Overweight, Obesity, and Cardiovascular Risk




Key Points





  • Obesity is the leading public health crisis of our time. It is a primary target to reduce an avoidable disease burden in the United States.



  • Obesity is an independent risk factor for major cardiovascular events, including coronary heart disease, heart failure, and stroke.



  • Body mass index is a vital sign for assessment of patients with excess body weight and for stratification of treatments according to the likelihood of underlying disease risk.



  • A series of metabolic abnormalities in obesity culminate in a clustering of risk factors for cardiovascular disease and type 2 diabetes mellitus, a condition known as the metabolic syndrome.



  • Framingham risk score assessment for cardiovascular disease does not account for obesity. Risk assessment should include body mass index, waist circumference, blood serum biomarkers, and physical fitness.



  • Major studies show that lifestyle change leading to weight loss can reduce or reverse risks associated with cardiovascular disease, including sleep apnea, hypertension, type 2 diabetes, and coronary heart disease.



  • In patients intractable to lifestyle intervention alone, pharmacotherapy can facilitate weight loss to reduce risk of comorbid conditions. In cases of severe obesity, bariatric surgery is associated with significant weight loss and improvement in diabetes, hypertension, and obstructive sleep apnea.



  • Obesity prevention and cardiovascular risk reduction will require a new approach that takes into account the sociopolitical, economic, and environmental forces that interact to create an obesogenic environment.



Obesity is the leading public health crisis of our time. The most recent data from the National Health and Nutrition Examination Survey (NHANES 2005-2006) indicate that the prevalence of obesity (BMI >30 kg/m 2 ) among adults is 34% ; for extreme obesity, the figure is 6%. Minorities are disproportionately affected. Approximately 53% of non-Hispanic African American women and 51% of Mexican American women 40 to 59 years of age are obese compared with an estimated 39% of non-Hispanic white women of the same age. Together, overweight and obesity affect more than 66% of the adult population.


Rates of childhood obesity reflect those for adults. The proportion of 18- to 29-year-olds who were obese in 2004-2006 more than tripled from 8% in 1971-1974 to 24%. NHANES data for the combined years of 2003-2006 indicate that 16.3% of children and adolescents 2 to 19 years of age are obese, defined as at or above the 95th percentile of the 2000 BMI-for-age growth charts; 11.3% of children and adolescents in the same age group are above the 97th percentile, or extremely obese.


Low-income and minority children, like adults, are disproportionately affected. The rates of obesity in Hispanic and non-Hispanic black children are 18.5% and 11.8%, respectively, compared with 12.6% in non-Hispanic white children. Evidence suggests that obesity-associated morbidity may increase with longer duration of the disease, adding even more urgency to the need to reverse the trend and to reduce future morbidity.


Modern therapies, such as statins, and lifesaving procedures have reduced the rate of mortality due to heart disease in the United States. There are, however, concerning trends in both nonfatal events and the disability that results from major cardiovascular events. Risk factor levels continue to rise in the United States at alarming rates. Addressing these risk factors will be the first step in alleviating avoidable burdens on patients and our health care system.


Obesity is an independent risk factor for cardiovascular events in the general population, patients with established cardiovascular disease (CVD), and elderly persons. During the last decade, more than 100 prospective cohort studies and three meta-analyses (with more than 90 prospective studies and 1.1 million participants) have confirmed obesity’s central role in the development of CVD.




Etiology and Pathophysiology


Many potential mechanisms have been proposed to explain the association of obesity with cardiovascular events, including increased severity of CVD, systemic inflammation, insulin resistance, neurohormonal activation, and abnormalities in adipokine pathways ( Fig. 19-1 ). Excess weight exacerbates a number of cardiovascular and metabolic risk factors ( Box 19-1 ). Inflammatory adipokines may increase insulin resistance and diabetes, and abnormal lipid metabolism, which is common in those with obesity, can lead to atherosclerotic plaque.




FIGURE 19-1


Adipokines serve as the cellular mediators of metabolic syndrome and endothelial dysfunction.

(From Lau DC, Dhillon B, Yan H, et al: Adipokines: molecular links between obesity and atherosclerosis. Am J Physiol Heart Circ Physiol 288:H2031, 2005.)


