Combining Rosuvastatin with Sartans of Different Peroxisome Proliferator-Activated Receptor-γ Activating Capacity Is Not Associated with Different Changes in Low-Density Lipoprotein Subfractions and Plasma Lipoprotein-Associated Phospholipase A 2

Abstract

Background:

Rosuvastatin reduces low-density lipoprotein cholesterol (LDL-C) and plasma lipoprotein-associated phospholipase A₂ (Lp-PLA₂). Some sartans partially activate peroxisome proliferator-activated receptor-γ (PPARγ), possibly having a favorable effect on metabolic parameters. Telmisartan is the most potent partial PPARγ activator, followed by irbesartan, whereas olmesartan does not hold such capacity. In an open-label randomized study, we assessed the effects of combining sartans of different PPARγ- activating capacity with rosuvastatin on LDL subfractions and plasma Lp-PLA₂ in patients with mixed dyslipidemia, hypertension, and prediabetes.

Methods:

Following dietary intervention, patients were allocated randomly to rosuvastatin (10 mg/day) plus telmisartan 80 mg/day (RT group, n = 52) or irbesartan 300 mg/day (RI group, n = 48) or olmesartan 20 mg/day (RO group, n = 51). After 6 months of treatment, changes in LDL subfraction cholesterol and plasma Lp-PLA₂ activity and mass were evaluated blindly.

Results:

A total of 151 patients (73 male; mean age 60 years) were included. Large LDL-C decreased in the RT (−36%), RI (−39%), and RO (−41%) groups (P < 0.001 for all vs. baseline). Small dense LDL-C decreased in the RT (−67%), RI (−58%), and RO (−61%) groups (P < 0.001 for all vs. baseline). All regimens increased LDL particle size versus baseline (RT + 1.4%, P = 0.002; RI + 1.0%, P = 0.04; and RO + 1.4%, P = 0.001). No difference for the change of LDL subfractions and LDL size was noticed among groups. Plasma Lp-PLA₂ activity decreased equally in all groups (RT −38%, RI −38%, RO −43%) (P < 0.001 for all vs. baseline). Plasma Lp-PLA₂ mass decreased similarly in all groups versus baseline (RT −28%, P = 0.001; RI −32%, P = 0.01; and RO −27%, P = 0.001). No difference for the change of Lp-PLA₂ mass or activity was noticed among groups.

Conclusions:

The combination of rosuvastatin with sartans of different PPARγ-activating capacity did not differentiate alterations of LDL subfraction cholesterol and plasma Lp-PLA₂ activity and mass.

Introduction

L ow-density lipoprotein cholesterol (LDL-C) is strongly associated with the development and progression of cardiovascular disease (CVD).¹ LDL is not homogeneous but consists of multiple subfractions with different sizes and densities.² There has been evidence that apart from the levels of LDL-C, the distribution of LDL particles can also influence CVD risk.³ Indeed, small dense LDL (sdLDL) particles have the most deleterious effect on atherosclerosis.¹

Lipoprotein-associated phospholipase A₂ (Lp-PLA₂) is a calcium (Ca²)-independent PLA₂ that degrades platelet activating factor (PAF) and oxidized phospholipids by catalyzing the hydrolysis of the ester bond at the sn-2 position.⁴ In human plasma, it is associated (70%–80%) mainly with LDL particles, whereas the remaining amount is associated mainly with high-density lipoprotein (HDL).⁵ Within LDL subfractions, Lp-PLA₂ shows a preferential binding to the sdLDL particles. Indeed, Lp-PLA₂ activity is a marker of sdLDL in plasma.⁶ Several studies^7
–9 and a recent meta-analysis¹⁰ showed that Lp-PLA₂ is significantly associated with CVD, even when adjusting for conventional CVD risk factors.

