[Pharmacogenomic Biomarkers for the Prediction of Statin Efficacy and Safety].
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ABSTRACT:
SUBMITTER: Baldassarre D
PROVIDER: S-EPMC4353572 | biostudies-literature | 2013 Nov
REPOSITORIES: biostudies-literature
Publications
[Pharmacogenomic Biomarkers for the Prediction of Statin Efficacy and Safety].
Baldassarre Damiano D Amato Mauro M Frigerio Beatrice B Columbo Gualtiero G Binkley Philip F PF Pandey Saurabh R SR Suhy Adam M AM Hartmann Katherine K Kitzmiller Joseph P JP
Giornale italiano dell'arteriosclerosi 20131101 4
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Project description:Although statins are generally well tolerated, the most common adverse drug reaction from statin therapy is myopathy. This article reviews the current pharmacogenomic knowledge of statin-induced myopathy. Furthermore, we will discuss the importance of recent pharmacogenetic advances for the treatment and management of statin-induced myopathy. Variation in the SLCO1B1 gene is associated with increased incidence of statin-induced myopathy, particularly with simvastatin and less so with other statins. If different pharmacokinetic enzymes and transporters are responsible for susceptibility to myopathy, this may explain differences in the occurrence of statin-induced myopathy in individual patients. Genotyping in patients suffering from statin-induced myopathy may help to personalize the choice of statin for the lowest chance of developing myopathy.
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Project description:Background Inability to tolerate statins because of muscle symptoms contributes to uncontrolled cholesterol levels and insufficient cardiovascular risk reduction. Bempedoic acid, a prodrug that is activated by a hepatic enzyme not present in skeletal muscle, inhibits ATP -citrate lyase, an enzyme upstream of β-hydroxy β-methylglutaryl-coenzyme A reductase in the cholesterol biosynthesis pathway. Methods and Results The phase 3, double-blind, placebo-controlled CLEAR (Cholesterol Lowering via Bempedoic acid, an ACL-Inhibiting Regimen) Serenity study randomized 345 patients with hypercholesterolemia and a history of intolerance to at least 2 statins (1 at the lowest available dose) 2:1 to bempedoic acid 180 mg or placebo once daily for 24 weeks. The primary end point was mean percent change from baseline to week 12 in low-density lipoprotein cholesterol. The mean age was 65.2 years, mean baseline low-density lipoprotein cholesterol was 157.6 mg/dL, and 93% of patients reported a history of statin-associated muscle symptoms. Bempedoic acid treatment significantly reduced low-density lipoprotein cholesterol from baseline to week 12 (placebo-corrected difference, -21.4% [95% CI, -25.1% to -17.7%]; P<0.001). Significant reductions with bempedoic acid versus placebo were also observed in non-high-density lipoprotein cholesterol (-17.9%), total cholesterol (-14.8%), apolipoprotein B (-15.0%), and high-sensitivity C-reactive protein (-24.3%; P<0.001 for all comparisons). Bempedoic acid was safe and well tolerated. The most common muscle-related adverse event, myalgia, occurred in 4.7% and 7.2% of patients who received bempedoic acid or placebo, respectively. Conclusions Bempedoic acid offers a safe and effective oral therapeutic option for lipid lowering in patients who cannot tolerate statins. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 02988115.
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Project description:BackgroundStatin-associated muscle symptoms (SAMS) are the most frequently reported adverse events for statin therapies. Previous studies have reported an association between the p.Val174Ala missense variant in SLCO1B1 and SAMS in simvastatin-treated subjects; however, evidence for genetic predictors of SAMS in atorvastatin- or rosuvastatin-treated subjects is currently lacking.MethodsODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; n=18 924) was a double-blind, randomized, placebo-controlled study evaluating the efficacy and safety of alirocumab (a PCSK9 [proprotein convertase subtilisin/kexin type 9] inhibitor) in acute coronary syndrome patients receiving high-intensity statin therapy. The goal of this pharmacogenomic analysis was to identify genetic variants associated with atorvastatin- and rosuvastatin-mediated SAMS among ODYSSEY OUTCOMES subjects who consented to participate in the genetic study (n=11 880). We performed multi-ancestry exome-wide and genome-wide association studies and gene burden analysis across 2 phenotypes (clinical SAMS [n=10 617] and creatine kinase levels [n=9630]).ResultsA novel genome-wide significant association for an intronic variant (rs6667912) located within TMEM9 (odds ratio [95% CI], 1.39 [1.24-1.55]; P=3.71×10-8) for patients with clinical SAMS (cases=894, controls=9723) was identified. This variant is located ≈30 kb upstream of CACNA1S, a locus associated with severe SAMS. We replicated 2 loci, at LINC0093 and LILRB5, previously associated with creatine kinase levels during statin treatment. No association was observed between p.Val174Ala (rs4149056) in SLCO1B1 and SAMS (odds ratio [95% CI], 1.03 [0.90-1.18]; P=0.69).ConclusionsThis study comprises the largest discovery exome-wide and genome-wide association study for atorvastatin- or rosuvastatin-mediated SAMS to date. These novel genetic findings may provide biological/mechanistic insight into this drug-induced toxicity, and help identify at-risk patients before selection of lipid-lowering therapies.
