Statins and Multiple Noncardiovascular Outcomes

He, Yazhou; Li, Xue; Gasevic, Danijela; Brunt, Eleanor; McLachlan, Fiona; Millenson, Marisa E.; Timofeeva, Maria; Ioannidis, John P. A.; Campbell, Harry; Τheodoratou, Evropi

doi:10.7326/m18-0808

Cited by 72 publications

(44 citation statements)

References 83 publications

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“…However, in a large-scale clinical trial, statin treatment failed to protect kidney function better than non-statin treatment in CKD patients with dyslipidemia [14]. Recently, an umbrella review of meta-analyses was performed, which concluded that the effect of statins on CKD progression is still uncertain [13].…”

Section: Discussionmentioning

confidence: 99%

“…Statins are recommended as the drug of choice for lowering low-density lipoprotein (LDL) cholesterol and preventing cardiovascular disease [9]. Because dyslipidemia is considered a risk factor 2 of 12 for CKD [10,11], statins have also been presumed to protect kidney function; however, the results of previous studies are inconsistent [12][13][14].…”

Section: Introductionmentioning

confidence: 99%

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Comparison of Renal Effects of Ezetimibe–Statin Combination versus Statin Monotherapy: A Propensity-Score-Matched Analysis

Bae

Hong

Lee

et al. 2020

JCM

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Neither lowering of blood lipid levels nor treatment with statins definitively improves renal outcomes. Ezetimibe, a non-statin antilipidemic agent, is known to not only decrease blood lipid levels but also reduce inflammatory response and activate autophagy. We evaluated the effect of adding ezetimibe to a statin on renal outcome compared with statin monotherapy by analyzing longitudinal data of 4537 patients treated with simvastatin 20 mg plus ezetimibe 10 mg (S + E) or simvastatin 20 mg alone (S) for more than 180 days. A propensity-score-based process was used to match baseline characteristics, medical history, and estimated glomerular filtration rate (eGFR) between S + E and S groups. Changes in serum creatinine and incidence of renal events, defined as doubling of serum creatinine to ≥1.5 mg/dL or occurrence of end-stage renal disease after the first day of treatment initiation, were compared between the groups. Among 3104 well-matched patients with a median follow-up of 4.2 years, the S + E group showed a significantly lower risk of renal events than the S group (hazard ratio 0.58; 95% CI 0.35-0.95, P = 0.032). In addition, the S + E group tended to preserve renal function compared with the S group throughout follow-up, as assessed by serum creatinine changes (P-values for time-group interactions <0.001). These data support the beneficial effects on renal function when combining ezetimibe with a statin.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Comparison of Renal Effects of Ezetimibe–Statin Combination versus Statin Monotherapy: A Propensity-Score-Matched Analysis

Bae

Hong

Lee

et al. 2020

JCM

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“…XO inhibitors could be equally useful for diabetic patients [71]. Although statins have been used widely for many decades as HMGR inhibitors, they are marked with muscular disorders, diabetes, liver diseases, and so on [30], [72]. Novel HMGR inhibitors are called for minimizing these side effects.…”

Section: Discussionmentioning

confidence: 99%

In-SilicoAnalysis of Secondary Metabolites that Modulates Enzymes of Cholesterol Target

