Management of Dyslipidemia in the Metabolic Syndrome: Recommendations of the Spanish HDL-Forum

Am J Cardiovasc Drugs 2007; 7 (1): 39-58REVIEW ARTICLE 1175-3277/07/0001-0039/$44.95/0

2007 Adis Data Information BV. All rights reserved.

Management of Dyslipidemia in theMetabolic SyndromeRecommendations of the Spanish HDL-Forum

Juan Ascaso,1 Pedro Gonzalez Santos,2 Antonio Hernandez Mijares,3 Alipio Mangas Rojas,4 Luis Masana,5

Jesus Millan,6 Luis Felipe Pallardo,7 Juan Pedro-Botet,8 Francisco Perez Jimenez,9 Xavier Pinto,10 Ignacio Plaza,11

Juan Rubies12 and Manuel Zuniga13

1 Endocrinolgy Service, Clinic University Hospital, University of Valencia, Valencia, Spain2 Department of Internal Medicine, University Hospital “Virgen de la Victoria”, University of Malaga, Malaga, Spain3 Endocrinology Service, University Hospital “Peset”, University of Valencia, Valencia, Spain4 Internal Medicine Service, University Hospital “Puerta del Mar”, University of Cadiz, Cadiz, Spain5 Department of Medicine, University of Reus, Tarragona, Spain6 Department of Medicine, University Hospital “Gregorio Maranon”, University Complutense, Madrid, Spain; Coordinator

of HDL-Forum7 Endocrinology and Nutrition Service, University Hospital “La Paz”, Autonomous University of Madrid, Madrid, Spain8 Department of Internal Medicine, Hospital del Mar, Autonomous University of Barcelona, Barcelona, Spain9 Lipid and Atherosclerosis Unit, Internal Medicine Service, University Hospital “Reina Sofia”, University of Cordoba,

Cordoba, Spain10 Lipid and Atherosclerosis Unit, Internal Medicine Service, University Hospital of Bellvitge, Barcelona, Spain11 Cardiology Service, Hospital Ramon y Cajal, Madrid, Spain12 Department of Medicine, Autonomous University of Barcelona, Barcelona, Spain13 Department of Internal Medicine, University Hospital “Marques de Valdecilla”, Santander, Spain

Contents

Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401. Key Elements of Lipid Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 412. Visceral Obesity and Lipid Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42

2.1 Role of the Adipose Tissue in the Metabolic Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 422.2 Derangements in Lipoprotein Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42

2.2.1 Increase in Apo B and Small, Dense Low-Density Lipoprotein (LDL) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 422.2.2 Small High-Density Lipoprotein (HDL) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

3. Insulin Resistance as the Nexus of the Various Lipidic Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 443.1 Effect of Insulin Resistance on Very Low-Density Lipoprotein and Triglyceride Profiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 443.2 Effect of Insulin Resistance on Variations in LDL-Cholesterol (LDL-C) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 453.3 Influence of Insulin Resistance on Changes in HDL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

4. Diagnosis of Dyslipidemia in the Metabolic Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 454.1 Quantitative Alterations in Lipoprotein Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

4.1.1 Hypercholesterolemia and LDL-C Increase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 454.1.2 Increased Non-HDL-C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 464.1.3 Hypertriglyceridemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 464.1.4 Low HDL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

4.2 Laboratory Diagnosis of Dyslipidemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 464.2.1 The Atherogenic Triad . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 464.2.2 Postprandial Hyperlipidemia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47

5. Overall Therapeutic Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475.1 Overweight and Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47

40 Ascaso et al.

5.2 Arterial High BP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485.3 Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 485.4 Lipid Goals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48

6. Pharmacologic and Non-Pharmacologic Treatment of Metabolic Syndrome Dyslipidemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 496.1 Lifestyle Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

6.1.1 Diet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 496.1.2 Physical Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

6.2 Pharmacologic Intervention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 506.2.1 Statins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 516.2.2 Fibrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 526.2.3 Combination Drug Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 526.2.4 Combination Therapy with Other Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 546.2.5 An Overall Strategy for Pharmacologic Therapy of Metabolic Syndrome Hyperlipidemia . . . . . . . . . . . . . . . . . . . . . . . . . . 54

7. Final Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55

In order to characterize the metabolic syndrome it becomes necessary to establish a number of diagnosticAbstractcriteria. Because of its impact on cardiovascular morbidity/mortality, considerable attention has been focussedon the dyslipidemia accompanying the metabolic syndrome.

The aim of this review is to highlight the fundamental aspects of the pathophysiology, diagnosis, and thetreatment of the metabolic syndrome dyslipidemia with recommendations to clinicians.

The clinical expression of the metabolic syndrome dyslipidemia is characterized by hypertriglyceridemia andlow levels of high-density lipoprotein-cholesterol (HDL-C). In addition, metabolic syndrome dyslipidemia isassociated with high levels of apolipoprotein (apo) B-100-rich particles of a particularly atherogenic phenotype(small dense low-density lipoprotein-cholesterol [LDL-C]. High levels of triglyceride-rich particles (very low-density lipoprotein) are also evident both at baseline and in overload situations (postprandial hyperlipidemia).Overall, the ‘quantitative’ dyslipidemia characterized by hypertriglyceridemia and low levels of HDL-C and the‘qualitative’ dyslipidemia characterized by high levels of apo B-100- and triglyceride-rich particles, togetherwith insulin resistance, constitute an atherogenic triad in patients with the metabolic syndrome.

The therapeutic management of the metabolic syndrome, regardless of the control of the bodyweight, BP,hyperglycemia or overt diabetes mellitus, aims at maintaining optimum plasma lipid levels. Therapeutic goalsare similar to those for high-risk situations because of the coexistence of multiple risk factors. The primary goalin treatment should be achieving an LDL-C level of <100 mg/dL (or <70 mg/dL in cases with establishedischemic heart disease or risk equivalents). A further goal is increasing the HDL-C level to ≥40 mg/dL in men or50 mg/dL in women. A non-HDL-C goal of 130 mg/dL should also be aimed at in cases of hypertriglyceridemia.

Lifestyle interventions, such as maintaining an adequate diet, and a physical activity program, constitute anessential part of management. Nevertheless, when pharmacologic therapy becomes necessary, fibrates andHMG-CoA reductase inhibitors (statins) are the most effective drugs in controlling the metabolic syndromehyperlipidemia, and are thus the drugs of first choice. Fibrates are effective in lowering triglycerides andincreasing HDL-C levels, the two most frequent abnormalities associated with the metabolic syndrome, andstatins are effective in lowering LDL-C levels, even though hypercholesterolemia occurs less frequently. Inaddition, the combination of fibrates and statins is highly effective in controlling abnormalities of the lipidprofile in patients with the metabolic syndrome.

Vascular disease of atherosclerotic origin has a multiple etiolo- relevant. It is thus not uncommon to observe a clinical syndrome –gy. Major predisposing risk factors include tobacco (cigarette) metabolic syndrome – encompassing both cardiovascular andsmoking, high BP, dyslipidemia and diabetes mellitus. Genetic metabolic risk factors. Insulin resistance, often accompanied by anand environmental factors, particularly those related to the lifes- increase in visceral fat, is a key factor characterizing the metabolictyle, also play an important role in disease pathogenesis. The syndrome, sharply increasing the risk of cardiovascular disease.[1]

existence of some risk factors related to metabolism is particularly Because of its impact on cardiovascular morbidity/mortality, dys-

2007 Adis Data Information BV. All rights reserved. Am J Cardiovasc Drugs 2007; 7 (1)

Management of Dyslipidemia in the Metabolic Syndrome 41

Table I. Definitions of trial acronyms used in this review

Trial acronyms Definition

4S Scandinavian Simvastatin Survival Study

AF-TEX/CAPS Air Force–Texas Coronary Atherosclerosis Prevention Study

BIP Bezafibrate Infarction Prevention

CARE Cholesterol And Recurrent Events

CHESS Comparative HDL Efficacy and Safety Study

COMETS COmparative study with rosuvastatin in subjects with METabolic Syndrome

DAIS Diabetes Atherosclerosis Intervention Study

HHS Helsinki Heart Study

LIPID Long-term Intervention with Pravastatin in Ischemic Disease

PROCAM PROspective CArdiovascular Munster study

STELLAR Statin Therapies for Elevated Lipid Levels compared Across doses to Rosuvastatin

UKPDS UK Prospective Diabetes Study

VA-HIT Veterans Affairs–High-density lipoprotein cholesterol Intervention Trial

WOSCOPS West of Scotland Coronary Prevention Study

lipidemia accompanying the metabolic syndrome has become a particles liberate fatty acids to the adipose tissue and to the liver.major focus. The atherogenic profile characteristic of the metabol- These partially delipidated and smaller particles, termed residualic syndrome consists of borderline or mildly elevated low-density particles or chylomicron remnants, will then bind to hepatic recep-lipoprotein (LDL) but low high-density lipoprotein (HDL) levels; tors that are specific for apo E, the so-called receptor-relatedhypertriglyceridemia with a shifted distribution of LDL to small protein; they will thus be internalized and after hydrolysis releaseand dense particles, may to a considerable extent explain the into the hepatocyte, fatty acids and cholesterol derived from thesignificant increase in cardiovascular risk (see table I for trial intestine.[2,3]

acronyms). In the liver, the fatty acids provided by the chylomicron rem-nant particles, those provided by mobilization from adipose cells

