ezetimibe--simvastatin-drug-combination and Renal-Insufficiency--Chronic

Topics: Azetidines; Cardiovascular Diseases; Cholesterol; Disease Progression; Drug Combinations; Dyslipidemias; Ezetimibe, Simvastatin Drug Combination; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kidney Glomerulus; Kidney Tubules; Lipoproteins; Renal Insufficiency, Chronic; Risk Factors; Simvastatin

Chronic kidney disease (CKD) is characterized by increased oxidative stress (OS). In consideration of the well-known link between OS and DNA methylation we assessed DNA methylcytosine (mCyt) concentrations in CKD patients at baseline and during cholesterol lowering treatment.. DNA methylation and OS indices (malonyldialdehyde, MDA; allantoin/uric acid ratio, All/UA) were measured in 30 CKD patients randomized to three cholesterol lowering regimens for 12 months (simvastatin 40 mg/day, ezetimibe/simvastatin 10/20 mg/day, or ezetimibe/simvastatin 10/40 mg/day) and 30 age- and sex-matched healthy controls. DNA methylation was significantly lower in CKD patients vs. controls (4.06 ± 0.20% vs. 4.27 ± 0.17% mCyt, p = 0.0001). Treatment significantly increased mCyt DNA concentrations in all patients (4.06 ± 0.04% at baseline; 4.12 ± 0.03% at 4 months; 4.17 ± 0.03% at 8 months; and 4.20 ± 0.02% at 12 months, p = 0.0001 for trend). A trend for a greater effect on DNA methylation was observed with combined treatment ezetimibe/simvastatin 10/40 mg/day (+5.2% after one year treatment). The treatment-associated mCyt increase was significantly correlated with the concomitant reduction in MDA concentrations and All/AU ratios.. Our results demonstrate that CKD patients have a lower degree of DNA methylation and that cholesterol lowering treatment restores mCyt DNA concentrations to levels similar to healthy controls. The treatment-associated increase in DNA methylation is correlated with a concomitant reduction in OS markers. The study was registered at clinicaltrials.gov (NCT00861731).

Topics: 5-Methylcytosine; Aged; Allantoin; Biomarkers; Cholesterol; DNA Methylation; Down-Regulation; Ezetimibe, Simvastatin Drug Combination; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Italy; Male; Malondialdehyde; Middle Aged; Oxidative Stress; Renal Insufficiency, Chronic; Simvastatin; Time Factors; Treatment Outcome; Uric Acid

The dyslipidemia control through lipid lowering therapy is one of the targets for the treatment of CKD. By this pilot study we aimed to evaluate the effect of hypolipidemic drugs on the levels of low molecular weight (LMW) thiols bound to LDL in nephropatic patients. We enrolled thirty CKD randomized to receive three different hypolipidemic regimens: simvastatin alone (40 mg/day) or ezetimibe/simvastatin combined therapy (10/20 or 10/40 mg/day). LMW thiols in their reduced and total form, oxidative stress indices as malondialdehyde and allantoin/uric acid ratio were evaluated. LDL thiolation decreased in all treated patients, but a greater efficacy was attained from a combined therapy with a higher simvastatin dose, by which a 31% decrease of all S-bound thiols was reached after 1 year of therapy. In particular, in this patients group the reduction of apoB-Hcy was greater than 40%. The concomitant decrease of the oxidative stress indices during the therapy brings to the hypothesis that decreased levels of protein bound thiols may be a consequence of oxidative stress improvement. Therefore lipid lowering therapy may have beneficial effects also through the reduction of LDL-S-homocysteinylation that has been reported to have antiangiogenic and proatherogenic effect on endothelial vascular cells.

