Differential metabolic effects of rosuvastatin and pravastatin in hypercholesterolemic patients

International Journal of Cardiology 166 (2013) 509–515

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Differential metabolic effects of rosuvastatin and pravastatin in hypercholesterolemic patients ☆ Kwang Kon Koh a,⁎, Michael J. Quon b, Ichiro Sakuma c, Seung Hwan Han a, Hanul Choi a, Kyounghoon Lee a, Eak Kyun Shin a a b c

Cardiology, Gil Medical Center, Gachon University, Incheon, Republic of Korea Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland, USA Cardiovascular Medicine, Hokko Memorial Clinic, Sapporo, Japan

a r t i c l e

i n f o

Article history: Received 27 August 2011 Received in revised form 8 November 2011 Accepted 24 November 2011 Available online 26 December 2011 Keywords: Statins Adiponectin Glycated hemoglobin Insulin resistance Endothelial function

a b s t r a c t Background: Rosuvastatin and pravastatin have differential hydrophilicity and potency to inhibit hydroxymethylglutaryl-CoA reductase that may be relevant to changes in adiponectin levels, insulin resistance, and the rate of new onset diabetes in large clinical studies. Therefore, we hypothesized that rosuvastatin and pravastatin may have differential metabolic effects in hypercholesterolemic patients. Methods: This was a randomized, single-blind, placebo-controlled, parallel study. Age, gender, and body mass index were matched. Fifty-four patients were given placebo, rosuvastatin 10 mg, or pravastatin 40 mg, respectively once daily for 2 months. Results: When compared with pravastatin therapy, rosuvastatin therapy significantly reduced total, LDL cholesterol, and apolipoprotein B levels (P b 0.05 by post-hoc comparison), but comparably improved flow-mediated dilation after 2 months. Interestingly, rosuvastatin therapy significantly increased fasting insulin (mean % changes; 28%, P = 0.005). and HbA1c (1%, P = 0.038) while decreasing plasma adiponectin levels (9%, P = 0.010) and insulin sensitivity (assessed by QUICKI; 2%, P = 0.007) when compared with baseline. By contrast, pravastatin therapy significantly decreased fasting insulin (8%, P = 0.042), and HbA1c levels (1%, P = 0.019) while increasing plasma adiponectin levels (36%, P = 0.006) and insulin sensitivity (3%, P = 0.005) when compared with baseline. Moreover, these differential effects were evident when outcomes of rosuvastatin and pravastatin therapy were directly compared (P = 0.002 for insulin levels by ANOVA on Ranks, P = 0.003 for adiponectin, P = 0.003 for QUICKI, and P = 0.010 for HbA1c by ANOVA). Conclusions: While significantly reducing lipoprotein profiles, rosuvastatin therapy had unwanted metabolic effects in hypercholesterolemic patients when compared with pravastatin therapy, that may be clinically relevant in patients prone to metabolic diseases. © 2011 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Many patients on statin therapy have initial or recurrent coronary heart disease events despite reductions in low-density lipoprotein (LDL) cholesterol [1]. Coronary heart disease is characterized by endothelial dysfunction and frequently cluster with disorders of metabolic homeostasis characterized by insulin resistance [2,3]. These co-morbidities may be explained, in part, by reciprocal relationships between endothelial dysfunction and insulin resistance [3–5].

☆ We presented by oral in the AHA 2010 meeting in Chicago and by poster in the ESC 2011 meeting in Paris. ⁎ Corresponding author at: Vascular Medicine and Atherosclerosis Unit, Cardiology, Gil Medical Center, Gachon University, 1198 Kuwol-dong, Namdong-gu, Incheon, 405-760, Republic of Korea. Tel.: + 82 32 460 3683; fax: + 82 32 460 3117, + 82 32 467 9302. E-mail address: [email protected] (K.K. Koh). 0167-5273/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2011.11.028

With regard to beneficial effects of statins on endothelial dysfunction, all statins improve nitric oxide bioavailability resulting in improved flow-mediated dilator response to hyperemia that may be mediated by anti-inflammatory actions of statins in the vascular endothelium [6]. By contrast, not all statins are beneficial with respect to metabolic parameters including glucose tolerance and insulin sensitivity. Lipophilic statins may have adverse metabolic consequences that include impaired insulin secretion and promotion of insulin resistance [7–9]. For example, simvastatin and atorvastatin reduce plasma levels of adiponectin and insulin sensitivity in humans [10–12]. Recent large scale clinical studies and meta-analyses have demonstrated that some statins, particularly at high dose, increase the rate of onset of new diabetes [13–15]. By contrast, pravastatin improves insulin sensitivity in some patients [11,16,17]. A recent large scale clinical study demonstrates that pravastatin reduces the rate of onset of new diabetes by 30% [18]. However, no previous clinical studies have evaluated the effects of pravastatin on glucose tolerance.

