The "hypertriglyceridaemic waist" phenotype: review of evidence

• The "hypertriglyceridaemic waist" phenotype

The “hypertriglyceridaemic waist” phenotype: association with other features of the Metabolic Syndrome

• Total cholesterol/HDL-cholesterol ratio
• Postprandial hyperlipidaemia
• Fasting hyperinsulinaemia and type 2 diabetes
• "Hypertriglyceridaemic waist" phenotype trends

Conclusions
References

 The Metabolic Syndrome: role and importance of the lipid components

• Hypertriglyceridaemia
• Low HDL-cholesterol
• Pathophysiology
• Management of the lipid components of Metabolic Syndrome
  • Lifestyle
  • Therapeutics
  • References

The "hypertriglyceridaemic waist" phenotype: review of evidence

Patricia BLACKBURN, M.Sc., Isabelle LEMIEUX, Ph.D., Jean-Pierre DESPRÉS, Ph.D., FAHA Québec Heart Institute, Laval Hospital Research Center Ste-Foy (Québec), Canada

The Metabolic Syndrome increases the risk of cardiovascular disease and type 2 diabetes. The simultaneous measurement and interpretation of waist circumference and triglyceride level, "the hypertriglyceridaemic waist", may be a simple tool to identify individuals at high risk.

The National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III) has recognised the Metabolic Syndrome as a cluster of abnormalities increasing the risk of both cardiovascular disease (CVD) and type 2 diabetes. ¹ The NCEP-ATP III guidelines have also underlined the central role of abdominal obesity in the development of this syndrome. ¹ Nowadays, it is generally accepted that abdominal obesity is associated with numerous metabolic complications increasing the risk of type 2 diabetes and CVD (Figure 1). ² Results of the prospective Québec Cardiovascular Study have revealed that the presence of some features of Metabolic Syndrome found in viscerally obese men was predictive of a substantially increased risk of coronary heart disease (CHD). ³ For instance, it has been shown in this study that men with the simultaneous presence of fasting hyperinsulinaemia, elevated apolipoprotein B levels, and an increased proportion of small LDL particles (a cluster that we have referred to as the atherogenic metabolic triad) were characterised by a 20-fold increase in the risk of developing CHD over the 5year follow-up period of the study, compared with men without this cluster of non-traditional risk markers.³ In addition, the risk of CVD associated with the atherogenic metabolic triad remained significant even after adjustment for traditional risk factors such as LDL-cholesterol, triglyceride and HDL-cholesterol levels. ³

The "hypertriglyceridaemic waist" phenotype

Since most physicians do not have access to the measurement of these new metabolic markers of CHD risk, we were interested in developing a simple and inexpensive screening tool that could improve the ability of health professionals to identify individuals at high risk of developing CHD. In this regard, we have proposed that the simultaneous measurement and interpretation of waist circumference and of fasting triglyceride levels could be used to identify men characterised by the atherogenic metabolic triad (Figure 2). ⁴ For instance, a positive association had been found between visceral adipose tissue accumulation and apolipoprotein B or plasma insulin levels. ⁵ Unfortunately, the direct and precise measurement of visceral adipose tissue can only be obtained by sophisticated imaging techniques such as computed tomography and magnetic resonance imaging. However, visceral adipose tissue accumulation can be crudely estimated by measuring waist circumference. ⁶ On the other hand, fasting hypertriglyceridaemia has been reported to be the best predictor of the presence of small LDL particles. ^{7, 8}

Thus, on the basis of these observations, waist circumference and fasting triglyceride levels were tested for their ability to identify high-risk men who might be carriers of the atherogenic metabolic triad (hyperinsulinaemia, elevated apolipoprotein B, and small LDL particles). In this regard, sensitivity and specificity analyses conducted in a sample of adult men (aged between 28 and 63 years) showed that a cut-off point of 90 cm for waist circumference combined with a cut-off point of 2.0 mmol/l for triglyceride levels provided the best indication to identify men with these features of the Metabolic Syndrome (Figure 1). ⁴ For instance, 84% of men with the hypertriglyceridaemic waist phenotype (waist circumference ≥90 cm and fasting triglyceride levels ≥2.0 mmol/l) were carriers of the atherogenic metabolic triad. ⁴ Additional analyses also underlined the clinical importance of the hypertriglyceridaemic waist phenotype in the assessment of risk of coronary artery disease (CAD) and type 2 diabetes. ^4,9 Indeed, in a sample of 287 men who underwent coronary angiographic procedures for symptoms of CAD, it was found that men with both elevated waist circumference (≥90 cm) and triglyceride levels (≥2.0 mmol/l) were characterised by a 3.6-fold increase in the risk of CAD compared with men without the hypertriglyceridaemic waist phenotype.4 Moreover, the prevalent odds ratio of being affected by diabetes was also markedly increased (12-fold increase) in men with simultaneous elevations in waist circumference and triglyceride levels. ⁹