Among statins, rosuvastatin is associated with the greatest cholesterol reduction capacity.^11,12 We have shown that rosuvastatin has a high capacity of reducing both large and sdLDL-C and increasing LDL size,¹³ as well as decreasing plasma Lp-PLA₂ activity and mass.¹⁴

Dyslipidemia often co-exists with high blood pressure and impaired glucose homeostasis, as commonly seen in metabolic syndrome. Among sartans, telmisartan has unique properties and pleiotropic effects, which may further improve CVD risk beyond blood pressure reduction.¹⁵ These pleiotropic effects are partly due to its partial peroxisome proliferators-activated receptor-γ (PPARγ) -activating capacity. PPARγ plays an important role in regulating metabolic pathways, such as those involved in lipid and glucose metabolism.

Patients with multiple risk factors, such as dyslipidemia, hypertension, and impaired glucose homeostasis, need comprehensive treatment. Recently, we have shown that combining rosuvastatin with telmisartan improves glucose homeostasis indices when compared with the combination of rosuvastatin with sartans that are either weak (irbesartan) or no (olmesartan) PPARγ activators.^16,17 We now report on a prespecified analysis regarding the effects of these combinations on LDL subfraction cholesterol and plasma Lp-PLA₂ activity and mass.

Subjects and Methods

Subjects

Study details have been previously described.¹⁶ In brief, patients attending the Outpatient Lipid Clinic of the University Hospital of Ioannina, Greece, were recruited. Eligible patients were those with impaired fasting plasma glucose, mixed dyslipidemia, and stage 1 hypertension. Patients were excluded if they had any of the following: (1) History of diabetes, (2) history of CVD, (3) elevated triglycerides (TG) (>400 mg/dL; 4.52 mmol/L), (4) renal disease, (5) hypothyroidism, (6) liver dysfunction, (7) receiving lipid-lowering or antihypertensive treatment in the last 3 months prior to recruitment, and (8) females that did not take sufficient contraceptive measures.

All participants gave written informed consent and the study protocol was approved by our institutional ethics committee.

Study design

All patients (n = 159) received a 12-week dietary intervention in accordance with the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines and the Dietary Approaches to Stop Hypertension (DASH) diet.¹⁸ Patients (n = 151) who continued to meet the inclusion criteria after the dietary intervention period were randomly allocated to open label: (1) Rosuvastatin (10 mg/day) plus a sartan with partial PPARγ-activating capacity (telmisartan 80 mg/day; n = 52; RT group), (2) rosuvastatin (10 mg/day) plus a sartan with weak partial PPARγ-activating capacity (irbesartan 300 mg/day; n = 48; RI group), or (3) rosuvastatin (10 mg/day) plus a sartan without PPARγ-activating capacity (olmesartan 20 mg/day; n = 51; RO group).

Selected doses of studied drugs are the usual starting doses in clinical practice in our country. Moreover, sartan doses are equivalent in terms of lowering blood pressure. Compliance with study medication was assessed at week 24 by counting taken tablets; patients were considered compliant if they took 80%–100% of the prescribed number of tablets.

End points

This prespecified analysis was aimed to evaluate the changes of LDL subfraction cholesterol as well as mass and activity of plasma Lp-PLA₂ after 6 months of treatment.

Biochemical parameters

All laboratory determinations were carried out after an overnight fast. Clinical investigators were blinded to laboratory results. Electrophoresis was performed using a high-resolution 3% polyacrylamide gel tube and the Lipoprint LDL System (Quantimetrix, Redondo Beach, CA) according to the manufacturer's instructions, as previously described.¹⁹ LDL subfractions were estimated by the relative migration distance (Rf) between the very low-density lipoprotein (VLDL) fraction (Rf 0.0) and the HDL fraction (Rf 1.0). LDL is distributed from Rf 0.32 to Rf 0.64 as seven bands, whose Rfs are 0.32, 0.38, 0.45, 0.51, 0.56, 0.60, and 0.64 (LDL1 to LDL7, respectively). LDL1 and LDL2 are defined as large buoyant LDL, whereas LDL3 up to LDL7 are defined as sdLDL. The cholesterol concentration of each LDL subfraction is determined by multiplying the relative area under the curve (AUC) of each subfraction by the total cholesterol concentration of the sample. Mean particle size was provided by the Lipoprint LDL System. The coefficient of variation (CV) for the intraassay precision of LDL subfractions was for LDL1 = 3.58%, LDL2 = 3.64%, LDL3 = 1.65%, LDL4 = 2.45%, LDL5 = 1.72%, LDL6 = 4.62%, and LDL7 = 17.89%. The CV for the interassay precision of LDL subfractions was for LDL1 = 3.67%, LDL2 = 6.73%, LDL3 = 5.59%, LDL4 = 3.45%, LDL5 = 2.58%, LDL6 = 12.06%, and LDL7 = 33.9%.

