(3S-5S-6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3-5-dihydroxyhept-6-enoic-acid and Kidney-Diseases

Previous studies showed that statins reduce the progression of kidney function decline and proteinuria, but whether specific types of statins are more beneficial than others remains unclear. We performed a network meta-analysis of randomized controlled trials (RCT) to investigate which statin most effectively reduces kidney function decline and proteinuria. We searched MEDLINE, Embase, Web of Science, and the Cochrane database until July 13, 2018, and included 43 RCTs (>110,000 patients). We performed a pairwise random-effects meta-analysis and a network meta-analysis according to a frequentist approach. We assessed network inconsistency, publication bias, and estimated for each statin the probability of being the best treatment. Considerable heterogeneity was present among the included studies. In pairwise meta-analyses, 1-year use of statins versus control reduced kidney function decline by 0.61 (95%-CI: 0.27; 0.95) mL/min/1.73 m

Topics: Atorvastatin; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kidney; Kidney Diseases; Lovastatin; Network Meta-Analysis; Pravastatin; Proteinuria; Rosuvastatin Calcium; Simvastatin; Treatment Outcome

The current guidelines of statins for primary cardiovascular disease (CVD) prevention were based on results from systematic reviews and meta-analyses that suffer from limitations.. We searched in PubMed for existing systematic reviews and individual open-label or double-blinded randomized controlled trials that compared a statin with a placebo or another, which were published in English until January 01, 2018. We performed a random-effect pairwise meta-analysis of all statins as a class and network meta-analysis for the specific statins on different benefit and harm outcomes.. In the pairwise meta-analyses, statins as a class showed statistically significant risk reductions on non-fatal MI (risk ratio [RR] 0.62, 95% CI 0.53-0.72), CVD mortality (RR 0.80, 0.71-0.91), all-cause mortality (RR 0.89, 0.85-0.93), non-fatal stroke (RR 0.83, 0.75-0.92), unstable angina (RR 0.75, 0.63-0.91), and composite major cardiovascular events (RR 0.74, 0.67-0.81). Statins increased statistically significantly relative and absolute risks of myopathy (RR 1.08, 1.01-1.15; Risk difference [RD] 13, 2-24 per 10,000 person-years); renal dysfunction (RR 1.12, 1.00-1.26; RD 16, 0-36 per 10,000 person-years); and hepatic dysfunction (RR 1.16, 1.02-1.31; RD 8, 1-16 per 10,000 person-years). The drug-level network meta-analyses showed that atorvastatin and rosuvastatin were most effective in reducing CVD events while atorvastatin appeared to have the best safety profile.. All statins showed statistically significant risk reduction of CVD and all-cause mortality in primary prevention populations while increasing the risk for some harm risks. However, the benefit-harm profile differed by statin type. A quantitative assessment of the benefit-harm balance is thus needed since meta-analyses alone are insufficient to inform whether statins provide net benefit.

Topics: Atorvastatin; Cardiovascular Diseases; Cause of Death; Chemical and Drug Induced Liver Injury; Double-Blind Method; Fluvastatin; Headache; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kidney Diseases; Lovastatin; Middle Aged; Muscular Diseases; Nausea; Neoplasms; Network Meta-Analysis; Placebos; Pravastatin; Randomized Controlled Trials as Topic; Risk Assessment; Rosuvastatin Calcium; Simvastatin; Withholding Treatment