On the other hand, it has been suggested that the hypertriglyceridaemic waist phenotype (waist circumference ≥90 cm and fasting triglyceride levels ≥2.0 mmol/l) had a greater impact on CAD risk than the presence and/or absence of impaired fasting glucose. ¹⁰ Indeed, the hypertriglyceridaemic waist phenotype significantly increased the odds of finding CAD in men with either normal glucose levels or impaired fasting glucose state, whereas impaired fasting glucose was not predictive of CAD in the absence of hypertriglyceridaemic waist. ¹⁰ Similar results were obtained in a larger sample of men and women from the Hoorn Study.11 Irrespective of their plasma glucose levels, patients characterised by hypertriglyceridaemic waist (waist circumference ≥94 cm for men and ≥80 for women and fasting triglyceride levels ≥2.0 mmol/l) had markedly elevated risk of CVD.11 Although cardiovascular risk could be partly modulated by glycaemia, these results suggest that cardiologists aiming at an early identification of high-risk patients should pay more attention to the presence/absence of the hypertriglyceridaemic waist phenotype rather than to moderate hyperglycaemia.

The ability of the hypertriglyceridaemic waist phenotype to identify high-risk patients has also been investigated in other studies. ^12-15 Although cut-off values for waist circumference and triglyceride levels were slightly different across studies, similar conclusions were reached. Solati et al ¹³ have demonstrated that 75% of men characterised by the hypertriglyceridaemic waist phenotype had four to six risk factors for CVD. Kahn et al ¹² have also demonstrated that subjects with both elevated triglyceride and waist circumference values were characterised by a more deteriorated fasting metabolic profile compared with individuals without this phenotype. Other studies have also validated the ability of the hypertriglyceridaemic waist phenotype to identify women at high risk for CVD.^12,14,15 Indeed, LaMonte et al¹⁴ have demonstrated that more than 66% of women with the hypertriglyceridaemic waist phenotype were characterised by the simultaneous presence of hyperinsulinaemia, elevated apolipoprotein B levels and high LDL-cholesterol concentrations. However, in this study, only a few women were characterised by the hypertriglyceridaemic waist phenotype. ¹⁴ In another study conducted in indigenous Australian women, the risk of having hyperinsulinaemia and elevated apolipoprotein B levels was significantly increased (8 folds) in women with the hypertriglyceridaemic waist phenotype compared with women without this phenotype. 15 Thus, all these results emphasise the efficacy of the hypertriglyceridaemic waist phenotype to identify subjects at high risk for CVD and type 2 diabetes.

Figure 1. Metabolic abnormalities associated with abdominal obesity (A) and screening tools to identify abdominally obese individuals characterised by these metabolic alterations (B). WHO: “World Health Organization;” EGIR: “European Group for the study of Insulin Resistance.”

Figure 2. Atherogenic metabolic triad: importance of waist circumference and fasting triglyceride levels as screening tools

The “hypertriglyceridaemic waist” phenotype: association with other features of the Metabolic Syndrome

Total cholesterol/HDL-cholesterol ratio

The total cholesterol/HDL-cholesterol ratio is a well known predictor of CHD risk. ^16,17 We have recently shown that men characterised by the hypertriglyceridaemic waist phenotype had a substantially elevated total cholesterol/HDL-cholesterol ratio compared with those without this phenotype. ⁹ In this study, only 3% of men with waist circumference <90 cm and triglyceride levels <2.0 mmol/l had a total cholesterol/HDLcholesterol ratio of 6 or higher. ⁹ However, almost 50% of subjects characterised by the hypertriglyceridaemic waist phenotype had a ratio above 6. ⁹ Similar conclusions were reached in other study populations. ^10,12,15

