Effects of simvastatin and ezetimibe on interleukin-6 and high-sensitivity C-reactive protein

Figures & data

Table I. Baseline characteristics of the randomized patients.*

Parameter	All (n = 72)	Simvastatin (n = 24)	Ezetimibe (n = 24)	Ezetimibe plus simvastatin (n = 24)	P-value
Age (years)	31.5 ± 9.2	31.9 ± 8.8	28.6 ± 6.6	34.1 ± 11.2	0.11†
Height (cm)	181 ± 7	182 ± 6	181 ± 7	181 ± 7	0.84†
Weight (kg)	85 ± 12	87 ± 12	82 ± 11	84 ± 12	0.28†
Body mass index (kg/m^2)	25.7 ± 3.2	26.4 ± 3.2	25.0 ± 3.3	25.8 ± 3.1	0.35†
Smoker (n) Current smoker Former smoker Never smoker	21 (29%) 9 (13%) 42 (58%)	8 (33%) 2 (8%) 14 (58%)	7 (29%) 4 (17%) 13 (54%)	6 (25%) 3 (13%) 15 (63%)	0.90‡
Inflammation markers
Interleukin-6 (ng/l)	0.72 (0.57)	0.81 (0.63)	0.70 (0.56)	0.58 (0.67)	0.43†
High-sensitivity C-reactive protein (mg/l)	0.40 (0.65)	0.53 (1.1)	0.43 (0.71)	0.30 (0.42)	0.054†
Ratio hsCRP/IL-6 (mg/ng)	0.68 (1.61)	0.87 (2.22)	0.69 (0.66)	0.58 (1.56)	0.23†
Glucose and lipid metabolism
Fasting blood glucose (mmol/l)	4.9 ± 0.4	4.8 ± 0.4	4.8 ± 0.3	4.9 ± 0.5	0.34†
Fasting insulin (mU/l)	8.0 (3.9)	8.3 (3.6)	7.9 (3.4)	8.3 (5.3)	0.91†
HOMA index	1.73 (1.05)	1.62 (1.15)	1.68 (0.76)	1.93 (1.23)	0.84†
LDL cholesterol (mg/dl)	111 ± 30	113 ± 30	105 ± 23	116 ± 35	0.59†
Adipokines
Resistin (ng/ml)	13.3 (5.3)	12.0 (5.7)	14.4 (7.0)	13.4 (4.0)	0.74†
Adiponectin (μg/ml)	13.2 (18.7)	15.1 (9.0)	12.6 (11.4)	14.1 (6.0)	0.83†
High molecular weight adiponectin (μg/ml)	2.1 (2.3)	2.2 (2.7)	2.2 (2.4)	2.0 (1.6)	0.99†
Leptin (μg/ml)	2.0 (2.0)	2.6 (2.7)	1.9 (1.3)	2.0 (2.4)	0.38†
Hormones
Thyroid stimulating hormone (mU/l)	1.6 (0.8)	1.5 (0.7)	1.6 (0.8)	1.7 (0.9)	0.42†
Free triiodothyronine (ng/l)	3.7 ± 0.4	3.7 ± 0.5	3.7 ± 0.4	3.8 ± 0.4	0.70†
Free thyroxine (ng/l)	13.7 ± 1.7	13.5 ± 1.6	14.3 ± 1.7	13.3 ± 1.6	0.09†
Body composition
BIA body fat (%)	21.4 ± 5.7	22.5 ± 5.7	20.6 ± 5.4	21.1 ± 6.2	0.48†
BIA lean body mass (%)	66.0 ± 6.4	67.2 ± 6.0	64.7 ± 6.7	66.1 ± 6.4	0.38†
BIA ratio ECM/BCM	0.82 ± 0.09	0.81 ± 0.08	0.81 ± 0.08	0.83 ± 0.10	0.69†
BIA phase angle	6.7 ± 0.6	6.8 ± 0.6	6.8 ± 0.6	6.7 ± 0.7	0.76†
Other parameters
Blood neutrophils (10^3/μl)	2.6 (0.9)	2.9 (1.2)	2.6 (0.7)	2.6 (0.8)	0.36†
Creatinine (μmol/l)	85 ± 10.6	85 ± 11.5	85 ± 11.5	85 ± 9.7	0.98†

BIA, bioelectrical impedance analysis.

*Data are means ± SD or medians (interquartile range).

†P values were calculated by analysis of variance (ANOVA), in case of non-normally distributed values using the log-transformed values.

‡P values were calculated by Fisher's exact test.

Table II. Spearman's rank correlation coefficients between baseline parameters.