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Glucose tolerance is a metabolic parameter that is distinct from insulin resistance per se. Glucose tolerance is determined by multiple factors including insulin secretion and insulin action. Rosuvastatin is less hydrophilic than pravastatin [19]. Rosuvastatin does not change insulin sensitivity in patients with metabolic syndrome [20] or familial combined hyperlipidemia [21]. However, it increases the incidence of type 2 diabetes in a recent study [22]. Interestingly, rosuvastatin increases the rate of onset of new diabetes in a dosedependent manner (hazard ratio = 1.10, 1.14, and 1.26, respectively) [13]. Therefore, the mechanism of rosuvastatin to increase the rate of onset of new diabetes is very intriguing, but this has not yet been clearly elucidated in patients. Adiponectin is an anti-inflammatory adipocytokine and plasma levels of adiponectin are negatively correlated with adiposity and insulin resistance [23]. We recently reported that some drug therapies increase adiponectin levels and insulin sensitivity in patients without changing body mass index [24–27]. Thus, decreased levels of adiponectin in response to some drug therapy may promote insulin resistance rather than simply serving as a biomarker for insulin sensitivity. In addition, lower adiponectin levels may promote atherogenesis [23]. Accordingly, we investigated the effects of rosuvastatin and pravastatin on endothelial function and metabolic parameters including circulating adiponectin levels, glucose tolerance, and insulin sensitivity in hypercholesterolemic patients. 2. Methods 2.1. Study population and design We used a randomized, single-blind, placebo-controlled, parallel study design. Age, gender, and body mass index were matched among all subjects. We recruited patients from a primary care setting in the Cardiology Clinic, Gil Medical Center, Gachon University. Before and during the study period a dietitian educated patients to maintain a low fat diet. Patients with hypercholesterolemia (low-density lipoprotein cholesterol levels ≥ 130 mg/dl) participated in this study. We excluded patients with overt liver disease, chronic renal failure, hypothyroidism, myopathy, uncontrolled diabetes, severe hypertension, stroke, acute coronary events, coronary revascularization within the preceding 3 months, or alcohol abuse. No patient had taken any lipidlowering agent, hormone replacement therapy, or antioxidant vitamin supplements during the 2 months preceding our study. Each of the fifty-four patients was given placebo, rosuvastatin 10 mg, or pravastatin 40 mg, respectively once daily during a 2 month treatment period. A research nurse counted pills at the end of treatment to monitor compliance. The patients were seen at least every 14 days during the study. To minimize side effects, we measured serum asparate aminotransferase, alanine

aminotransferase, creatine kinase, blood urea nitrogen and creatinine before and after therapy. One patient on placebo and pravastatin 40 mg and two patients on rosuvastatin 10 mg withdrew from the study because they moved to other places and dropped out of the study. Thus, 53 patients on placebo, 52 patients on rosuvastatin 10 mg, and 53 patients on pravastatin 40 mg, respectively finished the study (Fig. 1). None of the patients was diabetic. Seven patients taking placebo, 7 patients taking rosuvastatin, and 9 patients taking pravastatin were smokers. Eight patients taking placebo, 9 patients taking rosuvastatin, and 9 patients taking pravastatin were also taking beta adrenergic blockers to control blood pressure. Five patients taking placebo, 6 patients taking rosuvastatin, and 7 patients taking pravastatin were also taking calcium channel blockers to control blood pressure. No additional medications including aspirin or non-steroidal anti-inflammatory drugs were allowed during the study period to avoid confounding effects of other drugs. Calcium channel or beta adrenergic blockers were withheld for ≥48 h before the study. This study was approved by the Gil Hospital Institutional Review Board and all participants gave written, informed consent. 2.2. Laboratory assays and vascular studies Blood samples for laboratory assays were obtained at approximately 8:00 a.m. following overnight fasting before and at the end of 2-month treatment period. These samples were immediately coded so that investigators performing laboratory assays were blinded to subject identity or study sequence. Assays for lipids, glucose, and plasma adiponectin were performed in duplicate by ELISA (R&D Systems, Inc., Minneapolis, Minnesota), assays for high sensitivity C-reactive protein (CRP) levels by latex agglutination (CRP-Latex(II)®, Denka-Seiken, Tokyo, Japan) and assays for plasma insulin levels by immunoradiometric assay (INSULIN-RIABEAD® II, SRL, Inc, Tokyo, Japan) and assays for ambient glycemia, glycated hemoglobin (HbA1C) by high performance liquid chromatography assay (VARIANT II TURBO®, BIORAD, Inc, Hercules, California) as previously described [10–12,24–28]. The interassay and intraassay coefficients of variation were b6%. Quantitative Insulin-Sensitivity Check Index (QUICKI), a surrogate index of insulin sensitivity based on fasting glucose and insulin levels, was calculated as follows (insulin is expressed in microU/ml and glucose in mg/ dl): QUICKI= 1 / [log(insulin) + log(glucose)] [29,30]. Imaging studies of the right brachial artery were performed using an ATL HDI 3000 ultrasound machine (ATL Philips, Bothell, WA, USA) equipped with a 10 MHz linear-array transducer, based on a previously published technique [10,11,24–28]. 2.3. Statistical analysis Data are expressed as mean ± SEM or median (range: 25%–75%). After testing data for normality, we used Student's paired t or Wilcoxon Signed Rank test to compare values between baseline and treatment at 2 months, as reported in Table 1. We used one way analysis of variance (ANOVA) or Kruskal–Wallis ANOVA on Ranks to compare baseline or treatment effects among treatment groups. Post-hoc comparisons between different treatment pairs were made using the Student–Newman–Keuls multiple comparison procedures or Dunn's method. Pearson or Spearman correlation coefficient analysis was used to assess associations between measured parameters, as reported in Table 1. We calculated that 40 subjects would provide 80% power for detecting an absolute increase of 1.7% or greater in flow-mediated dilation of the brachial artery

