Lack of interaction of apolipoprotein E phenotype with the lipoprotein response to lovastatin or gemfibrozil in patients with primary hypercholesterolemia

Sanllehy, C; Casals, Elena; Rodríguez‐Villar, C.; Zambón, Daniel; Ojuel, Júlia; Ballesta, Antonio M.; Ros, Emilio

doi:10.1016/s0026-0495(98)90240-2

Cited by 55 publications

(46 citation statements)

References 28 publications

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“…29 -31,48 Also, some studies have suggested that the response to hypolipidemic therapies could be related to apoE polymorphism, 49,50 even though there are also contradictory findings. 51,52 The present study did not reveal any such effects of either ERT treatment among these postmenopausal subjects. Recently, the LDL cholesterol levels in apoE4-negative subjects were reported to respond more favorably to HRT than did the levels in apoE4-positive subjects.…”

Section: Discussioncontrasting

confidence: 69%

Mechanisms Regulating LDL Metabolism in Subjects on Peroral and Transdermal Estrogen Replacement Therapy

Karjalainen

Heikkinen

Savolainen

et al. 2000

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Abstract-To study the mechanisms of low density lipoprotein (LDL) cholesterol lowering by peroral and transdermal estrogen replacement therapy (ERT), 79 hysterectomized postmenopausal women aged 48 to 62 years were randomized in a double-blind double-dummy trial to receive either peroral estradiol valerate (2 mg/d) or transdermal estradiol gel (1 mg/d) for 6 months. Plasma LDL cholesterol decreased from 4.19Ϯ0.83 (meanϮSD) to 3.39Ϯ0.78 mmol/L (PϽ0.001) in the peroral group and from 4.11Ϯ0.86 to 3.72Ϯ0.78 mmol/L (PϽ0.001) in the transdermal estrogen group. Peroral estrogen did, but transdermal treatment did not, enhance the fractional catabolic rate (FCR) and production of LDL apolipoprotein B (apoB). However, the decrease of LDL cholesterol was related to an increase in FCR for LDL apoB on both peroral and transdermal ERT (rϭϪ0.645, PϽ0.001 and rϭϪ0.627, PϽ0.001, respectively). These changes were associated with changes in the serum estrogen level. Both therapies reduced absorption of dietary cholesterol by 6% to 10% (PϽ0.05). The effects of estrogen were not modified by the polymorphisms of apoE and apoB or cholesterol 7␣-hydroxylase. In conclusion, the ERT-induced LDL cholesterollowering effect is related to changes in estrogen level, which presumably enhance LDL receptor activity, which is manifested as an increase in FCR for LDL apoB. The small decrease in the absorption efficiency of dietary cholesterol does not seem to contribute largely to the cholesterol lowering on either transdermal or peroral ERT. Key Words: estrogen replacement therapy Ⅲ LDL cholesterol Ⅲ menopause Ⅲ lipids A ccording to observational studies, up to 50% of cardiovascular mortality in postmenopausal women could be prevented by postmenopausal hormone replacement therapy (HRT). 1,2 However, a recent randomized secondary prevention study was not able to confirm these results. 3 At any rate, menopause is related to unfavorable alterations in lipids and lipoproteins. 4,5 The beneficial changes in lipids and lipoproteins observed during HRT in several previous studies have been assumed to explain 25% to 50% of the reduced cardiovascular risk. 1 Peroral estrogens decrease total and LDL cholesterol and Lp(a) and increase HDL cholesterol but also triglycerides, whereas less marked reduction in total and LDL cholesterol and no change in Lp(a), HDL cholesterol, and triglyceride levels have been observed during transdermal estrogen treatments. 6,7 The underlying mechanisms of action of estrogen administered via various routes are poorly known. The serum estrogen level is varied by the estrogen regimen and the route of estrogen administration. 8,9 After peroral administration, high levels of estradiol are catabolized into estrone, which induces protein synthesis in the liver. 10 When the transdermal route is used, induction of hepatic first-pass metabolism can be avoided, and a more physiological estrone/estradiol ratio is achieved. 11 Mainly based on animal studies 12,13 or the use of pharmacological doses of estrogen in prostate cancer, 14 the ...