BOX 19-1

Risk Factors for Atherosclerosis and Vascular Disease Associated with Obesity





  • Hypertension



  • Dyslipidemia



  • Diabetes mellitus (type 2)



  • Obstructive sleep apnea



  • Hyperinsulinemia, insulin resistance



  • Low levels of plasminogen activator inhibitor



  • High levels of C-reactive protein



  • Hyperviscosity



  • Framingham risk score




Excess adipose tissue, especially intra-abdominal, predisposes patients to type 2 diabetes, hypertension, dyslipidemia, or the metabolic syndrome largely through increased lipolysis that raises the production of free fatty acids and adipokines. The excess fatty acids interfere with insulin receptor signaling and lead to decreased glucose transport, often referred to as lipotoxicity. They also activate protein kinase C (through increased fatty acyl coenzyme A and diacylglycerols).


Protein kinase C serine phosphorylates insulin receptors, interfering with insulin signal transduction. Excess free fatty acids also impair phosphoinositide 3-kinase activation in response to insulin, leading to decreased activity of glucose transporter 4 (GLUT4), an important insulin-sensitive glucose transporter in muscle and fat. Growing evidence suggests that insulin resistance in liver, muscle, and adipose tissue is associated with and may be the result of increased proinflammatory cytokines.


In an obese state, some adipokines—proteins, such as tumor necrosis factor-α, or cytokines, such as interleukin-6—are elevated. Adipokines inhibit insulin action and contribute to proinflammatory effects, insulin resistance, and endothelial dysfunction. Adiponectin and resistin have recently been associated with incident heart failure.


This series of metabolic abnormalities culminates in a clustering of risk factors for CVD and type 2 diabetes mellitus, a condition known as the metabolic syndrome or prediabetes. The risk factors include raised blood pressure, dyslipidemia (increased triglycerides and lowered high-density lipoprotein cholesterol [HDL-C]), high fasting glucose concentration, and central obesity ( Table 19-1 ). Whereas obesity is an independent risk factor for CVD, the complex interaction between excess body weight, lipid oxidation, and hyperglycemia underlies a strong connection between insulin resistance and risk for CVD. Efforts to prevent CVD must focus strongly on prevention of excess weight gain, insulin resistance, and dyslipidemia.



TABLE 19–1

Criteria for Clinical Diagnosis of the Metabolic Syndrome






















3 of 5 Risk Factors Defining Level
Abdominal obesity Waist circumference *
Population- and country-specific definitions
Triglycerides (drug treatment for elevated triglycerides is an alternate indicator ) ≥150 mg/dL
HDL-C (drug treatment for reduced HDL-C is an alternate indicator ) Men <40 mg/dL
Women <50 mg/dL
Blood pressure (antihypertensive drug treatment in a patient with a history of hypertension is an alternate indicator) ≥130/ ≥85 mm Hg
Fasting glucose (drug treatment of elevated glucose is an alternate indicator) ≥100 mg/dL

* It is recommended that the International Diabetes Federation cut points be used for non-Europeans and either the International Diabetes Federation or American Heart Association/National Heart, Lung, and Blood Institute cut points be used for people of European origin until more data are available.


The most commonly used drugs for elevated triglycerides and reduced high-density lipoprotein cholesterol (HDL-C) are fibrates and nicotinic acid. A patient taking one of these drugs can be presumed to have high triglycerides and low HDL-C. High-dose omega-3 fatty acids presumes high triglycerides.


Most patients with type 2 diabetes mellitus will have the metabolic syndrome by the proposed criteria.





Obesity Assessment and Risk of Cardiovascular Disease


To stratify people in different demographic and ethnic groups according to their 10-year risk for coronary heart disease (CHD) events, clinicians use the Framingham risk score. Guidelines recommend use of the Framingham risk score, or a modified version of it, to identify high-risk individuals (10-year risk >20%) who can benefit from aggressive risk reduction measures. Although the Framingham risk score is widely used and highly valuable, it does not include measures of obesity or inflammation. This limits its clinical relevance in assessing intermediate risk for CHD.


