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Randomized Controlled Trial
. 2023 Jan 1;8(1):74-80.
doi: 10.1001/jamacardio.2022.4250.

Statin-Associated Muscle Symptoms Among New Statin Users Randomly Assigned to Vitamin D or Placebo

Mark A Hlatky  1 , Pedro Engel Gonzalez  2 , JoAnn E Manson  3   4 , Julie E Buring  3   4 , I-Min Lee  3   4 , Nancy R Cook  3   4 , Samia Mora  3   5 , Vadim Bubes  3 , Neil J Stone  2
Affiliations
Randomized Controlled Trial

Statin-Associated Muscle Symptoms Among New Statin Users Randomly Assigned to Vitamin D or Placebo

Mark A Hlatky et al. JAMA Cardiol. .

Abstract

Importance: Statin-associated muscle symptoms (SAMS) are common and may lead to discontinuation of indicated statin therapy. Observational studies suggest that vitamin D therapy is associated with reduced statin intolerance, but no randomized studies have been reported.

Objective: To test whether vitamin D supplementation was associated with prevention of SAMS and a reduction of statin discontinuation.

Design, setting, and participants: Men 50 years or older and women 55 years or older, free of cancer and cardiovascular disease, were enrolled in a randomized, placebo-controlled, double-blind clinical trial of vitamin D supplementation. Participants who initiated statin therapy after randomization were surveyed in early 2016. The data were analyzed in early 2022.

Interventions: Daily cholecalciferol (2000 international units) or placebo with assessment of statin prescriptions during follow-up.

Main outcomes and measures: Muscle pain or discomfort lasting several days (primary outcome) and discontinuation of a statin due to SAMS (secondary outcome).

Results: Statins were initiated by 1033 vitamin D-assigned participants and 1050 placebo-assigned participants; mean (SD) age was 66.8 (6.2) years and 49% were women. Over 4.8 years of follow-up, SAMS were reported by 317 participants (31%) assigned vitamin D and 325 assigned placebo (31%). The adjusted odds ratio (OR) was 0.97 (95% CI, 0.80-1.18; P = .78). Statins were discontinued by 137 participants (13%) assigned to vitamin D and 133 assigned to placebo (13%) with an adjusted OR of 1.04 (95% CI, 0.80-1.35; P = .78). These results were consistent across pretreatment 25-hydroxy vitamin D levels (interaction P value = .83). Among participants with levels less than 20 ng/mL, SAMS were reported by 28 of 85 vitamin D-assigned participants (33%) and 33 of 95 placebo-assigned participants (35%). For those with levels less than 30 ng/ml, SAMS were reported by 88 of 330 vitamin-D assigned participants (27%) and 96 of 323 of placebo-assigned participants (30%).

Conclusions and relevance: Vitamin D supplementation did not prevent SAMS or reduce statin discontinuation. These results were consistent across pretreatment 25-hydroxy vitamin D levels.

Trial registration: ClinicalTrials.gov Identifier: NCT01169259.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Manson reported grants from the National Institutes of Health during the conduct of the study and grants from the National Institutes of Health and Mars Edge outside the submitted work. Dr Buring reported grants from the National Institutes of Health during the conduct of the study, personal fees from Pharmavite (spouse), and membership on a scientific advisory board of Pharmavite, who provided the vitamin D and placebo for the study, outside the submitted work. Dr Lee reported grants from the National Institutes of Health during the conduct of the study. Dr Cook reported grants from the National Institutes of Health to the institution during the conduct of the study. Dr Mora reported grants from the National Heart, Lung, and Blood Institute (R01HL134811), nonfinancial support from Quest Diagnostics, and committee fees from Pfizer outside the submitted work. Dr Bubes reported grants from the National Institutes of Health during the conduct of the study. Dr Stone reported a grant from the Hyperlipidemia Research Fund at Northwestern University and an honorarium for educational activity for Knowledge to Practice. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Flow Diagram of Study Participants
SAMS indicates statin-associated muscle symptoms; VITAL, Vitamin D and Omega-3 trial.
Figure 2.
Figure 2.. Statin-Associated Muscle Symptoms and Statin Discontinuation
Figure 3.
Figure 3.. Statin-Associated Muscle Symptoms (SAMS) in Participants With 25-OHD Levels Measured Prior to Randomization
SI conversion factor: To convert to nmol, multiply by 2.496. The frequency of SAMS are shown for placebo-assigned and vitamin–D assigned participants. A, Data are displayed from left to right, from all 1397 participants with 25-OHD levels measured (far left), then from the 744 participants with levels 30 ng/mL or more (middle left), then from the 473 participants with levels 20 to 30 ng/mL (middle right), and finally from the 180 participants with levels less than 20 ng/mL (far right). B, Data from the 744 participants with levels 30 ng/mL or more are compared with the 653 participants with levels less than 30 ng/mL on the left side and data from the 1217 participants with levels 20 ng/mL or more are compared with the 180 participants with levels less than 20 ng/mL on the right side.
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Comment in

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