Thomson

1Departments of Pharmacotherapy, Cardiology and Cardiothoracic Surgery, Academic Medical Centre, Amsterdam, The Netherlands, and 2Department of Cardiology, Free University Medical Centre, Correspondence: Prof.Dr P.A. van Zwieten, Departments of Pharmacotherapy, Cardiology and Cardiothoracic Surgery, Academic Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
Tel: +31 20 566 49 76; fax: +31 20 696 8704 Patients with the metabolic syndrome have a clustering of the following risk factors: detrimental changesin glucose tolerance and insulin resistance, abdominal (visceral) obesity, atherogenic dyslipidemia,hypertension. In addition to appropriate changes in lifestyle, the majority of patients with the syndromewill require pharmacological treatment, usually for the remainder of their lives. We present here anexhaustive and critical review of the drug treatment of the risk factors associated with the metabolicsyndrome. Emphasis will be upon antihypertensive treatment and on the influence of various drugs oninsulin resistance, an important background to the metabolic syndrome.
Keywords: Metabolic syndrome, insulin resistance, antihypertensive drugs, diabetes mellitus(type 2), obesity, hyperlipidemia have established definitions of the metabolic syndromethat are fairly similar. Both definitions comprise mar- The most relevant components of the metabolic syn- kers for abdominal obesity, glucose and lipid metab- olism, and blood pressure. The WHO definitioncontains, in addition, criteria for urinary albumin  unfavorable changes in glucose tolerance ( # ) and excretion as a marker for renal damage, and in more general terms as a sensitive predictor for cardiovascular The pathophysiological backgrounds of metabolic syndrome, a very heterogenous syndrome, are com-plex. Two major issues are discussed as possible Taking into account the complex character of the common backgrounds of the metabolic syndrome: metabolic syndrome, it is not surprising that its defi- (a) insulin resistance/glucose intolerance (see Figure 1) nition and nomenclature have been subject to con- and (b) hyperactivity of the sympathetic nervous sys- siderable and even polemic discussions and debate.
tem. Both phenomena and their relationship with the Secondary to the initial term ‘syndrome X’, other metabolic syndrome have been discussed exhaus- names for metabolic syndrome have been proposed, such as ‘insulin resistance syndrome’, ‘Reaven’s Metabolic syndrome is associated with important syndrome’ and ‘metabolic cardiovascular syndrome’ cardio/cerebrovascular and metabolic risks. Preven- tion and treatment are therefore of great importance.
Both the National Cholesterol Education Programme Preventive measures involving lifestyle are mandatory.
(NCEP) and the World Health Organization (WHO) In addition, patients with the metabolic syndrome will Figure 1. Pathological processes that have roles in the metabolic syndrome and can hence lead to cardio/cerebrovasculardiseases. Insulin resistance appears to be of pivotal importance as a background to several pathological mechanisms.
require pharmacological treatment, usually for the alcohol consumption), and by more and regular Taking into account the heterogenous character of  Hyperlipidemia: as discussed above for obesity the metabolic syndrome and its various components, the pharmacological interventions are bound to be  Hypertension: as discussed above for obesity etc.; complex. Consequently, the evaluation of pharmaco- in addition, moderation of salt (Naþ) and alcohol logical interventions will require appropriately designed, rather complicated clinical trials.
The present survey will deal with the various From a more general perspective, all patients are aspects of pharmacological treatment of the meta- urgently advised to stop smoking. On the basis of the bolic syndrome, including some newer therapeutic concept that the metabolic syndrome is associated with sympathetic hyperactivity, preventive measuresaiming at reducing this hyperactivity could be con-sidered. Correction of overweight and enhanced physical activity may be expected to reduce sympath- etic hyperactivity somewhat. Prevention of the pro-thrombotic condition can be achieved only by It goes without saying that prevention is a crucial approach for reducing the various risks brought aboutby the metabolic syndrome. The preventive approachholds for virtually all important components of meta- bolic syndrome, such as glucose intolerance/insulinresistance, diabetes mellitus type 2, obesity, hyperli- pidemia, and hypertension. Generally speaking, therecommended changes in lifestyle run parallel to Although the preventive measures described above reduction of risk for these pathophysiological pro- should always be the primary approach to interven- cesses. Accordingly, the following recommendations tion in patients with the metabolic syndrome, this for intervention should be taken into account as pre- approach is not always successful, in particular in the long term. Accordingly, the vast majority ofpatients with the metabolic syndrome require  Obesity, glucose intolerance, insulin resistance, pharmacological treatment, in spite of all the good diabetes mellitus type 2: correction of overweight intentions with respect to prevention and lifestyle by adequate changes in diet (Mediterranean diet, improvements. Once established, drug treatment less saturated fat, fewer calories, reduction of has to be followed daily, and usually for the remainder Metabolic syndrome: pharmacological treatment of the patient’s life. Guidelines on prevention of cardiovascular disease do not usually make extensive reference to the metabolic syndrome When they do, they usually advise that this condition is predo-minantly approached by improvements in lifestyle. Itis likely that this conservative approach will change in the future towards a more interventional one, with amore important role of pharmacological treatment Figure 2. Chemical structure of rimonabant, an inhibitor ofthe cannabinoid (CB1) receptor in the endocannabinoid Pharmacological treatment of obesity had been endocannabinoid system and its receptors can be attempted for several decades, but so far this approach thought of as an interesting target for new drugs.
