HYPERTENSION IN METABOLIC SYNDROME: WHAT IS THE ROLES OF IRBERSARTAN

Metabolic syndrome (Mets) or syndrome Dismetabolik or Resistance Syndrome is a term for a group of disorders with different clinical consequences, which is characterized by: impaired glucose tolerance, insulin resistance, dyslipidemia, hypertension, coagulation abnormalities and visceral obesity (Tjokroprawiro, 2005). All co-morbid factors above in synergy to cause atherosclerosis early, so that the individual has increased risk of developing heart disease and blood vessel (Schunkert 2002).

Abnormalities that cause the Mets are grouped into 10 components: 1) visceral obesity, 2) insulin resistance (a Glucose Tolerance Bothered Bothered or Fasting Glucose or DM type-2), 3) Dyslipidemia (elevated levels of: triglycerides of fasting and 2 h post prandial, HDL, LDL, apolipoprotein-B, Lipoproteinemia Remnant, the ratio of LDL: apo-B and decreased HDL levels), 4) hypertension, 5) Increased pro-inflammatory components (CRP, TNF , IL-1 , IL-6 , Fibrinogen), 6) Improvement Protrombotik component (PAI-1, factor VII, Fibrinogen, vWF, and adhesion molecules), 7) Vascular Disorders, 8) Hiperurikemia, 9) Increased Adrenal gland (cortisol, ACTH), 10) fatty acids excess (Tjokroprawiro, 2005).
Hypertension is a key component of the Mets. Both are important risk factors for the emergence of Cardiovascular Disease which can lead to heart attacks and strokes. Hypertension, if not treated properly can lead to various conditions that can be life-threatening, such as kidney damage and heart failure.
Hypertension is a disorder that is often obtained, and can result in various threat risks, may remain asymptomatic or arrive at a relatively advanced stage. Several studies have shown that insulin resistance can increase blood pressure. This is due to the increased levels of insulin can cause atherosclerosis, which can directly affect the diameter of blood vessels.
This paper will be submitted clinical data Mets in Surabaya, the recommendation of a special hypertension clinic Mets management by the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC) (2007), and explores the role of irbesartan as an antihypertensive that has the potential both for patients Mets

Hypertension on the Mets in Surabaya (Pranoto et al, 2005)
This research is a descriptive study with research subjects general-checkup participants (healthy) at Graha Amrita Dr.Soetomo-Hospital. Period of this study for 1 month (December 2004 - January 2005). Subjects were employees of Animal Husbandry Department, Agency for Electronic Data Processing and Environmental Impact Management Agency of the Government of East Java Province. This study was an observational, no action on the subject of intervention (Pranoto et al, 2005).
Participants were asked to fill kwesioner about a history of diabetes and hypertension, daily activity level, frequency and type of exercise, smoking habits and the type, amount and duration of the habit. Also done a diagnose on the level of consumption (food intake).
Laboratory variables examined, among others, LDL-3 fibrinogen, proteinuria, microalbuminuria, leukocyte count, uric acid, HDL cholesterol, triglycerides, fasting blood sugar, blood glucose 2 hours post prandial, fasting insulin, insulin resistance calculated by HOMA-R (fasting insulin Law / ml x fasting blood sugar in mmol / L, divided by 22.5).
Mets criteria used is according to the modification of the criteria for the National Cholesterol Education Program - Adult Treatment Panel (NCEP-ATP III), which was introduced in 2001, with adjustments to the criteria of Body Mass Index (BMI) and waist circumference that is used is based on the adjusted BMI for Asian people is called obese if BMI ≥ 25kg/m2 and waist circumference ≥ 80 cm in women or men ≥ 90 cm.
Criteria Mets modification NCEP-ATP III, 2001 which is used in this research is that if there are at least 3 criteria from among other things 1) abdominal obesity (central obesity), abdominal circumference ≥ 80 cm female or male abdominal circumference ≥ 90 cm, 2) Triglycerides ≥ 150mg/dL, 3) HDL cholesterol women <50mg/dL men or HDL cholesterol <40mg/dL, 4) Blood pressure ≥ 130/85mmHg, 5) Fasting Blood Sugar ≥ 110mg/dL.
Mets prevalence obtained in this study amounted to 34 people out of 100 people following the study (34%) consisted of women with a proportion of 6 / 34 (17.64%) and men with a proportion of 28/34 persons (82,35%), the proportion of group age of four decades of 19/34 people (55.88%), fifth decade age group the proportion of 15/34 people (44.11%), all have daily activities that are categorized sedenter, the proportion of subjects who smoked was the 9 / 34 (26.47 %), the proportion who have never done sports 2 / 34 (5.88%), the proportion who exercise 1-3 X / week 25/34 (73.53%), the proportion who exercise 4 times / week 7 / 34 (20:58%).
Profile clinic according to the criteria of NCEP-ATP modification Mets III 2001 in this study, the proportion of central obesity 29/34 (85.29%), hypertriglyceridemia proportion of 29/34 (85.29%), the proportion of low HDL cholesterol 18/34 (52 , 94%), the proportion of increase in systolic blood pressure of 28/34 (82.35%), diastolic blood pressure increase in the proportion of 19/34 (55.88%), Fasting Blood Sugar improvement 14/34 (41.17%).