184 Patients were assessed for eligibility 22 Were excluded 7 Did not meet inclusion criteria 15 Declined to participate 162 Underwent randomization

54 Placebo 1 Discontinued the study moved to other place

53 Completed Placebo

54 Rosuva 10 mg 2 Discontinued the study moved to other places

52 Completed Rosuva 10 mg Fig. 1. Flow chart.

54 Prava 40 mg 1 Discontinued the study moved to other place

53 Completed Prava 40 mg

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Table 1 Effects of placebo, rosuvastatin 10 mg, and pravastatin 40 mg in hypercholesterolemic patients. Variables

Age Sex (M:F) BMI, kg/m2 Lipids (mg/dl) Total cholesterol Triglycerides LDL cholesterol Apo B HDL cholesterol Apo A1 Vasomotor FMD dilation (%) NTG dilation (%) Inflammation CRP (mg/l) Insulin resistance ADP (μg/ml) Insulin (μU/ml) Glucose (mg/dl) QUICKI HbA1C (%)

Placebo (P) (n = 53)

Rosuvastatin (R) (n = 52)

Pravastatin (M) (n = 53)

Baseline

Treatment

Baseline

Treatment

Baseline

56 ± 1 22:31 23.95 ± 0.35

23.92 ± 0.34

55 ± 1 22:30 24.00 ± 0.43

23.96 ± 0.42

54 ± 1 21:32 23.75 ± 0.40

23.72 ± 0.39

248 ± 4 138 ± 10 166 ± 4 126 ± 3 54 ± 1 153 ± 2

234 ± 4 ‡ 145 ± 11 153 ± 5 ‡ 123 ± 3 51 ± 1* 155 ± 3

246 ± 3 136 ± 8 166 ± 4 127 ± 3 53 ± 2 152 ± 3

170 ± 4 ‡ 122 ± 8 92 ± 3 ‡ 83 ± 3 ‡ 53 ± 1 160 ± 2 ‡

241 ± 4 136 ± 8 165 ± 3 128 ± 3 51 ± 1 151 ± 3

184 ± 3‡ 115 ± 7* 110 ± 3‡ 94 ± 3 ‡ 51 ± 1 151 ± 3

4.57 ± 0.27 17.61 ± 0.64

4.57 ± 0.25 17.03 ± 0.73

4.46 ± 0.22 17.81 ± 0.61

7.57 ± 0.31‡ 17.82 ± 0.69

4.49 ± 0.26 18.17 ± 0.64

7.41 ± 0.32 ‡ 18.14 ± 0.68

0.60 (0.30–1.20)

0.60 (0.30–1.75)

0.60 (0.40–1.27)

0.50 (0.30–0.80)+

0.70 (0.40–1.35)