	IL-6	Ratio hsCRP/IL-6	Neutro	Age	BMI	HOMA index	% body fat	% lean body mass	Ratio ECM/BCM	Leptin	HMW adiponectin	Creatinine	fT3	fT4
hsCRP	0.33***	0.67****	0.39****	0.30***	0.57****	0.18	0.54****	0.36***	−0.08	0.55****	−0.26**	0.22*	0.11	0.01
IL-6		−0.40****	0.37***	0.08	0.23*	0.08	0.23*	0.27**	0.03	0.22*	0.02	−0.05	0.13	0.04
Ratio hsCRP/IL-6			0.07	0.22*	0.37***	0.05	0.33***	0.15	−0.06	0.36***	−0.28**	0.24**	−0.09	−0.007
Neutro				0.30***	0.30**	0.10	0.21*	0.30***	0.05	0.26**	−0.02	0.07	0.13	0.01
Age					0.40****	0.02	0.23*	0.37***	0.07	0.26**	−0.20*	0.12	−0.14	−0.33***
BMI						0.25**	0.75****	0.67****	−0.34***	0.77****	−0.40****	0.21*	0.07	−0.01
HOMA index							0.40****	0.006	−0.07	0.45****	−0.08	0.04	−0.10	−0.24**
% body fat								0.35***	−0.12	0.80****	−0.32***	0.09	0.03	−0.20*
% lean body mass									−0.16	0.36***	−0.20	0.19	0.18	0.02
Ratio ECM/BCM										−0.11	0.26**	−0.05	−0.27**	−0.17
Leptin											−0.35***	0.19	0.05	−0.21*
HMW adiponectin												−0.09	0.11	0.11
Creatinine													−0.08	−0.003
fT3														0.36***

The data represent measurements at baseline.

hsCRP, high-sensitivity C-reactive protein; IL-6, interleukin-6; neutro, blood neutrophil count; BMI, body mass index; HOMA, homeostasis model assessment; ECM, extracellular mass; BCM, body cell mass; HMW, high-molecular weight; fT3, free triiodothyronine; fT4, free thyroxine.

*P < 0.1; **P< 0.05; ***P< 0.01; ****P<0.001.

Figure 1. Baseline serum levels of interleukin-6 (upper panels) and high-sensitivity C-reactive protein (lower panels) in healthy male subjects (N = 24 per group) before and after treatment with (A) simvastatin 40 mg/day, (B) ezetimibe 10 mg/day or (C) simvastatin 40 mg/day + ezetimibe 10 mg/day.

Table III. Effects of treatment on main outcome parameters. Data are medians (interquartile range).

Parameter	Treatment (N = 24 in each group)	Baseline	2-weeks	Median percent difference (IQR)	Unadjusted P-value*	Multivariable adjusted P-value**
Interleukin-6 (ng/l)	Simvastatin	0.81 (0.58 to 1.21)	0.615 (0.36 to 1.155)	−21.8 (−43.3 to ± 0)	0.10	0.008
	Ezetimibe	0.70 (0.31 to 0.865)	0.55 (0.26 to 0.845)	−5.3 (−36.1 to +30.4)	0.68
	Simvastatin +ezetimibe	0.58 (0.345 to 1.01)	0.79 (0.45 to 1.13)	+14.9 (−15.2 to +85.9)	0.30
High-sensitivity C-reactive protein (mg/l)	Simvastatin	0.53 (0.28 to 1.38)	0.46 (0.24 to 1.49)	−30.1 (−43.7 to +18.8)	0.068	0.1
	Ezetimibe	0.43 (0.11 to 0.82)	0.61 (0.21 to 1.13)	+9.4 (−22.3 to +107)	0.67
	Simvastatin +ezetimibe	0.30 (0.22 to 0.64)	0.30 (0.20 to 0.67)	+0.6 (−29.6 to +49.3)	0.53
Ratio hsCRP/IL-6 (mg/ng)	Simvastatin	0.87 (0.30 to 2.53)	0.82 (0.37 to 2.37)	+13.4 (−33.2 to +81.7)	0.49	0.12
	Ezetimibe	0.69 (0.39 to 1.05)	0.94 (0.46 to 1.85)	+19.8 (−0.4 to +55.3)	0.032
	Simvastatin +ezetimibe	0.58 (0.31 to 1.86)	0.50 (0.23 to 1.10)	+4.2 (−38.2 to +53.7)	0.95

*Wilcoxon signed rank test.

**Generalized linear model, adjusted for age, BMI, body fat, lean body mass, neutrophil count, HOMA, leptin, HMW adiponectin, resistin, creatinine, TSH, fT3, fT4, and the respective baseline values of IL-6, hsCRP, and the ratio of hsCRP to IL-6.