Christina Kostara

Atherogenic lipid profile is a feature characteristic of patients with early rheumatoid arthritis: effect of early treatment – a prospective, controlled study

We investigated lipid profiles and lipoprotein modification after immuno-intervention in patients with early rheumatoid arthritis (ERA). Fifty-eight patients with ERA who met the American College of Rheumatology (ACR) criteria were included in the study. These patients had disease durations of less than one year and had not had prior treatment for it. Smokers or patients suffering from diabetes mellitus, hypothyroidism, liver or kidney disease, Cushings syndrome, obesity, familiar dyslipidemia and those receiving medications affecting lipid metabolism were excluded from the study. Sixty-three healthy volunteers (controls) were also included. Patients were treated with methotrexate and prednisone. Lipid profiles, disease activity for the 28 joint indices score (DAS-28) as well as ACR 50% response criteria were determined for all patients. The mean DAS-28 at disease onset was 5.8 ± 0.9. After a year of therapy, 53 (91.3%) patients achieved the ACR 20% response criteria, while 45 (77.6%) attained the ACR 50% criteria. In addition, a significant decrease in the DAS-28, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were observed. ERA patients exhibited higher serum levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglycerides, whereas their serum high-density lipoprotein cholesterol (HDL-C) levels were significantly lower compared to controls. As a consequence, the atherogenic ratio of TC/HDL-C as well as that of LDL-C/HDL-C was significantly higher in ERA patients compared to controls. After treatment, a significant reduction of the atherogenic ratio of TC/HDL-C as well as that of LDL-C/HDL-C was observed, a phenomenon primarily due to the increase of serum HDL-C levels. These changes were inversely correlated with laboratory changes, especially CRP and ESR. In conclusion, ERA patients are characterized by an atherogenic lipid profile, which improves after therapy. Thus, early immuno-intervention to control disease activity may reduce the risk of the atherosclerotic process and cardiovascular events in ERA patients.

Effects of rosuvastatin combined with olmesartan, irbesartan, or telmisartan on indices of glucose metabolism in Greek adults with impaired fasting glucose, hypertension, and mixed hyperlipidemia: a 24-week, randomized, open-label, prospective study.

