statine 8

Atherosclerosis 215 (2011) 2329

Contents lists available at ScienceDirect

Atherosclerosis

journa l homepage: www.e lsev ier .com/ loc

Review

The rel

Ankur GuCardiology, Ha

a r t i c l

Article history:Received 26 OReceived in re24 NovemberAccepted 25 NAvailable onlin

Keywords:StatinsMyopathyMuscleSkeletal musclHMG-CoA redLipidsVitamin DVitamin D deciency

that that increasing vitamin D levels can reverse the myalgia. Nevertheless, given the quality and paucityof studies examining this possibility, additional studies are needed to examine the potential role of vita-minDdeciency in statinmyopathy. It is presently premature to recommend vitaminD supplementationas treatment for statin associatedmuscle complaints in the absence of low vitaminD levels although suchsupplementation could be tried in patients with decient or reduced vitamin D levels.

2011 Elsevier Ireland Ltd. All rights reserved.

Contents

1. Introd2. Metho3. Overv4. Effect5. Effect6. Effect7. Molec8. Vitam9. Vitam10. Conc

Refer

1. Introdu

Statins oreductase ital muscleelevations

CorresponE-mail add

0021-9150/$ doi:10.1016/j.uction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23ds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24iew of vitamin D metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24s of vitamin D on serum lipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24of vitamin D levels on the lipid response to statins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25of statins on vitamin D levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25ular actions of vitamin D in muscle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26in D and muscle function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26in D deciency and statin myopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26lusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27ences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

ction

r 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA)nhibitors are associated with a spectrum of skele-complaints, ranging from myalgia and asymptomaticof creatine kinase (CK) to frank rhabdomyolysis. Risk

ding author. Tel.: +1 860 545 2880; fax: +1 860 545 2882.ress: [email protected] (P.D. Thompson).

factors for statin-associated muscle complaints include geneticpredisposition [1], high-dose statin treatment [2], advanced age,hypothyroidism, hepatobiliary disease, renal disease and theconcomitant administration of drugs that interfere with statinmetabolism [3,4], especially gembrozil [5]. The exact mechanismof statin-induced myopathy is not clear, but suggested mecha-nisms include decreased sarcolemmal [6], or sarcoplasmic reticularcholesterol [7], decreased production of ubiuquinone or coen-zyme Q10 [8,9], decreased production of prenylated proteins [6],changes in fatmetabolism [10], increased skeletalmuscle uptake of

see front matter 2011 Elsevier Ireland Ltd. All rights reserved.atherosclerosis.2010.11.039ationship of vitamin D deciency to statin myopathy

pta, Paul D. Thompson

rtford Hospital, 80 Seymour Street, Hartford, CT 06102, United States

e i n f o

ctober 2010vised form2010ovember 2010e 5 December 2010

euctase inhibitors

a b s t r a c t

Objective: Our goal was to examine the interaction between vitamin D and statins and the possible roleof vitamin D deciency in statin myopathy.Background: The vitamin D receptor is present in skeletal muscle and vitamin D deciency can causemyopathy. Statins (3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors) are generally well tolerated,but have been associated with a spectrum of skeletal muscle complaints, ranging from myalgia andasymptomatic mild elevations of creatine kinase (CK) to rhabdomyolysis. There has been recent interestin thepossible interactionbetweenstatinmyopathyandvitaminDdeciency.Weperformeda systematicmedical literature review to examine this possible relationship.Methods: We identied English language articles relating statins, vitamin D and statin myopathy via aPubMed search through July 2010. Articles pertinent to the topic were reviewed in detail.Results/conclusions: Our review suggests that some but not all statins increase 25(OH) D levels. Two crosssectional studies have associated vitamin D deciency with statin-associated myalgias, and suggestedate /a therosc leros is

24 A. Gupta, P.D. Thompson / Atherosclerosis 215 (2011) 2329

cholesterol [11] or phytosterols [12], failure to catabolize damagedmuscle protein via the ubiquitin pathway [13], disruption of cal-cium metabolism [14], inhibition of selenoprotein synthesis [15],mitochondrial dysfunction [16] and activation of mild inheritedmyopathies

A recenties [99,101]suggestingpossible remin D decatherosclerwhere [17linking statidence for thmyopathy.

