Drug Therapy for Obesity

LORI M. DICKERSON, PHARM.D., and PETER J. CAREK, M.D., M.S. Medical University of South Carolina, Charleston, South Carolina

A patient information handout about weight loss, written by the authors of this article, is provided on page 2143.

Obesity is a common health problem in the United States, and effective treatment is challenging. Obesity is associated with an increased mortality rate and risk factors such as hypertension, hyperlipidemia and diabetes mellitus. Numerous treatments are available for obesity. Behavioral therapy, surgery and pharmacologic treatment have been used with varying degrees of success. Older anorectic agents have significant side effects and limited benefit, and some have even been withdrawn from the U.S. market because of a possible association with cardiovascular complications. The safety of newer agents must be extensively evaluated before widespread use is recommended. Therefore, behavioral therapy, including regular exercise and the development of healthy eating habits, continues to be the best treatment for long-term weight loss. (Am Fam Physician 2000;61:2131-8,2143.)

Obesity is one of the most common and serious health problems in the United States. Excess weight is independently associated with an increased mortality rate in multiple conditions (Table 1).^1,2 Approximately one fourth of American adults (more than 60 million people) are overweight.² Given this statistic, the Western cultural obsession with being thin and the societal and psychologic stigma of obesity, it is not surprising that, at any time, 50 percent of American women and 25 percent of American men are trying to lose weight, with an annual expenditure of $30 billion on weight loss treatments.^2,3

TABLE 1 Common Conditions Associated with Obesity Type 2 diabetes mellitus* Hypertension Dyslipidemia Macrovascular disease Cancer (endometrial, ovarian, breast, gallbladder, prostate, colon) Menstrual irregularities, decreased fertility, hirsutism Gallbladder disease Restrictive lung disease, sleep apnea Osteoarthritis Gout Thromboembolic disease *--Formerly called non­insulin-dependent diabetes mellitus. Information from Pi-Sunyer FX. Medical hazards of obesity. Ann Intern Med 1993;119:655-60, and Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults--the evidence report. National Institutes of Health. Obes Res 1998;6(suppl 2):51S-209S. Available at http://www.nhlbi.nih.gov/guidelines/obesity/ ob_gdlns.htm.

Etiology

In most persons, obesity is primary--no obvious cause exists other than an imbalance in energy intake and expenditure. Medical disorders such as Cushing's syndrome, hypothyroidism and hypogonadism rarely cause obesity. Genetic factors play a role, but the specific mechanism is unclear. Recently, a mutation in the gene coding for the beta₃-adrenergic receptor has been found to be associated with an increased capacity to gain weight in some morbidly obese persons.⁴ In theory, low beta₃-adrenergic activity could promote obesity by slowing lipolysis, causing retention of lipids in fat cells.⁵ Regardless of recent developments in understanding this problem, obesity should be considered a condition with multiple causes. Genetic, cultural, socioeconomic, behavioral and situational factors all play a role in dietary habits and weight control.

Evaluation

Assessment of the overweight or obese person should begin with a careful history and physical examination. The patient's weight history from childhood should be reviewed, including various methods of weight loss that have been attempted and the results of each attempt. Activity level and dietary history should also be reviewed. Because weight gain is a common side effect of certain medications (Table 2), a history of medication use is an important aspect of the initial evaluation.⁶ Weight gain is also common during the initial phases of smoking cessation.⁷

"Overweight" is defined as a body mass index (BMI) of 25.0 to 29.9 kg per m2. "Obese" is defined as a BMI greater than 30 kg per m2.

Body weight for height, gender and body-frame size has traditionally been used as the fundamental assessment of obesity. The National Institutes of Health and the National Heart, Lung, and Blood Institute recommend that all adults receive periodic measurement of height and weight by body mass index (BMI = weight in kilograms divided by height in meters squared) using standard tables (Figure 1)⁸ of suggested weights, along with the assessment of other factors such as medical conditions or waist-to-hip circumference ratio, as a basis for further evaluation, intervention or referral to specialists.² "Overweight" is defined as a BMI of 25.0 to 29.9 kg per m², and "obese" is defined as a BMI greater than 30 kg per m².² It may be useful to determine the distribution of body weight between fat and lean body mass in some patients attempting to lose weight; however, the effectiveness of these measurements in all patients is unknown.