BACKGROUND Statin therapy has been reported to be associated with new-onset diabetes. Angiotensin II-receptor blockers (ARBs) are effective antihypertensive drugs that have been reported to activate peroxisome proliferator-activated receptor gamma (PPARgamma) to differing extents, with favorable effects on glucose metabolism and the incidence of new-onset diabetes. Among the ARBs, telmisartan is a partial activator of PPARgamma, irbesartan is a weak partial activator, and olmesartan has no effect on PPARgamma activation. OBJECTIVE The goal of this study was to evaluate the effects on glucose homeostasis of combining rosuvastatin with ARBs of varying PPARgamma-activating potency in Greek adults with impaired fasting glucose, mixed dyslipidemia, and stage 1 hypertension. METHODS This was a 24-week, randomized, open-label study. Inclusion criteria were impaired fasting plasma glucose (FPG) (100-125 mg/dL [5.6-6.9 mmol/L]), mixed dyslipidemia (LDL-C >160 mg/dL [4.14 mmol/L] and triglycerides >150 mg/dL [1.69 mmol/L]), and stage 1 hypertension (systolic blood pressure 140-159 mm Hg and/or diastolic blood pressure 90-99 mm Hg). After 12 weeks of dietary intervention, patients were randomly allocated to receive rosuvastatin 10 mg/d plus telmisartan 80 mg/d (RT group), irbesartan 300 mg/d (RI group), or olmesartan 20 mg/d (RO group) for 24 weeks. The primary end point was change in the following indices of glucose metabolism after 6 months of treatment: FPG, homeostasis model assessment of insulin resistance (HOMA-IR), HOMA of beta-cell function (HOMA-B), and glycosylated hemoglobin (HbA(1c)). Secondary end points included changes in anthropometric variables, blood pressure, serum lipids, and high-sensitivity C-reactive protein (hs-CRP). Tolerability was monitored throughout the study. RESULTS After the 12-week dietary intervention, 151 white patients (78 female, 73 male) met the inclusion criteria and were randomized to receive RT (n = 52), RI (n = 48), or RO (n = 51). The mean (SD) age of the 3 groups was 60 (10), 60 (10), and 58 (12) years, respectively; their mean weight was 79 (11), 81 (12), and 78 (11) kg. At 6 months, the RT group had a 29% decrease in HOMA-IR (from a median [range] of 2.6 [0.6-6.6] to 1.8 [0.5-5.1]), the RI group had a 16% increase (from 2.5 [0.5-6.2] to 2.9 [0.5-8.1]), and the RO group had a 14% increase (from 2.4 [0.5-7.9] to 2.7 [0.5-5.2]) (all, P < 0.05 vs baseline). The improvement in the RT group was statistically significant compared with the RI group (P < 0.01) and the RO group (P < 0.05). The changes from baseline in FPG and HbA(1c) were not significant in any group. Fasting serum insulin decreased by 21% in the RT group (from 10.4 [2.4-28.1] to 8.2 [2.4-18.8] microU/mL), whereas it increased by 12% in the RI group (from 9.1 [2.0-26.5] to 10.2 [2.0-25.2] microU/mL) and by 8% in the RO group (from 10.1 [2.0-29.6] to 10.9 [2.0-19.1] microU/mL) (all, P < 0.05 vs baseline). Again, there was a significant difference between the RT group and the RI group (P < 0.01) and RO group (P < 0.05). Levels of hs-CRP decreased by 44% in the RT group (from 2.2 [0.3-7.9] to 1.2 [0.4-7.0] mg/L), by 12% in the RI group (from 2.2 [0.3-12.3] to 1.9 [0.2-11.4] mg/L), and by 22% in the RO group (from 2.1 [0.7-4.0] to 1.7 [0.7-6.2] mg/L). The difference was statistically significant for the RT group compared with baseline and with the RI and RO groups (all comparisons, P < 0.05). Blood pressure was significantly reduced from baseline in all 3 groups, with no significant differences between groups. No serious adverse events were reported during the study, nor were there any clinically significant elevations in aminotransferases or creatine kinase. CONCLUSION In this small, randomized, open-label study, the RT combination had favorable effects on HOMA-IR, fasting serum insulin, and hs-CRP compared with the RI and RO combinations in Greek adults with impaired fasting glucose, mixed hyperlipidemia, and stage 1 hypertension.

Plasma lipoproteins and triacylglycerol are predictors of small, dense LDL particles.

Recently published data suggest that the assessment of LDL subfraction profiles may contribute to the determination of the cardiovascular risk. In this study, we tested the ability of various metabolic parameters to estimate the presence or the preponderance of small, dense LDL particles (sdLDL). One hundred and fifty individuals attending the Outpatient Clinics of the University Hospital of Ioannina for suspected metabolic abnormalities were included in the study. Individuals were excluded if they were found to be diabetic or if they had a history of cardiovascular disease. Patients with thyroid dysfunction, liver or kidney diseases as well as those receiving drugs that may interfere with lipids or glucose metabolism were also excluded from the study. The ability of the various parameters to identify individuals with pattern B LDL phenotype or, alternatively, with measurable quantities of sdLDL particles was tested with the calculation of the areas under the ROC curves. The ratio of triglycerides to HDL-C was the best predictor of the presence of the pattern B LDL phenotype. Nevertheless, when the variable of interest was the presence of measurable quantities of sdLDL subfractions, the ratio of apoB to apoAI had the best predictive ability. In conclusion the ratios of apoB to apoAI and of triglycerides to HDL-C can reliably predict the presence of measurable quantities of sdLDL particles and of the pattern B LDL phenotype, respectively. However, since the quantitative determination of sdLDL concentrations may contribute to the determination of the cardiovascular risk, whereas the role of the LDL particle size remains controversial, apoB to apoAI ratio could provide more valuable information compared to markers that simply predict the presence of the pattern B LDL phenotype.