Lp-PLA₂ activity in total plasma was determined by the trichloroacetic acid precipitation procedure using [³H]PAF (100 μmol/L final concentration) as a substrate.²⁰ Lp-PLA₂ activity was expressed as nmol PAF degraded per min per mL of plasma. The intraassay and the interassay CVs are 3.3%–4.2% and 7.1%–8.0%, respectively.

Lp-PLA₂ mass in total plasma was determined by a dual monoclonal antibody immunoassay standardized to recombinant Lp-PLA₂ (PLAC test, diaDexus, Inc.), following the manufacturer's instructions, as previously described.⁶ The intraassay and the interassay CVs were 4.1%–6.2% and 4.6%–8.5%, respectively.

Statistical analysis

Values are given as mean ± standard deviation (SD) and median (range) for parametric and nonparametric data, respectively. Continuous variables were tested for lack of normality by the Kolmogorov–Smirnov test, and logarithmic transformations were accordingly performed for nonparametric variables. The paired-sample t-test was used for assessing the effect of treatment in each group. Analysis of covariance (ANCOVA), adjusted for baseline values, was used for comparisons between treatment groups. Multiple regression analysis included factors that significantly affected changes in sdLDL-C and Lp-PLA₂ activity in univariate analysis. Age, gender, smoking, waist circumference, body mass index, choice of drug regimen, baseline sdLDL-C, LDL particle size, and Lp-PLA2 activity and mass as well as baseline levels and changes in TG, LDL-C, and homeostasis model assessment insulin resistance (HOMA-IR) were used as candidate predictive variables. Significance was defined as P < 0.05. Analyses were performed using the Statistical Package for the Social Sciences (SPSS) 15.0 (SPSS Inc, Chicago, IL). In a post hoc calculation, given the effect size, the a level, and the sample size, we calculate that the achieved power of this prespecified analysis to find a significant difference for both the sdLDL-C and the Lp-PLA2 activity and mass was above 95%.

Results

A total of 159 patients (76 males, mean age 60 years) were enrolled. Of them, 151 (73 males, mean age 60 years) continued to meet the inclusion criteria after the dietary intervention period and were randomized to the three groups. No significant differences in baseline data were found across groups regarding demographic characteristics (Table 1), serum metabolic parameters (Table 2), LDL subfraction cholesterol concentration (Table 3), LDL size (Table 3), and plasma Lp-PLA2 activity and mass (Table 3). No patient dropped out and compliance was >80% in all patients. The effects of all combinations on metabolic parameters have been previously described.¹⁶ In brief, after study end, no differentiation in anthropometric variables and blood pressure was observed between groups. In addition, lipid profile was similarly altered in all groups (Table 2).¹⁶ However, as we have previously reported the HOMA-IR decreased only in the RT group whereas an increase was observed in the other two regimens (Table 2).¹⁶ Moreover, fasting plasma glucose remained unchanged in all groups, as previously reported (Table 2).¹⁶

Table 1.