Postprandial hyperlipidaemia

Case-control studies have suggested that postprandial triglyceride levels may be more closely associated with atherogenic risk than fasting triglyceride concentrations ^18-20 and it has even been suggested that postprandial hyperlipidaemia may be an independent cardiovascular risk factor. ^19,20 Although this point remains an issue of considerable debate, these results underline the relevance of exploring postprandial lipoprotein levels. Recent data have reported that men with the hypertriglyceridaemic waist phenotype showed the most substantial increase in triglyceride concentrations during the postprandial state. 21 These data also indicate that the presence of both abdominal obesity and elevated triglyceride levels may be a better predictor of postprandial hyperlipidaemia than triglyceride levels or waist circumference measured in isolation. ²¹

Fasting hyperinsulinaemia and type 2 diabetes

The hypertriglyceridaemic waist phenotype has also been associated with fasting hyperinsulinaemia. ²² Indeed, it has been reported that 68% of men subjects with simultaneous elevations in waist circumference and triglyceride levels had increased fasting insulin levels (greater than 85 pmol/l). ²² However, only 4% of men with waist circumference <90 cm and triglyceride levels <2.0 mmol/l presented fasting hyperinsulinaemia. ²² In this study, the hypertriglyceridaemic waist phenotype was also a better tool to predict fasting hyperinsulinaemia than waist circumference or fasting triglyceride levels considered in isolation.22 The hypertriglyceridaemic waist phenotype has also been associated with a marked increase in the prevalence of diabetes in adult men and women. ^9,12 Indeed, it was reported that more than 25% of men and women aged between 40 and 74 years and characterised by the hypertriglyceridaemic waist phenotype had diabetes. ¹² Lemieux et al⁹ have also found an increased proportion of diabetic patients among men who were carriers of the hypertriglyceridaemic waist phenotype compared with men with normal waist circumference and triglyceride levels. Moreover, in this study, men with the hypertriglyceridaemic waist phenotype were characterised by a metabolic profile which was as deteriorated as the one observed among patients with diabetes. ⁹

Thus, these results suggest that the hypertriglyceridaemic waist phenotype may be useful in the screening of patients with many features of Metabolic Syndrome (Table), such as an elevated total cholesterol/HDL-cholesterol ratio, postprandial hyperlipidaemia, fasting hyperinsulinaemia and additional risk factors. In addition, approximately 75% to 80% of type 2 diabetic patients are characterised by the presence of Metabolic Syndrome which may contribute to increase their risk of CVD beyond hyperglycaemia. As type 2 diabetic patients could be identified by the simultaneous measurement of waist circumference and fasting triglyceride levels, these results underline the clinical importance of the hypertriglyceridaemic waist phenotype as a simple approach to better evaluate CHD risk in individuals with abdominal obesity.

"Hypertriglyceridaemic waist" phenotype trends

By using a representative sample of the Québec population, we have quantified the prevalence of the hypertriglyceridaemic waist phenotype in a sample of adult men from the Québec Health Survey. ⁹ Results of this study revealed that 19% of these men had simultaneously a waist circumference of 90 cm or greater and elevated triglyceride concentrations (2.0 mmol/l or higher). ⁹ In the Tehran Lipid and Glucose Study, Solati et al ¹³ quantified the prevalence of the hypertriglyceridaemic waist phenotype in a large cohort of 4000 adult men (aged between 18 and 70 years). They found that this high-risk clinical phenotype was also highly prevalent in this population (19%). ¹³ The prevalence of the hypertriglyceridaemic waist phenotype was quantified in a sample of 4448 men and 4735 women from the third National Health and Nutrition Examination Survey (NHANES III). ¹² In this study, Kahn and Valdez¹² found that, irrespective of sex, the estimated prevalence of enlarged waist and increased triglyceride levels was about 25%. They also found that the estimated prevalence of this phenotype was higher (>40%) in men and women aged between 55 and 74 years. ¹² Recently, it has been suggested that the prevalence of obesity, especially abdominal obesity as estimated by waist circumference, is increasing in our population. ²³ Therefore, we have to keep in mind that the prevalence of the hypertriglyceridaemic waist phenotype is also likely to increase in the coming years.

Conclusions

In summary, the hypertriglyceridaemic waist phenotype represents a simple and inexpensive marker allowing general physicians and other health professionals to better identify individuals at high risk of CVD and/or type 2 diabetes. Prospective studies are needed to determine which variables of Metabolic Syndrome are more critical in the determination of the risk of CVD and/or type 2 diabetes. Furthermore, using the hypertriglyceridaemic waist phenotype to identify individuals characterised by features of Metabolic Syndrome will have to be validated with optimal cut-off values determined for waist circumference and fasting triglyceride levels in various populations (different age and ethnic groups in both genders).

