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Abstract

  1. Top of page
  2. Abstract
  3. Overview of the MetS
  4. Therapeutic Implications of the MetS
  5. MetS in Asians
  6. Conclusions
  7. References

Metabolic syndrome (MS) is a cluster of multiple cardio-metabolic risk factors in the same individual. People with MS are at high risk for the development of cardiovascular disease (CVD), chronic kidney disease (CKD), and cerebrovascular disease (CeVD). The excessive presence of MS in South Asians is likely responsible for significant morbidity in this population. This review discusses the scope of MS in South Asians and measures to combat its effects by preventive and therapeutic measures. J Clin Hypertens (Greenwich). 2012;00:00–00. ©2012 Wiley Periodicals, Inc.

Despite an encouraging decline in age-adjusted mortality rates, cardiovascular disease remains the most common cause of death in developed countries. However, cardiovascular disease is not limited to developed countries and multiple epidemiologic studies have demonstrated a dramatic increase in the incidence, prevalence, and severity of atherosclerosis in developing countries.1 Atherosclerosis is a syndrome with multiple predisposing factors, but a unifying hypothesis that explains all aspects of the initiation and propagation of obstructive vascular disease has remained elusive. Studies have demonstrated that risk factors for atherosclerosis such as obesity, hypertension, and dyslipidemia appear to cluster together in certain individuals with the postulate that insulin resistance is the unifying factor in these apparently disparate conditions.2 Although the term insulin resistance syndrome or Syndrome X was initially introduced to encompass these multiple risk factors, it has since been replaced by the term metabolic syndrome (MetS) to avoid the implication that insulin resistance is the primary or sole cause of all of the associated components of the syndrome.3 The increasing incidence of cardiovascular disease in South Asia has given rise to considerable interest in the role of the MetS as a predisposing factor for atherosclerosis in developing countries.

Overview of the MetS

  1. Top of page
  2. Abstract
  3. Overview of the MetS
  4. Therapeutic Implications of the MetS
  5. MetS in Asians
  6. Conclusions
  7. References

The MetS is a grouping of several interrelated risk factors that have been demonstrated to be associated with an enhanced hazard ratio for the development of cardiovascular disease. The concept of the MetS is supported by the common soil hypothesis for the development of atherosclerosis.4 The common soil hypothesis was initially proposed following the determination that inflammation and oxidative stress is coexistent in the early phase of multiple risk factors including hypertension, dyslipidemia, diabetes, and obesity (especially with a truncal distribution). The prevalence of these risk factors has been increasing in a worldwide distribution due to an alteration of lifestyle changes such as increased caloric consumption with resultant obesity coupled with the reduction in physical activity that has become progressively more common with urbanization. Despite recent controversy regarding its clinical usefulness,5 the term MetS is supported by epidemiologic studies that have demonstrated patients who fulfilled diagnostic criteria for the MetS have been demonstrated to exhibit a 2-fold risk for the development of cardiovascular disease over the next 5 to 10 years.6 The American Heart Association has established the diagnosis of the MetS, which requires any 3 of the 5 major criteria7

  •  Waist circumference: Increased waist circumference ≥102 cm (≥40 inches) in men or ≥88 cm (≥35 inches) in women;
  •  High-density lipoprotein (HDL) cholesterol: HDL cholesterol <40 mg/dL (1.03 mmol/L) in men or <50 mg/dL (1.3 mmol/L) in women and the utilization of pharmacologic therapy for low HDL;
  •  Hypertriglyceridemia: Elevated triglycerides ≥150 mg/dL (1.7 mmol/L) or pharmacologic treatment for hypertriglyceridemia;
  •  Hypertension: Elevated blood pressure (BP) as defined as measurements ≥130 mm Hg systolic pressure or ≥85 mm Hg diastolic pressure and the use of antihypertensive therapy in a patient with a history of hypertension;
  •  Hyperglycemia: Elevated fasting blood glucose ≥100 mg/dL or drug therapy for hyperglycemia.

Multiple other criteria (Figure 1, Figure 2, and Figure 3) have been proposed for inclusion as criteria of the MetS including inflammatory markers, prothrombotic state, body mass index (BMI), urinary albumin excretion, and others, although controversies exist as to the usefulness of these markers.8

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Figure 1.  Insulin resistance as a component of metabolic syndrome.

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Figure 2.  Definition of metabolic syndrome.

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Figure 3.  International Diabetes Federation ethnic- and sex-specific criteria for central obesity.