0.40 (0.25–0.75)‡

2.05 (1.32–6.07) 5.19 (3.08–7.73) 96 ± 2 0.378 ± 0.006 5.78 ± 0.04

2.68 (1.33–5.71) 5.35 (3.86–7.85) 97 ± 2 0.376 ± 0.007 5.80 ± 0.04

2.05 (1.37–3.75) 5.40 (3.93–8.15) 97 ± 1 0.369 ± 0.005 5.73 ± 0.04

1.90 (1.07–3.19)+ 6.31 (4.12–10.97)+ 99 ± 1 0.361 ± 0.006* 5.79 ± 0.04*

2.00 (1.22–4.12) 6.01 (4.50–8.93) 98 ± 1 0.359 ± 0.004 5.83 ± 0.04

2.29 (1.21–5.49)+ 5.90 (3.29–8.49)* 97 ± 1 0.370 ± 0.005 + 5.78 ± 0.03*

ANOVA

P/R

R/M

P/M

b0.001 0.031 b0.001 b0.001 0.043 0.041

b 0.05 b 0.05 b 0.05 b 0.05 b 0.05 b 0.05

b 0.05 NS b 0.05 b 0.05 NS b 0.05

b 0.05 b 0.05 b 0.05 b 0.05 NS NS

b0.001 0.367

b 0.05

NS

b 0.05

0.007

NS

NS

b 0.05

0.003 0.002 0.400 0.003 0.010

b 0.05 NS

b 0.05 b 0.05

NS NS

NS NS

b 0.05 b 0.05

b 0.05 b 0.05

Treatment 0.443 0.951

Data are expressed as means ± SEM or median (25th percentile–75th percentile). There were no significant differences among each baseline values. *P b 0.05, + P b 0.01, ‡P b 0.001 for comparison with each baseline value. BMI = body mass index, CRP = high-sensitivity C-reactive protein, ADP = adiponectin, HbA1c = glycated hemoglobin. Quantitative Insulin-Sensitivity Check Index (QUICKI) = 1 / [log(insulin) + log(glucose)] [29,30]. P/R = placebo vs rosuvastatin 10 mg, R/M = rosuvastatin 10 mg vs pravastatin 40 mg, P/M = placebo vs pravastatin 40 mg. NS = not significant.

between baseline and pravastatin, with α = 0.05 based on our previous studies [11]. The comparison of endothelium-dependent dilation was prospectively designated as the primary end-point of the study. All other comparisons were considered secondary. A value of P b 0.05 was considered to represent statistical significance.

3. Results There were no significant differences between groups for any of the baseline measurements (Table 1). 3.1. Effects on lipids Placebo treatment significantly reduced total, LDL cholesterol, and high-density lipoprotein (HDL) cholesterol levels from baseline. Rosuvastatin and pravastatin therapy also significantly reduced total cholesterol, LDL cholesterol, and apolipoprotein B levels from baseline (both P b 0.001 by paired t-test) after 2 month administration. These beneficial effects of rosuvastatin and pravastatin were also significant when compared with placebo treatment (P b 0.001 by ANOVA; Fig. 2A). Pravastatin significantly reduced triglyceride levels from baseline (P b 0.05 by paired t-test) after 2 month administration. Rosuvastatin significantly increased apolipoprotein AI levels from baseline (P b 0.001 by paired t-test) after 2 month administration. Of note, when compared with pravastatin therapy, rosuvastatin therapy significantly reduced total, LDL cholesterol, and apolipoprotein B levels and increased apolipoprotein AI levels (P b 0.05 by post-hoc comparison). 3.2. Effects on vasomotor function and high sensitivity C-reactive protein Placebo treatment did not significantly improve flow-mediated dilator response to hyperemia (FMD) relative to baseline measurements. By contrast, both rosuvastatin and pravastatin significantly improved FMD after 2 month therapy when compared with baseline (P b 0.001 by paired t-test) or when compared with placebo treatment (P b 0.001 by ANOVA; Fig. 2B). Brachial artery dilator responses to nitroglycerin were not significantly different between any of the

therapies. Placebo treatment did not significantly change high sensitivity CRP levels relative to baseline measurements. Rosuvastatin and pravastatin significantly reduced high sensitivity CRP levels after 2 month therapy when compared with baseline (both P b 0.01 by Wilcoxon Signed Rank test) or when compared with placebo treatment (P = 0.007 by ANOVA on Ranks). 3.3. Effects on adiponectin, glycated hemoglobin, and insulin resistance Placebo treatment did not significantly change insulin or glucose levels from baseline. Rosuvastatin and pravastatin did not significantly change glucose levels after 2 month administration when compared with baseline. However, rosuvastatin significantly increased fasting insulin levels after 2 month therapy when compared with baseline (P = 0.005 by Wilcoxon Signed Rank test). Pravastatin significantly reduced fasting insulin levels after 2 month therapy when compared with baseline (P = 0.042 by Wilcoxon Signed Rank test). The effects of rosuvastatin treatment to raise fasting insulin levels were significant when compared with pravastatin treatment (P = 0.002 by ANOVA on Ranks; Fig. 2B). We observed significant inverse correlations between baseline adiponectin and baseline insulin levels (r = −0.374, P = 0.006 before placebo; r = −0.343, P = 0.013 before rosuvastatin 10 mg; r = −0.305, P = 0.026 before pravastatin 40 mg) and significant correlations between baseline adiponectin levels and baseline QUICKI (r = 0.506, P b 0.001 before placebo; r = 0.399, P = 0.003 before rosuvastatin 10 mg; r = 0.338, P = 0.013 before pravastatin 40 mg). Placebo did not significantly change plasma adiponectin levels, insulin sensitivity (determined by QUICKI), or HbA1c levels relative to baseline measurements. Rosuvastatin significantly decreased plasma adiponectin levels (P = 0.010 by Wilcoxon Signed Rank test), insulin sensitivity (P = 0.007 by paired t-test), and increased HbA1c levels (P = 0.038 by paired t-test) when compared with baseline. Pravastatin significantly increased plasma adiponectin levels (P = 0.006 by Wilcoxon Signed Rank test), insulin sensitivity (P = 0.005 by paired t-test) and decreased HbA1c levels (P = 0.019 by paired t-test) when compared with baseline.