References

1. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002;106:3143-421.
2. Després JP, Lemieux I, Prud’homme D. Treatment of obesity: need to focus on high risk abdominally obese patients. BMJ 2001;322:716-20.
3. Lamarche B, Tchernof A, Mauriège P, et al. Fasting insulin and apolipoprotein B levels and low-density lipoprotein particle size as risk factors for ischemic heart disease. JAMA 1998;279:1955-61.
4. Lemieux I, Pascot A, Couillard C, et al. Hypertriglyceridemic waist: a marker of the atherogenic metabolic triad (hyperinsulinemia; hyperapolipoprotein B; small, dense LDL) in men? Circulation 2000;102:179-84.
5. Lemieux S, Prud’homme D, Tremblay A, et al. Anthropometric correlates to changes in visceral adipose tissue over 7 years in women. Int J Obes Relat Metab Disord 1996;20:618-24.
6. Lemieux S, Prud’homme D, Bouchard C, et al. A single threshold value of waist girth identifies normal-weight and overweight subjects with excess visceral adipose tissue. Am J Clin Nutr 1996;64:685-93.
7. Tchernof A, Lamarche B, Prud’homme D, et al. The dense LDL phenotype. Association with plasma lipoprotein levels, visceral obesity, and hyperinsulinemia in men. Diabetes Care 1996;19:629-37.
8. McNamara JR, Jenner JL, Li Z, et al. Change in LDL particle size is associated with change in plasma triglyceride concentration. Arterioscler Thromb 1992;12:1284-90.
9. Lemieux I, Alméras N, Mauriège P, et al. Prevalence of “hypertriglyceridemic waist” in men who participated in the Québec Health Survey: Association with atherogenic and diabetogenic metabolic risk factors. Can J Cardiol 2002;18:725-32.
10. St-Pierre J, Lemieux I, Vohl MC, et al. Contribution of abdominal obesity and hypertriglyceridemia to impaired fasting glucose and coronary artery disease. Am J Cardiol 2002;90:15-8.
11. Bos G, Dekker JM, Heine RJ. Non-HDL cholesterol contributes to the "hypertriglyceridemic waist" as a cardiovascular risk factor: the Hoorn study. Diabetes Care 2004;27:283-4.
12. Kahn HS, Valdez R. Metabolic risks identified by the combination of enlarged waist and elevated triacylglycerol concentration. Am J Clin Nutr 2003;78:928-34.
13. Solati M, Ghanbarian A, Rahmani M, et al. Cardiovascular risk factors in males with hypertriglycemic waist (Tehran Lipid and Glucose Study). Int J Obes Relat Metab Disord 2004;28:706-9.
14. LaMonte MJ, Ainsworth BE, DuBose KD, et al. The hypertriglyceridemic waist phenotype among women. Atherosclerosis 2003;171:123-30.
15. Hiura Y, Acklin F, Newman J, et al. Hypertriglyceridemic waist as a screening tool for CVD risk in indigenous Australian women. Ethn Dis 2003;13:80-84.
16. Lemieux I, Lamarche B, Couillard C, et al. Total cholesterol/HDL cholesterol ratio vs LDL cholesterol/HDL cholesterol ratio as indices of ischemic heart disease risk in men: the Québec Cardiovascular Study. Arch Intern Med 2001;161:2685-92.
17. Kinosian B, Glick H, Preiss L, et al. Cholesterol and coronary heart disease: predicting risks in men by changes in levels and ratios. J Investig Med 1995;43:443-50.
18. Zilversmit DB. Atherogenesis: a postprandial phenomenon. Circulation 1979;60:47385.
19. Patsch JR, Miesenbock G, Hopferwieser T, et al. Relation of triglyceride metabolism and coronary artery disease. Studies in the postprandial state. Arterioscler Thromb 1992;12:1336-45.
20. Boquist S, Ruotolo G, Tang R, et al. Alimentary lipemia, postprandial triglyceride-rich lipoproteins, and common carotid intima-media thickness in healthy, middle-aged men. Circulation 1999;100:723-8.
21. Blackburn P, Lamarche B, Couillard C, et al. Postprandial hyperlipidemia: another correlate of the "hypertriglyceridemic waist" phenotype in men. Atherosclerosis 2003;171:327-36.
22. Scarsella C, Alméras N, Lemieux I, et al. Importance of hypertriglyceridemic waist as a screening tool for the identification of hyperinsulinemic men (abstract). Can J Cardiol 2002;18:171B-72B.
23. Ford ES, Mokdad AH, Giles WH. Trends in waist circumference among U.S. adults. Obes Res 2003;11:1223-31.

