Thomson

ESH position statement The metabolic syndrome in hypertension: European society ofhypertension position statementJosep Redon, Renata Cifkova, Stephane LaurentPeter NilssoKrzysztof NarkiewiczSerap Erdineand Giuseppe Mancia, on behalf ofthe Scientific Council of the European Society of Hypertension The metabolic syndrome considerably increases the risk of compelling indications are present for its use. If a cardiovascular and renal events in hypertension. It has been combination of drugs is required, low-dose diuretics can be associated with a wide range of classical and new used. A combination of thiazide diuretics and b-blockers cardiovascular risk factors as well as with early signs of should be avoided. J Hypertens 26:1891–1900 Q 2008 subclinical cardiovascular and renal damage. Obesity and Wolters Kluwer Health Lippincott Williams & Wilkins.
insulin resistance, beside a constellation of independentfactors, which include molecules of hepatic, vascular, and immunologic origin with proinflammatory properties, have Journal of Hypertension 2008, 26:1891–1900 been implicated in the pathogenesis. The close relationships among the different components of the Keywords: antihypertensive drugs, blood pressure goals, hypertension, lifestyle, metabolic syndrome syndrome and their associated disturbances make it difficult to understand what the underlying causes and Abbreviations: ACE, Angiotensin-Converting Enzyme; ACEi, Angiotensin-Converting Enzyme inhibitors; ARA II, Angiotensin II-AT1 Receptor blockers; consequences are. At each of these key points, insulin ARB, Angiotensin II-AT1 Receptor Blockers; ARB, Angiotensin Receptor resistance and obesity/proinflammatory molecules, Blocker; ATP III, Adult Treatment Panel III; CB1 receptor blockers,Cannabinoid type 1 Receptor Blockers; CB1, Cannabinoid type 1; CCB, interaction of demographics, lifestyle, genetic factors, and Calcium-Channel Blocker; CPR, C-Reactive Protein; DREAM, Diabetes environmental fetal programming results in the final Reduction Assessment with Ramipril and Rosiglitazone Medication; EGIR,European Group of Insulin Resistance; EKG, Eelektrokardiogramm; ELSA, phenotype. High prevalence of end-organ damage and poor European Lacidipine Study on Atherosclerosis; FFA, Free Fatty Acid; GFR, prognosis has been demonstrated in a large number of Glomerular Filtration Rate; HDL, High-Density Lipoprotein; IDF, InternationalDiabetes Federation; IFG, Impairing Fasting Glucose; IMT, Intima-Media cross-sectional and a few number of prospective studies.
Thickness; LDL, Low-Density Lipoprotein; LVH, Left Ventricular Hypertrophy; The objective of treatment is both to reduce the high risk of MDRD, Modification of Diet in Renal Disease; NHANES III, National Healthand Nutrition Examination Survey III; NHBLI, National Heart Blood and Lung a cardiovascular or a renal event and to prevent the much Institute; PAMELA, Pressioni Arteriose Monitorate E Loro Associazioni; greater chance that metabolic syndrome patients have to PPAR-g, Proliferator-Activated Receptor-Gamma; PWV, Pulse Wave Velocity; develop type 2 diabetes or hypertension. Treatment STAR, The Study of Trandolapril/Verapamil SR and Insulin Resistance;VALUE, Valsartan Antihypertensive Long-term Use Evaluation consists in the opposition to the underlying mechanisms of the metabolic syndrome, adopting lifestyle interventions University of Valencia and CIBER 06/03 Physiopathology of Obesity and Nutrition, Institute of Health Carlos III, Madrid, Spain, bDepartment of Preventive that effectively reduce visceral obesity with or without the Cardiology, Institute for Clinical and Experimental Medicine, Prague, Czech use of drugs that oppose the development of insulin Republic, cDepartment of Pharmacology and INSERM U872, European HospitalGeorges Pompidou, Paris, France, dDepartment of Clinical Sciences Medicine, resistance or body weight gain. Treatment of the individual University Hospital, University of Lund, Malmo, Sweden, eDepartment of components of the syndrome is also necessary. Concerning Hypertension and Diabetology, Medical University of Gdansk, Gdansk, Poland, fIstanbul University Cerrahpasa, School of Medicine, Cardiology, Department, blood pressure control, it should be based on lifestyle Istanbul, Turkey and gClinica Medica, Ospedale S Gerardo, Universita di Milano- changes, diet, and physical exercise, which allows for Bicocca, Monza, Italy weight reduction and improves muscular blood flow. When Correspondence to Josep Redon, Internal Medicine, Hospital Clinico, University antihypertensive drugs are necessary, angiotensin- of Valencia, Avda Blasco Ibanez, 17, 46010 Valencia, SpainTel: +34 96 3862647; fax: +34 96 3862647; e-mail: converting enzyme inhibitors, angiotensin II-AT1 receptor blockers, or even calcium channel blockers are preferable Received 20 February 2008 Revised 22 March 2008 over diuretics and classical b-blockers in monotherapy, if no Accepted 27 March 2008 alone, supporting the existence of a discrete disorder, Arterial hypertension is often part of a constellation of the so-called metabolic syndrome. The metabolic syn- anthropometric and metabolic abnormalities that include drome is currently considered to confer an increased risk abdominal (or visceral) obesity, characteristic dyslipide- of cardiovascular events attributable, in part, to the mia (low high-density lipoprotein cholesterol and high individual risk factors that concur in defining it and, in triglycerides), glucose intolerance and insulin resistance, part, to a cluster of other factors such as hyperuricemia, and hyperuricemia. These features occur simultaneously a proinflammatory state, impaired fibrinolysis, and oxi- to a higher degree than would be expected by chance dative stress, which usually go along with it.