Baseline Demographic Characteristics of Study Participants ^a

Characteristic	RT Group	RI Group	RO Group	P
N (females/males)	25/27	26/22	27/24	N.S.
Age (years)	60 ± 10	60 ± 10	58 ± 12	N.S.
Smokers (%)	22	27	23	N.S.
Body mass index (kg/m²)	29 ± 4	29 ± 5	28 ± 4	N.S.
Waist circumference (cm)	101 ± 9	101 ± 11	100 ± 8	N.S.
Systolic blood pressure (mmHg)	153 ± 14	152 ± 11	151 ± 11	N.S.
Diastolic blood pressure (mmHg)	91 ± 10	90 ± 9	93 ± 8	N.S.

Values are expressed as mean ± standard deviation (SD).

RT, rosuvastatin + telmisartan; RI, rosuvastatin + irbesartan; RO, rosuvastatin + olmesartan; N.S., not significant.

Table 2.

Serum Metabolic Parameters at Baseline and After 6 Months of Treatment ^a

	Baseline^a	6 Months^a	Percentage change
Total cholesterol [mg/dL (mmol/L)]
RT group	271 ± 29 (7.0 ± 0.8)	177 ± 28 (4.6 ± 0.7)	−35%^‡
RI group	269 ± 23 (7.0 ± 0.6)	170 ± 30 (4.4 ± 0.8)	−37%^‡
RO group	274 ± 27 (7.0 ± 0.7)	175 ± 32 (4.5 ± 0.8)	−36%^‡
Triglycerides [mg/dL (mmol/L)]
RT group	180 (152–290) [2.0 (1.7–3.3)]	135 (81–270) [1.5 (0.9–3.1)]	−25%^‡
RI group	173 (151–276) [3.3 (1.7–3.1)]	125 (77–252) [1.4 (0.9–2.9)]	−28%^‡
RO group	187 (153–289) [2.1 (1.7–3.3)]	147 (76–210) [0.9 (1.7–2.4)]	−23%^‡
HDL-C [mg/dL (mmol/L)]
RT group	55 ± 7 (1.4 ± 0.2)	56 ± 7 (1.4 ± 0.2)	+ 1%
RI group	58 ± 11 (1.5 ± 0.3)	59 ± 15 (1.5 ± 0.4)	+ 1%
RO group	53 ± 9 (1.4 ± 0.2)	54 ± 10 (1.3 ± 0.3)	+ 2%
LDL-C [mg/dL (mmol/L)]
RT group	182 ± 23 (4.7 ± 0.6)	105 ± 28 (2.7 ± 0.7)	−42%^‡
RI group	176 ± 23 (4.6 ± 0.6)	99 ± 22 (2.6 ± 0.6)	−44%^‡
RO group	183 ± 22 (4.7 ± 0.6)	99 ± 31 (2.6 ± 0.8)	−46%^‡
Fasting plasma glucose [mg/dL (mmol/L)]
RT group	112 ± 10 (6.2 ± 0.6)	113 ± 9 (6.3 ± 0.5)	+ 1.1%
RI group	110 ± 10 (6.1 ± 0.6)	112 ± 7 (6.2 ± 0.4)	+ 1.8%
RO group	114 ± 11 (6.3 ± 0.6)	114 ± 8 (6.3 ± 0.4)	0.0%
HOMA-IR
RT group	2.6 (0.6–6.6)	1.8 (0.5–5.1)	−29%^†,¶,§
RI group	2.5 (0.5–6.2)	2.9 (0.5–8.1)	+ 16%^†
RO group	2.4 (0.5–7.9)	2.7 (0.5–5.2)	+ 14%^†

Values are expressed as mean SD [except for triglycerides and HOMA-IR that are expressed as median (range)].

†

P < 0.05 vs. baseline, ^‡ P < 0.001 vs. baseline, ^¶ P < 0.01 vs. RI group, ^§ P < 0.05 vs. RO group.

RT, rosuvastatin + telmisartan; RI, rosuvastatin + irbesartan; RO, rosuvastatin + olmesartan; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; HOMA-IR, homeostasis model assessment of insulin resistance.

Table 3.