has been disappointing. In most European countries, In recent years, several hormones involved in the two drugs are registered for the treatment of obesity: regulation of appetite and saturation have been dis- covered, such as leptinÃ, ghrelin, resistin and peptide Sibutramine, an anorexant chemically derived PYY. It is conceivable that derivatives, analogs, ago- from amphetamine, inhibits the reuptake of both nists, or antagonists of these hormones may provide norepinephrine and serotonin by their respective the basis for the development of new drugs that can be nerve endings, in both the periphery and the central nervous system. Consequently, appetite is reducedand energy expenditure is increased. Adverse Glucose intolerance, insulin resistance, and responses to sibutramine can be problematic as a result of activation of the sympathetic nervous system.
Long-term beneficial effects of the drug are the subject In addition to the classical oral antidiabetic drugs (tolbutamide and related sulfonylurea derivatives, gli- Orlistat reduces the intestinal absorption of nutri- nides, and acarbose), the biguanide, metformin, has tional fat by inhibition of the enzyme lipase in the experienced a renaissance of interest since it was pancreas and the stomach. Orlistat, indeed, appears discovered that it exhibits insulin-sensitizing activity.
to be able to reduce body weight in the long term, but For this and other reasons, metformin is considered its adverse reactions (mainly gastrointestinal) are most the oral antidiabetic drug of choice in patients with unpleasant, leading to poor patient compliance.
Metformin, a biguanide-type antidiabetic agent, is Glitazones, such as pioglitazone and rosiglitazone, not classified as an anti-obesity drug, but in diabetic are the newer type of insulin sensitizer. They reduce patients treated with this agent, body weight is usually insulin resistance via the activation of the peroxisome- proliferator-activated receptor subtype g (PPAR-g). On Rimonabant, an antagonist of cannabinoid (CB1- theoretical grounds, they would be beneficial oral type) receptors in the endocannabinoid system of antidiabetic agents in patients with metabolic syn- the brain, offers a new approach in the management drome. Their position will be established by means of of obesity. Stimulation of CB1 receptors is involved in an increase in appetite, increased accumulation of fatin adipocytes, and increased motivation to smoke.
Conversely, blockade of the CB1 receptor by anantagonist will counteract both hyperphagia/obesity As insulin resistance is now widely recognized as an and the increased motivation to smoke. Rimonabant important background to the various components of (Figure 2), the first clinically applicable CB1 receptor the metabolic syndrome, it appears useful to review antagonist, exhibits these beneficial effects, to date in the differential influences of the various cardiovascu- studies lasting 1 year Further and large-scale lar and antidiabetic drugs used in the management of studies will be required to establish the position of rimonabant, which appears to offer a new approach in Table I, insulin resistance can be modulated in a the management of obesity, including in patients with differential manner by various types of drugs. In particular, various types of antihypertensive agent Overall, the pharmacological treatment of obesity display a clearly differential activity. As will be dis- has to date been largely disappointing. Appropriate cussed in the next paragraph, this issue is of vital improvements are highly desirable. In this respect, the importance, in particular with respect to the long-term Table I. Overview of the effects of cardiovascular and antidiabetic drugs that influence insulin resistance.
a1-Adrenoreceptor antagonists (eg, doxazosin) Angiotensin II receptor antagonists (AT1-blockers; Centrally acting antihypertensives (clonidine; ACE, angiotensin-converting enzyme; ARB, angiotensin II type 1 receptor blocking agent; AT1, angiotensin II type 1; DOPA,dihydroxyphenylalanine; PPAR, peroxisome proliferator activated receptor.
treatment of essential hypertension, which is usually A recent review paper by Opie and Schall dealt in detail with the metabolic, and in particular thediabetogenic, actions of various groups of antihyper-tensive agents. In this connection, ‘older’ and ‘mod- ern’ antihypertensive drugs were distinguished.
Thiazide diuretics and b-blockers were classified as Taking into account that patients with the metabolic the ‘older’ antihypertensive agents, whereas calcium syndrome are clearly at increased cardio/cerebro- antagonists, ACE inhibitors and AT1 receptor blockers vascular risk, strict control of blood pressure is man- were considered to be the ‘modern’ antihypertensive datory, aiming at values of 130/85 mm Hg or even drugs. These two categories of drug were compared less. Although it has not been studied in a specific by means of a meta-analysis, including seven large- trial, it seems very likely that patients with the meta- scale intervention trials, involving 58 010 patients. In bolic syndrome including hypertension would also a follow-up period of 4 years, particular attention was benefit from decreasing their blood pressure by paid to newly developed diabetes. ACE inhibitors and pharmacological treatment, probably almost irrespec- AT1 blockers reduced the number of new cases of tive of the type of drug used. However, in this con- diabetes by 20%, whereas for the calcium antagonists nection it should be borne in mind that the this reduction amounted to 16%. In contrast, the development of diabetes and other metabolic pro- ‘older’ antihypertensives significantly increased the blems are associated with the long-term use of certain incidence of new cases of diabetes, probably by a The European Society of Hypertension/European Furthermore the Antihypertensive Treatment and Society of Cardiology 2003 guidelines proposed Lipid Profile in the North of Sweden Efficacy Evaluation five groups of antihypertensive drugs as first-line treat- (ALPINE) trial performed in patients with hyper- ment of hypertension: thiazide diuretics, b-blockers, tensive metabolic syndrome, has demonstrated import- calcium antagonists, angiotensin-converting enzyme ant metabolic differences between two different (ACE) inhibitors, and angiotensin II receptor anta- treatment regimens: hydrochlorothiazide þ atenolol, gonists (angiotensin II type 1 [AT1] blockers; angio- and candesartan þ felodipine. Both treatment sche- tensin II type 1 receptor blocking agents; sartans).
