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Pioglitazone improves the cardiovascular profile in patients with uncomplicated systemic lupus
erythematosus: a double-blind randomized clinical trial
JG Juárez-Rojas, AX Medina-Urrutia, E Jorge-Galarza, NA Caracas-Portilla, R Posadas-Sánchez, GC Cardoso-Saldaña, MV Goycochea-Robles, LH Silveira, L Lino-Pérez, J Mas-Oliva, O Pérez-Méndez and C Posadas-Romero 2012 21: 27 originally published online 12 October 2011 The online version of this article can be found at: can be found at:
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Pioglitazone improves the cardiovascular profile in patients with uncomplicated systemic lupus erythematosus: a double-blind JG Jua´rez-Rojas1,2, AX Medina-Urrutia1, E Jorge-Galarza1, NA Caracas-Portilla1, R Posadas-Sa´nchez1, GC Cardoso-Saldan˜a1, MV Goycochea-Robles3, LH Silveira4, L Lino-Pe´rez5, J Mas-Oliva6, O Pe´rez-Me´ndez7 and 1Endocrinology Department, National Institute of Cardiology ‘‘Ignacio Cha´vez’’, Mexico; 2Doctorate Program of Biomedical Sciences from the National Autonomous University of Mexico, Mexico; 3Clinical Epidemiology Research Unit, Number 1 Regional Hospital from the Mexican Institute of the Social Security, Carlos McGregor Sa´nchez Navarro, Mexico; 4Rheumatology Department, National Institute of Cardiology ‘‘Ignacio Cha´vez’’, Mexico; 5Rheumatology Department, Mexican General Hospital, Mexico; 6Cellular Physiology Institute, National Autonomous University of Mexico, Mexico; and 7Molecular Biology Department, National Institute of Cardiology ‘‘Ignacio Cha´vez’’, Mexico Objective: We studied the effect of pioglitazone on insulin levels, inflammation markers, high-density lipoprotein (HDL) composition and subclasses distribution, in young women withuncomplicated systemic lupus erythematosus (SLE).
Methods: This double-blind trial included 30 premenopausal women (30 Æ8 years old) withSLE, who were randomized to pioglitazone (30 mg/day) or placebo treatment for 3 months.
Plasma and HDL lipids were determined by colorimetric enzymatic assays, insulin by radio-immunometric assay, inflammation by immunonephelometry and HDL size and subclassesdistribution by a native 4–30% polyacrylamide gradient gel electrophoresis.
Results: Compared with placebo, pioglitazone significantly increased HDL-cholesterol plasmalevels (14.2%), reduced fasting insulin plasma levels (23.6%) and the homeostasis modelassessment-insulin resistance (31.7%). C-reactive protein (70.9%) and serum amyloid A(34.9%) were also significantly reduced with the pioglitazone use, whereas the HDL particlesize was increased (8.80 nm vs. 8.95 nm; p ¼ 0.044) by changes in the distribution of HDL2b,HDL3b, and HDL3c subclasses. The change in HDL size correlated with a rise in free andcholesterol–ester content in the HDL particles.
Conclusion: Pioglitazone significantly enhanced insulin sensitivity, reduced inflammation, andmodified HDL characteristics, suggesting a potential beneficial effect of this drug in patientswith SLE with a risk to develop cardiovascular disease.
Trial registration: This trial is registered at ClinicalTrials.gov Protocol Registration System,with the number NCT01322308.
