Effect of atorvastatin on lipid parameters, LDL subtype distribution, hemorrheological parameters and adhesion molecule concentrations in patients with hypertriglyceridemia

Nutr Metab Cardlovasc Dis (2003) 13:87-92

87

ORIGINAL ARTICLE

Effect of atorvastatin on fipid parameters, LDL subtype distribution, hemorrheological parameters and adhesion molecule concentrations in patients with hypertriglyceridemia K. Empen, H.-C. Geiss, M. Lehrke, C. Otto, P. Schwandt, and K.G. Parhofer Medical Department II, Ludwlg-Maxlmilians-Umverslty,Munich, Germany

Abstract Background and Aim: Hypertriglyceridemia is a risk factor for atherosclerosis that is typtcally associated with high concentrations of adhesion molecules, impaired hemorrheology and an unfavourable low-density lipoprotein (LDL) subtype distribution. We hypothesised that some of these risk markers might be beneficially influenced by lipid-lowering therapy with atorvastatin in hypertriglyceridemic patients. Methods and Results: Nineteen patients with primary hypertriglyceridemia were given I0 mg of atorvastatin per day for four weeks. Their cholesterol, triglyceride, LD L and high-density lipoprotein cholesterol (HDL-C) levels, LDL subtype profile, hemorrheological parameters and Eselectin, vascular cell adhesion molecule-1 and intercellular adheston molecule-I concentrations were measured before and at the end of atorvastatin therapy. The levels of total and LDL cholesterol respectively decreased by 25% and 24% (both p
Key words E-selectln, ICAM-1, VCAM-1, viscosity Correspondence to K.G. Parhofer, M D., Medical Department II, Khmkum Grosshadern, D-81366Munchen, Germany E-mad [email protected] Recewed 19 December 2002, accepted" 24 January 2003

and 16% (both p
Introduction Hypertriglyceridemia is associated with low high-density lipoprotein cholesterol (HDL-C) concentrations (1), high plasma viscosity (2), a predominance of small-dense lowdensity lipoproteins (LDLs) (3, 4), and increased adhesion molecule concentrations (5-7). Epidemiological studies have found that these cardiovascular risk markers are associated with cardiovascular morbidity and mortality. The association of a predominance of small-dense LDLs, low HDL-C concentrations, and high triglyceride levels is common in the atherogenic lipoprotein phenotype (1) and diabetic dyslipoproteinemia (8). Apart from these interrelationships, a meta-analysis has shown that hypertriglyceridemia is an independent cardiovascular risk factor (9), and primary (10) and secondary (11) prevention trials have shown that triglyceride-lowering fibrate treatment reduces the incidence of cardiovascular endpoints. The beneficial

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effect was greatest in the patients with the highest triglyceride levels, but it is not known whether it is mediated by triglyceride lowering per se or by an improvement in the associated risk factor profile. 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase inhibitors have been found to reduce cardiovascular mortality in primary (12) and secondary (13) prevention trials and, in cases of hypercholesterolemia, their use is associated with beneficial effects on triglyceride (12,13) and adhesion molecule concentrations (6). As atorvastatin seems to be more efficacious than other HMG CoA reductase inhibitors in lowering triglyceride levels (14), we investigated its effects on the LDL subtype profile, hemorrheological parameters and adhesion molecule concentrations in patients with primary hypertriglyceridemia.

Methods Study population Nineteen patients (five women and 14 men aged 49+14 years; body mass index 27.4_+4.5 Kg/m 2) were recruited from the outpatient clinic of Medical Department II, University of Munich. All of them had primary hypertriglyceridemia (triglycerides >200 mg/dL) insufficiently responsive to dietary therapy. The exclusion criteria were clinical evidence of secondary hypertriglyceridemia (eg diabetes meltitus, hypothyroidism, nephrotic syndrome), a medical history of statin incompatibility, LDL-cholesterol (LDL-C) >160 mg/dL or any acute illness. All of the patients received 10 mg of atorvastatin daily at bedtime for four weeks. Blood samples were drawn before and after the treatment period. The study was approved by the Ethics Committee of the Ludwig-Maximilians-University, Munich, and all of the patients gave their informed consent. Laboratory measurements After an overnight fast, venous blood was collected in EDTA tubes and heparinised tubes for E-selectin assessment. Cholesterol, triglyceride, HDL-C, LDL-C, very low-density lipoprotein (VLDL)-cholesterol and VLDL-triglyeeride levels were determined as previously described (15). Fibrinogen concentrations were measured in deep-frozen plasma by means of nephelometry (Behringwerke, Marburg, Germany) using specific antibodies. To avoid assay drift, these measurements were made in one assay at the end of the study. LDL-subtype distribution was determined by isolating LDL subfractions using isopycnic density gradient ultracentrifugation (Beckmann SW 40 Ti rotor; 40,000 rpm; 48 hours;

