Therapeutic Options for Modifying Obesity and Cardiometabolic Risk Factors

Louis J. Aronne

Kathy Keenan Isoldi

Dennis T. Roarke

Excess fat mass is associated with an increased risk of developing a plethora of chronic and life-threatening diseases. Most concerning is the ability of excess fat to promote the development of illnesses with high rates of morbidity and mortality, such as type 2 diabetes mellitus (T2DM), hypertension, hyperlipidemia, and cardiovascular disease (CVD). The personal toll incurred from obesity, in terms of both physical and psychosocial detriment, is abundant. In addition, the societal burden borne from obesity, in terms of loss of productivity and health care cost, is staggering.

Adopting a healthy lifestyle that supports a lean body mass appears to be an obvious insulator against developing obesity and concurrent disease. However, obesity has become a pandemic of the 21st century, with prevalence rates rising in both developed and developing countries. Genetics plays an integral role in the development of obesity; however, genetic predisposition cannot explain the recent exponential rise in obesity prevalence. Many environmental changes that have increased food availability and decreased the need for physical labor undoubtedly initiate obesity in those genetically predisposed. Once the process begins, a “feed-forward” mechanism appears to take hold, driving weight ever higher and resisting weight loss.

A calorie-deficit diet and increase in physical activity are recommended as the first course of action to take in treating overweight and obese patients or for preventing further weight gain. However, low rates of weight loss success and high rates of weight regain in the majority of patients seeking treatment require that physicians consider more aggressive treatment options. In addition to lifestyle modifications, several pharmacologic and surgical treatment options are available to manage obesity. The goal of utilizing these treatments is to simultaneously treat the multiple complications of obesity.

Identifying Patients at Risk for Obesity and Obesity Related Illnesses

The body mass index (BMI) calculated in kg/m² has been increasingly accepted as a valid, indirect measure of adiposity. Overweight in adults is defined as a BMI between 25 and 29.9 kg/m². Obesity is categorized as class 1 with BMI readings of 30 to 34.9 kg/m², class 2 with BMI readings of 35 to 39.9 kg/m², and class 3 with BMI readings of ≥40 kg/m² (1). It is more difficult to assess overweight and obesity in children due to linear growth, muscle acquisition, and timing of puberty. In 2000, the Centers for Disease Control and Prevention (CDC) formulated age-specific and gender-specific BMI charts, based on extensive data collected from national surveys, to guide health care providers in determining weight status for children aged 2 to 20 years. Children who have a BMI between the 5th and 84th percentile for gender and age are considered to be normal weight. Children who have a BMI between the 85th and 94th percentile are overweight, and those with a BMI at or above the 95th percentile are considered obese.

The Importance of Waist Circumference Measurement

Visceral fat mass, also referred to as central or intra-abdominal adipose tissue, is strongly correlated with increased risk of developing T2DM and CVD in both men and women. Waist circumference measurement has emerged as a strong surrogate for visceral adiposity. A simple waist circumference measurement correlates well with abdominal adiposity and is therefore a very useful tool in disease risk assessment. Obtaining waist measurement along with a BMI reading will improve accuracy in evaluating CVD risk. Waist measurements can also be very useful in monitoring a patient’s response to weight loss intervention, as aerobic exercise can reduce waist circumference and cardiometabolic risk without change in BMI.

Optimum waist circumference cutoffs may vary according to ethnicity. Optimal waist measurement cutoffs for evaluation of health risk according to the American Heart Association and the National Heart, Lung and Blood Institute (AHA/NHLBI) are ≥88 cm and ≥102 cm for women and men, respectively (2). However, the International Diabetes Federation (IDF) recommends lower cutoffs for several racial/ethnic groups as disease risk is associated with lower waist measurement in these populations (3). Optimal waist circumference measurements for various racial/ethnic groups are summarized in Table 24.1. Additional research aimed at establishing optimal waist circumference measurements for all ethnic groups to offer better cardiometabolic risk factor assessment is needed.

