CHAPTER 27: OBESITY AND CARDIOVASCULAR DISEASE

Prevalence of obesity has increased sharply worldwide over the past 30 years.¹ Globally, the proportion of adults with a body mass index (BMI) of 25 kg/m² or greater increased between 1980 and 2013 from 28.8% to 36.9% in men, and from 29.8% to 38.0% in women.² Prevalence has increased substantially in children and adolescents in developed countries to the point where 23.8% of boys and 22.6% of girls were overweight or obese in 2013.² In the United States, data from the National Health and Nutrition Examination Survey (NHANES) show that roughly two out of three US adults are overweight or obese, more than one-third are obese, and 17% of children are obese.^3,4 This has created a global health crisis with a profound impact on morbidity, mortality, and healthcare costs largely attributable to weight-related complications.

In recent years, accumulating scientific evidence has confirmed that obesity is a chronic disease with interacting genetic, environmental, and behavioral determinants resulting in serious complications.^5,6 In addition, exciting advances have occurred in all three treatment modalities for obesity: lifestyle intervention; pharmacotherapy; and weight-loss procedures, including bariatric surgery.^6,7,8,9,10 Clinical trials have established the efficacy of lifestyle and behavioral interventions in the treatment of obesity, and refinements in surgical approaches and improved preoperative and postoperative care have improved outcomes of bariatric surgery. Importantly, there are now five weight-loss medications approved by the US Food and Drug Administration (FDA) for chronic management.^6,7,8,9 These new therapeutic tools together with advances in our scientific understanding of obesity have led to the development of rational medical care models and evidence-based therapeutic approaches with the goal of improving patient health.

Obesity is a Chronic Disease

The pathophysiology of obesity produces excess adiposity sufficient to impair health and results from an imbalance between caloric intake and energy expenditure in favor of fat accretion. In 2012, the American Association of Clinical Endocrinologists (AACE) published a position statement designating obesity as a disease.⁵ Subsequently, following a proposition submitted by AACE together with multiple other professional organizations, the American Medical Association (AMA) also recognized obesity as a chronic disease in June, 2013.¹¹ Like many other chronic diseases, genetic factors constitute a substantial component of disease risk¹² that can explain 50% to 60% of individual variation in body weight in monozygotic/dizygotic twin studies. Monogenic forms of the disease are rare, such as in families with leptin or leptin receptor mutations or deletion of the SNORD116 gene cluster in patients with Prader-Willi syndrome. Susceptibility to obesity in the majority of individuals results from the inheritance of multiple genes, with each allele conferring a very small relative risk for the disease. Genome-wide association studies have identified more than 100 susceptibility loci for obesity.¹³ Particularly strong association signals have been detected for the fat mass- and obesity-associated gene (FTO) and the melanocortin-4 receptor (MC4R) gene, but even these variants confer odds for obesity of less than 1.7.^14,15 The multiple susceptibility genes interact with each other and with the environment, behavior, and biological factors to produce individual variation in the risks of obesity, as illustrated in Fig. 27–1. The development of excess adiposity is a complex process; however, those individuals who inherit larger subsets of obesity susceptibility genes will tend to be more overweight in any given environment.^16,17 Progressive weight gain is not a lifestyle choice and cannot be viewed in terms of a simple thermodynamic equation of greater energy in than energy out. Rather, gene-environment interactions generate a human biological and behavioral interface unique to each individual that not only determines body weight but also explains individual variation in the net effect on body weight for any given amount of food intake or physical activity. To this point, among monozygotic twin pairs, the intra-twin changes in body weight are highly correlated in response to overfeeding¹⁸ and underfeeding¹⁹ of the same number of calories, such that if one member of the twin pair lost a greater or lesser amount of weight, so too did the corresponding twin. Thus, the genetic background and/or the common shared environment determined differences in the amount of weight gained or lost in response to an identical degree of caloric excess or deficit.²⁰

Obesity fulfills the three essential criteria for a disease established by the AMA (report 4 A-05 of the AMA Council on Scientific Affairs), which are (1) characteristic signs or symptoms, (2) an impairment in normal functioning of some aspect of the body, and (3) a process that results in harm or morbidity. A defining sign of obesity is an excess of adipose tissue widely measured as BMI, calculated as weight in kilograms divided by height in meters squared (Table 27–1). There are two salient examples of pathophysiology that contribute to an understanding of the obese state: hypothalamic dysfunction and cardiometabolic risk.

