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 .
| 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.
Centrally Acting Drugs
Centrally acting drugs affect a variety of pathways within the hypothalamus. Fig. 5.3 reviews the complex interplay between anorexigenic (loss of appetite) and orexigenic (appetite stimulant) signaling in the key areas such as the nucleus accumbens neuron, the dorsal vagal complex, paraventricular nucleus, lateral hypothalamic area, and the arcuate nucleus. Different therapeutic agents will inhibit orexigenic or augment anorexigenic pathways, but the redundancy in the different pathways highlights why single agents are often ineffective in achieving significant weight loss.
Lifestyle and Diet Interventions
ifestyle and diet can typically achieve a clinically relevant 5% to 10% weight loss, though it requires dedicated interventions to activate and sustain patients over time. Current guidelines recommend that a program have at least 14 direct patient–provider interventions to activate and sustain a patient in a program of calorie-reduced diet, increased exercise, and physical activity as well as the behavioral support. Most patients will achieve the greatest weight loss over the first 6 months; however, sustaining long-term weight loss is challenging and generally requires increased physical activity
Several studies have evaluated the intermediate to long-term effect of diet and lifestyle on cardiovascular outcomes. The Diabetes Prevention Program (DPP) randomized 3234 patients with impaired glucose tolerance and a mean baseline BMI of 34 kg/m 2 to placebo, metformin, or a lifestyle-modification program that included a goal of at least 7% weight loss and 150 minutes of physical activity per week. Over an average of 2.8 years of follow-up, the incidence of diabetes was 11.0, 7.8, and 4.8 cases per 100 person-years in the placebo, metformin, and the lifestyle groups, respectively. The lifestyle intervention was significantly more effective than metformin for preventing diabetes, though both strategies were superior to placebo. After 15 years of follow-up, the incidences of diabetes were 55%, 56%, and 62%, respectively, though there was no difference in the aggregate rates of microvascular disease.
One of the most rigorous lifestyle intervention study, the Look AHEAD (Action for Health in Diabetes) Study, randomized 5145 obese or overweight patients with type 2 diabetes to either an intensive lifestyle intervention or a control group report that received education only. Over a median follow-up of almost 10 years, the intervention group achieved greater weight loss (8.6% versus 0.7% at 1 year; 6% versus 3.5% at study end), and had greater reductions in glycemic indices; however, much of this early benefit deteriorated over the subsequent years such that the early improvement was attenuated by year 3. There was no corresponding effect on the primary outcome of cardiovascular death, myocardial infarction, stroke or hospitalization for angina (hazard ratio [HR] 0.95; 95% CI 0.83–1.09; P = 0.51). Unfortunately, much of the early benefit in terms of weight loss, reductions in waist circumference, and improved physical fitness deteriorated after the first year such that one cannot tell if the absence of cardiovascular benefit was because weight loss does not affect cardiovascular events or if weight loss was not sustained sufficiently to assess benefit.
The longest follow-up of a randomized lifestyle and diet intervention is from the Da Qing Study, which started in 1986 in China. Five hundred seventy-seven adults with impaired glucose tolerance were randomized to either control or one of three interventions (diet, exercise, or diet plus exercise). The latest update is now 30 years from the start of the study, with 94% follow-up. The combined intervention group had a median delay of diabetes by 3.96 years, and fewer cardiovascular events (HR 0.74, 95% CI 0.59–0.92, P = 0.006), cardiovascular deaths (HR 0.67, 95% CI 0.48–0.94; P = 0.022), and all-cause deaths (0.74, 95% CI 0.61–0.89; P = 0.0015), and an average increase in life expectancy of 1.44 years (95% CI 0.20–2.68; P = 0.023) ( Fig. 5.4 ).
Lifestyle and diet will always be the cornerstone of the management of weight loss and a key component to an overall healthy life, but multiple studies demonstrate that this alone is unlikely to meaningfully alter the major complications associated with obesity. Economic, societal, and regulatory interventions that encourage and support large populations to eat more healthily and increase overall physical activity are likely the only methods by which population-level weight loss management can be achieved and sustained, in particular among the younger population.