15°C) as previously described (15). The cholesterol concentration was measured in each LDL subfraction. The seven LDL-subfractlons (LDL1-LDL7) were pooled to measure large-buoyant LDL (LDLI+LDL2, 1.020-1.029 g/mL); intermediate-dense LDL (LDL3+LDL4, 1.030-1.040 g/mL); and small-dense LDL (LDL5+LDL6+LDL7, 1.041-1.066 g/mL). Hematocrit was determined after centrifugation in a capillary hematocrit centrifuge (Hettlch, Tuttlingen, Germany). The viscosity and red blood cell aggregation measurements were made within four hours of blood sampling. Plasma viscosity and blood viscosity were measured at 37°C using a Contraves 30 low shear rotation viscosimeter (Contraves AG, Zurich, Switzerland) at continuously increasing shear rates from 1/s to 115/s. The temperature was kept at a constant 37°C by means of an automatic heating control unit. The shear rates were recorded by a scanner integrated in the viscosimeter. Blood viscosity was determined for native hematocrit (native blood viscosity) as well as after standardlsation to a hematocrlt level of 0.45 with autologous plasma or erythrocytes (standardised blood viscosity). Red blood cell aggregation was determined photometrically at native and standardised hematocrit levels using an erythrocyte aggregometer (Myrenne GmbH, Roetgen, Germany). The measurements were made at stasis and low shear (3/s). The levels of E-selectin, vascular cell adhesion molecule1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) were assessed using commercially available enzyme-linked immunosorbent assay kits (R&D Systems, Wiesbaden, Germany) and a photometer (Sunrise, Tecan, Crailsheim, Germany) at 450 rim. To exclude any bias due to inter-assay variability, the measurements were made in one session after the end of the study.

Statistical analysis The statistical procedures were performed using the current SPSS version 10.0 (SPSS Inc., Chicago, IL). The pre- and post-therapy values were compared using Wilcoxon's test for paired samples. The correlation coefficients between two sets of quantitative data were obtained using Pearson's or Spearman's algorithm. A two-sided probability value <0.05 was considered significant for all of the analyses. Results Baseline values The patients had a typical primary hypertriglyceridemia lipid pattern: high triglyceride and low HDL-C levels, and a

Atorvastatin in hypertnglycendemta

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p<0.05, standardised blood viscosity r=-0.59, p<0.01), and positively correlated with erythrocyte deformability (r=0.54,p<0.05). Fibrinogen concentrations correlated positively with total cholesterol (r=0.51, p<0.05) and triglyceride levels (r=0.75, p<0.001), and plasma viscosity (r=0.68, p<0.01), and negatively with HDL-C levels (r=-0.56, p<0.05). VCAM-1 concentrations positively correlated with fibrinogen concentrations (r=0.60, p<0.05). ICAM-1 levels showed a negative association with triglyceride and total cholesterol levels (r--0.47 and -0.57,p<0.05). E-selectin concentrations had a negative association with VCAM-1 levels (r=-0.66, p<0.01).

TABLE 1

Lipid parameters of 19 hypertnglyceridemlcpatients before and during therapy with atorvastatin 10 mg/day.All of the data are expressed as mean values_+SDexceptfor tnglycerides,whichare gwen as median values (range) becauseof their skeweddistribution. (mg/dL)

Before

During

Change

Cholesterol

252±54

190±50

-25% ***

350 (206-2109)

272 (115-1111)

-9%

HDL-C

34±9

34±9

-1%

LDL-C

109±28

79±25

-24% ***

16±7

10±3

-28% **

Intermediate-dense LDL-C 36±15

28±12

-11% **

Small, dense LDL-C

41±17

-27% ***

Triglycerides (medtan)

Large-buoyant LDL-C

58±18

**p<0 01, ***p<0 001

preponderance of small-dense LDL (53% of total LDL-C) (Table 1). The baseline hemorrheological parameters are shown in Table 2. Triglyceride concentrations correlated negatively with LDL-C (r=-0.53, p<0.05) and positively with plasma viscosity (r=0.61, p<0.01). HDL-C levels were negatively associated with plasma (r=-0.61, p<0.05), and blood viscosity (native blood viscosity at low and medium shear r=-0.52,

