OBESITY–An Epidemic

OBESITY: Addressing the Perils of a Growing Epidemic

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CME Information

Learning Objectives

Upon completion of this activity, the learner should be able to
1. Using appropriate methods, diagnose obesity and morbid obesity that is associated with serious comorbidities such as hypertension, cardiovascular disease, and diabetes with their resultant long-term effects on patient health
2. Effectively communicate to patients about weight reduction and weight loss maintenance using proven strategies
3. Assess patients’ BMI and determine how much weight the patient needs to lose to achieve a clinically significant weight loss and a meaningful reduction in cardiovascular comorbidities to their patients by comparing the surgical therapies, pharmacologic therapies, and nonpharmacologic agents that are currently used to help support weight loss and those in development

Introduction

The prevalence of obesity is at epidemic proportions in the United States and worldwide,[1,2] representing the second leading cause of preventable death. Over the past decade, the incidence of obesity in adults in the United States has consistently represented more than one-fourth of the population, with men and women being equally affected (Figure 1). Moreover, the epidemic of obesity and its severity likewise persists across racial groups.[3]

Assessment of Obesity

Obesity is a complex, chronic condition that is defined by excess body fat. Body mass index (BMI), as calculated by kilograms of weight divided by height in meters squared (ie, kg/m2), is an abbreviated measure of total body fat that can easily be calculated in the office environment. Currently, obesity is defined by a BMI of 30 or greater, with the severity of obesity further divided into classes, each of which conveys a mortality risk for obesity-related diseases (Table 1).


Primary care clinicians and other healthcare providers play a pivotal role in identifying and managing obesity.[4] Obesity-related disease complications increase healthcare utilization and costs (representing almost 10% of US healthcare expenditures),[5] reduce quality of life, and decrease life expectancy, underscoring the need for the effective management of obesity. Evidence-based clinical guidelines consistently recommend that clinicians screen all adult patients for obesity by determining their BMI.[4,6] Waist circumference is an independent risk factor for increased cardiometabolic risk and should also be evaluated in patients with BMIs less than 35.

The presence of comorbid conditions contributes to patients’ overall health risk associated with obesity and should therefore be assessed and the need for intervention based on their risk stratification. Prospective studies have confirmed that obesity is a significant risk factor for increased morbidity and mortality from cardiovascular disease (CVD) and metabolic disorders (eg, diabetes).[7,8] Significant associations are also recognized between obesity and a broad range of comorbid diseases such as cancer, gastrointestinal diseases, osteoarthritis, liver and kidney disease, sleep apnea, respiratory diseases, and depression[9-13] (Figure 2). Finally, all cause mortality and CVD and cancer mortality specifically are significantly associated with obesity.

Impact of Weight Loss

A key factor in successful weight management is the establishment of realistic goals. It is important to determine weight loss goals and assess the patient’s readiness to achieve them. Patients may be motivated by taking small, incremental steps and observing the significant benefit on health outcomes. While large weight reductions may be necessary to achieve ideal or normal weight, data suggest that even modest weight reductions of 5% to 15% of initial body weight confer significant improvements in cardiometabolic risk factors and may therefore potentially decrease mortality risk.[15-18] In essence, weight loss does not have to be huge to be clinically significant. Table 2 demonstrates the risks associated with obesity and the degree to which weight loss can impact obesity-related comorbidities and mortality.

Management of Obesity

The National Heart, Lung, and Blood Institute (NHLBI) has updated and expanded their recommendations for the management of obesity,[4] with another update planned for release in Fall 2011. The overall goals of weight management are to reduce body weight and to maintain a lower long-term body weight. Prevention of further weight gain is the minimum goal. In addition, given the severity of the health consequences associated with obesity, the goals of medical management extend beyond mere weight loss, but also encompass the reduction in cardiometabolic risk factors and their associated mortality risk. Both clinicians and patients must recognize that obesity management is a lifelong task. While short-term weight loss, up to 6 months, may be successful, long-term weight management is often associated with nonadherence, failures, and attrition. Clinicians and other healthcare professionals face a considerable challenge in assisting overweight and obese patients to not only lose weight but also achieve weight loss maintenance.[28]

