Clinical response to statins: Mechanism(s) of variable activity and adverse effects

Figures & data

Table I. Summary of the genetic factors controlling responses to statins.

References	Drug	Polymorphism/mutations	Population/study	Effects/results/conclusions
CYPs
Kirchheiner et al. 2003 (8)	fluvastatin	CYP2C9*2 (Arg144Cys); CYP2C9*3 (Ile359Leu)	24 healthy non-smoker volunteers	CYP2C9*2 and *3 caused an increased area under the curve for the active fluvastatin enantiomer and reduced the hypocholesterolemic response
Kajinami et al. 2004 (9)	atorvastatin	CYP3A4 (A-290G); CYP3A4 (F189S); CYP3A4 (M445T)	344 hypercholesterolemic patients	The A-290G variant allele was associated with higher levels of post-treatment LDL-C, whereas the M445T variant was associated with lower levels of LDL-C before and after treatment
Willrich et al. 2008 (10)	atorvastatin	CYP3A5*3C (A6986G)	139 hypercholesterolemic patients	CYP3A5*3A is associated with reduced cholesterol-lowering response to atorvastatin in non-African individuals
Zuccaro et al. 2007 (13)	simvastatin fluvastatin	CYP2D6*1/*4; CYP2D6*4/4	100 hypercholesterolemic patients	The CYP2D6*1/*4 and *4/*4 poor metabolizer status is associated with a higher efficacy
ABCB1/ABCG2
Fiegenbaum et al. 2005 (20)	simvastatin	ABCB1 (1236C > T, 2677G > A/T)	116 hypercholesterolemic patients	Carriers of the ABCB1 1236T variant allele had a greater reduction in total and LDL-C after simvastatin; similar results were observed for the 2677G > A/T polymorphism
Bercovich et al. 2006 (21)	fluvastatin	ABCB1-h4 haplotype (GCCTA)	76 Familial Hypercholesterolemia (FH) patients	ABCB1-h4 causes an increased hypocholesterolemic response to fluvastatin
Tomlinson et al. 2010 (28)	rosuvastatin	ABCG2 (c.421AA versus c.421CC genotypes)	305 Chinese hypercholesterolemic patients	Male carriers of the ABCG2 c.421AA genotype had a significantly larger reduction in LDL-C (−58.4% versus −47.6%) after rosuvastatin
SLCO1B1
Couvert et al. 2008 (30)	fluvastatin	SLCO1B1*14 allele (c.463C)	724 hypercholesterolemic patients	The *14 allele causes enhanced lipid-lowering efficacy of fluvastatin
Igel et al. 2006 (31)	pravastatin	SLCO1B1(388A > G); SLCO1B1(521T > C); SLCO1B1(-11187G > A)	16 healthy volunteers	There was no significant difference in the lipid-lowering efficacy of pravastatin between the variant haplotype and control groups
Hedman et al. 2006 (32)	pravastatin	SLCO1B1 (521TC/TT)	20 Heterozygous Familial Hypercholesterolemia (HeFH) children and 12 cardiac transplant recipients	Decrease in LDL-C by pravastatin is smaller, and increase in HDL-C is larger in the 521TC carriers as compared with the 521TT carriers
CETP
Kuivenhoven et al. 1998 (38)	pravastatin	CETP B1/B2 variants	The Regression Growth Evaluation Statin Study Group	Pravastatin therapy slowed the progression of coronary atherosclerosis in B1B1 carriers but not in B2B2 carriers
van Venrooij et al. 2003 (41)	atorvastatin	CETP B1/B2 variants	217 patients with type 2 diabetes	B1B1 carriers have a more atherogenic lipid profile, including low HDL, and they respond better to statin therapy
Winkelmann et al. 2003 (44)	various statins	SNPs1-9 haplotype (TTCAAAGGG); SNPs4-9 haplotype (AAAGGG); SNPs1-6 haplotype (TTCAAA)	98 hypercholesterolemic patients	TTCAAA haplotype is in linkage to the HDL-C rising effect of statins, the TTCAAAGGG and AAAGGG haplotypes associated with triglyceride lowering potency of statins
ApoE
Ballantyne et al. 2000 (47)	fluvastatin	ApoE three common alleles (ε2, ε3, ε4)	724 hypercholesterolemic patients	Subjects with the ε4 allele had less reduction in LDL-C with fluvastatin, but no difference was recorded in terms of CAD progression
De Knijff et al. 1990 (48)	simvastatin	ApoE three common alleles (ε2, ε3, ε4)	120 FH patients	Female FH patients with the apoE3E3 phenotype responded better to treatment than male FH patients with the apoE3E3 genotype.
Hubacek et al. 2005 (56)	various statins	ApoA5 (c.-1131T > C); apoA5 (c.56C > G); apoA5 (c.4576 > A)	187 adult Caucasians	Carriers of C-1131 allele responded significantly less to statin treatment as compared to the common T-1131 homozygotes (LDL-C −29.9% ± 12.5% versus −36.6% ± 15.1%)

Table II. Summary of the basic mechanisms and genetic factors underlying statin myopathy.

