Advertisement

Low vitamin D does not predict statin associated muscle symptoms but is associated with transient increases in muscle damage and pain

      Highlights

      • We assessed associations between Vitamin D and development of statin-associated muscle symptoms (SAMS).
      • Baseline Vitamin D and changes in Vitamin D with simvastatin did not predict SAMS.
      • Clinical Vitamin D deficiency and insufficiency did not predict SAMS.
      • Low Vitamin D was associated with transient increases in creatine kinase and pain.
      • Future studies are needed to clarify the relationship between Vitamin D and SAMS.

      Abstract

      Background and aims

      Low vitamin D (VITD) may contribute to statin-associated muscle symptoms (SAMS). We examined the influence of baseline and change in VITD in patients with verified SAMS.

      Methods

      SAMS was verified in 120 patients with prior statin muscle complaints using 8-week randomized, double-blind crossover trials of simvastatin (SIMVA) 20 mg/d and placebo. 25 (OH)vitamin D was measured at each phase of the trial.

      Results

      Forty-three patients (35.8%) experienced muscle pain on SIMVA but not placebo, exhibiting confirmed SAMS. VITD (mean ± standard deviation) prior to SIMVA treatment was not different between patients who did (31.7 ± 12.1 ng/mL, n = 43) or did not (31.6 ± 10.3 ng/mL, n = 77) develop SAMS and did not predict SAMS (p = 0.96). The change in VITD with SIMVA treatment was not different between patients with and without SAMS (0.3 ± 5.9 vs. 0.2 ± 8.3 ng/mL, respectively) and did not predict SAMS (p = 0.96). The proportion of patients classified as VITD deficient (<20 ng/mL) did not differ between patients with (n = 16) and without (n = 10) SAMS (χ2 = 1.45; p = 0.23), nor did the proportion of patients classified as VITD insufficient (<30 ng/mL) (n = 42 vs. 48; χ2 < 0.01 and p = 0.94). Both baseline and on-statin VITD were inversely related to the change in creatine kinase (CK) with statin therapy (p = 0.01 and 0.02, respectively), independent of SAMS (p = 0.36 and 0.35).