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Therapeutic Implications of the MetS

  1. Top of page
  2. Abstract
  3. Overview of the MetS
  4. Therapeutic Implications of the MetS
  5. MetS in Asians
  6. Conclusions
  7. References

The diagnosis of the MetS has several clinical implications for implementation of therapy. Obesity is a major predisposing cause for the development of cardiovascular disease and the Third Report of the Adult Treatment Panel (ATP III) of the National Cholesterol Education Program (NCEP) has recommended that reduction of increased BMI be a primary therapeutic target to reduce cardiovascular risk. The reduction of body weight by calorie restriction and increased level of physical activity may secondarily improve dyslipidemia, BP, and glucose levels and lead to a reduction in inflammatory markers and prothrombotic mediators. Insulin resistance has been long recognized as a major underlying factor in the pathogenesis in several components of the MetS.9 Individuals with insulin resistance have been demonstrated to exhibit increased production and impaired catabolism of triglyceride-rich lipoproteins with resultant hypertriglyceridemia. The reduction in the catabolism of very low-density lipoprotein (LDL) and secondary hypertriglyceridemia is correlated with low levels of HDL due to the resultant impaired transport of cholesterol between these two lipoproteins. Insulin resistance may be a primary phenomenon or secondarily related to increased BMI. Dietary restriction of caloric intake and increased physical activity has clearly been demonstrated to improve insulin sensitivity with the potential to improve metabolic parameters. Pharmacologic agents such as metformin and the thiazolidinediones (TZDs) have also been an attractive approach to insulin resistance in patients who do not optimize metabolic parameters by weight loss or exercise. However, a controversial meta-analysis has indicated an increase in myocardial infarction with rosiglitazone,10,11 and a meta-analysis of 16 clinical studies that evaluated 810,000 patients has suggested that TZDs can increase sodium retention and the incidence of congestive heart failure.12 Metformin therapy has been used for diabetes for many years and has been shown to reduce the incidence of coronary heart disease in patients with increased BMI coupled with the presence of type 2 diabetes.13 Additionally, in the Diabetes Prevention Program, individuals who demonstrated impaired glucose tolerance and received metformin therapy demonstrated reduction in the onset of type 2 diabetes.14

Dyslipidemia is a major feature of the MetS. Patients with MetS frequently exhibit the atherogenic lipid phenotype that is characterized by a relatively normal total cholesterol level but elevated triglycerides, low HDL, and small dense LDL.15 The use of non-HDL cholesterol targets all apolipoprotein (Apo) B–containing particles and has been advocated as a therapeutic target for optimization of the lipid profile, being a more accurate predictor of cardiovascular risk than LDL cholesterol.16 Non-HDL cholesterol levels are frequently abnormal in patients with the MetS. Statin therapy has a predominant effect on LDL, improves HDL, and lowers triglycerides and should be considered a mainstay of treatment in patients for whom lifestyle modification is insufficient. Subgroup analysis of statin trials demonstrates a reduction in cardiac events in patients who fit the diagnostic criteria of the MetS.17 The use of fibric acid derivatives is also theoretically attractive, as the mechanism of peroxisome proliferator-activated receptors are to increase the activity of lipoprotein lipase with reduction in triglycerides and an increase in HDL. Post hoc analysis of primary prevention trials with gemfibrozil demonstrates a reduction of cardiac events in individuals with the lipid triad.18 However, the Fenofibrate Intervention and Event Reduction in Diabetes (FIELD) trial, which employed fenofibrate in diabetic patients, was disappointing although methodological problems were encountered in the trial design.19 Additionally, the combination of statin and fibric acid derivatives in individuals with the MetS is under active investigation.

Elevated BP is a major factor in the determination of cardiovascular risk in patients with MetS. Lifestyle intervention should always be given an adequate trial prior to consideration of antihypertensive pharmacologic therapy. Modulators of the renin angiotensin system (angiotensin-converting enzyme inhibitors and angiotensin receptor blockers) have been considered theoretically advantageous antihypertensive agents in the MetS, but, as yet, they have not been fully evaluated. However, the use of ramipril in the Heart Outcomes Prevention Evaluation (HOPE) trial appeared to demonstrate a decrease in the incidence of diabetes mellitus in normotensive patients with multiple risk factors.20 No class of antihypertensive agents is considered to be uniquely efficacious in patients with the MetS.

