Statin therapy and the risk of rhabdomyolysis in hypercholesterolemic populations

  • Hanifah Fazilatun Nisa
    The Republic of Indonesia Defense University
    Indonesia
  • Syahrul Tuba 
    The Republic of Indonesia Defense University
    Indonesia

Abstract

Statins remain the gold-standard pharmacologic therapy for hypercholesterolemia, but their use is occasionally limited by statin-associated muscle symptoms (SAMS), of which rhabdomyolysis is the most severe form (Dicken et al., 2022; Safitri et al., 2021). To systematically synthesize evidence published between 2010 and 2025 on the incidence, molecular mechanisms, genetic determinants, and preventive management of statin-induced rhabdomyolysis in hypercholesterolemic populations, and to identify what current evidence still leaves unresolved. A narrative literature review was conducted using Google Scholar and PubMed with the Boolean strategy ("statin*" OR "HMG-CoA reductase inhibitor*") AND ("rhabdomyolysis" OR "myopathy" OR "statin-associated muscle symptoms") AND "hypercholesterolemia". Screening followed a three-stage PRISMA-style process (identification, title/abstract screening, full-text eligibility), and included studies were appraised narratively for design, sample size, and completeness of reported outcomes, prioritizing peer-reviewed sources indexed in Scopus or Sinta and published in 2021-2025, while retaining seminal 2010-2018 randomized trials as primary sources of the quantitative incidence data. Six primary clinical studies (n = 24 to 584,784) reported rhabdomyolysis incidences ranging from 0.003% with statin monotherapy to 4.17% under high-dose oncology co-administration; risk rose sharply with fibrate co-therapy (particularly gemfibrozil), high-dose or lipophilic statins, and loss-of-function SLCO1B1 variants (Turongkaravee et al., 2021). Rhabdomyolysis attributable to statin monotherapy is rare (generally <0.1%), but risk increases materially with high-dose or lipophilic statins, fibrate co-administration, strenuous physical exertion, and genetic predisposition. Individualized risk assessment-incorporating dose selection, drug-interaction screening, and, where available, SLCO1B1 genotyping-together with creatine kinase monitoring can help preserve the cardiovascular benefit of statins while minimizing myotoxic risk.

Keywords
  • Hypercholesterolemia, Statin, Rhabdomyolysis, Blood pressure
Lisensing Information
Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

