Comparative Study Between High-Dose Fluvastatin and Low-Dose

Endocrine Journal 2011, 58 (3), 171-175

Or i g i n a l Comparative study between high-dose fluvastatin and low- dose fluvastatin and ezetimibe with regard to the effect on endothelial function in diabetic patients

Yoshiaki Kawagoe, Yoshiyuki Hattori, Ayuko Nakano, Chie Aoki, Seiichi Tanaka, Satoshi Ohta, Toshie Iijima, Atsuko Tomizawa, Teruo Jojima, Hiroyuki Kase and Kikuo Kasai

Department of Endocrinology and Metabolism, Dokkyo University School of Medicine, Mibu, Japan

Abstract. It is well established that statins improve the prognosis of patients with coronary artery disease. However, it is still unclear whether the protective effects of statins relate to lipid lowering alone or whether other pleiotropic effects may contribute. Thus, we compared the endothelial function among two groups of diabetic patients treated with fluvastatin 60 mg (F60) or fluvastatin 20 mg combined with ezetimibe 10 mg (F20/E10). The endothelial function was evaluated by measuring flow-mediated vasodilatation (FMD) at baseline and follow-up at 10 weeks. Similar improvements in FMD were observed in the two groups. The reduction in low-density lipoprotein cholesterol (LDL-C) was less pronounced in the F60 group, compared with the F20/E10 group. A significant reduction in remnant-like lipoprotein particles cholesterol (RLP-C) was observed in the F20/E10 group, but not in the F60 group. A correlation between the observed reduction in LDL-C or RLP-C and the improvement in FMD was observed in F20/E10 group. These results suggest that high-dose fluvastatin might have pleiotropic effects of potential clinical benefit, and that the combination of ezetimibe with a reduced dose of fluvastatin may also significantly improve endothelial function with reduction of LDL-C and RLP-C.

Key words: Statin, Endothelial function, Pleiotropic effects, Diabetes

Cholesterol-lowering therapy with 3-hy- simvastatin 80 mg or a combination of simvastatin 10 droxymethlglutaryl coenzyme A reductase inhibitors mg and ezetimibe 10 mg. The observed improvements (statins) decreases mortality and morbidity in patients in endothelial function did not differ significantly with cardiovascular disease, particularly in patients with between the two groups. Likewise, similar reductions type 2 diabetes mellitus [1, 2]. However, it remains in LDL-C were observed among the two groups (45% uncertain whether the protective effects of statins relate to 50%), suggesting that the lipid-lowering effect of to their lipid-lowering effect alone, or whether other therapy might be a more important mediator of flow- pleiotropic effects may contribute. Experimental data mediated dilation than pleiotropic effects. In another suggest that statins have pleiotropic effects, but the study, Liu et al. [5] compared the effect of simvasta- clinical relevance of these effects remains uncertain. tin 40 mg daily, and a combination of simvastatin 10 Since ezetimibe has been observed to provide signif- mg and ezetimibe 10 mg daily, with placebo in three icant incremental reductions in low-density lipoprotein groups of patients with low-density lipoprotein choles- cholesterol (LDL-C) when co-administered with statin terol readings >130 mg/dL and less than two cardiovas- therapy [3], Settergren et al. [4] compared the endothe- cular risk factors. The groups were compared based on lial function of two groups of patients with dysgly- relative changes in Rho-associated coiled-coil contain- cemia and coronary artery disease treated with either ing protein kinase activity as the primary endpoint, and endothelial function as a secondary endpoint. They Received Oct. 1, 2010; Accepted Jan. 4, 2011 as K10E-289 Released online in J-STAGE as advance publication Feb. 4, 2011 concluded that high-dose statin monotherapy induced Correspondence to: Yoshiyuki Hattori, Department of a greater reduction in Rho-associated coiled-coil con- Endocrinology and Metabolism, Dokkyo University School of taining protein kinase activity and improved endothe- Medicine, Mibu, Japan. E-mail: [email protected] lial function as measured by flow-mediated dilation, ©The Japan Endocrine Society 172 Kawagoe et al. compared with combination therapy of a low-dose sta- Table 1 Lipid, CRP and HbA1c at baseline and follow-up tin with ezetimibe. The authors feel this suggests ben- F60 (n=12) Baseline Follow-up p eficial pleiotropic effects of statins in humans. total cholesterol 236±33 186±23 <0.005 In addition to these studies, a number of other stud- LDL-C 154±26 106±15 <0.005 ies have investigated the pleiotropic effects of statins HDL-C 55.4±16 58.1±18 0.16 with varying results [4-7]. These results stress the Triglyceride 115±28.9 102±28.6 0.07 need for mechanistic study of an individual statin and RLP-C 7.18±2.48 5.78±1.99 0.16 multicenter study examining whether there is a clini- C-reactive protein 1.23±1.1 0.58±0.54 <0.05 cal benefit of a particular statin beyond its lipid-low- HbA1c 6.17±0.86 6.49±1.05 0.07 ering effect. In the present study, we tested diabetic F20/E10 (n=12) Baseline Follow-up p patients with high-dose fluvastatin or a combination of total cholesterol 244±36 176±23 <0.005 low-dose fluvastatin with ezetimibe. One of anum- LDL-C 164±33 96±22 <0.005 ber of statins that have been introduced to the market, HDL-C 57.2±18 60.5±20 0.12 fluvastatin appears to act directly on the blood vessel Triglyceride 128±57.9 94±29.3 0.06 wall to stabilize plaques in situ (agents that share this RLP-C 10.55±4.88 5.86±4.30 <0.005 property have been termed vascular statins). We have C-reactive protein 1.01±0.61 0.42±0.33 <0.05 recently reported a protective effect of fluvastatin on HbA1c 6.50±0.62 6.77±0.72 0.06 vascular endothelial cells, despite its less potent cholesterol-lowering effect in diabetic patients [8]. When co-administered with statin therapy, ezetimibe has dard linear regression methods. A value of p<0.05 been reported to provide significant incremental reduc- was considered statistically significant. The study tions in LDL-C and TG, as well as increases in HDL-C. was carried out in accordance with the Declaration of Thus, we compared the endothelial function among Helsinki (2000) of the World Medical Association, and two groups of diabetic patients with fluvastatin 60 mg was approved by the Ethics Committees of the hospi- or fluvastatin 20 mg combined with ezetimibe 10 mg. tal. Written informed consent was obtained from each patient after full explanation of the purpose, nature and Materials and Methods risk of the procedure.