Defects in Hypothalamic Regulation of Appetite

Homeostatic dysregulation in the hypothalamus adversely affects appetite and satiety as they respond to peripheral hormones that register fuel storage and availability. With obesity, these mechanisms drive an increase in appetite producing a positive energy balance, which generates and maintains a higher body weight.^21,22 By way of illustration, this pathophysiology is fully operational in response to weight loss when compensatory changes in hypothalamic processes result in increased hunger and energy storage, driving weight regain back to the previous high level of body weight.²¹ As shown in Fig. 27–2, following a weight-loss intervention, secretion of ghrelin from the stomach is increased above baseline both before and after meals. Ghrelin stimulates neuropeptide Y (NPY) and Agouti-related peptide neurons in the arcuate nucleus of the hypothalamus, causing release of NPY, which activates orexigenic neural pathways leading to an increase in appetite. At the same time, hormones from the gastrointestinal tract and pancreas (eg, leptin, cholecystokinin, glucagon-like peptide-1, amylin, and peptide YY) are reduced below baseline levels.²¹ These latter hormones circulate to the hypothalamus and stimulate proopiomelanocortin-expressing neurons in the arcuate nucleus to produce α-melanocyte-stimulating hormone (MSH). The α-MSH binds upstream MC4R receptors to activate anorexigenic neural pathways, resulting in suppression of appetite. The fall in these satiety-producing hormones has an additional effect to stimulate appetite. Furthermore, in response to weight loss, resting energy expenditure rates are decreased, and the energy that muscles use for any given amount of work is also decreased (ie, increased muscle energy efficiency). These energetic changes also promote weight regain.²³ Finally, psychological food preferences become oriented to food of greater caloric density with high fat and sugar content.

All of these factors promote weight regain and help to maintain a degree of excess adiposity that is harmful to health. In this sense, obesity protects obesity in that hypothalamic set points protect the obese state and resist efforts to reduce adiposity. This makes it challenging for people to maintain a healthy weight. To maintain weight loss, individuals must adhere to therapeutic behaviors or take weight-loss medications that oppose these pathophysiological adaptations (ie, recalcitrant set points) as well as other factors favoring weight regain.

Dysfunctional Adipose Tissue and the Cardiometabolic Disease Process

The second dysfunctional aspect of the obese state is adipose tissue itself and the role it plays affecting other organ systems. The BMI is used to estimate overall adiposity; however, an important consideration is the distribution of body fat, which can have significant implications for disease risk. With increases in body weight, accumulation of intra-abdominal fat is central to the pathophysiology of cardiometabolic disease.²⁴ Cardiometabolic disease risk represents a spectrum of disease manifestations due to common underlying pathophysiological mechanisms that begins with insulin resistance, progresses to the clinically identifiable high risk states of metabolic syndrome (MetS) and prediabetes, and finally to type 2 diabetes mellitus (T2D), cardiovascular disease (CVD), or both in individual patients.²⁵ Based on animal models, primarily murine, and human studies, fat accumulation in visceral adipose tissue is accompanied by an influx of macrophages, the production of proinflammatory cytokines (eg, interleukin-6 [IL-6]), adipocyte insulin resistance, and the dysregulated secretion of adipokines such as adiponectin and resistin.^26,27,28,29 Altered levels of circulating adipokines affect metabolism in various organs (eg, liver, muscle, vascular wall), and this helps produce the MetS trait complex. For example, serum adiponectin levels are decreased, which exacerbates systemic insulin resistance and promotes atherogenesis through loss of adiponectin’s effect to suppress foam cell formation.³⁰

Another aspect of dysfunctional fat is the diminished ability to store lipid. This causes a redistribution of fat to the intra-abdominal compartment and the accummulation of lipid within muscle cells and hepatocyes, which further exacerbates insulin resistance at the level of these organs and contributes to abnormal glucose tolerance. Generalized obesity can exacerbate insulin resistance by augmenting lipid accumulation in muscle, liver, and the visceral compartment, and thus it further impels progression of cardiometabolic disease toward the end-stage manifestations of overt T2D and CVD.³¹ Obesity alone, however, is not a prerequisite for cardiometabolic disease, and is not sufficient as a cause of such disease because even lean individuals can be insulin resistant, and obese indivuals can be insulin sensitive with no manifestations of MetS.²⁵ Nevertheless, weight loss in overweight/obese individuals with insulin resistance and cardiometabolic disease represents highly effective therapy. These principles and the spectrum of cardiometabolic disease are illustrated in Fig. 27–3.

Obesity, Circadian Rhythms, Sleep, and Cardiometabolic Risk

Lifestyle plays a central role in the expression of the obese state comprising not only dietary patterns, physical activity, and stress, but other factors as well, including sleep hygiene and the emerging science of chronobiology.³² Hierarchical regulatory levels ultimately determine circadian changes in appetite, energy consumption, adipocyte function, and body composition. These grossly consist of (1) photic entrainment by the retinal-hypothalamic pathway, (2) oscillators in the suprachiasmatic nuclei of the hypothalamus (master clock), (3) neuronal and hormonal (eg, glucocorticoid) coordination of peripheral clocks (eg, gastrointestinal, pulmonary, and fat), (4) transcription-translation feedback loops involving clock genes (eg, Clock, Bmal1, Per1-3, Cry1-2, Chrono, Rev-erbα, and Rorα), and many downstream clock-controlled genes.³² Food intake also entrains circadian rhythmicity via nutrients (eg, glucose, amino acids, sodium, ethanol, caffeine, thiamin, and retinoic acid), hormones (eg, glucagon, leptin, and ghrelin), cellular energy signals, and various transcription factors.³² Chronodisruptors that are associated with obesity include frequent flying, shift work, disturbed eating patterns, and certain macronutrient distributions (eg, high fat).³² Considering the increased risk of myocardial infarction from 6:00 a.m. to noon, it is not surprising that there may be chronobiological mechanisms mediating the association of obesity with CVD.³³