0263-6352 ß 2008 Wolters Kluwer Health Lippincott Williams & Wilkins Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Journal of Hypertension 2008, Vol 26 No 10 The clinical significance of diagnosing the metabolic names have been given to various clusters of cardiovascular syndrome in an individual has been challenged recently.
risk factors but, today, the most commonly used name are Some authors and scientific societies have claimed that the metabolic syndrome or cardiometabolic syndrome.
the metabolic syndrome is not a single pathophysiological Similarly, the criteria employed to identify the metabolic entity, that its identification has neither pedagogical nor syndrome have changed over the years .
clinical utility, and that clinical emphasis should rather be After the more mechanistic World Health Organization placed on effectively treating any cardiovascular risk and European Group for Insulin Resistance definitions, factor that is present However, although the causes the Adult Treatment Panel III (ATP III), one of the and mechanisms of the metabolic syndrome may indeed metabolic syndromes presented in 2001 was more be diversified (which is what the term ‘syndrome' clinically oriented. More recently, the International implies), there is evidence that the overall cardiovascular Diabetes Federation definition aims at considering risk accompanying this condition may be greater than the research needs but also at offering an accessible diagnostic sum of its identifiable components Furthermore, tool suitable for worldwide use. The most important new these components are often defined by values that are element, as compared to other definitions, is that, although lower than those meeting the definition of risk factors by the pathogenesis of the metabolic syndrome and the many guidelines, which may thus fail to detect the contribution of each of its components is complex and presence of a high cardiovascular risk in several individ- still not well understood, central obesity and insulin resist- uals with metabolic syndrome. Finally, the simple and ance are regarded as the most important causative factors.
easy identification of the metabolic syndrome favors the The last of the definitions was released by the American use of this approach in clinical practice, which resists use Heart Association/National Heart Blood and Lung Insti- of the more complex charts for total cardiovascular risk tute) (AHA/NHBLI) It has given support to the ATP quantification, ultimately helping implementation of III criteria, except for a reduction in the threshold of the impaired fasting glucose component from 6.1 to 5.6 mmol/l(110–100 mg/dl) in line with the recent modification pro- The metabolic syndrome is extremely common world- posed by the American Diabetes Association This wide and can be found in approximately one-third of lower cut-off point was not adopted in Europe and is not patients with essential hypertension in whom it consider- recommended by the WHO ably increases the risk of cardiovascular and renal events,even in the absence of overt diabetes. Its presence has Mechanisms of hypertension in the metabolic been associated with a wide range of classical and also new cardiovascular risk factors as well as with early signs Mechanisms involved in the metabolic syndrome are of subclinical cardiovascular and renal damage. In the obesity, insulin resistance and a constellation of inde- present study, the prevalence, mechanisms, prognostic pendent factors, which include molecules of hepatic, significance, and treatment of the metabolic syndrome in vascular, and immunologic origin with proinflammatory hypertensive patients are reviewed. Management recom- properties. Although insulin resistance is associated with mendations are given and areas in need of future research obesity and central adipose tissue, not all obese subjects and improved knowledge are recognized.
