appetite and food intake.
Liraglutide
This is a human GLP-1 analog approved by the FDA in 2010 for the treatment of adult type 2 diabetes. It is prescribed together with diet and exercise in diabetic patients who have not responded to initial diabetes therapy. In a nondiabetic population, a 20-week trial 158 with a 2-year extension, 159 liraglutide (subcutaneous dose) was evaluated for weight loss, safety, and drug tolerability. Other groups in the study were treated with orlistat or placebo. Over the 2-year study, the liraglutide group had persistent weight loss that was greater than that for orlistat and placebo. There was a decrease in prediabetes and metabolic syndrome prevalence and a reduction in cardiovascular risk factors. 159 There were improvements in blood pressure and lipid values. The most frequent drug-related side effects were mild to moderate—transient nausea and vomiting.
Ghrelin
This is a peptide hormone discovered in 1999. It is produced in the stomach and secreted into the circulation. It stimulates food intake. Ghrelin is elevated in the fasting state and is suppressed in the postprandial state 160 ; however, compared with nonobese individuals, obese individuals exhibit a lower decrease in plasma ghrelin after a meal. 151 A drug that inhibits ghrelin action may potentially be a target for obesity treatment. 161 A study that measured ghrelin levels after Roux-en-Y gastric bypass surgery raised the possibility that surgical suppression of ghrelin is one mechanism by which the gastric bypass surgery reduces body weight. 162 A study investigating the effects of low- or high-dose intravenous ghrelin on food intake in 12 lean and 12 obese adults suggested that inhibiting circulating ghrelin may be a useful therapeutic target in the treatment of obesity. 163 Other GI peptides can affect the stimulatory action of ghrelin on food intake. New treatments for obesity drugs may result from such a research focus. 164
Peptide YY (PYY)
This GI hormone may be involved in energy expenditure regulation. It may delay gastric emptying and reduce acid secretion. 151 PYY is secreted postprandially from the gut and appears to decrease hunger and calorie intake in that state in both obese and nonobese individuals. Lower PYY levels are associated with increased appetite. 165 It is observed that a fatty meal results in a greater release of PYY compared with that of a similar calorie meal of carbohydrates or protein. 165
An 8-week weight loss study compared the effects of a low-fat versus a low-carbohydrate energy-restricted diet on fasting and postprandial serum PYY levels when measured at baseline and after 8weeks. 166 Both diet plans demonstrated weight loss that was associated with measured lower PYY levels at the end of the study. The authors suggest that after consuming an energy-restricted diet, low PYY levels would indirectly stimulate hypothalamic neurons containing NPY and agouti-elated protein and lead to a stimulation of appetite and food intake. The difficulty obese patients have losing weight following calorie restriction diets may be partly a result of PYY regulation. Reduced PYY levels following weight loss represents part of a compensatory response to maintain energy homeostasis. 166 A study comparing the effects of similar amounts of medical or surgical weight loss on PYY levels led to the conclusion that the weight loss effects of Roux-en-Y gastric bypass surgery and vertical sleeve gastrectomy are associated in part with an increase in PYY, and satiety enhanced weight lost.165,167,168 A PYY study used subcutaneous injections of PYY for 5 days in succession. In this study, 100 mm visual analog scales were used to assess satiety, hunger, fullness, prospective food consumption, well-being, nausea, and thirst. PYY induced lower subjective hunger and thirst ratings and higher satiety. 169 A study on brain function and PYY using functional magnetic resonance imaging reports that this protein modulates neural activity within the brain and that high plasma PYY concentrations mimic the fed state, whereas with low levels of PYY, hypothalamic activation predicts food intake. 170 Changes in neural activity in the caudolateral orbital frontal cortex seem to predict feeding behavior separate from sensory meal stimuli. 170 The authors concluded that the presence of a postprandial satiety factor switches food intake regulation from a homeostatic to a hedonic, corticolimbic area. A further understanding of how such homeostatic and higher brain functions are integrated may lead to the development of new treatment strategies for obesity. 170
Who Should Receive Pharmacotherapy and When?