Body mass index (BMI) is an important screening tool to assess patients with excess body weight and to stratify treatments according to the likelihood of underlying disease risk ( Fig. 19-2 ). BMI is calculated as weight in kilograms divided by height in meters squared (kg/m 2 ) and categorizes obesity into three classes: class I, BMI of 30 to 34.9; class II, BMI of 35 to 39.9; and class III, BMI ≥40, or extreme obesity ( Box 19-2 ). Across genders and ethnicities, increased BMI is associated with larger comorbidity burden ( Fig. 19-3 ). BMI may provide a better determination of global disease risk than weight alone, but it is of limited diagnostic value in very muscular individuals and those with little muscle mass, such as elderly patients.




FIGURE 19-2


Diagnosis of overweight and obese: using body mass index (BMI).

(From The Practical Guide: identification, evaluation, and treatment of overweight and obesity in adults , Bethesda, Md, 2000, National Heart, Lung, and Blood Institute, Department of Health and Human Services. NIH publication 00-4084.)


BOX 19-2

Standard Criteria for Body Mass Index

























BMI, kg/m 2
Underweight 18.5
Healthy weight 18.5-24.9
Overweight 25.0-29.9
Obese 30-39.9
Morbid obesity ≥40




FIGURE 19-3


Prevalence of one and two or more overweight- and obesity-related morbidities by weight status category for sex, race, and ethnic subgroups.

(From Must A, Spadano J, Coakley EH, et al: The disease burden associated with overweight and obesity. JAMA 282:1523, 1999.)


Waist circumference as a measure of abdominal or central obesity has attracted particular attention because of its inclusion as a prerequisite for the diagnosis of metabolic syndrome. It provides important additional prognostic information, especially when an unhealthy level of excessive adiposity is suspected. A higher risk for diabetes, dyslipidemia, hypertension, and CVD has been associated with a waist circumference ≥102 cm (≥40 inches) in men and ≥88 cm (35 inches) in women (although the International Diabetes Federation has specified lower cut points of ≥94 cm in men and ≥80 cm in women for European whites and ≥90 cm in men and ≥80 cm in women for certain Asian populations and for those of central or South American ancestry; Table 19-2 ). A study showed that either BMI or waist circumference independently predicted or was associated with type 2 diabetes.



TABLE 19–2

Current Recommended Waist Circumference Thresholds for Abdominal Obesity by Organization













































































Recommended Waist Circumference Threshold for Abdominal Obesity
Organization Men Women
Europid IDF ≥94 cm ≥80 cm
Caucasian WHO ≥94 cm (increased) ≥80 cm (increased risk)
≥102 cm (still higher risk) ≥88 cm (still higher risk)
United States AHA/NHLBI (ATP III) * ≥102 cm ≥88 cm
Canada Health Canada ≥102 cm ≥88 cm
European European Cardiovascular Societies ≥102 cm ≥88 cm
Asian (including Japanese) IDF ≥90 cm ≥80 cm
Asian WHO ≥90 cm ≥80 cm
Japanese Japanese Obesity Society ≥85 cm ≥90 cm
China Cooperative Task Force ≥85 cm ≥80 cm
Middle East, Mediterranean IDF ≥94 cm ≥80 cm
Sub-Saharan African IDF ≥94 cm ≥80 cm
Ethnic Central and South American IDF ≥90 cm ≥80 cm

IDF, International Diabetes Federation; AHA/NHLBI, American Heart Association/National Heart, Lung, and Blood Institute; WHO, World Health Organization.

From Alberti KG, Eckel RH, Grundy SM, et al: Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 120:1640, 2009.

* Recent AHA/NHLBI guidelines for metabolic syndrome recognize an increased risk for CVD and diabetes at waist circumference thresholds of ≥94 cm in men and ≥80 cm in women and identify these as optional cut points for individuals or populations with increased insulin resistance.



Unlike in definitions of obesity in adults, the growth curve needs to be taken into account in children. The 2000 growth chart developed by the Centers for Disease Control and Prevention (CDC) is based on national height and weight data for children 2 to 19 years of age. The CDC and the National Heart, Lung, and Blood Institute (NHLBI) have defined obesity in children as a BMI ≥95% on the 2000 growth chart and overweight as ≥85%. These cutoff points are arbitrary and, unlike adult definitions of overweight and obesity, are not based on health risk data.


