The metabolic syndrome (MetS) is a recently defined clustering of cardiovascular risk factors associated with increased insulin resistance and a high risk of developing type II diabetes mellitus. Systemic lupus erythematosus (SLE) is associated with an increased prevalence of the MetS and patients also show evidence of increased insulin resistance. Controversy remains, however, regarding the precise definition of the MetS and its exact role in predicting long-term coronary heart disease risk both in SLE and in the general population. The major benefit of identifying the MetS in patients with SLE is likely to be from highlighting patients for focused lifestyle interventions and helping to guide individualized therapeutic regimes that take into account cardiovascular risk.
The impact of coronary heart disease (CHD) on morbidity and mortality in patients with established systemic lupus erythematosus (SLE) has assumed increasing importance in their long-term management. Classic CHD risk factors and lupus-specific factors, such as antiphospholipid antibodies, seem to be important in determining long-term cardiovascular risk, but the role of metabolic derangement, specifically the metabolic syndrome (MetS), is gaining increasing prominence in the literature. The extent to which MetS is associated with long-term CHD in the general population, and whether its presence can predict those patients at increased risk of CHD over and above existing risk scores, does remain controversial. This article considers what is known about MetS in SLE and also considers what is known about the impact of MetS on vascular risk in the lupus population.
CHD in SLE
The bimodal mortality pattern in SLE has been recognized for over 30 years. Mortality in established disease is frequently caused by manifestations of atherosclerotic disease in coronary or cerebrovascular vessels. In a retrospective cohort study of 498 women with SLE incidence rates of myocardial infarction were found to be increased fivefold to sixfold compared with the Framingham Offspring cohort. Most strikingly, two thirds of events in the lupus cohort occurred before the age of 55 years, and the rate ratio was increased more than 50-fold in the 35- to 44-year age group. Similarly, a Swedish study linking death registry data to the records of 4700 lupus patients found a standardized mortality ratio from CHD of 15.9 in SLE. An increased burden of subclinical atherosclerosis has also been noted in patients with SLE. Autopsy studies of patients with SLE have demonstrated significant generalized atherosclerosis in approximately 50% of cases, regardless of underlying cause of death, and coronary artery atherosclerosis is particularly prevalent (up to 42% of patients) in those patients who have received steroids for at least 1 year. Many groups have subsequently demonstrated the presence of subclinical atherosclerosis in SLE patients in cross-sectional studies using a variety of measures, most commonly the presence of carotid plaque but also CT detection of coronary artery calcification, large artery stiffness, and impaired endothelial function.
The contribution of classic Framingham risk factors for CHD to this increased burden of cardiovascular disease has been the subject of extensive investigation. The Toronto Risk Factor Study reported that women with SLE who were free of CHD were more likely to be hypertensive, diabetic, and suffer from dyslipidemia compared with age-matched healthy controls. Similarly, over half the Hopkins Lupus Cohort had three or more CHD risk factors, despite a mean age of 38.3 years. Classic Framingham risk factors alone do not entirely explain the disparity in prevalence of clinical and subclinical cardiovascular disease in lupus cohorts. In a large Canadian cohort with a mean follow-up of 8.6 years, Esdaile and colleagues assessed baseline classic risk factor frequency and adverse vascular outcomes. After controlling for the presence of classic risk factors, lupus patients still had a 10-fold increase in relative risk (RR) for nonfatal myocardial infarction than is expected using the Framingham model alone. Subsequent studies using measures of subclinical cardiovascular disease (eg, carotid plaque and endothelial dysfunction) have also found that after adjustment for classic risk factors, SLE remains associated with an increased burden of premature atherosclerosis.
SLE can be considered an independent risk factor for CHD and disease-specific factors, such as antiphospholipid antibodies, renal disease, complement, and inflammatory pathways, all influence long-term cardiovascular risk. The effect of metabolic derangement, and in particular the role of MetS, on cardiovascular risk in SLE has gained attention because it may also contribute to this enhanced risk.