Potential targeted interventions addressing chronodisruptor-related weight gain include healthy dietary patterns, structured and consistent sleep-wake cycles, decreasing artificial light exposures, and improved sleep hygiene, with pharmacological modalities currently under investigation.^32,34 More specifically, disrupted sleep during critical weight gain periods in young adulthood, as well as short sleep durations (< 6–9 hours/night) and other causes of sleep debt (eg, television/computer screen time and long commuting hours), affect appetite and energy balance (via hormones, such as insulin, cortisol, ghrelin, leptin, NPY, and orexin). Poor sleep hygiene is associated with obesity, T2D, CVD, and total mortality, and it should be targeted therapeutically.^{35,36,37,38,39,40,41}

Obesity markedly augments risk of obstructive sleep apnea, which interrupts normal sleep with periods of hypoxia. This establishes a vicious cycle whereby progressive weight gain exacerbates sleep apnea and sleep apnea promotes further weight gain.^38,42 Obstructive sleep apnea adversely affects psychological health, causing fatigue and depression, metabolic health by predisposing to metabolic syndrome and T2DM, and cardiovascular health as an independent risk factor for refractory hypertension, stroke, and CVD.^{43,44,45,46,47} The therapeutic options for obstructive sleep apnea include continuous positive airway pressure therapy and weight loss.^48,49 Severity of sleep apnea is quantified by the apnea-hypopnea index (AHI), which reflects the average number of apneic/hypopneic episodes per hour during a polysomnography study.⁴⁵ Weight loss, whether achieved by lifestyle therapy⁴⁹ or obesity medications,⁴⁹ can dramatically improve both AHI scores and symptomatology; however, therapeutic benefits are most predictably achieved with at least 10% weight loss.^48,50

The association between obesity and CVD has been extensively investigated using the end points of CVD events, CVD mortality and all-cause mortality, which are interrelated given that CVD is the most common cause of death in many societies. Numerous epidemiological cohort studies have reported a U-shaped or J-shaped relationship between mortality and BMI. In all studies, there is an optimal range of BMI above and below which increasing or decreasing BMI values begin to be associated with increasing rates of CVD events and mortality. The controversy essentially involves BMI in the overweight range (25–29.9 kg/m²). When compared with lean subgroups (18.5–24.9 kg/m²), various studies have reported that the overweight subgroup is associated with either increased, decreased, or unchanged rates of CVD and mortality rates.^{51,52,53,54,55} Therefore, the optimal BMI with respect to mortality has not been identified over a range that includes both normal and overweight individuals, and it is affected by gender, ethnicity, age, and body fat distribution. One criticism of studies reporting that overweight status is associated with reduced mortality versus the lean subgroup is the confounding effects of reverse causality where preexisting diseases in the lean subjects both increase mortality and cause weight loss (eg, cigarette smoking and cancer).^55,56 The Prospective Studies Collaboration conducted a meta-analysis assessing the association between BMI and mortality in 894,576 participants in 57 prospective studies and observed that mortality was lowest at BMI 22.5 to 25 kg/m².⁵⁷ Above this range, each 5 kg/m² higher BMI was on average associated with about 30% higher overall mortality, including significant increments in mortality risk within the overweight subgroup. BMI below 22.5 kg/m² was associated with greater overall mortality, largely resulting from respiratory disease and lung cancer.

It is important to consider that the association between BMI and CVD is largely explained by its association with other risk factors, such that independent risk conferred by BMI is usually minimized in multivariate analyses. For example, when adjusted for waist circumference or the presence of MetS, BMI is no longer a significant independent risk factor for CVD or becomes a much weaker predictor.^25,58,59,60 Cardiometabolic disease risk (ie, risk for both CVD and T2D) conferred by BMI and MetS traits has been examined in the Atherosclerosis Risk in Communities Study (ARIC) over a 20-year follow-up.⁶¹ Regarding overall survival, coronary heart disease cumulative incidence, and stroke cumulative incidence, the presence of MetS was more predictive of outcomes than BMI status, as shown in Fig. 27–4. Subjects with MetS at baseline had higher risks of CVD outcomes than metabolically healthy individuals with no MetS traits, regardless of BMI status. BMI status as lean, overweight, and obese did not substantially affect risk in patients with the MetS or in metabolically healthy subjects having no MetS traits. Risk for T2D was somewhat different (see Fig. 27–4). In the metabolically healthy subgroup, cumulative rates of T2D remained low; however, the relative risk did increase with progressive increases in BMI from lean to overweight to obese. Among patients with the MetS, cumulative incidence rates of T2D where much higher, and the rise in BMI produced a much greater effect to augment cumulative incidence. Notably, lean unhealthy subjects with MetS displayed a more than two-fold increase in cumulative diabetes when compared with obese metabolically healthy individuals. Thus, weight gain against an insulin-sensitive background (ie, metabolically healthy) exerts a relatively small effect to increase cumulative incidence of T2D but can significantly augment T2D risk in insulin-resistant patients with MetS.⁶¹