Bariatric Surgery and Medical Devices
The two most common surgical interventions for weight loss are sleeve gastrectomy and Roux-en-Y gastric bypass. Roux-en-Y gastric bypass is the most effective weight loss therapy available, with up to 40% of weight loss at 1 year and sustained weight loss of over 25% by 5 years. The weight loss with sleeve gastrectomy is slightly less than Roux-en-Y, but still achieves up to 30% weight loss at 1 year and 20% over 5 years. Sleeve gastrectomy is a less complex surgery than the Roux-en-Y, with fewer complications, and therefore is performed more commonly.
There has been one randomized trial of bariatric surgery versus medical therapy together with several large observational studies. The Surgical Treatment and Medications Potentially Eradicate Diabetes Efficiently (STAMPEDE) study randomized 150 patients with diabetes to receive either intensive medical therapy alone or medical therapy plus Roux-en-Y gastric bypass or sleeve gastrectomy. The primary outcome of the study was an achieved glycated hemoglobin (hemoglobin A1c) of less than 6% with or without the use of diabetes medications. After 5 years of follow-up only 2% of the medical therapy group achieved the primary endpoint compared to 29% of patients who had gastric bypass and 23% with sleeve gastrectomy. The absolute reduction in hemoglobin A1c was 2.1% with surgery versus 0.3% with medical therapy ( P = 0.003). Gastric bypass surgery resulted in the greatest weight loss (23.3 kg), followed by sleeve gastrectomy (18.6 kg), which was much more than medical therapy alone (5.3 kg, P < 0.05 for all comparisons). This study was not powered for clinical outcomes and the cardiovascular event rates were low; however, the favorable metabolic effects of sustained weight loss are clinically impressive.
Two large observational studies have reported an association between bariatric surgery and lower risk of cardiovascular events. The Swedish Obese Subjects (SOS) study was a prospective nonrandomized study of 4047 subjects who underwent either bariatric surgery or conventional standard of care. Over 15 years of follow-up, patients in the surgical group had 16% more weight loss, 78% lower risk of developing incident diabetes, a 33% lower risk of cardiovascular death, myocardial infarction, or stroke, and a 24% lower risk of all-cause mortality. Another observational study, a cohort study of 2287 patients who underwent surgery and 11,435 controls matched for diabetes and BMI, found that metabolic surgery was associated with almost 15% weight loss and more than 1% absolute reduction in hemoglobin A1c, 41% reduction in all-cause mortality, and a 62% reduction in the risk of heart failure. Despite the large numbers and extended follow-up, the studies were observational and cannot prove a causal association between surgery and outcomes. Bariatric surgery should be considered in obese patients with diabetes and is recommended in most guidelines for appropriate patients because of the improvement in glycemic indices, hypertension, dyslipidemia, and overall quality of life metrics.
There are several medical devices approved for the treatment of obesity that achieve weight loss through different mechanisms, including intragastric balloons, neural stimulation systems to increase satiety, and external drainage systems. These tend to lead to weight loss of less than 10% compared to placebo and have a variety of complications depending on the actual device.
Pharmacologic Therapy
Pharmacotherapy should be considered for either obese patients (BMI ≥ 30 kg/m 2 ) or overweight patients (BMI ≥ 25 kg/m 2 ) with a weight-related comorbidity such as diabetes, fatty liver, or sleep apnea. Unfortunately, there are very few head-to-head studies of weight loss drugs so that determining which agent is the most “effective” remains a clinical challenge. Moreover, most weight loss studies are performed in relatively young and healthy populations, are often not more than a year in duration, and are plagued by high rates of drug discontinuation (either due to lack of weight loss or side effects). In practice, if a patient does not achieve at least a 5% weight loss by 12 weeks, then they are unlikely to benefit from longer-term treatment. Pharmacotherapy has only been studied in addition to diet and lifestyle modification. Because obesity is a heterogeneous disease with multiple underlying pathophysiologic axes, individual patients may respond differently based on the drugs’ mechanism of action. Thus it is common for patients to cycle through several different classes of agents to identify the most effective.