The MetS
Recently defined, the term “metabolic syndrome” is used to describe the presence of certain metabolic abnormalities and cardiovascular risk factors in an individual with increased adiposity. The clustering of metabolic disorders in certain individuals, however, has been recognized for much longer; as early as the 1920s the association between hyperglycemia, hypertension, and gout was described, and in 1980 the association of obesity with dyslipidemia was made. By 1988, Reaven had coined the term “syndrome X” to describe the association between insulin-resistance, type 2 diabetes mellitus, hypertension, and cardiovascular disease and in 1998 the first formal definition of MetS was proposed by the World Health Organization (WHO). Over the subsequent years the literature on MetS has expanded significantly despite, or perhaps in part because of, its controversial clinical significance and conflicting definitions.
Since first described in 1998, there have been a further four definitions of MetS published by different working groups, and one significant modification and one consensus statement. Each definition differs with regard to the most suitable measure of obesity, the thresholds used for each criterion, and most importantly in the method used to assess disordered insulin metabolism ( Table 1 ). The initial WHO recommendation, published as part of wider definition and classification of diabetes, was mainly designed as a guideline and not necessarily a complete definition of MetS. This recommendation considered MetS to have at its core disordered insulin metabolism and insulin resistance (IR), and hence it is viewed as part of the diabetic spectrum. It has, however, been criticized for the inclusion of microalbuminuria and its measure of IR (using a euglycemic clamp), which is not easily applicable to either routine clinical practice or large-scale research studies. In 1999, the European Group for the Study of Insulin Resistance modified this definition. They excluded diabetic subjects, used waist circumference as a measure of adiposity, and used fasting insulin levels as a surrogate for IR. In contrast, the Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (ATPIII) of 2001, modified in 2005 by the American Heart Association and National Heart, Lung, and Blood Institute (NHLBI), considers MetS as a precursor to diabetes and excluded those with overt type 2 diabetes. More applicable to clinical practice, the NCEP does not include any essential criteria and does not measure IR, instead using fasting glucose levels as a surrogate. Most recently, the International Diabetes Federation (IDF) definition has an essential criterion of (ethnic-specific) central obesity, removing the presence of documented IR and focusing instead on the presence of impaired glycemic control. Justifying their modifications, the authors emphasize the need for a simple definition to increase the clinical applicability of the syndrome by using criteria that are easy to measure, are widely available, and are applicable to different ethic populations.
| WHO 1998 | EIGR 1999 | NCEP ATPIII 2001 | AACE 2003 | IDF 2006 | |
|---|---|---|---|---|---|
| Essential | IR | IR | IGT | Central obesity | |
| High insulin or IFG or IGT | Top 25% of fasting insulin values in nondiabetics | (ethnicity specific) | |||
| Plus | Two or more of | Two or more of | Any three of | Two or more of | Two or more of |
| Hypertension | Hypertension | Hypertension | Hypertension | Hypertension | |
| BP >140/90 a mm Hg | BP 140/90 mm Hg | BP >130/85 mm Hg | BP 130/85 mm Hg | BP >130/85 mm Hg | |
| Dyslipidemia | Dyslipidemia | Dyslipidemia | Dyslipidemia | Dyslipidemia | |
| TG >1.7 mmol/L | TG >2 mmol/L | TG >1.7 mmol/L | TG >1.7 mmol/L | TG >1.7 mmol/L | |
| +/or low HDL-C | HDL-C <1 mmol/L | Low HDL-C | HDL-C | Low HDL-C | |
| ♂ <0.9 mmol/L | ♂ <1 mmol/L | ♂ <1 mmol/L | ♂ <1.03 mmol/L | ||
| ♀ <1 mmol/L | ♀ < 1.25 mmol/L | ♀ <1.25 mmol/L | ♀ <1.29 mmol/L | ||
| Central obesity | Central obesity | Central obesity | |||
| ♂ WHR >0.9 | ♂ WC >94 cm | ♂ WC >102 cm | |||
| ♀ WHR >0.85 | ♀ WC >80 cm | ♀ WC >88 cm | |||
| or BMI >30 kg/m 2 | |||||
| Microalbuminuria | Fasting glucose >6.1 mmol/L | Fasting glucose >5.6 mmol/L |
Recently, to resolve outstanding contentious issues and harmonize the criteria a Joint Interim Statement from the IDF, NHLBI, American Heart Association, World Heart Federation, International Atherosclerosis Society, and International Association for the Study of Obesity was published with agreement reached regarding a new definition of MetS ( Table 2 ). Unfortunately, consensus has still to be achieved regarding thresholds for abdominal obesity until further evidence is available. The lack of longer-term prospective studies on which the criteria are based is a major criticism of each definition, as is the lack of evidence to support the alteration of individual thresholds for each criterion, such as the IDF’s decision to reduce the threshold for waist circumference from 102 to 94 cm. Consequently, the existence of multiple definitions has hampered comparison between studies, hence even the basic population prevalence of the syndrome is difficult to ascertain with any certainty.
