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 Table of Contents  
Year : 2015  |  Volume : 7  |  Issue : 7  |  Page : 339-340

Statin intolerance and vitamin D supplementation

Cholesterol, Metabolism, and Thrombosis Center, Department of Internal Medicine, Jewish Hospital and Mercy Hospitals, 2135 Dana Avenue, Suite 430, 45207, USA

Date of Web Publication21-Jul-2015

Correspondence Address:
Maksim Khayznikov
Cholesterol, Metabolism, and Thrombosis Center, Department of Internal Medicine, Jewish Hospital and Mercy Hospitals, 2135 Dana Avenue, Suite 430, 45207
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Source of Support: None, Conflict of Interest: None

PMID: 26258085

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How to cite this article:
Khayznikov M, Kumar A, Wang P, Glueck CJ. Statin intolerance and vitamin D supplementation. North Am J Med Sci 2015;7:339-40

How to cite this URL:
Khayznikov M, Kumar A, Wang P, Glueck CJ. Statin intolerance and vitamin D supplementation. North Am J Med Sci [serial online] 2015 [cited 2022 Aug 10];7:339-40. Available from: https://www.najms.org/text.asp?2015/7/7/339/161256

Recent epidemiologic studies have added substantial support to the hypothesis that vitamin D deficiency modifies the risk of musculoskeletal symptoms experienced with statin use. [1],[2],[3]

We [4] recently reported studies in 74 men and 72 women intolerant to ≥2 statins because of myalgia, myositis, myopathy, or myonecrosis, found to be vitamin D deficient. Their statin intolerance was safely resolved in most cases (88-95%) by vitamin D supplementation (50,000-100,000 units/week). [4] Backes et al., [5] have reported that in 34 patients intolerant to three or more statins, repletion of serum vitamin D to ≥30 ng/ml (median 44 ng/ml) allowed 18 (53%) patients to "…utilize some form of alternative or daily statin dosing or a higher dose for at least 4 months…" Plausible reasons for the difference in resolution of statin intolerance in these two reports [4],[5] included a higher serum vitamin D on treatment in our [4] versus their [5] study (53-55 vs. 44 ng/ml), and our predominant use of Crestor, a well-tolerated statin, [6] as the challenge statin after vitamin D repletion.

Although we have not done a formal dose-response study with vitamin D supplementation in recent report of 146 statin-intolerant patients with low serum vitamin D (<32 ng/ml) at study entry, [4] the higher the serum vitamin D within the normal range on vitamin D supplementation, the greater the likelihood of being able to tolerate the re-challenge statin without myalgia-myositis. On vitamin D (50,000-100,000 units/week for a median duration of 14 months), 131 of the 146 patients (88%) were free of myalgia, on the re-challenge statin, but 15 (12%) still had myalgia and could not tolerate the re-challenge statin. Comparing these two groups, there were no differences (P > .05) in age, race, gender and vitamin D at pre-treatment study entry, but the myalgia-free group had higher serum vitamin D after 14 months of vitamin D supplementation (55 ± 20, median 53, vs. 42 ± 13, median 36 ng/ml, P = .005). Serum vitamin D also increased more in the myalgia-free than myalgia persistent group (33 ± 21, median 30, vs. 21 ± 13, median 18 ng/ml, P = .02). With myalgia (no vs. yes) after 14 months of vitamin D supplementation, by stepwise logistic regression, with explanatory variables such as race, sex, age and serum vitamin D at study entry, serum vitamin D at follow up, and change of serum vitamin D on treatment from baseline were significant independent predictors of statin tolerance without myalgia, P = .02. For each unit higher in serum vitamin D, statin tolerance increased (OR = 1.04, 95% CI, 1.007-1.078; AUC = 0.726).

Given the high likelihood of substantial placebo effect [4],[7],[8],[9] of vitamin D supplementation in vitamin D deficient, statin-intolerant patients, we have repetitively and consistently [4],[7],[8],[9] emphasized the importance of definitive placebo-controlled, double blind studies. Within this frame of reference, The ODYSSEY ALTERNATIVE, a randomized phase 3 trial [10] is of seminal importance. Total 314 statin intolerant subjects (unable to take ≥2 statins because of muscle-related adverse events [AES]) first received single-blind subcutaneous and oral placebo for 4 weeks, and were removed from the subsequent study if they developed muscle-related AES on placebo. [10] Continuing patients were randomized (2:2:1 ratio) to Alirocumab 75 mg every two weeks, or Ezetimibe 10 mg/day, or Atorvastatin 20 mg/day for 24 weeks. [10] The Alirocumab dose was increased to 150 mg every 2 weeks at week 12 depending on week 8 LDL-C levels. [10] In data presented as an American Heart Abstract in 2014, [11] 6.9% of subjects were excluded in the placebo run-in, establishing a threshold (without statins) of muscle AES. As noted by Backes et al., [5] "…75% of the previously intolerant patients tolerated the Atorvastatin 20 mg daily for the duration of the 24-week study period. [11]" Backes et al., [5] concluded that "…such results strongly highlight the subjectivity of statin intolerance and the major influence of a placebo effect in many patients." Of great importance, the preliminary data [11] presented for the ODYSSEY ALTERNATIVE study, suggests that Alirocumab [10] will be effective and well tolerated in patients who were statin-intolerant due to muscle AES.