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Moreover, these beneficial effects of pravastatin were significant when compared with either placebo or rosuvastatin (P = 0.003 for adiponectin, P = 0.003 for QUICKI, and P = 0.010 for HbA1c by ANOVA; Fig. 2C). The magnitude of change in fasting insulin, adiponectin, QUICKI, and HbA1c was in significantly opposite directions when results from rosuvastatin and pravastatin therapy were compared despite both therapies resulting in comparable improvements in lipoprotein profiles and FMD. We investigated whether changes in percent flow-mediated dilator response to hyperemia, plasma levels of adiponectin, insulin,

A %Change in Total Cholesterol

%Change in LDL Cholesterol 0

0

-10 -10 -20 -20

P<0.001 by ANOVA

-30

P<0.001 by ANOVA

-40 -30

-40

Pl

B

R10

80

P<0.05

P<0.05

-60 Pl

P40

%Change in FMD

100

P<0.05

-50

P<0.05 P<0.05 P<0.05

R10

40 P<0.05

30 20

60

P40

%Change in Insulin

P<0.05 P<0.05

P<0.001 by ANOVA

P=0.002 by ANOVA on Ranks

10

40

0

20

-10 -20

0 Pl

R10

Pl

P40

R10

P40

C %Change in Adiponectin

%Change in QUICKI 5 4 3 2 1 0 -1 -2 -3 -4 -5

60

40

P=0.003 by ANOVA

P<0.05

P<0.05

20

0

-20 Pl

R10

P<0.05 P<0.05

P=0.003 by ANOVA

Pl

P40

%Change in HbA1c 2.0

P<0.05

1.5 P<0.05

1.0 0.5 0.0 -0.5

P=0.010 by ANOVA

-1.0 -1.5

Pl

R10

insulin resistance, or HbA1c were related to changes in total, LDL and HDL cholesterol, triglycerides and apolipoprotein AI and B levels. There were no significant correlations between changes in these parameters and changes in lipoprotein levels following any of therapies. There were inverse correlations between percent changes in adiponectin levels and percent changes in insulin (r = −0.295, P = 0.032 after placebo; r = −0.333, P = 0.016 after rosuvastatin 10 mg; r = −0.345, P = 0.012 after pravastatin 40 mg) and correlations between percent changes in adiponectin levels and percent changes in QUICKI (r = 0.326, P = 0.017 after placebo; r = 0.346, P = 0.012 after rosuvastatin 10 mg; r = 0.392, P = 0.004 after pravastatin 40 mg) and inverse correlations between percent changes in QUICKI and percent changes in insulin (r = −0.898, P b 0.001 after placebo; r = −0.927, P b 0.001 after rosuvastatin 10 mg; r = −0.938, P b 0.001 after pravastatin 40 mg). Because CRP inhibits adiponectin gene expression and production [31], we investigated these correlations. There were no significant correlations between adiponectin and CRP levels before or following therapies. We investigated whether changes in plasma levels of adiponectin, insulin, insulin resistance, or HbA1c were related to age. There were no data showing that elderly patients significantly increased insulin, insulin resistance, or HbA1c levels or decreased adiponectin levels following any of therapies.

P40

R10

P40

4. Discussion We observed that rosuvastatin and pravastatin both significantly reduced total cholesterol, LDL cholesterol, and apolipoprotein B after 2 month administration, when compared with placebo. Of note, when compared with pravastatin therapy, rosuvastatin therapy significantly reduced total, LDL cholesterol, and apolipoprotein B levels and increased apolipoprotein AI levels. Rosuvastatin and pravastatin both significantly improved endothelium-dependent dilation to a comparable extent after 2 month therapy when compared with placebo. However, rosuvastatin significantly increased fasting insulin and HbA1c levels and decreased adiponectin levels and insulin sensitivity. By contrast, pravastatin significantly increased adiponectin levels and insulin sensitivity and decreased insulin and HbA1c levels. Thus, while significantly reducing lipoprotein profiles, rosuvastatin had deleterious effects on metabolic parameters, but pravastatin had beneficial metabolic effects in hypercholesterolemic patients while less reducing lipoprotein profiles. Due to reciprocal relationships between endothelial dysfunction and insulin resistance [3–5], we hypothesized that improvements in endothelial dysfunction may be accompanied by simultaneous improvement in metabolic parameters. However, rosuvastatin significantly reduced

