Obesity has increased in epidemic proportions in the United States over the last decade and is fast becoming an urgent health problem. The percentage of obese individuals in this country was reported to be nearly 31% in the year 2000?which translates to 60 million people.1-4
Obesity is associated with premature mortality2 and multiple comorbidities, including stroke, heart disease, sleep disorders, and the triad of disease states? hypertension, diabetes, and hyperlipidemia?often referred to as metabolic syndrome.5-7
Obesity, as defined by the World Health Organization, in adults is determined by the body mass index (BMI). BMI is defined as weight in kilograms divided by height in meters squared. A value of 25 to 29.9 indicates that an individual is overweight, whereas a value of 30 or higher defines obesity. In children and adolescents, obesity has not yet been defined.2-4
Treatment of obesity may be successful with nonpharmacologic interventions, primarily focusing on dietary interventions and changing behaviors. Total therapeutic lifestyle changes that focus on behavioral therapy, education, and structured meal planning may be necessary for success.8-11 Patients with metabolic syndrome require proper disease management, dietary modification, and exercise programs to control their obesity.5,12-18
Surgical options for obesity, including bariatric surgery procedures, usually are reserved for the morbidly obese, defined as having a BMI of >40 kg/m2.19-21
Although nonpharmacologic interventions may be successful, in some patients may need adjunct pharmacologic management.22 Whereas numerous medications have been studied and evaluated for weight loss, at the present time only 3 classes of drugs (Table) are used for the treatment of obesity. These agents include sibutramine (Meridia), orlistat (Xenical), and the older anorexigenic, central-acting amphetamine congeners, which have a high risk of rebound weight gain and abuse.23-25
Sibutramine is a central-acting noradrenergic drug that increases the amount of serotonin (5HT) and norepinephrine and, to a smaller extent, dopamine through reuptake inhibition. Through its action on these neurotransmitters, sibutramine reduces food intake by causing satiety after eating and providing dose-dependent weight loss.25
Studies have reported weight loss in patients ranging from 5% to 10%, versus patients receiving diet and exercise alone.26-31 Maintaining initial weight loss at 2 years was reported to be greater with sibutramine, compared with exercise and diet regimens.32-33
Because of the drug's potential to increase blood pressure and heart rate, careful monitoring and/or consideration of the risk-benefit ratio is necessary in patients with a history of hypertension or cardiac disease.30 Other potential side effects include insomnia, headache, and dry mouth.25,34
Orlistat is an intestinal lipase inhibitor; it blocks the enzyme pancreatic lipase. This activity results in decreased fat absorption in the intestines. It has an indirect effect on appetite by encouraging compliance with a low-fat diet.34,35
Studies with orlistat for the treatment of weight loss over 1 to 2 years have reported weight-loss percentages ranging from 4% to 10%, versus placebo.36-40 Weight loss with orlistat appears to peak at 6 months and is maintained for up to 2 years.37-40 Combination therapy with orlistat and metformin in patients with diabetes produced additive benefits and resulted in improved blood glucose control and cardiovascular factors.37-39
Adverse effects include gastrointestinal problems in patients noncompliant with low-fat diets, in addition to concerns about malabsorption of fatsoluble vitamins (A, D, E, and K), necessitating concurrent multivitamin supplementation.36,41,42
When comparing sibutramine and orlistat in combination therapy, the limited data available showed no additive benefits.43 Both of these agents may have a role in the treatment of obesity in type 2 diabetes.44
Other Anorexigenic Agents
Central-acting amphetamine congeners include phentermine (Adipex-P) and diethylpropion (Tenuate)?both of which are Federal Controlled Substances Schedule IV (C-IV) drugs?and benzphetamine (Didrex) and phendimetrazine (Bontril)?both of which are C-III drugs. These drugs are used as an adjunct to caloric restriction in the short-term (a few weeks) management of obesity.24
Phentermine was marketed a few years ago with fenfluramine in a combination product that was associated with valvulopathy and was withdrawn from the market.45-47 Phentermine in monotherapy does not appear to be associated with valvulopathy.47,48
