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Geographic variation in HMG-CoA reductase inhibitor use in dialysis patients.

ABSTRACT: Despite uncertainty about their effectiveness in chronic dialysis patients, statin use has increased in recent years. Little is known about the demographic, clinical, and geographic factors associated with statin exposure in end-stage renal disease (ESRD) patients.To analyze the demographic, clinical, and geographic factors associated with use of statins among chronic dialysis patients.Cross-sectional analysis.Prevalent dialysis patients across the U.S.55,573 chronic dialysis patients who were dually eligible for Medicaid and Medicare services during the last four months of 2005.Using Medicaid prescription drug claims and United States Renal Data System core data, we examined demographics, comorbid conditions, and state of residence using hierarchical logistic regression models to determine their associations with statin use.Prescription for a statin.Factors associated with a prescription for a statin.Statin exposure was significantly associated with older age, female sex, Caucasian (versus African-American) race, body mass index, use of self-care dialysis, diabetes, and comorbidity burden. Moreover, there was substantial state-by-state variation in statin use, with a greater than 2.3-fold difference in adjusted odds ratios between the highest- and lowest-prescribing states.Among publicly insured chronic dialysis patients, there were marked differences between states in the use of HMG-CoA reductase inhibitors above and beyond patient characteristics. This suggests substantial clinical uncertainty about the utility of these medications. Understanding how such regional variations impact patient care in this high-risk population is an important focus for future work.

SUBMITTER: Wetmore JB

PROVIDER: S-EPMC3475809 | biostudies-other | 2012 Nov

REPOSITORIES: biostudies-other

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Geographic variation in HMG-CoA reductase inhibitor use in dialysis patients.

Wetmore James B JB Mahnken Jonathan D JD Mukhopadhyay Purna P Hou Qingjiang Q Ellerbeck Edward F EF Rigler Sally K SK Spertus John A JA Shireman Theresa I TI

Journal of general internal medicine 20120614 11

<h4>Background</h4>Despite uncertainty about their effectiveness in chronic dialysis patients, statin use has increased in recent years. Little is known about the demographic, clinical, and geographic factors associated with statin exposure in end-stage renal disease (ESRD) patients.<h4>Objective</h4>To analyze the demographic, clinical, and geographic factors associated with use of statins among chronic dialysis patients.<h4>Design</h4>Cross-sectional analysis.<h4>Setting</h4>Prevalent dialysis ...[more]

PMID: 22696256

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Project description:BackgroundStatins are first-line therapy for cardiovascular disease prevention, but their systemic effects across lipoprotein subclasses, fatty acids, and circulating metabolites remain incompletely characterized.ObjectivesThis study sought to determine the molecular effects of statin therapy on multiple metabolic pathways.MethodsMetabolic profiles based on serum nuclear magnetic resonance metabolomics were quantified at 2 time points in 4 population-based cohorts from the United Kingdom and Finland (N = 5,590; 2.5 to 23.0 years of follow-up). Concentration changes in 80 lipid and metabolite measures during follow-up were compared between 716 individuals who started statin therapy and 4,874 persistent nonusers. To further understand the pharmacological effects of statins, we used Mendelian randomization to assess associations of a genetic variant known to mimic inhibition of HMG-CoA reductase (the intended drug target) with the same lipids and metabolites for 27,914 individuals from 8 population-based cohorts.ResultsStarting statin therapy was associated with numerous lipoprotein and fatty acid changes, including substantial lowering of remnant cholesterol (80% relative to low-density lipoprotein cholesterol [LDL-C]), but only modest lowering of triglycerides (25% relative to LDL-C). Among fatty acids, omega-6 levels decreased the most (68% relative to LDL-C); other fatty acids were only modestly affected. No robust changes were observed for circulating amino acids, ketones, or glycolysis-related metabolites. The intricate metabolic changes associated with statin use closely matched the association pattern with rs12916 in the HMGCR gene (R(2) = 0.94, slope 1.00 ± 0.03).ConclusionsStatin use leads to extensive lipid changes beyond LDL-C and appears efficacious for lowering remnant cholesterol. Metabolomic profiling, however, suggested minimal effects on amino acids. The results exemplify how detailed metabolic characterization of genetic proxies for drug targets can inform indications, pleiotropic effects, and pharmacological mechanisms.