dules caused a satisfactory and similar control of blood Other drugs that can be considered are the a-block- pressure. Interestingly, treatment with the diuretic þ ers and the older centrally acting antihypertensives b-blocker combination appeared to be associated with such as clonidine and a-methyl-dihydroxyphenylala- a significantly larger number of new cases of diabetes nine. If used correctly, these various agents have mellitus type 2, and was accompanied by higher largely comparable blood pressure decreasing activi- plasma triglyceride concentrations. In contrast, treat- ties. However, recent investigations indicate that the ment with combination candesartan þ felodipine, metabolic changes associated with the various leading to the same degree of decrease in blood categories of antihypertensive agent are differential, pressure, was not accompanied by any significant and therefore highly relevant within the framework of metabolic/endocrine changes. The former treatment also enhanced the occurrence of new cases of the Metabolic syndrome: pharmacological treatment metabolic syndrome, whereas the latter treatment did let drug, has always been used. According to the general advice of the American Heart Association, Taking together the findings of Opie and Schall and aspirin prophylaxis should be applied in patients with ALPINE, the potential diabetogenic action of thiazide a ! 10% risk of developing a coronary event within a diuretics and b-blockers would speak against their use period of 10 years, based upon the criteria of the in patients with the metabolic syndrome, for whom Framingham risk schedule Some, but not all, the more modern antihypertensive agents (ACE inhibi- patients with the metabolic syndrome will meet tors, AT1 receptor blockers, calcium antagonists) Irrespective of the occurrence of the metabolic syndrome, it should be assumed that young hyperten- sive patients will be treated for several decades.
Accordingly, these modern antihypertensive agents The awareness of the metabolic syndrome as a well- appear to be preferable over the metabolically unfa- defined and relevant pathological entity has stimu- vorable thiazide diuretics or b-blockers.
lated interest in pharmacological intervention. The Finally, it may be of interest to note the dual activity heterogenous backgrounds of the syndrome mean of the AT1 blocker, telmisartan, which is also an that clinical trials concerning drug treatment of the insulin sensitizer, thanks to its PPAR-g-stimulating syndrome are bound to be complex and difficult activity The clinical relevance of these dual to design. Furthermore, drug treatment targeting the activities remains to be established.
various components of the metabolic syndromehas been demonstrated to be largely differential for the categories of the drugs required for this pur-pose.
Improvement in the diet, already mentioned with The recognition that insulin resistance is an import- respect to prevention and general measures, remains ant background to the metabolic syndrome has led to the cornerstone of the treatment of atherogenic dysli- a new classification of antihypertensive drugs, to be pidemia; this is true also for patients with the meta- differentiated into ‘old’ and ‘new’ categories. Newer bolic syndrome. A significant percentage of the latter drugs, such as ACE inhibitors, AT1 blockers (ARBs), patients additionally require treatment with lipid- and probably also the calcium antagonists, appear to decreasing drugs (antilipemics, hypolipemics). In this offer a better metabolic profile than the older thiazide context, antilipemic drug treatment will be mandatory diuretics and b-blockers, in particular for the long- more and more often in patients with hypertension or term treatment of young patients who have hyperten- sion and the metabolic syndrome. The same holds The management of hyperlipidemia in patients with for the treatment of type 2 diabetes mellitus, for which the metabolic syndrome is performed according to the the newer insulin sensitizers, the thiazolidinediones same principles as in patients without this syndrome, (glitazones), offer a potentially more favorable meta- and is based upon aberrations in the plasma lipids.
bolic profile than the classical oral antidiabetic The hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins) have acquired and maintained a The pharmacological treatment of atherogenic dys- very important position. In most countries, several lipidemia has made substantial progress, in particular statins are registered. To date, it is not possible to owing to the development of the statins. Although express a preference for one particular preparation to little studied in specific trials targeting the metabolic be used in patients with the metabolic syndrome. The syndrome, the use of statins in patients with the widest experience in various categories of patients has metabolic syndrome who have hyperlipidemia been acquired with simvastatin, now available as a appears to be mandatory, although to date none of the statins can be put forward as preferable over the The importance of the high triglyceride concen- others. Furthermore, the relevance of decreasing trations in patients with the metabolic syndrome increased triglyceride concentrations and increasing may require the additional use of fibrates, nicotinic high-density lipoprotein concentrations by means of acid or its derivatives, or both. (For reviews of lipid fibrates or derivatives of nicotinic acid is now decreasing treatment, see references and accepted widely, including in patients with themetabolic syndrome.
Enhanced coagulability (prothrombotic state) Finally, the pharmacological treatment of obesity remains a difficult and disappointing issue. The two If necessary, enhanced coagulability can be corrected drugs registered for this purpose (sibutramine and by means of an antithrombotic drug; in practice, orlistat) are far from optimal and are difficult to use acetylsalicylic acid (ASA, aspirin), a classic antiplate- in the long term. New approaches based on modulating the endocannabinoid system by means of the CB 7. Grundy SM, Hansen B, Smith SC Jr et al. Clinical management of metabolic syndrome: report of the American Heart Associa- receptor antagonist, rimonabant, do at least offer a tion/National Heart, Lung, and Blood Institute/American potentially new route of intervention. In addition, Diabetes Association conference on scientific issues related improved knowledge of the several hormones to management. Circulation. 2004;109:551–556.
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Metabolic syndrome and its management