Key words: atherosclerosis; inflammation; insulin resistance; lipoproteins; systemic lupuserythematosus one of the most frequent causes of morbidity andmortality in young women.1 The etiology and path- Systemic lupus erythematosus (SLE) is an autoim- ogenesis of atherosclerosis in SLE are only partially mune inflammatory disease in which accelerated explained by traditional risk factors.1,2 Several atherosclerosis and its sequelae are recognized as studies have reported non-traditional markers ofincreased risk for atherosclerotic cardiovasculardisease in patients with SLE, as higher prevalence Correspondence to: Posadas-Romero Carlos, Juan Badiano 1, Seccion inflammation,5 abnormal high-density lipoprotein Received 20 June 2011; accepted 4 August 2011 ! The Author(s), 2011. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav Pioglitazone improves the cardiovascular profile in patients with uncomplicated SLE composition,6,7 as well as higher proportions of Insulin insensitivity is known to be associated with accelerated atherosclerosis and appears to bea risk marker for both myocardial infarction and This was a prospective, randomized, double-blind, stroke.10–13 The impact of insulin resistance may placebo-controlled, parallel group study conducted involve proinflammatory disturbances due to dys- in Mexico City. Eligible participants were preme- functional insulin signaling in different tissues; in nopausal women with SLE older than 18 years, addition to the higher prevalence of insulin resis- attending the outpatient Rheumatology Clinic at tance in SLE patients, it is well known that auto- three Mexico City community tertiary care hospi- immune and chronic inflammatory disorders are tals; the National Institute of Cardiology ‘‘Ignacio associated with the development of accelerated car- Cha´vez’’, the number 1 Regional Hospital from the Mexican Institute of the Social Security and the HDLs vary in composition, size, charge, and bio- Mexican General Hospital. All fulfilled the 1982 logical activities. It has been reported that some of American College of Rheumatology criteria for these lipoprotein characteristics may be more the classification of SLE,27 and to avoid the effect important than the HDL plasma concentrations of other cardiovascular risk factors, we excluded patients with clinical evidence of menopause, dia- (CHD).15 Abnormal distribution of HDL sub- betes, thyroid dysfunction, neurological, renal or classes, characterized by low large HDL levels liver disease, personal history of high blood pres- and high small HDL plasma levels, has been sure, CHD, cerebrovascular events, chronic or reported in patients with SLE,6,7 and in other insu- acute infections, malignancy, and use of drugs or lin resistance states.16,17 Moreover, it has been alcohol abuse. At the time of the study, none of the reported that in SLE patients, HDL particles are patients was smoking, pregnant, breast-feeding, or enriched in triglycerides and depleted of choles- taking hormonal or lipid-regulation drugs. None of terol-esters.6 These abnormalities may result in them was positive to anticardiolipin antibodies, lupus anticoagulant or antibeta-2-glycoprotein-1.
anti-inflammatory effect19 and lower capacity to Subjects were included in the study after they promote cholesterol efflux,20 which is the first step signed the informed consent form for participation (Figure 1). The protocol was approved by the Pioglitazone is an insulin-sensitizing compound Institutional Ethics Committee of each hospital of the thiazolidinedione (TZD) type. TZD activates nuclear receptors called peroxisome proliferator- activated receptors (PPAR), which regulate the The study took place at the National Institute of transcription of genes with key roles in the metab- Cardiology ‘‘Ignacio Cha´vez’’ from March 2007 to olism of carbohydrates and lipids as well as inflam- April 2010, where information about current and mation.21–23 The qualitative effects of pioglitazone cumulative drug therapy or any disease was on HDL may also be important, because it has obtained through a questionnaire and physical been shown to increase the mean HDL size and examination applied to all participants. SLE dis- reduce the core triglyceride content relative to cho- ease activity was assessed using the Mexican mod- lesterol-esters in HDLs from subjects with and ification of the Systemic Lupus Erythematosus Disease Activity Index (MEX-SLEDAI).28 Based Although it has been previously shown that pio- on the MEX-SLEDAI, at time of the evaluation glitazone reduces several cardiovascular risk factors patients were considered to have active disease and renal inflammation in a lupus-prone murine when the score was higher than 5. Height (m), model,14 there are no studies that have examined weight (kg) and blood pressure were measured, the effect of this drug on insulin plasma levels, and body mass index calculated by dividing inflammation markers and HDL composition together with the distribution of their subclasses in patients with SLE. Therefore, the objective ofthis work was to study the effect of treatment The eligibility screening (visit 1) occurred 4 weeks with pioglitazone upon these parameters in non- before randomization. During this visit, qualified diabetic patients with SLE in clinical remission personnel provided dietary counseling on the American Heart Association weight-maintaining Pioglitazone improves the cardiovascular profile in patients with uncomplicated SLEJG Jua´rez-Rojas et al.
Flow chart for the selection and enrollment of patients.