1. Key Elements of Lipid Metabolismaccording to the organism’s requirements and those synthesized denovo from carbohydrates will be esterified and together with theThe concentration and composition of the plasma lipoproteinsintestine-derived cholesterol and that synthesized by the hepato-depends on the balance between a number of factors such as thecyte and apo B-100 – also synthesized by the liver – will give riseformation or production of the lipoprotein particles and of theirto the formation of very low-density lipoproteins (VLDL), whichcomponents, the transformations occurring in the particles them-are secreted into the blood plasma. The triglycerides contained inselves, the exchange of lipid and protein components betweenthe circulating VLDL particles will be hydrolyzed in the muscleparticles, and finally the uptake of the particles into the cells,tissue capillaries through the action of apo C-II-activated LPL, aswhich may or not be mediated by specific cell receptors. In theis the case with chylomicrons, and as a result fatty acids will beintestine, the diet-derived fatty acids with <12 carbon atoms inreleased to the peripheral tissues, mainly the skeletal muscle andtheir molecule are absorbed and pass into the portal blood trans-adipose tissues. The partially delipidated VLDL particles, nowported by albumin. Those with longer carbon chains are re-termed intermediate-density lipoproteins (IDL) follow two differ-esterified to triglycerides, and the same process occurs with theent paths of metabolism: one pathway is internalization in the liverabsorbed cholesterol. In the small intestine wall, the conjugationbecause of their apo E contents, in a similar way to theof these substrates with various apolipoproteins (apo) synthesizedchylomicron remnants; in the second pathway, IDL will undergoin the intestinal wall, particularly apo B-48, will generate thehydrolysis of their triglycerides through the action of hepaticchylomicrons; these are carried by the lymph system, via thelipase, leading to their transformation into LDL. Through their apothoracic duct, into the general circulation. In the course of theirB-100 content, the LDL particles interact with the LDL receptorscirculation in the blood plasma chylomicrons acquire apo C-II andin the peripheral parenchymatous tissues or in the liver itself, thusapo E, which are fundamental for their metabolism. Apo C-IIclosing the circuit through which energy has been provided to therenders the chylomicrons hydrolyzable in the capillary vessels by

the action of the enzyme lipoprotein lipase (LPL), so that the peripheral tissues in the form of fatty acids and cholesterol has


42 Ascaso et al.

been provided from the liver to those same peripheral tissues. A down their uptake by macrophages in the arterial wall intima.HDL particles also exhibit antithrombotic effects and anti-inflam-fraction of the circulating LDL, after undergoing oxidativematory actions by inhibiting the expression of adhesion moleculeschange, may be taken up and internalized by the macrophagesfor circulating monocytes. All these factors result in HDL particlesthrough a mechanism mediated by scavenger receptors. This phe-reducing the risk of cardiovascular disease.[3,4]nomenon is a key factor in the pathogenesis of atherosclerosis, as

the parenchymal cells have a very fine balance with a feedback2. Visceral Obesity and Lipid Metabolismsystem in which LDL-receptor activity adapts to the metabolic

requirements and to the magnitude of the intracellular cholesteroldeposits, whereas macrophages internalize the modified LDL par- 2.1 Role of the Adipose Tissue in the Metabolic Syndrometicles without any control and quickly change into foam cells with

A number of metabolic and epidemiologic studies have shownhigh concentrations of cholesterol in their vacuolae.[2,3]

that an increase in abdominal fat is a risk factor for cardiovascularAs the human organism does not possess enzymes able to break disease.[1] The concept of ‘visceral obesity’ specifically refers to

and catabolize the cyclo-penthane-perhydro-phenantrene moiety the accumulation of adipose tissue in and on the abdominal vis-of the cholesterol molecule, this molecular structure must be cera, and this condition may be visualized through a number ofaltered after transformation in the liver into bile acids. For this to imaging techniques. The anthropometric indices, such as the waistoccur, cholesterol is transported from the peripheral tissues to the circumference, indirectly reflect abdominal fat, even though theyliver coupled to HDL. The disc-shaped nascent HDL particles do not discriminate between the subcutaneous or visceral location,synthesized in the liver and the intestine rapidly turn in the plasma they are strongly associated to the accumulation of visceral fat.into spherical particles when, through the action of the enzyme Although abdominal obesity is a major component for thelecithin : cholesterol acyl transferase (LCAT) cholesterol is esteri- identification of the metabolic syndrome both in the Adult Treat-fied and accedes to the core of the HDL particles. A large propor- ment Panel (ATP) III[5] and in the WHO criteria,[6] it has not beention of the cholesterol in the HDL particles originates from the clearly established whether the visceral or intraabdominal fat iscells in the peripheral tissues, which transfer it to the HDL intimately related to the various metabolic changes such as insulinparticles through the ATP binding cassette (ABC) system. In the resistance, dyslipidemia and high BP, representing a high risk of‘maturation’ process of the HDL particles the incorporation of diabetes mellitus and cardiovascular disease.components from the surface of triglyceride-rich particles releasedin the course of hydrolysis also plays a role. Through the action of 2.2 Derangements in Lipoprotein Metabolismthe cholesterol ester transfer protein (CETP), the HDL transferesterified cholesterol to other lipoprotein particles bound for the 2.2.1 Increase in Apo B and Small, Dense Low-Density

Lipoprotein (LDL)liver; at the same time, the HDL take up triglycerides from theVLDL, for hydrolysis by the hepatic lipase (HL) at a later stage. The dyslipidemia in patients with the metabolic syndrome isThe spectrum of available HDL particles is quite heterogeneous; more complex than a simple quantitative derangement of certainthere are particles in this density range which contain only apo A-I, lipoprotein particles (table II). The patients exhibit insulin resis-whereas others contain also apo E. Evidence from epidemiologic tance and it is quite probable that this factor, which is related tostudies very strongly suggest that the HDL particles play a funda- visceral adiposity, may be the determinant for the overall impair-mental role in reducing the risk of experiencing cardiovascular ments observed (table III). Patients with a metabolic syndromedisease. One of the major mechanisms involved is that HDL show a marked increase in the number of apo B-100-carryingpromote the efflux of cholesterol from the peripheral cells, includ- particles, particularly small, dense LDL.[1] This phenomenon caning the macrophages and the foam cells in the arterial wall, for be detected in clinical practice through an increase in plasma apouptake in the liver through the action of the hepatocyte SR-BI B-100. The increase in small, dense LDL particles is a conse-receptor; this receptor binds to the HDL lipids but, in contrast to quence of hypertriglyceridemia. The hyperafflux of free fatty acidsother receptors, does not internalize the complete particle. to the liver, a signal and classical feature of insulin resistanceThrough the action of the ester transfer protein, the HDL transfer states such as the metabolic syndrome or type 2 diabetes mellitus,cholesterol esters, while they circulate in the blood plasma, to the is a consequence of an impairment of nonesterified free fatty acidIDL and LDL particles, which are ultimately bound for the liver. (NEFA) storage in adipose tissue, possibly because of a functionalFurthermore, the HDL contribute to reducing the risk of develop- impairment of the acetylation-stimulating protein (ASP) and of ament and progression of the atherogenic process through other predominance of hormone-sensitive hepatic lipase activity, result-mechanisms, such as reducing oxidation of LDL, thus slowing ing in a net imbalance favoring adipocyte lipolysis and increased



increased number of particles transporting triglycerides will havean impact on the whole metabolic cascade of lipoproteins, fromVLDL through to LDL.[7] During their period of plasma residence,the lipoproteins undergo an important metabolic exchange withVLDL and LDL exchanging triglycerides for cholesterol esters;upon the cession of one triglyceride molecule from the VLDL tothe LDL, the latter cedes one molecule of cholesterol ester. Thisnormal metabolic pathway is regulated by CETP and, under nor-mal conditions, produces LDL particles that cede a part of theircholesterol in exchange for triglycerides, which are subsequentlyeliminated through the action of various lipases, such as LPL andHL.[8] The balance of this interactive exchange is regulated by thetriglyceride concentration in the VLDL particles, so that in situa-tions of triglyceride excess, the result is triglyceride-enriched andrelatively cholesterol-depleted LDL particles. These LDL parti-cles, after the action of lipases that leads to the loss of the excesstriglycerides, turn into smaller, denser particles, as they contain asmaller number of lipid molecules.[9] The size of the LDL particlesis variable in all individuals, but predominance of the small, denseLDL particles over the less dense ones has been associated with anincrease in coronary risk. This situation, which is usual in type 2diabetes mellitus, is also present in genetic impairments of lipidmetabolism such as combined familial hyperlipidemia, or in insu-lin resistance states such as the metabolic syndrome. The impor-tance of this phenomenon is the fact that this LDL phenotype ishighly atherogenic.[10] Small, dense LDL particles are more dam-aging to the arterial wall. It has been documented that the disposi-tion of the apo B-100 molecule in the LDL particle facilitates theaction of free oxygen radicals rendering them more readily oxi-dized; furthermore, in type 1 diabetes mellitus these particles aremore readily glycosylated so that their deposition in the vesselwall increases. It has also been observed that these LDL particlesexhibit a greater affinity for the glycosaminoglycanes of the ex-tracellular matrix. The particles are entrapped for longer periods inthe subendothelial zone and, consequently, their exposure to oxi-dizing substances increases. From a clinical standpoint, this meta-bolic situation may be detected by assessing the plasma apo B-100concentrations. An increase in apo B-100 levels beyond the nor-

Table II. A summary of the lipoprotein profile in metabolic syndrome andtheir likely causes

Increased chylomicron remnants

Postprandial increase of apo B 48, triglycerides, and retinol palmitate

Decreased activity of the LDL receptors, LRP and LPL

Increased intestinal secretion of apo B-48 particles (animal models)

Increased apo B-VLDL

Expansion of the visceral adipose tissue (subcutaneous fat and decreaseof adiponectin)

Increased portal inflow of fatty acids to the liver stimulates apo Bsecretion, increasing cholesterol ester and triglyceride secretion

Absent inhibitor effect of insulin on hepatic apo B secretion (VLDL1 >VLDL2)

Decreased LDL receptor and LPL activity

Genetic factors associated with apo B secretion: SP, apo E, CETP andMTP

SP24/CETP B1B1 apo B allelic combination

Increased IDL-apo B

Direct effect of IR on the LDL, LRP receptor and proteoglycans (heparansulfate) and/or indirect effect derived from competition with chylomicronremnants for the hepatic receptors

IDL-apo B FCR decreased in 30% in obesity/IR

Low HDL-C and apo A1

Increased VLDL triglyceride pool in relation to reduced LPL activity

Increased catabolic rate (CETP and HL)

Nonenzymatic glycosylation of apo A-1 LDL increases HDL2 particlecatabolism in type 2 diabetes mellitus

LDL-apo B

Moderate increase of LDL-C

B phenotype: small dense LDL (subclass LDL3), more readily oxidizableand with greater atherogenic capacity

Increased CETP and HL activity

Modifications in lysine and arginine that decrease their catabolism viathe LDL receptor

apo = apolipoprotein; CETP = cholesterol ester transfer protein; FCR =fraction catabolic rate; HDL-C = high-density lipoprotein-cholesterol; HDL2= subfraction 2 of HDL; HL = hepatic lipase; IDL = intermediate-densitylipoproteins; IR = insulin reasistance; LDL = low-density lipoprotein; LDL-C= LDL-cholesterol; LPL = lipoprotein lipase; LRP = LDL receptor-relatedprotein; MTP = microsomal triglyceride transfer protein; SP = stimulatingprotein; VLDL = very low-density lipoprotein.