TABLE 24.1 WAIST CIRCUMFERENCE CUTOFFS FOR VARIOUS ETHNIC/RACIAL GROUPS

Country/ethnic group	Gender	Waist circumference cutoffs
Europids	Male	≥94 cm
	Female	≥80 cm
South Asians (based on a Chinese, Malay, and Asian Indian population)	Male	≥90 cm
	Female	≥80 cm
Chinese	Male	≥90 cm
	Female	≥80 cm
Japanese	Male	≥85 cm
	Female	≥90 cm
Ethnic South and Central Americans		Use South Asian recommendations until more specific data are available
Sub-Saharan Africans		Use European data until more specific data are available
Eastern Mediterranean and Middle East (Arab) populations		Use European data until more specific data are available
It is recommended that ethnicity-specific cutoffs should be used for people regardless of place and country of residence. From the International Diabetes Federation. Consensus worldwide definition of the metabolic syndrome. International Diabetes Federation, 2006, with permission.

Trends in Overweight and Obesity Prevalence

The rise in the prevalence of obesity in all continents has made this recent malady a global health crisis. The World Heath Organization (WHO) estimates that there are more than 300 million individuals worldwide who are obese and 1 billion who are overweight. Although there has been a universal rise in obesity, prevalence rates have been found to vary greatly around the world. Obesity prevalence ranges from <5% in rural China, Japan, and some African countries to as high as 75% in the adult population in urban Samoa (4).

With increased affluence and fewer communicable diseases, inhabitants of developed countries during the 20th century started to gain proportionally more weight than height, and by the 1930s, insurance companies were already using body weights to estimate mortality risk and determine client premiums (5).

More recently, the United States has experienced a steep rise in obesity prevalence over just the past three decades. In a relatively short span of time, obesity prevalence has increased two- to threefold in adults and children aged 2 to 19 years. According to the United States National Health and Nutrition Examination Survey (NHANES) data from 2004, an estimated two-thirds of all adult Americans and one-third of all American children were overweight. In addition, 32% of adults and 17% of children met the criteria for obesity (2,6). Based on current trends, it has been estimated that by 2015, 75% of all adults will be overweight and 41% obese (7). Most concerning is the fact that the greatest increase in prevalence rates has been in those who are the most severely obese. Researchers analyzed data from the Behavioral Risk Factor Surveillance System (BRFSS) during 2000 to 2005 and reported that obesity prevalence in those with a BMI >30, >40, and >50 kg/m² increased 24%, 40%, and 75%, respectively (8).

There are notable differences in obesity prevalence rates in several minority populations in the United States. Compared to the 64.2% prevalence rate of overweight in whites, non-Hispanic blacks and Mexican Americans had more than a 10% higher rate of prevalence. Prevalence rates for overweight were 76.1% and 75.8% for non-Hispanic blacks and Mexican Americans, respectively. More than 80% of non-Hispanic black women were found to be overweight, with more than 50% reaching obesity status (7). NHANES did not collect enough data to determine overweight and obesity prevalence in other ethnic groups. However, data from the 2001 BRFSS reported that obesity among Asian Americans was much lower than among other racial/ethnic groups, estimated at about 5%. Additionally, both Native American and Pacific Islanders were found to have higher obesity prevalence rates of 34.3% and 33.0%, respectively, compared to the 2001 prevalence in whites of 21.8% (7).

THEORETICAL CONSIDERATIONS

Biochemistry-Adipose Tissue as an Endocrine Organ

Leptin

Fat mass functions as an active endocrine organ, secreting adipokines that influence body weight regulation, inflammation, thrombosis, and vascular integrity. Leptin is a weight-regulating adipokine secreted by adipocytes in amounts proportional to total body fat mass. Leptin crosses the bloodbrain barrier to bind to its receptor in the hypothalamus to activate signals that inhibit food intake and increase energy expenditure. The discovery of leptin and its subsequent cloning have greatly improved our understanding of endogenous
mechanisms regulating body weight. Laboratory mice with defects in leptin production exhibit hyperphagia that results in obesity. Most obese individuals have elevated peripheral levels of leptin, and it has been postulated that feedback from adipose tissue to the brain is reduced by leptin resistance, leading to reduced satiety and metabolic consequences that produce even greater weight gain. When fat mass is reduced, as occurs during calorie restriction, there is a decrease in circulating leptin levels, which in turn stimulates and suppresses production of several neuropeptides, which results in the defense of body fat as a survival strategy. Thus, fat mass reduction is associated with a state of relative leptin insufficiency that makes weight loss and maintenance of a reduced body mass extremely difficult (9). Other unrelated mechanisms are clearly involved in body weight regulation, but leptinergic pathways serve as the best-studied example of the phenomenon.

