EVALUATION OF RISK MARKERS FLUCTUATION DURING AN INITIAL THERAPY WITH ROSIGLITAZON IN PATIENTS SUFFERING FROM METABOLIC SYNDROME

Th e aim of this study was to examine the eff ects of hypoglycaemic drug-agonists of PPAR-gama receptors-rosiglitazone (Avandia, mg Glaxo Smith Kline) on values of wide-spread risk-markers: fi brinogen, C-reactive protein and uric acid and glicolysated haemoglobin HbAC as parameter of metabolic control. We examined forty patients who satisfi ed criteria for metabolic syndrome and distributed them into groups of diabetic and prediabetic patients according to criteria of IDF (International Diabetic Federation). Th ese risk markers and glicolysated haemoglobin HbAC were observed at the beginning of therapy, then four, eight and twelve weeks into therapy and results were compared and statistically processed. Th ree months initial therapy with rosiglitazone signifi cantly reduced values of HbAC, fi brinogen and CRP but not uric acid in prediabetic patients. Rosiglitazone initial three months therapy signifi cantly reduced HbAC, fi brinogen and uric acid, but not CRP in diabetic patients.


Introduction
Th e number of patients diagnosed with non-infectious diseases and the related mortality is alarmingly rising daily in all the world, especially in developing countries.Th ese facts infl uence the accelerated manifestation of new risk-markers for cardiovascular diseases.Th e appearance of multiple risk-factors, known as metabolic syndrome, includes: central obesity, hypertension, increased triglycerides and low HDL-cholesterol, as well as increased fasting plasma glucose values.In pathophysiological base of this syndrome lies insulin resistance that, in the process of blood coagulation, leads to hypofi brinosis together with blood coagulation disorder in blood vessels.Major part of those eff ects in insulin resistance, as well as the changes in coagulation and in endothelium confi rm the existence of infl ammation (, ).Also, in insulin resistance, breakdown of nucleic acids accelerates the accumulation of uric acid and development of related consequences.Several factors are influenced by insulin resistance, such as change in contractility of smooth muscles of small blood vessels, changes in their endothelium, changes in blood coagulation and hypertension.All the mentioned factors lead to changes in cardio-vascular system, marking it the cause of the most massive mortality in persons with metabolic syndrome.It has already been accepted for years to regard Creactive protein as an acute infl ammation reactant, fibrinogen as a part of coagulant system, and, recently, the values of uric acid as important risk-markers and possible statistic predictors of cardiovascular incidents.C-reactive protein is an important newly identified potential risk factor, which provides a strong prediction of future risk for cardiovascular events (,).It has been demonstrated that reducing CRP levels causes a reduction in cardiovascular diseases (,,).CRP in not only a marker of infl ammation; this protein, itself, contributes to atherogenesis.It appears to help monocytes infiltrate the arterial wall, starting the process of plaque formation.Thiazolidinediones, metformin, aspirin and statins reduce CRP in varying degrees ().
Recent intervention studies have also demonstrated the distinct effi cacy of diff erent anti-diabetes treatments on the variety of cardiovascular risk markers.Treatment with peroxisome proliferator-activated receptor gamma has lead to substantial reduction of hsCRP and other cardiovascular risk markers in several comparative studies.Since this eff ect was shown to be independent of the degree of glycemic improvement, it can be regarded as a class-specifi c eff ect ().Fibrinogen is an acute phase reactant with active participation in endothelial function, thrombosis and infl ammation.It has proven to be an independent variable in cardiovascular risk together with its participation in resistance phenomena in different antithrombotic approaches.Reasons behind fibrinogen elevated levels in cardiovascular diseases and atherosclerosis are, in general, incompletely understood; but all cells involved in the atherogenetic process are able to produce cytokines, which induce an acute phase reaction that increases fi brinogen levels in plasma.Analyses of the retrospective studies suggest that fibrinogen is an important and independent cadiovascular risk marker and factor, clearly associated with conventional risk factor and genetic polymorphisms (,) .Uric acid is a final breakdown product of purine metabolism in man.Th ere is a growing body of evidence which indicates that elevated uric acid levels increase the probability of developing hypertension and cardiovascular disease, especially coronary artery disease ().Several studies have reported that changes in serum cholesterol follow the changes in serum uric acid both in order and magnitude.Most recently, hyperuricaemia has been added to the constellation of abnormalities that comprise metabolic syndrome.The patophysiology of hyperuricaemia and link between hyperuricaemia, hypertension and cardiovascular disease are poorly understood.It is entirely possible that hyperuricaemia is a part of pathologic process that underlies fundamental alterations in renal function, as well as other metabolic pathophysiologies that ultimately lead to hypertension and cardiovascular disease (,,,) .Given the increased cardiovascular risk associated with both types of diabetes mellitus and metabolic syndrome on one hand, and the convincing overall consistency of the reported findings and potential value of the additional information provided by determination of CRP about the chronic vascular inflammatory state before, during and after therapeutic interventions on the other hand, introduction of these markers into routine diagnostic procedures and guidelines for diagnosis and treatment of diabetes mellitus is recommended.While the diet and exercise are still the cheapest and most effective ways to reduce cardiovascular risk, diff erent drugs, like statins and PPAR gamma agonists, have been demonstrated to effectively reduce CRP levels and other risk-markers (-).