have insulin resistance. Skeletal muscle and the liver, notadipose tissue, are the two key insulin-response tissues involved in maintaining glucose balance, although abnor- There is no universally accepted definition for the meta- mal insulin action in the adipocytes also plays a role in bolic syndrome. Since the description by Reaven many development of the syndrome. At each of these key Criteria for diagnosing the metabolic syndrome according the different scientific organisms Principal criteria Abdominal obesity
150 (1.7 mmol/l) W  39 (1.02 mmol/l) <40 (1.03 mmol/l) M
102 cmW
88 cm M  40 (1.03 mmol/l)
150 (1.7 mmol/l) W  50 (1.29 mmol/l) M  40 (1.03 mmol/l) W  (1.29 mmol/l) M  40 (1.03 mmol/l) W  (1.29 mmol/l) Diagnosis of metabolic syndrome is based on: principal criteria plus at least two other; in those without principal criteria, at least three. Shaded area denotes the definitionsbased on carbohydrate metabolism abnormalities. The remaining are based on abdominal obesity. AHA, American Heart Association; ATP III, Adult Treatment Panel III; BP,blood pressure; DM, diabetes mellitus; EGIR, European Group for the Study of Insulin Resistance; FI, fasting insulin; GI, glucose intolerance; IDF, International DiabetesFederation; IR, insulin resistance; M, men; TG, triglycerides; W, women; WHO, World Health Organization. a Or in treatment for.
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Metabolic syndrome in hypertension Redon et al.
points, insulin resistance and obesity/proinflammatory associated with and dependent on a BP elevation such as molecules are interactions of demographics, lifestyle, left ventricular hypertrophy (LVH), arterial stiffening and genetic factors, and environmental fetal programming.
increased urinary protein excretion Some of these Superimposing upon these are infections and/or chronic types of organ damage, however, show an increased preva- exposure to certain drugs that can also make their lence also in individuals who have the metabolic syndrome contribution. All interact to create the final individual without a BP elevation, suggesting that other components phenotype Likewise, they interact lead- of this condition play a role independently of BP.
ing to changes in the blood pressure (BP) regulatorymechanisms.
In general, the metabolic syndrome components arecharacterized by a high degree of interaction, one con- Hypertension is frequent in the metabolic syndrome, and tributing to the establishment of the abnormality of the more so is the BP abnormality, with values in the high other and vice versa. It has been recognized for many years, normal range, that represents one of the five components for example, that two main components of the metabolic that lead to the identification of this condition. In syndrome, obesity and insulin resistance, may play an the Pressioni Arteriose Monitorate E Loro Associazioni important role in the increment of BP and the develop- (PAMELA) population study, for example, a BP in the high ment of hypertension, although the precise mechanisms normal or frankly hypertension range was found in more that are involved remain partially unresolved. Factors than 80% of individuals with the metabolic syndrome, commonly associated with and partly dependent on followed in a decreasing order of prevalence by visceral obesity and insulin resistance, such as overactivity of the obesity, lipid abnormalities, and impaired fasting glucose sympathetic stimulation of the renin–angioten- The high prevalence of BP abnormalities in the sin–aldosterone system abnormal renal sodium hand- metabolic syndrome explains the very frequent occurrence ling and endothelial dysfunction need to of subclinical organ damage of the type that is frequently be considered.
Cross-sectional studies analyzing the association of the metabolic syndrome with hypertension-induced organ damage Increases riskRelated to the number of components Increases risk of large atrial size Increases risk (twice risk)Related to the number of components Burchfiel et al. Increases risk (twice)Related to the number of components Schillachi et al. Increases riskMore in women (OR ¼ 4.3)Related to the number of components Increases risk (OR ¼ 1.43)Related to the number of components Enlarged left atrial size 24-h urinary albumin excretion Albumin/creatinine ratio Increases risk (OR ¼ 2.0)Related to the number of components 24-h urinary albumin excretion Palaniappan et al. 5659 (NHANES III) Albumin/creatinine ratio Low glomerular filtration rate GFR <60 ml/min/1.73 m2 MDRD formula Increases risk (OR ¼ 1.43) Carotid ultrasound Increases risk (16%) Carotid ultrasound IIncreases risk (OR ¼ 1.56)Related to the number of components Carotid ultrasound Increases risk (OR ¼ 2.0) Zanchetti et al. Carotid ultrasound Increased risk mean maximum IMT at common carotids and bifurcations Vascular stiffness B-mode ultrasonography-derived calculation Increases risk (32%) Schillaci et al. Applanation tonometry ATP III, Adult Treatment Panel III; GFR, glomerular filtration rate; IMT, intima-media thickness; LVH, left ventricular hypertrophy; MDRD, modification of diet in renal disease;MS, metabolic syndrome; NHANES III, National Health and Nutrition Examination Survey III; OR, odds ratio. a Population-based study. b Baltimore Longitudinal Study onAging.