Adipokines

Several adipokines have been found to elicit a proinflammatory response. A connection between the immune system and adipose tissue has been identified. The ability to fight infection and the need to store energy for use during times of food deficit are physiologic functions that enhance survival, and it is believed that these two systems evolved together. Therefore, overexpansion of fat mass overstimulates the innate immune system and fosters a state of chronic, low-level inflammation that ultimately initiates disease. The adipokines that mediate inflammation include, but are not limited to, interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), plasminogen activation inhibitor-1 (PAI-1), and angiotensinogen (2). Levels of IL-6 have been reported to be 10-fold higher in obese versus lean individuals (10).

Free Fatty Acids

Obesity also increases circulating serum levels of free fatty acids (FFA), which promotes insulin resistance and disease propagation. Serum levels of FFA are a product of the balance between the release from intravascular lipolysis of triglyceride (TG)-rich lipoproteins and lipolysis of adipose tissue TG stores. In the presence of a positive net energy balance, FFA are elevated and are used preferentially as a substrate for energy in lieu of glucose. High circulating FFA create a negative feedback signal on insulin secretion and action, increase hepatic glucose production, and stimulate the production of very low density lipoproteins (VLDL) in the hepatocyte. The insulin resistance induced by elevated FFA also reduces the action of lipoprotein lipase, an enzyme that normally degrades the TG in VLDL, resulting in elevated TG (see also Chapter 7). Elevated circulating VLDL particles, in turn, result in the production of small dense, atherogenic low-density lipoprotein (LDL) particles and reduce high-density lipoprotein (HDL) particles (2) (see also Chapter 8).

Adiponectin

Adiponectin is a unique adipokine that confers disease protection through its anti-inflammatory action, ability to increase insulin sensitivity, and positive influence on endothelial integrity. Adiponectin positively influences vasculature by several mechanisms, some of which include enhancing endothelium-dependent and independent vasodilation, suppression of atherosclerosis, reduction in levels of TNF-α, suppression of the effect of TNF-α on the endothelium, inhibition of endothelial cell effect of oxidized LDL, enhanced production of nitric oxide, and stimulation of angiogenesis. Adiponectin levels are reduced in obese individuals and are particularly low in those with increased visceral adiposity (11).

PHYSIOLOGY

Physiologic Consequences of Obesity

In a state of positive energy balance, “mismanagement of energy” can result in increased visceral and ectopic (muscle and liver) fat deposition (12). Excess fat mass results in increased secretions of proinflammatory and prothrombotic adipokines, as well as higher levels of circulating FFA and decreased levels of adiponectin, which serves to increase the risk of developing CVD, T2DM, certain forms of cancer, gallstones, osteoarthritis, nonalcoholic fatty liver disease (NAFLD), sleep apnea, and asthma (Fig. 24.1).

Investigating the connection between weight status and mortality, Adams et al. (13) conducted a prospective study that followed a cohort of more than 61,000 men and women aged 50 to 71 years for up to 10 years. Increased risk of death was correlated with increasing BMI across all racial/ethnic and age categories. The association of risk of death and BMI was stronger in participants identified as healthy nonsmokers. The study reported a 20% to 40% increased risk of death among overweight and a two- to threefold increase in risk in obese nonsmokers, compared with nonsmoking participants with a normal BMI (13).