Fig. 2. A. Rosuvastatin and pravastatin significantly reduced total cholesterol (mean % changes; 31 and 23%) and LDL cholesterol (44 and 33%) from baseline (both P b 0.001) after 2 month administration. And these effects of rosuvastatin and pravastatin were also significant when compared with placebo (P b 0.001 by ANOVA). Pl= placebo, R10 = rosuvastatin 10 mg, P40 = pravastatin 40 mg. Standard error of the mean is identified by the bars. B. Rosuvastatin and pravastatin significantly improved flow-mediated dilator response to hyperemia (FMD) (mean % changes; 79 and 77%) after 2 month therapy when compared with baseline (both P b 0.001). All of these effects were also significant when compared with placebo (P b 0.001 by ANOVA). Rosuvastatin significantly increased insulin levels (mean % changes; 28%) after 2 month therapy when compared with baseline (P = 0.005). Pravastatin significantly reduced insulin levels after 2 month therapy (mean % changes; 8%) when compared with baseline (P = 0.042). The effects of rosuvastatin treatment to raise fasting insulin levels were significant when compared with pravastatin treatment (P = 0.002 by ANOVA on Ranks). Pl = placebo, R10 = rosuvastatin 10 mg, P40 = pravastatin 40 mg. Standard error of the mean is identified by the bars. C. Rosuvastatin significantly decreased plasma adiponectin levels (P = 0.010), insulin sensitivity (P = 0.007), and increased HbA1c levels (P = 0.038) when compared with baseline. Pravastatin significantly increased plasma adiponectin levels (P = 0.006), insulin sensitivity (P = 0.005) and decreased HbA1c levels (P = 0.019) when compared with baseline. Moreover, these effects of pravastatin were significant when compared with either placebo or rosuvastatin (P = 0.003 for adiponectin, P = 0.003 for QUICKI, and P = 0.010 for HbA1c by ANOVA). Pl = placebo, R10 = rosuvastatin 10 mg, P40 = pravastatin 40 mg. Standard error of the mean is identified by the bars.

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adiponectin levels and insulin sensitivity and increased insulin and HbA1c levels despite improvement of endothelium-dependent dilation in hypercholesterolemic patients. Further, there were no significant correlations between endothelial dysfunction and metabolic parameters. By contrast, pravastatin significantly increased adiponectin levels and insulin sensitivity with improvement of endothelium-dependent dilation in hypercholesterolemic patients. In previous studies with some drugs, improvement in endothelial dysfunction was accompanied by simultaneous improvement in insulin sensitivity and increased adiponectin levels [24–27]. One possible interpretation of this data is that not all mechanisms for improving endothelial dysfunction are tightly coupled to metabolic homeostasis. Alternatively, potential improvements in insulin sensitivity and adiponectin levels caused by improvement in endothelial function after rosuvastatin therapy may be masked by other endothelial-independent effects of rosuvastatin that worsen insulin resistance and lower adiponectin and increase HbA1c levels. The fact that some statins improve insulin sensitivity while others do not is consistent with this interpretation. In particular, lipophilic statins including simvastatin and atorvastatin cross the blood–brain barrier where they may exert central actions that have negative metabolic consequences. Pravastatin, a hydrophilic statin, would not suffer from this potential downside. Indeed, we recently demonstrated differential beneficial metabolic consequences of pravastatin relative to simvastatin in hypercholesterolemic patients [11]. Adiponectin is an adipose-derived factor that augments and mimics metabolic and vascular actions of insulin [23]. In our study, rosuvastatin and pravastatin therapies changed adiponectin levels in opposite directions. Because we did not measure fat mass change by fat CT scan, it might be possible that fat mass change is different in the two groups. However, both drugs may be directly altering adiponectin levels independent of adiposity because we looked at the different effects of rosuvastatin and pravastatin without a corresponding change in body mass index. Indeed, pravastatin enhances adiponectin secretion from 3T3-L1 adipocytes. Moreover, pravastatin treatment causes an increase in adiponectin mRNA levels and increases plasma levels of adiponectin in C57BL/6J mice (without body weight changes) that is associated with enhanced insulin sensitivity [32] and in the visceral adipose tissue in patients [33]. By contrast, rosuvastatin 2.5 mg does not increase production of adiponectin in the visceral adipose tissue in patients [33]. In the current study, we used rosuvastatin 10 mg dose, which increased the new onset of diabetes in the large scale clinical studies [34,35]. In humans, pravastatin therapy significantly increases plasma adiponectin levels and insulin sensitivity without a corresponding change in body mass index in patients with impaired glucose tolerance and coronary artery disease [17]. Pravastatin also significantly increases plasma adiponectin levels in samples from the WOSCOPS biobank [32] and significantly increases insulin sensitivity [11,16]. Decreasing adiponectin levels are predicted to worsen insulin sensitivity by multiple mechanisms [23,36,37]. In the current study, there were correlations between percent changes in adiponectin levels and percent changes in insulin or QUICKI before and following therapies. There may be additional mechanisms to reduce insulin sensitivity, adiponectin, and HbA1c levels following rosuvastatin therapies. Lovastatin treatment down-regulates expression of the insulin-responsive glucose transporter GLUT4 and up-regulates GLUT1 in 3T3-L1 adipocytes. This is associated with marked inhibition of insulin-stimulated glucose transport. Under these conditions, lovastatin had no effect on cell cholesterol levels but the adverse metabolic effects were reversed by mevalonate. This suggests that inhibition of isoprenoid biosynthesis causes insulin resistance in 3T3-L1 adipocytes [8]. By using isolated aorta from normocholesterolemic rats, investigators examined the effects of simvastatin, atorvastatin, or pravastatin on vascular smooth muscle responsiveness. Transient contraction caused by phenylephrine is inhibited by simvastatin and atorvastatin but not by pravastatin. These adverse effects of simvastatin and atorvastatin were reversed by mevalonate. Thus, inhibition of hydroxymethylglutaryl-CoA reductase

