Statin and Vitamin D Interaction
There is no pharmacokinetic drug-drug interaction between statins and vitamin D, but vitamin D deficiency is strongly associated with statin-induced myalgia and should be checked and corrected in patients experiencing muscle symptoms on statin therapy. 1, 2
No Direct Drug Interaction
The comprehensive 2016 American Heart Association guidelines on statin drug-drug interactions do not identify vitamin D as having any clinically significant pharmacokinetic or pharmacodynamic interaction with statins. 3 The guidelines extensively review interactions mediated through CYP450 enzymes, P-glycoprotein, and various transporters, but vitamin D supplementation does not affect these pathways relevant to statin metabolism. 3
Strong Association with Statin Myalgia
Despite the absence of a direct drug interaction, vitamin D deficiency is significantly associated with statin-associated muscle symptoms (SAMS):
A large cross-sectional study of 1,210 statin-treated patients found that vitamin D deficiency (<30 nmol/L) had 77% sensitivity and 63.4% specificity for diagnosing SAMS, with a moderate-to-strong odds ratio for both deficient and insufficient vitamin D status. 2
Women with statin-related myalgia who remained on alternative-day dosing (due to intolerance) had significantly lower mean vitamin D levels (29 ng/mL) compared to those tolerating daily dosing (47.5 ng/mL, p=0.0307). 4
Clinical Management Algorithm
For Patients with Statin-Induced Myalgia:
Step 1: Check vitamin D levels
- Measure serum 25-hydroxyvitamin D [25(OH)D] in all patients reporting statin-associated muscle symptoms. 1, 5
Step 2: Supplement if deficient (<30-32 ng/mL)
- Administer 50,000 units of vitamin D2 twice weekly for 3 weeks, then continue once weekly. 5
- Target serum 25(OH)D levels >30 ng/mL. 5
Step 3: Rechallenge with statin after 3 weeks
- After vitamin D normalization, restart the statin (can use the previously failed statin or an alternative). 5, 6
- Monitor for recurrent myalgia at 3 months. 5
Evidence for Effectiveness:
In a prospective case series of 68 hypercholesterolemic patients with statin intolerance due to myalgia and vitamin D deficiency, 91% (62/68) successfully tolerated statins after vitamin D supplementation, with mean vitamin D rising from 22 to 43 ng/mL and LDL cholesterol falling from 162 to 101 mg/dL (both p<0.0001). 5
A retrospective cohort of 27 veterans with statin-induced myopathy showed 100% maintained statin therapy without myalgia after vitamin D replenishment, with 40.7% tolerating their previously failed statins. 6
Important Caveats
The evidence supporting vitamin D supplementation for statin myalgia consists primarily of observational studies and uncontrolled case series—no placebo-controlled, double-blind randomized trials have been published. 1, 5 However, given the safety of vitamin D supplementation, the high prevalence of vitamin D deficiency, and the consistent observational evidence, checking and correcting vitamin D deficiency is reasonable in patients with statin-associated muscle symptoms. 1
Do not discontinue statins while awaiting vitamin D results or during supplementation in patients with established atherosclerotic cardiovascular disease, as the cardiovascular risks of stopping statin therapy far outweigh concerns about myalgia. 7 Consider alternative-day dosing or switching to a different statin while correcting vitamin D deficiency. 4
The mechanism may involve the vitamin D receptor present in skeletal muscle, as vitamin D deficiency itself can cause myopathy independent of statin use. 1 Some statins may increase 25(OH)D levels, though this effect is not consistent across all statins. 1