Regarding congestive heart failure (CHF), the presence of overweight or obesity may be protective against mortality, referred to as the obesity paradox. Elevations in BMI are associated with increased risk of developing CHF in part by predisposing to hypertension, T2D, sleep apnea, and CVD. However, once patients present with CHF, the presence of overweight and/or obesity has been observed to be protective regarding risks of future CVD mortality and hospitalizations when compared with lean individuals.^62,63,64 Again, better outcomes in overweight or obese subjects may reflect reverse causality resulting from processes that both lower body weight and increase mortality (eg, cardiac cachexia and cigarettes).

Body Mass Index: The Anthropometric Component of the Diagnosis of Obesity

The BMI is widely used in the screening, diagnoses, and classification of patients with obesity. The criteria established by the World Health Organization in 1998⁶⁵ are shown in Table 27–1. BMI values 18.5 to 24.9 kg/m² are indicative of lean individuals, BMIs 25 to 29.9 kg/m² overweight, and BMIs of 30 kg/m² or more represent obesity categorized as obese class I (BMI 30–34.9), obese class II (BMI 35–39.9), or obese class III (BMI ≥ 40). The BMI values are used in conjunction with waist circumference measurements as an addition indicator of comorbidity risk. These criteria were soon thereafter adopted by the National Institutes of Health,⁶⁶ which promulgated their widespread application in epidemiology and medicine. In South Asian, East Asian, and Southeast Asian populations, health is adversely affected at lower levels of BMIs, and alternate criteria have been advocated, with BMIs of 18.5 to 22.9 kg/m² indicative of normal weight, 23 to 24.9 kg/m² overweight, and 25 or more kg/m² obese.⁶⁷ Waist circumference cutoff points to indicate increased risk of cardiometabolic disease also exhibit regional and ethnic variations.⁶⁸

BMI is an anthropometric measure that interrelates the height and weight of individuals, and, therefore, is only an indirect measure of adiposity of total body fat mass. BMI incorporates fat mass as well as lean mass, bone mass, and fluid status, all of which can vary independently from fat mass. BMI will overestimate adiposity in athletes with high muscle mass and in patients with edema, and will underestimate adiposity in elderly patients with sarcopenia. For this reason, patients with elevated BMI measurements must be clinically evaluated to confirm excess adiposity.

Weight-Related Complications: The Clinical Component of the Diagnosis of Obesity

Another limitation of BMI is that it does not indicate the impact of excess adiposity on the health of individual patients.⁶⁹ The adverse effect of excess adiposity on health is manifest by the development of weight-related complications and the emergence of risk factors for those complications. Although the likelihood of weight-related complications generally increases as a function of progressive obesity, there can be a poor correlation between BMI and the development of complications. Patients with obesity need not have weight-related complications and can be free of disease-related morbidity and mortality, as illustrated in Fig. 27–4. Therefore, individuals who meet the anthropometric criterion for overweight or obesity must then undergo a clinical evaluation for the presence or absence of weight-related complications.^7,69 The identification of complications and their severity are important for two reasons in patients with overweight or obesity. First, the presence and severity of complications or relevant risk factors will indicate the need for more aggressive therapy to improve the health of individual patients. Second, because these complications can be improved or reversed by weight-loss therapy, the evaluation will establish therapeutic targets for weight loss and the integration of these goals as desired outcomes into the therapeutic plan. From this perspective, the goals of weight-loss therapy are to improve the health of patients with obesity by treating and preventing weight-related complications. This is consistent with the “complications-centric” approach to obesity management advocated by the AACE.^5,69,70

The evaluation for the presence and severity of weight-related complications represents the clinical component of the diagnostic evaluation for obesity.⁶⁹ Health-care professionals should screen patients for common weight-related complications as illustrated in Table 27–2. The identification of complications does not involve an extensive or extraordinary degree of testing but can be ascertained in the course of an initial patient evaluation consisting of medical history, review of systems, physical examination, and laboratory studies. In the initial evaluation, the clinician will need to (1) pay particular attention to the relevant aspects of the history and examination and (2) conduct an obesity-focused review of systems assessing potential symptomatology of weight-related complications. In many cases, the information gathered in the initial examination is sufficient for the diagnosis of certain weight-related complications. For other complications, the initial information augments the degree of suspicion, and additional testing consistent with standards of care is then necessary to confirm the diagnosis and for staging the severity of the complication. Depending on the expertise of the clinician, referral may be indicated for further evaluation and treatment of specific complications.