LDL Subfraction Cholesterol Concentration, LDL Size, and Plasma Lp-PLA2 Activity and Mass at Baseline and After 6 Months of Treatment *

	Baseline^*	6 months^*	Percentage change
Large LDL cholesterol [mg/dL (mmol/L)]
RT group	75 ± 20 (1.9 ± 0.5)	48 ± 13 (1.2 ± 0.3)	−36%^†
RI group	81 ± 16 (2.1 ± 0.4)	49 ± 12 (1.3 ± 0.3)	−39%^†
RO group	78 ± 16 (2.0 ± 0.4)	46 ± 13 (1.2 ± 0.3)	−41%^‡
Small dense LDL cholesterol [mg/dL (mmol/L)]
RT group	17 (2–69) [0.4 (0.1–1.8)]	5.5 (0–31) [0.1 (0.0–0.8)]	−67%^†
RI group	15 (7–44) [0.4 (0.2–1.1)]	6.4 (1–18) [0.2 (0.0–0.5]	−58%^†
RO group	17 (2–78) [0.4 (0.1–2.0)]	6.7 (1–27) [0.2 (0.0–0.7)]	−61%^†
LDL particle size (Å)
RT group	261 ± 7	265 ± 6	+ 1.4%^¶
RI group	262 ± 4	265 ± 5	+ 1.0%^§
RO group	262 ± 6	266 ± 4	+ 1.4%^§§
Plasma Lp-PLA₂ activity (nmol/mL/min)
RT group	57 ± 17	35 ± 12	−38%^†
RI group	53 ± 11	33 ± 9	−38%^†
RO group	58 ± 14	33 ± 10	−43%^†
Plasma Lp-PLA₂ mass [ng/mL]
RT group	277 ± 40	200 ± 30	−28%^††
RI group	301 ± 20	203 ± 30	−32%^¶¶
RO group	304 ± 34	220 ± 46	−27%^††

Values are expressed as mean standard deviation (SD) [except for small dense LDL that are expressed as median (range)].

†

P < 0.001 vs. baseline, ^‡ P = 0.003 vs. baseline, ^¶ P = 0.002 vs. baseline, ^§ P = 0.04 vs. baseline, ^§§ P = 0.001 vs. baseline, ^†† P = 0.001 vs. baseline; ^¶¶ P = 0.01 vs. baseline.

RT, rosuvastatin + telmisartan; RI, rosuvastatin + irbesartan; RO, rosuvastatin + olmesartan; LDL, low-density lipoprotein; Lp-PLA₂, lipoprotein-associated phospholipase A₂.

Changes in LDL subfraction phenotype

After 6 months of treatment, a similar reduction of LDL subfraction cholesterol was seen in all groups (Table 3) [P = not significant (N.S.) for all comparisons between groups]. Levels of sdLDL-C showed a decrease numerically more in the RT group (−67%; P < 0.001 vs. baseline) compared with the RO (−61%; P < 0.001 vs baseline) and RI (−58%; P = 0.003 vs. baseline) groups. Large LDL-C was equally decreased in the RT (−36%; P < 0.001 vs. baseline), RI (−39%; P < 0.001 vs. baseline), and RO groups (−40%; P < 0.001 vs. baseline). An increase of LDL particle size was observed in the RT group (+1.4%; P = 0.002 vs. baseline), the RI group (+1.0%; P = 0.04 vs. baseline), and the RO group (+1.4%; P = 0.001 vs. baseline) (P = N.S. for the comparison between groups). In multiple regression analysis, only baseline sdLDL-C levels and changes in TG levels were significantly and independently correlated with the changes of sdLDL-C in all groups (Table 4).

Table 4.