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Journal of Hypertension 2008, Vol 26 No 10 Metabolic syndrome and hypertension- with large artery stiffening has been found. It is associ- induced organ damage ated with metabolic syndrome irrespective of age and the systolic BP value The metabolic syndrome has Several studies have demonstrated that the metabolic also been associated with a faster progression of aortic syndrome is associated with a high prevalence of LVH in stiffness with age, independently of major individual hypertensive patients and that this is the case throughout cardiovascular risk factors suggesting that it may a wide age spectrum Moreover, the number promote premature vascular senescence. Not only aortic, of metabolic syndrome components has been directly but also carotid stiffness has been shown to increase with related to the risk of having electrocardiogram (EKG) the number of metabolic syndrome components and echocardiographic LVH although thishas not been confirmed in other studies The An association between metabolic syndrome and carotid effect of the metabolic syndrome on left ventricular intima-media thickness (IMT) has been observed in structure has been reported to be more pronounced in several studies although to women than in men, and shown to be partly independent a weaker degree than that observed for markers of organ of the effect of hemodynamic and nonhemodynamic damage such as LVH and microalbuminuria, with the determinants of left ventricular mass including BP factors involved being not only hypertension, but also values over 24 h An analysis of the components of impairing fasting glucose (IFG), low-density lipoprotein- left ventricular mass has shown that posterior wall and cholesterol, GFR, and smoking. In a large survey of interventricular septal thickness were significantly and Japanese subjects , it was found that the prevalence independently associated with the number of metabolic of carotid atherosclerosis increased progressively with the syndrome components, in contrast with the left ventri- number of metabolic syndrome components in hyper- cular chamber size for which no such association was tensive patients but not in normotensive individuals.
found Atrial enlargement, a prognostic factor for thedevelopment of atrial fibrillation and stroke, has also been Although data are available concerning small artery damage associated with overweight, high fasting glucose and the in patients with type 2 diabetes, reduced endothelium- metabolic syndrome, independently of left ventricular dependent vasodilatation and inward hypertrophic remo- mass and geometry deling data on the effects of the components ofmetabolic syndrome on small arteries are lacking, despite the fact that microvascular dysfunction has been claim as an An increase in the prevalence of abnormal urinary albu- explanation for the associations among hypertension, min excretion has been observed among hypertensive obesity, and impaired-mediated glucose disposal patients with the metabolic syndrome, as compared tothose without the metabolic syndrome , and Prognostic value of the metabolic syndrome indeed microalbuminuria has been considered a diag- nostic element for the metabolic syndrome in early A limited number of studies have examined definitions of this condition The prevalence the prognostic importance of the metabolic syndrome and of microalbuminuria has been shown to increase with the of its individual components in hypertension. The gen- number of metabolic syndrome components, a finding eral characteristics and the main results of the studies are seen also in nondiabetic subjects Hyperinsuline- shown in Overall, the presence of the metabolic mia, as an expression of insulin resistance, has been syndrome was an independent predictor of cardiovascular associated with microalbuminuria in hypertensive sub- events or cardiovascular and all-cause mortality even when the other cardiovascular risk factor weretoken in to account. Moreover, the risk increased with the The metabolic syndrome was also associated with lower number of metabolic syndrome components In glomerular filtration rate (GFR), as estimated using the contrast, in the European Lacidipine Study on Athero- modification of diet in renal disease formula, in a cross- sclerosis (ELSA) study, a large cohort of well treated sectional survey of hypertensive patients seen in primary patients, outcomes were not different between metabolic care. Furthermore, the number of metabolic syndrome syndrome and nonmetabolic syndrome patients, sug- components was linearly related to the prevalence of gesting that effective antihypertensive treatment may GFR less than 60 ml/min/1.73 m2 largely counteract the obnoxious effects of metabolicsyndrome Large and small arteriesEvidence is available that aortic pulse wave velocity The impact of metabolic syndrome in intermediate (PVW), a marker of aortic stiffness and an independent objectives such as PWV or IMT has been prognostic factor for cardiovascular morbidity and evaluated. While progression on PWV was significantly mortality, is higher in hypertensive patients with the higher in subjects with the metabolic syndrome than in metabolic syndrome, and an association of this condition subjects with zero, one, or two factors, even after adjust- Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Metabolic syndrome in hypertension Redon et al.
