Endothelial Effect of Statin Therapy at a High Dose Versus Low Dose Associated with Ezetimibe

Garcia, Maristela Magnavita Oliveira; Varela, Carolina Garcez; Silva, Patricia Fontes; Lima, Paulo Roberto Passos; Góes, Paulo Meira; Rodrigues, Marilia Galeffi; Silva, Maria de Lourdes Lima Souza e; Ladeia, Ana Marice Teixeira; Guimarães, Armênio Costa; Correia, Luis Claudio Lemos

doi:10.5935/abc.20160048

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Original Articles, Atherosclerosis/Endothelium/Vascular • Arq. Bras. Cardiol. 106 (4) • Apr 2016 • https://doi.org/10.5935/abc.20160048 copy

Endothelial Effect of Statin Therapy at a High Dose Versus Low Dose Associated with Ezetimibe

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Background:

The effect of statins on the endothelial function in humans remains under discussion. Particularly, it is still unclear if the improvement in endothelial function is due to a reduction in LDL-cholesterol or to an arterial pleiotropic effect.

Objective:

To test the hypothesis that modulation of the endothelial function promoted by statins is primarily mediated by the degree of reduction in LDL-cholesterol, independent of the dose of statin administered.

Methods:

Randomized clinical trial with two groups of lipid-lowering treatment (16 patients/each) and one placebo group (14 patients). The two active groups were designed to promote a similar degree of reduction in LDL-cholesterol: the first used statin at a high dose (80 mg, simvastatin 80 group) and the second used statin at a low dose (10 mg) associated with ezetimibe (10 mg, simvastatin 10/ezetimibe group) to optimize the hypolipidemic effect. The endothelial function was assessed by flow-mediated vasodilation (FMV) before and 8 weeks after treatment.

Results:

The decrease in LDL-cholesterol was similar between the groups simvastatin 80 and simvastatin 10/ezetimibe (27% ± 31% and 30% ± 29%, respectively, p = 0.75). The simvastatin 80 group presented an increase in FMV from 8.4% ± 4.3% at baseline to 11% ± 4.2% after 8 weeks (p = 0.02). Similarly, the group simvastatin 10/ezetimibe showed improvement in FMV from 7.3% ± 3.9% to 12% ± 4.4% (p = 0.001). The placebo group showed no variation in LDL-cholesterol level or endothelial function.

Conclusion:

The improvement in endothelial function with statin seems to depend more on a reduction in LDL-cholesterol levels, independent of the dose of statin administered, than on pleiotropic mechanisms.

Keywords:
Endothelium / physiology; Cholesterol; Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use; Ezetimibe; Anticholesterolemic Agents

	Simvastatin 80	Simvastatin 10/Ezetimibe	Placebo	p
Sample	16	16	14
Age (years)	41 ± 8.6	48 ± 8.1	40 ± 12	0.05
BMI (kg/m²)	35 ± 4.3	36 ± 4.4	36 ± 8.6	0.90
Waist circumference (cm)	107 ± 7.6	108 ± 9.9	107 ±17	0.94
Waist/hip	0.92 ± 0.71	0.92 ± 0.67	0.91 ± 0.56	0.84
SBP (mmHg)	133 ± 15	132 ± 18	130 ± 18	0.86
DBP (mmHg)	85 ± 9	86 ± 13	81 ± 14	0.52
Total cholesterol (mg/dL)	205 ± 29	225 ± 47	206 ± 33	0.26
HDL-cholesterol (mg/dL)	49 ± 11	52 ± 12	49 ± 11	0.75
LDL-cholesterol (mg/dL)	133 ± 26	149 ± 43	136 ± 27	0.50
Triglycerides (mg/dL)	125 ± 51	121 ± 67	115 ± 41	0.46
CRP (mg/dL)	3.9 (2.1 – 8.1)	3.0 (1.8 – 5.1)	3.3 (1.2 – 7.2)	0.70
Blood glucose (mg/dL)	96 ± 12	103 ± 24	94 ± 19	0.39
Urea (mg/dL)	29 ± 7.3	29 ± 8.3	26 ± 6	0.42
Creatinine (mg/dL)	0.83 ± 0.11	0.79 ± 0.12	0.85 ± 0.18	0.55
AST (U/L)	18 ± 5.1	20 ± 4.6	20 ± 11	0.71
ALT (U/L)	18 ± 5.1	20 ± 4.6	20 ± 11	0.71
GGT (U/L)	32 ± 11.74	42 ± 22.99	42 ± 23.70	0.27
CPK (mg/dL)	123 ± 60	168 ± 88	109 ± 62	0.07
Hypertension	5 (31%)	6 (38%)	8 (57%)	0.33
ACEi	2 (13%)	0 (0%)	4 (29%)	0.07
ARB	1 (6.3%)	2 (13%)	2 (14%)	0.75
Menopause	1 (6.3%)	4 (25%)	2 (14%)	0.33
Smoking	0 (6.3%)	1 (6.3%)	0 (0%)	0.38
Sedentary lifestyle	11 (69%)	8 (50%)	8 (57%)	0.55
Low-calorie diet	6 (38%)	7 (44%)	6 (43%)	0.93
Diabetes	0 (0%)	1 (6.3%)	3 (21%)	0.10
Coffee consumption	14 (88%)	14 (88%)	12 (86%)	0.99
FMV	8.4% ± 4.3%	7.6% ± 3.9%	9.8% ± 4.5%	0.31