Effects of Weight Loss on Cardiovascular Disease Risk Factors

Weight loss, whether due to lifestyle therapy, weight-loss medications, or bariatric surgery, has been shown to (1) enhance insulin sensitivity; (2) improve hepatic steatosis and reduce intracellular lipid content in skeletal muscle as well as liver; (3) prevent or delay progression to T2D, particularly in high-risk patients with prediabetes or MetS; (4) effectively reduce CVD risk via improvements in blood pressure and lipids; and (5) improve biomarkers of CVD risk, including C-reactive proteins, IL-6 and other markers of inflammation, fibrinogen levels, and serum adiponectin concentrations.⁷¹ Thus, weight loss is perhaps the most effective therapeutic approach for treating and preventing the progression of cardiometabolic disease (see Fig. 27–3) via improvements in the core physiological processes that confer risk of future T2D and CVD events.

Three major randomized clinical trials—the Diabetes Prevention Program,⁷² the Finnish Diabetes Study,⁷³ and the Da Qing Study⁷⁴—all demonstrated the impressive efficacy of lifestyle/behavioral therapy to prevent T2D. In these studies, lifestyle modifications generally involved reductions in caloric intake by 500 to 1000 cal/d, behavioral interventions, and increases in physical activity. The Diabetes Prevention Program study randomized subjects with impaired glucose tolerance to ordinary care, metformin, and lifestyle intervention subgroups, and after 4 years, lifestyle modification reduced progression to T2D by 58% and metformin by 31%, compared with placebo. Subjects achieved approximately 6% mean weight loss at 2 years and approximately 4% weight loss at 4 years in the lifestyle intervention arm, and there was a progressive 16% reduction in T2D risk with every kilogram of weight loss.⁷⁵ With observational follow-up after termination of the study, there was still a significant reduction in the cumulative incidence of T2D in the lifestyle treatment group at 10 years, despite the fact that BMI levels had equalized among the three treatment arms.⁷² In addition to the reductions in T2D, there was also evidence in the Da Qing Study that CVD events and mortality were reduced after 23 years when comparing the combined subgroups treated with diet and exercise with the controls.⁷⁶

Hypertension is an established consequence of overweight and obesity. It is, therefore, not surprising that one of the associated benefits of weight reduction is lowering blood pressure. A meta-analysis of eight studies involving more than 2100 participants who were randomized to either a weight-reducing diet or a control intervention demonstrated that weight loss led to decrements in blood pressure of 4.5/3.2 mm Hg together with a 4.0 kg decrease in body weight compared with the control groups after follow-up of 6 to 36 months.⁷⁷ The results of this meta-analysis are consistent with earlier analyses suggesting that BP decreased by 1.2/1.0 mm Hg for every kilogram of weight lost. A weight-reducing diet based on the Dietary Approaches to Stop Hypertension (DASH) plan with a lower sodium intake and moderate or no alcohol intake has been shown to be an effective nonpharmacologic approach to reduce blood pressure.⁷⁸

The dyslipidemia associated with obesity and insulin resistance is characterized by elevations in triglyceride levels (eg, 150–400 mg/dL); reduced high-density lipoprotein (HDL) cholesterol; and increased concentrations of small, dense low-density lipoprotein (LDL) particles.⁷⁹ Hypertriglyceridemia is largely due to excess production of large triglyceride-enriched very low-density lipoprotein (VLDL) particles by the liver, and it is responsive to alterations in macronutrient composition, increased physical activity, and restriction of alcohol. Because carbohydrates can drive hepatic VLDL production, ingested carbohydrates, particularly sugars and refined carbohydrates, should be reduced and replaced with unsaturated fats and protein.⁸⁰ Weight loss has additional beneficial effects on lipids and lipoproteins. Weight loss of 5% to 10% has been shown to amplify the benefits of changes in macronutrient composition, resulting in a 20% decrease in triglycerides, a 15% reduction in LDL cholesterol, and an 8% to 10% increase in HDL cholesterol. However, greater degrees of weight loss can achieve progressive improvements in dyslipidemia. Meta-analyses have reported that for every kilogram of weight loss, triglyceride levels decrease about 1.9% or 1.5 mg/dL.⁸¹ Furthermore, there are beneficial effects of weight loss on LDL subclasses characterized by reductions in small, dense LDL particle concentrations and an increase in medium and large LDL particles, coupled to a mean increase in LDL particle size and reductions in total LDL particle concentration.^82,83

Staging and Stratification of Cardiometabolic Disease Risk

The prevalence of overweight and obesity can approximate 70% of the population in some societies, and not all obese patients are insulin resistant with cardiometabolic disease. The presence of overweight/obese subjects with no MetS risk factors (metabolically healthy obese) has been well documented, and these individuals exhibit lower rates of future T2D, CVD events, and mortality.^{25,84,85,86,87} Therefore, estimates of cardiometabolic disease risk can be used to identify patients at greatest risk for future T2D and CVD in order to target more aggressive weight-loss therapy to those individuals who will receive the greatest benefit.

The clinician should evaluate patients for MetS and prediabetes, because this effectively identifies individuals at high risk for future T2D and CVD. However, MetS and prediabetes have high specificity but low sensitivity for identifying patients with insulin resistance and cardiometabolic disease,^86,88 and these entities alone will not identify significant proportions of at-risk patients. Various indices using information from history and physical examination—such as the American College of Cardiology (ACC)/American Heart Association (AHA) Omnibus risk estimator,⁸⁹ Framingham Coronary Heart Disease Risk Score,⁹⁰ the Reynolds Risk Score,⁹¹—or commercial products that use clinical laboratory assays can be used to stage risk in insulin–resistant patients whether or not they meet diagnostic criteria for MetS or prediabetes.