Follow-up studies on the impact of the metabolic syndrome in prognosis of hypertension Number of subjects (race) Outcome assessment (follow-up) Diagnostic criteria for MS 2906 (white) population-based Events-rate (8 years) Higher risk in subjects triglycerides and HDL which combine hypertensionand dyslipidemia Schillaci et al. 1742 (white) hypertensive patients Cardiac and cerebrovascular Twice risk for both cardiac events-rate (10.9 years) and cerebral events 2225 (white) hypertensive patients Cardiovascular morbidity Plasma triglycerides and HDL Higher the risk in subjects and mortality (4.1 years) with dyslipidemia 1564 (white) Population-based Cardiovascular morbidity and ATP III, WHO, EGIR, ACE mortality (10 years) 2051 (white) population-based All-cause death (148 months) Zanchetti et al. Cardiovascular morbidity and No significant difference mortality (4 years) was found between patientswith and without MS ACE, angiotensin-converting enzyme; ATP III, Adult Treatment Panel III; EGIR, European Group of Insulin Resistance; HDL, high-density lipoprotein; MS, metabolicsyndrome.
ments for confounding factors , the progression of of simple carbohydrates and increased intake of fruits, IMT was also slightly greater in metabolic syndrome vegetables, and whole grains is recommended. Extremes patients but significance was lost when adjusted for in intakes of either carbohydrates or fats should be avoided Smoking cessation is mandatory. Accumu-lating evidence suggests that the majority of individuals Management of hypertension with the who develop the metabolic syndrome do not engage in metabolic syndrome recommended levels of physical activity and do not In the metabolic syndrome, the objective of treatment is follow dietary guidelines, for fat consumption in particu- both to reduce the high risk of a cardiovascular or a renal event and to prevent the much greater chance thatmetabolic syndrome patients have to develop type 2 diabetes or hypertension. It is also to delay or prevent There have been, to date, two types of drugs interfering progression (as well as to favor regression) of the fre- with the mechanisms of the metabolic syndrome, the quently present types of organ damage carrying an insulin-sensitizers and the endogenous cannabinoid type adverse prognostic significance.
1 receptor blockers (CB1 receptor blockers). Althoughthe former increase peripheral glucose disposal by acting Targeting metabolic syndrome mechanisms in the peroxisome proliferator-activated receptor-gamma Lifestyle measures (PPAR-g), the latter reduce abdominal obesity leading to The underlying factors promoting development of the favorable modifications in the status of adipose-tissue metabolic syndrome are overweight and obesity, physical typical of this condition.
inactivity, and an atherogenic diet. Most individuals whodevelop the metabolic syndrome first acquire abdominal (a) PPAR-g agonists: The PPAR-g regulates genes obesity without risk factors but, with time, multiple risk involved in adipocyte differentiation, fatty acid uptake factors tend to appear, initially with only borderline and storage, and glucose uptake, with a stimulating effect elevations but then with progressive worsening. Thus, a on intravascular lipolysis . Thiazolidinediones, drugs reduction in body weight by a proper low-calorie diet and acting as PPAR-g ligands, may increase lipogenesis in an increase in physical activity address the very mech- adipose tissue, which decreases serum free fatty acid anism of the metabolic syndrome and are hence recom- (FFA) concentrations and increases subcutaneous adi- mended as just first-line therapy by all current guidelines pose tissue mass and body weight. Adipose tissue expres- A modest caloric reduction (500–1000 cal/day), on sion and serum levels of adiponectin also increase with the contrary, is usually effective and beneficial for long- administration of thiazolidinediones. This, together with term weight loss. A realistic goal is to reduce body weight the lowering of serum FFA levels, may contribute to the by 7–10% over a period of 6–12 months. Long-term increased hepatic insulin sensitivity, the reduction of maintenance of weight loss is then best achieved when hepatic fat content and the inhibition of hepatic glucose regular exercise is part of weight reduction management production that are followed by a decrease in plasma Current guidelines recommend a daily minimum of glucose and serum insulin levels as well as a reduction of 30 min of moderate-intensity physical activity plasma triglyceride and an increase in high-density lipo- Additional increases in physical activity appear to protein (HDL)-cholesterol levels. Thiazolidinediones enhance beneficial effects.