How to Cite
Nisa, H. F., & Tuba, S. (2026). Statin therapy and the risk of rhabdomyolysis in hypercholesterolemic populations. Lentera Negeri, 7(1), 1966–1973. https://doi.org/10.29210/993720
Endnote/Zotero/Mendeley (RIS) BibTeX
References
  1. A S Wierzbicki, PJ Lumb, G Chik, M. A. C. (2018). Comparison of therapy with simvastatin 80 mg and atorvastatin 80 mg in patients with familial hypercholesterolaemia. International Journal of Clinical Practice, 53(8), 609–611. https://doi.org/10.35790/ebm.6.2.2018. 22174
  2. Adhyatma, M., & Priyana, A. (2023). Pengaruh hiperkolesterolemia terhadap skor kalsium arteri koroner. Jurnal Ilmu Kedokteran dan Kesehatan, 10(12), 3385–. https://ejurnalmalahayati.ac.id/index.php/kesehatan/article/download/12696/pdf
  3. Aman, A. M., Soewondo, P., Soelistijo, S. A., Arsana, P. M., Wismandari, Zufry, H., & Rosandi, R. (2019). Pedoman pengelolaan dislipin dumia di Indonesia 2019. Perkumpulan Endokrinologi Indonesia, 1–65.
  4. Andrew L. Mammen MD, Ph. (2021). Statin-Associated Myalgias and Muscle Injury— Recognizing and Managing Both While Still Lowering the Low Density Lipoprotein. 105, 20892.
  5. Armed Forces Health Surveillance Division. (2025). Update: Exertional rhabdomyolysis among active component members of the U.S. Armed Forces, 2020–2024. MSMR, 32(6). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12266732/
  6. Bell, G., Thoma, A., Hargreaves, I. P., & Lightfoot, A. P. (2024). The role of mitochondria in statin-induced myopathy. Drug Safety, 47(7), 643–653. https://doi.org/10.1007/s40264-024-01413-9 (PDF gratis: https://researchonline.ljmu.ac.uk/id/eprint/22822/1/The%20role%20of%20mitochondria%20in%20statin%20induced%20myopathy.pdf)
  7. Bosco, G., Di Giacomo Barbagallo, F., Spampinato, S., Lanzafame, L., Di Pino, A., Piro, S., Purrello, F., & Scicali, R. (2023). Management of statin intolerant patients in the era of novel lipid lowering therapies: A critical approach in clinical practice. Journal of Clinical Medicine, 12(6), 2444. https://doi.org/10.3390/jcm12062444
  8. Brian G. Collin, Dheeraj Raju, S. K. (2021). Statins, Enzyme CoQ10 Supplement Use, and Cognitive Functioning. Statins, Enzyme CoQ10 Supplement Use, and Cognitive Functioning, 35(5). https://doi.org/10.1186/s42269-023-01 160-4
  9. Cooper-DeHoff, R. M., Niemi, M., Ramsey, L. B., Luzum, J. A., Tarkiainen, E. K., Straka, R. J., Gong, L., Tuteja, S., Wilke, R. A., Wadelius, M., Larson, E. A., Roden, D. M., Klein, T. E., Yee, S. W., Krauss, R. M., Turner, R. M., Palaniappan, L., Gaedigk, A., Giacomini, K. M., … Voora, D. (2022). The Clinical Pharmacogenetics Implementation Consortium guideline for SLCO1B1, ABCG2, and CYP2C9 genotypes and statin-associated musculoskeletal symptoms. Clinical Pharmacology & Therapeutics, 111(5), 1007–1021. https://doi.org/10.1002/cpt.2557 (teks lengkap: https://pmc.ncbi.nlm.nih.gov/articles/PMC9035072)
  10. Cziraky, M. J., Willey, V. J., Mckenney, J. M., Kamat, S. A., Fisher, M. D., Guyton, J. R., Jacobson, T. A., & Davidson, M. H. (2013). Risk of hospitalized rhabdomyolysis associated with lipid-lowering drugs in a real-world clinical setting. Journal of Clinical Lipidology, 7(2), 102-108. https://doi.org/10.1016/j.jacl.2012.06.0 06
  11. Deka Purnama, Anggunan, T Mawar Nusri, R. K. (2023). HUBUNGAN ANTARA KADAR KOLESTEROL TOTAL DENGAN DERAJAT HIPERTENSI PADA PASIEN PRA LANSIA DI RSUD DR. H. ABDUL MOELOK PROVINSI. Jurnalmalahayati, 10(3), 1672–1680.
  12. Desrelia, R., Apriza, & Azzahri, L. M. (2020). Efektifitas Jus Buah Pepaya Terhadap Penurunan Kolesterol Pada Penderita Hiperkolesterol Di Puskesmas Kampar. Farmaka, 4, 11–20.
  13. Dicken, W., Mehta, A., Karagiannis, A., Jain, V., Vavuranakis, M., Sperling, L., & Cassimatis, D. (2022). Statin associated muscle symptoms: An update and review. In Progress in Cardiovascular Diseases (Vol. 75, pp. 40–48). https://doi.org/10.1016/j.pcad.2022.11. 010