The physical complications of excess fat mass have also been observed in children. Many pediatricians have begun to treat obese children for diseases such as T2DM, NAFLD, hypertension, and dyslipidemia, disorders traditionally reserved for the adult population (2). Most concerning is the development of T2DM and CVD, which account for staggering health care costs each year for both direct and indirect care. In addition to the physical and financial burden of obesity, there is a substantial psychosocial burden borne by overweight and obese individuals that spans all age categories. Obese individuals are often stigmatized, experience depression, are targets of discrimination, and score low on health-related quality of life surveys (2).

Obesity and Diabetes Risk

The risk of developing diabetes is influenced by genetics, aging, physical inactivity, and the accumulation of fat mass. Obesity is reported as one of the strongest diabetes risk factors, and visceral fat in particular is strongly associated with a decrease in peripheral insulin sensitivity and increase in gluconeogenesis. Insulin resistance is proportional to visceral fat mass, independent of BMI. Interestingly, if hyperplasia continues during fat mass expansion, patients are less likely to develop insulin resistance. However, when fat cells respond to expansion by becoming hypertrophic, the cells become insulin resistant, creating the dysmetabolic state (12). Impaired glucose tolerance (IGT) and T2DM exhibit a dual deficit in insulin sensitivity and insulin secretion. In IGT, reduced insulin action is accompanied by upregulation of insulin secretion, and normoglycemia is maintained by this compensatory
mechanism. T2DM ensues once insulin secretion cannot compensate for insulin resistance. Diabetes has been on the rise globally in developed as well as developing countries.

FIGURE 24.1 Fat cell hormones and cytokines and disease propagation. DM, diabetes mellitus; FFA, free fatty acids; PAI-1, plasminogen activator inhibitor-1; TNF-α, tumor necrosis factor alpha; IL-6, inter-leukin-6; ASCVD, arteriosclerotic cardiovascular disease. (© 2007 Dr Louis J. Aronne.)

Obesity and Cardiovascular Disease Risk

Framingham Heart Study

Overweight and obesity are highly correlated with the prevalence of CVD. Wilson et al. (14) investigated the long-term outcome of overweight and obesity as a risk factor in the development of CVD as well as disease outcome in over 5,000 men and women in the Framingham Heart Study. Study participants, aged 35 to 75 years, were followed prospectively for up to 44 years. Significant correlations were identified between overweight and obesity and the development of hypertension, angina pectoris, total coronary heart disease (CHD), and total CVD. The multivariate-adjusted relative risk of developing hypertension for obese men and women was reported as 2.23 and 2.63, respectively. The relative risk of developing angina pectoris was reported as 1.81 and 1.63 in obese men and women, respectively. The relative risk for total CHD was 1.43 and 1.58 for overweight and obese men, respectively, and was 1.22 and 1.54 for overweight and obese women, respectively. Relative risk for total CVD risk was equally elevated in obese men and women at 1.38 for both groups (14).

Multi-Ethnic Study of Atherosclerosis

Data from the Multi-Ethnic Study of Atherosclerosis (MESA) were analyzed to evaluate the impact of obesity on CVD risk factors and subclinical vascular disease in a cohort of 6,814 men and women, aged 45 to 84 years, who were free of clinical CVD at baseline (15). The association of overweight and obesity with traditional CVD risk factors, such as blood pressure, lipids, and diabetes, as well as subclinical vascular markers, such as carotid intimal medial thickness (CIMT), left ventricular (LV) mass, and coronary calcium score (CCS), was investigated. Researchers found a strong relationship between obesity and traditional CVD risk factors. A higher BMI was associated with adverse levels of blood pressure, lipoproteins, and fasting glucose. After adjustment for race, gender, age, and risk factors, obesity was significantly associated with a 1.2 fold increase in the presence of coronary artery calcium. Adjusting for race, gender, and age revealed that the obese group had a 32% and 45% greater risk of internal carotid artery IMT and common carotid artery IMT, respectively. Adjusting the model further to account for CVD risk factors attenuated the risk for internal carotid artery IMT to marginally significant (p = 0.07); however, the risk for common carotid artery IMT remained significant (p < 0.001). The relative risk of increased LV mass was 1.65 and 2.3 in the overweight and obese groups, respectively, compared to the normal body weight group in the multivariate-adjusted model (15).