Hypertension on the Mets in Indonesia
Reports of patients with endocrine clinic of Dr Kariadi Semarang 2008, the Mets component group of people with hypertension 123/278 (68.3%) (Nugroho et al, 2008).
Research conducted on 208 people who perform routine health checks at various polyclinic hospital in Medan, mendaspatkan hypertension 23 people (24.7%) (Septina et al, 2008).
Adam et al (2005), in Napier research results reported hypertension prevalence of 34%.
Widodo et al (2008), the DM group and the Mets acquired Hypertension by 82.9%. There arterial stiffness in the Mets 85.7% and 31.4% control group. Significant association between metabolic syndrome on arterial stiffness DMT2 risk by 13 times greater than patients without Mets DMt2. Components of hypertension have significant association with arterial stiffness, as well as other components such as hypertriglyceridemia, and decreased HDL cholesterol.

Hypertension Therapy at Mets
There are no specific recommendations on group therapy Mets. Algorithm hypertension treatment algorithm hypertension is in accordance with generally.
 The main strategy Mets patient is a low-calorie diet and physical exercise, in order to lose weight. Realistic weight loss amounted to 70-10% over the span of 6 to 12 months, with a lower caloric intake levels are approximately 500-1000 calories per day, which generally gives better results when compared with an extreme diet approach. Nutritional therapy includes the advice to consume low-SAFA, tuff, cholesterol, and simple carbohydrate and regular in the long run to lose weight significantly, for example with moderate exercise for 30 minutes per day. In the study of Diabetes Prevention Study (DPP) and The Finish Study, lifestyle modification can decrease the progression to DM to 60%, where the effect is much larger when compared with the effects of hypertension decreased to normal, which is a more common component of the Mets. Even so the effect of optimal blood pressure reduction is still not been investigated. In the secondary analysis of the DPP study after 3.2 years in the lifestyle intervention group prevalence Mets fell from 51% to 43%, whereas in the conventional groups there is an increase from 55% to 66% (Orchad et al, 2005). Lifestyle modification therapy shown to have protective value.
 In patients Mets, components of hypertension, diabetes, or hyperlipidemia requiring drug therapy. Cardiovascular risk in the group of high cukuip Mets, so it is important to control hypertension, though the optimal blood pressure on the group Mets have not been investigated. In group Mets beta-blocker class of drugs should be avoided, unless there are special indications, given the possible side effects on body weight (Pischon & Sharma, 2001) and the incidence of diabetes mellitus, insulin sensitivity and lipid profiles (Jacob et al, 1998). However a new generation of drugs, beta blockers failed to give effect, such as carvedilol and nebivolol (Kaiser et al, 2006; Poole-Wilson et al, 2003).
Drugs that have the effect or effects diabetogenik dismetabolik thiazida eg high-dose diuretic drugs (Mancia et al, 2006), not recommended. Antihypertensive Class to be reckoned with its use are the ones Angiotensin Receptor antagonist or ACE inhibitors, given the low rates associated with diabetes incidence compared with other classes of drugs (Mancia et al, 2006; Opie & Schall, 2004; Eliot & Meyer, 2007; Abuissa et al , 2005). If hypertension can not be controlled with monotherapy and require combination drug, the drug can be selected as the addition of dihydropyridine or non-dihydropyridine calcium antagonist, considering the class of calcium antagonist is neutral and has a beneficial effect on organ damage.
The combination of drugs that affect a blockade on the renin-angiotensin system and calcium antagonist was shown to lower incidence of diabetes compared with conventional therapy of diuretics and beta blockers (Dahlof et al, 2005; Pepine et al, 2003). Considering the Mets are often associated with obesity and have the nature of the salt-sensitive blood pressure, then the use of low-dose thiazide-type diuretic is an important option for treatment of stage 2 or 3. Low-dose thiazide diuretics nevertheless still have dismetabolik effect, ie there may be the effect of mild decrease in potassium levels, which allows aggravate the effects of hypokalemia on insulin resistance, carbohydrate intolerance and diabetes and the incidence of new (Pepine et al, 2003; Mancia et al, 2006; Bakris et al, 2006). Maintenance of blood potassium levels can neutralize the effects of glucose intolerance are triggered by a thiazide, for example the use of a combination of thiazide with potassium-sparing diuretics drug will have a metabolic advantage when compared with the use of thiazide alone (Helderman et al, 1983; Conn, 1965).
Lack of specific research on the Mets cause there is no strong clinical recommendation whether lifestyle modifications, antihypertensive therapy can be targeted at non-DM group and non-Hypertension with the Mets, although it is known that there have been several clusters of risk factors associated with damage to several organs which causes high cardiovascular risk. Still there are pros and cons for therapy aimed at blockade of the renin-angiotensin system on the group of patients with normal blood pressure threshold is high. We can conclude that today's lifestyle therapy is a modality for the Mets, although in some limited cases can be considered the use of blockade on the renin-angiotensin system, have the potential to delay onset of diabetes and delay the onset of new hypertension cases. Not yet also no evidence to prove that anti-diabetic drugs given in the Mets do provide a favorable outcome.
The use of several prospective studies, the drug alpha-glucosidase inhibitors in the group of fasting tolerance disorders, can be proven incidence DMT2 peneurunan effect. Nevertheless no significant differences were found on mortality, a variety of other causes of death, to the decrease of HbA1c and blood pressure
 drugs thiazolidinedione class of insulin sensitizers are drugs that have gained recognition in the treatment DMT2, with its ability to stimulate the peroxisome proliferator-activated receptor-gamma (PPRg), which actually has little effect as an angiotensin receptor antagonist. One of the TZD class of rosiglitazone on glucose tolerance disorders group has an effective ability to prevent new DMT2 Onsen. These drugs have the effect of fluid retention, so the use of non-diabetic population ontuk benefits are still not really clear. Group TZD pioglitazone showed the effect of lowering the incidence rate macrovascular events, also has a mild effect of lowering blood sugar.
 The use of drug-receptor blocker rimonabant endocannabinoidC1, in the long term could prove to lose weight and waist circumference, as well as against the Mets risk some components such as plasma glucose, HDL cholesterol, triglycerides and insulin resistance. Also reported that this drug also has mild effects of lowering blood pressure, effects on risikom kadiovaskuler still unclear.

