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Drug Class Overview and Guidelines
Obesity is a worldwide societal and medical problem. The most recent estimates (2017) suggest that more than 1.9 billion people in the world are overweight (body mass index [BMI] 25–29 kg/m 2 ) and over 650 million are obese (BMI ≥ 30 kg/m 2 ). In the United States, over 39% of the adult population are obese and 33% are overweight, and obesity rates have doubled over the last 20 years. Globally, rates of obesity have tripled since 1975 with most of the global population living in countries where overweight and obesity kills more people than poor nutrition. There is a well-accepted relationship between BMI and overall mortality with a steady increase in risk starting at a BMI greater than 25. It is estimated that there are between 115,000 and 300,000 obesity-related deaths in the United States each year and over 2.8 million deaths attributable to obesity worldwide. The costs associated with obesity are estimated to be almost $150 billion a year in the United States alone.
There is a consensus that losing weight is important to improve health, in particular for prevention of diabetes and other obesity-related diseases such as sleep apnea, fatty liver, and polycystic ovary disease. Even relatively small weight loss (5%–10%) will result in favorable metabolic improvements. However, it has been challenging to identify either weight loss strategies or specific medical therapies that achieve meaningful and sustained weight loss. Moreover, the history of pharmacotherapy for weight loss includes many instances of drugs that caused serious side effects and therefore limited the interest in the clinical use of pharmacotherapy for the treatment of obesity. More challenging is the fact that no study of the weight loss strategy or therapy has definitively demonstrated cardiovascular benefit. While multiple weight loss studies have improved glycemic indices or reduced cardiac risk factors, none resulted in reductions in cardiovascular events such as myocardial infarction, stroke, revascularization, heart failure, or cardiovascular death. The absence to date of any study demonstrating cardiovascular benefit of weight loss has raised the question whether there is truly a causal relationship between obesity and cardiovascular outcomes, or whether obesity simply exacerbates other known cardiovascular risk factors, or is just a marker of worse metabolic health.
Weight Loss Intervention
The clinical challenge in choosing weight loss therapies is that the most effective weight loss strategy is bariatric surgery, which is invasive and only available to a relatively small proportion of patients. Bariatric surgery tends to be used in younger patients with fewer comorbidities but significant burden of obesity-related risks. At the other end of the therapeutic spectrum for obesity therapy are the diet and lifestyle interventions, for which there are many different programs (some with better evidence than others) but that in general attain modest weight loss that is difficult to maintain over time. Pharmacologic therapy falls in between the ends of the therapeutic spectrum but historically provided only modest weight loss at relatively high cost and with treatment-limiting side effects. There is therefore great clinical need to bridge this spectrum by discovering more effective weight loss pharmacotherapy that can achieve greater and sustained weight loss without safety concerns and therefore expand the potential patients population that could achieve significant and sustained weight loss ( Fig. 5.1 ).
Historical and Regulatory Perspective
The past several decades unfortunately witnessed several notable failures among pharmacologic weight loss therapy. In 1997, the combination pill fenfluramine–phentermine, a nonselective serotonin agonist, was found to increase the risk of valvulopathy and pulmonary hypertension after a relatively short treatment duration, leading to its removal from the market. Rimonabant, a cannabinoid antagonist, received approval for use in Europe. A large randomized study subsequently demonstrated an unacceptable increase in neuropsychiatric side effects that led to its withdrawal. Another drug, Sibutramine, a sympathomimetic, facilitates weight loss; however, in a randomized trial, it increased myocardial infarction and stroke. A full list of drugs withdrawn or not approved in the United States is presented in Table 5.1 .
Table 5.1
Historical list of medications used for managing body weight that were withdrawn or not approved in the United States
Adapted from Bray GA Heisel WE, Afshin A, et al. The science of obesity management: an Endocrine Society scientific statement. Endocr Rev. 2018;39(2):79–132.
| Drug | Year introduced or withdrawn | Comments |
|---|---|---|
| Thyroid | 1892 | Mimics endogenous thyroxine/triiodothyronine Associated with tachycardia and increase in metabolic rate |
| Dinitrophenol | 1932 | Uncouples oxidative phosphorylation Associated with cataracts, neuropathy, and death |
| Amphetamine | 1937 | Noradrenergic-dopaminergic drug Associated with recreational abuse and pulmonary hypertension |
| Aminorex | 1965 | Noradrenergic drug Associated with pulmonary hypertension |
| Fenfluramine, dexfenfluramine | 1997 | Serotonergic drugs Both associated with cardiac valvulopathy and primary pulmonary hypertension |
| Phenylpropanolamine | 1998 | Noradrenergic agonist Associated with strokes and cardiovascular deaths |
| Ephedra alkaloids | 2003 | Noradrenergic drugs Associated with heart attacks, strokes, and death |
| Rimonabant | 2008 | Cannabinoid receptor antagonist Associated with depression and suicidality |
| Sibutramine | 2010 | Norepinephrine-serotonin reuptake inhibitor Associated with elevated blood pressure and death |
| Locaserin | 2020 | Selective serotonin (5HT) C2 receptor agonist Concern for increased cancer risk |
Based on this history, the US Food and Drug Administration (FDA) provided new guidance for the industry developing products for weight management, which required that to achieve approval, a drug must first demonstrate efficacy for weight loss, defined as both (1) greater than or equal to 5% weight loss compared to placebo, and (2) that the proprotion of patients who achieve at least 5% weight loss must be overall greater than 35% and twice the rate of placebo. In addition, the FDA required that any new agent must demonstrate cardiovascular safety through a post-marketing cardiovascular outcome trial, where the trial must exclude an excess risk defined by a noninferiority boundary of the upper amount of the 95% confidence interval (CI) < 1.4 for a composite major adverse cardiovascular endpoint. As in the diabetes area, this guidance has dramatically changed the development programs for obesity-related medications.
Guidelines
Weight loss treatment must be multimodal and address underlying medical, behavioral, and lifestyle conditions that can often prevent adequate and sustained weight loss. Guidelines recommend that all obese and overweight patients receive lifestyle therapy (reduced-calorie healthy meal plan/physical activity/behavioral interventions). For all obese patients (BMI ≥ 30 kg/m 2 ) and those overweight patients (BMI ≥ 25 kg/m 2 ) with adiposity-related complications, weight loss medications are recommended if lifestyle therapy does not achieve adequate weight loss. Bariatric surgery is recommended for those overweight and obese patients with at least one severe complication.
Pathophysiology and Mechanism of Action
The pathophysiology of obesity is a complex lifelong interplay between genetic, societal, cultural, behavioral, psychological, and medical factors, to name just a few, that result in the final heterogeneous manifestation of excess weight gain. The simplest calculation for obesity is the relationship between energy (caloric) intake and energy expenditure. However, each side of this balance becomes much more complicated based on nutritional content, central signaling, metabolic set points, and hormonal variations. Fig. 5.2 provides a broad overview of energy balance together with potential areas for prevention. In general, one can tilt this scale by (1) blocking food uptake, (2) suppressing appetite, (3) increasing metabolism, or (4) altering adiposity signaling.
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