Ingestive behavior and obesityA concise review on the therapeutics of obesity
Introduction
Drug treatment for obesity has been tarnished by a number of unfortunate problems.1 Since the first drug was used to treat obesity in 1893, almost every drug treatment that has been tried in obese patients has generated undesirable outcomes that have resulted in the drug’s termination. Thus, caution must be used in accepting any new drugs for treatment of obesity, unless the safety profile would make it acceptable for almost everyone.
An additional serious negative aspect to the use of drug treatment for obesity is the negative reputation spread by the addictive properties of amphetamine.2 Amphetamine stands for alpha-methyl-β-phenethylamine, which is an addictive β-phenethylamine that reduces food intake. The addictiveness of amphetamine is probably related to its effects on dopaminergic neurotransmission. On the other hand, its anorectic effects are probably caused by its modulation of noradrenergic neurotransmission. Because this β-phenethylamine is addictive, other β-phenethylamine derivatives were presumed to be addictive. Whether actually addictive or not, they were guilty by association. This has led to restrictions on the use of this entire class of drugs by the US Drug Enforcement Agency.
Drugs such as phentermine, diethylpropion, fenfluramine, sibutramine, and the antidepressant venlafaxine are all β-phenethylamines. Phentermine and diethylpropion are sympathomimetic amines, like amphetamine, but differ from amphetamine in having little or no effect on dopamine release at the synapse. Abuse of either phentermine or diethylpropion is rare. Fenfluramine, on the other hand, has no effect on reuptake or release of either norepinephrine or dopamine in the brain, but increases serotonin release and partially inhibits serotonin reuptake. Sibutramine, likewise, has no evident abuse potential. Thus, derivatives of β-phenethylamine have a wide range of pharmacologic effects. However, if examined uncritically, they could all be lumped with amphetamine and carry its negative reputation. It is thus misleading to use “amphetamine-like” in reference to appetite-suppressant β-phenethylamine drugs except amphetamine and methamphetamine because of the negative linguistic images.
A third issue in drug treatment of obesity is the perception that because patients regain weight when drugs are stopped that the drugs are ineffective. Quite the contrary is true. Overweight is a chronic disease that has many causes. Cure, however, is rare, and treatment is thus aimed at palliation. As clinicians we do not expect to cure such diseases as hypertension or hypercholesterolemia with medications. Rather, we expect to palliate them. When the medications for any of these diseases are discontinued, we expect the disease to recur. This means that medications work only when used. The same arguments apply for medications used to treat obesity. It is a chronic incurable disease for which drugs work only when used.
Recent reports of valvular heart disease associated with the use of fenfluramine, dexfenfluramine, and phentermine have provided the most recent problem for drug treatment of obesity.3 This problem is an example of the “law of unintended consequences.” The report of valvulopathy in up to 35% of patients treated with the combination of fenfluramine and phentermine was totally unexpected. The finding, however, will add caution to any future drugs that are marketed to treat obesity and will provide support for those who believe drug treatment of obesity is inappropriate.
Section snippets
Mechanism of drug treatment for obesity
Obesity results from an imbalance between energy intake and energy expenditure. Drugs can reduce food intake, alter metabolism, and/or increase energy expenditure. This approach will be used in discussing the available and potential drug leads for treatment of obesity.1, 4
Drugs that reduce food intake
Table II summarizes the effects of a number of drugs used to treat obesity.1, 4, 5 They are discussed in more detail here.
Drugs approved by the FDA
Orlistat is the only drug approved by the FDA to treat obesity that directly alters metabolism.
Drugs approved by the FDA for an indication other than obesity
The only thermogenic drug combination that has been widely tested is ephedrine and caffeine. Ephedrine and caffeine each have FDA approval, but not for the treatment of obesity.
Patient selection for drug treatment
Those patients who have a BMI above 30 are potential candidates for drug therapy. The presence of comorbidities such as dyslipidemia, hypertension, diabetes or impaired glucose tolerance, symptomatic osteoarthritis, or sleep apnea lowers the acceptable BMI to >27. The currently available sympathomimetic drugs can reduce body weight but only sibutramine is approved for long-term use. This drug should not be used in patients with stroke, congestive failure, or myocardial infarction. The approval
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