It can be concluded that the Mets group with hypertension, then the implementation should be more extensive diagnostic procedures given its association with the high prevalence rate of multiple organ damage and increased inflammatory markers. If the blood pressure of 140/90 mmHg, the anti-hypertensive drugs should have started with the priority axis of therapies aimed at blocking the renin-angiotensin system and if necessary can be added to the calcium antagonist or low-dose thiazide diuretics. Recommendations of the renin-angiotensin system blockers are given to groups of normal blood pressure at a high threshold, in order to prevent organ damage and to prevent the onset of new diabetes or hypertension, generally is still not widely accepted. This has some similarities with a given least obaat anti-diabetic or insulin sensitizers drug class on impaired glucose tolerance group. Group of patients given statins, also show the results that can be considered (Deedwania et al, 2006).
Mets pharmacological therapy in patients with non-hypertensive and non-DM have been studied and shown to vary, the actual circumstances that could comply with lifestyle therapy and who successfully maintain weight loss is generally very low (Wing & Phelan, 2005).

The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC), issued guidelines for treatment of hypertension (2007), specifically for the population of the Mets, giving some clinical practice recommendations as follows ( Mancia et al, 2007):
 Mets are clinical syndromes with the characteristics of some combination of visceral obesity and some changes in glucose metabolism, lipid metabolism and blood pressure. Mets prevalence is high in the middle age and old age.
 Patients mikroalbuminurua Mets also have a high prevalence, left ventricular hypertrophy, and arterial stiffness compared with the normal group. High cardiovascular risk and the possibility to develop into a very high DM
 Patient Mets should have to undergo various diagnostic procedures including in-depth examination of the possibility of sub-clinical organ damage. It is advisable to conduct periodic checks of blood pressure independently at home.
 intensive lifestyle therapy should be recommended to all psien Mets. Antihypertensive drug treatment is recommended for groups who do not trigger the occurrence of DM. It is recommended that the drug class of blockers of the renin-angiotensin system, and if necessary can be added to calcium antagonist drugs or low doses of thiazide diuretics. Clinical advantage is very beneficial if blood pressure is cultivated within normal limits.
 The use of antihypertensive drugs on the Mets with high normal blood pressure is still not have a strong base of clinical evidence, so until now there is no strong recommendations. Some evidence of drug use group reported blockers of the renin-angiotensin system is proven to delay the occurrence of hypertension.
 If there are dyslipidemia and diabetes, it can digungkan anti-diabetic drugs or drugs Statins. Use of the drug class of sensitizers isulin proven to delay the onset of new diabetes, but its use in disturbance tolerance Glucose Tolerance Impaired fasting or in groups Mets still must be proven.