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with simvastatin or atorvastatin, but not pravastatin, has effects on vascular smooth muscle cell responsiveness that involve alteration of Ca2 + homeostasis through a mevalonate-dependent pathway [38]. Similar findings were reported in another study using a β-cell line, MIN6 cells, to demonstrate that high doses of simvastatin and atorvastatin, but not pravastatin, decrease insulin secretion, either due to hydroxymethylglutaryl-CoA reductase inhibition or cytotoxicity [39]. Other mechanism including potential CNS actions of lipophilic statins to impair glucose homeostasis may be an important factor. Also, statins may differentially alter glycemic control by decreasing various isoprenoids that enhance glucose uptake via GLUT4 in adipocytes and contribute to insulin release [40]. This speculation may be supported by the view that rosuvastatin is strongest in inhibiting hydroxymethylglutaryl-CoA reductase and the synthesis of various isoprenoids. Indeed, recent large scale clinical studies have demonstrated that rosuvastatin dosedependently increases the rate of onset of new diabetes (hazard ratios 1.10, 1.14, 1.26) [22,34,35]. Analysis of data pooled from clinical trials shows that intensive-dose statin therapy increases risk of new-onset diabetes when compared with moderate-dose therapy [14,15]. In our study, rosuvastatin 10 mg increased small absolute HbA1c levels from 5.73 to 5.79%, but significantly when compared with baseline. Therefore, we expect rosuvastatin 20 mg and 40 mg would significantly increase more absolute HbA1c levels, which may be clinically important. To determine whether individual statins have differential effects on insulin sensitivity in patients without pre-existing diabetes mellitus, a systematic review and meta-analysis was conducted [41]. Trials were included if they compared pravastatin, atorvastatin, rosuvastatin or simvastatin to placebo/control, excluded patients with diabetes, and reported data on insulin sensitivity/resistance. Insulin sensitivity data was pooled and evaluated as standardized mean differences (SMDs) and 95% confidence interval (CI) using a random-effects model. 16 studies (n= 1146) were included. When each statin was analyzed separately versus placebo/control, pravastatin significantly improved insulin sensitivity [SMD 0.342 (95% CI 0.032 to 0.621); P = 0.03], atorvastatin [SMD −0.019 (−0.243 to 0.205); P = 0.87] and rosuvastatin [SMD −0.037 (95% CI −0.223 to 0.148); P = 0.69)] tended to worsen insulin sensitivity, and simvastatin significantly worsened insulin sensitivity [SMD −0.321 (95% CI −0.526 to −0.117); P = 0.002]. When the studies comparing atorvastatin, rosuvastatin and simvastatin to placebo/ control were combined, a significant worsening of insulin sensitivity was seen [SMD −0.149 (95% CI −0.284 to −0.013); P = 0.03]. This demonstrates that statins do not have a ‘class effect’ on insulin sensitivity in patients without diabetes. Thus, differences between individual statins likely exist that may partially explain the findings of previously conducted meta-analyses examining the impact of statins on the development of diabetes. A recent meta-analysis observed that statin treatment significantly increases the risk of new onset diabetes with a hazard ratio 1.13 [42]. Another meta-analysis of randomized controlled trials suggests potential differences between individual statins, with pravastatin showing a trend towards a reduction in risk (RR 0.84) and atorvastatin, rosuvastatin and simvastatin together demonstrating a significant increase in risk (RR 1.14) versus placebo [43]. A recent meta-analysis reports that statin therapy is associated with a 9% increase in risk for incident diabetes and little heterogeneity between trials. Risk of development of diabetes with statins was highest in trials with older participants [13]. However, trials with pravastatin reduce development of diabetes in participants below mean age of 65 years old. Further, only pravastatin tended to be in heterogeneity (P = 0.090). We investigated whether changes in plasma levels of adiponectin, insulin, insulin resistance, or HbA1c were related to age in the current and our previous studies [10–12]. There were no data showing that elderly patients significantly increased insulin, insulin resistance, or HbA1c levels or decreased adiponectin levels following statin therapies. Also, although the meta-analysis failed to show a significant relationship between magnitude of LDL cholesterol reduction and