Primary care physicians see 11.3% of the US population monthly, and obese patients represent a significant proportion of those visits.171,172 In the most recent National Ambulatory Medical Care Survey (2005 and 2006 data), in medical practices where BMI was routinely captured, 31% of patients were overweight, and 37% were obese. Only 30% of the obese patient visits included a recorded diagnosis of obesity. 171 Increased physician awareness through continuing medical education and the use of an electronic medical record may help in the documentation of the obese and overweight patient. 173 Better and earlier documentation of BMI values may lead to more preventive care and appropriate obesity management, including for those who would benefit from pharmacotherapy.
There is also a wide spectrum of medical and surgical subspecialists who are clinically involved in treating weight-related obesity comorbidities. These referral specialists would benefit from obesity education as it relates to their fields of practice. Better-educated subspecialists would further enhance timely obesity treatment and patient compliance with obesity management.
Without well-defined physician guidance, there is a large variance in how and when the subject of unhealthy body weight is addressed during an office visit. Physicians who have an expertise and comfort level in their ability to treat obesity are more likely to have an early discussion about weight control options with overweight and obese patients. Some clinicians wait until a patient requests help. Others use the BMI value, but even the BMI values used vary among clinicians. Still others show concern only when comorbidities are present.174,175 Clinicians who use health issues as their main approach to initiate a conversation about body weight may be unsuccessful from the onset. Patients can be self-motivated to lose weight because they perceive that their health has already suffered; however, health issues are usually not the most common personal motivator. Improved health may be a strong motivator for compliance while in a program. Patients may have one or several personal motivators for wanting to lose weight. Once personal motivators have been identified, one or more of them can be used to discuss treatment options. Patients who claim cosmetic reasons for wanting to lose weight should not necessarily be denied treatment. Vanity can be a motivating force. Failure to lose weight in previous attempts or even yo-yo dieting are not contraindications to drug treatment.
The great majority of overweight and obese individuals that present themselves to a medical clinic will claim to have been on many different diets or would currently be on some kind of a diet. However appropriate or inappropriate previous diet plans may have been for these experienced dieters, providers have to be careful in their initial plan. Yet another diet plan unaccompanied by a more comprehensive approach will likely be rejected. This patient type may also suggest a prescription medicine as an adjunct, and it may be appropriate here. It is not uncommon to include pharmacotherapy sooner rather than later in the course of treatment. This may mean drug therapy at the onset of a comprehensive program. 176 Although it has been attempted on a limited scale, the pharmacological treatment of obesity has no established and proven algorithm. 177 The ideal obesity pharmacotherapy has yet to be developed.
A decision to use pharmacotherapy beyond FDA guidelines is not prohibited by the FDA. Treating obesity in patients older than 65 years should be done with caution. 47
To significantly improve a physician’s ability to pick an appropriate time to initiate treatment and to obtain maximum benefit from pharmacotherapy, a gauge of patient compliance and the ability and willingness to follow program directions is recommended. There are screening questionnaires that could provide such information. 178 However, patients who insist on being prescribed a pill to lose weight as their initial and only weight management plan could most likely be one of the least successful patients.
The Expert Panel BMI Guidelines for Identifying Overweight and Obesity and Evaluation and Treatment are to be followed by physicians and health care professionals (National Heart, Lung, and Blood Institute, National Institutes of Health. Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults: The Evidence Report. Bethesda, MD: National Institutes of Health; September 1998. NIH publication No. 98-4083). According to these guidelines, obesity pharmacotherapy is appropriate in patients with a BMI of 30 or greater or those with a BMI of 27 or more if concomitant obesity risk factors or comorbid diseases exist. Clinically severe obesity is defined as a BMI of 40 or greater or BMI greater than 35 with serious comorbid conditions. The severely obese should be considered candidates for bariatric surgery. The Expert Panel defined the following diseases as high absolute risk: coronary heart disease and other atherosclerotic diseases, type 2 diabetes, and sleep apnea. Three or more of the following risk factors when found together confer high absolute risk: hypertension, cigarette smoking, elevated LDL cholesterol, impaired fasting glucose, and a family history of early cardiovascular disease (age 45 years or less in men and age 55 years in women).
According to the Expert Panel, pharmacotherapy may be considered an appropriate adjunct to the combined treatment of behavior therapy, nutrition change, and increased physical activity, especially in situations where such combined therapy was unsuccessful.
