How to cite this article: Vera-Lastra OL, Olvera-Acevedo A, Hernández-González C, Medina G, Carrillo-González AL, Ángeles-Garay U, Peralta-Amaro AL, Jara-Quezada LJ. Effect of pravastatine plus ezetimibe on carotid intima media thickness in patients with lupus erythematosus. Rev Med Inst Mex Seguro Soc. 2015;53 Supl 1:S74-9.

PubMed: http://www.ncbi.nlm.nih.gov/pubmed/26020669

SURGICAL SPECIALITIES

Received: October 22^nd 2014

Accepted: March 6^th 2015

Effect of pravastatine plus ezetimibe on carotid intima media thickness in patients with lupus erythematosus

Olga Lidia Vera-Lastra,^a Arturo Olvera-Acevedo,^a Claudia Hernández,^b Gabriela Medina,^c Ana Laura Carrillo-González,^d Ulises Ángeles-Garay,^e Ana Lilia Peralta-Amaro,^a Luis Jara^f

^aDepartamento de Medicina Interna

^bDepartamento de Radiodiagnóstico

^cUnidad de Epidemiologia Clínica

^dDepartamento de Admisión Continua

^eDivisión de Epidemiología

^fDirección de Investigación y Educación en Salud

Hospital de Especialidades Centro Médico Nacional La Raza, Instituto Mexicano del Seguro Social

^a,c,fFacultad de Medicina, División de Estudios de Posgrado, Universidad Nacional Autónoma de México

Distrito Federal, México

Communication with: Olga Lidia Vera-Lastra

Telephone: (55) 5724 5900, extensión 23161

Email: olgavera62@yahoo.com.mx

Background: Patients with systemic lupus erythematosus (SLE) have accelerated atherosclerosis that can be assessed by the carotid intima media thickness (CIMT) measurement. A prompt hypolipidemic treatment should be a part of the integral management. The aim of this study is to determine the effect of therapy with pravastatin plus ezetimibe on the CIMT in SLE patients.

Methods: Longitudinal, prospective, quasi-experimental trial. Out of 60 SLE patients in whom a carotid ultrasound was performed, we chose 22 with a CIMT > 0.7 mm who were administered pravastatin plus ezetimibe during 6 months with determination of CIMT at the end of the study. We performed the following tests: total cholesterol (TC), HDL-cholesterol, LDL-cholesterol, tryglicerides, C-reactive protein (CRP), liver function, muscle enzimes and glucose, basal and at the end of treatment. Statistical analysis: descriptive statistics and Wilcoxon test were used.

Results: There were 22 women with an age of 42 ± 6.3 years, average disease evolution 7.5 ± 6.6 years, of whom, 18 concluded the study. Right basal CIMT was 0.829 ± 0.1448 vs. final 0.688 ± 0.1453, p < 0.003; left CIMT was 0.820 ± 0.1312 vs. 0.724 ± 0.1348, p < 0.004. TC 208 mg/dl vs 168 mg/dl, LDL-C 125 mg/dl vs. 72 mg/dl, p = 0.0004. CRP 3.12 vs. 2.25 p = 0.004. In 2 cases there were gastrointestinal, skin and muscle adverse effects.

Conclusions: Treatment with pravastatin plus ezetimibe decreases the CIMT with improvement in the concentration of total cholesterol, LDL-C and CRP levels with good toleration.

Keywords: Atherosclerosis, Systemic lupus erythematosus, Intima media thickness, Pravastatin, Ezetimibe

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Atherosclerosis is a multifactorial disease with an autoimmune component that affects the arterial system and is a histopathological substrate in cardiovascular disease (CVD).¹ Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by a bimodal pattern of mortality, in the early stages patients die from activity and infections, and in the late stage from accelerated atherosclerosis (AA).^2,3 In SLE, cardiovascular morbidity and mortality has increased,⁴ and women in the 35-44 age group have 50 times the risk of myocardial infarction.⁵ Increased AA in patients with SLE is multifactorial, due to chronic inflammation, chronic use of corticosteroids, immunomodulators that cause premature ovarian failure and loss of estrogen protection, autoantibodies, diabetes mellitus, hypertension, and endothelial dysfunction, among others.^6-9

In SLE patients increased carotid intima-media thickness (CIM) has been demonstrated, being a measure of early and widespread atherosclerosis, which can be determined by carotid ultrasound.^10-12 High prevalence of plaques has been reported in carotid arteries of SLE patients,¹³ as well as thickening of CIM in 32% of asymptomatic SLE patients from the cardiovascular point of view.¹⁴  Patients with CIM more than 1 mm thick have a 2.14 times increased CV risk.¹⁵ Statins lower the CV risk and have a pleiotropic effect.^16,17 Ezetimibe is a lipid-lowering drug that acts on the Niemann-Pick C1-like 1 protein (NPC1L1) with inhibition of the cholesterol synthesis exogenous pathway.^18,19 Co-administration of statins and ezetimibe leads to decreased LDL C, total cholesterol, and apolipoproteins B, with an increase in HDL cholesterol and reduction in inflammatory markers in contrast to monotherapy with other statins. Added to this, the combination therapy presented no increase in adverse events.^20-22

The aim of this study was to determine the effect of therapy with pravastatin plus ezetimibe on CIM thickening in patients with SLE.