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Section: Discussioncontrasting

confidence: 69%

Mechanisms Regulating LDL Metabolism in Subjects on Peroral and Transdermal Estrogen Replacement Therapy

Karjalainen

Heikkinen

Savolainen

et al. 2000

ATVB

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“…11 In terms of the association of APOE genotypes and LDL-C reduction with statin therapy, the majority of studies have reported greater LDL-C reduction in 2 carriers and lesser reductions in 4 carriers, 6 -8,12-14 although others have suggested either no significant relationship, 15 gender-specific findings, 16 or even the converse with lesser reductions in 2 carriers and greater reductions in 4 carriers. 17 Our analysis benefited from a large sample size, consistent statin dosing (including use of atorvastatin, one of the most commonly prescribed statins in the United States currently) and timing of blood sampling, central laboratory measurements, monitored compliance with statin therapy, and standardized follow-up for clinical events.…”

Section: Discussionmentioning

confidence: 99%

Identification of Genetic Variants Associated With Response to Statin Therapy

Mega

Morrow

Brown

et al. 2009

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Objective-The purpose of this study was to test the association between polymorphisms in genes involved in either LDL cholesterol (LDL-C) metabolism or statin pharmacokinetics and LDL-C reduction with statins. Methods and Results-49 tagging and candidate polymorphisms in 9 genes were genotyped in 1507 post-ACS subjects randomized to atorvastatin or pravastatin. Two polymorphisms (rs7412, rs429358) that define the 2, 3, and 4 isoforms of apolipoprotein E were significantly associated with percent reduction in LDL-C with atorvastatin (2 carriers 53.8%, 3/3 48.1%, and 4 carriers 46.4%, respectively, Pϭ0.00039) and replicated in the pravastatin arm (2 carriers 22.1%, 3/3 21.8%, and 4 carriers 16.6%, respectively, Pϭ0.00038). The proportion of subjects achieving an LDL-C Յ70 mg/dL at day 30 was higher for 2 than 4 carriers (Pϭ1.3ϫ10 Ϫ5 ). In the pravastatin group, the triallelic rs2032582 variant (G2677T/A) in ABCB1 was associated with the percent reduction in LDL-C (GG 23.3%, non-G heterozygote 20.3%, and non-G homozygote 17.4%, Pϭ0.042). Key Words: cholesterol-lowering drugs Ⅲ lipids Ⅲ pharmacogenetics L owering cholesterol with statins has been shown to reduce the risk of cardiovascular events. In multiple trials, intensive statin therapy has further decreased this risk and reversed the progression of coronary atherosclerosis. The reduction of low density lipoprotein cholesterol (LDL-C) in response to statin therapy, however, can vary by as much as 10% to 70% from person to person, with many individuals not reaching target goals. 1 Whereas diet, concomitant medications, and comorbidities can account for some of this variation, genetic determinants may also influence interindividual lipid parameters and responses to lipid-lowering medications. Family studies have suggested that the genetic contribution to baseline cholesterol levels is as high as 50%, 2 and genetic association analyses have demonstrated the impact of both rare and common genetic variants on baseline cholesterol levels. 3 Several studies also point to genetic variation contributing to the response to statin therapy. 4 -8 We therefore conducted a focused pharmacogenetic study in more than 1500 subjects in a large clinical trial in which patients were randomized to treatment with pravastatin or atorvastatin. We genotyped tagging and candidate variants in 9 genes involved in LDL-C metabolism or statin pharmacokinetics, and assessed the association between these genetic variants and baseline and percent reduction in LDL-C in the setting of statin therapy, as well as achieved cholesterol goals, inflammatory biomarkers, and cardiovascular events. Conclusion-Carriers Methods Patient PopulationPROVE IT-TIMI 22 enrolled patients hospitalized with an acute coronary syndrome (ACS) within the preceding 10 days and with a total cholesterol of Յ240 mg/dL. 9 Study participants were randomly assigned to receive atorvastatin 80 mg/d or pravastatin 40 mg/d and followed for an average of 24 months. For the current pharmacogenetic analysis, we limited our evaluatio...

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“…The consensus is that e4 carriers appear to have attenuated lipid-lowering response, and e2 carriers have enhanced response. 13,17,[58][59][60][61][62][63][64][65][66][67][68][69][70] Few studies have examined the effects of variations in genes encoding other apolipoproteins. There are reports that polymorphisms in APOB, the gene encoding the major structural protein in both LDL and triglyceride-rich lipoproteins, may alter LDLC response; whereas variation in the APOAI gene, encoding the major structural protein in HDL, may alter HDLC response.…”

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confidence: 99%