Our study aims to evaluate the efficacy and safety of long-term treatment of statins for coronary heart disease (CHD).. Efficacy outcomes included changes in blood lipids, risk of CHD mortality and all-cause mortality. Safety outcomes were evaluated by the risk of adverse events (AE). Bayesian network meta-analysis was used to compare the direct and indirect effects between different statins.. The systematic review showed that levels of blood lipids decreased during statin treatment. High dose of atorvastatin was the most obvious treatment for the reduction of blood lipids. Network meta-analysis showed that statins were significantly more effective than the control in reducing the risk of CHD mortality (Odds Ratio (OR) 0.69, 95% CI 0.61-0.77) and all-cause mortality (OR 0.84, 95% CI 0.80-0.87). In terms of reducing the risk of CHD morality, fluvastatin (77.3%), atorvastatin (72.3%) and lovastatin (68.4%) had higher cumulative probability than other statins, which were more effective treatments for the reduction of CHD morality. In terms of reducing all-cause mortality, atorvastatin (78.6%), fluvastatin (77.1%) and pitavastatin (74.1%) had higher cumulative probability than other statins, which were more effective treatment for reducing the all-cause mortality. Compared with placebo, statins increased the incidence risk of muscle disease (OR 1.05, 95% CI 1.00-1.10) and kidney disease (OR 1.11, 95% CI 1.05-1.72).. Statins significantly reduced levels of blood lipids, with a high dose of atorvastatin being the most effective in blood-lipid level modification. Statins reduced the risk of CHD mortality and all-cause mortality, with atorvastatin and fluvastatin being the most effective in reducing the risk of CHD mortality and all-cause mortality. Statins increased the risk of muscle disease and kidney damage.

Topics: Anticholesteremic Agents; Atorvastatin; Bayes Theorem; Coronary Disease; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Kidney Diseases; Lipids; Lovastatin; Muscles; Network Meta-Analysis; Patient Safety; Pravastatin; Quinolines; Randomized Controlled Trials as Topic; Simvastatin; Treatment Outcome

Topics: Cardiovascular Diseases; Cholesterol; Dyslipidemias; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunosuppressive Agents; Indoles; Kidney Diseases; Kidney Transplantation; Lipid Metabolism; Practice Guidelines as Topic; Renal Dialysis; Risk Factors; Triglycerides

Topics: Animals; Antioxidants; Fatty Acids, Monounsaturated; Fibrosis; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Kidney Diseases; Kidney Tubules; Oxidative Stress

Although short-term graft survival has improved substantially in renal transplant recipients, long-term graft survival has not improved over the last decades. The lack of knowledge of specific causes and risk factors has hampered improvements in long-term allograft survival. There is an uncertainty if inflammation is associated with late graft loss.. We examined, in a large prospective trial, the inflammation markers high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6) and their association with chronic graft dysfunction. We collected data from the Assessment of Lescol in Renal Transplant trial, which recruited 2102 maintenance renal transplant recipients.. Baseline values were hsCRP 3.8 ± 6.7 mg/L and IL-6 2.9 ± 1.9 pg/mL. Adjusted for traditional risk factors, hsCRP and IL-6 were independently associated with death-censored graft loss, the composite end points graft loss or death and doubling of serum creatinine, graft loss or death.. The inflammation markers hsCRP and IL-6 are associated with long-term graft outcomes in renal transplant recipients.

Topics: Adult; Anticholesteremic Agents; C-Reactive Protein; Creatinine; Double-Blind Method; Fatty Acids, Monounsaturated; Female; Fluvastatin; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Humans; Indoles; Inflammation; Interleukin-6; Kidney Diseases; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Prognosis; Prospective Studies; Survival Rate; Transplantation, Homologous

This open, prospective, randomized trial aimed to assess the effects of statins in chronic kidney disease patients on optimized antiproteinuric treatment with combined angiotensin-converting enzyme inhibition and angiotensin receptor blockade.. After 1-month benazepril therapy followed by 1-month benazepril-valsartan combined therapy (run-in), 186 consenting patients with residual proteinuria >0.5 g/24 h were randomized to 6-month benazepril-valsartan therapy alone or combined with fluvastatin. Between-groups changes in proteinuria (primary outcome), serum lipids, and GFR were compared by ANCOVA. Analyses were blinded and by intention to treat.. During the run-in, proteinuria decreased more on benazepril-valsartan than on benazepril alone. Proteinuria reduction correlated with concomitant reduction in total, LDL, and HDL cholesterol, and apolipoprotein B and apolipoprotein A levels. After randomization, median proteinuria similarly decreased from 1.2 (0.6 to 2.2) to 1.1 (0.5 to 1.7) g/24 h on fluvastatin and from 1.5 (0.8 to 2.7) to 1.0 (0.5 to 2.4) g/24 h on benazapril-valsartan therapy alone. Fluvastatin further reduced total and LDL cholesterol and apolipoprotein B versus benazepril-valsartan alone, but did not affect serum triglycerides and GFR. Treatment was well tolerated.. In chronic kidney disease patients with residual proteinuria despite combined angiotensin-converting enzyme inhibitor and angiotensin receptor blockade therapy, add-on fluvastatin does not affect urinary proteins, but further reduces serum lipids and is safe. Whether combined angiotensin-converting enzyme inhibitor, angiotensin receptor blockade, and statin therapy may improve cardiovascular outcomes in this high-risk population is worth investigating.