Lipotoxicity in cardiac and skeletal muscle

Current definition of the metabolic™syndrome

Prevalence of the metabolic™syndrome

Perspective - the search for a unifying™concept

Metabolic imaging in the metabolic syndrome

Imaging techniques for quantification of myocardial™metabolism

Magnetic resonance™spectroscopy

Applying these imaging approaches to the metabolic™syndrome

Myocardial metabolism in abdominal obesity and insulin™resistance

Myocardial metabolism in diabetes™mellitus

Myocardial substrate metabolism in™hypertension

Myocardial substrate metabolism in™hyperlipidemia

Metabolic syndrome: pharmacological treatment

Prevention and general aspects of™intervention

Drug therapy and the metabolic™syndrome

Glucose intolerance, insulin resistance, and type 2 diabetes™mellitus

Enhanced coagulability (prothrombotic state)

Effect of selective 3-ketoacyl coenzyme A thiolase inhibition on glucose metabolism in cardiac patients

Effects of selective 3-ketoacyl coenzyme A thiolase inhibition on glucose™metabolism

Therapeutic approach to abnormal glucose metabolism in cardiac™patients

Effects of trimetazidine on endothelial™function

Effects of trimetazidine on glucose™metabolism

Hypercalcemia and the cardiovascular system

Definition of insulin™resistance

Mechanism of insulin™resistance

Etiology of insulin™resistance

Prevalence of insulin™resistance

Insulin resistance and type 2 diabetes™mellitus

Insulin resistance and™hypertension

Insulin resistance and the cardiometabolic™syndrome

Laboratory studies to identify insulin™resistance

Treatment of insulin™resistance

Obesity, insulin resistance, and the metabolic syndrome: determinants of endothelial dysfunction in Whites and Blacks

Impaired coronary blood flow in patients with metabolic syndrome: documented by Thrombolysis in Myocardial Infarction (TIMI) frame count method

Peroxisome proliferator-activated receptor alpha (MHC-PPARα)

Glycophosphatidylinositol-linked lipoprotein™lipase

Ectonucleotide pyrophosphatase/phosphodiesterase™1

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