MetS in Asians

  1. Top of page
  2. Abstract
  3. Overview of the MetS
  4. Therapeutic Implications of the MetS
  5. MetS in Asians
  6. Conclusions
  7. References

Epidemiologic studies performed in South Asian countries have demonstrated a progressive and alarming increase in the incidence of cardiovascular disease over the past several decades together with a two-fold increase in the prevalence of type 2 diabetes over the past 30 years.21 The reasons that underlie this disturbing trend are multifactorial and have been related in varying degrees to urbanization, lifestyle alterations (diet and exercise), economic influences, and increased life expectancy. Epidemiologic studies conducted in Indian population centers have estimated a prevalence of the MetS to encompass approximately one third of patients residing in large cities.22 The prevalence rate of the components of the MetS may also have a genetic basis with different expressions in various populations, although quantification of the relative contribution of lifestyle modifications relative to interactions of genetic tendencies is difficult to separate. South Asians who do not live in urban centers tend to have a low BMI when compared with Caucasians, Hispanics, or blacks.23 However, individuals and their progeny who migrate to urban centers have been demonstrated to exhibit a significant increase in BMI. Additionally, South Asians tend to have a higher prevalence of truncal obesity, fatty infiltration of the liver, and ectopic fat deposition and a higher percentage of body fat compared with Caucasians, Hispanics, or blacks, despite the lower average BMI values. Importantly, excess adiposity in South Asians appears to manifest itself as an increased prevalence of the major components of the MetS including hypertension, diabetes, and dyslipidemia. The anatomic distribution of adiposity may also be different in South Asians, abdominal obesity being increased especially when associated with a BMI >25 kg/m2.24 In recognition of these differing metabolic characteristics, the National Obesity and Metabolic Syndrome Summit revised diagnostic cutoffs for BMI and waist circumference for South Asians. The normal values for BMI were established to be 18 to 22.9 kg/m2. The definition of an overweight BMI was 23 to 24.9 kg/m2 and the diagnosis of obesity was established if the BMI exceeded 25 kg/m2. Additionally, abnormal waist circumference was considered to be >90 cm for men and ≥80 cm for women.25 The role that diet and exercise plays in BMI and waist circumference in South Asians has not been adequately studied. The traditional Indian vegetarian diet was low in saturated fat and simple carbohydrates and was accompanied by a relatively higher level of insoluble dietary fiber. Progressive urbanization has resulted in an increase in simple carbohydrates and fat intake coupled with a reduction in fiber, which has been postulated to play a significant role in the inter-relationship between obesity and type 2 diabetes documented in the Indian population.26 Additionally, progressive urbanization has led to a more sedentary lifestyle relative to other ethnic groups, prompting a consensus statement recommending a nationwide increase in aerobic activity as a means to reduce the risk for the development of the MetS and other cardiovascular issues.27 In addition to the alteration of dietary and physical activities in the urban Indian population, several gene polymorphisms are present in South Asians that have been demonstrated to alter lipid and carbohydrate metabolism and may play a significant role in the development of the components of the MetS. For example, glucokinase gene polymorphisms are present in Asian Indians and may have a significantly adverse impact on hepatic and whole body insulin sensitivity.28 Additionally, the presence of increased levels of plasma cell glycoprotein-1K121Q and insulin receptor substrate-1 G972A polymorphisms are associated with primary insulin resistance and the gene frequencies are increased in South Asians providing a genetic predisposition for the development of glucose intolerance.29 South Asians may also exhibit polymorphisms of the Apo CPIII gene complex characterized by an increased predisposition for the development of dyslipidemia due to impaired catabolism of very LDL and subsequent increases in triglyceride levels.30

Dyslipidemia is felt to be a major modifiable cause of the excess burden of atherosclerosis in Asian Indians. Although the high prevalence of a vegetarian diet would be predicted to be associated with a relatively low total cholesterol level, epidemiologic studies have demonstrated that vegetarian and non-vegetarian Indians express a similar lipid phenotype and risk for the development of coronary artery disease. One explanation for this may be the utilization of high quantities of saturated fats and transfatty acids in the process of deep frying of vegetables. Additionally, the practice of overcooking has been demonstrated to result in the destruction of multiple nutrients including folic acid, a reduced level of which has been linked to risk for coronary artery disease. The characteristic lipid pattern of the MetS is a triad comprised of the combination of hypertriglyceridemia, low HDL cholesterol, and small dense LDL particles. The total cholesterol may be normal or only slightly elevated despite the presence of the atherogenic lipid phenotype. The lipid phenotype of the MetS is highly atherogenic and has been demonstrated to have characteristic differences in the South Asian population. Over the past decade, the level of LDL in urban India has significantly increased.31 The presence of atherogenic small dense LDL can be predicted using the triglyceride/HDL ratio. Levels in South Asians individuals in excess of 3.8 provide an indication for intensive lipid modification.32 The utilization of non–HDL cholesterol may be employed as a marker for cardiovascular risk and circumvents the problems associated with remnant particles that are common in the MetS. Non–HDL cholesterol would include very LDL, lipoprotein remnant particles, and LDL and lipoprotein (a). The non–HDL cholesterol goals are 30 mg/dL, higher than the targets for LDL cholesterol levels. Asian Indians appear to have generally similar levels of non–HDL cholesterol when compared with Americans and Europeans.33 However, when hypertriglyceridemia is associated with an increase in non–HDL cholesterol that includes all Apo B–containing lipoproteins, an increase in cardiovascular risk has been determined.