The role of irbesartan on the lipid
Irbesartan shows the effect on the lipid profile of patients Mets, indicated by the report Kintscher (2007), that provide significant improvement of HDL cholesterol and decreased triglycerides, anticipated effects of the improvement through the effects of ARBs as SPPARMs modulate PPARγ. Morawitetz et al (1999), reported that angiotensin II in vitro and in vivo regulate the lox-1. Induction of lox-1 mediated by AT-1 receptor, and lox-1 mRNA induction is inhibited by the AT1 receptor blockers (ARBs) and ACE inhibitors. ARBs have the effect of pressure and prevent the initial formation and progression of atherosclerosis.


Irbersartan role in obesity
Adipose or fatty tissue is one of the manufacture of angiotensinogen (AGT). AGT plasma levels correlated with blood pressure and body mass index, have been reported by several studies. In experimental animals obese mice showed a higher AGT mRNA> 50% compared with lean mice. In human visceral fat has AGT mRNA levels higher than those found in the subcutaneous. High blood pressure can be caused by excessive increase of AGT.
Ang II has an important role in the growth and difderensiasi adipocytes. Prostaglandin I2 in adipocytes to increase produkasinya by Aug II, which in turn would stimulate differentiation of pre-adipocytes adipogenik into mature adipocytes. Lipid synthesis and storage in adipocytes is also regulated by ANG II.
Irbesaratan clinically proven to have the effect of abdominal circumference were significantly lower in patients Mets in both men and women (Kintscher et al, 2007).

Irbersartan role in oxidative stress and pro-inflammatory status
On the Mets and patient diabetic vascular complications of atherosclerosis is a common occurrence, and is caused due to inflammation. This inflammation can be triggered by oxLDL in such a way that allows the event of a atherosclerosis. Various markers of inflammation through the modification of ox LDL can be detected, among others, vascular adhesion molecule-1 (VCAM-1) and tumor necrosis factor-II (sTNF-αRII).
Warnholtz et al (1999), concluded that the activation of angiotensin II type 1 receptor (AT-1) can increase levels of super oxide. Increased super oxide causes oxidation of LDL and inhibition of NO and prostacyclin. The condition of these components allows the occurrence of endothelial dysfunction in atherosclerosis. Constraints on the AT-1 receptor this would reduce the adverse effects of super oxide in vascular.
Navalkar et al (2001), make a hypothesis that drugs that have the effect of antioxidants such as ARBs, have therapeutic potential in the management of atherosclerosis by reducing oxidation of LDL, which in turn has the potential to reduce the impact of inflammation on aterogenesis.
Sola et al (2005) in the irbesartan and lipoic Acid in Endothelial Dysfunction
(ISLAND) Study, showed positive effects of the use of irbesartan and / or lipoic acid for 4 weeks can improve the parameters of endothelium-dependent flow-mediated vasodilation in the brachial artery, by increasing the flow capacity by 67%, 44%, and 75% in the irbesartan group, lipoic acid, and irbesartan plus lipoic acid groups, respectively, compared with placebo. Irbesartan therapy and / or lipoic acid associated with a significant decrease in interleukin-6 and plasminogen activator-1, and lower levels of 8-isoprostane. It can be concluded that the use ibersartan and lipoic acid improve endothelial function and reduce markers inflammatory markers, namely the factors associated with the pathogenesis of atherosclerosis.