Changes during atorvastatin therapy Atorvastatin treatment significantly (p<0.001) reduced total cholesterol (-25%) and LDL-C (-24%), but had little effect on triglyceride concentrations (-9%, p=0.10). In two patients whose triglyceride levels decreased (by respectively 53% and 72%) we observed an increase in LDL-C (respectively from 48 to 63 mg/dL and from 87 to 128 mg/dL). Cholesterol was lowered in all seven LDL-subfractions (p<0.05), but the degree of the reduction in the individual LDL subfractions was not homogeneous, being respectively -28% and -27% in large-buoyant and smalldense LDL, but only -11% in intermediate-dense LDL (p=0.09, intermediate-dense vs large-buoyant and smalldense cholesterol). Atorvastatin therefore changed the LDL-subtype profile with a relative increase in intermedi-

Before

During

Change

Hematocrit

0 442+0 028

0.447+0.027

+2+5%

Plasma viscosity (mPas)

1 398+0 084

1 370±0 060

-2±2%*

351 ±95

328±76

-5±11%

SBV (shear 4/s) (mPas)

8 93±1 69

7 43±1 78

-16±26%*

SBV (shear 41/s) (mPas)

5 87±0 24

5.77±0 31

-1±7%

SBV (shear 113/s) (mPas)

4 95±0 17

4.88±0.22

-1 ±5%

RCA (stasts) (U)

6.13+1 41

6 22±1.16

+5+29%

RCA (3/s) (U)

11.11 +1 74

11 06±1 55

0±18%

RCD (30/s)

28.96±4 26

28 81 ±3.24

-3±11%

RCD (120/s)

46 00±4.35

45 85±3.36

-2±7%

RCD (600/s)

54.55±4 46

54 42±3 66

-1±5%

Fibnnogen (mg/dL)

SBV standardised blood viscosity, RCA red cell aggregatton, RCD red cell deformability * p<0 05

TABLE 2

Hemorrheologicalparameters of 19 patients with hypertriglyceridemla before and after four weeks' treatment with atorvastatm10 mg/day.

K Empen, etal

90

ate-dense LDL. Furthermore, there was a positive correlation between the relative change in triglycerides and the relative change in the small-dense LDL fraction (r=0.51, p<0.025). Plasma viscosity and standardised blood viscosity at low shear rates (4/s) were reduced (p<0.05) by respectively 2% and 16% (Table 2).The change in red cell deformability positively correlated with the reduction in LDL-C (r=0.6, p
Subgroup analysis Comparison of the patients whose triglyceride levels decreased during atorvastatin therapy (responders, n=12) with those whose triglyceride levels increased (non-responders, n=7) did not reveal any significant differences in terms of the changes in adhesion molecule concentrations and hemorrheological parameters. However, the reduction in fibrinogen concentrations tended to be greater in the responders than the non-responders (7_+13% vs 1_+5%, p=0.08). Furthermore, the responders showed an improvement in the LDL subtype profile with a relative increase in intermediate-dense LDL (+21%) and a relative decrease in small-dense LDL (-4%) (p<0.01 for difference), whereas the non-responders showed no significant change in subtype distribution. Lipid concentrations before and during treatment are shown in Table 3, stratified by the triglyceride response to atorvastatin therapy.

Discussion The 24% reduction in LDL-C observed in this study is within the range of the results of previous studies of atorvastatin 5, 10 and 20 mg (14, 16). However, the non-significant 9% reduction in tnglyceride levels is in contrast with the significant reductions observed in other studies (14,16). As the study of Bakker-Arkema showed the clear dosedependency of the triglyceride-lowering effect of atorvastatin, our result may be explained by the low atorvastatin dose as well as the relatively small number of patients. A higher dose would probably have induced a greater and therefore statistically significant decrease in triglyceride levels. Atorvastatin decreased the level of cholesterol in all of the LDL-subffactions, a result that is similar to those of other studies using the same atorvastatin dose in patients with diabetic dyslipoproteinemia (17,18) or combined hyperlipoprotelnemia (19). However, the reduction in cholesterol was less marked in intermediate-dense LDL, thus leading to a change in LDL-subtype distribution. Furthermore, a subgroup analysis showed that only the patients whose triglyceride levels decreased during treatment experienced an improvement in the LDL-subtype profile with a significant shift of cholesterol from small-dense to intermediate-dense LDL-subtypes. This finding is in accordance with those of previous studies showing that changes in LDL-size or density are closely related to changes in triglyceride concentrations (4, 18, 19) and may be explained by the known interaction between

TABLE 3 Lipid parameters of the12 hypertnglycerldemlc patients showing a decrease in plasma trlglyceride concentrations during therapy with atorvastatin 10 mg/day (responders) and the seven showing an increase in plasma triglycerides (non-responders). All data are expressed as mean values _+SD except for triglycerldes, which are given as the median values (range) because of their skewed distribution.

