Increased body fat levels are related to a large number of comorbid conditions, such as cardiac disease, diabetes, and cancer. Currently available drugs are useful but do not always bring about the desired goal. Weigle reviewed the past, present, and future of pharmacologic treatments for obesity.

Past treatments included thyroid hormone therapy, but patients lost lean body mass, and calcium and nitrogen excretion increased. Patients often developed symptoms of hyperthyroidism such as tachycardia and arrhythmias, and weight was rapidly regained after therapy was stopped. Amphetamines also were used as weight loss agents, but their use often resulted in hypertension, addiction, and adverse myocardial events. Fenfluramine, which increased serotonin levels, was used alone or in combination with the sympathomimetic agent phentermine. Fenfluramine was an effective long-term treatment for obesity, but its use resulted in cases of primary pulmonary hypertension. Fenfluramine later was associated with valvular heart disease. Phenyl-propanolamine, another sympathomimetic drug, was removed from the market recently because of resultant hemorrhagic strokes. Ephedra has been associated with hypertension, tachycardia, stroke, seizures, and death.

Current pharmacologic treatments for obesity are listed in the accompanying table. The two major mechanisms of action are an increase in norepinephrine and serotonin levels in the central nervous system, which promotes anorexia, and decreased fat absorption from the gut. Sibutramine blocks norepinephrine and serotonin reuptake and promotes weight loss with long-term therapy, increasing the likelihood that patients who lose weight will not regain it. Side effects include elevated blood pressure and heart rate, headache, insomnia, dry mouth, and constipation. Orlistat inhibits gastrointestinal lipases, resulting in decreased fat absorption. Because the drug is not systemically absorbed, side effects are confined to the gastrointestinal tract; loose stools, increased defection, fecal urgency, and oily stools have been reported in patients taking orlistat. Patients taking sibutramine or orlistat generally lose less than 10 percent of their body weight, and many patients regain weight after they stop treatment.

The National Institutes of Health recommends diet modification, exercise, and behavior therapy for initial weight loss. If these methods do not result in weight loss of 10 percent of body weight within six months, pharmacotherapy can be started in patients with a body mass index (BMI) of at least 30 kg per m², or in patients with a BMI of at least 27 kg per m² who have other morbidity-related risk factors such as hypertension, dyslipidemia, diabetes, coronary artery disease, or sleep apnea. If weight loss does not occur within the first four weeks of pharmacotherapy, the medication or its dosage should be reevaluated.

The current pharmacologic therapies for obesity are inadequate, and weight reduction generally is limited to 10 percent of body weight. Even with weight loss, physiologic signals that increase appetite and decrease energy expenditure make maintenance of weight loss difficult. Newer antiobesity drugs may modulate these long-acting hormonal signals that affect energy balance sites in the central nervous system. Leptin, insulin, and ghrelin regulation may allow more favorable energy balance by affecting hunger.

The author concludes that current medications to enhance weight loss are marginally effective, especially for long-term therapy. Improved knowledge about the regulation of body fat and total body energy stores will result in better medications.