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Pharmacogenetic predictors of statin-mediated low-density lipoprotein cholesterol reduction and dose response.

ABSTRACT: There is interindividual variation in low-density lipoprotein cholesterol (LDLc) lowering by statins and limited study into the genetic associations of the dose dependant LDLc lowering by statins.Five hundred nine patients with hyperlipidemia were randomly assigned atorvastatin 10 mg, simvastatin 20 mg, or pravastatin 10 mg (low-dose phase) followed by 80 mg, 80 mg, and 40 mg (high-dose phase), respectively. Thirty-one genes in statin, cholesterol, and lipoprotein metabolism were sequenced and 489 single nucleotide polymorphisms with minor allele frequencies >2% were tested for associations with percentage LDLc lowering at low doses using multivariable adjusted general linear regression. Significant associations from the analysis at low dose were then repeated at high-dose statins. At low doses, only 1 single nucleotide polymorphism met our experiment-wide significance level, ABCA1 rs12003906. Twenty-six subjects carried the minor allele of rs12003906, which was associated with an attenuated LDLc reduction (LDLc reduction in carriers versus noncarriers -24.1+/-2.6% versus -32.2+/-1.5%; P=0.0001). In addition, we replicated the association with the APOE epsilon3 allele and a reduced LDLc reduction. At high doses, carriers of the minor allele of ABCA1 rs12003906 and the APOE epsilon3 allele improved their LDLc reduction but continued to have a diminished LDLc reduction compared with noncarriers (-30.5+/-4.0% versus -42.0+/-2.4%; P=0.005) and (-38.5+/-1.9% versus -45.3+/-2.8%; P=0.009), respectively.An intronic single nucleotide polymorphism in ABCA1 and the APOE epsilon3 allele are associated with reduced LDLc lowering by statins and identify individuals who may be resistant to maximal LDLc lowering by statins.

SUBMITTER: Voora D

PROVIDER: S-EPMC2995295 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Pharmacogenetic predictors of statin-mediated low-density lipoprotein cholesterol reduction and dose response.

Voora Deepak D Shah Svati H SH Reed Carol R CR Zhai Jun J Crosslin David R DR Messer Chad C Salisbury Benjamin A BA Ginsburg Geoffrey S GS

Circulation. Cardiovascular genetics 20081209 2

<h4>Background</h4>There is interindividual variation in low-density lipoprotein cholesterol (LDLc) lowering by statins and limited study into the genetic associations of the dose dependant LDLc lowering by statins.<h4>Methods and results</h4>Five hundred nine patients with hyperlipidemia were randomly assigned atorvastatin 10 mg, simvastatin 20 mg, or pravastatin 10 mg (low-dose phase) followed by 80 mg, 80 mg, and 40 mg (high-dose phase), respectively. Thirty-one genes in statin, cholesterol, ...[more]

PMID: 20031551

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Project description:Low-density lipoprotein cholesterol (LDL-C) is an important modifiable risk factor for atherosclerotic cardiovascular disease. It is unclear whether the percentage LDL-C lowering with pharmacotherapies differs on the basis of baseline LDL-C levels. To evaluate the association between baseline LDL-C levels and the percentage LDL-C reduction with a statin, ezetimibe, and a PCSK9 inhibitor. This secondary exploratory study analyzed data from 3 randomized placebo-controlled clinical trials (Aggrastat to Zocor-Thrombolysis in Myocardial Infarction 21 [A to Z-TIMI 21], Improved Reduction of Outcomes: Vytorin Efficacy International Trial [IMPROVE-IT], and Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk [FOURIER]) of lipid-lowering therapies (statin, ezetimibe, and a PCSK9 inhibitor) and included participants with atherosclerotic cardiovascular disease. Analyses took place form April to October 2020. In A to Z-TIMI 21, 1:1 randomization to simvastatin, 40 mg, daily for 30 days followed by 80 mg daily thereafter vs placebo for 4 months followed by simvastatin, 20 mg, daily thereafter. In IMPROVE-IT, 1:1 randomization to ezetimibe, 10 mg, daily plus simvastatin, 40 mg, daily vs placebo plus simvastatin, 40 mg, daily. In FOURIER, 1:1 randomization to evolocumab, 140 mg, every 2 weeks or 420 mg monthly vs matching placebo. The percentage LDL-C reduction at either 1 month (A to Z-TIMI 21, IMPROVE-IT) or 3 months (FOURIER) as a function of baseline LDL-C level. Data were modeled using a generalized linear regression model. A total of 3187 patients from A to Z-TIMI 21, 10 680 patients from IMPROVE-IT, and 25 847 patients from FOURIER were analyzed. There was a higher percentage reduction in LDL-C levels with evolocumab in patients with lower baseline LDL-C levels, ranging from 59.4% (95% CI, 59.1%-59.8%) in patients with a baseline LDL-C level of 130 mg/dL to 66.1% (95% CI, 65.6%-66.6%) in patients with a baseline LDL-C level of 70 mg/dL (P < .001). In contrast, across the same range of baseline LDL-C level, there was a more modest difference for simvastatin (44.6% [95% CI, 43.9%-45.2%] vs 47.8% [95% CI, 46.4%-49.2%]; P < .001) and minimal difference with ezetimibe (25.0% [95% CI, 23.3%-26.6%] vs 26.2% [95% CI, 24.2%-28.1%]; P = .007). The percentage LDL-C reduction with statins, ezetimibe, and PCSK9 inhibition is not attenuated in patients starting with lower baseline LDL-C levels and is 6.6% greater for PCSK9 inhibition. These data are encouraging for the use of intensive LDL-C-lowering therapy even for patients with lower LDL-C levels.