Hypercholesterolemic patients were randomly Results assigned to receive 60 mg fluvastatin (the F60 group: 12 diabetic patients) or 20 mg fluvastatin combined The two groups were well balanced with regard to with ezetimibe 10 mg (the F20/E10 group: 10 dia- age (F60: 65.1 ± 7.2 years vs. F20/E10: 64.2 ± 7.2 betic and 2 IGT patients) for 10 weeks, and measured years) and gender (male: F60 5/12 vs. F20/E10 6/12). flow-mediated vasodilatation (FMD), total cholesterol All patients in the F60 group were diabetics, while the (TC), LDL-cholesterol (LDL-C), HDL-cholesterol F20/E10 group contained 10 diabetics and two patients (HDL-C), triglyceride (TG), remnant-like lipopro- with IGT. tein particles cholesterol (RLP-C), and high-sensitiv- As shown in Table 1, TC (mg/dL) decreased from ity (hs) C-reactive protein (CRP). FMD following 236 ± 33 to 186 ± 23 and LDL-C (mg/dL) decreased forearm ischemia of the brachial artery and also nitro- from 154 ± 26 to 106 ± 15 in the F60 group, while glycerine-induced vasodilatation of the brachial artery TC decreased from 244 ± 36 to 176 ± 23 and LDL-C were assessed in a high-resolution ultrasound system decreased from 164 ± 33 to 96 ± 22 in the F20/E10 equipped with 2-dimensional imaging software with a group. The decrease in LDL-C in the F60 group was pulse Doppler flow velocimeter (Unex, Tokyo, Japan). 42.7 ± 22.7, while that in the F20/E10 group was 64.8 The study was performed in the morning under fast- ± 17.3 (p<0.05 compared with F60). The observed ing conditions, after resting quietly for 30 minutes in a changes in HDL-C and TG were not statistically signif- light- and temperature-controlled room. Data are pre- icant in either group. A significant reduction in RLP-C sented as the mean ± SD. Comparisons of data were was observed in the F20/E10 group, while there was performed by paired or unpaired Student’s t-test, and no significant change in RLP-C in the F60 group. A the correlation coefficient was determined using stan- significant reduction in hsCRP was observed in both Cholesterol and endothelial function 173

Fig. 1 Absolute changes in flow-mediated endothelium- dependent vasodilatation (dFMD) in the F60 and F20/E10 group from baseline to follow-up. Data are depicted as medians and quartiles; n = 12 in the F60 group and n = 12 in the F20/E10 group.