Topics: Adult; Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzazepines; Blood Pressure; Chi-Square Distribution; Chronic Disease; Drug Therapy, Combination; Fatty Acids, Monounsaturated; Female; Fluvastatin; Glomerular Filtration Rate; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Italy; Kidney Diseases; Lipids; Male; Middle Aged; Prospective Studies; Proteinuria; Renin-Angiotensin System; Tetrazoles; Time Factors; Treatment Outcome; Valine; Valsartan

Mild renal impairment is an important risk factor for late cardiovascular complications. This substudy of the Lescol Intervention Prevention Study (LIPS) assessed the effect of fluvastatin on outcome of patients who had renal dysfunction and those who did not. Complete data for creatinine clearance calculation (Cockcroft-Gault formula) were available for 1,558 patients (92.9% of the LIPS population). Patients were randomized to fluvastatin or placebo after successful completion of a first percutaneous coronary intervention. Follow-up time was 3 to 4 years. The effect of baseline creatinine clearance on coronary atherosclerotic events (cardiac death, nonfatal myocardial infarction, and coronary reinterventions not related to restenosis) was evaluated. Baseline creatinine clearance (logarithmic transformation) was inversely associated with an incidence of adverse events among patients who received placebo (hazard ratio 0.99, 95% confidence interval 0.982 to 0.998, p = 0.01). However, no association was noted between creatinine clearance and the incidence of adverse events among patients who received fluvastatin (hazard ratio 1.0, 95% confidence interval 0.99 to 1.0, p = 0.63). No further deterioration in creatinine clearance was observed during follow-up, regardless of baseline renal function or allocated treatment. Occurrence of adverse events was not related to changes in renal function during follow-up. Fluvastatin therapy markedly decreased the risk of coronary atherosclerotic events after percutaneous intervention in patients who had lower values of creatinine clearance at baseline. The benefit of fluvastatin was unrelated to any effect on renal function.

Topics: Age Factors; Aged; Angioplasty, Balloon, Coronary; Coronary Artery Disease; Creatinine; Europe; Fatty Acids, Monounsaturated; Female; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Kidney Diseases; Lipoproteins; Male; Middle Aged; Multivariate Analysis; Proportional Hazards Models; Severity of Illness Index; Sex Factors

