Safety, Efficacy and Ethical Issues Regarding Weight-Loss Medications

Michael William Lee

Disclosures

Expert Rev Clin Pharmacol. 2009;2(2):111-113. 

In This Article

Safety & Efficacy

The pharmacologic treatment of obesity has resulted historically in the questionable use of various medications, with often significant adverse effects. Dinitrophenol was used in the 1930s to increase metabolic rate; overdoses lead to fatal hyperthermia. 'Rainbow pills', popular from the 1940s to the 1960s, were composed of amphetamines, thyroid hormone, digitalis, and diuretics. The anorectic stimulant aminorex was introduced in Europe in 1965, but soon withdrawn due to reports of resultant pulmonary hypertension. Excess thyroid hormone supplementation, widely used until the 1980s, often resulted in iatrogenic hyperthyroidism. The serotonergic agent fenfluramine was removed from the market in 1997 after being linked to valvular heart disease. Phenylpropanolamine, a sympathomimetic compound subsequently associated with hemorrhagic stroke in young women, was taken off the market in 2000.

It is also increasingly apparent that the physiological mechanisms regulating caloric intake and bodyweight are highly integrated, complex and redundant.[1] Short-acting signals in response to meals include gut hormones (e.g., cholecystokinin, ghrelin, glucagon-like peptide 1 and peptide YY3-36) and signals from vagal afferent neurons within the GI tract. Long-acting signals regarding adipose tissue mass are provided by leptin and insulin. Hypothalamic and hindbrain integration of such neural and humoral signals results in precise regulation of appetite and energy expenditure.

Within the context of such interrelated systems, adverse effects should not be unexpected when a pharmacologic treatment of obesity targets a specific pathway. For example, cannabinoid (CB) type 1 receptors are located in both central structures (e.g., the hypothalamus) and peripheral organs (e.g., adipose tissue). CB1 receptor antagonists, such as the aforementioned rimonabant and taranabant, were found to regulate food intake and adipose tissue metabolism, resulting in weight loss and favorable blood lipid changes. Unfortunately, CB1 receptor inhibition also increased the incidence of psychiatric adverse effects, such as anxiety and depression.[2] Other centrally acting small-molecule anorectics in development will undoubtedly face similar safety concerns; as detailed below, the US FDA addresses such issues in its most recent Guidance for Industry statement.

In February 2007, the FDA updated guidance to industry regarding the development of products for weight management. Key efficacy and safety recommendations were as follows[104]:

"...weight loss and weight maintenance should be demonstrated over the course of at least 1 year before a product can be considered effective for weight management."
"The difference in mean weight loss between the active-product and placebo-treated groups is at least 5% and the difference is statistically significant," or "The proportion of subjects who lose greater than or equal to 5% of baseline body weight in the active-product group is at least 35%, is approximately double the proportion in the placebo-treated group, and the difference between groups is statistically significant."
"A reasonable estimation of the safety of a weight-management product upon which to base approval can be made when a total of approximately 3000 subjects are randomized to active doses of the product and no fewer than 1500 subjects are randomized to placebo for 1 year of treatment."
"In addition to routine safety monitoring, it may be appropriate for the development programs of some weight-management products to have specialized safety assessments" (e.g., neuropsychiatric function and abuse liability studies for centrally acting products)

While these recommendations will probably result in safer weight-management products, fewer medications will receive FDA approval in the near future. Enrolling over 4500 research individuals in clinical trials requires significant expense and planning. Retention of such individuals (particularly those in the placebo group) for at least 1 year will be a difficult challenge for the primary investigators and study sponsors, as weight-management studies often have high dropout rates. Centrally acting compounds will also have to meet a higher standards of safety monitoring; in contrast, peripheral peptide hormones (e.g., glucagon-like peptide 1) may carry less risk for significant adverse effects.

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