Cardiometabolic Risk Factors and the Metabolic Syndrome

Identifying and targeting patients at risk for developing obesity-induced T2DM and CVD is essential in reducing the prevalence of devastating health complications. Factors that contribute to cardiometabolic risk include nonmodifiable components, such as age, ethnicity, gender, and family history, and modifiable factors, such as smoking, obesity, hyperglycemia, dyslipidemia, hypercoagulation, elevated blood pressure, inflammation, and physical inactivity. A “clustering” of risk factors that enhances disease progression has been identified and has been referred to as syndrome X, or the metabolic syndrome (MetS). This syndrome includes dyslipidemia, hypertension, abdominal adiposity, and glucose intolerance. Currently, there are five working medical society definitions proposed for MetS. Diagnostic criteria, with slight variations, have been set forth by the WHO, European Group for the Study of Insulin Resistance (EGIR), American College of Endocrinology/American Association of Clinical Endocrinologists (ACE/AACE), IDF, and AHA/NHLBI, which refers to the
updated National Cholesterol Education Program Adult Treatment Plan III (NCEP ATP III) definition (16).

Criteria sets outlined for diagnosing MetS were designed to offer a quick and easy way for physicians to identify those patients at increased cardiometabolic risk. However, concerns regarding the utility of diagnosing a patient with MetS based on current standards focus on the lack of a universally accepted set of diagnostic criteria and the question of whether the syndrome has a single cause or is simply a cluster of risk factors. There are reports of significant differences in prevalence rates of MetS based on which set of criteria was used for diagnosis. Additionally, although insulin resistance is a main component of cardiometabolic risk, the IDF and the AHA/NHLBI do not include a direct marker for insulin resistance in their criteria. Another issue of concern is that each criterion for MetS is decided by determining whether the physical component in question is “present” or “absent.” This crude system of determining risk limits the usefulness of the screening tool on an individual level, especially in comparison to a system of evaluating each criterion of MetS based on a continuous variable (12).

Regardless of the above concerns, results of research support a strong connection between the development of MetS and the development of CVD. Wilson et al. (17) followed a cohort of 3,323 adult men and women for 8 years to investigate the link between the diagnosis of MetS with CVD and T2DM outcome. MetS was diagnosed according to the NCEP ATP III criteria. Glucose was adjusted to capture all those with fasting blood glucose levels of 100 to 125 mg/dL (5.5 to 7 mmol/L) and to exclude those diagnosed with T2DM. In those men who had ≥3 risk factors for MetS, there was a 6.92 age-adjusted relative risk of developing T2DM and a 2.88 relative risk of developing CVD. Women in the study with ≥3 risk factors had a 6.90 age-adjusted relative risk of developing T2DM and a 2.25 relative risk of developing CVD versus those with 0 to 2 risk factors for MetS (17).

Two major organizations have urged clinicians to identify and treat cardiometabolic risk factors aggressively. The American Diabetes Association (ADA) and the AHA joined forces and published a consensus stating that the importance of identifying and treating the core set of risk factors in the development of CVD “cannot be overstated.” These core risk factors are the components of MetS: prediabetes, hypertension, dyslipidemia, and abdominal obesity (2). It should be noted that some investigators warn against using the diagnosis of MetS alone to assess CVD risk. Accordingly, physicians are advised to first focus on traditional risk factors. The most comprehensive, global cardiometabolic risk can be assessed by adding the risk ascertained from abdominal obesity and MetS to classical risk factors (12).

TREATMENT OF OBESITY

Treatment Options

Obesity’s physical and psychosocial toll on the individual patient, as well as the financial burden incurred by society due to health care costs, demands a strong call for action from all health care providers to tackle obesity aggressively. Dietary intervention and lifestyle modification remain the cornerstone of obesity treatment and protection against the development of CVD. Practice guidelines for treating overweight and obesity have been outlined by the NHLBI. Recommendations include dietary and lifestyle interventions for overweight individuals with a BMI of 25 to 29.9 kg/m². NHLBI recommends that if dietary and lifestyle interventions fail to produce favorable outcome in those with a BMI ≥27 kg/m² and weightrelated comorbidities, as well as those with a BMI ≥30 kg/m², the treatment plan may include weight loss medication. Surgical options are reserved for those with a BMI ≥40 kg/m² or for those with a BMI ≥35 and obesity-induced illness (2).