In the United States, 23 million adults with no history of CVD are classified as intermediate risk by the Framingham score (a 10-year risk for major CHD events of 10% to 20%). New or emerging risk factors, particularly inflammatory markers and markers of atherosclerotic burden, offer promise as screening tools for these individuals. However, current data from the U.S. Preventive Services Task Force conclude that there is sufficient evidence to recommend the use of high-sensitivity C-reactive protein (hsCRP) among initially intermediate-risk persons. At the discretion of the physician, hsCRP measurements may help direct further evaluation and therapy in primary prevention of CVD.


Childhood Obesity


Childhood obesity has wide-ranging comorbidities with clinical, psychosocial, and economic ramifications. Children who are obese in their preschool years are more likely to be obese in adolescence and adulthood. They are also more likely to develop diabetes, hypertension, hyperlipidemia, asthma, and sleep apnea. Other risk factors for development of CVD and type 2 diabetes in children include a sedentary lifestyle, family history of type 2 diabetes, high low-density lipoprotein cholesterol (LDL-C) levels, hyperinsulinemia, insulin resistance, and high total cholesterol concentration.


With the worldwide epidemic of childhood obesity, disorders once mainly found in adults, such as metabolic syndrome, are occurring in children. The term pediatric metabolic syndrome includes a cluster of cardiovascular risk factors, such as insulin resistance, dyslipidemia (including increased triglycerides and decreased HDL-C), hypertension, and obesity. Children with metabolic syndrome have significantly higher BMI and glucose and triglyceride levels and lower HDL-C than do those without the syndrome. Prevalence of the metabolic syndrome in obese children is reported at 30%.


A study of 214 overweight and obese Costa Rican children up to 10 years of age found that obese children had lower mean serum levels of HDL-C and significantly higher mean serum concentrations of insulin, hsCRP, and triglycerides than their overweight peers did. They also had higher insulin resistance.


Maffeis and colleagues tested 1044 Italian children aged 6 to 11 years for blood pressure, serum triacylglycerides, total cholesterol, HDL-C, glucose, insulin, and alanine aminotransferase. The prevalence of high blood pressure in overweight boys and girls was 14.3% and 6.4%, respectively; in obese boys and girls, it was 40.4% and 32.8%, respectively. High blood pressure increased progressively with BMI z -score categories and waist-to-height ratio. Hypertensive children had significantly higher insulin and insulin resistance.


Adult Obesity


Because of its maladaptive effects on various cardiovascular risk factors and its adverse effects on cardiovascular structure and function, obesity has a major impact on cardiovascular diseases, such as heart failure, CHD, sudden cardiac death, and atrial fibrillation. A large body of literature shows that obesity can cause and exacerbate many chronic diseases, such as diabetes, hypertension, dyslipidemia, stroke, and obstructive sleep apnea. It more than doubles the risk of heart failure.


Epidemiologic data suggest a linear relationship between BMI and CHD. Jee and coworkers conducted an analysis of BMI and CHD incidence among 133,740 participants during 9 years of follow-up. The authors found that after adjustment for age, gender, and smoking status, each unit increase in BMI was associated with a 14% higher risk of incident CHD. Even a normal BMI of 24 to 24.9 was associated with a twofold increased risk of CHD.


A 20-year follow-up analysis of the Nurses’ Health Study cohort showed a graded relationship between increasing BMI and incidence of CHD. Compared with normal-weight women, the relative risk of CHD in overweight women was 1.43. For obese women, it was 2.44. In the Women’s Health Initiative, overweight and obesity were significantly associated with CHD incidence in both white and black women.


The Framingham Heart Study, which observed more than 5000 individuals for up to 44 years, also reported substantial cardiovascular risk linked to overweight and obesity. One analysis found that overweight and obesity were independently associated with an increased risk for CVD as well as established risk factors, including hypertension, hypercholesterolemia, and type 2 diabetes. A prospective study of more than 17,000 healthy female U.S. nurses with an average age of 50 years found that women who were obese at midlife were 79% less likely to be healthy at the age of 70 years compared with those who were lean in their 40s and 50s. The odds of being healthy among those who were obese at the age of 18 years and then gained more than 22 pounds by middle age were reduced by 82%.