References	Drug	Polymorphism/mutations/biopsies	Population/study	Effects/results/conclusions
Basic mechanism(s)
Philips et al. 2002 (5)	various statins	muscle biopsy	30 patients with normal CK	Patients reported muscle symptoms. Muscle biopsies showed mitochondrial dysfunction, including abnormally increased lipid stores
Draeger et al. 2006 (62)	various statins	muscle biopsy	22 patients	Patients had skeletal muscle damage including break-down of the T-tubular system and subsarcolemmal rupture
Mohaupt et al. 2009 (63)	various statins	muscle biopsy	83 patients	Patients with muscular pain, in particular those with muscular side-effects persisting several months after statin withdrawal
Pierno et al. 2006 (66)	various statins	muscle	male Wistar rats	Statins are antagonists of the Cl channels at the muscle membrane level. This mechanism may result in complete paralysis in rats after very high doses of statins, inducing myalgia
Hanai et al. 2007 (69)	lovastatin	muscle biopsy	humans with statin myopathy; mice myotubes and zebra fish embryos	Lovastatin may induce the expression of atrogin-1, a key gene involved in skeletal muscle atrophy
CYPs
Frudakis et al. 2007 (73)	atorvastatin/simvastatin	CYP2D6*4	case control study	CYP2D6 polymorphism may be associated with statin-induced myopathy
Wilke et al. 2005 (76)	atorvastatin	CYP3A5*3 homozygosis	case control study (137 patients)	Carriers developed myalgia and had higher plasma CK levels versus heterozygotes
ABCB1/ABCG2
Keskitalo et al. 2008 (85)	atorvastatin/simvastatin	ABCB1 haplotypes (c.1236T-c.2677T-c.3435T-c.1236C-c.2677G and c.3435C)	24 healthy Finnish volunteers	Homozygote carriers of the c.1236T-c.2677T-c.343T haplotype showed increases in the AUC of simvastatin acid and atorvastatin, both approximately 60%
Keskitalo et al. 2009 (27)	atorvastatin, rosuvastatin	ABCG2 (c.421AA and c.421CC genotypes)	32 healthy Finnish volunteers	The AUC of atorvastatin about 70% higher and that of rosuvastatin 144% higher in carriers of the ABCG2 c.421AA genotype
SLCO1B1
Morimoto et al. 2004 (82)	pravastatin/atorvastatin	SLCO1B1*15 allele rare novel mutation (1628T > G)	Japanese study	All subjects presented with myopathy. In one patient with this rare novel mutation in exon 12 of SLCO1B1 it resulted in myopathy after pravastatin
Link et al. 2008 (83)	simvastatin 80 mg	rs4149056 C variant (Val174Ala)	SEARCH study (85 cases/90 controls)	This variant has an OR for myopathy of 4.5 per copy of the C allele and 16.9% for two alleles. CC homozygotes have an 18% cumulative risk of myopathy during the first year of treatment
Voora et al. 2009 (84)	atorvastatin/simvastatin/ pravastatin	SLCO1B1*5 allele	STRENGTH study (509 patients)	Carriers were at a 2-fold relative risk of mild statin-induced side-effects despite normal CK levels
MHC-I
Needham et al. 2007 (86)	various statins	muscle biopsy	8 patients with myopathy	The mechanism of myopathy may involve an endoplasmic reticulum stress response with associated up-regulation of MHC-I expression and antigen presentation by muscle fibers
Vascular homeostasis genes
Ruano et al. 2005 (87)	various statins	19 SNPs	102 patients	SNPs in the angiotensin II type 1 receptor and nitric oxide synthase 3 genes were significantly associated with CK activity

Kirchheiner J, Kudlicz D, Meisel C, Steinbach N, Roots I, Brockmöller J. Influence of CYP2C9 polymorphisms on the pharmacokinetics and cholesterol-lowering activity of (−)-3S,5R-fluvastatin and (+)-3R,5S-fluvastatin in healthy volunteers. Clin Pharmacol Ther. 2003;74:186–94.