2. Method

We searthe relationusing the secle, HMG-CD deciencJuly 2010 wmyopathy asearched thlanguage abreview in o

3. Overvie

Bioactivmone [20]calcium andthe humansure, it is stiin geographmake enougeographiccontent, anand vitaminbeen identithat this ho

Cholesteendogenouto vitaminVitamin Dplementatio(ergocalcifeanimals. Trsidered equstudies hav[25(OH)D],min D 1,25-than vitamilife and a lovitamin D h

D2 or D3and 25(OH)D. Most oldfrom 25(OHhydroxylativitamin D hAll forms obound to ca

protein. The half-life of 25(OH)D is several weeks, while that of1,25-(OH)2D is only a few hours [28].

VitaminDhas historically been known to act on organs involvedin calcium metabolism including bone, kidney, and intestine [29].

scov0 tissmyocskin,leu

n Dsetab

)D(35(OHon-rmote bgulatolismmL)tamihype unvitampme

cts o

mincardinismeffecn D a]. Foed dtamiDL,itamect onD3ngescontrum3geighto (ppar

se wg o-lossterol(12chocoulecreoapsed c

ids toding

46].leastted tof

erides [47

ally t[1].case report [96], case series [95] and crossectional stud-have linked vitamin D insufciency and statin myalgiavitamin D as possible therapy for statin myalgia. Thislationship may be especially important because vita-iency has been identied as a possible risk factor forotic cardiovascular disease, a topic summarized else-19]. We performed a systematic review of the evidencenmyopathyandvitaminD toexamine the scienticevi-e hypothesis that vitamin D may contribute to statin

s

ched PubMed for English language articles examiningship between statins, vitamin D and statin myalgiaarch words: statins, myopathy, muscle, skeletal mus-oA reductase inhibitors, lipids, vitamin D, and vitaminy alone and in combination. Articles published throughere reviewed and those articles pertinent to statin

nd vitamin D were examined in detail. In addition, wee reference citations of all identied articles. Englishstracts of non-English articles are also included in thisrder to provide a comprehensive review of the topic.

w of vitamin D metabolism

e vitamin D or calcitriol (1,25-(OH)2D3) is a steroid hor-that has an important role in regulating body levels ofphosphorus and in bone mineralization. Even though

body can synthesize vitamin D in skin from sun expo-ll considered a vitamin sincemanypeople despite livingical locations with adequate sunlight exposure do not

gh vitamin D and require an exogenous source. Season,latitude, time of day, cloud cover, smog, skin melanind sunscreen use affect ultraviolet radiation exposureD synthesis [21,22]. Vitamin D receptors have recently

ed in a wide variety of cells [23], and it is now clearrmone has biologic effects beyond mineral metabolism.rol is used to synthesize 7-dehydrocholesterol (7-DHC)sly. Vitamin D is produced when 7-DHC is convertedD3 (cholecalciferol) in the skin by ultraviolet B light.is also obtained from dietary sources and oral sup-n. Dietary sources are in the form of vitamin D2rol) from plants and vitamin D3 (cholecalciferol) fromaditionally, vitamin D2 and vitamin D3 have been con-ivalent [24] and interchangeable. However, severale shown that the serum level of 25 hydroxyvitamin Dthe precursor to the biologically active form of vita-(OH)2D, is increased more effectively with vitamin D3n D2 [25,26]. Vitamin D2 also has a shorter plasma half-wer afnity for the vitamin D binding protein, hepaticydroxylase, and for the vitamin D receptor [25].is converted by hepatic 25-hydroxylase to 25(OH)D2

D3 respectively, the major circulating forms of vitaminer assays for 25(OH)D cannot differentiate, 25(OH)D2)D3 [27]. 25(OH)D2 and 25(OH)D3 undergo 1 alpha-on in the kidney to produce the biologically activeormone, 1,25(OH)2D2 and 1,25-(OH)2D3, respectively.f vitamin D are hydrophobic and transported in bloodrrier proteins. The major carrier is vitamin D-binding