Risk Factors


Visceral Adiposity


Data show that central obesity poses a more significant CVD risk than total obesity and that waist circumference and waist-to-hip ratio, common surrogates for abdominal or central obesity, may be better predictors of atherosclerosis and CVD risk than BMI. Adipose tissue, especially intra-abdominal visceral fat, has an independent endocrine function that leads to the release of inflammatory adipokines, including tumor necrosis factor-α, interleukin-6, and plasminogen activator inhibitor type 1.


Inflammatory adipokines may increase insulin resistance and diabetes in obesity and heighten risk for thrombosis. They may also affect the progression of endothelial dysfunction, further increasing inflammation and the risk for atherosclerosis. Free fatty acids, produced more readily in the visceral abdominal fat, may decrease insulin sensitivity, impair vascular reactivity, and also increase endothelial dysfunction.


Low Birth Weight


The relationship between low birth weight and increased risk of obesity, hypertension, type 2 diabetes, stroke, and CVD later in life is well documented in epidemiologic studies. These associations remain strong even after adjustment for such lifestyle factors as smoking, physical activity, occupation, dietary habits, and childhood socioeconomic status.


A large number of studies have linked low birth weight to the later development of central adiposity. A landmark cohort study of 300,000 men by Ravelli and coworkers showed that exposure to the Dutch famine of 1944-1945 during the first half of pregnancy resulted in low birth weight associated with significantly higher obesity rates at the age of 19 years. Subsequent research has confirmed the relationship between low birth weight and later development of visceral or central adiposity as well as metabolic syndrome and higher blood pressure later in life. Blood pressure is influenced by size at birth as well as by weight gain in childhood. Abnormalities are accompanied by functional changes in the vascular tree, and evidence of early alterations in vascular function has been described in children and adolescents with low birth weight.


Hypertension


In 2003-2006, 36% of men and women between the ages of 45 and 54 years had hypertension compared with 65% of men and 80% of women 75 years of age and older. Large differences in blood pressure by ethnic group exist among adults. The National Health Interview Survey found that in 2007, 23% of U.S. adults had been told by a physician or health professional on two or more visits that they had hypertension. The condition in adults is associated with increased risk of myocardial infarction, stroke, and cardiovascular mortality. Hypertension often increases with rising body weight. It also affects 1% to 5% of children and adolescents. The condition increases progressively with higher BMI and can be detected in approximately 30% of overweight children (BMI >95th percentile).


In a cross-sectional study of 710 subjects aged 20 to 25 years, Dimkpa and Oij found a significant correlation between BMI and systolic and diastolic blood pressure and resting heart rate after controlling for age and physical activity status. Overweight and obese subjects had a significantly higher risk of hypertension than non-overweight or obese controls did, and the prevalence of hypertension and tachycardia rose with increases in BMI.


Like adults, children and adolescents with severe elevation of blood pressure are at risk of adverse outcomes including cerebrovascular accidents and congestive heart failure. Two autopsy studies in adolescents and young adults found significant relationships between the level of blood pressure and the presence of atherosclerotic lesions in the aorta and coronary arteries. Childhood levels of blood pressure are also associated with carotid intima-media thickness, large artery compliance, decreased brachial artery flow-mediated vasodilation, and left ventricular hypertrophy at a level associated with a fourfold greater risk of adverse cardiovascular outcomes in adults. Overweight and high blood pressure are also components of metabolic syndrome, a condition of multiple metabolic risk factors for CVD as well as type 2 diabetes. These outcomes underscore the need to prevent obesity early in life to protect against future life-threatening consequences.


Sleep Apnea


Obstructive sleep apnea is independently associated with increased cardiovascular risk. It has also been linked to insulin resistance and glucose intolerance and is independently associated with impaired glycemic control and type 2 diabetes in patients who report excessive sleepiness. Obstructive sleep apnea is strongly correlated with intra-abdominal fat, and serum lipid levels are elevated in patients who have obstructive sleep apnea. Prospective findings from up to 15 years of follow-up data from the Wisconsin Sleep Cohort Study indicate that untreated sleep apnea predicts increases in blood pressure, hypertension, stroke, depression, and mortality.


Obesity causes and exacerbates obstructive sleep apnea, and increases in weight have been associated with a rising prevalence of obstructive sleep apnea. Data show a fourfold rise in obstructive sleep apnea with each increase in the standard deviation of BMI. In patients with class II and class III obesity, obstructive sleep apnea is common. Lopez and colleagues found the prevalence of obstructive sleep apnea to be greater than 70% in those with class II and class III obesity and more than 90% in patients with a BMI ≥60.