      Conclusions

      Baseline VITD, VITD deficiency/insufficiency and changes in VITD with statin therapy do not predict SAMS in patients with rigorously verified SAMS. However, low VITD may exacerbate statin-induced muscle injury and could contribute to SAMS development with a longer duration of statin treatment.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Parker B.A.
        • Capizzi J.A.
        • Grimaldi A.S.
        • Clarkson P.M.
        • Cole S.M.
        • Keadle J.
        • et al.
        Effect of statins on skeletal muscle function.
        Circulation. 2013; 127: 96-103
        • Bruckert E.
        • Hayem G.
        • Dejager S.
        • Yau C.
        • Begaud B.
        Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients–the PRIMO study.
        Cardiovasc Drugs Ther. 2005; 19: 403-414
        • Banach M.
        • Rizzo M.
        • Toth P.P.
        • Farnier M.
        • Davidson M.H.
        • Al-Rasadi K.
        • et al.
        Statin intolerance - an attempt at a unified definition. Position paper from an International Lipid Expert Panel.
        Arch. Med. Sci. 2015; 11: 1-23
        • Pittman D.G.
        • Chen W.
        • Bowlin S.J.
        • Foody J.M.
        Adherence to statins, subsequent healthcare costs, and cardiovascular hospitalizations.
        Am. J. Cardiol. 2011; 107: 1662-1666
        • Franklin J.M.
        • Krumme A.A.
        • Tong A.Y.
        • Shrank W.H.
        • Matlin O.S.
        • Brennan T.A.
        • et al.
        Association between trajectories of statin adherence and subsequent cardiovascular events.
        Pharmacoepidemiol Drug Saf. 2015; 24: 1105-1113
        • Wei M.Y.
        • Ito M.K.
        • Cohen J.D.
        • Brinton E.A.
        • Jacobson T.A.
        Predictors of statin adherence, switching, and discontinuation in the USAGE survey: understanding the use of statins in America and gaps in patient education.
        J. Clin. Lipidol. 2013; 7: 472-483
        • Morioka T.Y.
        • Lee A.J.
        • Bertisch S.
        • Buettner C.
        Vitamin D status modifies the association between statin use and musculoskeletal pain: a population based study.
        Atherosclerosis. 2015; 238: 77-82
        • Michalska-Kasiczak M.
        • Sahebkar A.
        • Mikhailidis D.P.
        • Rysz J.
        • Muntner P.
        • Toth P.P.
        • et al.
        Analysis of vitamin D levels in patients with and without statin-associated myalgia - a systematic review and meta-analysis of 7 studies with 2420 patients.
        Int. J. Cardiol. 2015; 178: 111-116
        • Mergenhagen K.
        • Ott M.
        • Heckman K.
        • Rubin L.M.
        • Kellick K.
        Low vitamin D as a risk factor for the development of myalgia in patients taking high-dose simvastatin: a retrospective review.
        Clin. Ther. 2014; 36: 770-777
        • Khayznikov M.
        • Hemachrandra K.
        • Pandit R.
        • Kumar A.
        • Wang P.
        • Glueck C.J.
        Statin intolerance because of myalgia, myositis, myopathy, or myonecrosis can in most cases be safely resolved by vitamin D supplementation.
        N. Am. J. Med. Sci. 2015; 7: 86-93
        • Eisen A.
        • Lev E.
        • Iakobishvilli Z.
        • Porter A.
        • Brosh D.
        • Hasdai D.
        • et al.
        Low plasma vitamin D levels and muscle-related adverse effects in statin users.
        Isr. Med. Assoc. J. 2014; 16: 42-45
        • Kurnik D.
        • Hochman I.
        • Vesterman-Landes J.
        • Kenig T.
        • Katzir I.
        • Lomnicky Y.
        • et al.
        Muscle pain and serum creatine kinase are not associated with low serum 25(OH) vitamin D levels in patients receiving statins.
        Clin. Endocrinol. (Oxf). 2012; 77: 36-41
        • Taylor B.A.
        • Lorson L.
        • White C.M.
        • Thompson P.D.
        A randomized trial of coenzyme Q10 in patients with confirmed statin myopathy.
        Atherosclerosis. 2015; 238: 329-335
        • Nissen S.E.
        • Stroes E.
        • Dent-Acosta R.E.
        • Rosenson R.S.
        • Lehman S.J.
        • Sattar N.
        • et al.
        Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: the GAUSS-3 randomized clinical trial.
        JAMA. 2016; 315: 1580-1590
        • Parker B.A.
        • Gregory S.M.
        • Lorson L.
        • Polk D.
        • White C.M.
        • Thompson P.D.
        A randomized trial of coenzyme Q10 in patients with statin myopathy: rationale and study design.
        J. Clin. Lipidol. 2013; 7: 187-193