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development of diabetes, there was a strong trend that the occurrence of diabetes was more frequent with greater reductions in LDL cholesterol levels (P = 0.10) [13]. Therefore, while beneficial effects of lowering LDL cholesterol have been substantiated in multiple clinical trials, there remains uncertainty regarding optimal LDL cholesterol targets. Moreover, understanding risks of specific statins including cancer, type 2 diabetes, insulin resistance, myopathy, and liver toxicity is of great clinical importance as physicians and patients balance risk versus benefit for optimal personalized healthcare. Recent randomized clinical trials raise important caveats to understand when considering aggressive lowering of lipids by specific statins [44]. In summary, rosuvastatin significantly increased fasting insulin and HbA1c levels and decreased adiponectin levels and insulin sensitivity. By contrast, pravastatin significantly increased adiponectin levels and insulin sensitivity and decreased insulin and HbA1c levels. Cardiovascular complications in patients with diabetes are clearly determined, in part, by the degree of hyperglycemia (measured clinically with the use of HbA1c) [45,46]. While significantly reducing lipoprotein profiles, rosuvastatin therapy had deleterious metabolic effects in hypercholesterolemic patients when compared with pravastatin therapy, that may be clinically relevant in patients prone to metabolic diseases. However, there is a demonstrated relationship between cardiovascular outcomes and the magnitude of the reduction in LDL cholesterol, the impression of both sides — a greater hazard and benefit with rosuvastatin should be highlighted. Disclosures M.J. Quon is a member of the Merck Speaker Bureau. Acknowledgment This study was supported by grants from established investigator award (2008-1, 2009-1) (K.K. Koh), Gachon University Gil Hospital and by the Intramural Research Program, National Center for Complementary and Alternative Medicine, National Institutes of Health (M.J. Quon). The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology. References [1] Sacks FM, Tonkin AM, Shepherd J, et al. Effect of pravastatin on coronary disease events in subgroups defined by coronary risk factors: the Prospective Pravastatin Pooling Project. Circulation 2000;102:1893–900. [2] Park H-W, Kwon TG, Kim K-Y, Bae J-H. Diabetes, insulin resistance and atherosclerosis surrogates in patients with coronary atherosclerosis. Korean Circ J 2010;40: 62–7. [3] Kim J, Koh KK, Quon MJ. The union of vascular and metabolic actions of insulin in sickness and in health. Arterioscler Thromb Vasc Biol 2005;25:889–91. [4] Kim J, Montagnani M, Koh KK, Quon MJ. Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms. Circulation 2006;113:1888–904. [5] Han SH, Quon MJ, Koh KK. Reciprocal relationships between abnormal metabolic parameters and endothelial dysfunction. Curr Opin Lipidol 2007;18:58–65. [6] Koh KK. Effects of statins on vascular wall: vasomotor function, inflammation, and plaque stability. Cardiovasc Res 2000;47:648–57. [7] Yada T, Nakata M, Shiraishi T, Kakei M. Inhibition by simvastatin, but not pravastatin, of glucose-induced cytosolic Ca2 + signalling and insulin secretion due to blockade of L-type Ca2 + channels in rat islet beta-cells. Br J Pharmacol 1999;126:1205–13. [8] Chamberlain LH. Inhibition of isoprenoid biosynthesis causes insulin resistance in 3T3-L1 adipocytes. FEBS Lett 2001;507:357–61. [9] Kanda M, Satoh K, Ichihara K. Effects of atorvastatin and pravastatin on glucose tolerance in diabetic rats mildly induced by streptozotocin. Biol Pharm Bull 2003;26:1681–4. [10] Koh KK, Quon MJ, Han SH, et al. Simvastatin improves flow-mediated dilation, but reduces adiponectin levels and insulin sensitivity in hypercholesterolemic patients. Diabetes Care 2008;31:776–82. [11] Koh KK, Quon MJ, Han SH, et al. Differential metabolic effects of pravastatin and simvastatin in hypercholesterolemic patients. Atherosclerosis 2009;204:483–90.

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