A population-based prospective cohort study from 1989-2000 found that a 10% weight gain predicted an approximate 32% increase in the apnea-hypopnea index and a sixfold rise in the risk for development of moderate to severe obstructive sleep apnea. The Sleep Heart Health Study showed a similar relationship between BMI and obstructive sleep apnea severity; the odds ratio for moderate to severe obstructive sleep apnea was 1.6 for each standard deviation increment in BMI.


Dyslipidemia


Atherogenic dyslipidemia is associated with an increased risk of CVD, peripheral vascular disease, and stroke. The condition is characterized by elevated triglycerides and low plasma levels of HDL-C, often with elevated apolipoprotein B and non–HDL-C. It is prevalent in patients with type 2 diabetes, metabolic syndrome, or established CVD.


Obesity heightens the risk of type 2 diabetes, hypertension, CVD, and dyslipidemia and reduces average life expectancy. Metabolic syndrome is closely associated with obesity and a clustering of CVD risk factors, including a dyslipidemia characterized by high levels of triglycerides and LDL-C and low levels of HDL-C, a combination that significantly increases the relative risk of cardiovascular or cerebrovascular events. Triglycerides, HDL-C, and LDL-C, the components of atherogenic dyslipidemia, are interrelated, and each predicts CHD risk.


Individuals with obesity and metabolic syndrome present with increased concentrations of very-low-density lipoprotein (VLDL) particles, increased triglycerides and small-particle LDL, increased LDL particle number, and decreased HDL particle size. These lipoproteins can undergo a process of oxidation that results in the formation of foam cells and enhanced monocyte binding, which leads to the early stages of atherosclerotic plaque. Small-particle LDL has greater atherogenic potential and is more common in individuals with diabetes. As risk indicators, total cholesterol/HDL and LDL/HDL ratios have greater predictive value than isolated parameters used independently, particularly LDL.


Elevated triglyceride concentrations are associated with greater circulating numbers of triglyceride-rich VLDL particles and higher levels of VLDL cholesterol, an environment that alters the metabolism of LDL-C and HDL-C and contributes to atherogenic potential. Atherogenic dyslipidemia, characterized by elevated triglycerides and low levels of HDL-C, often with elevated apolipoprotein B and non–HDL-C, is common in patients with established CVD, type 2 diabetes, or metabolic syndrome and contributes to both macrovascular and microvascular residual risk.


Extensive evidence from large prospective clinical trials involving patients at different levels of risk shows that lipid and lipid protein abnormalities are responsible for residual CVD risk in patients receiving statin therapy. A recent meta-analysis including 90,056 subjects (18,686 with diabetes) from 14 randomized trials reported that for each millimole per liter decrease in LDL-C, statin therapy reduced the risk of major vascular events by 21%. Nonetheless, 14% of patients in the statin group suffered a cardiovascular event compared with 18% randomized to placebo.


The importance of dyslipidemia as a major contributor to CVD risk is underscored by the INTERHEART study, a global case-control trial in 52 countries, in which dyslipidemia was responsible for 54% of population attributable risk for myocardial infarction. Extensive evidence supports elevated triglycerides and low HDL-C levels as predictors for CVD, independent of LDL-C. Observational trials, such as the Prospective Cardiovascular Münster (PROCAM) study, have reported a clear prognostic inverse relation between HDL-C levels and coronary artery disease morbidity and mortality, regardless of LDL-C levels. These outcomes reflect the need to identify ways to optimize management of patients with metabolic disorders, such as diabetes, obesity, and dyslipidemia.


Diabetes


CVD affects millions of adults with diabetes and is a major cause of morbidity and mortality. Evidence indicates that the CVD burden among diabetics is increasing. Between 1997 and 2007, those aged 35 years or older with diabetes and a diagnosed CVD condition (i.e., CHD, stroke, or other heart condition) increased from approximately 4 million to almost 6 million. Between 1994 and 2007, there were also unfavorable upward trends in the age-adjusted percentage of obesity in adults with diabetes, an increase from 34.9% to 53.0%. During that same period, the percentage of overweight or obese adults with diabetes increased from 70% to 83%.