Materials and Methods
Over the period of three months, the values of fibrinogen as well as C-reactive pro- tein, HbAC and uric acid were observed prospectively in patients with metabolic syndrome featured by at least four of the following six criteria: -abdominal obesity (waist circumference more than  cm in women and  cm in men) -atherogenic dyslipidemia (triglycerides > , mmol/l, HDL < , mmol/l) -high blood pressure (>/ mmHg) -insulin resistance + glucose intolerance (impaired glucose tolerance test-two hours after ingestion of  mg glucose, serum glucose level is more than , mmol/l) -increased level of pro-infl ammatory factors (mostly known serum infl ammation markers are in excess) -increased level of pro-thrombotic factors (coagulation system balance tends to excess of procoagulants)

Methods
Patients were divided into the group of  prediabetics according to IDF (International Diabetic Federation) criteria (fasting plasma glucose value between , and , mmol/l, impaired glucose tolerance test with postprandial glycaemia between , and , mmol/l), and the group of  diabetic patients (fasting plasma glucose value more than , mmol/l and postprandial hyperglycaemia more than , mmol/l).Initial labora-tory values of the mentioned parameters were recorded.Therapy with  tablet of rosiglitazone  mg (Avandia, Glaxo Smith Klein, United Kingdom) was introduced in the morning, without any correction in former therapy.Mentioned parameters were observed ,  and  weeks into therapy, and the obtained data statistically and graphically elaborated.

Statistical analysis
For statistical analysis we used tables and graphs (histogram and pie) and following statistical measures: mean, standard deviation, with average linear de-

Results
The values of fibrinogen in the two groups of patients measured before the beginning of the therapy and ,  and  weeks into therapy The values of C-reactive protein in the two groups of patients measured before the beginning of the therapy and ,  and  weeks into therapy.The values of uric acid in the two groups of patients measured before the beginning of the therapy and ,  and  weeks into therapy.The values of HbAC in the two groups of patients measured before the beginning of the therapy and ,  and  weeks into therapy. of  prediabetic patients (,) with HbAC >,  achieved HbAc < ,  after three initial months therapy of rosiglitazone  mg.
In total,  patients were screened,  prediabetics and  diabetic patients.All patients were already using therapy which was not changed during the study.Rosiglitazone was well tolerated and no patient showed significant side effects other than headache, dizziness and gastrointestinal complaints.In the prediabetic group, values of fibrinogen (Table ) were slowly decreasing during the three months of initial therapy with Rosiglitazone, but the decrease was statistically significant, p<,.Significant decrease in fibrinogen values was also observed in the group of diabetics after treat-ment with rosiglitazone (Table ).Average value of fibrinogen varied from , at the beginning of the study to  The most important parameter of metabolic control in this group of patients is glicolysated haemoglobin-HbAC and we studied values of this parameter during this period (data shown in Table , and ).This examination suggests very favourable effects of initial therapy of rosiglitazone on glycemic control in metabolic syndrome patients.
Values of HbAC were significantly reduced in both group of patients.In ,  prediabetic patients with HbAC more than ,  achieved values lower than ,  and tendency to normoglycaemia.

