The Association Between Statin Drugs and Rhabdomyolysis: An Analysis of FDA Adverse Event Reporting System (FAERS) Data and Transcriptomic Profiles

Abstract

Background/objectives: Rhabdomyolysis, a dangerous breakdown of skeletal muscle, has been reported as an adverse event in those prescribed a statin therapy for the treatment of hypercholesterolemia. Statin drugs are some of the most prescribed treatments for elevated cholesterol levels. The purpose of this comparative study was to determine the association between the statin drugs used and the risk of rhabdomyolysis using the FDA Adverse Event Reporting System (FAERS) and transcriptomic data.

Methods: A disproportionality analysis was performed to compare the risk of rhabdomyolysis between the reference statin drug (simvastatin) and the treatment group, with patient age assessed as a possible confounder. In addition, association rule mining was utilized to both identify other adverse events that frequently presented with rhabdomyolysis and identify possible drug-drug interactions (DDIs). Finally, public transcriptomic data were explored to identify the possible genetic underpinnings highlighting these differences in rhabdomyolysis risk across statins.

Results: Rhabdomyolysis is a commonly reported adverse event for patients treated with statins, particularly those prescribed simvastatin. Simvastatin was associated with a more than 2-fold increased likelihood of rhabdomyolysis compared to other statins. Men were twice as likely to report rhabdomyolysis than women regardless of statin treatment, with the highest risk observed for pravastatin (ROR = 2.30, p < 0.001) and atorvastatin (ROR = 2.03, p < 0.0001). Several possible DDIs were identified, including furosemide/Lasix, allopurinol clopidogrel/Plavix, and pantoprazole, which may elevate rhabdomyolysis risk through impaired muscle function and delayed statin metabolism. Finally, nine myopathic genes were identified as possible regulators of statin-induced rhabdomyolysis, including DYSF, DES, PLEC, CAPN3, SCN4A, TNNT1, SDHA, MYH7, and PYGM in primary human muscle cells.

Conclusions: Simvastatin was associated with the highest risk of rhabdomyolysis. The risk of rhabdomyolysis was more pronounced in men than women. Several possible DDIs were identified including furosemide/Lasix, allopurinol clopidogrel/Plavix, and pantoprazole.

Keywords: DDI; FAERS; RNA-seq; association rules; drug interactions; kidney injury; muscle disease; pharmacovigilance; rhabdomyolysis; statins.

Figure 1

Top 10 reported adverse events for 5 statin drugs.

Figure 2

Association rule mining of ADEs associated with Rhabdomyolysis for five statins (lift cutoff value = 1.5).

Figure 3

Association rule mining of DDIs associated with elevated rhabdomyolysis risk for five statins (lift cutoff value = 1.5).

Figure 4

Differentially expressed genes for simvastatin-treated primary muscle cells (A) and rosuvastatin-treated primary muscle cells (B) compared to DMSO-treated control cells. In both cases, significantly downregulated genes are indicated in green while significantly upregulated genes are indicated in red.