Although weight-loss benefits are reported with these agents, tolerance of their anorexigenic effect can develop in as little as 2 weeks, so short-term use is recommended. Adverse effects include insomnia, nervousness, psychosis, depression, rash, dry mouth, constipation, palpitations, and increased blood pressure.49-55
Various anticonvulsants continue to be evaluated for the treatment of obesity and weight loss. Topiramate, in doses ranging from 100 to 1400 mg daily, has been studied in both retrospective and clinical trials for up to 30 months in the treatment of weight loss and binge-eating disorders.56-62 Although efficacy has been reported, potential concerns about central nervous system side effects? including difficulty with concentrating, language problems, and memory problems? have limited its use in clinical practice.63-64
Zonisamide (Zonegran), a more recently approved anticonvulsant, also has been reported to be effective and well-tolerated for weight loss in short-term studies in obese patients.65,66 Adverse effects reported with zonisamide ranged from fatigue to nephrolithiasis, and more studies are needed.66,67
Small trials with levetiracetam (Keppra), another newer anticonvulsant, reported no significant effects on weight loss.68 Although the potential mechanism of action of weight reduction with anticonvulsants is not completely understood, multiple modes of action have been considered.58,65
Numerous selective serotonin reuptake inhibitors have been studied in short-and long-term trials in the treatment of obesity, including fluoxetine, sertraline, citalopram, and fluvoxamine.69-75 Using higher than standard antidepressant doses, many of these trials reported initial weight loss and binge-eating reduction, although they often were followed by rebound weight gain.73-77 Presently, these agents are not recommended for the management of obesity, although their future roles in certain populations may need further study.77
Bupropion, a norepinephrine and dopamine reuptake inhibitor, was evaluated in short-and long-term trials, which reported significant weight-loss effects.78-82 One long-term trial reported a lack of rebound weight gain with this agent in depressed patients.81 Venla-faxine, a serotonin-norepinephrine reuptake inhibitor, was evaluated in a case series study and was reported to cause weight loss and reduced binge eating.83
Herbals and Other Products
Numerous supplements containing a variety of herbals and other substances used alone and in combination continue to be promoted for their potential weight-loss benefits. Many of these products are unregulated and have limited or no data to support their utility for weight loss.84-87 Products containing ephedrine and ephedra (ma huang; an herbal form of the same) were banned by the FDA in 2004, because of concerns about cardiac and psychiatric problems.84-90
Other herbals and substances promoted and/or used for weight loss may include chromium picolinate, green tea, hydroxycitrate, garcinia, guarana, germander, bitter orange, biotin, barley, flaxseed oil, country mallow, chaparral, bladderwort, chitosan, pyruvate, and citrus aurantium. Some of these products have been found to contain fenfluramine and thyroid gland extracts, which have the potential for causing harm to patients. Because of the limited evidence supporting their efficacy and their often unknown safety profiles, these agents are not recommended for weight loss.91-93
Research and drug development for the treatment of obesity include a variety of agents and targets. Two new diabetes treatments, exenatide and pramlintide, have been reported to cause weight loss in patients with diabetes.94,95 Other investigational therapies include the 5HT 2C modulators,96 the cannabinoid blockers (eg, rimonabant),97 and leptin supplements.98
Obesity and its management continue to be a growing challenge for health care providers in the United States. Prevention and nonpharmacologic interventions are key to the management of obesity. Although the present pharmacotherapies offer some benefits, more effective and tolerable agents are needed.
Dr. DeMaagd is an associate professor of pharmacy practice at Ferris State University, At the time of assisting in writing this article, Dr. Chipperi was a PharmD candidate at Ferris State University.
For a list of references, send a stamped, self-addressed envelope to: References Department, Attn. A. Rybovic, Pharmacy Times, Ascend Media Healthcare, 103 College Road East, Princeton, NJ 08540; or send an email request to: email@example.com
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