have also been reported to decrease circulating or urinarymarkers of vascular inflammation that have been shown Nutritional therapy calls for low intake of saturated fats, to be independent predictors of cardiovascular risk, such trans fatty acids, and cholesterol. Reduced consumption as plasminogen-activator inhibitor type 1, C-reactive Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Journal of Hypertension 2008, Vol 26 No 10 protein, matrix metalloproteinase 9, and urinary endothe- on cardiovascular risk needs to be assessed in prospective studies that also need to collect more data on side effectsemerging from the available database, that is, an increase Thiazolidinediones have received approval to be used as in the incidence of depression and a small but signifi- part of type 2 diabetes treatment but, to date, their use is cantly greater risk, in depressed people, of suicide.
not recommended for the treatment of insulin resistancein the absence of diabetes, although recent data from the Targeting high blood pressure Diabetes Reduction Assessment with Ramipril and Rosi- The threshold for intervention in BP values is based on glitazone Medication (DREAM) study have shown that the recognition that underlying risk factors raise BP to long-term administration of rosiglitazone to subjects with ranges that increase the risk of cardiovascular disease.
impaired fasting glucose has resulted into a major Consequently, 130/85 mmHg should be the threshold reduction in the incidence of new-onset diabetes for intervention in the absence of diabetes. Hyperten-sive patients with the metabolic syndrome should Systematic reviews of the literature have found no receive hypertensive drugs according to the 2007 Euro- notable benefits of thiazolidinediones with regard to pean Society of Hypertension/European Society of BP, although some evidence points to some BP-lowering Cardiology (ESH/ESC) guidelines on hypertension effect, at least in type 2 diabetic individuals and in those diagnosis and treatment that is, in addition to with refractory hypertension The increase in body recommendations to undergo intense lifestyle modifi- weight resulting from the shift in fat storage from visceral cations, antihypertensive drugs should be given when- to subcutaneous fat and fluid retention are the main side ever BP is persistently 140 mmHg systolic at least or effects of the drugs, which limits their use. The fluid 90 mmHg diastolic at least. In the presence of diabetes, retention increases the risk to develop congestive heart the threshold for drug intervention should be lower, failure . Concern has also been generated by the that is, BP values 130 mmHg systolic at least or report of a meta-analysis in which rosiglitazone admin- 85 mmHg diastolic, whereas the goal BP values istration resulted in an increased incidence of cardiovas- should in both instances be less than 130/80 mmHg cular events, although the number of events collected by in line with the goal that is recommended whenever the data pooling was too small to make the conclusion a total cardiovascular risk is high Similar definitive one . The increase in cardiovascular risk goals and an even lower threshold for drug intervention claimed for rosiglitazone has not been found for piogli- (
130/80 mmHg) should be considered when the tazone according to a recent meta-analysis .
metabolic syndrome is present in subjects with a veryhigh cardiovascular risk, such as manifest cardio- (b) Endocannabinoid C1 receptor blockers: Over the last few vascular or advanced renal disease. Which threshold years, research has been directed on the role of the BP for drug intervention should be considered in endocannabinoid system on appetite, energy expendi- metabolic syndrome individuals with the metabolic ture, and metabolism. Cannabinoids and endocannabi- syndrome who have no diabetes, history of cardiovas- noids act via G protein-coupled receptors, the majority of cular, or advanced renal disease is a difficult question their metabolic-related actions being linked to the because no trial has tested the benefit of antihyper- endogenous CB1 receptor represented mostly, tensive drug interventions in this specific population.
though not exclusively, in the central nervous system.
When microalbuminuria or other types of organ The overall effect of inhibition of CB1 receptors is to damage of prognostic significance (LVH, carotid decrease appetite and lipogenesis as well as to increase atherosclerosis, arterial stiffening) are present, in peripheral energy expenditure addition to intense lifestyle changes, administration ofantihypertensive drugs should be at least considered A beneficial impact on most of the metabolic syndrome with the goal of lowering BP at least to less than 140/ components has been observed with the administration 90 mmHg and below. Treatment should aim at prevent- of rimonabant, a CB1 receptor blocker, in trials ing progression or causing regression of the existing organ carried out in overweight and obese subjects with or damage as well as at reducing the much greater chance an without dyslipidemia. Body weight and waist circumfer- individual with the metabolic syndrome has to develop ence were significantly reduced with the administration new-onset diabetes or hypertension. This calls for avoid- of the drug that also reduced plasma glucose, plasma ance of some antihypertensive agents and elective use of triglycerides, and insulin resistance beyond that expected some others as outlined in the following section.