Multiple Regression Analysis for the Prediction of Changes in sdLDL Cholesterol (R ² = 0.852)^a

	RT group		RI group		RO group
	Beta	P	Beta	P	Beta	P
Baseline sdLDL-C	0.604	0.001	0.625	0.001	0.617	0.003
ΔTG	0.384	0.005	0.205	0.03	0.320	0.035

In multiple regression analysis, age, gender, smoking, waist circumference, body mass index, choice of regimen, baseline sdLDL-C, LDL particle size, and Lp-PLA₂ activity and mass as well as baseline levels and changes in TG, LDL-C, and homeostasis model assessment of insulin resistance (HOMA-IR) were used as candidate predictive variables. Variables included in the model were those that were significantly associated with the changes of sdLDL-C in univariate analysis. Only significant predictors are shown.

sdLDL-C, small dense low-density lipoprotein cholesterol; ΔTG, changes in triglycertide levels; RT, rosuvastatin + telmisartan; RI, rosuvastatin + irbesartan; RO, rosuvastatin + olmesartan.

Changes in plasma Lp-PLA₂

Similar were the results for the plasma Lp-PLA₂ activity and mass (Table 3). Plasma Lp-PLA₂ mass equally decreased in the RT (−28%; P = 0.001 vs. baseline), RI (−32%; P = 0.01 vs baseline), and RO (−28%; P = 0.001 vs baseline) groups (P = N.S. for the comparison between groups). Also, plasma Lp-PLA₂ activity similarly decreased in all groups versus baseline (RT −36%; P < 0.001, RI −38%; P < 0.001, and RO −42%; P < 0.001) (P = N.S. for the comparison between groups). In multiple regression analysis, only changes of sdLDL-C and baseline Lp-PLA₂ activity were significantly and independently correlated with the changes in Lp-PLA₂ activity in all groups (Table 5).

Table 5.

Multiple Regression Analysis for the Prediction of Changes in Lp-PLA ₂ Activity (R ² = 0.435) ^a

	RT group		RI group		RO group
	Beta	P	Beta	P	Beta	P
Baseline Lp-PLA₂ activity	0.489	0.002	0.486	0.008	0.581	< 0.001
ΔsdLDL-C	0.215	0.036	0.224	0.029	0.432	0.003

In multiple regression analysis age, gender, smoking, waist circumference, body mass index, choice of drug regimen, baseline LDL particle size, and Lp-PLA₂ activity and mass as well as baseline levels and changes in TG, LDL-C, homeostasis model assessment of insulin resistance (HOMA-IR), and sdLDL-C were used as candidate predictive variables. Variables included in the model were those that were significantly associated with the changes in Lp-PLA₂ activity in univariate analysis. Only significant predictors are shown.

RT, rosuvastatin + telmisartan; RI, rosuvastatin + irbesartan; RO, rosuvastatin + olmesartan; Lp-PLA₂, lipoprotein-associated phospholipase A₂; ΔsdLDL-C, changes of small dense low-density lipoprotein cholesterol.

Discussion

In the present study, we examined for the first time the effects of combining rosuvastatin with sartans of different PPARγ-activating capacity on the LDL-C subfractions and on Lp-PLA₂ mass and activity. All of the combinations had similar efficacy in decreasing both large LDL-C and sdLDL-C. In addition, the mean LDL particle size equally increased in all groups. Moreover, a similar decrease in both plasma Lp-PLA₂ activity and mass was observed among groups.

To our knowledge, no study has evaluated the effects of telmisartan monotherapy on LDL subfractions. There is a direct link between insulin resistance and increased levels of sdLDL-C.^21,22 PPARγ affects a wide range of genes that control various metabolic parameters, including lipid and glucose homeostasis. Pioglitazone, a full PPARγ agonist, decreased sdLDL subfraction cholesterol levels, and increased LDL particle size independently of fasting TG and HDL-C levels.^23,24 Thus, the coadministration of telmisartan with rosuvastatin would be anticipated to result in greater sdLDL-C reduction compared with the other two regimens. Although, the rosuvastatin plus telmisartan group experienced a numerically greater reduction of sdLDL-C, this was not significantly different compared with the other two combinations. In our study, telmisartan improved glycemic homeostasis indices when combined with rosuvastatin.¹⁶ However, the univariate analysis did not reveal a significant correlation between HOMA-IR (both baseline value and changes) and changes of sdLDL-C. Moreover, telmisartan, is only a partial PPARγ activator, whereas a full PPARγ agonist, as in the case of pioglitazone, may be necessary to decrease sdLDL-C significantly. Indeed, partial PPARγ activators like telmisartan lead to diverse but overlapping gene expression compared with full PPARγ activators.¹⁵ Furthermore, not all PPARγ activators lead to a decrease of sdLDL-C. Rosiglitazone, also a full PPARγ activator, has been shown not to reduce sdLDL subfraction cholesterol.²⁵ Therefore, the different PPARγ-activating capacity and unique pharmacological properties of each PPARγ activator may lead to different results concerning sdLDL changes.