Another approach to cardiometabolic disease risk stratification for the patient with obesity is the Cardiometabolic Disease Staging system (CMDS)^25,92 shown in Fig. 27–5. CMDS defines five stages of risk that are based on established physiological and epidemiological observations. These are (1) the presence of the metabolically healthy obese with no MetS traits (stage 0); (2) the fact that patients with one or two risk factors are at increased risk of T2D and CVD even if they do not meet criteria for MetS or prediabetes (stage 1); (3) the documented risk conferred by the presence of having only one of the risk states of MetS or impaired fasting glucose or impaired glucose tolerance (stage 2); (4) the augmented risk for T2D and CVD in patients having both MetS and prediabetes (stage 3); and (5) patients with end-stage cardiometabolic disease who have either T2D (a CVD risk equivalent) and/or CVD (stage 4). Advancement of CMDS stage 0 to 4 was validated to predict increasing risk of diabetes using data from the national Coronary Artery Risk Development in Young Adults (CARDIA) cohort, as well as all–cause and CVD mortality using NHANES data.^25,92 Thus, CMDS utilizes information that is readily available to the clinician in the context of routine clinical practice to quantitatively stratify risk of both T2D and CVD.

Effects of Weight Loss on Cardiovascular Disease Events and Mortality

It is difficult to assess an independent effect of weight loss on CVD events and CVD mortality for several reasons: (1) the confounding effect of treatment targeted to risk factors can affect mortality (eg, statins, angiotensin-converting enzyme inhibitors); (2) the need to include only intentional weight loss in cohort studies and exclude unintentional weight loss; (3) studies that largely do not differentiate between patients with obesity with and without CVD risk factors, which could be the basis of heterogeneity in the response to weight loss; and (4) the need for long-term interventions and follow-up. Weight loss produces improvements in CVD risk factors, as indicated by improvements in blood pressure, lipids, glycemia, waist circumference, and various biomarkers. However, the question remains whether these effects translate into reductions in CVD events and mortality.

There are few, if any, long-term randomized clinical trials (RCTs) assessing effects of weight loss on CVD events and/or mortality as a predetermined primary outcome measure. Most RCTs involve short-term lifestyle interventions and do not demonstrate significant reductions in mortality when compared with control groups. One example is the Action for Health in Diabetes (Look AHEAD) study in patients with T2D randomized to intensive lifestyle therapy versus standard care, which prespecified mortality as an outcome. Although weight loss improved glycemia, lowered blood pressure, and improved lipids, the Look AHEAD study was discontinued prematurely because lack of effect of the intensive lifestyle intervention on mortality compared with standard care.⁹³ However, two meta-analyses of relevant RCTs have demonstrated that lifestyle-induced weight loss was associated with decreased mortality and CVD outcomes.^94,95 Large cohort studies have shown that intentional weight loss is associated with reduced mortality, particularly in subjects with weight-related complications such as T2D,^96,97 including long-term follow-up following a lifestyle intervention in the Da Qing study⁷⁷ and following bariatric surgery in case-control cohort studies such as the Swedish Obese Subjects study⁹⁸ and a study involving Veterans Affairs Medical Centers.⁹⁹ The data suggest that weight loss of more than 15% body weight is more likely to be associated with efficacy in this regard. Cardiovascular outcome trials assessing all four weight-loss medications approved by the FDA between 2012 and 2014 (see below) are ongoing or planned.

Treatment of patients with obesity incorporates three therapeutic modalities: lifestyle therapy, pharmacotherapy, and bariatric surgery.^6,7,8,9

Lifestyle Therapy

Lifestyle therapy is the cornerstone of therapy for patients with obesity. It can constitute the sole approach to treatment, but it must also accompany treatment using weight-loss medications or bariatric surgery. The components of lifestyle therapy include a reduced-calorie healthy meal plan, a prescription for increased physical activity, and a package of behavioral interventions that are designed to promote adherence with the meal plan and physical activity. Lifestyle therapy is most effective for weight loss when delivered as a structured program with flexibility to accommodate the personal and cultural preferences of patients. The components of a structured lifestyle intervention can be delivered by a multidisciplinary team consisting of primary or specialty medical care professionals, health educators, dietitians, nurses, exercise trainers, and psychologists, and it may involve a variety of venues in the clinic and in the community. Commercial programs featuring meal substitutes or delivered meals and interventions using remote technologies (telephone, text, Internet) have also been shown to be effective.

Reduced Calorie Healthy Meal Plan

The most important aspect of lifestyle therapy is a reduction in caloric intake, amounting to a 500- to 1000-kcal/d deficit in most instances. This can be achieved in the format of a healthy meal plan that provides all needed micronutrients and avoids processed foods. Examples of healthy meal plans include low carbohydrate, low fat, low glycemic index, DASH, Mediterranean, and vegetarian. The macronutrient composition is less important than the patient’s ability to adhere with the diet. Therefore, the meal plan should be individualized and selected to be compatible with the personal and cultural preferences of the patient. The use of meal substitutes in the form of shakes and bars add structure to the diet and have been shown to be effective. The patient should also be instructed in approaches to portion control and stimulus control.