with weight reduction alone. The effects were beingcomplemented by a reduction in HDL–cholesterol. Con- cerning the BP values, rimonabant 20 mg led to modest Ideally, treatment of high BP in the metabolic syndrome but significant SBP and DBP reductions in overweight/ should be based on lifestyle changes, diet, and physical obese patients, although the effect appears to be exercise, which allows for weight reduction and improves mediated by weight loss . The impact of rimonabant muscular blood flow.
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Metabolic syndrome in hypertension Redon et al.
Management recommendations for hypertension and the metabolic syndrome Thiazide-like diuretics should be avoided in monotherapy or in high-dose First choice: ACEi or ARB b-Blockers should be avoided if not compelling Second choice: CCB or b-blockers indication exists with vasodilating activity Combination of thiazide diuretics plus b-Blockers should be avoided ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BP, blood pressure; CCB, calcium-channel blocker; MS, metabolic syndrome. a Seecomment in the text.
Concerning antihypertensive drugs, whether or not a conclusions, in part, due to the different dose of the drugs particular antihypertensive agent is superior to others used, particularities of drug mechanisms of action even has not been tested in trials including individuals specifi- within the same therapeutic group, duration of treatment cally with the metabolic syndrome. A large body of and, mainly, because of the different characteristics of the information, however, is available from both long-term individuals included. Age and hormonal status have been antihypertensive trials with major outcomes as well as recognized as important modulators of drug impact but, from a myriad of shorter studies.
besides these, personal or family histories of metabolicdisorders were among the most important factors.
After changes in lifestyle are introduced, the drugs to bepreferred should be those that may induce reduction of The most recognized metabolic change associated with insulin resistance and subsequent changes in the lipid the antihypertensive drug classes is insulin resistance: it profile and in glucose levels. Therefore, angiotensin- is induced by a combination of different mechanisms converting enzyme inhibitors (ACEi), angiotensin II- including a reduction of the microcirculatory flow in the AT1 receptor blockers (ARA II) or even calcium channel muscle and a reduction in the rate of intracellular glucose blockers are preferable over diuretics and b-blockers in disposal. The former is a consequence of the use of monotherapy, if no compelling indications are present for b-blockers, as b-blockade activity goes unopposed by its use. If a combination of drugs is required, low-dose the a-receptors. The latter is not well understood.
diuretics can be used. A combination of thiazide diuretics b-Blocker agents with additional properties can reduce and b-blockers should be avoided the impact of the pure b-blockade and even exert par-tially beneficial effects. The simultaneous a-blockade of Impact on other metabolic syndrome components carvedilol or the increment in the nitric oxide bioa- The impact of particular antihypertensive drugs on other vailability of nebivolol have shown a neutral effect on components of the metabolic syndrome is an important glucose metabolism indexes and a trend towards a favor- clinical issue with consequences for the success of the able lipid profile treatment. Changes in metabolic components, mainly inthe lipid profile and insulin resistance, during antihyper- The potential effect of b-blockers in favoring gaining tensive treatment with diuretics and b-blockers have weight needs to be mentioned. A large review concerning been claimed as the culprit of lower reductions than weight changes in studies using b-blockers showed they expected in coronary heart disease morbidity and tend to increase body weight as a consequence of redu- mortality On the contrary, reductions in the rates cing fuel expenditure . The clinical consequences of of new-onset diabetes have been observed during treat- the gain of weight during b-blocker treatment, however, ment with ACEi, angiotensin II-AT1 receptor blockers seem to be negligible.