The major health risks and complications associated with obesity, in conjunction with the enormous burden on healthcare resources, have catapulted the treatment of overweight and obese individuals into a public health crisis of epic proportions.[4] Practice guidelines suggest that initial treatment entail implementation of lifestyle changes, including increased physical activity, dietary modifications, and intensive behavioral modification. While for some overweight and obese individuals behavior modification alone will be sufficient to achieve clinically significant weight loss, for others behavior modification alone will be insufficient, and pharmacotherapy or weight loss surgery (WLS) will be required in addition to lifestyle and dietary modifications for any sustained weight loss. The presence of comorbidities alters the landscape of treatment, whereby more aggressive intervention is warranted in overweight and obese patients with obesity-related health risks (Table 3).

Diet Therapy, Physical Activity, and Behavior Therapy

An initial goal of up to 10% reduction in body weight in 6 months is reasonable. A caloric deficit of 500 to 1000 kcal/d aimed at achieving a weight loss of 1 to 2 pounds per week is recommended. A greater weight loss does not yield a better result at the end of 1 year. If these goals are met at 6 months, weight maintenance is the priority. Not only does such a target have proven health benefits, but defining success in realistic terms improves motivation. After 6 months, weight loss usually plateaus due to a decrease in resting metabolic rates and the body’s attempt to maintain its previous weight setpoint. If a patient wishes to lose more weight after a period of weight maintenance, the procedure for weight loss can be repeated. Prescribing specific strategies can help patients stay motivated. Patients are often instructed to lose weight but are not provided specific advice on how to do so. The Centers for Disease Control and Prevention has weight loss recommendations from its practice series, including the following[29]:

  • Limit eating away from home
  • Eat a nutritious breakfast
  • Eat more fruits and vegetables
  • Avoid large portion sizes
  • Avoid sugar sweetened drinks to almost none
  • Be physically active for at least 30 minutes on most or all days of the week
  • Keep a food diary

In conjunction with reductions in caloric intake and increases in physical activity, the NHLBI practice guidelines also recommend adjunctive behavioral therapy, including self-monitoring (for example, via a food diary), stimulus control, problem-solving, contingency management, cognitive restructuring, and social support.[4] It has been demonstrated that weight loss is often augmented when behavioral therapies are incorporated into the treatment plan.[30]

Treatment Options Beyond Behavior Modification

Pharmacotherapy
Weight loss drugs can be useful adjuncts to dietary therapy and physical activity for some patients with a BMI of 30 or greater and no concomitant risk factors or diseases or for patients with a BMI of 27 or greater accompanied by risk factors or diseases. Drugs previously approved by the Food and Drug Administration (FDA) for weight loss include phentermine, orlistat, and sibutramine.[31,32] Phentermine is among the oldest anti-obesity agents and is approved for the short-term (up to 12 weeks) treatment of obesity. Relative to placebo, phentermine has demonstrated a 3.6 kg of additional weight loss; however, it has been associated with cardiovascular side effects such as tachycardia, palpitations, and increased blood pressure. A recent clinical trial of a diffuse-controlled release formulation of phentermine demonstrated 75% of patients achieved at least 5% weight loss and 58% of patients achieved at least 10% weight loss (placebo-subtracted), with significant improvements in lipid parameters. The most common adverse effects were dry mouth and insomnia.[33]

A recent meta-analysis including 16 randomized clinical trials of orlistat and 10 randomized clinical trials of sibutramine revealed modest weight reduction of 3% to 5% of body weight over 6 to 12 months (Table 4).[31] However, sustained weight loss beyond 1 to 2 years was difficult to achieve with either drug. Moreover, each agent is associated with troublesome side effects. With orlistat, noted side effects include increase in diarrhea, flatulence, and bloating/abdominal pain/dyspepsia. In May 2010, the FDA approved a labeling change regarding new safety information on rarely reported severe liver injury.[34] While sibutramine may produce a greater weight loss than orlistat, it has demonstrated an increase in nonfatal myocardial infarction and stroke,[35] prompting the manufacturer of sibutramine to voluntarily withdraw it from the market in October 2010 at the request of the FDA.[36] These results reiterate the challenges faced by clinicians in identifying the best treatment options in overweight and obese patients with concomitant comorbidities.