Characteristics	Follow-up (weeks)	Treatment groups
Characteristics	Follow-up (weeks)	Simvastatin 80	Simvastatin 10/Ezetimibe	Placebo	p
BMI (kg/m²)	4 8	35 ± 4.3 34 ± 4.4	35 ± 4.4 35 ± 4.3	35 ± 6.6 36 ± 9.3	0.87 0.77
SBP (mmHg)	4 8	133 ± 13.5 133 ± 14.5	132 ± 15.3 133 ± 15.5	130 ± 15.71 32 ± 15.1	0.84 0.82
DBP (mmHg)	48	86 ± 7.3 84 ± 9.4	83 ± 9.3 84 ± 9.4	81 ± 12 81 ± 12	0.39 0.49
HDL-cholesterol (mg/dL)	4 8	49 ± 9.8 51 ± 12	53 ± 14 52 ± 13	52 ± 14 50 ± 8	0.76 0.89
Triglycerides (mg/dL)	4 8	91 ± 29 99 ± 39	124 ± 60 122 ± 73	132 ± 38 127 ± 52	0.30 0.34
Blood glucose (mg/dL)	4 8	93 ± 11 95 ± 10	102 ± 22 102 ± 18	111 ± 54 103 ± 32	0.28 0.32
Urea (mg/dL)	4 8	31 ± 5.0 29 ± 6.3	28 ± 4.7 28 ± 6.4	28 ± 4.7 27 ± 5.3	0.30 0.43
Creatinine (mg/dL)	4 8	0.84 ± 0.14 0.82 ± 0.12	0.85 ± 0.15 0.80 ± 0.12	0.78 ± 0.12 0.87 ± 0.19	0.42 0.37
AST (U/L)	4 8	17 ± 4 19 ± 5	22 ± 9 23 ± 10	17 ± 7 18 ± 5	0.17 0.17
ALT (U/L)	4 8	17 ± 6 21 ± 8	26 ± 15 25 ± 12	17 ± 10 18 ± 10	0.12 0.17
GGT (U/L)	4 8	31 ± 9.3 32 ± 11.1	41 ± 18.8 38 ± 15.3	44 ± 30.8 42 ± 33.1	0.32 0.53
CPK (mg/dL)	4 8	136 ±64 155 ± 84	185 ± 127 195 ± 118	103 ± 60 120 ± 67	0.12 0.10
CRP (mg/dL)	4 8	3.3 (2.1 – 6.4) 2.9 (1.9 – 8.3)	2.0 (1.7 – 4.2) 2.0 (1.6 – 4.2)	4.0 (2.4 – 8.2) 4.4 (2.7 – 8.3)	0.19 0.43