The diover 3cardiolium,humanvitamicium m25(OHverts 2latter nmay beadequaD to remetab(30ng/that vilead toited thnewerdevelo

4. Effe

Vitaroticmechaing anvitami[3840providlow vitotal, Lplus Vthe effvitamino cha

Inon serof 83.overwplaceb7% comor obe1200mweightcholeseridesin HDLeffectscould dcium sincreasbile action leaacids [

Athas notertilestriglycD statuespeciery of vitamin D receptors (VDRs) for 1,25(OH)2D inues [30] including parathyroid glands, skeletal muscle,ytes, brain, vascular smooth muscle cells, endothe-cancer cells, endocrine tissue, reproductive glands,

cocytes and malignant cells has increased interest inrole in metabolic activities not directly related to cal-olism. Many of these tissues also contain the enzyme

)-1alpha-hydroxylase, encoded byCYP27B1,which con-)D to 1,25(OH)2D3 [29]. Regulation of CYP27B1 in theseenal tissues appears todiffer fromthat in thekidneyandre substrate dependent. This has led to the concept thatlood levels of 25(OH)D must be maintained for vitamine physiologic functions not involved with bone mineral[31]. A desirable 25(OH)D concentration is 75nmol/L[32,33]. The NIH Ofce of Dietary Supplements statesn D levels consistently >200ng/mL (>500nmol/L) canercalcemia and hypercalcuria. This side effect has lim-bridled use of vitamin D and related metabolites, butin D analogues without hypercalcemia toxicity are in

nt.

f vitamin D on serum lipids

D deciency may be a novel risk factor for atheroscle-ovascular disease [17,34,35]. Numerous potentials have been proposed for this vitamin D effect includ-t on the atherosclerotic process in diabetics [36,37], butppears to have little or no effect on serum lipid levelsr example, 1020mcg (400800Units) of vitamin D3aily for 1 year to 173 subjects of Pakistani origin withn D status living in Denmark produced no change inHDL and VLDL cholesterol [41]. Similarly, the Calciumin D Trial of the Womens Health Initiative comparedf placebo vs. 1 g elemental Ca as carbonate plus 400 IU/day in 1191postmenopausalwomen [42] and observedin plasma lipids over 5 years.ast, some studies suggest a small vitamin D effectlipids. Vitamin D supplementation at a high dose(3332 IU) of cholecalciferol for 12 months in 200subjects decreased triglycerides 16.5% more than

A. Gupta, P.D. Thompson / Atherosclerosis 215 (2011) 2329 25

Table 1Studies on effect of statins on serum vitamin D levels.

Study Participants Intervention Duration LDL cholesterolreduction in statin

Results

Rejnmark et ks

Ismail et al. ks foratin afor pla

Yavuz et al. s

Ertugrul et a s

tein lipaseThird Natiosignicantlylevels [92.5nmoThe prevalelowest quarlevels, p< .0

Taken tohas a smallon this and

5. Effect of

Vitaminapy, and so>30nmol/Lels [50]. Atreated wittatin, there16451mgor LDL cholin patients(12.02ng/m(12.020.0nexpected rerides. Simvitamin D (apy (453vs. 1693(p150mg/dl was 32.8% in thetile and 23.8% in the highest quartile of serum 25(OH)D01.gether these studies suggest that vitamin D probablyeffect in reducing triglycerides, but that conclusive dataother lipid effects of this vitamin require further study.