| Measure | Categorical Cut Points |
|---|---|
| Elevated waist circumference | Population and country-specific definitions |
| Elevated triglycerides (or drug therapy) | >1.7 mmol/L |
| Reduced high-density lipoprotein cholesterol (or drug therapy) | <1 mmol/L in males <1.3 mmol/L in females |
| Elevated blood pressure (or drug therapy) | >130/85 mm Hg |
| Elevated fasting glucose (or drug therapy) | >5.6 mmol/L |
The MetS
Recently defined, the term “metabolic syndrome” is used to describe the presence of certain metabolic abnormalities and cardiovascular risk factors in an individual with increased adiposity. The clustering of metabolic disorders in certain individuals, however, has been recognized for much longer; as early as the 1920s the association between hyperglycemia, hypertension, and gout was described, and in 1980 the association of obesity with dyslipidemia was made. By 1988, Reaven had coined the term “syndrome X” to describe the association between insulin-resistance, type 2 diabetes mellitus, hypertension, and cardiovascular disease and in 1998 the first formal definition of MetS was proposed by the World Health Organization (WHO). Over the subsequent years the literature on MetS has expanded significantly despite, or perhaps in part because of, its controversial clinical significance and conflicting definitions.
Since first described in 1998, there have been a further four definitions of MetS published by different working groups, and one significant modification and one consensus statement. Each definition differs with regard to the most suitable measure of obesity, the thresholds used for each criterion, and most importantly in the method used to assess disordered insulin metabolism ( Table 1 ). The initial WHO recommendation, published as part of wider definition and classification of diabetes, was mainly designed as a guideline and not necessarily a complete definition of MetS. This recommendation considered MetS to have at its core disordered insulin metabolism and insulin resistance (IR), and hence it is viewed as part of the diabetic spectrum. It has, however, been criticized for the inclusion of microalbuminuria and its measure of IR (using a euglycemic clamp), which is not easily applicable to either routine clinical practice or large-scale research studies. In 1999, the European Group for the Study of Insulin Resistance modified this definition. They excluded diabetic subjects, used waist circumference as a measure of adiposity, and used fasting insulin levels as a surrogate for IR. In contrast, the Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (ATPIII) of 2001, modified in 2005 by the American Heart Association and National Heart, Lung, and Blood Institute (NHLBI), considers MetS as a precursor to diabetes and excluded those with overt type 2 diabetes. More applicable to clinical practice, the NCEP does not include any essential criteria and does not measure IR, instead using fasting glucose levels as a surrogate. Most recently, the International Diabetes Federation (IDF) definition has an essential criterion of (ethnic-specific) central obesity, removing the presence of documented IR and focusing instead on the presence of impaired glycemic control. Justifying their modifications, the authors emphasize the need for a simple definition to increase the clinical applicability of the syndrome by using criteria that are easy to measure, are widely available, and are applicable to different ethic populations.