Increased Physical Activity

A physical activity prescription can modestly increase caloric expenditure and is particularly helpful for maintaining lean body mass during weight loss and in helping sustain weight loss over a longer interval. The physical activity program optimally includes aerobic exercise, which should begin at a low level allowing the patient to increase the intensity and duration of the exercise over time. Ideally, the patient will achieve at least 150 minutes per week of moderately intense aerobic exercise accomplished in three to five sessions.¹⁰⁰ The combination of aerobic and resistance exercise provides better outcomes than either form of exercise per se. Therefore, a resistance exercise program should be added and should consist of single-set repetitions targeting the major muscle groups two to three times per week. A final component of a physical activity program is to reduce sedentary behavior and increase active leisure activity. The physical activity prescription should be compatible with patient preferences and take into account any health-related or physical limitations.

Behavioral Therapy

Lifestyle therapy in patients with overweight or obesity should include behavioral interventions that enhance adherence to prescriptions for a reduced-calorie meal plan and increased physical activity. RCTs have not only demonstrated the efficacy of lifestyle therapy programs that include behavioral interventions but have underscored those practices that are most likely to be associated with success.^73,74,75,101 Effective practices include self-monitoring of weight, food intake, and physical activity. Patient education is also advantageous pertaining to obesity, nutrition, and physical activity, which can be delivered face-to-face, in group meetings, or using remote technologies (telephone, texting, and Internet). The program should also feature clear and reasonable goal setting, strategies for stimulus control, and systematic approaches for problem solving and stress reduction. Other components can include cognitive restructuring (ie, cognitive behavioral therapy), motivational interviewing, behavioral contracting, and mobilization of social support structures. Obesity can often be associated with depression, disordered eating (eg, binge eating disorder), anxiety, and other psychiatric disorders, which can impair the effectiveness of lifestyle interventions. For this reason, psychological counseling and psychiatric care may be necessary. The behavior intervention package is effectively accomplished by a multidisciplinary team that can include combinations of the following: dietitians, nurses, health educators, physical activity trainers or coaches, and clinical psychologists. As with the meal plan and physical activity components, behavioral lifestyle intervention should be tailored to a patient’s ethnic, cultural, socioeconomic, and educational background.

Weight-Loss Medications

Since 2012, there have been four new weight-loss medications approved for the chronic treatment of obesity by the FDA.^6,7,8,9 These medications are in addition to orlistat (120 mg), approved in 1999, which was the only preexisting medication for long-term pharmacotherapy and the only one currently permitted in Europe and many other countries. The newer medications include lorcaserin, phentermine/topiramate extended-release (ER), naltrexone ER/bupropion ER, and high-dose liraglutide (3 mg). The availability of these new medications has greatly expanded treatment options for patients with obesity and has led to more robust approaches to patient management.⁷ All these medications are approved in the United States as adjuncts to lifestyle modification in overweight patients with BMIs of 27 to 29.9 kg/m² having at least one weight-related comorbidity (generally taken to be diabetes, hypertension, or dyslipidemia), or obese patients (BMI ≥ 30 kg/m²) whether or not comorbidities are present. Orlistat is the only approved long-term drug for obese adolescents aged at least 12 years; all others are only approved for adult patients. Orlistat acts as a lipase inhibitor in the gut to impair digestion and absorption of ingested lipids. The other approved weight-loss medications act on the mechanisms regulating appetite and satiety, helping to combat the pathophysiological adaptations that drive and sustain weight gain. In clinical trials, the addition of pharmacotherapy to lifestyle promotes greater weight loss and sustains weight loss for a greater period of time than that attributable to lifestyle interventions alone. The available data, which only encompass 2 years or fewer of follow-up, demonstrate that these pharmacotherapies sustain weight loss even when patients randomized to lifestyle plus placebo are regaining weight (Table 27–3).

Although studies of the recently approved weight-loss medications have not yielded long-term results, it is important to consider that obesity is a lifelong disease and requires long-term management. Given the need to maintain weight loss, clinical experience needs to be developed in using medications to sustain weight loss over the patient’s lifetime. Postmarketing cardiovascular outcome trials are planned or ongoing for the four new weight-loss medications, and these studies should provide information pertinent to longer duration of therapy.

Surgery

Bariatric surgery is the most effective method for treating class II and III obesity^102,103 and can be considered in patients with (1) BMIs of 35 kg/m² or more and associated comorbidities or (2) BMIs of 40 kg/m² whether or not accompanied by comorbidities, particularly after failure of lifestyle modification and medical therapies. Bariatric surgery can provide substantial weight loss (15% to more than 40%), but this varies by procedure.¹⁰³ The most commonly performed procedures are Roux-en-Y gastric bypass (RYGB), adjustable gastric banding, sleeve gastrectomy, and biliopancreatic diversion with or without duodenal switch. Many patients achieve long-term weight loss; however, it is not uncommon for patients to gradually regain weight over time.¹⁰⁴ Sustained weight loss also depends on ongoing lifestyle therapy, patient reeducation in terms of active lifestyle changes, and long-term medical follow-up.