        • Tan G.
        • Jensen M.P.
        • Thornby J.I.
        • Shanti B.F.
        Validation of the Brief pain inventory for chronic nonmalignant pain.
        J. Pain. 2004; 5: 133-137
        • De Boland A.R.
        • Boland R.L.
        Non-genomic signal transduction pathway of vitamin D in muscle.
        Cell Signal. 1994; 6: 717-724
        • Boland R.L.
        VDR activation of intracellular signaling pathways in skeletal muscle.
        Mol. Cell Endocrinol. 2011; 347: 11-16
        • Ziambaras K.
        • Dagogo-Jack S.
        Reversible muscle weakness in patients with vitamin D deficiency.
        West J. Med. 1997; 167: 435-439
        • Mastaglia S.R.
        • Seijo M.
        • Muzio D.
        • Somoza J.
        • Nunez M.
        • Oliveri B.
        Effect of vitamin D nutritional status on muscle function and strength in healthy women aged over sixty-five years.
        J. Nutr. Health Aging. 2011; 15: 349-354
        • Marantes I.
        • Achenbach S.J.
        • Atkinson E.J.
        • Khosla S.
        • Melton 3rd, L.J.
        • Amin S.
        Is vitamin D a determinant of muscle mass and strength?.
        J. Bone Min. Res. 2011; 26: 2860-2871
        • Ismail F.
        • Corder C.N.
        • Epstein S.
        • Barbi G.
        • Thomas S.
        Effects of pravastatin and cholestyramine on circulating levels of parathyroid hormone and vitamin D metabolites.
        Clin. Ther. 1990; 12: 427-430
        • Rejnmark L.
        • Vestergaard P.
        • Heickendorff L.
        • Mosekilde L.
        Simvastatin does not affect vitamin d status, but low vitamin d levels are associated with dyslipidemia: results from a randomised, controlled trial.
        Int. J. Endocrinol. 2010; 2010: 957174
        • Ertugrul D.T.
        • Yavuz B.
        • Cil H.
        • Ata N.
        • Akin K.O.
        • Kucukazman M.
        • et al.
        STATIN-D study: comparison of the influences of rosuvastatin and fluvastatin treatment on the levels of 25 hydroxyvitamin D.
        Cardiovasc Ther. 2011; 29: 146-152
        • Yavuz B.
        • Ertugrul D.T.
        • Cil H.
        • Ata N.
        • Akin K.O.
        • Yalcin A.A.
        • et al.
        Increased levels of 25 hydroxyvitamin D and 1,25-dihydroxyvitamin D after rosuvastatin treatment: a novel pleiotropic effect of statins?.
        Cardiovasc Drugs Ther. 2009; 23: 295-299
        • Pereda C.A.
        • Nishishinya M.B.
        Is there really a relationship between serum vitamin D (25OHD) levels and the musculoskeletal pain associated with statin intake? A systematic review.
        Reumatol. Clin. 2016; 16: 30001-30008
        • Ovesjo M.L.
        • Skilving I.
        • Bergman P.
        • Rane A.
        • Ekstrom L.
        • Bjorkhem-Bergman L.
        Low vitamin D levels and genetic polymorphism in the vitamin D receptor are associated with increased risk of statin-induced myopathy.
        Basic Clin. Pharmacol. Toxicol. 2016; 118: 214-218
        • Jetty V.
        • Glueck C.J.
        • Wang P.
        • Shah P.
        • Prince M.
        • Lee K.
        • et al.
        Safety of 50,000-100,000 Units of vitamin D3/week in vitamin D-deficient, hypercholesterolemic patients with reversible statin intolerance.
        N. Am. J. Med. Sci. 2016; 8: 156-162
        • Riphagen I.J.
        • van der Veer E.
        • Muskiet F.A.
        • DeJongste M.J.
        Myopathy during statin therapy in the daily practice of an outpatient cardiology clinic: prevalence, predictors and relation with vitamin D.
        Curr. Med. Res. Opin. 2012; 28: 1247-1252
        • Buettner C.
        • Davis R.B.
        • Leveille S.G.
        • Mittleman M.A.
        • Mukamal K.J.
        Prevalence of musculoskeletal pain and statin use.
        J. Gen. Intern Med. 2008; 23: 1182-1186
        • Cham S.
        • Evans M.A.
        • Denenberg J.O.
        • Golomb B.A.
        Statin-associated muscle-related adverse effects: a case series of 354 patients.
        Pharmacotherapy. 2010; 30: 541-553
        • Taylor B.A.
        • Panza G.
        • Thompson P.D.
        Increased creatine kinase with statin treatment may identify statin-associated muscle symptoms.
        Int. J. Cardiol. 2016; 209: 12-13
        • Muntean D.M.
        • Thompson P.D.
        • Catapano A.L.
        • Stasiolek M.
        • Fabis J.
        • Muntner P.
        • et al.
        Statin-associated myopathy and the quest for biomarkers: can we effectively predict statin-associated muscle symptoms?.
        Drug Discov. Today. 2016; 16: 30321