Topics: Allantoin; Apolipoproteins B; Azetidines; Cholesterol, LDL; Drug Combinations; Dyslipidemias; Ezetimibe, Simvastatin Drug Combination; Female; Homocystine; Humans; Hypolipidemic Agents; Lipid Metabolism; Male; Malondialdehyde; Middle Aged; Oxidative Stress; Pilot Projects; Renal Insufficiency, Chronic; Simvastatin; Sulfhydryl Compounds; Uric Acid

Triglyceride-rich lipoproteins may contribute to the high cardiovascular risk of patients with CKD. This study evaluated associations of apo-B and markers of triglyceride-rich lipoproteins with cardiovascular events in people with CKD.. Analyses were conducted in 9270 participants with CKD in the Study of Heart and Renal Protection (SHARP): 6245 not on dialysis (mean eGFR 26.5 ml/min per 1.73 m. During a median follow-up of 4.9 years (interquartile range, 4.0-5.5 years), 1406 participants experienced at least one atherosclerotic vascular event. In multivariable adjusted models, positive associations with atherosclerotic vascular events were observed for apo-B (HR per 1 SD, 1.19; 95% confidence interval, 1.12 to 1.27), triglycerides (1.06; 1.00 to 1.13), the ratio of triglyceride to HDL cholesterol (1.10; 1.03 to 1.18), and triglyceride-rich lipoprotein cholesterol (1.14; 1.05 to 1.25). By contrast, inverse associations with nonatherosclerotic vascular events were observed for each of these lipid markers: apo-B (HR per 1 SD, 0.92; 0.85 to 0.98), triglycerides (0.86; 0.81 to 0.92), the ratio of triglyceride to HDL cholesterol (0.88; 0.82 to 0.94), and triglyceride-rich lipoprotein cholesterol (0.85; 0.77 to 0.94).. Higher apo-B, triglycerides, ratio of triglyceride to HDL cholesterol, and triglyceride-rich lipoprotein cholesterol concentrations were associated with increased risk of atherosclerotic vascular events in CKD. Reducing triglyceride-rich lipoproteins using novel therapeutic agents could potentially lower the risk of atherosclerotic cardiovascular disease risk in the CKD population.

Topics: Aged; Anticholesteremic Agents; Apolipoprotein B-100; Biomarkers; Cardiovascular Diseases; Dyslipidemias; Ezetimibe, Simvastatin Drug Combination; Female; Glomerular Filtration Rate; Heart Disease Risk Factors; Humans; Kidney; Lipoproteins; Male; Middle Aged; Prognosis; Randomized Controlled Trials as Topic; Renal Dialysis; Renal Insufficiency, Chronic; Risk Assessment; Time Factors; Triglycerides

Markers of inflammation, including plasma C-reactive protein (CRP), are associated with an increased risk of cardiovascular disease, and it has been suggested that this association is causal. However, the relationship between inflammation and cardiovascular disease has not been extensively studied in patients with chronic kidney disease. To evaluate this, we used data from the Study of Heart and Renal Protection (SHARP) to assess associations between circulating CRP and LDL cholesterol levels and the risk of vascular and non-vascular outcomes. Major vascular events were defined as nonfatal myocardial infarction, cardiac death, stroke or arterial revascularization, with an expanded outcome of vascular events of any type. Higher baseline CRP was associated with an increased risk of major vascular events (hazard ratio per 3x increase 1.28; 95% confidence interval 1.19-1.38). Higher baseline LDL cholesterol was also associated with an increased risk of major vascular events (hazard ratio per 0.6 mmol/L higher LDL cholesterol; 1.14, 1.06-1.22). Higher baseline CRP was associated with an increased risk of a range of non-vascular events (1.16, 1.12-1.21), but there was a weak inverse association between baseline LDL cholesterol and non-vascular events (0.96, 0.92-0.99). The efficacy of lowering LDL cholesterol with simvastatin/ezetimibe on major vascular events, in the randomized comparison, was similar irrespective of CRP concentration at baseline. Thus, decisions to offer statin-based therapy to patients with chronic kidney disease should continue to be guided by their absolute risk of atherosclerotic events. Estimation of such risk may include plasma biomarkers of inflammation, but there is no evidence that the relative beneficial effects of reducing LDL cholesterol depends on plasma CRP concentration.

Topics: Aged; Anticholesteremic Agents; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Cholesterol, LDL; Down-Regulation; Dyslipidemias; Ezetimibe, Simvastatin Drug Combination; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Inflammation Mediators; Male; Middle Aged; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic; Risk Factors; Severity of Illness Index; Time Factors; Treatment Outcome