Step 1 and selected patients instructed to follow this Ethylenedinitrilotetraacetate plasma was prepared diet. At visit 2, selected patients were randomly by centrifugation at 4C at 2500 rpm for 20 min assigned into two study arms; they had been and used for glucose, lipids, and lipoprotein mea- informed, as part of the consent, that they would surements, or stored frozen at À70C until their anal- be receiving either a fixed dose of pioglitazone ysis. Aprotinin (100 KIU/ml) and benzamidine (30 mg) or placebo for 12 weeks once daily in the (1 mM) were used as protease inhibitors. Plasma glu- morning. Clinic visits occurred every 4 weeks from cose, total cholesterol, triglycerides, and HDL-cho- visit 3 to visit 5. At all visits, patients were received in lesterol were measured using standardized enzymatic the morning after fasting for at least 10 h. All patients procedures in a Hitachi 902 analyzer (Hitachi LTD, use a reliable contraceptive method throughout the Tokyo, Japan) and were considered within a normal entire study. Pioglitazone and placebo were dis- range when their values were < 100 mg/dl, < 200 mg/ pensed as pills similar in form and appearance.
They were pre-packed in bottles and consecutively Accuracy and precision in our laboratory are under numbered. Each patient was assigned a treatment periodic surveillance by the Centers for Disease number and received the pills in the corresponding Control and Prevention Service (Atlanta, GA, pre-packed bottle. An independent pharmacist dis- USA). Low-density lipoprotein (LDL) cholesterol pensed the corresponding bottle according to a com- was estimated by using the Friedewald formula as puter-generated randomization number list, and modified by De Long et al.30 Total high sensitive participants, care providers and researchers were C-reactive protein (hsCRP), serum amyloid A blinded at treatment assignment. Compliance was (SAA), apolipoprotein B-100 (apo B-100) and apo- assessed every clinic visit by tablet counting.
lipoprotein AI (apo AI) levels, were determined byimmunonephelometry on a BN Pro Spec nephelom-eter (Dade Behring Marburg GmbH, Germany) according to the manufacturer’s method. Inter- At visit 2 and visit 5, venous blood samples were assay coefficients of variation were less than 3%.
Plasma insulin concentrations were determined by Pioglitazone improves the cardiovascular profile in patients with uncomplicated SLE SD/(m0 – m1)]2 ¼ [(1.65 þ 0.84) 0.25 / (8.4 – 8.6)]2.25 Diagnostic Products, Los Angeles, California, Ten patients were needed in each group to have USA). Insulin resistance was estimated with the use 80% power at the 5% significance level. We of the homeostasis model assessment-insulin resis- recruited and randomize 15 patients in each treat- tance (HOMA-IR).31 The normal values for insulin respectively, according to the 75th percentile from a sample of healthy women, previously described.6 All analyses were carried out using statistical soft-ware SPSS 13.0 for WINDOWS (SPSS inc., Chicago IL, USA). Results are expressed as HDL separated from plasma by ultracentrifugation mean Æ standard deviation (SD) for normally dis- at a density of 1.21 g/ml was loaded into a native tributed variables or median (interquartile range) 4–30% polyacrylamide gradient gel. After poly- for those with non-normal distribution. There acrylamide gradient gel electrophoresis, gels were were no outlier values in our study sample.
stained for proteins with Coomassie brilliant blue R-250, scanned and digitalized in a GS-670 Bio- Student’s-t-test or Mann–Whitney U for indepen- Rad densitometer, using the software Molecular dent groups, and within-group differences were AnalystTM. Migration distance intervals of each analyzed by Student’s t-test or Wilcoxon for gel was calculated by computing a standard curve paired samples. Spearman correlation coefficients of the protein-stainable high molecular weight stan- dards (thyroglobulin, 17 nm; ferritin, 12.2 nm; cat- between all variables studied and the HDL size.
alase, 10.4 nm; lactate dehydrogenase, 8.2 nm; and All results with p < 0.05 were considered statisti- albumin, 7.1 nm) as a function of their relative migration distance.32,33 The relative proportion ofeach HDL subclass was estimated with the follow-ing size intervals: HDL 7.76–8.17 nm; HDL3a 8.17–8.77 nm; HDL2a 8.77–9.71 nm; and HDL2b 9.71–12.93 nm. The coefficient All 30 randomized patients followed and finished of variation for each subclass was less than 10%.
