Secretory phospholipase A2 (sPLA2) is an enzyme that plays an important role in the pathogenesis of atherosclerosis and of adverse cardiovascular events. It is currently the target of emerging therapeutic agents. Our study was designed to investigate the effect of aggressive lowering of low-density lipoprotein (LDL) cholesterol with ezetimibe and atorvastatin on sPLA2 activity. We randomized 100 patients with stable coronary artery disease (CAD) or CAD equivalent (diabetes, stroke, or peripheral vascular disease) to receive ezetimibe 10 mg/day in association with atorvastatin 40 mg/day (combination therapy group) versus atorvastatin 40 mg/day and placebo (monotherapy group). Patients on statin therapy before inclusion were allowed to enter the study as long as the potency of the statin was lower than atorvastatin 40 mg/day. Lipid profile, high-sensitivity C-reactive protein (hs-CRP), and sPLA activity were measured at baseline and after 8 weeks of therapy. The decrease in LDL cholesterol was more significant in the combination therapy group, but the decrease in hs-CRP was similar. sPLA2 activity significantly decreased in the ezetimibe/atorvastatin group from 29 U/ml (interquartile range 23 to 35) to 26 U/ml (23 to 29, p = 0.001) but remained similar in the placebo/atorvastatin group (23 U/ml, 19 to 32, vs 22 U/ml, 19 to 28, p = NS). In a multivariate stepwise linear regression model, change in sPLA2 correlated with change in hs-CRP (p <0.001), baseline LDL cholesterol level (p = 0.001), body mass index (p = 0.003), diabetes mellitus (p = 0.04) and combination therapy with ezetimibe/atorvastatin (p = 0.05). In conclusion, this study demonstrates that coadministration of ezetimibe and atorvastatin decreases sPLA2 activity.
Secretory phospholipase A2 (sPLA2) is an enzyme associated with incident coronary atherosclerosis in healthy men and women and with recurrent adverse cardiovascular events in patients with acute coronary syndromes. Ezetimibe is a cholesterol absorption inhibitor that is frequently added to statins in patients with lower than optimal levels of low-density lipoprotein (LDL) cholesterol. Although ezetimibe is very effective in providing additional lowering of LDL cholesterol when coadministered with statins, the effects of ezetimibe/statin coadministration “beyond” LDL lowering such as the effect on sPLA2 remain unknown. Given the more potent LDL decrease obtained with coadministration of statins and ezetimibe, it is likely that this regimen will result in better lowering of atherogenic markers such as sPLA2. Our study was designed to test the effect of a very aggressive LDL-lowering approach using ezetimibe in coadministration with high-dose atorvastatin versus high-dose atorvastatin alone on sPLA2 activity in patients with stable coronary artery disease (CAD) or CAD equivalent.
Methods
This was a prospective, randomized, double-blind, placebo-controlled trial. The objective was to investigate the effect of ezetimibe 10 mg/day coadministered with atorvastatin 40 mg/day on sPLA2 activity compared to coadministration of placebo and atorvastatin 40 mg/day in patients with CAD or CAD equivalent. The protocol was approved by the Hotel Dieu de France Hospital ethics committee and written informed consent was obtained from all patients.
Patients were included in the study if they had stable CAD or CAD equivalent. Stable CAD was defined by history of myocardial infarction, history of coronary revascularization, or documented coronary artery stenosis ≥50% on coronary angiogram. CAD equivalent was defined by presence of diabetes mellitus requiring medications, history of ischemic stroke, or history of peripheral vascular disease. Lipid levels were not entry criteria. Patients who were receiving statins were allowed to enter the study as long as the potency of the statin used was atorvastatin ≤20 mg/day. This meant that patients who were statin naive or patients who were taking atorvastatin 10 to 20 mg/day, simvastatin 10 to 40 mg/day, pravastatin 10 to 40 mg/day, or fluvastatin 80 mg/day could be enrolled in the study. All patients receiving atorvastatin ≥40 mg/day and those receiving any dose of rosuvastatin were excluded. Also excluded were patients >80 years of age, those who received ezetimibe or niacin or fibrate within the previous 3 months, patients with a history of acute coronary syndromes or coronary revascularization within the previous 3 months, patients with an ejection fraction <35% or history of severe heart failure (New York Heart Association class >II), and patients with a creatinine clearance <30 ml/min or creatine phosphokinase or aspartate aminotransferase >2 times the upper normal limit.
Patients were initially seen in the fasting state for measurement of total cholesterol, LDL cholesterol, very LDL cholesterol, high-density lipoprotein cholesterol, sPLA2 activity, high-sensitivity C-reactive protein (hs-CRP), and creatine phosphokinase and aspartate aminotransferase. Patients were then equally randomized to receive atorvastatin 40 mg/day plus ezetimibe 10 mg/day (combination therapy group) or atorvastatin 40 mg/day plus placebo (monotherapy group). Patients who were receiving statin therapy before randomization had their initial statin stopped and replaced by atorvastatin 40 mg/day, as mentioned previously. Duration of treatment was 8 weeks, at the end of which patients had the same blood tests performed.
Serum sPLA2 activity was measured using a new fluorimetric method (Aterovax, Paris, France) on serum samples that were stored at −80°C and that were thawed only 1 time. All samples were tested in duplicate and serum activity was expressed as units per milliliter. The minimum detectable activity was 10 U/ml and the intra- and interassay coefficients of variation were <13%.