Discussion
The main result of the present study is the finding that three months initial therapy with Rosiglitazone caused significant reduction in fibrinogen and CRP values in the group of prediabetics.Fibrinogen values showed significant decrease after three months therapy with Rosiglitazone in the group of diabetics, but the values of CRP did not significantly change.Statistically, uric acid did not significantly change during three month initial therapy with rosiglitazone in the group of prediabetics.
In the group of diabetics, uric acid showed statisticaly significant decrease during three month initial therapy with rosiglitazone, as opposed to the group of prediabetics where it was not no-ticed.This figure suggests the necessity of observing uric acid in diabetics with cardiovascular incidents, which can be a good predictor of further incidents.Th e goal of the research was to demonstrate possible effects of rosiglitazone on well-known risk-markers of cardiovascular events.As these markers are strong predictors of atherosclerosis, this may convey increased protection against cardiovascular disease in these patients.Early eff ects of treatment are especially important due to the fact that a great number of these patients, more precisely about two thirds, die of macrovascular diseases.In the present study, rosiglitazone has signifi cant implications to the level of risk markers in patients with metabolic syndrome, and possibly infl uences also other pro-infl ammatory components which are in excess during an acute cardiovascular incident.Increased hyperuricaemia is a common feature in diabetics as frequent as dyslipidaemia, and is associated with accelerated atherosclerosis and higher cardiovascular risk.Statistically significant decrease of uric acid in diabetics group (p<,) during initial three month therapy with Rosiglitazone was observed in this study.Whether these effects are sufficient to produce clinical benefit is an open issue.However, it is tempting to hypothesize that the antiatherosclerotic effects observed with Rosigitazone may involve the lowering of risk markers-fibrinogen, CRP and uric acid.These markers are well known predictors of acute cardiovascular events.Another interesting aspect of the study is that the recorded effects of rosiglitazone succeed the effects of statin treatment, because our patients used statins before administration of rosiglitazone therapy.
In our opinion, this is of interest because statins are used by majority of patients with type  diabetes, and they have been shown to improve risk markers It confi rms the fact that this drug should be applied during acute cardiovascular incident to all patients with metabolic syndrome as soon as possible.And, probably, this drug should fi nd its place among the drugs recommended for treatment of acute cardiovascular incidents in patients with centripetal obesity, but other large studies are needed to off er a defi nite confi rmation for that.
A change of life-style and diet is especially important for risk decreasing, but, surely, a signifi cant help can be achieved through drug therapy, which should be combined.Function and the eff ect of this drug in the reduction of numerous essential risk factors in the very core of the obesity problem and insulin resistance offers indicates that this drug will surely be highly positioned in the combined therapy of acute vascular incidents, aiming at the reduction of cardiovascular mortality in patients with metabolic syndrome.

Conclusion
Th is study has demonstrated good tolerability and effi cacy of rosiglitazone (Avandia,  mg, Glaxo Smith Cline) in the therapy of patients with metabolic syndrome.Th ree months initial therapy with rosiglitazone signifi cantly reduced values of HbAC, fi brinogen and CRP but not uric acid in prediabetic patients with metabolic syndrome according to IDF criteria.Th ree months initial therapy with rosiglitazone signifi cantly reduced HbAC, fi brinogen and uric acid, but not CRP in diabetic patients with criteria for metabolic syndrome.

List of Abbreviations
viation, coeffi cient of variation, χ test for descriptive variables and Student`s test for quantitative variables.All data were analysed in SPSS . for Windows statistical program, and Microsoft Excel  program.

TABLE 2 .
Group of diabetics 002Average value of fi brinogen showed a signifi cant decrease (from 4,55 at the beginning of the research to 4,00 after 12 weeks)-p<0,006

TABLE 3
. Group of prediabetics 003 Value of CRP signifi cantly decreased in relation to initial measuring in the group of prediabetics.P<0,0001.

TABLE 4
, after  weeks p<,.Rosiglitazone significantly reduced CRP values in prediabetic group (Table).Value of CRP significantly decreased in relation to initial mea-.Group of diabetics 004 After 12 week therapy with Rosiglitazon the value of CRP did not signifi cantly change in relation to the initial value in the group of diabetics (p=0,199).TABLE 5. Group of prediabetics 005Values of uric acid did not signifi cantly change after 12 week therapy in relation to initial values in the group of prediabetic (p=0,527).AMRA MACIĆDŽANKOVIĆ ET AL.: EVALUATION OF RISK MARKERS FLUCTUATION DURING AN INITIAL THERAPY WITH ROSIGLITAZON IN PATIENTS SUFFERING FROM METABOLIC SYNDROME suring in the group of prediabetics.P<,.There was no significant reduction in CRP values in the group of diabetics after three months of initial therapy with Rosiglitazone (data shown in Table) p=,.During the first month of therapy CRP was significantly reduced, but later, dur-ing the following two months there was no significant difference compared with earlier results.Values of uric acid tended to be lower after treatment with Rosiglitazone in group of diabetic patients (data shown in Table), p<, but there was no significant change after  week therapy in relation to initial