Obesity clearly increases the risk for development of type 2 diabetes; inflammatory adipokines may also play a role. Large population studies have confirmed the links between excess weight and the development of insulin resistance and type 2 diabetes. In the Nurses’ Health Study, which observed close to 85,000 female nurses, a BMI ≥25 was the single most important factor for the development of type 2 diabetes during a 16-year period.


A 20-year follow-up study of ethnicity, obesity, and risk of type 2 diabetes in a Nurses’ Health Study cohort of 78,419 apparently healthy women found that for each 5-unit increment in BMI, the multivariate relative risk of diabetes was 2.36 for Asians, 2.21 for Hispanics, 1.96 for whites, and 1.55 for blacks. For each 5-kg weight gain between the age of 18 years and the year 1980, the risk of diabetes increased by 84% for Asians, 44% for Hispanics, 38% for blacks, and 37% for whites.


A study of 91,246 patients in 27 European countries investigated the impact of adiposity on the frequency of diabetes and CVD. Data showed that waist circumference predicted increased age- and BMI-adjusted risks of CVD and diabetes. In women, odds ratios for CVD per 1 SD increase in waist circumference were 1.28 in northwest Europe, 1.26 in southern Europe, and 1.10 in eastern Europe. Values for diabetes were 1.72, 1.45, and 1.59. Despite regional differences in cardiovascular risk factors and CVD rates, abdominal obesity had a similar impact on the frequency of diabetes across Europe. The authors concluded that increasing abdominal obesity may offset future declines in CVD, even where CVD rates are lower.


Diabetes is a serious weight-related condition in adolescents. The incidence of type 2 diabetes in this age group has increased in tandem with obesity, rising by a factor of more than 10 in the past two decades. This trend in children and adolescents is accelerating in both developed and developing countries. As the prevalence of obesity increases, its health implications are becoming more evident. The earliest alterations are abnormalities in glucose metabolism that can lead to type 2 diabetes.


In adults, the likelihood of the progression of patients with impaired glucose tolerance or impaired fasting glucose to diabetes is 25% during 3 to 5 years. The only longitudinal study published thus far on the natural history of normal and impaired glucose tolerance in children and adolescents showed that children with impaired glucose tolerance who had greater degrees of obesity at baseline and those who continued to gain weight rapidly developed type 2 diabetes. Smaller studies of at-risk populations also suggest a high likelihood of progression to type 2 diabetes. Preliminary data from Canada indicate that adolescents with type 2 diabetes will be at high risk for limb amputation, kidney failure requiring dialysis, and premature death.


The SEARCH for Diabetes in Youth study found significant ethnic variations in the prevalence of type 2 diabetes in children aged 10 to 19 years. The disease accounted for only 6% of all diabetic cases diagnosed in non-Hispanic whites compared with 22% of all diabetic cases diagnosed in Hispanics. In American Indians, type 2 diabetes has overtaken type 1 in prevalence among children, accounting for 72% of all cases of diabetes. Data for this study were obtained largely through chart review and may underestimate the prevalence of type 2 diabetes. As the ethnic diversity of the U.S. population continues to increase, the epidemic of childhood obesity may make pediatric type 2 diabetes a growing public health concern.




Effect of Weight Loss on Obesity Comorbidities


Losing weight has proven benefits on established risk factors for CVD, including diabetes, hypertension, and dyslipidemia ( Fig. 19-4 ). The Look AHEAD (Action for Health in Diabetes) study, a National Institutes of Health–funded clinical trial conducted in 5145 overweight or obese adults with type 2 diabetes, investigated the effectiveness of intentional weight loss in reducing CVD events. At 1 year, participants in the intensive lifestyle intervention group achieved an average weight loss of 8.6% of initial body weight and a 21% improvement in cardiovascular fitness. The intensive lifestyle intervention was associated with an increase from 46% to 73% of participants who met the American Diabetes Association (ADA) goal of A1c <7% and a doubling in the percentage of individuals who met all three of the ADA goals for glycemic control, hypertension, and dyslipidemia.




FIGURE 19-4


Effect of moderate weight loss on cardiometabolic risk factors.