Effect of rosuvastatin monotherapy or in combination with fenofibrate or ω-3 fatty acids on lipoprotein subfraction profile in patients with mixed dyslipidaemia and metabolic syndrome

Background:  Raised triglycerides (TG), decreased high‐density lipoprotein cholesterol (HDL‐C) levels and a predominance of small dense low density lipoproteins (sdLDL) are characteristics of the metabolic syndrome (MetS).

Effects of rosuvastatin with or without ezetimibe on clinical outcomes in patients undergoing elective vascular surgery: results of a pilot study.

Objective: Cardiovascular complications represent a major cause of morbidity and mortality in patients undergoing vascular surgery. This was a prospective randomized, open-label study to investigate the effect of lipid-lowering treatment by statin monotherapy or intensified by combining statin with ezetimibe on a 12-month prognosis after vascular surgery. Methods: Patients were randomly assigned to receive rosuvastatin (RSV) 10 mg/d or rosuvastatin 10 mg/d plus ezetemibe (RSV/EZT) 10 mg/d, starting prior to scheduled surgical procedure. The primary end point was the first major cardiovascular event, including death from cardiac causes, nonfatal myocardial infarction, ischemic stroke, and unstable angina. Results: A total of 136 patients assigned to RSV and 126 to RSV/EZT completed the study protocol. As many as 6.6% of patients in the RSV group experience a major cardiovascular event within 30 days after surgery versus 5.6% in the RSV/EZT group (P = .72). From month 1 to 12 of the follow-up period, primary end point was observed (9 taking RSV vs 2 in the RSV/EZT group [P = .04]). Intensified lipid-lowering therapy with RSV/EZT was associated with a greater decrease in low-density lipoprotein cholesterol levels compared with RSV (75.87 ± 31.64 vs 87.19 ± 31.7, P = .004), while no differential effect on triglyceride, high-density lipoprotein cholesterol or high-sensitivity C-reactive protein levels was noted between groups. Conclusion: Our findings indicate that statin therapy intensified by ezetimibe may reduce the incidence of cardiovascular events within the first 12 months after vascular surgery. Nonetheless, whether the use of ezetimibe as an add-on therapy to reduce cardiovascular risk in these patients needs to be tested in larger future studies.

NMR-based lipidomic analysis of blood lipoproteins differentiates the progression of coronary heart disease.

Abnormal lipid composition and metabolism of plasma lipoproteins play a crucial role in the pathogenesis of coronary heart disease (CHD). A (1)H NMR-based lipidomic approach was used to investigate the correlation of coronary artery stenosis with the atherogenic (non-HDL) and atheroprotective (HDL) lipid profiles in 99 patients with CHD of various stages of disease and compared with 60 patients with normal coronary arteries (NCA), all documented in coronary angiography. The pattern recognition models created from lipid profiles predicted the presence of CHD with a sensitivity of 87% and a specificity of 88% in the HDL model and with 90% and 89% in the non-HDL model, respectively. Patients with mild, moderate, and severe coronary artery stenosis were progressively differentiated from those with NCA in the non-HDL model with a statistically significant separation of severe stage from both mild and moderate. In the HDL model, the progressive differentiation of the disease stages was statistically significant only between patients with mild and severe coronary artery stenosis. The lipid constituents of lipoproteins that mainly characterized the initial stages and then the progression of the disease were the high levels of saturated fatty acids in lipids in both HDL and non-HDL particles, the low levels of HDL-phosphatidylcholine, HDL-sphingomyelin, and omega-3 fatty acids and linoleic acid in lipids in non-HDL particles. The conventional lipid marker, total cholesterol, found in low levels in HDL and in high levels in non-HDL, also contributed to the onset of the disease but with a much lower coefficient of significance. (1)H NMR-based lipidomic analysis of atherogenic and atheroprotective lipoproteins could contribute to the early evaluation of the onset of coronary artery disease and possibly to the establishment of an appropriate therapeutic option.