Another possible explanation for the lack of any added benefit with telmisartan may be the high efficacy of rosuvastatin to decrease all LDL subfraction cholesterol, thus overshadowing any additive effect of telmisartan. In addition, all study groups experienced a similar decrease of TG levels. It is well known, there is a strong correlation between TG levels and sdLDL-C.²⁶ Indeed, in the multiple regression analysis, changes in TG levels were significantly and independently correlated with changes of sdLDL-C. As a result, the similar changes of TG levels seen in all groups justify the lack of differentiation regarding changes in sdLDL-C.

Lp-PLA₂ mass and activity were similarly decreased in all groups. Rosuvastatin has been shown to decrease both mass and activity of plasma Lp-PLA₂.¹⁴ Therefore, the potent rosuvastatin-mediated decrease of Lp-PLA₂ may conceal any additional mild decrease related to the use of sartans.

Studies with the full PPARγ agonist pioglitazone have shown controversial results regarding its effects on Lp-PLA₂.^27,28 In one study, pioglitazone did not alter Lp-PLA₂ levels,²⁷ whereas an increase of Lp-PLA₂ production was observed in another study.²⁸ Therefore, it is possible that either partial PPARγ activation is not enough to alter Lp-PLA₂ or PPARγ activation is not associated with changes of Lp-PLA₂. In addition, the few studies that have evaluated the effects of some sartans on Lp-PLA₂ have not found any significant effect.^29,30 As a result, the similar alteration of Lp-PLA₂ mass and activity could be attributed solely to the rosuvastatin activity.

Furthermore, Lp-PLA₂ activity is associated with levels of sdLDL-C.⁶ Indeed, multiple regression analysis identified changes of sdLDL-C as well as baseline Lp-PLA₂ activity as predictors for the changes of Lp-PLA₂ activity. Because sdLDL-C levels decreased similarly in all groups and all groups had similar baseline Lp-PLA₂ levels, no differentiation would have been expected regarding changes in Lp-PLA₂.

Study limitations

This was an open-label study. However, end points were assessed blindly. A control group receiving rosuvastatin as monotherapy was not included because it was considered not ethical to further delay antihypertensive treatment in these patients.

Conclusion

The combination of rosuvastatin with sartans of different PPARγ-activating capacities did not differentiate the effects of statin treatment on LDL subfraction cholesterol or plasma Lp-PLA₂ activity and mass.

Footnotes

Author Disclosure Statement

The authors state no conflict of interest and have received no payment in preparation of this manuscript. Some of the authors have given talks, attended conferences, and participated in trials and advisory boards sponsored by various pharmaceutical companies.

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Combining Rosuvastatin with Sartans of Different Peroxisome Proliferator-Activated Receptor-γ Activating Capacity Is Not Associated with Different Changes in Low-Density Lipoprotein Subfractions and Plasma Lipoprotein-Associated Phospholipase A 2

Abstract

Background:

Methods:

Results:

Conclusions:

Introduction

Subjects and Methods

Subjects

Study design

End points

Biochemical parameters

Statistical analysis

Results

Changes in LDL subfraction phenotype

Changes in plasma Lp-PLA2

Discussion

Study limitations

Conclusion

Footnotes

Author Disclosure Statement

References

Changes in plasma Lp-PLA₂