Marahatha

Basnet

Bhattarai

et al. 2020

Preprint

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Hypercholesterolemia has posed a serious threat of heart diseases and stroke worldwide. Xanthine oxidase (XO), the rate-limiting enzyme in uric acid biosynthesis, is regarded as the root of reactive oxygen species (ROS) that generates atherosclerosis and cholesterol crystals. β-Hydroxy β-methylglutaryl-coenzyme A reductase (HMGR) is a rate-limiting enzyme in cholesterol biosynthesis. Although some commercially available enzyme inhibiting drugs have effectively reduced the cholesterol level, most of them have failed to meet the requirements of being apt drug candidates. Here, we have carried out an in-silico analysis of secondary metabolites that have already shown good inhibitory activity against XO and HMGR. Out of 118 secondary metabolites reviewed, sixteen molecules inhibiting XO and HMGR were taken based on IC50 values reported in vitro assays. Further, receptor-based virtual screening was carried out against secondary metabolites using GOLD Protein-Ligand Docking Software, combined with subsequent post-docking, to study the binding affinities of ligands to the enzymes. In-Silico ADMET analysis was carried out to study their pharmacokinetic properties, followed by toxicity prediction through ProTox-II. The molecular docking of amentoflavone (1) (GOLD score 70.54), and ganomycin I (9) (GOLD score 59.61) evinced that the drug has effectively bind at the competitive site of XO and HMGR, respectively. Besides, 6-paradol (3) and selgin (4) could be potential drug candidates to inhibit XO. Likewise, n-octadecanyl-O-α-D-glucopyranosyl(6’→1”)-O-α-D-glucopyranoside (10) could be potential drug candidates to maintain serum cholesterol. In-silico ADMET analysis showed that the sixteen metabolites were optimal within the categorical range in comparison to commercially available XO and HMGR inhibitors, respectively. Toxicity analysis through Protox-II revealed that 6-gingerol (2), ganoleucoin K (11), and ganoleucoin Z (12) are toxic for human use. This computational analysis supports earlier experimental evidence towards the inhibition of XO and HMGR by natural products. Further study is necessary to explore the clinical efficacy of these secondary molecules, which might be alternatives for the treatment of hypercholesterolemia.Graphical abstract

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“…In accordance with previous umbrella reviews [32][33][34][35][36], we adopted criteria to grade the strength of the evidence of the associations between clinical interventions and all-cause mortality of CKD patients. For meta-analysis of OSs, we graded the evidence level to five categories: convincing, highly suggestive, suggestive, weak, and not significant, in terms of p-value under random effects, the number of deaths, statistical significance of the largest component study, heterogeneity, 95% prediction interval, estimate under credibility ceiling, and presence of biases.…”

Section: Credibility Assessmentmentioning

confidence: 99%

Clinical Interventions and All-Cause Mortality of Patients with Chronic Kidney Disease: An Umbrella Systematic Review of Meta-Analyses

Kim

Steingroever

Lee

et al. 2020

JCM

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Patients with chronic kidney disease (CKD) have altered physiologic processes, which result in different treatment outcomes compared with the general population. We aimed to systematically evaluate the efficacy of clinical interventions in reducing mortality of patients with CKD. We searched PubMed, MEDLINE, Embase, and Cochrane Database of Systematic Reviews for meta-analyses of randomized controlled trials (RCT) or observational studies (OS) studying the effect of treatment on all-cause mortality of patients with CKD. The credibility assessment was based on the random-effects summary estimate, heterogeneity, 95% prediction intervals, small study effects, excess significance, and credibility ceilings. Ninety-two articles yielded 130 unique meta-analyses. Convincing evidence from OSs supported mortality reduction with three treatments: angiotensin-converting-enzyme inhibitors or angiotensin II receptor blockers for patients not undergoing dialysis, warfarin for patients with atrial fibrillation not undergoing dialysis, and (at short-term) percutaneous coronary intervention compared to coronary artery bypass grafting for dialysis patients. Two treatment comparisons were supported by highly credible evidence from RCTs in terms of all-cause mortality. These were high-flux hemodialysis (HD) versus low-flux HD as a maintenance HD method and statin versus less statin or placebo for patients not undergoing dialysis. Most significant associations identified in OSs failed to be replicated in RCTs. Associations of high credibility from RCTs were in line with current guidelines. Given the heterogeneity of CKD, it seems hard to assume mortality reductions based on findings from OSs.

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Statins and Multiple Noncardiovascular Outcomes

Cited by 72 publications

References 83 publications

Comparison of Renal Effects of Ezetimibe–Statin Combination versus Statin Monotherapy: A Propensity-Score-Matched Analysis

Comparison of Renal Effects of Ezetimibe–Statin Combination versus Statin Monotherapy: A Propensity-Score-Matched Analysis

In-SilicoAnalysis of Secondary Metabolites that Modulates Enzymes of Cholesterol Target

Clinical Interventions and All-Cause Mortality of Patients with Chronic Kidney Disease: An Umbrella Systematic Review of Meta-Analyses

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