Emerging Pharmacotherapies
Several drugs in late stage development offer new approaches for safe and effective, sustained weight loss with significant improvement in cardiometabolic risk factors. These drugs provide either novel mechanisms of action or are combinations of older drugs that exert additive or synergistic effects on weight loss mechanisms. These also offer a decrease in side effects often observed in current pharmacotherapies. In contrast to older drugs, the current regulatory environment requires that approval of any new drug for weight loss demonstrate a mean weight loss of 5% or greater of body weight at 1 year and the number of patients achieving this milestone must be double that of placebo. In addition, evidence of significant effects on cardiometabolic risk factors including blood pressure, glycemic control, and dyslipidemia is required.[37]

Lorcaserin hydrochloride is being developed for the treatment of obesity.[38] Lorcaserin is the first in a new class of obesity drugs targeting the 5-HT2C serotonin receptor, which is located in the hypothalamus, a key area of the brain associated with regulation of food intake and metabolism.[39,40] Upper respiratory infections, headache, dizziness, and nausea are among the most common adverse events.[41] In October 2010, the FDA rejected the immediate approval of lorcaserin, noting tumors observed in early stage testing and only marginal weight loss.[40]

Novel investigational strategies in the management of obesity also include the use of combination therapies. For example, phentermine is a stimulant indicated for short-term treatment of obesity, whereas topiramate is an anticonvulsant commonly used for migraine prophylaxis. Phentermine releases high levels of catecholamines, which boost metabolic rate, increasing energy expenditure and decreasing appetite.[42] Topiramate has a direct metabolic effect of increasing feelings of satiety and decreasing food intake.[42] A controlled release (CR) formulation of the combination of phentermine and topiramate (PHEN/TPM) at 1/4 to 1/8 the dosage normally prescribed has been under FDA review for the treatment of obesity.[43] In October 2010, the FDA declined to approve PHEN/TPM citing the need for additional data on its teratogenic potential and safety risks associated with increased heart rate and whether that is related to major cardiovascular events.[44] Additional analyses to address these concerns are planned.

Another combination strategy under investigation is naltrexone SR/bupropion SR. Naltrexone is an opioid receptor antagonist used in the treatment of addiction, and bupropion is an atypical antidepressant. The combination of naltrexone and bupropion has undergone extensive clinical evaluation[45,46] and is currently under FDA review. Nausea, headache, dizziness, and constipation are among the most frequently reported adverse events.

Each of these emerging therapies has demonstrated clinical efficacy and safety in achieving weight loss of at least 5% (Table 5); however, contrary to existing pharmacotherapies, these investigational therapies also produce impressive cardiometabolic benefits in the absence of increased side effects. As one of the key goals of obesity therapy is the reduction of cardiovascular and metabolic risk factors and the health risks they impose, these emerging therapies, as adjunctive therapies to behavioral strategies, show great promise.

Additional agents under investigation for the management of obesity include pramlintide, liraglutide, and tesofensine. Pramlintide is a synthetic analog of the naturally occurring hormone, amylin, which acts with insulin to re-establish more normal glucose concentrations especially in the postprandial period.[48,49] Relative to placebo or as a single agent, pramlintide has demonstrated greater clinical efficacy in achieving weight loss when used in combination with phentermine and metreleptin, as well as sibutramine prior to its withdrawal from the market in October, 2010[50,51] (Table 6). Mild-to-moderate nausea and insulin-induced hypoglycemia are the most common adverse effects.

Liraglutide, a glucagon-like peptide-1 compound approved for once daily subcutaneous treatment of type 2 diabetes in adults, delays gastric emptying and suppresses appetite and energy intake.[52] Treatment with liraglutide, in conjunction with behavior therapy, has demonstrated sustained, clinically relevant, dose-dependent weight loss that was significantly greater than that achieved with placebo or orlistat (Table 6). Weight loss was accompanied by reductions in waist circumference, systolic and diastolic blood pressure, and frequency of both metabolic syndrome and prediabetes. Phase 3 studies of liraglutide for the management of obesity are ongoing. Gastrointestinal events, such as nausea and vomiting, are the most frequently reported adverse effects.