Evidence of experimental research on the suppression of atherosclerosis irbesartan
In experimental animals diabetic apoE-null mice 6 weeks old Estela at induction with streptozotocin injection, were randomly assigned to placebo, irbersartan and amlodipine for 2 weeks. Irbesartan showed protective effects against the atero sclerosis, the amount of collagen tissue, cell proliferation, and macrophage infiltration, and smooth muscle actin, while the group does not give effect Amlodipine is indicated by indicated by increased expression of platelet-derived growth factor-B (PDGF-B) , monocyte chemoattractant protein-1 (MCP-1), and vascular cell adhesion molecule-1 (VCAM-1) (Candido et al, 2004).


The role of irbesartan on glucose metabolism
Hypertension with resistance in the clinic has a close relationship, although in theory the relationship patomekanismenya still not really clear.
There are associations between blood pressure with the proportion of type II skeletal muscle fibers that are less sensitive to insulin than type 1 fibers are more sinsitif to insulin (Sowers, 2004). Higashiura et al (2000), reported that the use of ACE inhibitors and ARBs can affect and increase the proportion of type I skeletal muscle fibers so that can improve insulin on muscle tissue snsitifitas skleletal.
Hemodynamic improvement of the renin-angiotensin system may improve the flow and transport of insulin which improves glucose uptake and metabolism in muscle tissue and other tissues sensitive to insulin. Use of ACE inhibitors and ARBs can increase skeletal muscle blood flow by eliminating the effects of angiotensin II vasoconstriction (Bergstorm et al, 2002).
ARBs have been shown to have activity of Selective Peroxisome Proliferator Activated Receptor Modulators (SPPARMs), a molecule involved in the modulation of PPARγ. PPARγ activation improves insulin sensitivity through the process of insulin signaling and the synthesis of GLUT4 and repair of mertabolisme fat.
Several studies have reported that the use of ARBs may delay the onset of new-onset diabetes mellitus as reported by several investigators, and several other positive effects on various peneitian can be seen as follows:
1. The losartan Intervention for Endpoint Reduction in Hypertension (LIVE) Study, the results of this study indicate that losartan lowered the relative risk for the occurrence of DMT2 by 25%, compared with the use of atenolol (Stump et al, 2006).
2. Research candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) study, with research subjects for 7601 patients, provision of candesartan 32 mg / day for an average of 37.7 months may reduce the relative risk of 22% compared DMT2 placebo (Joseph et al, 2005)
3. CHARM-preserved study involving patients with heart failure class II to IV on plate, followed prospectively until a mean time of 36.6 months, candesartan DMT2 lower relative risk of 39% compared to placebo (Joseph et al, 2003)
4. The valsartan antihypertensive Research Long-Term Use Evaluation (VALUE) trial showed excess valsartan to amlodipine, which lowered the relative risk of the emergence of new DMT2 by 23%, 4.2 years after treatment, in hypertensive patients aged 50 years or older with a high risk of attack heart (Julius et al, 2004)
5. Research A sub analysis of the Treat to Target post authorization survey, reported in subjects use Irbersartan Mets, after the use of monotherapy for 9 months to produce a significant decrease in blood pressure (systolic pressure - 26.3 ± 10.1 mmHg / diastolic pressure and -13.0 ± 6.6 mmHg, both p <0.0001). Accompanied by improvement of several other cardiovascular risk factors eg HDL cholesterol (+3.6 ± 7.2 mg / dl in men, +3.8 ± 6.5 mg / dl in women, both p <0.0001), serum triglicerida (-28.6 ± 52.1 mg / dl , p <0.0001), fasting blood glucose (-8.4 ± 25.1 mg / dl, p <0.0001) and waist circumference (-2.4 ± 11.9 cm in men, -1.2 ± 14.2 in women, both p <0.0001). Irbesartan combination therapy (12.5 mg HCTZ) in patients with hypertension Mets: menhghasilkan decreased blood pressure (Systolic Pressure: -27.5 ± 10.1 mmHg / Diastolic Pressure: -14.1 ± 6.6 mmHg, both p <0.0001, improvement of HDL cholesterol (+4.0 ± 6.8 mg / dl in men, +3.4 ± 6.8 in women, both p <0.0001), triglicerida (-34.1 ± 52.6 mg / dl, p <0.0001), fasting blood glucose (-10.0 ± 24.7, p <0.0001dan waist circumference ( -3.2 ± 12.7 cm in men, -1.7 ± 14.4 in women, both p <0.0001). irbesartan patients generally can tolerate it well, there are few associated side effects, namely 0.6%. It can be concluded that monotherapy and combination therapy to irbesartan result in improved blood pressure and metabolic risk factors improved significantly. Improvement of cardiovascular risk with the use of irbesartan as monotherapy or combination showed no difference (Kintscher et al, 2007).