Effects of a statin group drug, pravastatin, on the insulin resistance in patients with metabolic syndrome

Biomedicine & Pharmacotherapy 58 (2004) 614–618 http://france.elsevier.com/direct/BIOPHA/

Dossier: Diabetes: Basic Research and Clinical Approach

Effects of a statin group drug, pravastatin, on the insulin resistance in patients with metabolic syndrome Feyzullah Güçlü a, Bilgin Özmen b,*, Zeliha Hekimsoy b, Cengiz Kirmaz a a

b

Department of Internal Medicine, Faculty of Medicine, Celal Bayar University, Manisa, Turkey Division of Endocrinology of Internal Medicine, Faculty of Medicine, Celal Bayar University, Manisa, Turkey Received 4 May 2004 Available online 13 October 2004

Abstract Background. – In West of Scotland Coronary Prevention Study (WOSCOPS), development of type 2 diabetes mellitus (DM) was found to decrease by 30% in pravastatin-treated patients. In the study, it is suggested that pleiotropic effects of pravastatin may be responsible too as well as its lipid lowering effect. Objective. – The aim of this study was to assess the effects of pravastatin treatment on the insulin resistance in patients with metabolic syndrome with impaired glucose tolerance (IGT), by Homeostasis Model Assessment (HOMA) test, insulin sensitivity indices and glucose half activation time (glucose t1/2). Methods. – Study population consisted of 25 women who were diagnosed with metabolic syndrome. At baseline and 10 weeks after the 20 mg/daily tablet pravastatin treatment, waist/hip circumference, body weight and arterial blood pressure measurements, plasma glucose, total cholesterol, triglyceride, high density lipoprotein (HDL)-cholesterol, transaminases, glycosylated haemoglobin (A1C) and insulin level measurements were obtained along with HOMA test and insulin tolerance test after 12 h of fasting. Insulin sensitivity indices and glucose t1/2 were assessed. Results. – After the treatment, a statistically significant decrease was observed in arterial blood pressure values (P < 0.0001). While plasma total cholesterol, low density lipoprotein (LDL)-cholesterol, and triglyceride levels were found to decrease significantly and HDL-cholesterol levels increased significantly, a decrease in baseline insulin levels, an increase in insulin sensitivity levels were observed along with an decrease in glucose t1/2. Related to the improvement in aforementioned parameters, statistically significant decreases were noted in HOMA, postprandial and fasting glucose levels and A1C values (P < 0.0001). Conclusion. – Our study suggests that using pravastatin in the dyslipidemia treatment of metabolic syndrome with IGT may be an effective approach by its advantageous effects on insulin resistance. Based on this result, it is possible to say that this can be a risk lowering treatment approach for the development of type 2 DM. © 2004 Elsevier SAS. All rights reserved. Keywords: Insulin resistance; Metabolic syndrome; Pravastatin; Hyperlipidemia; HOMA-IR

1. Introduction Metabolic syndrome patients are at increased risk for developing cardiovascular morbidity and mortality [1]. The increasing prevalence of the metabolic syndrome in various asymptomatic populations has been well documented, however, limited information is available about the prevalence in manifest atherosclerotic vascular disease patients [2]. * Corresponding author. Plevne Bulvarı No. 14, D. 9, Alsancak, ˙Izmir 35220, Turkey. E-mail address: [email protected] (B. Özmen). 0753-3322/$ - see front matter © 2004 Elsevier SAS. All rights reserved. doi:10.1016/j.biopha.2004.09.005

Metabolic syndrome is a disorder in which insulin resistance is the main component of the pathogenetic mechanism. In 1988, Reaven [3], upon observing the more than coincidental existence of obesity, diabetes, hypertension, hyperlipidemia and atherosclerotic coronary diseases concomittantly in a single patient, suggested that these are caused by a single metabolic disorder. On the basis of this conclusion, he defined the “insulin resistance syndrome” (syndrome X) which consists of insulin resistance, hyperinsulinemia, obesity, glucose intolerance, hypertriglyceridemia, reduced high density lipoprotein (HDL)-cholesterol level, hypertension and coronary arterial diseases, prothrombotic state (e.g., high fibrinogen or