NEFA flow towards the liver. The large influx of NEFA into thehepatocyte in turn acts as a direct stimulus for VLDL particleproduction. Together with an increased synthesis of cholesteroland apo B-100, VLDL particles are generated through the actionof the microsomal triglyceride transfer protein. The resultingVLDL particles are usually large and triglyceride-rich. This situa-tion where there is an increase in VLDL production with an

Table III. Abnormalities in lipid metabolism in individuals with visceralobesity and insulin resistance

Increased hepatic apo B secretion

Increased inflow of fatty acids into the liver

Loss of the inhibitory effect of insulin on VLDL and TG secretion

Increased expression of MTP

Increased ex novo lipogenesis

apo = apolipoprotein; MTP = microsomal triglyceride transfer protein; TG =triglycerides; VLDL = very low-density lipoprotein.


44 Ascaso et al.

mal ~120 mg/dL level signals an increase in the number of VLDL,IDL, and LDL particles carrying one single apo B-100 mole-cule.[11] Considering that the half-life of VLDL particles is about12 hours, whereas that of LDL particles exceeds 4 days, it can bereadily understood that an increase in apo B is usually indicative ofan increase mainly in LDL, as these are the apo B-100-carryingparticles predominant in plasma. This increase in LDL levels,without a corresponding increase in cholesterol implies that thereare more particles available for transporting the same amount ofcholesterol, and that the lipoproteins must be smaller. This gener-ates a metabolic situation of high vascular risk regardless of amassive cholesterol increase. A number of population-based stud-ies have established that the production of small, dense LDLparticles secondary to hypertriglyceridemia begins at triglycer-idemia levels ≥150 mg/dL. It should be also kept in mind that the

Table IV. Consequences of visceral obesity and insulin resistance on thelipid profile

Visceral obesity

Modifications in apo B-VLDL metabolism

Greater proportion of dense LDL as a result of increased VLDL–LDLinterchange

Postprandial lipemia

Accumulation of lipoprotein remnants in plasma

Insulin Resistance

Decreased expression and activity of the LDL receptor through a directmechanism

Decrease of apo B-containing lipoprotein clearance

Chronic hyperinsulinemia increasing the expression of SREBP-1c andother lipogenic enzymes

apo = apolipoprotein; LDL = low-density lipoprotein; SREBP-1c = sterolregulatory element binding protein 1c; VLDL = very low-density lipoprotein.situation of the patient with metabolic syndrome, and therefore

with insulin resistance, is also accompanied by a defect in VLDLfatty acids increases, and these free fatty acids arrive in greatlipolysis because of a functional impairment in LPL, an insulin-quantities into the liver where they are used for the synthesis ofsensitive enzyme.[8] This causes another component to exist in thetriglycerides which are then incorporated into VLDL. The hyper-hypertriglyceridemia of these patients, namely the catabolic defi-insulinemia that usually coexists with increased insulin resistanceciency, besides the already discussed hypersecretion.is also a direct stimulus for VLDL synthesis. Insulin resistance and

2.2.2 Small High-Density Lipoprotein (HDL)hyperinsulinemia also stimulate the hepatic synthesis of apo

A direct consequence of the derangement in lipid metabolism,B-100, probably because they induce an increase in protein-tyrosin

as described in the section above, is the reduced formation of HDLphosphatase-1B activity together with a reduction in cysteine

particles. This is because one of the main sources of these lipopro-protease activity that catalyzes apo B, leading to increased hepatic

teins is the catabolic product of triglyceride-rich particles withapo B synthesis. This explains the reason for the increase in

poor efficacy in cholesterol extraction from the cell membranes.hepatic VLDL synthesis and secretion, which has been demon-

HDL particles also undergo changes in composition in states ofstrated through lipoprotein kinetics studies, and constitutes a ma-

hypertriglyceridemia through metabolic mechanisms similar tojor factor in the pathogenesis of the lipid and lipoprotein changes

those already discussed for LDL. The CETP-mediated interchangeassociated to insulin resistance states.[11,13-16]

of triglycerides for cholesterol esters and the subsequent action ofAnother mechanism that may contribute to the increase inHL involves an increase in small HDL concentrations in plasma,

plasma VLDL concentrations is the reduction of their catabolismand particularly of the subfraction 3 at the expense of a reductionas a result of the reduction of LPL activity (regulated by insulin),in small HDL2 concentrations, which seem to be epidemiological-which might be induced by insulin resistance either directly orly associated with greater vascular protection.[12]

through an increase in apo C-III, as it has been shown that insulininhibits the expression of the gene regulating this apoprotein3. Insulin Resistance as the Nexus of the Variouswhich, in turn, induces LPL inhibition. This decreased lipolyticLipidic Factorsactivity, together with the increased VLDL production, determine

Insulin resistance plays a major role in most of the lipid and an increase in postprandial lipemia.[8,16]

lipoprotein derangements observed in the metabolic syndrome[7]The relationship of insulin resistance and hyperinsulinemia to

(table IV).hypertriglyceridemia has been well documented through experi-mental manipulations that modify the action of insulin or its

3.1 Effect of Insulin Resistance on Very Low-Densityplasma concentrations, that determine predictable changes in

Lipoprotein and Triglyceride ProfilesVLDL secretion and in plasma triglyceride concentrations.[17] A

The antilipolytic action of insulin in the adipose tissue, as close correlation has also been described between hyperinsu-opposed to the lipolytic action of glucagon, is widely known. As a linemia and hypertriglyceridemia in population-based studies[7,18]

result, in cases of impaired insulin sensitivity, the release of free on healthy normoponderal individuals. Similarly, an association



has been described between the plasma levels of insulin and them more susceptible to the action of HL, an enzyme that acts ontriglycerides in normoinsulinemic individuals.[10,18] the subfraction 2 of HDL (HDL2) particles and transforms them

into smaller HDL3 particles, which are rapidly catabolized. An3.2 Effect of Insulin Resistance on Variations in increase in HL activity has been documented and induced directlyLDL-Cholesterol (LDL-C) by insulin resistance.[9,24,25]

Tato et al.[12] have observed that the inverse correlation betweenThe increased hepatic VLDL secretion predisposes to enhanced triglycerides and HDL is relatively strong when the triglyceride

LDL formation, although this phenomenon is modulated by the levels are within the normality range but not when they reach highreduction in lipolysis. There are, however, studies showing that values, and this led them to examine the contribution of otherinsulin resistance or hyperinsulinemia stimulate the synthesis of potential mechanisms and precisely of the CETP, LCAT, HL andcholesterol and reduces its intestinal absorption rate in normo- LPL activities; they concluded that the HDL-C concentration inglycemic individuals. The increase in synthesis occurs probably patients with hypertriglyceridemia is to a great extent dependentthrough the insulin stimulus on the liver X receptors (LXRs); this, on the activities of these enzymes, which jointly determine almostin turn, might determine increased expression of the intestinal one-half of the HDL-C variation, whereas the increase in triglyc-ABCG5 and ABCG8 genes, which would explain reduced absorp- erides by itself has only a modest contribution. Now, as alreadytion.[19]

discussed, insulin resistance induces a variation in at least two ofConversely, the hypertriglyceridemia induced by insulin resis- these enzymes: LPL and HL.

tance results in increased concentrations of small dense LDL; anincrease in triglyceride-rich lipoproteins causes an increased ex-

4. Diagnosis of Dyslipidemia in thechange of triglycerides for cholesterol esters from the LDL

Metabolic Syndromethrough the mediation of CETP, so that the LDL particles becometriglyceride-enriched and constitute a good substrate for the actionof HL, which hydrolyzes the LDL triglycerides, leading to the 4.1 Quantitative Alterations in Lipoprotein Metabolismformation of these smaller and denser particles. The decrease inthe mean size of the particles tends to reduce the LDL-C levels, as

4.1.1 Hypercholesterolemia and LDL-C Increasethe cholesterol content of each particle is variable and depends onPatients with the metabolic syndrome evidence a greater preva-its size, whereas the plasma apo B levels depend exclusively on the

lence of dyslipidemia than the general population. Although pa-number of particles; this leads to a decrease of the LDL-C/apo Btients may have hypercholesterolemia through an increase in LDL-ratio. The atherogenic potential of the small, dense LDL is current-C, this is not the most common derangement, nor probably thely well documented, and is attributed – as already pointed out – tomost important one. In patients with the metabolic syndrome, it istheir greater susceptibility to oxidation and to their prolongedusual to see a lipid profile characterized by increased triglyceridesretention in the circulation because of the fact that they bind moreand low HDL-C. Prevention strategies focus on the reduction ofreadily to the arterial wall proteoglycanes.[20-23]

LDL-C, which is the therapeutic target par excellence. The prima-ry prevention studies with statins in populations with varying risk3.3 Influence of Insulin Resistance on Changes in HDLlevels (WOSCOPS and AF-TEX/CAPS), as well as secondary

The fundamental change is a decrease in the cholesterol con- prevention studies (4S, CARE, LIPID)[26] have shown that in thetent, which is almost constantly present and which determines the diabetic patient subgroups, where most patients evidence insulinwell known inverse relationship between the plasma levels of resistance and a metabolic situation similar to that of the metabolictriglycerides and HDL-C. The triglyceride levels by themselves syndrome, reducing the LDL levels is associated with a decreasehave an influence on HDL-C reduction, probably through the in coronary episodes. These studies have established the scientificfollowing mechanism: similar to what happens with LDL, the evidence for the current therapeutic recommendations. The VA-increase in plasma triglycerides increases the transfer of choles- HIT study,[27] involving patients who survived a first myocardialterol esters in exchange for triglycerides from the HDL particles to infarction and who had normal LDL-C but low HDL-C concentra-the triglyceride-rich lipoproteins through the action of CETP; it tions, showed that therapy with gemfibrozil, which did not causehas been observed that, for a given CETP level, the cholesterol any change in LDL but considerably decreased triglycerides andester transfer increases in the presence of hypertriglyceridemia, discretely increased HDL, had beneficial effects, with a 22%and this would determine the decrease in HDL-C. On the other reduction of the relative risk of a second myocardial infarction inhand, the triglyceride enrichment of the HDL particles renders both diabetic and nondiabetic patients.