Methods

A transversal study was done in 60 patients with SLE according to the classification criteria of the American College of Rheumatology, over 18 and under 40, who gave their written consent. The study was to determine CIM thickness by carotid Doppler US with Siemens equipment Elegra, transducer 7.5 MHz multifrequency, linear, with Doppler power, performed by the same radiologist. CIM thickness > 0.7 mm was taken as significant. The study excluded patients with other autoimmune rheumatic diseases such as antiphospholipid syndrome, vasculitis, mixed connective tissue disease, overlap syndrome, systemic sclerosis, and rheumatoid arthritis. Change in CIM thickness was determined as a change greater than 0.1 mm, comparing pre- and post-treatment results. All patients with CIM thickness > 0.7 mm, with or without plaque, were invited to participate in the next phase, which involved the administration of pravastatin 40 mg/day in the evening plus ezetimibe 10 mg/day for 6 months. Before administering medications, they were interviewed to investigate medication use data for inhibitors of hydroxymethyl coenzyme A reductase (HMG-CoA reductase), fibrates, hypoglycemics, antihypertensives, and the duration of administration.

Subsequently researchers measured fasting serum concentrations of glutamic pyruvic transaminase (GPT), glutamic oxaloacetic transaminase (GOT), albumin, bilirubin, creatinine, total cholesterol (TC), LDL cholesterol (LDL C), HDL cholesterol, triglycerides, and C-reactive protein, in baseline samples. This was done every two months during the 6 months of treatment. Combination therapy of ezetimibe plus pravastatin was administered for six months. A questionnaire was applied to detect the main manifestations suggestive of adverse effects of drugs, especially liver and muscular damage.^21-23 In the presence of data suggestive of liver damage with more than 1.5 times elevation of the upper reference value of transaminase, or hyperbilirubinemia greater than 3 mg/dl, as well as data suggestive of myopathy with CPK elevation, therapeutic intervention was suspended. 

After 6 months of treatment with pravastatin plus ezetimibe, the second Doppler US was performed to determine the CIM thickness after treatment. CIM thickness change was determined as a change greater than 0.1 mm, compared to previous results. The study was performed by the same radiologist, who randomly reviewed 10 studies for measurement of CIM thickness obtaining an intra-observer coefficient of 0.7.

To monitor therapeutic adherence, every month patients were asked for the empty box of medication, before refilling.

Statistical analysis

Descriptive statistics and measures of central tendency were used for demographic data. For comparison of figures of the lipid profile, CRP, and CIM thickness via ultrasound, Wilcoxon test was used. SPSS version 12 for Windows was used.

Results

Of 60 female patients aged 42 ± 6.3 years and with an average disease duration of 7.5 ± 6.6 years who participated in the first phase of the study, it was found that 28 of them had CIM thickness greater than or equal to 0.7 mm. Of these patients, only 22 agreed to continue in the protocol, and 18 completed treatments. Of the 4 patients who did not complete the study, 2 were lost and 2 had adverse effects (one had skin rash, abdominal pain, and muscle weakness, the other nausea and abdominal pain), which led to discontinued treatment. In Table I baseline and final CIM thickness data are observed, showing a statistically significant thinning of CIM. 

Table I Carotid intima-media thicknessin patients with systemic lupus erythematosus at baseline and after treatment with pravastatin plus ezetimibe
	Initial right CIM thickness	Final right CIM thickness	Initial left CIM thickness	Final left CIM thickness
Patients with LSEn=	22	18	22	18
Mean ± standard deviation	0.829±0.1448 *	0.688±0.1453 *	0.820±0.1312 *	0.724 ± 0.1348 *
*p-value= 0.003. ** .004

Figure 1 shows CIM thickness at baseline and after treatment. Only 3 patients had atherosclerotic plaques, 2 with a time of SLE duration less than 3 years. Initial level of total cholesterol was 208 mg/dl and final level was 168 mg/dl, LDL cholesterol 125 mg/dl and 72 mg/dl (p = 0.0004). Furthermore, CRP levels had a reduction in their determination, with average initial values ​​3.12 and final 2.25, with statistically significant difference (p = 0.004) (Table II). Glucose and triglyceride levels showed elevations from 87 mg/dl to 92 mg/dl in the former, and from 120 to 130 mg/dl in triglycerides, without statistical significance. (p = 0.2 and p = 0.7, respectively). Table III shows the CRP results before and after treatment.