HDL also exists in a family of particles with a variable impact on cardiovascular risk. The level of HDL cholesterol is generally inversely related to cardiovascular risk and has been classified as a negative risk factor by the NCEP ATP III. Asian Indians have been demonstrated to exhibit a significant decrease in the larger more protective HDL particles coupled with an increase in smaller particles.34,35

Lipoprotein (a) is a complex lipoprotein that consists of an LDL molecule coupled to Apo (a) by the presence of sulfhydryl groups.36 The levels of lipoprotein (a) are primarily genetically determined and display minimal response to pharmacologic therapy (with the exception of nicotinic acid and estrogens), diet, or physical activity. Asian Indians have been demonstrated to have increased circulating levels of lipoprotein (a) with a mean level of 20 mg/dL, which is considered to be the threshold for increased atherosclerotic risk.37 Determinations of lipoprotein (a) in Asian Indians have been correlated with the presence and severity of atherosclerosis. However, the quantification of the atherosclerotic risk transmitted by lipoprotein (a) is complicated by the presence of a variety of isoforms that have a variable impact on risk and are not generally determined with standard biochemical assays.

Elevated BP is the most common risk factor for cardiovascular morbidity and mortality. The prevalence of hypertension is progressively increasing in developing countries due to lifestyle modifications, increased BMI, reduced physical activity, increased sodium intake, and increased survival to older age groups where vascular pathology is more prevalent. Epidemiologic studies that were conducted in the decade including the 1940s demonstrated a prevalence of hypertension of 1.2% to 4.2% in India, which has risen to a rate of 15% to 25% in the decade encompassing the 1990s.38 The increase in BP in Asian Indians is not limited to adults. School-aged children in the 11- to 17-year-old age group have a prevalence of hypertension of 6.6% in urban areas, which is predicted to increase if trends in obesity and reduced physical activity continue.39 The high prevalence of diabetes and insulin resistance in India may play a significant role in the risk for the development of hypertension. The prevalence of type 2 diabetes mellitus was estimated to be 23 million patients in the year 2000, with a projected increase to 57 million by the year 2025.40

Dietary influences have also been demonstrated to play a major role in the pathogenesis of hypertension in South Asia. Studies performed in urban centers of India have demonstrated a significant increase in sodium intake to levels above that recommended by the World Health Organization (5 g/d) with resultant hypertension.41 However, epidemiologic data for the prevalence of severity and hypertension are conflicting when comparing South Asians with other ethnic groups and may be dependent on multiple variables, including differences in smoking, physical activity, dietary factors, and socioeconomic conditions.42 It is likely that South Asians migrating to the west may face an added burden of MetS due to the changes in diet and “environmental stressors.” Future research should explore the basis for enhanced risk of MetS in South Asians and separate the “inherited” factors from the “environmental” contributors.

Conclusions

  1. Top of page
  2. Abstract
  3. Overview of the MetS
  4. Therapeutic Implications of the MetS
  5. MetS in Asians
  6. Conclusions
  7. References

The term MetS was initially proposed to describe a grouping of cardiovascular risk factors that appeared to coexist with greater frequency than would be expected by chance alone with the implications for metabolic pathways. The MetS is characterized by hypertension, hypertriglyceridemia, low HDL cholesterol, increased waist circumference, and glucose intolerance. The epidemiologic data have demonstrated that the prevalence of the MetS is significantly increased in South Asians and the associated increased cardiovascular risk begins at an early age. The impact of rapid urbanization, mechanization, socioeconomic factors, and alterations to the traditional diet are all thought to play a major role in the increased incidence and prevalence of the MetS in South Asian populations. The MetS in South Asians is correlated with a distinct phenotype including excess body fat, abdominal obesity, truncal subcutaneous fat, and ectopic fat deposition. Community-based programs aimed at promoting beneficial lifestyle modifications have been recommended as a means to reduce the prevalence of the MetS.43

References

  1. Top of page
  2. Abstract
  3. Overview of the MetS
  4. Therapeutic Implications of the MetS
  5. MetS in Asians
  6. Conclusions
  7. References
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