46 Ascaso et al.

4.1.2 Increased Non-HDL-C concentrations, the risk was neutralized. The protective mecha-In the clinical environment, the LDL-C concentration is not nisms of HDL appear to be diverse. First, they have a function as

measured directly but calculated using the Friedewald formula. cholesterol extractors from the peripheral tissues for conveyanceThis formula does not apply when the triglyceride levels exceed to the liver or to other lipoprotein particles, so that cholesterol may400 mg/dL, as is quite often the case in patients with the metabolic be eliminated. Although an extraction mechanism through thesyndrome. However, mild hypertriglyceridemia (200–399 mg/ passive transfer of cholesterol to HDL in the presence of apo-AIdL), a more common situation in patients with type 2 diabetes and phospholipids seems to exist, it has recently been reported thatmellitus and/or metabolic syndrome is accompanied by an under- this function is largely determined by the presence of a membraneestimation of LDL-C concentrations with this formula. Under transporter (ABC A1, or ABC-A1), which acts as a cholesterolthese conditions the use of ‘non-HDL-C’ has been recommended donor for the HDL.[4] Absence of this membrane transporterby the National Cholesterol Education Program (NCEP)-ATP III, molecule is associated with practical disappearance of HDL fromwhich is the result of subtracting the HDL-C level from the total plasma, as in Tangier disease.[4] There is at present active investi-cholesterol concentration. The recommended values for therapeu- gation in search for molecules that increase the expression oftic strategies are comparable with those of LDL-C, plus 30 mg/dL. ABC-A1, such as the peroxisome proliferator-activated receptor

(PPAR) agonists that act through activation of the hepatic4.1.3 Hypertriglyceridemia

LXRs.[29] The latter action is mediated by para-oxonase and plate-The effects of triglycerides per se on the arterial wall seem to let-activating factor (PAF) hydrolase in the HDL particles. Thus,

depend on the lipoprotein particle containing them. Thus, patients the presence of HDL in a pro-oxidative environment protects LDLwith a deficiency of LPL or of its co-factor, apo CII, exhibit severe from oxidation. Furthermore, the HDL particles seem to exert achylomicronemia but cardiovascular disease is not a feature of this scavenger role for products derived from lipid oxidation, such asprocess. The size of the chylomicrons or even of the nascent hydroperoxides, thus preventing their accumulation in tissues andVLDL renders interaction between the particles and the arterial particularly in the arterial wall. Beyond this, the HDL particleswall practically impossible. However, whenever the increase in have an anti-inflammatory role.triglycerides is the result of an accumulation of smaller andpartially metabolized particles, such as the postprandial chylomi-

4.2 Laboratory Diagnosis of Dyslipidemiacron remnants and, particularly, VLDL, or IDL particles, as is thecase in dys-β-lipoproteinemia, the risk of cardiovascular disease

4.2.1 The Atherogenic Triadincreases. This seems to be due in part to a direct toxic effect ofA high-risk metabolic constellation is sketched in patients withthese lipoproteins on the vessel wall and particularly on the

the metabolic syndrome, which may be clinically defined as theendothelium, inducing endothelial dysfunction. Patients with typejoint presence of increased concentrations of triglycerideIII hyperlipoproteinemia, who accumulate IDL, are at high cardio-≥150 mg/dL, and apo B-100 ≥120 mg/dL, and decreased concen-vascular risk. A metabolic situation often seen in patients with thetrations of HDL-C ≤40 mg/dL in men and ≤50 mg/dL in women.metabolic syndrome is that of remnant accumulation in the contextThis combined metabolic derangement is known as ‘atherogenicof postprandial hyperlipidemia. This metabolic derangement isdyslipidemia’ (table V). When faced with this situation, the clini-characteristic for a number of clinical conditions featuring insulincian must come to the interpretation that the patient has an overallresistance, such as obesity (particularly the perivisceral form),impairment of his or her metabolism despite the absence of acombined familial hyperlipidemia, and obviously diabetes mel-quantitative increase in LDL-C concentrations. A patient’s LDLlitus.particles could be small and dense, more toxic, and more readily

4.1.4 Low HDL

The association of low HDL concentrations, and more specifi-cally of the HDL2 subfraction which is composed of larger-sizedparticles, with coronary risk is well established. All the observa-tional epidemiologic studies clearly demonstrate the inverse corre-lation between HDL and coronary risk. In the PROCAM study,[28]

the LDL/HDL ratio was the best coronary risk indicator, with adramatic increase of the latter when the former was at least 5.Interestingly, in this study, triglycerides were risk predictors if theabove ratio was high however, in the presence of high HDL-C

Table V. Characteristic features of dyslipidemia in the metabolic syndrome

Hypertriglyceridemia

Low HDL-C (HDL2) levels

Increased apo B levels

Appearance of small, dense LDL particles, with increased LDL-C levelsat times

apo = apolipoprotein; HDL-C = high-density lipoprotein-cholesterol; HDL2= subfraction 2 of HDL; LDL = low-density lipoprotein; LDL-C = LDL-cholesterol.



oxidable, and besides this the patient’s HDL may be unable to consensus document available regarding management of the meta-oppose the development of vascular lesions. This constellation is a bolic syndrome, though the available data suggest that lifestylefeature of the metabolic syndrome and of type 2 diabetes mellitus, modifications for the prevention or avoidance of obesity andbut it may be generalized both to insulin resistance as a whole and adequate pharmacologic therapy for each of the components of theto predominantly perivisceral obesity, combined familial hyper- syndrome may represent a reasonable strategy.lipidemia, a number of cases of high arterial BP, and several other

5.1 Overweight and Obesityconditions.[14]

4.2.2 Postprandial Hyperlipidemia There is strong and widespread belief that lifestyle modifica-The insulin resistance state not only impairs the lipolytic bal- tions aimed at weight loss are an effective therapy for obesity

ance of the organism impairing the LPL activity, but also impairs associated with the metabolic syndrome.[32] Obesity and excessivetriglyceride storage in the adipose tissue through interference with weight are quite closely correlated to the development of type 2hormone-sensitive lipase (HSL) gene ((Author: please confirm)) diabetes mellitus. Furthermore, obesity is an independent riskand ASP activities. The net result is that the triglyceride-rich factor both for hypertension and dyslipidemia as well as cardio-postprandial particles have a slower plasma clearance and remnant vascular disease. In order to define overweight and obesity, theparticles with a capacity for endothelial toxicity and arterial wall body mass index (BMI) is used – calculated from the ratio betweendeposition are accumulated. the bodyweight (kg) and the square of the height expressed in

To investigate postprandial hyperlipidemia, patients need stan- meters. The resulting index is expressed in kg/m2. The WHO hasdardized oral fat challenge tests with periodic blood sampling over postulated a classification of obesity based on the BMI indexa 6- to 12-hour period to quantify the concentrations of triglycer- (table VI). A further aspect to consider is the bodily fat distribu-ides, apo B-48, or retinol added to the test meal. Patients with the tion, as the central distribution of fat represents a higher cardiovas-metabolic syndrome usually present a larger area under the con- cular risk regardless of the total amount of adipose tissue. Thecentration-time curve (AUC), greater peak levels, and increased waist-hip ratio has long been accepted as an indicator of centralbaseline values. obesity and, even though the risk cut-off values have not been

A further option for the assessment of this situation is the clearly defined, limit values of <1 in men and <0.90 in womenquantification of capillary blood triglycerides during the day, have been proposed.[33] The simple measurement of the waistusing dry chemistry techniques. This provides a simple analysis of circumference has been used in the last few years as an indicator ofthe triglyceride load during the patient’s standard day. Patients central adiposity and a risk marker; it is generally accepted thatwith the metabolic syndrome exhibit a larger AUC, greater incre- obesity-associated risk appears beyond a value of 94cm in menmental values from baseline, and higher baseline levels. However, and 80cm in women.[34]

since the quantification of capillary blood triglyceride concentra- Therefore, in the management of patients with the metabolictions is not widely accepted and the recommendations for the syndrome the following general principles are proposed:evaluation of postprandial hyperlipidemia are controversial, its usein clinical practice is limited.