Orlistat
Orlistat inhibits gastric and pancreatic lipases, thus preventing fat hydrolysis and absorption and increasing fecal fat excretion. With a normal diet, orlistat inhibits the absorption of 25% to 30% of the calories from fat. The 1-year placebo-subtracted weight loss with orlistat is only about 3%, but in one randomized trial of 3304 obese or overweight patients, orlistat reduced the incidence of diabetes after 4 years (6.2% with orlistat versus 9% in the placebo). In another study of 892 subjects, orlistat 120 mg three times daily led to an 8 mg/dL reduction in fasting low-density lipoprotein (LDL) cholesterol levels compared to placebo. Patients must take multivitamins to compensate for the malabsorption of fat-soluble vitamins. While there are no systemic side effects of orlistat because it is not absorbed, its mechanism of action will lead to fecal urgency, incontinence, and flatus, which often limits adherence. Oxalate-induced acute kidney injury has also been reported with orlistat and may be due to the binding of intraintestinal calcium leading to higher oxalate absorption.
Sympathomimetic Drugs
Sympathomimetic drugs induce weight loss by promoting early satiety through increased norepinephrine release or inhibiting its reuptake in the central nerve terminals that signal satiety in the hypothalamus. Because these drugs are all related to amphetamines, they also increase blood pressure and heart rate. There are four sympathomimetic drugs approved by the FDA for the short-term treatment (12 weeks) of obesity: phentermine, diethylpropion, benzphetamine, and phendimetrazine. Sibutramine, another sympathomimetic drug that also blocks serotonin reuptake, was withdrawn from the market because of the higher risk of myocardial infarction and stroke, despite promoting weight loss. Long-term use of sympathomimetic drugs is discouraged because of side effects and potential for abuse. Phentermine is by far the most commonly prescribed drug in this class, and overall is the most commonly used weight loss drug in the United States. In short-term randomized control trials, phentermine 30 mg/day led to about 4% to 6% weight loss relative to placebo. In addition to increase in heart rate and blood pressure, this class of drugs can cause insomnia, nervousness, and dry mouth.
Phentermine/Topiramate
In 2012, the FDA approved a combination capsule of phentermine and the extended-release antileptic drug topiramate for obese patients with a BMI ≥ 30 kg/m 2 or with a BMI ≥ 27 kg/m 2 with at least one weight-related comorbidity. Topiramate, an inhibitor of sodium and calcium channels that also inhibits the effect of gamma-aminobutyric acid (GABA), was noted to facilitate weight loss in other disease areas. In several dedicated weight loss studies, this combination appeared to be the most potent oral obesity therapy on the market, with placebo-subtracted 1-year weight loss from 8.6% to 9.3%. The CONQUER study randomized 2487 patients to placebo or the combination phentermine/topiramate for 56 weeks. A total of 70% of patients in the higher-dose group achieved a 5% weight loss compared to 62% in the lower-dose group and 21% in the placebo group. The corresponding rates for 10% weight loss at 56 weeks were 48%, 37%, and 7%, respectively ( Fig. 5.5 ). The most common side effects were dry mouth, constipation, insomnia, and dizziness. Because of the sympathomimetic actions of phentermine, this combination increases heart rate and should be used cautiously in patients with established cardiovascular disease or hypertension. This combination is contraindicated in pregnancy because of an increased risk of cleft palate for infants exposed during the first trimester. Women of childbearing age are required to have a pregnancy test before starting and monthly thereafter. The drug should be prescribed within a Risk Evaluation and Medication Strategy (REMS), which requires formal training and certification for physicians and pharmacies.