Tesofensine, a dopamine, norepinephrine, and serotonin reuptake inhibitor, has exhibited weight loss effects in animal models and obese subjects with neurological disorders.[53] In a Phase 2 clinical trial, tesofensine demonstrated clinically significant, dose-dependent weight loss relative to placebo (Table 6). Based on these results, a Phase 3 program comprising 4 placebo-controlled clinical trials is planned in obese patients with and without comorbidities, 2 of which were to include sibutramine but will likely be amended given sibutramine’s withdrawal from the market. The most common adverse events caused by tesofensine are dry mouth, nausea, constipation, hard stools, diarrhea, and insomnia.

Weight Loss Surgery
Weight loss from diet and exercise, even in conjunction with pharmacotherapy, is not always sufficient to reduce weight to healthy levels. Subsequently, there has been a marked increase in weight loss surgery (WLS) procedures in the United States over the past decade. From 1998 to 2004, the total number of bariatric surgeries increased 9-fold, from more than 13,000 to more than 121,000,[54] a figure that nearly doubled in 2008.[55]

Practice guidelines recommend bariatric surgery for obese people with a BMI of 40 or greater, and for people with a BMI of 35 or greater and serious coexisting medical conditions such as diabetes.[4] In these groups, WLS is an effective option for patients who have not achieved sufficient weight loss with nonsurgical approaches.[56,57] Surgery can result in a 60 to 80 lb weight loss, maintained for up to 8 years, in class III obesity,[6] reducing chronic disease risk factors, improves health, and confers a survival benefit.[58]

There are 3 types of bariatric surgeries: restrictive, malabsorptive, and a combination of the 2. Restrictive procedures make the stomach smaller and thereby reduce food intake. They confer a mortality risk of 0.05% to 0.4%, with complications that include spillage/pouch dilatation, esophageal dilatation, and stomach obstruction.[59] Malabsorptive procedures, on the other hand, impede caloric absorption by shortening the duodenum and/or altering where it connects to the stomach, limiting the amount of food digested. Malabsorptive procedures generate the greatest amount of weight loss as well as the most significant improvements in obesity-related comorbidities, but they pose a higher risk both in terms of malnutrition and mortality. The risk of mortality is 0.3% to 7.6%, and early complications include anastomotic leak, hemorrhage, venous thromboembolism, and bowel obstruction. Late complications include stomal stenosis and incisional hernia, as well as diarrhea, iron deficiency, and calcium and vitamin D malabsorption manifesting as hyperparathyroidism.[59] Table 7 depicts common WLSs and their impact on health outcomes. In general, WLS is superior to medical therapy both in terms of amount of weight loss and the amelioration of obesity-related comorbidities; however, it is not without its risks. Surgery should be reserved for well-informed, highly motivated patients that meet the criteria of class III obesity or class II obesity with comorbid conditions.

Summary

Key Messages:

  • Obesity has a substantial effect on morbidity and mortality, which is exacerbated by the presence of cardiometabolic comorbidities
  • Nonpharmacologic therapies offer only a short-term benefit in most patients
  • Drug therapy, as an adjunct to behavior modification, offers the potential to significantly reduce weight and improve cardiometabolic risk factors among obese patients
  • Bariatric surgery offers an option for seriously obese patients or those with significant comorbidities

Recognition of the association between obesity and comorbidities is essential for patient diagnosis and management by primary care clinicians. For clinicians who care for overweight or obese patients, the high risk of accompanying comorbid disorders, such as diabetes, CVD, and cancer should be an important factor in their overall management. Primary care clinicians need to be aware of and identify these comorbidities and their impact on outcomes to allow early diagnosis and to identify the patients most likely to benefit from weight loss.

 

 

Michelle Look, MD, FAAFP
Published on November 23, 2010

 

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