5. Overall Therapeutic Objectives

The inclusion of the metabolic syndrome as a second-lineobjective in the third report on the NCEP expert panel on detec-tion, evaluation and treatment of high blood cholesterol in adults[5]

and its inclusion in the 9th Revision of the International Classifica-tion of Diseases (ICD code 277.7[30]) stresses the importance ofthis clinically significant condition. In general, the diagnostic stepsbegin with the detection of clinical or analytical evidence of thepresence of one or more of the syndrome’s components whichforms the basis of appropriate therapy. In clinical practice, earlydetection of arterial high BP and dyslipidemia, with ensuingtherapeutic management, significantly and effectively reduce theprogress of the metabolic syndrome.[31] There is, at present, no

Table VI. Criteria for the body mass index (BMI)-based classification ofobesity (WHO) and arterial BP in adults >18 years[35]

Classification Criteria

Bodyweight BMI (kg/m2)

Normal weight 18–24.9

Overweight 25–29.9

Obesity

grade I 30–34.9

grade II 35–39.9

grade III >40

BP class SBP/DBP (mm Hg)

Normotensive <120 and /<80

Prehypertensive 120–139 or /80–89

Hypertensive, phase 1 140–159 or /90–99

Hypertensive, phase 2 ≥160 or /≥100


48 Ascaso et al.

1. Maintain BMI at levels between 20 and 25 kg/m2. (self-analysis, capillary blood glycemia), baseline or preprandialglycemia 70–90 mg/dL, and postprandial glycemia 70–135 mg/2. Consumption of at least five portions of fresh fruit and vegeta-dL.[42] Over the last decade a number of studies have been carriedbles, daily.out with the aim of preventing or at least delaying the onset of type3. Reduction of the fat intake, in particular the saturated fat2 diabetes mellitus as a result of glucose intolerance, by either theintake.use of drugs or modifying patient lifestyle, for example, diet and4. Aerobic physical exercise at least 30 minutes 4 days/week.physical activity achieving a 58% reduction in the incidence ofovert diabetes.[43,44] The following incidence reductions in diabe-5.2 Arterial High BPtes mellitus have been achieved with treatment with pharmacolog-

Arterial hypertension (or ‘arterial high BP’, or simply ‘hyper- ic drugs relative to placebo: metformin 31%,[44] troglitazone (intension’ or ‘high BP’) is a common co-morbidity associated with women with previous gestational diabetes) 56%,[45] and acarboseconditions such as diabetes mellitus and obesity. Hypertension is 36%.[46] Acarbose therapy in type 2 diabetic patients[47] and inusually associated with obesity and carbohydrate intolerance or individuals with glucose intolerance[48] have also achieved signifi-diabetes mellitus forming an integral component of the metabolic cant reductions in the incidence of myocardial infarction andsyndrome. Table VI shows the classification of the arterial BP cardiovascular episodes.levels in adults, according to the Joint National Committee on The American Diabetes Association has recommended lipidPrevention, Detection, Evaluation, and Treatment of High Blood screenings at least annually and more frequently as needed toPressure (JNC)-7 criteria.[36]

achieve goals.[49] Patients with diabetes mellitus and overt cardio-The prevalence of high BP is three times higher among obese vascular disease should be considered at very high risk for further

adults than in normoponderal individuals.[37] Furthermore, in cardiovascular events, and it is recommended they be pharmaco-obese individuals the BMI correlates closely with arterial hyper- logically treated to achieve an LDL-C goal of <100 mg/dL. Atension and lipid derangements.[38] Hypocaloric diets reduce arte- lower LDL-C goal of <70 mg/dL is an option in this very high-riskrial BP through a reduction in insulin resistance and sympathetic group.[49]

nerve activity.[39]

For most subjects, arterial BP levels ≤140/90mm Hg are a5.4 Lipid Goals

desirable goal in order to restrict cardiovascular episodes. Thearterial BP criteria for the diagnosis of metabolic syndrome are

The fundamental goal is to achieve adequate LDL-C levels,levels ≥130/85mm Hg. In the case of individuals with diabetes

because the increase in the levels of these lipoproteins is themellitus or enhanced cardiovascular risk (10-year risk >20%) the

fundamental cause of cardiovascular disease. Table VII providestarget goes down to 130/80mm Hg. Pharmacologic treatment

the classification of the LDL-C levels. Besides high LDL-C con-should generally be instituted when the BP levels are ≥160/

centrations there are other cardiovascular risk determinants, such100mm Hg. When conditions such as diabetes mellitus or in-

as coexisting ischemic heart disease and other forms of cardiovas-creased cardiovascular risk coexist, drug therapy should be initiat-

cular disease. Based on these risk determinants, three categories ofed at BP levels of SBP 140–159mm Hg and DBP 90–99mm Hg.

risk have been identified that lead to modifications in the LDL-Clevel goals. The highest risk situation is associated with ischemic5.3 Diabetes Mellitusheart disease or its risk equivalents (>20% at 10 years). The riskequivalents are atherosclerotic disease, diabetes mellitus, and theThe UKPDS study showed that, in patients with type 2 diabetescoexistence of multiple cardiovascular risk factors. Assuming thatmellitus, the occurrence of new cardiovascular episodes correlatedLDL-C <100 mg/dL is considered a minimum goal, recent stud-with increased LDL-C, decreased HDL-C, and increased triglycer-ies[50-54] have demonstrated that achieving LDL-C levels <70 mg/ide levels, as well as high BP, tobacco smoking, increased blooddL in high-risk patients afford an additional and significant bene-glucose, and glycosylated hemoglobin (HbA1c) levels.[40] Thefit. Patients to be included in this additional goal would be thoserecommended goals for diabetic individuals, according to thewith ischemic heart disease associated with: multiple risk factorsAmerican Diabetes Association,[41] are as follows: HbA1c <7%(particularly diabetes mellitus), persistence of tobacco smoking,(this is the primary goal of glycemic control), preprandial (fasting)presence of the metabolic syndrome, and patients with acuteblood glucose 90–130 mg/dL, and 1–2 hours postprandialcoronary syndromes.[41]glycemia <180 mg/dL. The European Joint Task Force on Cardio-

vascular Prevention, recommends the following goals of good In the metabolic syndrome there are a number of associated riskmetabolic control: HbA1c ≤6.1%, baseline glycemia <110 mg/dL factors that, jointly, increase the cardiovascular risk independently



crease in HDL-C is fundamentally related to insulin resistance,increased triglycerides, excess bodyweight and obesity, sedentarylifestyle, tobacco smoking, and type 2 diabetes mellitus. There isno concrete goal for the HDL-C level; however, in all individualswith low HDL-C levels the first priority should be to achieve theLDL-C goals. Once these goals have been achieved, the nextobjective should be bodyweight decrease and increased physicalactivity. Whenever the HDL-C decrease is associated with hyper-triglyceridemia (200–499 mg/dL) the goal should be to achieveadequate levels of non-HDL-C. In the case of isolated HDL-Cdecrease, that is with normotriglyceridemia, drug therapy may beconsidered if established ischemic heart disease or risk equivalentscoexist.

Thus, the estimation of the cardiovascular risk, using the cur-rently accepted standards, has major problems in the metabolicsyndrome because of the short-term basis of the estimation. Con-sequently, the stratification into three different risk categories,according to APT III (low, moderate and high risk), allows forappropriate treatment. Using this approach, the LDL-C targetwould be <160 mg/dL in nearly 30% of low risk individuals (noneto 1 risk factor); however, the majority of cases would qualify foran LDL-C goal of <130 mg/dL (2 or more risk factors). In addi-tion, apo-B levels and the non-HDL-C levels could be considered

Table VII. Adult Treatment Panel (ATP) III Classification of the low-densitylipoprotein-cholesterol (LDL-C), total cholesterol (TC), high-density lipopro-tein-cholesterol (HDL-C) and triglyceride levels in metabolic syndrome[55]

Risk factor Defining level

LDL-C (mg/dL)

Optimal <100

Suboptimal 100–129

High normal 130–159

High 160–189

Very high ≥190

TC (mg/dL)

Desirable <200


High ≥240

HDL-C (mg/dL)

Low <40

High ≥60

Triglycerides (mg/dL)

Normal <150


High 200–499

Very high ≥500

as second level target goals in the treatment strategy of metabolicsyndrome patients with normal or nearly normal LDL-C levels andof the LDL-C levels; for this reason, the metabolic syndrome hastriglycerides >150 mg/dL. Non-HDL-C goals for individuals withbeen included as a secondary therapeutic objective in the ATPnone to 1 risk factor, 2 or more risk factors and those at high riskIII.[5] The two fundamental lipid abnormalities associated with theare <190, <160 and <130 mg/dL, respectively.

metabolic syndrome are increased triglycerides and decreasedHDL-C concentrations. Increased triglyceride levels have been 6. Pharmacologic and Non-Pharmacologicconsidered to represent an independent cardiovascular risk fac- Treatment of Metabolic Syndrome Dyslipidemiator.[5] This increase is related to obesity or overweight, lack of

Treatment of the metabolic syndrome is based on two precepts:physical exercise, tobacco smoking, alcohol consumption, andnon-pharmacologic intervention, which is based on lifestylecarbohydrate-rich (>60%) diets, as well as to certain other condi-changes, and pharmacologic intervention (drug therapy) as hastions, for example type 2 diabetes mellitus, β-adrenoceptor antag-recently been reviewed in the consensus statement of the Ameri-onists (β-blockers) and genetic conditions such as combined fa-can Heart Association.[55,56]

milial hyperlipidemia. In clinical practice, this is the lipid abnor-mality most often associated with the metabolic syndrome.