A few key studies help highlight outcomes of bariatric surgery. Adams and colleagues examined the association of RYGB surgery with weight loss, T2D, and other health risks 6 years after surgery.¹⁰² Weight-loss maintenance was superior in severely obese patients (BMI ≥ 35 kg/m²) undergoing RYGB compared with nonsurgical controls, with 76% of patients maintaining at least a 20% weight loss over 6 years. RYGB was also associated with higher rates of diabetes remission and lower CVD risk over 6 years. The Swedish Obese Subjects (SOS) study involved patients receiving any one of several bariatric procedures and matched conventionally treated obese controls (lifestyle intervention, behavior modification, or no treatment).¹⁰³ The mean reported body weight changes after 2, 10, 15, and 20 years were –23%, –17%, –16%, and –18% in the surgery group, and 0%, 1%, –1%, and –1% in the conventionally treated care group, respectively.¹⁰⁵ Compared with standard care, bariatric surgery reduced overall mortality and decreased the incidence of diabetes, CVD events, and cancer. However, Cooper and colleagues demonstrated that weight regain is a common complication following RYGB surgery.¹⁰⁴ In this study, the mean weight regain for all patients was 23.4% of maximum weight loss (mean 6.9 ± 4.9 years after surgery). Furthermore, more than one-third of patients experienced excessive weight regain (≥ 25% of lost weight).

Within the past decade there have been improvements in all three therapeutic modalities for obesity treatment: evidence-based lifestyle interventions, the new medications, and more refined bariatric surgery procedures. This has prompted the development of rational guidelines for how to best to use these tools to achieve the best outcomes while balancing efficacy, safety, and costs. While emphasizing the health benefits of weight loss, these guidelines can be viewed as falling along a continuum from a more BMI-centric approach, with a goal of losing a given amount of weight, to a complications-centric model focused on preventing and treating weight-related complications.^6,7 The BMI-centric approach is best illustrated by the obesity treatment guidelines set forth by the NHLBI in 1998,⁶⁶ as shown in Table 27–4. Under these guidelines, appropriate treatment was defined in terms of patients’ initial BMI, with those having a BMI of 25 to 26.9 kg/m² receiving dietary, physical activity, and behavior interventions, and pharmacotherapy and surgery being added in a stepwise manner for those with progressively higher BMIs. Although this approach does make some allowances for comorbidities, it depended largely on BMI as the major determinant and indication for appropriate treatment.

At the other end of the spectrum from the traditional NHLBI approach is the complications-centric approach developed by the AACE^69,70 shown in Fig. 27–6. In this model, weight loss becomes a therapeutic tool for the treatment of obesity-related complications, to a large extent independent of patients’ degree of general adiposity or BMI. This approach targets more aggressive therapies to those who will derive the greatest benefits from weight-loss therapy, namely those patients with weight-related complications, thereby optimizing benefit/risk, outcomes, and cost effectiveness. Therapy begins with evaluating patients for the presence and severity of obesity-related cardiometabolic or biomechanical complications, followed by identifying therapeutic targets for improvement in existing complications. Lifestyle modification is recommended for patients without complications regardless of their BMI; for those with BMIs of 27 kg/m² or more and complications, therapeutic options expand to include medications, and, for those with BMIs of 35 kg/m² or more, bariatric surgery. Targets for improvement in complications should be monitored, and intensification of all modalities (lifestyle, medication, and surgery) should be implemented if necessary—along with direct treatment of complications—to achieve the desired outcomes.

The evidence-based ACC/AHA/The Obesity Society (TOS) practice guidelines published in 2014 update the earlier NHLBI guidelines and were developed, using a formal and rigorous evidence review process, to provide guidance on five specific critical questions.¹⁰⁶ The ACC/AHA/TOS clinical practice guidelines and accompanying treatment algorithm generally advocate a sequential approach, recommending that individuals who have never participated in a comprehensive lifestyle management program should be encouraged to do so before considering weight loss medications or bariatric surgery. By comparison, the AACE algorithm does not stipulate that a stepwise, sequential approach is strictly necessary and indicate that the aggressiveness of initial therapy should be determined by the presence and severity of weight-related complications and their adverse impact on the health of the patient.

In all guidelines, obesity is recognized as a chronic disease, and therapy is directed at improving the health of the patient. As our scientific understanding of obesity has progressed, it has become clear that obesity is not a lifestyle choice and its treatment is not a cosmetic enterprise. The new perspective of obesity as a disease mandates that we bring the full force of our medical care model for prevention and treatment. An increasing effort is being expended in the development of new treatments and therapeutic approaches. With increased access to current and emerging therapies, we will be able to effectively combat the rising worldwide problem of obesity and mitigate the burden of patient suffering and social costs of the lifelong disease.