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plasminogen activator inhibitor [–1] (PAI-1) in the blood), proinflammatory state (e.g., elevated high-sensitivity C-reactive protein (h-CRP) in the blood) and polcystic ovarian syndrome [3–5]. Insulin resistance is defined as a decrease in endogenous (native) and/or exogenous insulin action. In other words, an impaired response to a specific insulin dose [3]. Many hereditary and acquired factors lead to an advance decrease in biological response of insulin by preventing the insulin binding to the receptors in target tissues or by impairing the receptor signaling pathways [3,6]. In order to meet the increased action, an excess insulin secretion occurs. Mild-moderate insulin resistance, a common clinical case, leads to impaired glucose tolerance (IGT), type 2 diabetes mellitus (DM), hypertension and early atherosclerosis [7]. All these clinical features that occur related to insulin resistance are significant mortality and morbidity factors. Given these facts, new approaches in the treatment of insulin resistance may prevent these diseases and also contribute to the treatment of such diseases. In West of Scotland Coronary Prevention Study (WOSCOPS), development of type 2 DM was found to decrease by 30% in pravastatin-treated patients [8]. In this study, it is suggested that anti-inflammatory and endothelial effects of pravastatin may be responsible as well as its lipid lowering effect. We aimed to detect the effects of pravastatin treatment on insulin resistance in cases having metabolic syndrome with IGT is assessed by Homeostasis Model Assessment (HOMA) test, insulin sensitivity indices (ISI) and glucose half activation time (glucose t1/2).

2. Materials and methods 2.1. Subject Our study consisted of 25 cases that met the ATP III criteria of metabolic syndrome [5] and thus diagnosed with metabolic syndrome between January 2002 and March 2003 in the Department of Endocrinology and General Internal Medicine out-patient clinic of Celal Bayar University Medical Faculty. All the patients were women with an average age of 55.56 ± 8.26 (min: 41, max: 68). Additional exclusion criteria that all selected patients met were: • being previously diagnosed with type 2 DM (fasting blood glucose ≥ 126/mg/dl or 2 h OGTT plasma glucose ≥ 200 mg/dl); • having a normal lipid profile (total cholesterol, triglyceride, low density lipoprotein (LDL)-cholesterol); • taking obesity treatment within last two months (diet or medical); • attending regular physical program or weight loss of more than 3% within the last 6 months; • having obesity due to endocrinologic diseases (hypothyroid, cushing syndrome, etc.);

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• being on drugs that may affect insulin resistance; for example, taking an angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker group drugs; • cases with acute coronary diseases; • patients on hormone replacement treatment (HRT) or those using selective estrogen receptor modulator (SERM); • presence of infection, severe physical or psychological trauma on the day of insulin tolerance test or any recent day, as these may affect the result of the test; • those who do not comply with the pravastatin treatment. Informed consent for the described investigations was obtained from all patients. Approval for the study was given by the ethics committee of our hospital. 2.2. Study design At the initial visit, waist/hip circumference, body weight and arterial blood pressure measurements and total cholesterol, HDL-cholesterol, LDL-cholesterol, triglyceride, fasting glucose levels, postprandial glucose levels, liver function tests, glycosylated haemoglobin (A1C) and baseline insulin level measurements tests were obtained from the patients chosen according to the metabolic syndrome diagnostic criteria of ATP III [5]. HOMA, ISI and glucose t1/2 of the patients were calculated. Pravastatin treatment (20 mg once daily at bedtime) was initiated in these patients. This treatment was continued until second visit, 10 weeks later. Aforementioned parameters were measured once again. Plasma glucose level, total cholesterol, triglyceride, HDLcholesterol, liver function tests and A1C measurements were analysed at Celal Bayar University, Medical Faculty Biochemistry Laboratory, using an automatic analyzer (Diagnostic Merck-Mega-2000 equipment). LDL-cholesterol levels were calculated by the Friedewald equation [9]. Serum insulin levels were assayed by radioimmunoassay (RIA) method. Commercial kits of DPC (Diagnostic Products Corporation, Los Angeles, USA) were used for the measurements. 2.3. Assessment of insulin tolerance test Following the tension arterial, weight, waist/hip measurements of the patients obtained after 12 h fasting and 30–45 min rest, they were instructed to lie in supine position on the examination bed and 22 G needle was used for venous access. Blood glucose measurement was obtained at –5 and 0 min followed by infusion of crystallized insulin IV at a rate of 0.1 unit/kg in the other arm. Blood glucose level measurements were obtained at 1, 2, 3, 5, 7, 10, 15 and 20 min. Hypoglycemic symptoms were monitored closely during the test. During these observations, no serious hypoglycemic symptom was observed except, mild sweat, tachycardia and starvation feeling towards the end of the test. At the end of 20 min, 500 ml 5% dextrose serum was infused at 150 ml/h for 2 or 3 h depending on the condition of the patient. Single dose (before bed time) 10 weeks 20 mg Pravastatin (pravachol™-Bristol-Myers Squibb) treatment was initiated.