6.1 Lifestyle InterventionsTriglyceride- and apo B-rich VLDL are partially degraded and

All the clinical guidelines on the therapeutic management of thebecome lipoprotein remnants, which are particles with a highmetabolic syndrome indicate that the preferred therapeutic inter-atherogenic potential. For this reason, the ATP III classificationventions are those which aim to modify the patient’s the lifestyle,has introduced a new concept, that of ‘non-HDL-C’ (non-HDL-Cachieve weight loss, and enhance physical activity.[42,55,56]= LDL-C + VLDL-C = total cholesterol – HDL-C), as a secondary

therapeutic goal in individuals with triglyceridemia in excess of 6.1.1 Diet200 mg/dL. The goal for non-HDL-C is 30 mg/dL higher than the The clinical guidelines for obesity stress the need to reducevalues accepted for LDL-C (table VII). bodyweight by using behavioral changes in order to reduce caloric

Low HDL-C levels is an independent cardiovascular risk factor (energy) intake and increase physical activity. The most effectivedefined as HDL-C <40 mg/dL according to ATP III.[5] The de- long-term diet involves a modest restriction of the energy intake,


50 Ascaso et al.

by some 500–1000 calories/day. An adequate goal is to achieve a therapeutic regimen should include a regular physical exercise7–10% bodyweight reduction over a period of 6–12 months. program. Regular physical exercise improves the metabolic risk

factors and decreases the risk of all-cause mortality, as well as theThe major lifestyle intervention has two main and fundamentaldevelopment of many chronic disease conditions.aspects: (i) an adequate caloric (energy) intake; and (ii) achieve an

Periodic, moderate physical exercise is recommended, for ex-increment in physical activity. A moderate decrease of the dailyample, 4–5 weekly sessions of 30–60 minutes’ duration. Physicalcaloric intake will achieve a slow but progressive weight reductionexercise is a signal lifestyle component that reduces cardiovascu-(~500 g/week). For most patients, the weight reduction dietslar risk[62] and exerts a positive influence on practically all theshould provide at least 1000–1200 kcal/day for women andcomponents of the metabolic syndrome. It has been demonstrated1200–1500 kcal/day for men.[41] The carbohydrate intake shouldthat regular and moderate aerobic exercise for some 30 minutes/represent 50–60% of the total calories. Fats should provideday considerably delays the onset of diabetes mellitus and reduces25–30% of the total calories; saturated fats should represent <7%its absolute incidence by about 20%.[63] In secondary prevention,and should be replaced by monounsaturated (olive oil) and poly-the ergometric results are the basis for the indication of exerciseunsaturated (fish) fats. The protein intake should range betweenintensity, which usually means maintaining about 70% of the0.7 and 0.8 g/kg/day, or about 15–20% of the total caloric intake.maximal heart rate recorded in symptom-free ergometric assess-The actual diet should have a high proportion of fruits and greenments. Sedentary leisure time activities (e.g. watching television)leaf vegetables in order to reduce cardiovascular risk;[57] a dailyshould be discouraged, whereas the acquisition of home exerciseintake of about 2g stanols and 10–25g of soluble fiber achievesapparatus (ergometric endless bands or the cyclostatic) should beappreciable LDL-C reductions. A reduction of the sodium intake isencouraged. It is recommended to incorporate short periods (somebeneficial: a diet containing 1.6g of sodium per day has an effect10–15 minutes) of physical activity into everyday activities, suchsimilar to that of monotherapy drug treatment.[58]

as fast walking. Physical exercise is convenient for achievingTherefore, information about lifestyle (behavioral) changesweight loss, and particularly for long-term maintenance of theshould include improvements in alimentary habits and informationweight loss achieved. The combination of increased physicalon foodstuffs that are suitable or should be avoided. The impor-activity and weight loss reduces the occurrence of new diabetestance of the family diet in order to render long-term dietarymellitus cases by one-half. There are no clinical trials demonstrat-compliance feasible should be stressed. Recourse to a nutritioning a reduction of cardiovascular risk upon increasing physicalspecialist is suggested for more thorough advice in dietary man-activity and losing weight; however, epidemiologic data do sup-agement. Overall, the recommended diet for metabolic syndromeport this hypothesis.[64] For this reason, the recommendation topatients is a hypocaloric one, poor in saturated fats, trans-fats, andinclude both components in a program for cardiovascular riskcholesterol. It should also have reduced amounts of simple sugarsreduction is fully warranted.and an increase in the consumption of vegetable, legume, leafy

vegetable, cereal, and fruits. At times, a high carbohydrate intakemay enhance dyslipidemia, and isocaloric replacement with 6.2 Pharmacologic Interventionmono- and polyunsaturated fats is recommended. The impact ofdietary intervention in the metabolic syndrome has been evaluated Dyslipidemia plays a major role in the pathophysiology of thein some intervention studies showing a beneficial effect in the metabolic syndrome, and its correction is a primary goal in orderdifferent components of the syndrome, such as lowering BP and to prevent cardiovascular disease in patients with the metabolicimproving insulin resistance.[59-61] syndrome. Statins and fibrates are the most effective drugs for

controlling dyslipidemia associated with insulin resistance.[65] Sta-6.1.2 Physical Activity tins act by reducing LDL-C concentrations, while fibrates decreaseLong-term maintenance of weight loss is better and more levels of triglycerides and small, dense LDL particles and increase

readily achieved when regular physical exercise is included in the HDL-C concentrations. Ezetimibe, a drug of the azetidinone fami-weight loss regime. A sedentary lifestyle is believed to be a major ly that selectively inhibits intestinal cholesterol absorption, iscomponent of the metabolic syndrome through multiple mecha- highly effective in potentiating the hypocholesterolemic effects ofnisms, mainly the weight gain that increases arterial BP and statins.[66] In combination with fibrates it is a promising alternativeworsens the metabolic profile causing hypergylcemia, increased for achieving overall control of the metabolic syndrome hyper-insulin resistance, and dyslipidemia with increased triglycerides lipidemia with significant reductions in LDL-C and non HDL-Cand LDL-C, and decreased HDL-C levels. Because of the relation- concentrations;[65] its clinical use is still pending authorization.ship between a sedentary lifestyle and the metabolic syndrome, the Resins, ω-3 fatty acids, phytosterols, and nicotinic acid are drugs



Table VIII. Main pharmacokinetic properties of HMG-CoA reductase inhibitors (statins)

Characteristic Lovastatin Pravastatin Simvastatin Atorvastatin Fluvastatin

Bioavailability (%) <5 17 <5 12 24

Plasma half-life (h) 2 1–2 1–2 14 1.2

Renal excretion (%) 10 20 13 2 <6

Fecal excretion (%) 4 70 60 >98 90

Protein binding (%) >95 50 95 ≥90 98

Mechanism of Liver metabolism CYP 3A4 Sulfation CYP 3A4 CYP 3A4 CYP 2C9

Lipophilicity Yes No Yes Yes No

Entry to CNS Yes No Yes No No

LDL-C reduction (%) with the 40 35 48 54 36maximum dose

CYP = cytochrome p450; LDL-C = low-density lipoprotein-cholesterol.

that, because of their lesser efficacy or more frequent adverse be to achieve the therapeutic LDL-C goal. Generally speaking, it iseffects, are considered to be second-option drugs in the treatment preferable to initiate therapy at low or intermediate dosages andof patients with the metabolic syndrome. then increase to the maximum dose if the therapeutic target has not

been achieved. Only in the case of modified-release pravastatin6.2.1 Statins and fluvastatin might therapy be begun with the respective 40 mg/Statins are the first-choice drugs for reducing LDL-C and the day and 80 mg/day maximum dosages.[66] Furthermore, a number

cholesterol fraction vehiculised in apo B-rich lipoproteins (non- of other pharmacologic aspects should be considered based onHDL-C).[67] They act by partially, reversibly, and competitively potential drug interactions and adverse effects, which will beinhibiting the enzyme HMG-CoA reductase, the rate limiting discussed in section 6.2.3.enzyme for intracellular cholesterol synthesis. These drugs reduce

In a study on prevention of primary and secondary cardiovascu-the cellular cholesterol content and induce enhanced expression of

lar disease where patients were treated with statins, those withthe LDL receptors, thus increasing the plasma clearance of LDL

diabetes mellitus benefited to a similar extent as non-diabeticparticles and, to a lesser extent, that of IDL and VLDL. The mainpatients.[65] The hypolipidemic efficacy of statins in patients withpharmacokinetic characteristics of the various statins are presentedthe metabolic syndrome has been demonstrated in post hoc analy-in table VIII. Using the maximum dosages of the more potentsis of 4S,[70] WOSCOPS[71] and in some recent clinical trials, suchstatins, the LDL-C levels can be decreased by >50%.[67] The HDL-as CHESS,[72] STELLAR,[73] and COMETS.[74] In the latterC levels increase, generally by some 5–15%, and the triglyceridesstudy,[74] therapy with atorvastatin and with a statin that is not yetshow a highly variable decrease depending on the phenotype of theavailable in the Spanish market, rosuvastatin, at a 10–20 mg/daydyslipidemia and on its severity, but generally decrease by aboutdosage, achieved LDL-C decreases in excess of 40% and, close to10–40%. In a meta-analysis of the clinical trials of treatment of50%, respectively. The triglyceride levels were reduced by somedyslipidemia with fluvastatin extended-release, the triglyceride25%, and the HDL-C levels increased by about 6–10%. On thelevels decreased by 31% in patients with baseline triglycerideother hand, it has been observed both in COMETS and in otherlevels ≥300 mg/dL (3.4 mmol/L), and by 17% in those with base-studies[71] that statins induce a marked decrease in the C reactiveline triglyceride levels <200 mg/dL (2.2 mmol/L).[68] In the sameprotein (CRP) levels, a protein which is a marker of inflammationanalysis, the increase in HDL-C concentrations was also moreand also an independent predictor of cardiovascular risk, rangingmarked in the patients with higher triglyceride levels at baseline.between 20% and 40%. The reduction in the incidence of diabetesThe effect of statins on the proportion of small dense LDL parti-mellitus observed in the WOSCOPS study[75] in the patient sub-cles is controversial. In studies that have measured LDL subfrac-group treated with pravastatin has been attributed, to the effects oftions using electrophoresis statins had no effect on small densethat drug on the CRP levels.[76]

LDL levels.[67] However, in other studies,[69] where ultracentrifu-gation was used for the separation of the LDL subclasses, statins The safety of statins has been assessed in depth for >15 yearshave been noted to decrease LDL subfractions. since their introduction into clinical practice; currently, statins are

considered to be extremely safe drugs.[77] The two major adverseIn deciding which statin and what dosage should be employedeffects are hepatic and muscular toxicity. The former is manifestedin managing a given patient, physicians the primary focus should