| WHO 1998 | EIGR 1999 | NCEP ATPIII 2001 | AACE 2003 | IDF 2006 | |
|---|---|---|---|---|---|
| Essential | IR | IR | IGT | Central obesity | |
| High insulin or IFG or IGT | Top 25% of fasting insulin values in nondiabetics | (ethnicity specific) | |||
| Plus | Two or more of | Two or more of | Any three of | Two or more of | Two or more of |
| Hypertension | Hypertension | Hypertension | Hypertension | Hypertension | |
| BP >140/90 a mm Hg | BP 140/90 mm Hg | BP >130/85 mm Hg | BP 130/85 mm Hg | BP >130/85 mm Hg | |
| Dyslipidemia | Dyslipidemia | Dyslipidemia | Dyslipidemia | Dyslipidemia | |
| TG >1.7 mmol/L | TG >2 mmol/L | TG >1.7 mmol/L | TG >1.7 mmol/L | TG >1.7 mmol/L | |
| +/or low HDL-C | HDL-C <1 mmol/L | Low HDL-C | HDL-C | Low HDL-C | |
| ♂ <0.9 mmol/L | ♂ <1 mmol/L | ♂ <1 mmol/L | ♂ <1.03 mmol/L | ||
| ♀ <1 mmol/L | ♀ < 1.25 mmol/L | ♀ <1.25 mmol/L | ♀ <1.29 mmol/L | ||
| Central obesity | Central obesity | Central obesity | |||
| ♂ WHR >0.9 | ♂ WC >94 cm | ♂ WC >102 cm | |||
| ♀ WHR >0.85 | ♀ WC >80 cm | ♀ WC >88 cm | |||
| or BMI >30 kg/m 2 | |||||
| Microalbuminuria | Fasting glucose >6.1 mmol/L | Fasting glucose >5.6 mmol/L |
Recently, to resolve outstanding contentious issues and harmonize the criteria a Joint Interim Statement from the IDF, NHLBI, American Heart Association, World Heart Federation, International Atherosclerosis Society, and International Association for the Study of Obesity was published with agreement reached regarding a new definition of MetS ( Table 2 ). Unfortunately, consensus has still to be achieved regarding thresholds for abdominal obesity until further evidence is available. The lack of longer-term prospective studies on which the criteria are based is a major criticism of each definition, as is the lack of evidence to support the alteration of individual thresholds for each criterion, such as the IDF’s decision to reduce the threshold for waist circumference from 102 to 94 cm. Consequently, the existence of multiple definitions has hampered comparison between studies, hence even the basic population prevalence of the syndrome is difficult to ascertain with any certainty.
| Measure | Categorical Cut Points |
|---|---|
| Elevated waist circumference | Population and country-specific definitions |
| Elevated triglycerides (or drug therapy) | >1.7 mmol/L |
| Reduced high-density lipoprotein cholesterol (or drug therapy) | <1 mmol/L in males <1.3 mmol/L in females |
| Elevated blood pressure (or drug therapy) | >130/85 mm Hg |
| Elevated fasting glucose (or drug therapy) | >5.6 mmol/L |
Epidemiology of MetS in the general population
The exact prevalence of MetS depends largely on the definition used and varies considerably between populations ( Table 3 ). Perhaps the only certainty regarding MetS is the fact that its prevalence is increasing over time in parallel with the rising prevalence of obesity. Although an extensive review of the many studies examining the prevalence of MetS around the world is outside the scope of this article, it is worth discussing two that demonstrate several important points. First, the San Antonio Heart Study of an ethnically mixed United States population (N >2500) reported a widely variable prevalence of MetS depending on the definition used: in white males the prevalence was 18.8% using the WHO definition, 24% using the ATPIII definition, and 28% using the IDF definition. The study also demonstrated a significant difference in prevalence of MetS between the two main ethnic groups (white and Hispanic), which does support the need for ethnic-specific criteria. Second, Ford and colleagues demonstrate the increasing prevalence of MetS over time in two cohorts (1988–1994 and 1999–2002) of the National Health and Examination Survey from 23.1% to 26.7% using the ATPIII criteria. Much of the difference was caused by a much larger age-adjusted increase in prevalence of MetS in women (23.5%) compared with men (2.2%) because of concurrent increases in rates of obesity.
| Number | Age | ATPIII | WHO | IDF | ||||
|---|---|---|---|---|---|---|---|---|
| M | F | M | F | M | F | |||
| Australia | 11,247 | >25 | 24.4 | 19.9 | 25.4 | 18.2 | 34.4 | 27.2 |
| Denmark | 2493 | 41–72 | 18.6 | 14.3 | 23.8 | 17.5 | ||
| Iran | 10,368 | >20 | 24 | 40.5 | 17 | 20 | 21 | 41 |
| Ireland | 890 | 50–69 | 21.8 | 21.5 | 24.6 | 17.8 | ||
| Mexico | 2158 | 20–69 | 28.5 | 25.2 | 13.4 | 13.8 | ||
| Taiwan | 5936 | 20–80 | 18.3 | 13.6 | 16.1 | 13.3 | ||
| United States a | 2559 | 25–64 | 24 | 16 | 18 | 12 | 28 | 24 |
| United States | 8608 | >20 | 24 | 23.4 | 27.9 | 22.6 | — | — |
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