(ARB) or even calcium channel blockers as comparedwith diuretics and b-blockers The reduction of glucose disposal is worse when insulinsecretion decreases. This can occur as a direct con- The recently published STAR study (The Study of sequence of the b-blockade, reducing the response of Trandolapril/Verapamil SR and Insulin Resistance) the pancreatic b-cell, and by hypokaliemia induced by reduced the risk of new-onset diabetes in obese patients thiazide-like diuretics. Reductions in glucose disposal and with impaired glucose tolerance, normal kidney function, in the compensatory insulin secretion lead to metabolic and hypertension treated with the fixed-dose combi- abnormalities of the glucose homeostasis and dyslipide- nation of trandolapril/verapamil as compared to losar- mia, as previously described and, in the ELSA study, the tan/hydrochlorothiazide-based therapy incidence of new metabolic syndrome was significantlygreater in patients under atenolol than lacidipine For many years, metabolic changes associated with theuse of antihypertensive drugs have received attention, Nevertheless, a beneficial impact of decreasing the risk for looking at both worsening and improvement in the meta- the development of diabetes with ACEi-based or ARB- bolic profile. However, not all the studies report the same based treatments has been described. Detailed systematic Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Journal of Hypertension 2008, Vol 26 No 10 reviews of the potential beneficial effects have been channel blockers, as well as other sympathicolytic drugs published recently. In general, treatment with these with central action, such as reserpine, a-methyl-dopa or classes of drugs reduces the rate of new-onset diabetes moxonidine. The pure peripheral a-blocker, doxasozin, as compared with the use of diuretic and/or b-blockers improves the lipid profile, reducing insulin resistance and Inhibiting the renin–angiotensin system may consequently increasing HDL-cholesterol, and reducing improve blood flow to muscles, decrease the activity of triglycerides A trend to reduce total cholesterol has the sympathetic nervous system, enhance insulin signal- also been described. The main mechanism implicated in ing, lower FFA levels, increase plasma adiponectin levels, the positive changes of a-blockers seems to be mediated and improve glucose disposal. Another putative mechan- by increasing microcirculation flow. Additional effects of ism by which the inhibition of the renin–angiotensin a-blockade on the activity of key enzymes of lipid metab- system may improve insulin sensitivity is through effects olism are less well known.
on PPAR-g, which is inhibited by angiotensin II A final question is the net effect of the interaction when The controversy over whether this effect is a con- two different kinds of drugs, with opposite effects, are sequence of the risk induced by diuretics or b-blockers combined. This is the case of combination treatments with and not a real beneficial effect was, in part, resolved by diuretics. Simultaneous administration of a thiazide diure- the observation that the reduction in new-onset diabetes tic with an ACEi or an ARB reduces the hypokaliemia and was also observed in a trial against placebo and by does not significantly modify the lipid and glucose profile.
data furnished by the VALUE study In this Whether or not this combination reduces at large the study, valsartan-based treatment significantly reduced beneficial effects in cardiovascular risk needs to be the rate of new-onset diabetes as compared with amlo- assessed. A recent publication points out that valsartan dipine, a calcium channel blocker. Mechanisms that led alone reduced the levels of high sensitivity C-reactive to improved glucose metabolism were increment in the protein In contrast, a combination of valsartan plus microcirculatory flow and in the bioavailability of the hydrochlorothiazide, despite a significantly larger BP Glut4 transporter. The results of the DREAM study reduction, was unable to reduce high-sensitivity CPR challenge the concept of protection against development values. No interaction with statins was demonstrated.
of new-onset diabetes by using drugs blocking the renin–angiotensin system. The study reports the effects of ramipril on the risk of diabetes in a randomized trial The metabolic syndrome is a highly prevalent condition designed with diabetes as a primary outcome in subjects currently considered to be a cluster of metabolic and who had impaired plasma glucose levels after an over- cardiovascular risk factors, including BP elevation. A night fast or impaired glucose tolerance. Rates of the higher risk for progression in metabolic syndrome indi- primary endpoint, mainly diabetes, were not significantly viduals with high–normal BP has been observed and, lower in the ramipril group. However, regression to when hypertension is established, this seems to confer a normoglycemia, a secondary outcome, was significantly higher cardiovascular risk on top of the risk induced more frequent in the ramipril group than in the placebo by BP elevation. Therefore, assessment of metabolic group, although the absolute difference between the syndrome components can result in a clinical utility groups was small. Several reasons may explain the strategy to manage hypertension based on individual negative result in the impact of ACEi in to reduce the risk to develop diabetes: there was only 43% of hyper-tensive patients in the study; these hypertensive patients Reviewers: Council Members of the European Society were under multiple treatments including diuretics and of Hypertension: E. Agabiti-Rosei, E. Ambrosioni, b-blockers; some of the effect can be masked by the M. Burnier, A. Coca, A.F. Dominiczak, S. Kjeldsen, treatment with rosiglitazone; and the follow-up of the A.J. Manolis, M.H. Olsen, R. Schmieder, H.A.J.
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