The Metabolic Syndrome: role and importance of the lipid components

Individuals with the Metabolic Syndrome, particulary those with abdominal obesity, exhibit a highly atherogenic lipid profile which may account for their high risk of cardiovascular disease and premature death.

The Metabolic Syndrome is characterised by the co-occurrence of obesity (especially central obesity), dyslipidaemia, hyperglycaemia, and hypertension. This cluster of metabolic and cardiovascular (CV) risk factors has been recognised by two expert groups, the World Health Organisation (WHO) and the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III). ^1,2 This syndrome is common, affecting about 40% of the population over 50 in the United States and nearly 30% in Europe. Furthermore, the prevalence of Metabolic Syndrome increases with age, affecting more than 40% of individuals over 60. ³

The presence of the Metabolic Syndrome is of relevance to public health since it has been linked to an increased risk of both cardiovascular disease (CVD) and type 2 diabetes. In particular, recent evidence shows that the presence of Metabolic Syndrome is associated with an increased risk of coronary heart disease (CHD), myocardial infarction, and stroke in both sexes. ^4,5 This substantially higher risk of CV morbidity and mortality associated with the presence of Metabolic Syndrome appears independent of other significant, potentially confounding factors such as smoking, plasma LDL cholesterol levels or alcohol consumption. ^4,5

Dyslipidaemia is an integral part of the Metabolic Syndrome since both definitions include hypertriglyceridaemia (defined as serum triglycerides >=150 mg/dl) and a low HDL cholesterol concentration (defined as HDL-C<40 mg/dl for men and <50 mg/dl for women by NCEP ATP III, or HDL-C <35 mg/dl for men and <40 mg/dl for women by WHO) as component traits. ^1,2 Individuals with the Metabolic Syndrome, particularly those with abdominal obesity, exhibit a highly atherogenic lipid profile which may account for their high risk of CVD.

Central fat accumulation and presence of insulin-resistance have both been associated with a cluster of dyslipidaemic features, i.e., elevated plasma triglyceride level, an increase in very-low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL), presence of small dense LDL particles, and a decrease in HDL-cholesterol. These abnormalities of lipoprotein metabolism are more likely to occur together than separately and constitute key component traits of the Metabolic Syndrome.

Hypertriglyceridaemia

Beyond the LDL-cholesterol level, the presence of elevated serum triglycerides substantially increases the risk of CVD. Recent prospective studies indicate that elevated triglycerides are an independent risk factor in CHD. ⁶

Hypertriglyceridaemia is associated with several atherogenic factors including increased concentrations of triglyceride-rich lipoproteins and the atherogenic lipoprotein phenotype consisting of small dense LDL particles, and low high- density lipoprotein (HDL) cholesterol. ⁷

Factors contributing to hypertriglyceridaemia in the general population include obesity, overweight, physical inactivity, excess alcohol intake, high-carbohydrate diet, type 2 diabetes, and some other diseases (e.g. chronic renal failure, nephrotic syndrome), certain drugs (e.g. corticosteroids, estrogens, retinoids, higher doses of adrenergic blocking agents), and genetic disorders (familial combined hyperlipidaemia, familial hypertriglyceridaemia, and familial dysbetalipoproteinemia).

In daily practice, elevated serum triglycerides are predominantly observed in persons with Metabolic Syndrome. Many previous studies indicate that hypertriglyceridaemia is strongly associated with all components of Metabolic Syndrome.

Patients with Metabolic Syndrome who have hypertriglyceridaemia most often exhibit elevated level of triglyceride-rich lipoproteins which are considered atherogenic. The latter are partially degraded VLDL, commonly called "remnant lipoproteins". In clinical practice, VLDL cholesterol is the most readily available measure of atherogenic remnant lipoproteins. Thus, VLDL cholesterol can be a target of cholesterol-lowering therapy. Recent guidelines identify the sum of LDL+IDL+VLDL cholesterol (termed "non-HDL cholesterol" [total cholesterol minus HDL cholesterol]) as a secondary target of therapy in persons with hypertriglyceridaemia. ²