Project description:HMG-CoA reductase (HMGR) is the target of statins, cholesterol-lowering drugs prescribed to millions of patients worldwide. More recent research indicates that HMGR could be a useful target in the development of antimicrobial agents. Over the last seven decades, researchers have proposed a series of increasingly complex reaction mechanisms for this biomedically important enzyme. The maturation of the mechanistic proposals for HMGR have paralleled advances in a diverse set of research areas, such as molecular biology and computational chemistry. Thus, the development of the HMGR mechanism provides a useful case study for following the advances in state-of-the-art methods in enzyme mechanism research. Similarly, the questions raised by these mechanism proposals reflect the limitations of the methods used to develop them. The mechanism of HMGR, a four-electron oxidoreductase, is unique and far more complex than originally thought. The reaction contains multiple chemical steps, coupled to large-scale domain motions of the homodimeric enzyme. The first proposals for the HMGR mechanism were based on kinetic and labeling experiments, drawing analogies to the mechanism of known dehydrogenases. Advances in molecular biology and bioinformatics enabled researchers to use site-directed mutagenesis experiments and protein sequencing to identify catalytically important glutamate, aspartate, and histidine residues. These studies, in turn, have generated new and more complicated mechanistic proposals. With the development of protein crystallography, researchers solved HMGR crystal structures to reveal an unexpected lysine residue at the center of the active site. The many crystal structures of HMGR led to increasingly complex mechanistic proposals, but the inherent limitations of the protein crystallography left a number of questions unresolved. For example, the protonation state of the glutamate residue within the active site cannot be clearly determined from the crystal structure. The differing protonation state of this residue leads to different proposed mechanisms for the enzyme. As computational analysis of large biomolecules has become more feasible, the application of methods such as hybrid quantum mechanics/molecular mechanics (QM/MM) calculations to the HMGR mechanism have led to the most detailed mechanistic proposal yet. As these methodologies continue to improve, they prove to be very powerful for the study of enzyme mechanisms in conjunction with protein crystallography. Nevertheless, even the most current mechanistic proposal for HMGR remains incomplete due to limitations of the current computational methodologies. Thus, HMGR serves as a model for how the combination of increasingly sophisticated experimental and computational methods can elucidate very complex enzyme mechanisms.

Project description:BackgroundThe current perspective for the search of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitor has been shifted towards a natural agent also having antioxidant property. Thus, this study was intended to isolate and identify the bioactive compounds from methanolic extract of Ficus virens bark (FVBM) and to evaluate their antioxidant, HMG-CoA reductase inhibitory and hypolipidemic activity.MethodsBioactivity guided fractionation and isolation of bioactive compound from FVBM extract has been done to isolate and characterize the potent HMG-CoA reductase (HMGR) inhibitor with antioxidant activity by using repeated extensive column chromatography followed by spectroscopic methods, including Infrared (IR), 1H & 13C nuclear magnetic resonance (NMR) and Mass spectrum analysis. The in vitro HMGR inhibition and enzyme kinetic assay was determined using HMG-CoA as substrate. In addition, antioxidant activity of the new isolated compound, was measured using 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay and FRAP value. In-silico molecular informatics of HMGR enzyme type inhibition and pharmacokinetics data of the new compound was further evaluated through molecular docking and ADME-T studies. Further, in-vivo hypolipidemic property of FVBM extract and newly isolated compound was also analyzed in triton-WR 1339 induced rats.ResultsThereby, we report the discovery of n-Octadecanyl-O-α-D-glucopyranosyl(6'→1″)-O-α-D-glucopyranoside (F18) as a novel HMG-CoA reductase inhibitor with strong antioxidant property. This inhibitor exhibited not only higher free radical scavenging activity but also marked HMG-CoA reductase inhibitory activity with an IC50 value of 84±2.8 ng/ml. This inhibitory activity concurred with kinetic study that showed inhibition constant (K i) of 84 ng/ml via an uncompetitive mode of inhibition. The inhibition was also corroborated by molecular docking analysis and in silico pharmacokinetics data. The in vivo study revealed that administration of FVBM extract (at higher dose, 100 mg/rat) and the inhibitor (1 mg/rat) to Triton WR-1339-induced hyperlipidemic rats significantly ameliorated the altered levels of plasma lipids and lipoproteins including hepatic HMG-CoA reductase activity; this effect was comparable to the effect of standard drug atorvastatin.ConclusionsThe in vitro, in silico and in vivo results clearly demonstrated the antioxidant potential and therapeutic efficacy of the inhibitor as an alternate drug against hyperlipidemia.

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Geographic variation in HMG-CoA reductase inhibitor use in dialysis patients.

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Geographic variation in HMG-CoA reductase inhibitor use in dialysis patients.

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