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2.4. Assessment of the results and statistical analysis

4. Discussion

Baseline insulin values, glucose t1/2 and dG values were taken into account in statistical analysis. dG was calculated by subtracting the 0 min blood glucose value from 20 min blood glucose level. G0 is the 0 min blood glucose level. Insulin sensitivity indices was calculated as (ISI) = dG/G0. Glucose t1/2 of the patients is the value that corresponds to the half of the G1 value in scatterplot graphics SPSS version 10. SPSS Version 10 was used for the assessment of all the statistical analysis. After calculating the average post- and pre-treatment values, “paired student’s t-test” was used for the statistical analysis. P values less than 0.05 were accepted as statistically significant. All data were expressed as ±SD.

In the last several years, there has been a decided shift in the focus of lipid trials from populations with high LDL cholesterol to populations with a more modest LDL cholesterol and the dyslipidemia that is characteristic of DM and metabolic syndrome [10]. Statins predominantly result in substantial LDL cholesterol lowering but generally also produce favorable, albeit smaller, changes in triglycerides and HDL cholesterol. With statin treatment in either the 4S [11], the CARE [12] or HPS [13], the changes in blood lipids and apoproteins were similar for subgroups with and without diabetes. Today, when factors such as nourishment habits and sedentary life are taken into account, obesity is a serious health problem which threatens life in a growing concern, because serious diseases such as hypertension, stroke, DM, dyslipidemia and atherosclerosis obesity are significant mortality and morbidity factors [12]. In our study, after a 20 mg tablet 10 weeks pravastatin treatment, an improvement was observed in arterial tension values of the cases of whose majority was stage 1 hypertensive at initial visits. Studies on pravastatin demonstrated a decrease in cardiac reactivity against angiotensin II and norepinephrine after 10–12 weeks treatment [14]. As a result, an improvement was observed in tension arterial values by pravastatin treatment. These results are in consistency with our study. In our study, when the post-treatment lipid profiles of the patients were evaluated, a decrease was noted in total cholesterol, LDL-cholesterol, triglyceride levels while there was an increase in HDL-cholesterol levels. Thus, pravastatin improved the lipid levels. Previous studies indicated that pravastatin provides an improvement in endothelial dysfunction related to its antioxidant effects while providing a statistically significant decrease in lipid levels especially in LDLcholesterol levels [15]. Studies have demonstrated that improvement in lipid profile related to using pravastatin, even only the decrease in LDL-cholesterol levels, is efficient for the development of endothelial-dependent vasodilation [16,17]. These events can be explained by an increase in nitric

3. Results Twenty-five patients that met the inclusion criteria completed the study. When the pre- and post-treatment parameters of the patients were compared, a statistically significance decrease was found in total cholesterol, LDLcholesterol and triglyceride levels (P < 0.0001), while there was a statistically significant increase in HDL-cholesterol levels (P < 0.0001) (Table 1). When the seventh report of the Joint National Committee (JNC VII) was taken into account and tension arterial values of the patients were evaluated, it was noted that 28% is prehypertensive, 48% is stage-1 hypertensive and 24% is normotensive. Following the treatment, a statistically significant decrease was observed in the tension arterial values of the controls (P < 0.0001) (Table 1). Besides an increase in baseline insulin levels (Table 1), a statistically significant difference was identified between the increase in ISI and decrease in glucose t1/2) (P < 0.0001) (Table 1 and Fig. 1). Related to the improvement in aforementioned parameters, statistically significant decreases were found in HOMA (Table 1 and Fig. 1), fasting and postprandial glucose and A1C values (P < 0.0001) (Table 1).