52 Ascaso et al.

by a usually mild increase in aminotransferase levels, not associat- those with coronary artery disease, by decreasing HDL-C levels[27]

ed with cholestasis and readily reversible soon after withdrawal of and slowing the progression of atherosclerosis in coronary arterytherapy. The incidence of aminotransferase increases greater than disease patients experiencing moderate dyslipidemia.[83] In laterthree times the maximum levels of the reference interval is <1%, analyses of the VA-HIT study,[27] the therapeutic benefit ofand <2–3% with the maximum dosages of statins.[65] Skeletal gemfibrozil therapy was reported to be greater in the sub group ofmuscle toxicity may manifest itself through myalgia, increased 627 diabetic patients; in a separate study[84] the therapeutic benefitlevels of muscular enzymes, or both; these manifestations are of gemfibrozil was greater in patients with high fasting insulinrather infrequent and revert to normal a few days or weeks after concentrations, and the cardiovascular preventive effects ofdiscontinuation of therapy.[65] Rather infrequently, a severe myop- gemfibrozil depended rather more on the presence or absence ofathy in the form of rhabdomyolysis may occur, mostly in patients insulin resistance than on the levels of HDL-C.[85] In the DAISwith predisposing factors such as concomitant treatment with study, 419 diabetic patients with moderate lipoprotein changes andazole antifungals, some immunosuppressive agents, and the coronary heart disease,[83] treated with fenofibrate over a period ofmacrolide antibacterials, and also in patients with hepatic or renal 3 years, showed decreased progression of angiography-assessedinsufficiency.[65] coronary lesions compared with the placebo group. A lesser inci-

dence of cardiovascular disease was seen in the intervention groupcompared with placebo, although this did not achieve statistical6.2.2 Fibratessignificance because of he small sample size for this variable. InThe drugs derived from fibric acid – fenofibrate, bezafibrate,the HHS trial, a primary prevention study in hypercholesterolemicand gemfibrozil – have a favorable effect on the three mainpatients treated with gemfibrozil, the greatest benefit in the pre-components of metabolic syndrome-related dyslipidemia, namelyvention of cardiovascular disease was seen in patients with thehypertriglyceridemia, decreased HDL-C, and excess small, densegreatest BMI and those with the highest triglyceride levels, and theLDL particles. Furthermore, fibrates reduce LDL-C, although to alowest HDL-C levels.[86] In the BIP study,[87] a secondary myocar-lesser extent than statins, and in this context fenofibrate anddial infarction prevention study with bezafibrate, a decrease inbezafibrate are more effective than gemfibrozil. The fibrates actcoronary heart disease was observed in patients with hypertriglyc-through activation of the PPAR-α which modulates the transcrip-eridemia, but not in patients with triglyceride concentrationstion of a number of genes, among them those participating in fatty>200 mg/dL.acid synthesis and oxidation and in the production of apo A-V and

Fibrates may cause mild, transient increases in the aminotrans-LPL enzyme. These drugs induce decreased synthesis and in-ferase levels in patients with no history of severe hepatitis. Pro-creased clearance of triglyceride-rich lipoproteins. Moreover, theygress to chronic liver disease has not been reported The incidenceincrease the expression of the genes coding for apo A-I and apo A-of myopathy associated with fibrates is scarce when used inII, and thus potentiate the production of HDL particles and reversemonotherapy except in situations of coexisting renal failure, wherecholesterol transport through a number of mechanisms includingthere is a marked increase in the plasma concentrations of theseincreased activity of the ABCA-1 system which extrudes choles-drugs.[81] With regard to clofibrate, a member of the fibrate familyterol from the cells to the HDL particles, and activity at the SR-B/of drugs that fell into pharmacologic disuse almost 2 decades ago,CLA-1 receptors, which mediate the recovery of HDL-C at theincreased bile lithogenicity, a phenomenon not convincinglyhepatocytes and steroidogenic cells.[78,79]

demonstrated with current fibrates, was documented.[80] FibratesFibrates reduce triglyceride levels by about 30–50%,[80] theirmay potentiate the effects of oral anticoagulants, so that theireffect being more marked in patients with hypertriglyceridemia.administration in patients treated with such agents requires closeThey increase HDL-C by about 10–20%, and reduce LDL-C to amonitoring of the prothrombin time.[81]highly variable extent, usually not >15%.[81] The most marked

effect of fibrates on LDL particles is the reduction of the propor-6.2.3 Combination Drug Therapytion of small dense LDL particles, thus reducing their atherogenic

potential; furthermore, fibrates reduce the thrombotic risk through The combination of fibrates and statins is highly effective fortheir effects on platelet aggregation and on the fibrinogen, factor the control of the lipid metabolism abnormalities of metabolicVII, plasminogen activator inhibitor-1 and CRP levels, even to a syndrome and diabetes mellitus, when such abnormalities cannotgreater extent than statins as indicated in the study by Malik et be corrected with monotherapy. The hypolipidemic effects ofal.[82] combined fibrate and statin are considerable.[88-90] Table IX enu-

Fibrates have proven to be efficacious in the secondary preven- merates the effects of the various combinations of fibrates andtion of cardiovascular disease in diabetic patients, particularly in statins on the lipid profile; remarkable among these is a marked



Table IX. Effect of combination therapy with HMG-CoA reductase inhibitors (statins) and fibrates on lipid profile in patients of various risk categories

Patient category Lipid profile

LDL-C (%) TG (%) HDL-C (%)

Combined familial hyperlipidemia[88]

Pravastatin 20 mg/day + gemfibrozil 1200 mg/day ↓ 35 ↓ 48 ↑ 14

Simvastatin 20 mg/day + gemfibrozil 1200 mg/day ↓ 39 ↓ 54 ↑ 25

Simvastatin 20 mg/day + ciprofibrate 100 mg/day ↓ 42 ↓ 57 ↑ 17

Diabetes mellitus with combined hyperlipidemia[89]

Atorvastatin 20 mg/day + fenofibrate 200 mg/day ↓ 46 ↓ 50 ↑ 22

Coronary heart disease with mixed hyperlipidemia[90]

Fluvastatin 40 mg/day + bezafibrate 400 mg/day ↓ 24 ↓ 38 ↑ 22

LDL-C = low-density lipoprotein-cholesterol; HDL-C = high-density lipoprotein-cholesterol; TG = triglycerides; ↓ indicates decrease; ↑ indicates increase.

decrease in the levels of triglycerides and an increase in HDL-C amiodarone, and tolbutamide should be mentioned. Cimetidinesignificantly greater than that achieved with statin monotherapy. and azole antifungals have a weak inhibitor effect on the 2C9However, the effect of statins in combination with fibrates is isoenzyme. Pravastatin is metabolized through sulfation reactionsmodest in patients with hypocholesterolemia. In addition, the which are independent of P450 cytochrome metabolism. The riskcombination of fibrates with statins entails a higher risk of adverse of rhabdomyolysis is reduced when statins are combined witheffects, particularly myopathy, requiring closer monitoring of fenofibrate rather than gemfibrozil.[92] Thus, the statin-gemfibrozilpatients. Particular caution is indicated in elderly patients, in combination should be avoided. The metabolism and excretion ofindividuals with a small corporal volume, and in those exposed to fibrates involves a glucuronide conjugation process involving thethe factors enumerated in table X. If these precautions are kept in uridin-diphosphate glucuronosyl transferase (UGT) enzyme, ofmind, the risk of myopathy is quite low. In a meta-analysis of

which a number of isoenzymes are known. Gemfibrozil is metabo-studies carried out with combined fluvastatin and fibrates,[91] in

lized through the action of the 1A1, 1A3, 1A9, 2B7, and 2B15which a total population of 1018 patients were treated for periods

isoenzymes, whereas fenofibrate is metabolized through the 1A9of 16–108 weeks, it was seen that the response to therapy was

and 2B7 pathways. It has been recently reported that a UGT-largely determined by the baseline lipid profile. Thus, the highermediated glucuronide conjugation process acting on the hydroxy-the baseline triglyceride concentration, the greater was the de-acids resulting from the P450 cytochrome-mediated oxidationcrease in triglycerides and the smaller the decrease in LDL-C andprocess is required for the metabolic elimination of statins.[93] Thenon-HDL-C. The HDL-C levels increased to a greater extent inUGT isoenzymes involved in the metabolism of gemfibrozil (1A1patients with marked hypo-α-lipoproteinemia (HDL-C <35 mg/dLand 1A3) are also responsible for metabolizing a number of other= <0.9 mmol/L) than in those with higher HDL-C concentrations.statins excluding fenofibrate and bezafibrate.[93] Furthermore, itAs for the occurrence of myopathy, increased levels of creatine

kinase >10-fold the maximum reference value were seen in only has been reported that the plasma concentrations of statins in-two patients (0.2%). crease markedly when given in combination with gemfibrozil,[94]

but not fenofibrate or bezafibrate. Table XI illustrates theIn order to prevent myopathy caused by the combination ofstatins and fibrates, it should be kept in mind that there are aseveral classes of pharmacologic drugs that can potentiate thetoxicity of statins.[88] Thus, the statins that are metabolized by the3A4 isoenzyme of cytochrome P450 (lovastatin, simvastatin, andatorvastatin) interact with drugs using or inhibiting this metabolicpathway. Among such drugs are azole antifungals, macrolideantibacterials, cyclosporin, calcium channel antagonists, hista-mine H2-receptor antagonists, omeprazole, tamoxifen, tricyclicantidepressants, fluoxetine, and sertraline. A smaller number ofdrugs inhibit the 2C9 isoenzyme which participates in the meta-bolic pathway of fluvastatin; among these ritonavir, omeprazole,

Table X. Recommendations for prevention of myopathy secondary to ther-apy with HMG-CoA reductase inhibitors (statins) and fibrates in patientswith metabolic syndrome