Effects of Weight Loss

A significant reduction in disease risk can be reaped with relatively small amounts of weight loss. A 5% to 10% reduction in body weight has been shown to improve lipid profile, insulin sensitivity, and endothelial function, as well as result in a reduction in thrombosis and inflammatory markers (2). The proposition of gaining significantly improved health through the loss of a small amount of body weight can be encouraging to the patient who believes that a 5% to 10% weight loss goal is achievable. However, those who wish to shed large amounts of body weight may be discouraged by a conservative weight loss goal. Informing patients of the many endogenous mechanisms that defend body fat is helpful in guiding them toward an improved understanding of physiologic obstacles to fat mass loss and will aid them in accepting a more reasonable weight loss goal (10).

Diabetes Prevention Program

Data from the Diabetes Prevention Program (DPP) illustrate the health benefit gleaned from a small amount of weight loss in derailing the development of disease in a group of participants at high risk for T2DM. Researchers enrolled 3,234 nondiabetic individuals with elevated fasting glucose levels to evaluate the effect of treatment with lifestyle intervention or daily treatment with metformin in delaying progression to T2DM. Participants were randomized to placebo, metformin, or intensive lifestyle treatment groups and were followed for an average of 2.8 years. The lifestyle intervention group received individual and group behavioral guidance and was counseled to exercise for 150 min/week. Weight loss totals were 0.1, 2.1, and 5.6 kg in the control, metformin, and lifestyle groups, respectively. Compared to the placebo-treated group, there was a 31% and 58% reduction in incidence of progression to T2DM in the metformin-treated and the lifestyle group, respectively (18).

In addition to reductions in the conversion of IGT to T2DM, the treatment groups of the DPP reported a reduced incidence of MetS in their participants. At baseline, 53% of the study participants met the criteria for MetS according to the NCEP ATP III criteria. The metformin-treated group experienced a 17% overall reduction in the incidence of MetS, and the lifestyle group reduced the incidence rate of MetS by 41%, compared to the placebo group (18).

Lifestyle Modification for Weight Loss Success

Weight loss interventions that focus on increasing physical activity and decreasing calorie consumption have been successful in helping dieters lose about 10% of initial body weight.
However, long-term weight loss success remains elusive for the majority of overweight and obese individuals. Emerging data reveal that weight loss maintenance is exceedingly difficult, in part, due to overlapping endogenous mechanisms that defend fat mass (9) (Fig. 24.2). In addition, our “obesogenic” environment counters efforts aimed at living an active lifestyle, eating a healthy diet, and thus maintaining a healthy body weight. Studies reveal that behavioral interventions aimed at building lifestyle habits to reduce calorie intake and increase energy expended in daily physical activities can result in as much as 10% total body weight loss during the first 6 months of treatment. However, one-third to two-thirds of lost weight is often regained within 1 year following end of treatment, and almost all weight is regained within 5 years post-treatment (10). Clearly, changing and maintaining daily diet and activity habits presents a real challenge. Experts now view obesity as a chronic illness, like diabetes or hypertension, which requires ongoing treatment. Behavioral support and guidance to reinforce healthy lifestyle modifications, coupled with medication or surgery, may result in improved long-term weight loss success.

The Role of Physical Activity in Weight Loss and CVD Risk

Exercise improves health, may ultimately attenuate some cardiovascular risk factors, and is a component of any weight loss intervention. Research results correlate several health benefits with physical fitness. Lee and colleagues (19) observed a cohort of 21,925 men aged 30 to 83 years to investigate the relationship between physical fitness and longevity. They found that moderate to high levels of physical fitness reduced mortality risk, regardless of body composition. Unfit lean men had a twofold greater mortality risk than did fit lean men, and obese men who were fit did not have an increased mortality risk (19). A separate analysis of 2,506 women and 2,860 men enrolled in the Lipid Research Clinics Study also reported an independent effect of fitness on all-cause mortality. In this cohort of subjects, higher quintiles of BMI conferred a higher mortality risk, but fitness was more strongly associated with mortality outcomes than BMI reading (20).