Evaluation of the proximal tubular function in individuals with primary renal hypouricemia: an NMR-based metabonomic study

Primary renal hypouricemia (PRH) refers to a rare condition of increased renal urate clearance, caused by an isolated inborn error of membrane transport of urate in the renal proximal tubule. Several cases of exercise‐induced acute renal failure and urolithiasis have been reported. This is the first study that assessed tubular function in PRH using NMR‐based metabonomic urine analysis. The study groups consisted of 36 unrelated asymptomatic subjects with PRH, defined as serum uric acid levels (sUA) <2.5 mg/dL and fractional excretion of uric acid (FEUA) >10%, after exclusion of diseases and drugs that may affect urate homeostasis, and 39 sex and age‐matched healthy individuals with normal sUA levels (>4.0 mmol/L) and FEUA<10%. Individuals with primary hypouricemia presented similar biochemical profiles to the controls without significant differences with regard to FE of electrolytes and renal threshold for phosphate excretion. Individuals with primary hypouricemia were differentiated from healthy individuals in the orthogonal signal correction/partial least‐squares–discriminant analysis models of the NMR data with a statistically significant separation. The components that contributed to this separation were the lower levels of hippurate, creatinine, and trimethylaminoxide, and the higher levels of phenylalanine, alanine, glycine, glutamate, acetate, and of an unidentified metabolite (3.3 ppm) observed in hypouricemic subjects compared with controls. Primary hypouricemia, though considered an isolated renal tubular defect, is often associated with a more generalized proximal tubular disorder that mimics a partial Fanconi syndrome. Copyright

Analysis of 6-month effect of orlistat administration, alone or in combination with fenofibrate, on triglyceride-rich lipoprotein metabolism in overweight and obese patients with metabolic syndrome

BACKGROUND Orlistat significantly reduced serum triglycerides (TG) in most clinical trials. Orlistat-induced TG reduction has not been studied to determine the factors contributing to TG alterations in clinical settings. OBJECTIVE We examined the factors influencing TG reduction during orlistat administration, alone or in combination with fenofibrate, and we investigated the effects of these treatments on apolipoprotein C-II (ApoC-II) and C-III (ApoC-III) levels. METHODS Patients with the metabolic syndrome were randomly allocated to receive orlistat 120 mg three times daily (n = 28, O group), micronized fenofibrate 200 mg/day (n = 28, F group), or both (n = 27, OF group) for 6 months. Plasma ApoC-II and ApoC-III were determined by an immunoturbidimetric assay. RESULTS In the O group, we observed reductions of plasma ApoC-III (P < 0.05) and ApoC-II (P = NS) levels. Fenofibrate administration significantly reduced concentrations of ApoC-II and ApoC-III, whereas the combination of orlistat and fenofibrate had an additive effect on these apolipoproteins. There were significant in-group reductions in serum TG levels in all treatment groups. Multivariate analysis showed that in O groups baseline TG levels were independently positively correlated, whereas the baseline ApoC-II levels were negatively correlated with TG-lowering. In the F group, baseline TG levels and ApoC-III reduction were significantly and independently correlated with TG reduction. OF groups baseline TG levels and ApoC-III reduction were independently positively correlated and baseline ApoC-II levels were negatively correlated with TG-lowering. CONCLUSIONS Orlistat-mediated TG-lowering is independently associated with baseline TG and ApoC-II levels. When orlistat is combined with fenofibrate, ApoC-III reduction is another independent contributor to TG alterations.

Effect of rimonabant, micronised fenofibrate and their combination on cardiometabolic risk factors in overweight/obese patients: a pilot study.