groups. HbA1c was not affected in either group. An improvement in FMD from 5.01% ± 1.59% to 7.29% ± 3.14% (p<0.05) was observed in the F60 group, while an improvement in FMD from 5.43% ± Fig. 2 Correlation of change in LDL-C (dLDL) and change in 2.25% to 7.61% ± 2.56% (p<0.005) was observed in FMD (dFMD) were presented in the F60 (A) and F20/ the F20/E10 group (Fig. 1). Endothelium-independent E10 (B) group from baseline to follow-up. p=0.5962 in vasodilation (nitroglycerin-induced dilation) did not (A), p=0.0472 in (B). differ significantly before and after statin treatment in either group. We examined if there might be a correlation between LDL-C and RLP-C. the observed changes in LDL-C and FMD or in RLP-C In the present study, the treatment with 60 mg flu- and FMD. A significant correlation between the vastatin caused a substantial reduction in LDL-C in the observed changes in LDL-C (dLDL) and FMD (dFMD) F60 group. Exposure of endothelial cells to LDL-C was observed in the F20/E10 group (dLDL=45.4 + 7.0 was found to up-regulate caveolin-1 expression, x dFMD, p=0.0472), but not in the F60 group (Fig. 2). with which eNOS forms an inhibitory complex [9]. Similarly, a significant correlation between the observed Conversely, lowering LDL-C appears to down-regulate changes in RLP-C (dRLP-C) and FMD (dFMD) was caveolin-1 in endothelial cells [10]. Thus, the favor- observed in the F20/E10 group (dRLP-C=2.47 + 0.45 able effects of decrease in LDL-C on vascular func- x dFMD, p=0.0416), but not in the F60 group. tion may be medited by disruption of the eNOS/caveolin-1 complex. Furthermore, fluvastatin appears to act Discussion directly on the blood vessel wall to stabilize plaques in situ (agents that share this property have been termed The main finding of this study is that lipid-lower- vascular statins)[11]. The ratio of the blood concentra- ing using the two treatment strategies, fluvastatin 60 tion of fluvastatin to the level required for inhibition (F60) mg and fluvastatin 20 mg in combination with of vascular smooth muscle cell (VSMC) proliferation ezetimibe 10 mg (F20/E10), did not differ with regard (Cmax/IC50) is 2:1 [11], which implies a direct effect to their effect on endothelial function. Thus, high-dose of fluvastatin on the blood vessel wall in vivo. Indeed, fluvastatin might have pleiotropic effects of potential the Lescol Intervention Prevention Study [LIPS] has clinical benefit, and that the combination of ezetimibe demonstrated that lipid lowering using fluvastatin in with a reduced dose of fluvastatin may also signifi- patients with mildly to moderately elevated LDL cho- cantly improve endothelial function with reduction of lesterol significantly reduces the secondary occurrence 174 Kawagoe et al. of cardiovascular events, irrespective of cholesterol endothelial function in the F20/E10 group, while the levels before treatment [12]. We have also recently observed reduction in RLP-C also paralleled FMD reported a protective effect of fluvastatin on vascular improvement in the same group. Thus, the RLP lower- endothelial cells, despite its less potent cholesterol- ing effect of ezetimibe might at least partly contribute lowering effect in diabetic patients [8]. Thus, it would to improvement in endothelial function. Considering seem that high-dose fluvastatin might have some ben- that the patients in the study by Liu et al [5] had a low eficial pleiotropic effects. cardiovascular risk, were not all naive to statin treat- Similarly, the treatment with fluvastatin 20 mg in ment, and did not include patients with diabetes mel- combination with ezetimibe 10 mg caused a substan- litus, RLP levels in these patients were probably lower tial reduction in LDL-C in the F20/E10 group more than those in the study by Settergren et al. [4]. than in the F60 group. In the F20/E10 group, not In conclusion, aggressive cholesterol-lowering only a profound decline in LDL-C but also a signifi- appears to improve endothelial function and reduce cant decrease in remnant-like lipoprotein particles cho- inflammatory markers in patients with dysglycemia lesterol (RLP-C) was observed. It is well established and CAD. The observed effects on endothelial func- RLP-C levels are increased in type 2 DM [13]. RLP at tion and inflammatory markers did not differ between concentrations similar to those found in the plasma of the two treatment strategies (fluvastatin 60 mg or com- patients with CAD have been observed to up-regulate bined therapy with fluvastatin 20 mg and ezetimibe the expression of intercellular adhesion molecule-1 and 10 mg). This suggests that, in addition to lipid low- vascular cell adhesion molecule-1 in cultured human ering, statin-mediated pleiotropic effects including endothelial cells [14]. RLP has also been shown to a reduction in RLP with ezetimibe might contribute increase the production of tissue factor, which is essen- to improvements in endothelial function. There are tial for initiation of thrombotic events in endothelial numerous studies supporting the notion that ‘the lower, cells [14]. The pro-atherothrombogenic effects of RLP the better’ with regard to cholesterol levels [17, 18]. may explain the association of high RLP-C levels with To achieve an aggressive reduction in LDL choles- impaired endothelial function and an increased preva- terol, higher doses of statins are required, which can be lence of future coronary events in type 2 DM patients. problematic since the side effects of statins tend to be Indeed, increased levels of RLP-C are significant and dose-related [19]. Combining a lower dose statin with independent risk factor of CAD and predict future cor- ezetimibe in order to achieve the same degree of lip- onary events in patients with CAD and type II DM [15]. id-lowering might therefore be an attractive alternative As shown in the present study as well as in previous considering the beneficial effects on endothelial func- studies [16], ezetimibe appears to decrease RLP. The tion and pro-inflammatory markers demonstrated in the observed reduction in LDL-C correlated with improved present study.

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