Statins reduce lipid levels, inflammation and cardiovascular events in patients with coronary artery disease; CKD patients show increased risk of cardiovascular and increased plasma levels of IL-6 and IL-8.. To evaluate the in vitro effect of simvastatin (S) or fluvastatin (F) on the lipopolysaccharide (LPS) stimulated secretion of IL-6 and IL-8 from monocytes of chronic kidney disease patients (CKD) in K-DOQI stages 3-5.. Monocytes enriched peripheral blood (PBMC) from 28 CKD (15 in K-DOQI stages 3-4, Group I, and 13 in K-DOQI stage 5 on hemodialysis, Group II) and 10 healthy subjects (HS), were isolated by Ficoll-gradient centrifugation. Cells were incubated with LPS 100 ng/ml or with LPS plus increasing doses of statins (from 10(-6) to 10(-8) M ) for 24 h. Surnatant IL-6 and IL-8 concentrations were determined by EIA.. Basally the mean concentration of IL-6 and IL-8 was higher in patients than in HS and in Group II than in Group I (IL6: HS 285 +/- 77 pg/ml, Group I 365 +/- 178 pg/ml, Group II 520 +/- 139 pg/ml- IL8 HS 180 +/- 75 pg/ml, Group I 1722 +/- 582 pg/ml, Group II 4400 +/- 1935 pg/ml). After addition of LPS the mean concentration of IL-6 and IL-8 increased in all groups (IL6: HS 1740 +/- 178 pg/ml, Group I 3754 +/- 672 pg/ml, Group II 4800 +/- 967 pg/ml; IL8: HS 450+/-132 pg/ml, Group I 9700+/-2837 pg/ml, Group II 11608 +/- 2316 pg/ml). After the addition of LPS plus increasing doses of S or F from 10(-10) to 10(-6) M, a significantly lower cytokine concentration compared to the data after LPS alone was observed (IL6: HS 45%, Group I 75%, Group II 50%; IL8: HS 100%, Group I 65%, Group II 35%).. These data confirm that cytokine release is increased in CKD patients and that is highest in the most severe patients. Furthermore they suggest that fluvastatin or simvastatin can be used in order to reduce the high cardiovascular risk.

Topics: Cardiovascular Diseases; Cells, Cultured; Chronic Disease; Cytokines; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Indoles; Interleukin-6; Interleukin-8; Kidney Diseases; Lipopolysaccharides; Monocytes; Simvastatin

Skeletal muscle injury by hypolipidemic drugs is not fully understood. An extensive analysis of the effect of chronic treatment with fluvastatin (5 mgkg(-1) and 20 mgkg(-1)), atorvastatin (10 mgkg(-1)) and fenofibrate (60 mgkg(-1)) on rat skeletal muscle was undertaken.. Myoglobinemia as sign of muscle damage was measured by enzymatic assay. Histological and immunohistochemical techniques were used to estimate muscle integrity and the presence of aquaporin-4, a protein controlling water homeostasis. Electrophysiological evaluation of muscle Cl(-) conductance (gCl) and mechanical threshold (MT) for contraction, index of intracellular calcium homeostasis, was performed by the two-intracellular microelectrodes technique.. Fluvastatin (20 mgkg(-1)) increased myoglobinemia. The lower dose of fluvastatin did not modify myoglobinemia, but reduced urinary electrolytes, suggesting direct effects on renal function. Atorvastatin also increased myoglobinemia, with slight effects on urinary parameters. No treatment caused any histological damage to muscle or modification in the number of fibres expressing aquaporin-4. Either fluvastatin (at both doses) or atorvastatin reduced sarcolemma gCl and changed MT. Both statins produced slight effects on total cholesterol, suggesting that the observed modifications occur independently of HMGCoA-reductase inhibition. Fenofibrate increased myoglobinemia and decreased muscle gCl, whereas it did not change the MT, suggesting a different mechanism of action from the statins.. This study identifies muscle gCl and MT as early targets of drugs action that may contribute to milder symptoms of myotoxicity, such as muscle cramps, while the increase of myoglobinemia is a later phenomenon.

Topics: Action Potentials; Animals; Aquaporin 4; Atorvastatin; Body Weight; Chloride Channels; Dose-Response Relationship, Drug; Eating; Fatty Acids, Monounsaturated; Fenofibrate; Fluvastatin; Heptanoic Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Indoles; Kidney Diseases; Lipids; Male; Membrane Potentials; Muscle Contraction; Muscle Fibers, Fast-Twitch; Muscle, Skeletal; Muscular Diseases; Myosin Heavy Chains; Organ Size; Pyrroles; Rats; Rats, Wistar; Rhabdomyolysis; Time Factors

Topics: Cardiovascular Diseases; Clinical Trials as Topic; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Indoles; Kidney Diseases; Kidney Transplantation; Quality Control; Risk Factors

Topics: Cardiovascular Diseases; Clinical Trials as Topic; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Indoles; Kidney Diseases; Kidney Transplantation; Quality Control; Risk Factors