	Baseline	8 Weeks	p	4 Weeks	p (4 versus8 weeks)
Simvastatin 80
LDL-cholesterol (mg/dL)	133 ± 26	95 ± 44	0.006	72 ± 23	0.15
Total cholesterol (mg/dL)	205 ± 29	166 ± 48	0.007	141 ± 26	0.12
HDL-cholesterol (mg/dL)	49 ± 11	51 ± 12	0.48	49 ± 9.8	0.97
Triglycerides (mg/dL)	125 ± 51	99 ± 39	0.01	91 ± 29	0.26
Blood glucose (mg/dL)	96 ± 12	95 ± 10	0.88	93 ± 11	0.28
Simvastatin 10/Ezetimibe
LDL-cholesterol (mg/dL)	149 ± 43	100 ± 45	< 0.001	97 ± 49	0.90
Total cholesterol (mg/dL)	226 ± 51	176 ± 54	< 0.001	169 ± 52	0.83
HDL-cholesterol (mg/dL)	54 ± 12	52 ± 13	0.98	53 ± 14	0.39
Triglycerides (mg/dL)	121 ± 67	122 ± 73	0.08	124 ± 60	0.52
Blood glucose (mg/dL)	103 ± 24	102 ± 18	0.28	102 ± 22	0.65
Placebo
LDL-cholesterol (mg/dL)	136 ± 27	137 ± 29	0.80	123 ± 30	0.21
Total cholesterol (mg/dL)	206 ± 33	212 ± 31	0.79	201 ± 35	0.32
HDL-cholesterol (mg/dL)	49 ± 11	50 ± 8	0.39	52 ± 14	0.50
Triglycerides (mg/dL)	115 ± 41	127 ± 52	0.27	132 ± 38	0.48
Blood glucose (mg/dL)	94 ± 19	103 ± 32	0.06	111 ± 54	0.40

	Baseline	4 Weeks	p	8 Weeks	p
Simvastatin 80
Body mass index (kg/m²)	35 ± 4.3	35 ± 4.3	0.51	34 ± 4.4	0.19
Aspartate aminotransferase (U/L)	18 ± 5.1	17 ± 4	0.73	19 ± 5	0.50
Alanine aminotransferase (U/L)	18 ± 5.1	17 ± 6	0.90	21 ± 8	0.05
Creatine phosphokinase (mg/dL)	123 ± 60	136 ±64	0.04	155 ± 84	0.03
CRP (mg/dL)	3.9 (2.1 - 8.1)	3.3 (2.1 - 6.4)	0.14	2.9 (1.9 - 8.3)	0.65
Simvastatin 10/Ezetimibe
Body mass index (kg/m²)	36 ± 4.4	35 ± 4.4	0.63	35 ± 4.3	0.27
Aspartate aminotransferase (U/L)	20 ± 4.6	22 ± 9	0.42	23 ± 10	0.22
Alanine aminotransferase (U/L)	20 ± 4.6	26 ± 15	0.21	25 ± 12	0.03
Creatine phosphokinase (mg/dL)	168 ± 88	185 ± 127	0.30	195 ± 118	0.11
CRP (mg/dL)	3.0 (1.8 – 5.1)	2.0 (1.7 – 4.2)	0.55	2.0 (1.6 – 4.2)	0.66
Placebo
Body mass index (kg/m²)	36 ± 8.6	35 ± 6.6	0.23	36 ± 9.4	0.81
Aspartate aminotransferase (U/L)	20 ± 11	17 ± 7	0.59	18 ± 5	0.24
Alanine aminotransferase (U/L)	20 ± 11	17 ± 10	0.20	18 ± 10	0.12
Creatine phosphokinase (mg/dL)	109 ± 62	103 ± 60	0.17	120 ± 67	0.25
CRP (mg/dL)	3.3 (1.2 – 7.2)	4.0 (2.4 – 8.2)	0.43	4.4 (2.7 – 8.3)	0.11

	Baseline	8 Weeks	p	4 Weeks	p
Simvastatin 80
FMV (%)	8.4 ± 4.3	11 ± 4.2	0.02	8.6 ± 3.6	0.03
FMV variation		+ 39% (2.2% – 105%)		+ 27% (-13% – 63%)	0.09
Simvastatin 10/Ezetimibe
FMV (%)	7.3 ± 3.9	12 ± 4.4	0.001	9.1 ± 4.3	0.03
FMV variation		+ 41% (13% – 227%)		+ 25% (-4% – 92%)
Placebo
FMV (%)	9.8 ± 4.5	10 ± 4	0.28	11 ± 2.2	0.93
FMV variation		+ 9% (-6.6% – 56%)		+13% (-8% – 31%)

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