Low HDL-cholesterol

Low levels of HDL-cholesterol are associated with increased risk of coronary artery disease (CAD). ^8,9 This relationship was observed irrespective of age, blood pressure level, obesity, total cholesterol or LDL-cholesterol levels. ^8,9 The term "isolated low HDL" has been used to describe the situation where total cholesterol or LDL-cholesterol are considered normal but HDL-cholesterol is low. Long-term follow-up of subjects with low HDL-C has demonstrated that their risk of developing CAD is similar to the risk for subjects with elevated total cholesterol or LDL-cholesterol. ^10,11 Low HDL-cholesterol is the strongest predictor of subsequent CV events in patients with angiographically proven CAD and levels of total cholesterol within the normal range. ¹²

According to current guidelines, the presence of low HDL-cholesterol should be considered a major CV risk factor, which modifies the goal for LDL-lowering therapy and is used as a risk factor to estimate the 10-year risk for CHD. ²

A low HDL-cholesterol level has several causes, some of which are associated with insulin resistance, i.e. elevated triglycerides, overweight and obesity, physical inactivity, and type 2 diabetes. The combination of a low HDL-C with elevated plasma triglyceride level has therefore been considered an insulin-resistant state. ¹³ It should be noted that certain drugs also reduce the level of HDL-C (e.g. beta-blockers, anabolic steroids, progestational agents).

Nevertheless, low HDL-cholesterol is an important component trait of Metabolic Syndrome and deserves close clinical attention and management since these patients are at high risk of CVD.

Pathophysiology

As shown in Figure 1, the lipoprotein abnormalities observed in Metabolic Syndrome are closely interrelated and rely on both insulin resistance and central obesity. Patients with Metabolic Syndrome who have hypertriglyceridaemia and a low HDL-C level usually exhibit both insulin resistance and central obesity. Furthermore, the atherogenic lipoprotein profile associated with obesity and insulin resistance, i.e. higher triglycerides, VLDL-C, IDL-C, LDL-C, and apolipoprotein B, as well as lower HDL-C, is largely attributable to intra-abdominal fat. ¹⁴

Figure 1: Dyslipidaemic profile associated with central obesity and Metabolic Syndrome

The presence of central fat is therefore a key pathophysiological mechanism underlying Metabolic Syndrome-associated dyslipidaemias (Figure 1). <;/p>

The cluster of dyslipidaemic components explains, at least in part, the increased CV risk associated with Metabolic Syndrome. In this regard, diabetic subjects with low HDL-C and elevated triglyceride levels have a substantially higher risk for major CV events than diabetics without these features, underscoring the importance of Metabolic Syndromerelated dyslipidaemia in the presence of type 2 diabetes.

Small, dense LDL particles have been associated with the metabolic disturbances observed in Metabolic Syndrome (hypertriglyceridaemia, low HDL-C, intolerance to glucose or type 2 diabetes). The atherogenic effect of Metabolic Syndrome may therefore be mediated by an increased occurrence of small LDL particles, insofar as several crosssectional and prospective studies have shown a greater risk of CAD in the presence of small LDL particles. ^15,16 Small LDL particles are modified to atherogenic oxidised LDL (oxLDL) more easily than large LDL particles, accounting for the increased risk of CHD associated with this phenotype.

In this regard, it has been shown that Metabolic Syndrome is accompanied by high plasma ox-LDL concentrations in association with increased atherosclerotic lesions (as assessed by increased carotid intima-media thickness) compared with those without the syndrome (Figure 2). ^17,18 Furthermore, ox-LDL significantly correlate with factors constituting Metabolic Syndrome (i.e., triglycerides, plasma insulin, body mass index, waist-to-hip ratio, and HDL-C). 18

Figure 2: Association between the Metabolic Syndrome, carotid atherosclerosis and LDL size (adapted from ref 17)

Ox-LDL also correlate with LDL particle size, apo-B, and LDL levels.¹⁸ A recent study in diabetic patients demonstrated the combined effect of small LDL particle size and other dyslipidaemias including hypertriglyceridaemia on the progression of coronary atherosclerosis. ¹⁹ In this study, LDL size modulated the progression of coronary atherosclerosis (as assessed by quantitative coronary angiography), so that patients with small LDL particles had a more pronounced progression of atherosclerosis than those with large particles. ¹⁹

Management of the lipid components of Metabolic Syndrome

Lifestyle

Lifestyle modifications leading to weight loss and increased physical activity are the cornerstones of treatment.

Physical activity (recommended as exercise for 30 minutes at least three to five times per week), weight loss (recommended as a 10% loss of body weight in the first year) and appropriate diet have a favourable impact on the components of Metabolic Syndrome, at least in the relatively short term.