all study. The baseline clinical characteristics were The average HDL particle size represents the over- similar in both groups (Table 1). For all studied all distribution of the HDL subclasses,32,33 and was women, the median SLE duration was 5.0 years calculated as the average size of each HDL subclass (interquartile range: 2.0–10.0) and disease activity interval (nm), multiplied by its relative area under was 2.5 (1.2–4.7). Use of prednisone (46.7%) and the densitometric scan. Coefficient of variation for antimalarials (83.3%) was similar in the two this determination was less than 1%.
groups. Three patients (20%) in the placebogroup and five (33%) in the pioglitazone group were taking more than 10 mg/day of prednisone, Total protein, total cholesterol, free cholesterol, and two patients (13%) in each group were taking phospholipids, and triglycerides content of isolated more than 200 mg/day of antimalarials. Patients of HDL were determined in a Hitachi 902 analyzer, every group were clinically and biochemically inac- using commercially available enzymatic assays.
tive and no changes in SLE activity, pharmacologytreatment, and blood pressure levels were observed Cholesteryl-esters were calculated by multiplying during the study. No changes in the median of body the difference between total and free cholesterol mass index (24.9 vs. 24.8; p ¼ NS), hemoglobin by 1.67.34 Apolipoprotein content (apo A-I, apo A-IV, apo-E and apo-Cs) was evaluated semi-quan- (39.1% vs. 38.4%; p ¼ NS), aspartate aminotrans- titatively by SDS–polyacrylamide gradient gel ferase (21.3 U/l vs. 21.7 U/l; p ¼ NS) and alanine aminotransferase (16.1 U/l vs. 17.3 U/l; p ¼ NS)were Similar results were observed in the placebo Sample size calculation was employed to detect group (data not shown). According to pill count, changes in HDL size using pioglitazone monother- all patients completed the study with an overall apy.25 We anticipated an increase in HDL size at 12 compliance of 94% (95% in placebo vs. 93% in weeks from baseline, and calculated as [(Za þ Zb) pioglitazone group; p ¼ NS). Adverse effects were Pioglitazone improves the cardiovascular profile in patients with uncomplicated SLEJG Jua´rez-Rojas et al.
Baseline demographic and clinical parameters Mean Æ S.D. or median (interquartile range).
a ¼ Student t-test for mean or Mann–Whitney U for median.
SLE, Systemic Lupus Erythematosus; MEX–SLEDAI, Mexican Modification of Systemic Lupus Erythematosus Disease Activity Index.
reported in three patients in the placebo group (headache, chest tightness, paresthesia, dizziness, observed that only free cholesterol increased signif- nausea and joint pain) and in two patients in the icantly after pioglitazone treatment compared with pioglitazone group (headache and insomnia). All the placebo group (þ6.82% vs. À4.87%; p ¼ 0.043).
these adverse effects disappeared after the 4th increase in the pioglitazone treatment compared Lipids, glucose, and insulin parameters are with the placebo group (þ5.03% vs. À1.68%; shown in Table 2. Pioglitazone increased HDL- p ¼ 0.09). The content of phospholipid and triglyc- cholesterol levels (14.2%; p ¼ 0.029) after 12 erides, as well as the apolipoprotein content of weeks of treatment. No changes were observed in HDL, was not different at the beginning and at the placebo group. Total and LDL cholesterol, tri- glycerides, apolipoproteins AI and B-100, as well as Spearman correlation analyses between anthro- glucose levels were similar between both groups at pometric measurements, systolic and diastolic baseline and after treatment. Fasting insulin levels blood pressure, activity and duration of SLE, and HOMA-IR were not statistically different lipid variables, insulin, HOMA-IR, CRP, SAA as between groups at baseline; however, both param- well as composition and size of HDL, showed that increases of free cholesterol in HDL particles p ¼ 0.006 and 31.7%; p ¼ 0.008, respectively), but concentration (r ¼ 0.522; p ¼ 0.003), cholesterol- decreased 70.9% vs. 0.3% in the pioglitazone and esters in HDL particles (r ¼ 0.443; p ¼ 0.023), and placebo groups, respectively (p ¼ 0.013), whereas apo AI (r ¼ 0.411; p ¼ 0.027), correlated with the SAA decreased 34.9% in the pioglitazone and increased 25.5% in the placebo group (p ¼ 0.029).