Project description:Background MEDI6012 is recombinant human lecithin cholesterol acyltransferase, the rate-limiting enzyme in reverse cholesterol transport. Infusions of lecithin cholesterol acyltransferase have the potential to enhance reverse cholesterol transport and benefit patients with coronary heart disease. The purpose of this study was to test the safety, pharmacokinetic, and pharmacodynamic profile of MEDI6012. Methods and Results This phase 2a double-blind study randomized 48 subjects with stable coronary heart disease on a statin to a single dose of MEDI6012 or placebo (6:2) (NCT02601560) with ascending doses administered intravenously (24, 80, 240, and 800 mg) and subcutaneously (80 and 600 mg). MEDI6012 demonstrated rates of treatment-emergent adverse events that were similar to those of placebo. Dose-dependent increases in high-density lipoprotein cholesterol were observed with area under the concentration-time curves from 0 to 96 hours of 728, 1640, 3035, and 5318 should be: mg·h/mL in the intravenous dose groups and 422 and 2845 mg·h/mL in the subcutaneous dose groups. Peak mean high-density lipoprotein cholesterol percent change was 31.4%, 71.4%, 125%, and 177.8% in the intravenous dose groups and 18.3% and 111.2% in the subcutaneous dose groups, and was accompanied by increases in endogenous apoA1 (apolipoprotein A1) and non-ATP-binding cassette transporter A1 cholesterol efflux capacity. Decreases in apoB (apolipoprotein B) were observed across all dose levels and decreases in atherogenic small low-density lipoprotein particles by 41%, 88%, and 79% at the 80-, 240-, and 800-mg IV doses, respectively. Conclusions MEDI6012 demonstrated an acceptable safety profile and increased high-density lipoprotein cholesterol, endogenous apoA1, and non-ATP-binding cassette transporter A1 cholesterol efflux capacity while reducing the number of atherogenic low-density lipoprotein particles. These findings are supportive of enhanced reverse cholesterol transport and a functional high-density lipoprotein phenotype. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02601560.

Project description:BACKGROUND:Robust evidence is lacking on optimal timing of statin administration and its impact on patient outcomes. OBJECTIVE:This study aims to evaluate among incident statin users the relationship between those prescribed evening vs. daily dosing instructions, medication adherence, and changes in low-density lipoprotein cholesterol (LDL-c). DESIGN:This is an observational cohort study at Sutter Health, a community-based healthcare system, 2010-2016. PARTICIPANTS:Patients were ??35 years of age as of the first statin prescription (baseline), with 12 to 36 months of electronic health record activity before and after baseline. Incident use was defined as no statin prescription in 12 months prior to baseline. MAIN MEASURES:Differences in medication adherence (proportion of days covered ??0.80) over 12 months from baseline and mean change in LDL-c between 12 and 24 months from baseline were measured using regression modeling, adjusting for baseline demographics and clinical, prescriber, and statin characteristics. KEY RESULTS:Among 31,252 patients with valid statin prescriptions between 2010 and 2016, 5099 eligible incident statin users (mean age, 63 years) were identified, of whom 53% were prescribed evening and 47% daily dosing instructions. No difference in likelihood of statin adherence over 12 months was observed for evening vs. daily dosing (adjusted odds ratio [OR] 0.90; 95% CI 0.75, 1.08). No differences were observed in mean change in LDL-c (adjusted mean difference 1.42 mg/dL; 95% CI -?1.02, 3.89) or likelihood of attaining LDL-c <?70 mg/dL (adjusted OR 0.83; 95% CI 0.67, 1.04) for evening vs. daily dosing over a mean of 19 months follow-up. CONCLUSIONS:Among incident statin users from a real-world clinical setting, those with daily and evening dosing instructions had similar adherence rates and mean changes in LDL-c. Given potential clinical equipoise for evening and daily dosing, clinicians should consider patient-tailored statin dosing instructions to reduce potentially unnecessary regimen complexity.

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Pharmacogenetic predictors of statin-mediated low-density lipoprotein cholesterol reduction and dose response.

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Pharmacogenetic predictors of statin-mediated low-density lipoprotein cholesterol reduction and dose response.

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