Clinical Considerations for Length of Treatment and Drug Discontinuation
The selection of an obesity drug should be personalized to accommodate a patient’s medical and social history, current medical and mental health issues, and current medications, including OTC drugs. Many obesity researchers and clinicians believe that long-term and possibly lifelong use of obesity drugs may be necessary for significantly obese individuals. 179 An understanding of the merits, limitations, adverse effects, and the mechanisms of action of available pharmacotherapy together with documentation of patient response to therapy and clinical experience should be considered when making a decision on an extended length of treatment.
Before deciding to discontinue obesity pharmacotherapy as a result of inadequate weight loss or side effects, there are several things to consider. Patient compliance should be discussed before terminating a drug. How often is the patient really taking the drug? What is the current prescribed dose? Is that the dose the patient is currently taking? Can the dose be increased? Or decreased? If the dose prescribed is below the recommended maximum dose, an increase may be appropriate. Side effects if mild may diminish by a decrease in dosage. Perhaps, a change in the timing of drug administration may promote better compliance. Are competing prescriptions or nonprescription drugs interfering with drug effectiveness or causing side effects wrongly attributed to an obesity drug? Is the rate and amount of weight loss appropriate for the patient’s medical needs and should the drug be now used to maintain the weight lost rather than discontinued?
The 2 newly approved obesity drugs lorcaserin and the combination of phentermine/topiramate have FDA-approved criteria in place for early discontinuation.
A relapse is possible if an obesity drug is discontinued. If a patient loses and/or maintains weight loss on an obesity drug and no serious side effects have been identified, the drug may be continued as long as drug efficacy and safety are monitored for the duration of its use. 180
Weight Regain and Pharmacotherapy
Obese patients will regain some if not all their lost weight over time, but the degree of weight loss and regain vary. A patient currently off his or her medicine who is returning for care after weight regain should be made aware that the causative possibilities may include metabolic reasons outside of their control. Weight regain may partly be a result of self-regulatory mechanisms of energy balance attempting to restore the body weight to a steady state.19-26,181 Any situational life events that may contribute to recidivism should be identified and addressed because some of these factors can be better controlled. Counseling should be provided to prevent a lapse from progressing to relapse and abandonment of the program.
A decision to restart a weight management program using the same plan may well be appropriate; however, a variation of that plan or a completely different approach may be more appropriate. This decision relies on the experience of the clinician and the capabilities of the management team. The same discussion needs to be had about pharmacotherapy. Is it to be the same or changed? Based on individual patient needs and obesity characteristics, bariatric surgery may be considered. Current guidelines to qualify for bariatric surgeries in the United States and Canada are a minimum BMI of 40 or a BMI of 35 with 1 or more severe comorbidities. 181 The minimum BMI for a laparoscopic insertion of a lap-band device is a BMI of 35 or a BMI of 30 with one or more severe comorbidities. 182
Summary and Conclusions
Being obese goes beyond moral failure or a character flaw. Obesity has the defining characteristics of a chronic disease for which there is no cure. It may require lifelong treatment, which may include pharmacotherapy. Experience with long-term use of obesity drugs is limited, but evidence suggests that pharmacotherapy can improve patient outcomes and patient outlook. With current obesity drugs, weight loss is usually modest but clinically significant, satisfying the FDA threshold for drug effectiveness. This weight loss is associated with clinically significant improvements in many obesity comorbidities and risk factors and could eliminate some risk factors with continued use. When used in conjunction with a comprehensive program for weight management, obesity drugs can reduce appetite or hunger, increase satiety, provide improved control over aberrant eating behaviors, and modify food-seeking behaviors.14-16 Pharmacotherapy can enhance weight loss and compliance during the periods of weight loss and help maintain that weight loss. The weight loss effects of current obesity drug therapy may have a value in empowering a person to adhere to behavioral change management, including reducing calorie intake, increasing physical activity, and focusing on making lifelong changes. Few patients treated for their obesity will reach their goal weight (usually unrealistic), and almost no one reaches “ideal” body weight. This is true with or without drug therapy. This, however, is not a reason to withhold pharmacotherapy. Behavioral treatment of obesity has limited success and pharmacotherapy should be given a serious consideration as an adjunct to enhance lifestyle management. There is sufficient clinical experience, research, and FDA oversight relating to these drugs to encourage their prudent use in the management of obesity.