(From Case CC, Jones PH, Nelson K, et al: Impact of weight loss on the metabolic syndrome. Diabetes Obes Metab 4:407, 2002.)


Weight loss also improves obstructive sleep apnea, strengthening the causal relationship with obesity. In a large, population-based prospective cohort study of 690 people, a 10% weight loss was correlated with a 26% decrease in the apnea-hypopnea index, showing that even minimal weight loss can be beneficial in patients with obstructive sleep apnea. A randomized study of the effect of a low-calorie diet and supervised lifestyle counseling on sleep-disordered breathing produced a 40% decrease in apnea-hypopnea index from baseline. At 3-month follow-up, 61% of the patients in the intervention group were considered cured of sleep apnea compared with 32% in the control group. Changes in apnea-hypopnea index were strongly correlated with changes in weight and waist circumference and were maintained at 1-year follow-up. Data indicate that not only is obesity a risk factor for development of obstructive sleep apnea, it may also be a consequence of obstructive sleep apnea, a finding that emphasizes the importance of treating both disorders.


Previous meta-analyses of clinical trials on the effects of weight reduction on blood pressure show that weight loss is important in the prevention and treatment of hypertension. In the Diabetes Prevention Program, a 2.8-year follow-up found that weight loss was about 5.6 kg in the lifestyle management arm, 2.1 kg in the metformin arm, and 0.1 in the placebo group. There was a small significant decrease of 3.3 mm Hg in systolic blood pressure and a decline of 3.1 mm Hg in diastolic blood pressure in the lifestyle management group, suggesting that at least in the short term, weight loss was associated with some degree of decrease in blood pressure.


PREMIER, an NHLBI-sponsored multicenter randomized trial of 810 adults with prehypertension or stage 1 hypertension, compared the effect of advice only with established lifestyle interventions (e.g., weight loss, dietary changes, and increased physical activity) for blood pressure control. The two intervention groups, established lifestyle interventions and established lifestyle interventions plus the DASH diet, reduced estimated 10-year CHD risk by 14% and 12%, respectively. Other investigations have reported a linear association between changes in systolic blood pressure and weight, even with a small amount of weight loss. They have also documented that weight loss is the most important determinant of decreases in systolic blood pressure.


Weight loss in overweight adolescents is also associated with a decrease in blood pressure as well as with reduced sensitivity of blood pressure to salt and other cardiovascular risk factors, such as dyslipidemia and insulin resistance. In studies that reduce BMI by about 10%, short-term reductions in blood pressure were in the range of 8 to 12 mm Hg. An analysis of 33 weight loss interventions found that for each 1 kg of weight loss, the mean change in CRP level was −0.13 mg/L, suggesting that weight loss is an effective nonpharmacologic strategy for lowering of serum CRP levels ( Fig. 19-5 ). Although difficult, weight loss, if it is successful, is extremely effective.




FIGURE 19-5


Box plots of percentage change in C-reactive protein (CRP) level from baseline over categories of percentage change in weight from baseline across all included weight loss interventions.

(From Selvin E, Paynter NP, Erlinger TP: The effect of weight loss on C-reactive protein: a systematic review. Arch Intern Med 167:31, 2007.)


Despite these findings, application of data from observational trials must be carefully considered. Numerous studies have documented an obesity paradox in which overweight and obese individuals with established CVD (including hypertension, heart failure, CHD, and peripheral arterial disease) have a better prognosis compared with patients who are not overweight or obese. Conversely, patients with a healthy weight BMI (18.5 to 24.9 kg/m 2 ) and high body fat are at high risk for cardiometabolic dysregulation, metabolic syndrome, and CVD.


These findings, however, are controversial. Data assessing mortality based on body fat and lean mass rather than on BMI or weight alone have shown that subjects who lose body fat rather than lean mass have a lower mortality. Estimates for all-cause mortality, obesity-related causes of death, and other causes of death showed no statistically significant or systematic differences between BMI and other variables. Although an obesity paradox exists with use of either baseline BMI or baseline percentage fat criteria, studies support the safety and potential long-term benefits of purposeful weight loss in overweight and obese patients with CHD.

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Jul 10, 2019 | Posted by in CARDIOLOGY | Comments Off on Overweight, Obesity, and Cardiovascular Risk
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