BMI Chart Weight (lb) Height (ft) 100 105 110 115 120 125 130 135 140 145 150 155 160 165 170 175 180 185 190 195 200 205 210 215 5'0" 20 21 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 5'1" 19 20 21 22 23 24 25 26 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 5'2" 18 19 20 21 22 23 24 25 26 27 27 28 29 30 31 32 33 34 35 36 37 38 38 39 5'3" 18 19 19 20 21 22 23 24 25 26 27 27 28 29 30 31 32 33 34 35 35 37 37 38 5'4" 17 18 19 20 21 21 22 23 24 25 26 27 27 28 29 30 31 32 33 33 34 36 36 37 5'5" 17 17 18 19 20 21 22 22 23 24 25 26 27 27 28 29 30 31 32 32 33 35 35 36 5'6" 16 17 18 19 19 20 21 22 23 23 24 25 26 27 27 28 29 30 31 31 32 34 34 35 5'7" 16 16 17 18 19 20 20 21 22 23 23 24 25 26 27 27 28 29 30 31 31 33 33 34 5'8" 15 16 17 17 18 19 20 21 21 22 23 24 24 25 26 27 27 28 29 30 30 32 32 33 5'9" 15 16 16 17 18 18 19 20 21 21 22 23 24 24 25 26 27 27 28 29 30 31 31 32 5'10" 14 15 16 17 17 18 19 19 20 21 22 22 23 24 24 25 26 27 27 28 29 30 30 31 5'11" 14 15 15 16 17 17 18 19 20 20 21 22 22 23 24 24 25 26 26 27 28 29 29 30 6'0" 14 14 15 16 16 17 18 18 19 20 20 21 22 22 23 24 24 25 26 26 27 29 28 29 6'1" 13 14 15 15 16 16 17 18 18 19 20 20 21 22 22 23 24 24 25 26 26 28 28 28 6'2" 13 13 14 15 15 16 17 17 18 19 19 20 21 21 22 22 23 24 24 25 26 27 27 28 6'3" 12 13 14 14 15 16 16 17 17 18 19 19 20 21 21 22 22 23 24 24 25 26 26 27 6'4" 12 13 13 14 15 15 16 16 17 18 18 19 19 20 21 21 22 23 23 24 24 25 26 26 Weight (lb) Height (ft) 220 225 230 235 240 245 250 255 260 265 270 275 280 285 290 295 300 305 310 315 320 325 330 335 5'0" 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 62 63 64 65 5'1" 42 43 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 60 61 62 63 5'2" 40 41 42 43 44 45 46 47 48 48 49 50 51 52 53 54 55 56 57 58 59 59 60 61 5'3" 39 40 41 42 43 43 44 45 46 47 48 49 50 50 51 52 53 54 55 56 57 58 58 59 5'4" 38 39 39 40 41 42 43 44 45 45 46 47 48 49 50 51 51 52 53 54 55 56 57 58 5'5" 37 37 38 39 40 41 42 42 43 44 45 46 47 47 48 49 50 51 52 52 53 54 55 56 5'6" 36 36 37 38 39 40 40 41 42 43 44 44 45 46 47 48 48 49 50 51 52 52 53 54 5'7" 34 35 36 37 38 38 39 40 41 42 42 43 44 45 45 46 47 48 49 49 50 51 52 52 5'8" 33 34 35 36 36 37 38 39 40 40 41 42 43 43 44 45 46 46 47 48 49 49 50 51 5'9" 32 33 34 35 35 36 37 38 38 39 40 41 41 42 43 44 44 45 46 47 47 48 49 49 5'10" 32 32 33 34 34 35 36 37 37 38 39 39 40 41 42 42 43 44 44 45 46 47 47 48 5'11" 31 31 32 33 33 34 35 36 36 37 38 38 39 40 40 41 42 43 43 44 45 46 46 47 6'0" 30 31 31 32 33 33 34 35 35 36 37 37 38 39 39 40 41 41 42 43 43 45 45 45 6'1" 29 30 30 31 32 32 33 34 34 35 36 36 37 38 38 39 40 40 41 42 42 43 44 44 6'2" 28 29 30 30 31 31 32 33 33 34 35 35 36 37 37 38 39 39 40 40 41 42 42 43 6'3" 27 28 29 29 30 31 31 32 32 33 34 34 35 36 36 37 37 38 39 39 40 41 41 42 6'4" 27 27 28 29 29 30 30 31 32 32 33 33 34 35 35 36 37 37 38 38 39 40 40 41 FIGURE 1. Body mass index (BMI) chart. (Dark blue shading = underweight; medium blue shading = minimal-risk BMI; white = low-risk BMI; light blue shading = elevated-risk BMI [BMI of: 27 to 29 = moderate risk; 30 to 34 = high risk; 35 to 39 = very high risk; and 40+ = extremely high risk.]) Adapted with permission from "Guidance for treatment of adult obesity,"--Shape Up America!, 6707 Democracy Blvd., Ste. 306, Bethesda, MD 20817, and American Obesity Association, 1250 24th St., NW, Ste. 300, Washington, DC 20037, 1996, 1998.

Treatment

A safe and effective treatment for obesity that will satisfy most patients' desire for rapid and long-lasting weight loss is not available.

Like diabetes or hypertension, obesity is a chronic medical condition that is rarely cured; most often, the goal of treatment is palliation. Unfortunately, a safe and effective treatment for obesity that will satisfy most patients' desire for rapid and long-lasting weight loss is not available. A caloric deficit of 3,500 kcal is necessary to lose 0.45 kg (1 lb) of adipose tissue. Because most experts recommend losing no more than 0.45 to 0.90 kg (1 to 2 lb) per week, weight loss is typically slow, and recidivism is high.⁹

Of the many options for controlling obesity, behavioral therapy, including dietary modification, is preferable. In earlier studies, behavioral therapy was shown to be more favorable and cost-efficient than pharmacologic treatment for maintenance of weight loss.¹⁰ Although the use of pharmacotherapy produced a more rapid initial weight loss, the weight loss obtained using behavioral therapy was better maintained at one year. Physical activity and exercise are key to successful weight loss and weight loss maintenance.

