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The aim of this study was to examine the effects of hypoglycaemic drug-agonists of PPAR-gama recep- tors-rosiglitazone (Avandia,4 mg - Glaxo Smith Kline) on values of wide-spread risk-markers: fibrinogen, C-reactive protein and uric acid and glicolysated haemoglobin HbA1C as parameter of metabolic control. We examined forty patients who satisfied criteria for metabolic syndrome and distributed them into groups of diabetic and prediabetic patients according to criteria of IDF (International Diabetic Federation).
These risk markers and glicolysated haemoglobin HbA1C were observed at the beginning of therapy, then four, eight and twelve weeks into therapy and results were compared and statistically processed.
Three months initial therapy with rosiglitazone significantly reduced values of HbA1C, fibrinogen and CRP but not uric acid in prediabetic patients.
Rosiglitazone initial three months therapy significantly reduced HbA1C, fibrinogen and uric acid, but not CRP in diabetic patients.
The number of patients diagnosed with non-infectious diseases and the related mortality is alarmingly rising daily in all the world, especially in developing countries. These facts influence the accelerated manifestation of new risk-markers for cardiovascular diseases. The 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 patho-physiological base of this syndrome lies insulin resistance that, in the process of blood coagulation, leads to hypofibrinosis together with blood coagulation disorder in blood vessels. Major part of those effects in insulin resistance, as well as the changes in coagulation and in en-dothelium confirm the existence of inflammation (1,2). 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-vas- cular system, marking it the cause of the most massive mortality in persons with metabolic syndrome. It has already been accepted for years to regard C-reactive protein as an acute inflammation reactant, fi-brinogen 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 (3,4). It has been demonstrated that reducing CRP levels causes a reduction in cardiovascular diseases (3,4,5). CRP in not only a marker of inflammation; this protein, itself, contributes to atherogenesis. It appears to help mono-cytes infiltrate the arterial wall, starting the process of plaque formation. Thiazolidinediones, metformin, aspirin and statins reduce CRP in varying degrees (5). Recent intervention studies have also demonstrated the distinct efficacy of different 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 effect was shown to be independent of the degree of glycemic improvement, it can be regarded as a class-specific effect (6). Fibrinogen is an acute phase reactant with active participation in endothelial function, thrombosis and inflammation. It has proven to be an independent variable in cardiovascular risk together with its participation in resistance phenomena in different antithrombotic approaches. Reasons behind fi-brinogen 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 fibrinogen levels in plasma. Analyses of the retrospective studies suggest that fi-brinogen is an important and independent cadiovascu-lar risk marker and factor, clearly associated with conventional risk factor and genetic polymorphisms (7,8). Uric acid is a final breakdown product of purine metabolism in man. There 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 (7). Several studies have reported that changes in serum cholesterol follow the changes in serum uric acid both in order and magnitude. Most recently, hyper-uricaemia has been added to the constellation of abnormalities that comprise metabolic syndrome. The patophysiology of hyperuricaemia and link between hy- peruricaemia, hypertension and cardiovascular disease are poorly understood. It is entirely possible that hyper-uricaemia 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 (9,10,11,12). 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, different drugs, like statins and PPAR gamma agonists, have been demonstrated to effectively reduce CRP levels and other risk-markers (13-15).
Over the period of three months, the values of fibrinogen as well as C-reactive pro- tein, HbAiC and uric acid were observed pro-spectively in patients with metabolic syndrome featured by at least four of the following six criteria:
Patients were divided into the group of 19 prediabet-ics according to IDF (International Diabetic Federation) criteria (fasting plasma glucose value between 6,1 and 7,0 mmol/l, impaired glucose tolerance test with postprandial glycaemia between 7,8 and 11,1 mmol/l), and the group of 21 diabetic patients (fasting plasma glucose value more than 7,0 mmol/l and postprandial hyperglycaemia more than 11,1 mmol/l). Initial laboratory values of the mentioned parameters were recorded. Therapy with 1 tablet of rosiglitazone 4 mg (Avan- dia, Glaxo Smith Klein, United Kingdom) was introduced in the morning, without any correction in former therapy. Mentioned parameters were observed 4, 8 and 12 weeks into therapy, and the obtained data statistically and graphically elaborated.