Table 1 Pre- and post-treatment parameters of our patients. SBP, systolic blood pressure; DBP, diastolic blood pressure; ISI, insulin sensitivity indices; HOMA, Homeostasis Model Assessment. All data were expressed as ±SD Total cholesterol Triglyceride HDL-C LDL-C SBP DBP Basaline insulin Glucose t1/2 ISI HOMA Fasting glucose Postprandial glucose A1C

Pre-treatment 233.68 ± 20.02 181.92 ± 54.04 45.08 ± 7.93 152.08 ± 25.06 129.88 ± 16.23 76.88 ± 14.58 15.98 ± 4.54 41.10 ± 10.9295 0.3267 ± 7.21E–02 4.48 ± 1.47 112.36 ± 8.76 148.24 ± 7.03 5.58 ± 0.44

Post-treatment 196.32 ± 7.50 161.12 ± 46.15 47.04 ± 7.39 117.40 ± 10.46 122.40 ± 15.08 66.80 ± 14.06 8.92 ± 3.23 27.452 ± 5.7048 0.3929 ± 0.00642 2.03 ± 0.78 91.52 ± 6.18 123.04 ± 9.15 5.14 ± 0.39

P <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001

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Fig. 1. Differences in ISI (insulin sensitivity index), HOMA-IR (Homeostasis Model Assessment-Insulin Resistance) and glucose t1/2 (glucose activation half time), respectively, a, b, c.

oxide release related to the improvement in endothelial function [17]. Animal studies demonstrated an increase in endothelial NO release following mevastatin usage [18]. It was shown in similar studies that tissue plasminogen (t-pa), excessive PAI-I and endothelial-I secretion were inhibited as well as an increase in NO secretion due to statin use [19,20]. Vasodilation occurs as a result of these mechanisms. This situation explains the antihypertensive efficacy related to the

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improvement in lipid profile, as we have found out in our study too. However, what is ideal for proving the antihypertensive activity adequately is performing the studies by monitoring the ambulatory blood pressure. However, as we did not aim to determine the antihypertensive activity, we did not monitor the ambulatory blood pressures of the patients. In our study, a decrease in baseline insulin levels, an increase in insulin sensitive indices and again a decrease in glucose t1/2 were noted. Significant increases were identified in HOMA, fasting and proglabin blood glucose and A1C values related to the improvement in these parameters. It has been proved in the literature that high blood lipid and lipoprotein levels increase the risk of diabetes [21,22]. There exist few studies on the usage of the drugs that change the blood lipid profile and have anti-inflammatory effects in metabolic syndrome [22,23]. It has been long known that an increase in serum triglyceride levels in metabolic syndrome increases the risk of impaired glucose tolerance [22]. In our study, serum triglyceride levels were found to decrease by pravastatin treatment. The decrease noted in fasting glucose, postprandial glucose, HOMA, A1C levels could have been caused by the alteration in plasma triglyceride levels. However, insulin resistance on its own cannot be seen as an improving factor. It should not be forgotten that fibric acid derivatives increase the triglyceride levels more compared to statins [24]. Another point to remember in this regard is that there exist a inverse linear correlation between HDL-cholesterol and insulin resistance in the previous studies [25]. At the end of 10 weeks, controls revealed an increase in HDL-cholesterol levels of the patients in our study too. Moreover, low degree inflammatory markers (TNF-a, IL-1, IL-6 and CRP) were shown to reflect type 2 DM development risk [22]. Inflammatory cytokines secreted by macrophage and T lenfosits modify the endothelial function, smooth muscle cell proliferation, collagen destruction and thrombosis [26,27]. In experimental models, the decrease in cholesterol levels were accompanied by an increase in the number of the inflammatory cells in atherosclerotic plaque [28,29]. This incident stops and even regresses the progression of atherosclerosis. Another important point is that statin group drugs (pravastatin) may play an important role in reducing insulin resistance related to their anti-inflammatory effects. Studies on pravastatin shows that pravastatin reduces the circulating interleukine-6 and TNF-a levels [30]. TNF-a and IL-6 have been known to inhibit the lipose activity of lipoprotein and stimulate the liposis in adipose tissue [31,32]. TNF-a lymphoid cell, which is a cytokine originates from fat cell and skeletal muscle, is increased in obese cases. TNF-a causes insulin resistance by reducing the insulin signaling and GLUT-4 expression [33]. It is argued that progression from central obesity towards insulin resistance can be interrupted by obtaining a decrease in these cytokines via pravastatin treatment. In our study, the increase in insulin resistance which was obtained by using pravastatin can be attributed to the inhibition of the above mentioned proinflammatory cytokines, even though not measured. Given all this information, it has been shown in our study that using statin in dyslipidemia treatment of metabolic syn-

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drome cases is a treatment approach having advantageous effects on insulin resistance. But longer-term clinical studies should be performed with larger numbers of patients to determine the effects of statins on the insulin resistance in the patients with metabolic syndrome.

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