Pharmacologic Therapy

TABLE 2 Medications Associated with Weight Gain Psychotropic agents Antidepresssant drugs (tricyclic antidepressants, monoamine oxidase inhibitors) Antipsychotic drugs Lithium Anticonvulsant agents Valproic acid (Depakene) Carbamazepine (Tegretol) Steroid hormones Corticosteroids Estrogen, progesterone, testosterone or other anabolic/androgenic steroids Insulin and most oral hypoglycemic agents Information from Pijl H, Meinders AE. Bodyweight change as an adverse effect of drug treatment. Mechanisms and management. Drug Saf 1996;14:329-42.

Appetite Suppressants
Various pharmacologic agents, referred to as anorectic drugs, are used as adjuncts to behavioral therapy in weight reduction programs. The two classes of anorectic drugs currently available are the noradrenergic and the serotonergic agents.

Noradrenergic Agents. Noradrenergic drugs affect weight loss through action in the appetite center.¹¹ Phenylpropanolamine (Dexatrim), a sympathomimetic drug and a synthetic derivative of ephedrine, is available as an over-the-counter appetite suppressant and decongestant. In studies lasting 14 weeks, the subjects who took phenylpropanolamine had a greater weight loss than those who took placebo, although the difference was minimal^12,13 (Table 3).^12-20 When taken in daily dosages of 20 to 75 mg, common adverse effects included nervousness, insomnia, dizziness, palpitations and headaches. Phenylpropanolamine in a dosage of 75 mg taken once daily was not associated with a clinically significant increase in blood pressure.¹³ When phenylpropanolamine is used in the treatment of obesity, the manufacturers recommend physician supervision if patients are also being treated for high blood pressure, depression or anxiety disorder, or if they have diabetes, heart disease or thyroid disease.¹¹

Phentermine (Ionamin) is structurally similar to amphetamine and modulates noradrenergic neurotransmission to decrease appetite; however, it has little or no effect on dopaminergic neurotransmission, which decreases its potential for abuse.¹¹ The use of phentermine as a single agent is usually limited by an intolerance to its stimulatory activity. Phentermine was previously used in combination with fenfluramine (Pondimin) to improve weight loss and counteract the adverse effects of use of phentermine. Because of the withdrawal of fenfluramine from the U.S. market, phentermine is now used as a single weight-loss agent.

In older clinical trials, the use of phentermine alone resulted in significant weight loss when compared with placebo¹⁴ (Table 3). In dosages ranging from 30.0 to 37.5 mg per day, phentermine is labeled for the management of exogenous obesity as a short-term (i.e., a few weeks) adjunct in a regimen of weight reduction based on caloric restriction. The most common adverse effects of phentermine include headache, insomnia, nervousness and irritability. Palpitations, tachycardia and elevations in blood pressure may also occur. Phentermine should not be taken by persons with hyperthyroidism, glaucoma, agitated states, advanced arteriosclerosis, symptomatic cardiovascular disease, moderate to severe hypertension or a history of drug abuse.¹¹

Serotonergic Agents. The serotonergic drugs partially inhibit the reuptake of serotonin and release serotonin into the synaptic cleft, thus acting on the hypothalamus to decrease satiety.¹¹ Fenfluramine and dexfenfluramine (Redux), the first serotonergic agents labeled for the treatment of obesity, were withdrawn from the U.S. market in September 1997 because of case reports of valvular heart disease and primary pulmonary hypertension.^21,22

Fluoxetine (Prozac) is a highly selective serotonin reuptake inhibitor (SSRI) that has been studied in the treatment of obesity.^15,16 Fluoxetine may increase energy expenditure by raising basal body temperature; however, weight loss has not been consistent among subjects in clinical trials. In a three-month study, fluoxetine did not significantly reduce weight when compared with placebo¹⁵ (Table 3). In a longer clinical trial, significantly greater weight loss was achieved in the subjects taking fluoxetine at 20 weeks, compared with the subjects taking placebo. However, after one year, weight loss was not different in the two groups.¹⁶

Of the many options for controlling obesity, behavioral therapy, including dietary modification, is preferable.

Although fluoxetine has been labeled by the U.S. Food and Drug Administration (FDA) for the treatment of depression, bulimia and obsessive-compulsive disorder, the FDA has not labeled fluoxetine for weight loss therapy.

Adrenergic/Serotonergic Agents. Sibutramine (Meridia) is an adrenergic/serotonergic agent recently labeled by the FDA for use in the management of obesity.¹¹ Sibutramine and its metabolite inhibit monoamine uptake, suppressing appetite in a fashion similar to SSRIs. Sibutramine may also stimulate thermogenesis by activating the beta₃-system in brown adipose tissue. Initially tested for its antidepressant activity, sibutramine was found to cause weight loss 1 to 2 kg (2.2 to 4.4 lb) in heal