Both caloric restriction and exercise training improve the lipid profile and are associated with reduction in abdominal fat as well as an increase in insulin sensitivity. ^20-23 However, the long-term effectiveness of such interventions needs to be tested at the population level.

Therapeutics

Clinical trial results suggest that raising HDL-C will reduce the risk of CVD, independently of changes in LDL-C level. ²⁴ However, no specific goal for HDL-C raising has yet been generally accepted.

In case of low HDL-C with normal triglyceride levels (isolated low HDL-cholesterol), HDLC raising drugs such as fibrates have to be considered, especially in persons with CHD and CHD risk equivalents. ² Furthermore, some studies have shown that the addition of fenofibrate to a statin leads to an additional decrease in VLDL + IDL cholesterol and a further increase in HDL cholesterol and in the ratio of large-to-small LDL particles. No significant side effects were observed with this combined drug therapy, albeit in a smallscale study. 25

When low HDL-cholesterol is associated with a high triglycerides level, weight reduction and increased physical activity are first recommended with correction of hyperglycaemia in case of diabetes and/or alterations in glucose metabolism. For atherogenic Metabolic Syndrome-associated dyslipidaemia (high triglycerides, small LDL, and low HDL-C), fibrates such as fenofibrate are potentially beneficial. Indeed, fibrates substantially increase HDL-C and reduce both triglyceride and LDL-C levels (Figure 3). Furthermore, through a dual effect on VLDL and LDL, fenofibrate may further reduce non-HDL cholesterol.

Figure 3: Effects of fibrate treatment on both HDL-C and triglycerides levels in diabetic and non-diabetic patients with a low HDL-C in secondary prevention (adapted from ref 26).

As shown in Figure 4, in the VA-HIT study, patients with coronary disease and a low HDLC who were treated for 5 years with a fibrate (gemfibrozil) had significantly fewer coronary events than those treated with a placebo, suggesting that this class of HDLraising drug is beneficial in CV secondary prevention. ²⁴

Figure 4: Effect of fibrate treatment (gemfibrozil) on major cardiovascular events (adapted from ref 24).

In this trial, nearly 40% of the patients were obese, and approximately 50% had diabetes or impaired glucose tolerance. In the VA-HIT study, the benefits conferred by the fibrate were particularly significant in the subgroup of patients with diabetes or hyperinsulinaemia alone (Figure 5), and with obesity. ²⁶

Figure 5: Reduction of cardiovascular events conferred by fibrate therapy in diabetic patients with a low HDL-C in secondary prevention (adapted from ref 26).

It was demonstrated recently in the DAIS study that treatment with fenofibrate significantly reduced progression of coronary atherosclerosis in diabetic patients (Figure 6). ²⁷ In this trial, as compared with the placebo group, fenofibrate treatment was associated with a substantial improvement in lipid profile (reduction in total cholesterol, LDL-C, triglycerides and increase in HDL-C). Although the trial was not designed to examine clinical end-points, there were fewer CV events and less coronary revascularisations in the fenofibrate group than in the placebo group (-23%, NS). ²⁷

Furthermore, in these patients, fenofibrate treatment induced a significant increase in LDL particle size in association with slowed progression of coronary atherosclerosis as compared with the placebo group. ¹⁹ These findings suggest that in addition to improving lipid profile, changes in LDL size account for part of the antiatherogenic effect of fenofibrate. In this respect, the results of the largest prospective trial in diabetics ever, the FIELD study, addressing the effect of fenofibrate on CV events, will be of great value in confirming the benefits of this fibrate in type 2 diabetic subjects.

In conclusion, the clinical approach to treatment of patients with dyslipidaemiasassociated Metabolic Syndrome requires a broad-based strategy that includes reversal of lipid abnormalities (low HDL-C, hypertriglyceridaemia, elevated LDL-C), reduction of atherogenic triglyceride-rich lipoproteins, and improvement of insulin-resistance. Lifestyle modifications (balanced diet and increased physical exercise) should first be proposed. Drug therapy targeting hypertriglyceridaemia and low HDL-C could be proposed in association with diet and exercise. In this respect, fibrates represent an attractive choice of first-line therapy for patients with dyslipidaemic components of the Metabolic Syndrome.