vitamin D levels on the lipid response to statins

D status may affect lipid changes during statin ther-me have suggested that adequate Vitamin D levelsmay be required for atorvastatin to reduce lipid lev-mong 63 patients with acute myocardial infarctionh low (1020mg) or high dose (4080mg) atorvas-wasno reduction in total cholesterol (17347mg/dl vs./dl), triglycerides (15149mg/dl vs. 17794mg/dl),

esterol (11148mg/dl vs. 92 45mg/dl) at 12 months

25-hydtase anunspeceffect wmin Dactivein LDL

6. Effe

Ascholesproducvitamiincreaswhich(Tablemin Dsomehavailabexplainsity anclassied as vitamin D decient (25(OH)D50nmol/L, (20.0ng/mL) had the

eduction in total and LDL cholesterol and triglyc-ilarly, in an additional study [51] supplemental800 IU/day) enhanced the effect of atorvastatin ther-3mg/day) on total and LDL cholesterol (157375mg/dl and 8330 vs. 9728mg/dl, respectively,

results appear paradoxical since 1,25-holecalciferol activates CYP3A4, which metabolizesto its main metabolites [52] in the intestine and liverhould decrease atorvastatin levels and the efcacytin in reducing total and LDL cholesterol, but higherevels appeared to enhance atorvastatins effect in this

hanism by which increased vitamin D potentiates theorvastatin on lipids may be mediated by vitamin DMG-CoA reductase activity. Hydroxylated vitamin Dinhibit HMG-CoA reductase activity [54] so decreased

vitamin D3replete, posing statinshnot taking sp


vastatin and atorvastatin appear to increase circulating 25(OH)Dand 1,25(OH)2D3 levels. Rosuvastatin 1020mg/d increased mean25(OH)D from 14.0 (range 3.767) to 36.3 (range 3.8117)ng/mL(p


on subjective reports of myalgia, lack placebo controls, and cannotbe used to determine denitely a causal association.

A post hoc analysis of the Treating to New Targets trial [98] thatincluded 1509 patients compared myalgia incidence between vita-min D decThe analysiels as wellbetween vitCI 0.621.27noted that spatients wivs. 34.21myalgic patvitamin D (eincrease in(p


[34] Zittermann A, Schleithoff SS, Koerfer R. Putting cardiovascular disease andvitamin D insufciency into perspective. Br J Nutr 2005;94:48392.

[35] Lee JH, OKeefe JH, Bell D, Hensrud DD, Holick MF. Vitamin D deciency animportant, common, and easily treatable cardiovascular risk factor? J Am CollCardiol 2008;52(December (24)):194956.

[36] Oh J, Wtion anddiabete

[37] Riek AEterol m(12)):4

[38] Carlsonserum1970;12

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[40] HeikkinD3 suping po1997;13

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[43] Major Gwith caplasma(1)):54

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[47] Rejnmanot affedyslipid2010;20

[48] Querfeland parSoc Nep

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[50] Prez-Crespons

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[53] Lennern2003;42

[54] Defay Rsynthesstimulaof sometives. Bi

[55] Guryevmetaboing cata2003;10

[56] Aloia JF,ber (8))

[57] DobsAStase inh

[58] Ismail Fcholestymetabo

[59] Montagon vitam9.

[60] Wilczekvitamin

[61] Wilzcekmetaboterolem

[62] Yavuz B, Ertugrul DT, Cil H, et al. Increased levels of 25 hydroxyvita-min D and 1,25-dihydroxyvitamin D after rosuvastatin treatment: a novelpleiotropic effect of statins?CardiovascDrugs Ther 2009;23(August (4)):2959.

[63] Prez-Castrilln JL, Vega G, Abad L, et al. Effects of Atorvastatin on vita-in D007;99rtugruf rosuv. Carde Bolain D ieglia Lare 20leasuretabo979;64oland986;7(bashi S968;18olandr the s995;11iuliantact ct 1984rittanred m

989;10emerer for 1nase Capiatif the vlls. J Crdnefects ciambataminhottGmpso3 rec5)):88l-Saidy wit

009;36ussellimanioatient994;20odmandepleeginatndrom

oland986;7:feifer Mt 2002oreirataminlderpelind coischofn fallsaud Rl Repeglia L008;29renseent byond) 1to Y,lar atndomhubeeakne)):157ruckermpto

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m2

[64] EoD

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[66] CC

[67] Pm1

[68] B1

[69] E1

[70] Bfo1

[71] GinIn

[72] Dtu1

[73] Ntoki

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