Vitamin D supplementation appears to benefit a majority of statin intolerant, vitamin D deficient patients, and some of the benefit arises from placebo effect. However, statin-induced myalgia has been reported in 27% of subjects treated with statins, [12] and vitamin D supplementation allows a majority of previously statin-intolerant patients to take enough statins consistently enough to reach current LDL targets. [4] When the PCSK9 drugs become available, as suggested by preliminary evidence [11] from ODYSSEY ALTERNATIVE (Alirocumab), [10] we speculate that they will provide a paradigm shift in the treatment of statin intolerance.

Financial support and sponsorship

This project has been funded with support from the Mashhad University of Medical Sciences.

Conflicts of interest

There are no conflicts of interest.

  References Top

Morioka TY, Lee AJ, 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.  Back to cited text no. 1
Mergenhagen K, Ott M, Heckman K, Rubin LM, 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;36:770-7.  Back to cited text no. 2
Michalska-Kasiczak M, Sahebkar A, Mikhailidis DP, Rysz J, Muntner P, Toth PP, et al., Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group. 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;178:111-6.  Back to cited text no. 3
Khayznikov M, Hemachrandra K, Pandit R, Kumar A, Wang P, Glueck CJ. 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.  Back to cited text no. 4
Backes JM, Barnes BJ, Moriarty PM. Statin intolerance and Vitamin d supplementation: Sunny, but a few clouds remain. N Am J Med Sci 2015;241:15.  Back to cited text no. 5
Glueck CJ, Aregawi D, Agloria M, Khalil Q, Winiarska M, Munjal J, et al. Rosuvastatin 5 and 10 mg/d: A pilot study of the effects in hypercholesterolemic adults unable to tolerate other statins and reach LDL cholesterol goals with nonstatin lipid-lowering therapies. Clin Ther 2006;28:933-42.  Back to cited text no. 6
Ahmed W, Khan N, Glueck CJ, Pandey S, Wang P, Goldenberg N, et al. Low serum 25 (OH) vitamin D levels (<32 ng/mL) are associated with reversible myositis-myalgia in statin-treated patients. Transl Res 2009;153:11-6.  Back to cited text no. 7
Glueck CJ, Abuchaibe C, Wang P. Symptomatic myositis-myalgia in hypercholesterolemic statin-treated patients with concurrent vitamin D deficiency leading to statin intolerance may reflect a reversible interaction between vitamin D deficiency and statins on skeletal muscle. Med Hypotheses 2011;77:658-61.  Back to cited text no. 8
Glueck CJ, Budhani SB, Masineni SS, Abuchaibe C, Khan N, Wang P, et al. Vitamin D deficiency, myositis-myalgia, and reversible statin intolerance. Curr Med Res Opin 2011;27:1683-90.  Back to cited text no. 9
Moriarty PM, Jacobson TA, Bruckert E, Thompson PD, Guyton JR, Baccara-Dinet MT, et al. Efficacy and safety of alirocumab, a monoclonal antibody to PCSK9, in statin-intolerant patients: Design and rationale of ODYSSEY ALTERNATIVE, a randomized phase 3 trial. J Clin Lipidol 2014;8:554-61.  Back to cited text no. 10
Moriarty PM, Cannon CP, Guyton JR, Bergeron J, Zieve FJ. ODYSSEY ALTERNATIVE: Efficacy and safety of the proprotein convertase subtilisin/kexin Thype 9 monoclonal antibody, Alirocumab, versus Ezetime, in patients with statin intolerance as defined by a placebo run-in and statin rechallenge arm. Americn Heart Association Scientific Sessions, November 17 th , 2014. 2014.  Back to cited text no. 11
Vandenberg BF, Robinson J. Management of the patient with statin intolerance. Curr Atheroscler Rep 2010;12:48-57.  Back to cited text no. 12


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