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Project description:Statins are a cornerstone in the pharmacological prevention of cardiovascular disease. Although generally well tolerated, a small subset of patients experience statin-related myotoxicity (SRM). SRM is heterogeneous in presentation; phenotypes include the relatively more common myalgias, infrequent myopathies, and rare rhabdomyolysis. Very rarely, statins induce an anti-HMGCR positive immune-mediated necrotizing myopathy. Diagnosing SRM in clinical practice can be challenging, particularly for mild SRM that is frequently due to alternative aetiologies and the nocebo effect. Nevertheless, SRM can directly harm patients and lead to statin discontinuation/non-adherence, which increases the risk of cardiovascular events. Several factors increase systemic statin exposure and predispose to SRM, including advanced age, concomitant medications, and the nonsynonymous variant, rs4149056, in SLCO1B1, which encodes the hepatic sinusoidal transporter, OATP1B1. Increased exposure of skeletal muscle to statins increases the risk of mitochondrial dysfunction, calcium signalling disruption, reduced prenylation, atrogin-1 mediated atrophy and pro-apoptotic signalling. Rare variants in several metabolic myopathy genes including CACNA1S, CPT2, LPIN1, PYGM and RYR1 increase myopathy/rhabdomyolysis risk following statin exposure. The immune system is implicated in both conventional statin intolerance/myotoxicity via LILRB5 rs12975366, and a strong association exists between HLA-DRB1*11:01 and anti-HMGCR positive myopathy. Epigenetic factors (miR-499-5p, miR-145) have also been implicated in statin myotoxicity. SRM remains a challenge to the safe and effective use of statins, although consensus strategies to manage SRM have been proposed. Further research is required, including stringent phenotyping of mild SRM through N-of-1 trials coupled to systems pharmacology omics- approaches to identify novel risk factors and provide mechanistic insight.
| S-EPMC7019839 | biostudies-literature
Project description:BackgroundRecent lipid guidelines recommend aggressive low-density lipoprotein (LDL) cholesterol lowering in patients with coronary artery disease. To clarify the evidence for this recommendation, we conducted a meta-analysis of randomized controlled trials that compared different intensities of statin therapy.MethodsWe searched electronic databases (MEDLINE, EMBASE, Cochrane Central Registery of Controlled Trials, Web of Science) for randomized controlled trials published up to July 19, 2007, that compared statin regimens of different intensities in adults with coronary artery disease and that reported cardiovascular events or mortality. Data were pooled using random-effects models to calculate odds ratios (OR).ResultsA total of 7 trials (29 395 patients) were included. Compared with less intensive statin regimens, more intensive regimens further reduced LDL levels (0.72 mmol/L reduction, 95% confidence interval [CI] 0.60-0.84 mmol/L), and reduced the risk of myocardial infarction (OR 0.83, 95% CI 0.77-0.91) and stroke (OR 0.82, 95% CI 0.71-0.95). Although there was no effect on mortality among patients with chronic coronary artery disease (OR 0.96, 95% CI 0.80-1.14), all-cause mortality was reduced among patients with acute coronary syndromes treated with more intensive statin regimens (OR 0.75, 95% CI 0.61-0.93). Compared with lower intensity regimens, more intensive regimens were associated with small absolute increases in rates of drug discontinuation (2.5%), elevated levels of aminotransferases (1%) and myopathy (0.5%), and there was no difference in noncardiovascular mortality. All 7 trials reported events by randomization arm rather than by LDL level achieved. About half of the patients treated with more intensive statin therapy did not achieve an LDL level of less than 2.0 mmol/L, and none of the trials tested combination therapies.InterpretationOur analysis supports the use of more intensive statin regimens in patients with established coronary artery disease. There is insufficient evidence to advocate treating to particular LDL targets, using combination lipid-lowering therapy to achieve these targets or for using more intensive regimens in patients without established coronary artery disease.
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Project description:Currently, statins are the first-line therapies for dyslipidemia and atherosclerotic cardiovascular disease, however, their hypolipidemic effects have not been satisfactory. We performed a meta-analysis to compare lipid-lowering efficacy and safety of ezetimibe and statin combination therapy with double-dose statin monotherapy in patients with high cardiovascular risk. Fourteen studies involving 3105 participants were included in the final analysis; 1558 (50.18%) participants received ezetimibe and statin combination therapy and 1547 (49.82%) received double-dose statin monotherapy. Eight studies reported the percentages of changes in several lipid parameters from baseline to endpoint in both groups. Lipid parameters changed more significantly in patients coadministered with ezetimibe and statin (low-density lipoprotein cholesterol [LDL-C]: MD = -9.39, 95% CI -13.36 to -5.42; non-high-density lipoprotein cholesterol [non-HDL-C]: MD = -10.36, 95% CI -14.23 to -6.50; total cholesterol [TC]: MD = -8.11, 95% CI -10.95 to -5.26; and triglyceride [TG]: MD = -5.96, 95% CI -9.12 to -2.80), with moderate to high heterogeneity among the studies. Two out of fourteen studies investigated several different statins. Our subgroup analysis showed that, compared with double-dose atorvastatin monotherapy, ezetimibe and atorvastatin combination therapy significantly decreased LDL-C, non-HDL-C, TC, and TG levels by 14.16%, 14.01%, 11.06%, and 5.96%, respectively (p < 0.001). No significant difference was found in the incidence of laboratory-related adverse events (AEs) between statin combination therapy and monotherapy. Overall, ezetimibe and statin combination therapy significantly decreased LDL-C, non-HDL-C, and TC levels in patients with high cardiovascular risk, among which ezetimibe combined with atorvastatin had the best therapeutic effect. Compared with ezetimibe and statin combination therapy, double-dose statin monotherapy did not increase the risk of AEs.
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2013-01-14 | E-GEOD-40841 | biostudies-arrayexpress