Check kidney and thyroid function

Give statins 12 hours apart from fibrate intake

Avoid interactions with other drugs

Give intermediate or low dosages of statins initially

Use preferably fenofibrate or bezafibrate

Monitor creatine kinase and muscular symptoms

Instruct patient about symptoms of myopathy


54 Ascaso et al.

with daily doses <2g.[97] The combination of statins with nicotinicacid has been shown to be effective in reducing the LDL-C andtriglyceride levels, increasing the HDL-C levels and inducingregression of atherosclerosis and preventing coronary heart dis-ease in angiographic follow-up studies.[98]

The ω-3 fatty acids are moderately effective in reducing trig-lycerides, and to a lesser extent LDL-C. Their efficacy in cardio-vascular prevention has been demonstrated in a number of stud-ies[99] and is attributed to their membrane-stabilizing effect and tothe consequent antithrombotic and anti-inflammatory actions be-sides there action on lipid levels. There is an increase in interest inthe use of these compounds for the management of patients with

Table XI. A summary of pharmacokinetic interactions between HMG-CoAreductase inhibitors (statins) and fibrates (reproduced from Davidson,[95]

with permission)

HMG-CoA reductase Gemfibrozil Fenofibrateinhibitor

Atorvastatin No data No data

Pravastatin Significant ↑ Cmax No effect

Fluvastatin No effect Not available

Simvastatin ~112% ↑ Cmax No effect

Cerivastatin 2- to 3-fold ↑ Cmax No effect

Rosuvastatin Not available No effect

Cmax = maximum concentration; ↑ indicates increase.

the metabolic syndrome.pharmacokinetic effects of combining various statins with gemfi- Vegetable sterols at doses of up to 2 g/day may decrease thebrozil or fenofibrate.[95] LDL-C levels by up to 15% and, administered as dietary supple-

ments together with various milk derivatives or vegetable oil-The combination of ezetimibe with fibrates maintains the lat-based margarines, they may be used in combination with bothter’s favorable effect on triglycerides, HDL-C, and the proportionfibrates and statins to enhance reductions in LDL-C.[100]of small dense LDL particles, and complements the decrease in

LDL-C and non-HDL-C achieved with fenofibrate monother-apy.[96] Combined therapy with ezetimibe does not alter the plasma 6.2.5 An Overall Strategy for Pharmacologic Therapy of

Metabolic Syndrome Hyperlipidemiaconcentrations of fenofibrate, but plasma concentrations of eze-Table XII illustrates the management of hyperlipidemia intimibe are increased by 50%, which is not considered to be

adults with the metabolic syndrome. For patients with the metabol-clinically relevant. In a study of patients with mixed hyper-ic syndrome and high triglyceride concentrations, the drugs of firstlipidemia the administration of fenofibrate (160 mg/day) togetherchoice are the fibrates. Statins may be moderately effective inwith ezetimibe (10 mg/day) achieved a 20% reduction in LDL-Cmoderate-severe hypertriglyceridemia, but they are usually notand a 30% reduction in non-HDL-C levels. Similar to monother-effective in severe hypertriglyceridemia (>1000 mg/dL orapy with fenofibrate, combination with ezetimibe more markedly11.2 mmol/L) or in the hyperchylomicronemia syndrome. Thedecreased LDL-C and non-HDL-C levels in patients with onlythird choice, nicotinic acid, is a further alternative; it is moremoderately increased triglyceride levels (<3.1 mmol/L) comparedeffective than the statins, but it associated with adverse effects.with those with hypertriglyceridemia, by 28% and 13%, respec-The ω-3 fatty acids may generally be used as an adjuvant therapytively. The incidence of adverse effects observed with the combi-to other drugs.nation was no higher than that with fenofibrate monotherapy.[96]

The combination of fenofibrate and ezetimibe has not yet received To achieve an increase in HDL-C levels, fibrates are the drugsapproval for clinical use in the treatment of derangements of lipid of first choice followed by nicotinic acid. Torcetrapib, a CETPmetabolism. inhibitor that may increase HDL-C by over 50% according to the

results of the first clinical trials, is currently in an advanced stageof research.[101]6.2.4 Combination Therapy with Other Drugs

Statins are the drugs of first choice for lowering LDL-C.Nicotinic acid is an effective drug for increasing HDL-C andMonotherapy with ezetimibe has a limited effectiveness and thedecreasing triglycerides and LDL-C, but it often causes flushing,drug is considered as second choice, along with fibrates, vegetableas an adverse effect causing a high percentage of patients tosterols, and resins.[102]withdraw from the therapy.[97] These adverse effects can be man-

Because of the high cardiovascular risk in patients with theaged by slow titration and the administration of low doses ofmetabolic syndrome, when the therapeutic goals are not achievedaspirin half an hour before the administration of nicotinic acid thuswith monotherapy, combination therapy should be considered, notmaintaining the beneficial effects of nicotinic acid on LDL-C,only for reducing the LDL-C levels, but also for improving theHDL-C, and triglyceride concentrations. In the US, modified-triglyceride metabolism, the reverse cholesterol transport, and therelease forms of nicotinic acid with fewer adverse effects havequalitative changes in lipoproteins. Regarding hypertriglycer-already been marketed. High-dose nicotinic acid may increase theidemia that is not controlled with monotherapy, fibrates in combi-serum glucose concentrations, but this does not usually happen



Table XII. Recommendations for pharmacologic therapy of metabolic syndrome dyslipidemia

Lipid factor Recommended therapy

Hypertrigliceridemia Fibrates; HMG-CoA reductase inhibitors (statins) [low efficacy]a nicotinicacid; ω-3 fatty acids

HDL-C deficiency Fibrates; nicotinic acid

Hypercholesterolemia (excess LDL-C) Statins; ezetimibe; fibrates; vegetable sterols; resinsb

Goals for LDL-C not achieved with monotherapy Statins + ezetimibe; statins + resinsb statins + nicotinic acid

Combined dyslipidemia (↑ LDL-C and ↑ triglycerides) Intermediate or high-dose statins (first choice); fibrates (second choice)

Therapeutic goals not achieved with monotherapy Statins + fibrates (first choice); statins + ezetimibea/fibrates + resinsb/statins + nicotinic acid (second choice)

a Alternatively, the combination of statins with fish oils may be considered.

b Consider the possible hypertriglyceridemic effect of resins.

HDL-C = high-density lipoprotein-cholesterol; LDL-C = low-density lipoprotein-cholesterol; ↑ indicates increase.

nation with ω-3 fatty acids or nicotinic acid should be considered, known atherogenic potential in patients with the metabolic syn-always bearing in mind adverse effects associated with nicotinic drome.acid. The combination of fibrates and ezetimibe may well be

Therefore, for the diagnosis of metabolic syndrome dys-defined in the near future as a good therapeutic alternative for

lipidemia both quantitative and qualitative assessments of the lipidmixed dyslipidemia in patients with the metabolic syndrome.

profile should be undertaken. Patients may exhibit hypercholester-olemia at the expense of LDL-C, but this is neither the mostfrequent nor the most important derangement. Hypertriglycer-7. Final Recommendationsidemia (≥150 mg/dL) and low HDL-C concentrations (<40 mg/dLin men or 50 mg/dL in women) are the characteristic features.The increased cardiovascular risk associated with the metabolicFurthermore, detection of a parallel increase in non-HDL-C issyndrome is largely due to the characteristic hyperlipidemia thatquite significant. The latter parameter is particularly useful inaccompanies it. This is an impairment of the lipid metabolism thatestablishing a diagnosis in the context of hypertriglyceridemia.is usually common to a number of clinical situations such as

visceral obesity, insulin resistance, well established type 2 diabe- The therapeutic management of the metabolic syndrome, re-tes mellitus, and the metabolic syndrome itself. This syndrome gardless of the control of the patient’s bodyweight, BP, hypergly-should be understood as a constellation of cardiovascular risk cemia or overt diabetes mellitus, aims at maintaining optimumfactors that usually appear together and for which it is frequent to plasma lipid levels, establishing therapeutic goals similar to thosefind a common pathogenesis, even though they may have diverse for high-risk situations. In this context, the LDL-C level thatorigins. should be considered as the priority goal will be <100 mg/dL (or

The clinical expression of the metabolic syndrome dys- <70 mg/dL in cases with established ischemic heart disease or risklipidemia, even though variable, has some characteristic features. equivalents). A further goal is increasing the HDL-C level toThese include hypertriglyceridemia and low HDL-C, which are >40 mg/dL in men or 50 mg/dL in women. A non-HDL-C goal ofvery relevant and constitute a part of the commonly established 130 mg/dL should also be aimed at because of coexisting hyper-diagnostic criteria for the metabolic syndrome. However, the triglyceridemia.dyslipidemia of the metabolic syndrome is rather more than a

Lifestyle interventions such as maintaining an adequate dietsimple quantitative alteration of plasma lipoproteins. These pa-and a physical activity program, constitute an essential part oftients have high levels of apo B-100-rich particles with a particu-therapy. Nevertheless, when pharmacologic therapy becomes nec-larly atherogenic phenotype (small dense LDL). On the otheressary, fibrates and statins are the most effective drugs in control-hand, the high levels of triglyceride-rich particles (VLDL) areling the metabolic syndrome hyperlipidemia, and are thus thedemonstrated both in the baseline situation and in overload (post-drugs of first choice, the former because of their effectiveness inprandial hyperlipidemia). Overall, ‘quantitative’ dyslipidemialowering triglycerides and increasing HDL-C, the two most fre-(hypertriglyceridemia and low HDL-C), ‘qualitative’ dyslipidemiaquent abnormalities, and the latter because of their effectiveness in(small, dense, apo B-100-rich LDL) and insulin resistance (in the

context of dyslipidemia) together constitute a triad with a well- lowering LDL-C. In addition, the combination of fibrates and


56 Ascaso et al.

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Management of Dyslipidemia in the Metabolic Syndrome: Recommendations of the Spanish HDL-Forum

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