For statistical analysis, categorical variables were expressed as absolute values and percentages and were compared using chi-square test. Continuous variables were represented as mean ± SD. Hs-CRP and sPLA2 were not normally distributed and were expressed as median and interquartile ranges. Pre- and post-treatment levels of these markers were compared in each group using nonparametric Wilcoxon signed-rank test and were compared between the 2 groups using nonparametric Mann–Whitney test. Correlations between changes in marker levels were performed using Pearson correlation. A forward stepwise linear regression model was used to test the correlation of change in sPLA2 with baseline clinical and biological variables. All tests were 2-tailed and p values ≤0.05 were considered statistically significant. SPSS 15.0 (SPSS, Inc., Chicago, Illinois) was used for statistical analysis.
Results
One hundred patients were included in the trial (50 in each group). Inclusion criteria are listed in Table 1 . Of note, 90% of patients were receiving statins before randomization. Simvastatin was most commonly used (53 patients), followed by atorvastatin (30 patients). Types and doses of statins used were similar between the 2 groups. Baseline demographics, clinical characteristics, and concomitant medical therapy are listed in Table 2 . All patients took their investigational treatment according to the protocol for a period of 8 weeks. None of the patients had an increase of creatine phosphokinase or aspartate aminotransferase >2 times the upper limit of normal.
| Variable | Ezetimibe + Atorvastatin | Placebo + Atorvastatin |
|---|---|---|
| (n = 50) | (n = 50) | |
| Coronary stenosis >50% | 19 (38%) | 23 (46%) |
| Previous myocardial infarction | 18 (36%) | 12 (24%) |
| Percutaneous coronary intervention | 23 (46%) | 15 (30%) |
| Coronary artery bypass grafting | 26 (52%) | 21 (42%) |
| Diabetes mellitus | 18 (36%) | 21 (42%) |
| Stroke | 1 (2%) | 1 (2%) |
| Peripheral vascular disease | 6 (12%) | 5 (10%) |
| Variable | Ezetimibe + Atorvastatin | Placebo + Atorvastatin |
|---|---|---|
| (n = 50) | (n = 50) | |
| Age (year) | 64 ± 8 | 65 ± 11 |
| Men | 44 (88%) | 41 (82%) |
| Smokers | 14 (28%) | 12 (24%) |
| Hyperlipidemia ⁎ | 47 (94%) | 43 (86%) |
| Hypertension † | 35 (70%) | 38 (76%) |
| Body mass index (kg/m 2 ) | 27 ± 3 | 28 ± 4 |
| Aspirin | 45 (90%) | 43 (86%) |
| Clopidogrel | 11 (22%) | 11 (22%) |
| Angiotensin-converting enzyme inhibitors or angiotensin receptor blocker | 41 (82%) | 34 (68%) |
| β Blockers | 37 (74%) | 35 (70%) |
| Calcium channel blockers | 8 (16%) | 18 (36%) ‡ |
| Nitrates | 10 (20%) | 11 (22%) |
| Diuretics | 6 (12%) | 6 (12%) |
| Oral antidiabetic drugs | 15 (30%) | 17 (34%) |
| Insulin | 6 (12%) | 6 (12%) |
⁎ Low-density lipoprotein cholesterol ≥130 mg/dl before initiation of lipid-lowering drugs.
† Blood pressure ≥140/90 mm Hg before initiation of antihypertensive therapy.
‡ p = 0.023; p = NS for all other comparisons between the 2 groups.
Values of different lipid parameters are listed in Table 3 . Patients were well treated with statins before inclusion in the study, as attested by mean baseline LDL cholesterol levels of 102 mg/dl in the combined therapy group and 99 mg/dl in the monotherapy group (p = NS). Coadministration of ezetimibe with atorvastatin resulted in a more important decrease in total LDL cholesterol compared to atorvastatin alone (average decrease 20% vs 10%, p = 0.01). Hs-CRP levels were similar at baseline and decreased equally in the 2 groups after treatment.
| Variable | Ezetimibe + Atorvastatin | Placebo + Atorvastatin | p Value |
|---|---|---|---|
| (n = 50) | (n = 50) | ||
| Total cholesterol (mg/dl) | |||
| Baseline | 176 ± 35 | 168 ± 26 | NS |
| Final | 145 ± 19 | 154 ± 20 | 0.025 |
| p Value | <0.001 | <0.001 | |
| Low-density lipoprotein cholesterol (mg/dl) | |||
| Baseline | 102 ± 29 | 99 ± 21 | NS |
| Final | 77 ± 10 | 86 ± 14 | <0.001 |
| p Value | <0.001 | <0.001 | |
| High-density lipoprotein cholesterol (mg/dl) | |||
| Baseline | 37 ± 8 | 37 ± 8 | NS |
| Final | 38 ± 7 | 37 ± 9 | NS |
| p Value | NS | NS | |
| Very low-density lipoprotein cholesterol (mg/dl) | |||
| Baseline | 36 ± 8 | 33 ± 10 | NS |
| Final | 29 ± 11 | 30 ± 9 | NS |
| p Value | 0.01 | NS | |
| High-sensitivity C-reactive protein (mg/L) | |||
| Baseline | 2 (1.3–4.8) | 2.4 (0.8–8) | NS |
| Final | 1.4 (0.8–2.5) | 1.5 (0.6–4.3) | NS |
| p Value | <0.001 | 0.014 | |
| Secretory phospholipase A2 (U/ml) | |||
| Baseline | 29 (23–35) | 23 (19–32) | 0.02 |
| Final | 26 (23–29) | 22 (19–28) | 0.02 |
| p Value | 0.001 | NS |
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