Exercise promotes favorable changes in energy balance that may result in weight loss and improvements in body composition and fat distribution. Although exercise clearly increases calorie expenditure, research suggests that increasing time spent exercising may not induce weight loss in the short term. However, exercise does prevent the loss of muscle mass during weight loss, confers independent cardiovascular and metabolic improvements that reduce mortality risk, and may prevent weight regain.

DIETARY TREATMENT OF OBESITY

Dietary Measures for Inducing Weight Loss

Several dietary options for weight loss exist, including low-fat, low-glycemic load, low-carbohydrate, and meal replacement diets. Although weight loss totals at the 1-year mark are often similar across studies investigating different dietary approaches, differences in results depending on baseline characteristics of
the patient (such as insulin sensitive vs. resistant), as well as improvements in outcomes such as lipid profile, offer vital information on diet benefit. These data question the appropriateness of placing all overweight and obese patients on the same diet plan. Thus, finding the right diet plan for the individual needs of each overweight or obese patient may take careful consideration. The purpose of this section is to review several dietary options for weight loss and cardiovascular improvement, but it is not intended as a comprehensive review of all possible dietary options for weight loss.

Very Low Calorie Diets

Very low calorie diets (VLCDs) were popular in the 1980s and 1990s and provided a diet plan that reduced intake to about 800 calories daily. Meeting protein and nutrient needs while restricting calories to such a low level was often accomplished with the use of liquid protein drinks. VLCDs have waned in popularity, although they do produce dramatic weight loss in a relatively short span of time. A meta-analysis of six randomized trials compared the efficacy of VLCDs and conventional low-calorie diets (LCDs) in producing weight loss (21). Significantly greater short-term weight loss was revealed in those treated with VLCDs versus LCDs—16.1% and 6.3%, respectively. However, long-term weight loss in those treated with VLCDs versus LCDs was comparable—6.3% versus 5.0%, respectively. VLCDs may have the greatest utility if followed by a long-term management plan providing additional therapeutic support, such as pharmacological and behavioral therapy to sustain the initial weight loss of 15% to 25% observed with VLCDs (21). The use of liquid meal replacements combined with regular food has been found to be a more successful strategy for long-term weight loss and maintenance than LCDs.

Low-glycemic Diets

The emphasis in the past on replacing fat in the diet with carbohydrate-rich foods did not serve the purpose of reducing obesity, T2DM, and CVD risk. Greater intake of dietary carbohydrate can increase fluctuations in postprandial hyperglycemia, serum insulin, and lipid levels in predisposed individuals. Elevations in serum glucose following food intake increase the production of superoxide and nitric oxide, which combine to form peroxynitrite—a very potent pro-oxidant molecule. This is the proposed mechanism that may account for the increase in CIMT and CVD risk found in those following a high-carbohydrate diet (22).

Glycemic Index

The glycemic index (GI) of food is a measure of how fast a food raises postprandial blood glucose levels. Low-GI foods are more slowly digested and absorbed than high-GI foods. The glycemic load (GL) is the mathematical product of the GI and the carbohydrate content of an average serving of food. High-GI and high-GL carbohydrate food sources include refined foods such as white bread, white rice, pasta, muffins, and bagels. Whole grains and high-fiber carbohydrates such as whole-wheat bread, whole-wheat pasta, brown rice, beans, lentils, and bulgur wheat are lower-GI and GL food sources. A low-GL diet reduces postprandial blood glucose, TG, insulin, and hunger levels and raises HDL cholesterol (HDL-C) more than a low-fat diet in patients with hallmarks of insulin resistance. These observations support the premise that a low-GL diet will result in improved outcome measurements. While low-GL diets tend to have less carbohydrate, they are not the same as the ketogenic low-carbohydrate diets that were once quite popular. It is our opinion that low-GL diets achieve the varied benefits of low-carbohydrate diets without the potential pitfalls.

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