References

1. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 1998;15:539-53.
2. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. 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 (Adult Treatment Panel III). JAMA 2001;285:2486-97.
3. Ford ES, Giles WH, Dietz WH. Prevalence of the Metabolic Syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 2002;287:356-9.
4. Lakka HM, Laaksonen DE, Lakka TA, et al. The Metabolic Syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 2002;288:2709-16.
5. Isomaa B, Almgren P, Tuomi T, et al. Cardiovascular morbidity and mortality associated with the Metabolic Syndrome. Diabetes Care 2001;24:683-9.
6. Eberly LE, Stamler J, Neaton JD; Multiple Risk Factor Intervention Trial Research Group. Relation of triglyceride levels, fasting and nonfasting, to fatal and nonfatal coronary heart disease. Arch Intern Med 2003;163:1077-83.
7. Campos H, Blijlevens E, McNamara JR, et al. LDL particle size distribution: results from the Framingham Offspring Study. Arterioscler Thromb 1992;12:1410-9.
8. Jacobs DR Jr, Mebane IL, Bangdiwala SI, et al. High density lipoprotein cholesterol as a predictor of cardiovascular disease mortality in men and women: the follow-up study of the Lipid Research Clinics Prevalence Study. Am J Epidemiol 1990;131:32-47.
9. Goldbourt U, Holtzman E, Neufeld HN. Total and high density lipoprotein cholesterol in the serum and risk of mortality: evidence of a threshold effect. Br Med J 1985;290:123943.
10. Lamarche B, Despres JP, Moorjani S, et al. Prevalence of dyslipidemic phenotypes in ischemic heart disease (prospective results from the Quebec Cardiovascular Study). Am J Cardiol 1995;75:1189-95.
11. Goldbourt U, Yaari S, Medalie JH. Isolated low HDL cholesterol as a risk factor for coronary heart disease mortality. A 21-year follow-up of 8000 men. Arterioscler Thromb Vasc Biol 1997;17:107-13.
12. Miller M, Seidler A, Kwiterovich PO, Pearson TA. Long-term predictors of subsequent cardiovascular events with coronary artery disease and “desirable” levels of plasma total cholesterol. Circulation 1992;86:1165-70.
13. Karhapaa P, Malkki M, Laakso M. Isolated low HDL cholesterol. An insulin-resistant state. Diabetes 1994;43:411-7.
14. Nieves DJ, Cnop M, Retzlaff B, et al. The atherogenic lipoprotein profile associated with obesity and insulin resistance is largely attributable to intra-abdominal fat. Diabetes 2003;52:172-9.
15. Austin MA, Breslow JL, Hennekens CH, et al. Low-density lipoprotein subclass patterns and risk of myocardial infarction. JAMA 1988;260:1917-21.
16. Gardner CD, Fortmann SP, Krauss RM. Association of small low-density lipoprotein particles with the incidence of coronary artery disease in men and women. JAMA 1996;276:875-81.
17. Hulthe J, Bokemark L, Wikstrand J, Fagerberg B. The Metabolic Syndrome, LDL particle size, and atherosclerosis: the Atherosclerosis and Insulin Resistance (AIR) study. Arterioscler Thromb Vasc Biol 2000;20:2140-7.
18. Sigurdardottir V, Fagerberg B, Hulthe J. Circulating oxidized low-density lipoprotein (LDL) is associated with risk factors of the Metabolic Syndrome and LDL size in clinically healthy 58-year-old men (AIR study). J Intern Med 2002;252:440-7.
19. Vakkilainen J, Steiner G, Ansquer JC, et al. Relationships between low-density lipoprotein particle size, plasma lipoproteins, and progression of coronary artery disease: the Diabetes Atherosclerosis Intervention Study (DAIS). Circulation 2003;107:1733-7.
20. Purnell JQ, Kahn SE, Albers JJ, et al. Effect of weight loss with reduction of intraabdominal fat on lipid metabolism in older men. J Clin Endocrinol Metab 2000;85:977-82.
21. Goldstein DJ. Beneficial health effects of modest weight loss. Int J Obes Relat Metab Disord 1992;16:397-415.
22. Katzel LI, Bleecker ER, Colman EG, et al. Effects of weight loss vs aerobic exercise training on risk factors for coronary disease in healthy, obese, middle-aged and older men. A randomized controlled trial. JAMA 1995;274:1915-21.
23. Schwartz RS, Cain KC, Shuman WP, et al. Effect of intensive endurance training on lipoprotein profiles in young and older men. Metabolism 1992;41:649-54.
24. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study