Responders (n=12)

Non-responders

(n=7)

mg/dL

Before

During

Change

Before

During

Change

Cholesterol

253+65

177+51

-30% **

250±35

211 ±44

-16% *

Tnglycendes (median)

656 (229-2109)

355 (115-1111)

-39% **

315 (206-462)

499 (243-842)

+55% *

HDL-C

32±8

33±9

+4%

38±9

34±8

-9%

LDL-C

103±30

76+22

-21% *

121 ±22

84±30

-24% *

13±5

9+3

-22% *

19+10

11 +4

-36% *

Intermediate-dense LDL-C

34±18

29±13

+2%

39±7

26±11

-33% *

Small, dense LDL-C

55±15

38±12

-26% **

62+21

47±24

-28% *

Large-buoyant LDL-C

* p<0 05 ** p<0 01

Atorvastatin in hypertnglyceridemla

triglyceride-rich lipoproteins and LDL-subtype metabolism (21, 22). Furthermore, the change in the LDL-subtype profile may be explained by other effects of atorvastatin, such as reduced cholesterol ester transfer protein activity (19), hepatic lipase activity (23) and VLDL-secretion (24). Baseline plasma viscosity and fibrinogen concentrations positively correlated with triglyceride levels, and baseline blood viscosity was within the range found in a previous study of hypertriglyceridemic patients (25). It is known that hypertriglyceridemic patients have higher plasma and blood viscosities than controls or patients with hypercholesterolemia but, despite these epidemiological associations, it seems to be unlikely that there is a causal relationship between high triglyceride levels and high blood and plasma viscosity because neither type of viscosity is associated with postprandial hypertriglyceridemia (26). Furthermore, in a study of gemfibrozil therapy, hemorrheological parameters remained unchanged despite a 52% reduction in triglyceride levels (26). Atorvastatin therapy decreased native and standardised whole blood viscosity at low shear rates (eg by 16% at 4/s for native blood viscosity). Interestingly, there was a small but significant reduction in plasma viscosity (p<0.05, Table 2) without an associated change in the other liemorrheological parameters. As red cell aggregation and deformability did not decrease during atorvastatin therapy, the reduction in blood viscosity may be at least partially due to the lower plasma viscosity. Similar findings have been observed during therapy with atorvastatin 80 mg (27). In addition to the higher atorvastatin dose, it is worth pointing out that the study involved eight patients with LDL-hypercholesterolemia, six with hypertriglyceridemia and six with mixed hyperlipoproteinemia, and so the less marked reduction in plasma viscosity observed by us may also have been due to differences in the underlying metabolic disorders. As there were no associations between the changes in lipid concentrations and plasma viscosity, the decrease in plasma viscosity during atorvastatin therapy in hypertriglyceridemia may be independent of lipoprotein metabolism. Atorvastatin therapy apparently has no effect on adhesion molecule concentrations in primary hypertriglyceridemia. The relationship between triglyceride and adhesion molecule levels in other statin trials has varied: atorvastatin has been found to lead to lower levels of E-selectin and VCAM-1 (6), but one study of simvastatin found no change in E-selectin and ICAM-1 levels (28). These differences may be due to differences in the underlying metabolic disorders or the different pharmacological approaches to hyperlipoproteinemia treatment, but it is also possible that

91

at least some of these effects are not lipoprotein-mediated and are thus pleiotropic. The administration of atorvastatin 10 mg/day to patients with hypertriglyceridemia led to an improvement in LDLsubtype distribution (a shift from small-dense to intermediate-dense LDL) and a reduction in plasma and blood viscosity. These beneficial effects were observed despite the fact that atorvastatin therapy did not significantly reduce plasma triglyceride levels.

Acknowledgement We would hke to thank Ms. E. Fleischer-Bnelmeier for her excellent technical assistance. This study was supported by a grant from Pfizer Inc.

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