Figure 1 A) Gray scale ultrasound of right common carotid artery showing intima-media thickness of 0.9 mm in patient with systemic Lupus erythematosus at beginning of treatment. B,C) Control study after treatment showing longitudinal and transversal intima-media of 0.7 mm.

Table II Values of lipids in patients with systemic lupus erythematosus at baseline and after treatment with pravastatin plus ezetimibe (N= 18)
	Initial Cholesterol	Final Cholesterol	Initial HDL C	Final HDL C	Initial LDL C	Final LDL C	Initial Triglycerides	Final Triglycerides
n	22	18	22	18	22	18	22	18
Mean ± SD	204.12 ± 59.607	150.59 ± 43.566	49.7 ± 17.036	48.9 ± 12.552	127.76 ± 45.008	73.71 ± 28.193	132.35 ± 57.737	137.29 ± 77.64
p	0.001		0.897		0.000		0.758

Table III protein C reactive in patients with systemic lupus erythematosus after treatment with Pravastatin and basal more ezetimibe
	PCR Initial 22	PCR Final 18
Mean ± standard deviation	4.4453 ± 2.16129	2.4588 ± 1.90402
p	-0.004

Discussion

The study found, after combined therapy with pravastatin plus ezetimibe, a significant decrease in CIM thickness, as well as improvement in total cholesterol, LDL cholesterol, and CRP levels. Several studies have reported different findings concerning subclinical atherosclerosis, manifested by CIM thickening and definite atherosclerotic lesions, i.e., presence of atheromatous plaques in connective tissue diseases, including a meta-analysis.²³ However, there are few clinical trials related to the administration of statins for the treatment of atherosclerosis in these patients. In a study evaluating the effect of rosuvastatin in vascular biomarkers and atherosclerosis in patients with SLE, a significant decrease in CRP levels with high sensitivity and CIM thickness was found after 2 years of treatment.²⁴ In our study we found a significant decrease in CRP; however, we could not make the high-sensitivity measurement of CRP and other vascular biomarkers.

There are studies with controversial results regarding the use of statins in patients with SLE and atherosclerosis. In a study of 200 patients with SLE who were prescribed atorvastatin 40 mg daily with helical tomography to determine calcium in the coronary arteries, and carotid Doppler for CIM thickness, at baseline and at two years follow-up measuring inflammation or endothelial cell activation markers, no reduction was found in subclinical atherosclerosis.²⁵ In a recent study in SLE patients who received treatment with fluvastatin 20 mg/day for a month, lipid levels, oxidative stress, and vascular inflammation were reduced, processes involved in the pathophysiology of atherosclerosis in patients with SLE.²⁶

At the moment there are no studies about combination therapy for atherosclerosis in SLE patients; however, these therapies have been used successfully in patients at high cardiovascular risk. On this topic, Barbosa et al.²⁷ reported that subjects with elevated CRP levels with high cardiovascular risk who were treated with atorvastatin, ezetimibe, or a combination of the two, had greater reduction of inflammation with the combined drugs.

The American College of Cardiology and the American Heart Association have recommended initiating statin therapy in patients with cardiovascular risk, this therapy becoming the cornerstone of lipid-lowering therapy for more than a quarter century. Results from studies of combination therapy with lipid-lowering drugs are controversial, they have been conducted in populations with diverse cardiovascular risk, such as patients with familial hypercholesterolemia. One study used combined simvastatin plus ezetimibe, which were well-tolerated and found a greater reduction in LDL C compared to simvastatin alone, in adolescents with familial hypercholesterolemia.²⁸

However, other studies with combination therapy reported no significant changes in CIM thickness from therapy with ezetimibe and simvastatin, despite the decrease in LDL C and CRP levels.²⁹ In this study, we were able to document treatment effect by the pleiotropic effect of statins and intensive reduction of LDL cholesterol in combination with the effect of inhibiting the exogenous synthesis pathway with ezetimibe with favorable effect on CIM thickness. 

Limitations of our study are the small sample size and follow-up time.

Conclusions

Treatment with pravastatin plus ezetimibe decreases CIM thickness with improvement in total cholesterol, LDL cholesterol, and CRP levels.

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