 PubMed Web of Science ®Google Scholar

Kajinami K, Brousseau ME, Ordovas JM, Schaefer EJ. CYP3A4 genotypes and plasma lipoprotein levels before and after treatment with atorvastatin in primary hypercholesterolemia. Am J Cardiol. 2004;93:104–7.

 PubMed Web of Science ®Google Scholar

Willrich MA, Hirata MH, Genvigir FD, Arazi SS, Rebecchi IM, Rodrigues AC, . CYP3A53A allele is associated with reduced lowering-lipid response to atorvastatin in individuals with hypercholesterolemia. Clin Chim Acta. 2008;398:15–20.

 PubMed Web of Science ®Google Scholar

Zuccaro P, Mombelli G, Calabresi L, Baldassarre D, Palmi I, Sirtori CR. Tolerability of statins is not linked to CYP450 polymorphisms, but reduced CYP2D6 metabolism improves cholesteraemic response to simvastatin and fluvastatin. Pharmacol Res. 2007;55:310–7.

 PubMed Web of Science ®Google Scholar

Fiegenbaum M, da Silveira FR, Van der Sand CR, Van der Sand LC, Ferreira ME, Pires RC, . The role of common variants of ABCB1, CYP3A4, and CYP3A5 genes in lipid-lowering efficacy and safety of simvastatin treatment. Clin Pharmacol Ther. 2005;78:551–8.

 PubMed Web of Science ®Google Scholar

Bercovich D, Friedlander Y, Korem S, Houminer A, Hoffman A, Kleinberg L, . The association of common SNPs and haplotypes in the CETP and MDR1 genes with lipids response to fluvastatin in familial hypercholesterolemia. Atherosclerosis. 2006;185:97–107.

 PubMed Web of Science ®Google Scholar

Tomlinson B, Hu M, Lee VW, Lui SS, Chu TT, Poon EW, . ABCG2 polymorphism is associated with the low-density lipoprotein cholesterol response to rosuvastatin. Clin Pharmacol Ther. 2010;87:558–62.

 PubMed Web of Science ®Google Scholar

Couvert P, Giral P, Dejager S, Gu J, Huby T, Chapman MJ, . Association between a frequent allele of the gene encoding OATP1B1 and enhanced LDL-lowering response to fluvastatin therapy. Pharmacogenomics. 2008;9:1217–27.

 PubMed Web of Science ®Google Scholar

Igel M, Arnold KA, Niemi M, Hofmann U, Schwab M, Lütjohann D, . Impact of the SLCO1B1 polymorphism on the pharmacokinetics and lipid-lowering efficacy of multiple-dose pravastatin. Clin Pharmacol Ther. 2006;79:419–26.

 PubMed Web of Science ®Google Scholar

Hedman M, Antikainen M, Holmberg C, Neuvonen M, Eichelbaum M, Kivistö KT, . Pharmacokinetics and response to pravastatin in paediatric patients with familial hypercholesterolaemia and in paediatric cardiac transplant recipients in relation to polymorphisms of the SLCO1B1 and ABCB1 genes. Br J Clin Pharmacol. 2006;61:706–15.

 PubMed Web of Science ®Google Scholar

Kuivenhoven JA, Jukema JW, Zwinderman AH, de Knijff P, McPherson R, Bruschke AV, . The role of a common variant of the cholesteryl ester transfer protein gene in the progression of coronary atherosclerosis. The Regression Growth Evaluation Statin Study Group. N Engl J Med. 1998;338:86–93.

 PubMed Web of Science ®Google Scholar

van Venrooij FV, Stolk RP, Banga JD, Sijmonsma TP, van Tol A, Erkelens DW, . Common cholesteryl ester transfer protein gene polymorphisms and the effect of atorvastatin therapy in type 2 diabetes. Diabetes Care. 2003;26:1216–23.

 PubMed Web of Science ®Google Scholar

Winkelmann BR, Hoffmann MM, Nauck M, Kumar AM, Nandabalan K, Judson RS, . Haplotypes of the cholesteryl ester transfer protein gene predict lipid-modifying response to statin therapy. Pharmacogenomics J. 2003;3:284–96.

 PubMed Web of Science ®Google Scholar

Ballantyne CM, Herd JA, Stein EA, Ferlic LL, Dunn JK, Gotto AM Jr, . Apolipoprotein E genotypes and response of plasma lipids and progression-regression of coronary atherosclerosis to lipid-lowering drug therapy. J Am Coll Cardiol. 2000;36:1572–8.