Objective: To assess the effect of rimonabant, micronised fenofibrate and their combination on anthropometric and metabolic parameters in overweight/obese patients with dyslipidaemia. Methods: All patients (n = 30) received a hypocaloric diet (∼ 600 kcal/day deficit) and were randomly allocated to receive open-label rimonabant (R) 20 mg/day (n = 10), micronised fenofibrate (F) 200 mg/day (n = 10) or rimonabant 20 mg/day plus fenofibrate 200 mg/day (RF) (n = 10). Anthropometric and metabolic parameters were assessed at baseline and 3 months after treatment initiation. Results: Compared with baseline similar significant reductions in body weight, body mass index and waist circumference were observed in the R (–6, –5 and –5%, respectively; p < 0.01) and RF group (–5% for all, p < 0.05), while improvements in these parameters were smaller in the F group (–2, –2.5 and –2%, respectively; p < 0.05). Triglycerides were reduced by 18% in the R group (p = NS), by 39% in the F group (p < 0.001) and by 46% in the RF group (p < 0.05). Importantly, combination treatment resulted in a 42% increase in high-density lipoprotein cholesterol (HDL-C) levels (p < 0.05), while HDL-C was not significantly altered in the two monotherapy groups. Subsequently, a more pronounced increase in apolipoprotein A-I (ApoA-I) levels (+25%) was observed in the RF group compared with changes in both monotherapy groups (p < 0.0001 vs R and p < 0.005 vs F group). Low-density lipoprotein cholesterol (LDL-C) levels were not significantly altered in any group. Apolipoprotein B (apoB) levels were reduced in all groups and this reduction was significantly more pronounced in the RF group (p < 0.05 vs baseline as well as p < 0.005 and p < 0.01 for RF vs R and F groups, respectively). ApoB/apoA-I ratio decreased by 3% with R (p = NS), by 18% with F (p < 0.05) and by 40% with RF treatment (p < 0.01). Total cholesterol to HDL-C ratio decreased by 20% with F (p < 0.0001) and by 33% with RF therapy (p < 0.005), while it was not significantly altered in R group. Conclusion: The combination of rimonabant and fenofibrate may further improve metabolic parameters in overweight/obese patients with dyslipidaemia compared with each monotherapy. This improvement is particularly pronounced for HDL-C levels.

Plasma triglyceride levels and body mass index values are the most important determinants of preβ-1 HDL concentrations in patients with various types of primary dyslipidemia

OBJECTIVE Experimental studies have shown that the prebeta-1 subclass of high-density lipoprotein particles (prebeta-1 HDL) may play an important role in the reverse cholesterol transport pathway as the initial acceptors of cellular cholesterol. The aim of the present study was the direct comparison of prebeta-1 HDL values in individuals with various types of primary dyslipidemias. METHODS Four hundred and eighty-six unrelated individuals were included in the study. According to their lipid values study participants were subdivided into four groups: control group (n=206), type IIA dyslipidemia group (n=148), type IIB dyslipidemia group (n=49) and type IV dyslipidemia group (n=83). RESULTS All dyslipidemic patients displayed higher concentrations of prebeta-1 HDL compared to control individuals. However, patients with dyslipidemias characterized by an abnormal catabolism of triglyceride-rich lipoproteins (such as dyslipidemias of type IIB and IV) tend to have higher prebeta-1 HDL values compared to patients with hypercholesterolemia, and this increase is proportional to the degree of hypertriglyceridemia. In addition, patients with metabolic syndrome exhibited significantly higher levels of prebeta-1 HDL compared to individuals that do not fulfill the criteria for the diagnosis of this syndrome. Multiple regression analysis revealed that serum triglyceride concentrations and body mass index (BMI) values were the most important determinants of prebeta-1 HDL levels in our population. CONCLUSION All dyslipidemic patients exhibit increased prebeta-1 HDL concentrations as compared to normolipidemic individuals. Whether this increase represents a defensive mechanism against atherosclerosis or it is indicative of impaired maturation of HDL particles and thus of a defective reverse cholesterol transport mechanism remains to be established.