Distribution of HDL subclasses was not different between groups before treatment. Although the proportion of HDL2b was the only subfractionthat showed significant increase after pioglitazonetreatment (11.9% vs. 13.3%; p ¼ 0.030), the per- To the best of our knowledge, this prospective ran- domized controlled trial for the first time indicates was different in the pioglitazone versus the placebo significant and potentially important changes in group (Figure 2). Pioglitazone favored an increase insulin levels, inflammation, HDL-cholesterol and HDL composition as well as subclass distribution p ¼ 0.044) and the mean percentage change was sig- in uncomplicated non-diabetic SLE patients during nificantly different than that observed in the pla- treatment with pioglitazone (3 months; 30 mg/day).
cebo group (þ0.77% vs. À0.67%; p ¼ 0.018).
These clinical effects, in addition to extensive Pioglitazone improves the cardiovascular profile in patients with uncomplicated SLE Lipidic, glucometabolic and inflammation parameters before and after treatment with placebo or pioglitazone Median (interquartile range).
a ¼ Wilcoxon test.
LDL, Low Density Lipoprotein; HDL, High Density Lipoprotein; HOMA-IR, homeostasis model assessment-insulin resistance; hsCRP, highsensitivity C reactive protein.
beyond their classical use as regulator for glycemiccontrol.
For a long time, it has been known that patients with lupus present substantially increased morbid-ity and mortality rates associated with cardiovascu-lar disease. Traditional risk factors, or lupus itselfand treatment-related factors, only partly accountfor the increased risk of CHD in patients withSLE.1,5 Insulin resistance, defined as the reducedability of insulin to stimulate glucose uptake inskeletal muscle and fat cells, is an emerging meta-bolic risk factor that may play a pivotal role inatherogenesis in lupus.35 We3 and others4 have pre-viously shown that patients with SLE presentedhigher fasting plasma insulin levels as well as Change in high-density lipoprotein subfraction dis- reduced insulin sensitivity related to cardiovascular tributions in patients with systemic lupus erythematosus, after12 weeks of pioglitazone (30 mg/day) or placebo treatment.
risk factors in SLE patients.35 The present studyshows that pioglitazone administration leads to asignificant decrease in insulin levels (23.6%) andHOMA-IR (31.7%). This finding correlates wellwith a study where a lupus-prone murine model in vitro and in vivo studies assessing anti-inflamma- showed improvement of insulin resistance and pro- tory and anti-atherosclerotic effects of PPAR ago- duced stable glucose levels after pioglitazone nist, indicate that these drugs may be powerful administration.14 Therefore, improving insulin sen- sitivity in patients at risk due to SLE may preventthe occurrence of cardiovascular complications, Pioglitazone improves the cardiovascular profile in patients with uncomplicated SLEJG Jua´rez-Rojas et al.
independently of glucose levels, as other investiga- pioglitazone raised HDL-cholesterol levels by tors have shown in patients with and without dia- 14.2%, similar to previous studies where pioglita- $10–20%.21 It has been suggested that PPAR sig- inflammatory disorders are associated with the naling may play a role in stimulating expression of development of accelerated atherosclerosis have the gene encoding ABCA1,50 which could increase been increasingly recognized.38 In our study, treat- the flux of cholesterol from cells on to apo AI.51 If ment with pioglitazone significantly decreased PPAR were involved in regulating ABCA1 gene hsCRP and SAA by 70.9% and 34.9%, respec- expression, additional effects on plasma HDL-cho- tively. Previous studies have shown that pioglita- lesterol levels and HDL particles might be seen.