 PubMed Web of Science ®Google Scholar

De Knijff P, Stalenhoef AF, Mol MJ, Gevers Leuven JA, Smit J, Erkelens DW, . Influence of apo E polymorphism on the response to simvastatin treatment in patients with heterozygous familial hypercholesterolemia. Atherosclerosis. 1990;83:89–97.

 PubMed Web of Science ®Google Scholar

Hubacek JA. Apolipoprotein A5 and triglyceridemia. Focus on the effects of the common variants. Clin Chem Lab Med. 2005;43:897–902.

 PubMed Web of Science ®Google Scholar

Phillips PS, Haas RH, Bannykh S, Hathaway S, Gray NL, Kimura BJ, . Statin-associated myopathy with normal creatine kinase levels. Ann Intern Med. 2002;137:581–5.

 PubMed Web of Science ®Google Scholar

Draeger A, Monastyrskaya K, Mohaupt M, Hoppeler H, Savolainen H, Allemann C, . Statin therapy induces ultrastructural damage in skeletal muscle in patients without myalgia. J Pathol. 2006;210:94–102.

 PubMed Web of Science ®Google Scholar

Mohaupt MG, Karas RH, Babiychuk EB, Sanchez-Freire V, Monastyrskaya K, Iyer L, . Association between statin-associated myopathy and skeletal muscle damage. CMAJ. 2009;181:E11–18.

 PubMed Web of Science ®Google Scholar

Pierno S, Didonna MP, Cippone V, De Luca A, Pisoni M, Frigeri A, . Effects of chronic treatment with statins and fenofibrate on rat skeletal muscle: a biochemical, histological and electrophysiological study. Br J Pharmacol. 2006;149: 909–19.

 PubMed Web of Science ®Google Scholar

Hanai J, Cao P, Tanksale P, Imamura S, Koshimizu E, Zhao J, . The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity. J Clin Invest. 2007;117:3940–51.

 PubMed Web of Science ®Google Scholar

Frudakis TN, Thomas MJ, Ginjupalli SN, Handelin B, Gabriel R, Gomez HJ. CYP2D6*4 polymorphism is associated with statin-induced muscle effects. Pharmacogenet Genomics. 2007;17:695–707.

 PubMed Web of Science ®Google Scholar

Wilke RA, Moore JH, Burmester JK. Relative impact of CYP3A genotype and concomitant medication on the severity of atorvastatin-induced muscle damage. Pharmacogenet Genomics. 2005;15:415–21.

 PubMed Web of Science ®Google Scholar

Keskitalo JE, Kurkinen KJ, Neuvoneni PJ, Niemi M. ABCB1 haplotypes differentially affect the pharmacokinetics of the acid and lactone forms of simvastatin and atorvastatin. Clin Pharmacol Ther. 2008;84:457–61.

 PubMed Web of Science ®Google Scholar

Keskitalo JE, Zolk O, Fromm MF, Kurkinen KJ, Neuvonen PJ, Niemi M. ABCG2 polymorphism markedly affects the pharmacokinetics of atorvastatin and rosuvastatin. Clin Pharmacol Ther. 2009;86:197–203.

 PubMed Web of Science ®Google Scholar

Morimoto K, Oishi T, Ueda S, Ueda M, Hosokawa M, Chiba K. A novel variant allele of OATP-C (SLCO1B1) found in a Japanese patient with pravastatin-induced myopathy. Drug Metab Pharmacokinet. 2004;19:453–5.

 PubMedGoogle Scholar

Link E, Parish S, Armitage J, Bowman L, Heath S, Matsuda F, . SLCO1B1 variants and statin-induced myopathy— a genomewide study. N Engl J Med. 2008;359:789–99.

 PubMed Web of Science ®Google Scholar

Voora D, Shah SH, Spasojevic I, Zhai J, Crosslin DR, Messer C, . The SLCO1B1*5 genetic variant is associated with statin-induced side effects. J Am Coll Cardiol. 2009;54:1609–16.

 PubMed Web of Science ®Google Scholar

Needham M, Fabian V, Knezevic W, Panegyres P, Zilko P, Mastaglia FL. Progressive myopathy with up-regulation of MHC-I associated with statin therapy. Neuromuscul Disord. 2007;17:194–200.

 PubMed Web of Science ®Google Scholar

Ruano G, Thompson PD, Windemuth A, Smith A, Kocherla M, Holford TR, . Physiogenomic analysis links serum creatine kinase activities during statin therapy to vascular smooth muscle homeostasis. Pharmacogenomics. 2005;6: 865–72.

 PubMed Web of Science ®Google Scholar