For statistical analysis we used tables and graphs (histogram and pie) and following statistical measures: mean, standard deviation, with average linear deviation, coefficient of variation, χ2 test for descriptive variables and Students test for quantitative variables. All data were analysed in SPSS 10.0 for Windows statistical program, and Microsoft Excel 2003 program.
The values of fibrinogen in the two groups of patients measured before the beginning of the therapy and 4, 8 and 12 weeks into therapy The values of C-reactive protein in the two groups of patients measured before the beginning of the therapy and 4, 8 and 12 weeks into therapy. The values of uric acid in the two groups of patients measured before the beginning of the therapy and 4, 8 and 12 weeks into therapy.
The values of HbA1C in the two groups of patients measured before the beginning of the therapy and 4, 8 and 12 weeks into therapy. 10 of 19 prediabetic patients (52,63%) with HbA1C >6,0 % achieved HbA1c < 6,0 % after three initial months therapy of rosiglitazone 4 mg.
In total, 40 patients were screened, 19 prediabet-ics and 21 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 1) were slowly decreasing during the three months of initial therapy with Rosiglitazone, but the decrease was statistically significant, p<0,001. Significant decrease in fibrinogen values was also observed in the group of diabetics after treat-ment with rosiglitazone (Table 2). Average value of fibrinogen varied from 4,55 at the beginning of the study to 4,00 after 12 weeks p<0,006. Rosiglitazone significantly reduced CRP values in prediabetic group (Table 3). Value of CRP significantly decreased in relation to initial mea-suring in the group of prediabetics. P<0,0001. 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 4) p=0,199. During the first month of therapy CRP was significantly reduced, but later, during 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 6), p<0,015 but there was no significant change after 12 week therapy in relation to initial values in the group of prediabetics (Table 5), p<0,527. The most important parameter of metabolic control in this group of patients is glicolysated haemo- globin-HbA1C and we studied values of this parameter during this period (data shown in Table 7, and and8).8). This examination suggests very favourable effects of initial therapy of rosiglitazone on glycemic control in metabolic syndrome patients. Values of HbA1C were significantly reduced in both group of patients. In 52,63 % prediabetic patients with HbA1C more than 6,0 % achieved values lower than 6,0 % and tendency to normoglycaemia.
The main result of the present study is the finding that three months initial therapy with Rosi-glitazone caused significant reduction in fibrino-gen 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 noticed. This figure suggests the necessity of observing uric acid in diabetics with cardiovascular incidents, which can be a good predictor of further incidents. The 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 effects of treatment are especially important due to the fact that a great number of these patients, more precisely about two thirds, die of mac-rovascular diseases. In the present study, rosiglitazone has significant implications to the level of risk markers in patients with metabolic syndrome, and possibly influences also other pro-inflammatory 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<0,015) 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 an-tiatherosclerotic effects observed with Rosigitazone may involve the lowering of risk markers-fibrin- ogen, 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 2 diabetes, and they have been shown to improve risk markers It confirms 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 find its place among the drugs recommended for treatment of acute cardiovascular incidents in patients with centripetal obesity, but other large studies are needed to offer a definite confirmation for that. A change of life-style and diet is especially important for risk decreasing, but, surely, a significant help can be achieved through drug therapy, which should be combined. Function and the effect 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.
This study has demonstrated good tolerability and efficacy of rosiglitazone (Avandia, 4 mg, Glaxo Smith Cline) in the therapy of patients with metabolic syndrome.
Three months initial therapy with rosiglitazone significantly reduced values of HbA1C, fibrinogen and CRP but not uric acid in prediabetic patients with metabolic syndrome according to IDF criteria.
Three months initial therapy with rosiglitazone significantly reduced HbA1C, fibrinogen and uric acid, but not CRP in diabetic patients with criteria for metabolic syndrome.
hs-CRP - high sensitive-C reactive protein
CRP - C reactive protein
HbA1C - glycosylated hemoglobin
IDF - International Diabetic Federation
HDL - high density lipoprotein
LDL - low density lipoprotein