zone decreases hsCRP plasma levels.21 However, Although it is a widely accepted notion that low to our knowledge, this is the first study where HDL-cholesterol levels constitute an independent SAA plasma levels were decreased by pioglitazone risk factor for premature atherosclerosis and use. SAA is the major acute-phase protein in verte- CHD, there is increasing evidence that HDL parti- brates and is synthesized in the liver in response to cle characteristics may be more important than quantity for atheroprotection.15 We6 and others7 Although other non-specific inflammatory markers have previously demonstrated that compared with such as hsCRP also correlate with cardiovascular control subjects, patients with SLE have triglycer- disease, the wider dynamic range as well as the ide enrichment and cholesterol-ester depletion of more rapid response and easier measurement of HDL, as well as low concentrations of large SAA has lead to the suggestion that it may be a HDLs and high levels of small HDL particles.
better marker of disease,40,41 and has been shown These abnormal HDL particles have been found in other hyperinsulinema states, and have been Thiazolidinediones such as rosiglitazone or trogli- associated with coronary heart disease52 and recur- tazone reduce SAA by about 30–50% in diabetic rence of coronary events.12 In fact, McMahon et al.
and non-diabetic subjects;44,45 however, only one reported that 48.2% from 276 SLE patients have previous report46 has evaluated the effect of piogli- proinflammatory HDLs, and that these proinflam- tazone treatment on SAA. That study46 showed matory HDLs contribute to a 17-fold increased that patients with diabetes mellitus did not present odds for the presence of atherosclerosis.9 Our changes in SAA plasma levels in spite of an results show that pioglitazone modified HDL par- improvement in insulin sensitivity. Since inflamma- ticle size and composition, and although we did not tion is associated with diabetes mellitus, it is possi- evaluate HDL atheroprotective functionality after ble that the anti-inflammatory effect of pioglitazone pioglitazone use, several studies have shown that could be more important in patients with SLE, small HDL particles and HDLs enriched in triglyc- where inflammation plays a central role in the erides or depleted of cholesterol show a diminished development of atherosclerosis.47,48 Our results atheroprotective function and are associated with a show that in addition to the improvement in insulin poor prognosis for cardiovascular disease.12,15,52 resistance, pioglitazone also reduces inflammation Therefore, our findings suggest that pioglitazone in a short time. It is important to highlight that could restore the HDL atheroprotective functions pioglitazone might reduce the risk of CHD in patients with uncomplicated SLE, by reducing the It is important to note that the small sample size alterations promoted by lupus itself. Longitudinal may explain the lack of significant differences in and epidemiological studies are needed to investi- plasma apo AI levels and HDL composition after gate the effect of this drug over long-term pioglitazone treatment. However, the 15 patients included in the pioglitazone arm were enough to Hypertriglyceridemia and low HDL-cholesterol detect changes in insulin, inflammation and HDL levels are components of insulin resistance states particle size. The clinical implications of these find- and of SLE dyslipidemia.5 In SLE, these lipidic ings are that even in SLE patients without addi- abnormalities correlate with drug therapy, disease tional risk factors, representing approximately activity, metabolic syndrome, and inflammatory 15% of our cohort, pioglitazone may have the potential to prevent premature CHD. We do not study,9 we found that HDL-cholesterol and triglyc- have hard endpoints in our study to confirm if all eride levels were normal in our group of patients, these qualitative and quantitative changes are possibly due to the fact that we selected subjects reflected in a prognostic improvement of patients with SLE. Longitudinal studies are necessary to Pioglitazone improves the cardiovascular profile in patients with uncomplicated SLE evaluate the cardiovascular effects of long-term pio- 2 Svenungsson E, Jensen-Urstad K, Heimbu¨rger M, et al. Risk fac- tors for cardiovascular disease in systemic lupus erythematosus.
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3 Posadas-Romero C, Torres-Tamayo M, Zamora-Gonza´lez J, et al.
In conclusion, the findings of our study indicate High insulin levels and increased low-density lipoprotein oxidiz- that pioglitazone treatment may exert multiple ben- ability in pediatric patients with systemic lupus erythematosus.
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eficial cardiovascular effects in uncomplicated nor- 4 El Magadmi M, Ahmad Y, Turkie W, et al. Hyperinsulinemia, moglycemic SLE patients. This drug significantly insulin resistance, and circulating oxidized low density lipoprotein enhanced insulin sensitivity, reduced inflammation in women with systemic lupus erythematosus. J Rheumatol 2006;33: 50–56.
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