  14. Dodulík, [inisial], et al. (2025). Triple non-statin therapy with ezetimibe, inclisiran, and bempedoic acid in patients with genetically confirmed statin-induced rhabdomyolysis: A dual case report. Pharmaceuticals, 18(6), 818. https://www.mdpi.com/1424-8247/18/6/818 (juga: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12195781/)
  15. Enger, C., Gately, R., Ming, E. E., Niemcryk, S. J., Williams, L., & McAfee, A. T. (2010). Pharmacoepidemiology safety study of fibrate and statin concomitant therapy. American Journal of Cardiology, 106(11), 1594–1601. https://doi.org/10.1016/j.amjcard.2010. 07.041
  16. Ericsson, S., Eriksson, M., Vitols, S., Einarsson, K., Berglund, L., & Angelin, B. (1991). Influence of age on the metabolism of plasma low density lipoproteins in healthy males. Journal of Clinical Investigation, 87(2), 591–596.https://doi.org/10.1172/JCI115034
  17. Faergeman, O., Kastelein, J. J. P., Olsson, A. G., Lindahl, C., & Tsai, J. (2015). Simvastatin for Secondary Prevention. 294(19), 2437–2446.
  18. Feng, Z., Li, X., Tong, W. K., He, Q., Zhu, X., Xiang, X., & Tang, Z. (2022). Real-world safety of PCSK9 inhibitors: A pharmacovigilance study based on spontaneous reports in FAERS. Frontiers in Pharmacology, 13, Article 894685. https://doi.org/10.3389/fphar.2022.894685
  19. Giugliano, R. P., Wiviott, S. D., Blazing, M. A., De Ferrari, G. M., Park, J. G., Murphy, S. A., White, J. A., Tershakovec, A. M., Cannon, C. P., & Braunwald, E. (2017). Long-term safety and efficacy of achieving very low levels of low-density lipoprotein cholesterol: A prespecified analysis of the IMPROVE-IT trial. JAMA Cardiology, 2(5), 547–555. https://doi.org/10.1001/jamacardio.201 7.0083
  20. Goss, G. D., Jonker, D. J., Laurie, S. A., Weberpals, J. I., Oza, A. M., Spaans, J. N., la Porte, C., & Dimitroulakos, J. (2016). A phase I study of high-dose rosuvastatin with standard dose erlotinib in patients with advanced solid malignancies. Journal of Translational Medicine, 14(1), 1–11. https://doi.org/10.1186/s12967-016-08 36-6
  21. Handayani, F., Winarsih, W., & Abidah, A. (2023). Peningkatan Derajat Kesehatan Lansia Jamaah Masjid Al Furqon Melalui Screening Tekanan Darah, Gula Darah, Asam Urat dan Kolesterol. Pengabdian Masyarakat Cendekia (PMC), 2, 19–22. https://doi.org/10.55426/pmc.v1i2.236
  22. Haynes, R., Jiang, L., Hopewell, J. C., Li, J., Chen, F., Parish, S., Landray, M. J., Collins, R., Armitage, J., Baigent, C., Chen, Z., Chen, Y., Pedersen, T., Bowman, L., Chen, F., Hill, M., Knott, C.,Rahimi, K., Tobert, J., … Peto, R. (2013). HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patient of ER niacin/laropiprant: Trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. European Heart Journal, 34(17), 1279–1291. https://doi.org/10.1093/eurheartj/eht0 55
  23. Hornsby, W. G., & Brynar, R. W. (2013). Clinical exercise physiology. Introduction to Exercise Science, 212–234. https://doi.org/10.2310/6640.2004.000 14
  24. Jiang, Y., Wang, Y., Ma, S., Qian, L., Jing, Y., Chen, X., & Yang, J. (2025). Efficacy and safety of PCSK9 inhibitors, potent statins, and their combinations for reducing low-density lipoprotein cholesterol in hyperlipidemia patients: A systematic network meta-analysis. Frontiers in Cardiovascular Medicine, 11, Article 1415668. https://doi.org/10.3389/fcvm.2024.1415668 (juga: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11836037/)
  25. Juwita, Makani, M., & J, P. D. C. (2023). Hubungan Tingkat Pengetahuan Terhadap Ketepatan Penggunaan Obat Simvastatin Pada Pasien Hiperkolesterolemia Di Posibindu Puskesmas Kumai Tahun 2023. 7(2).
  26. Kobuchi, S., Sugiyama, D., Iima, A., Obuchi, A., Osaka, A., Doi, A., Ueta, H., Yokoyama, S., Hosomi, K., Takada, M., & Sakaeda, T. (2025). Data mining of the FDA Adverse Event Reporting System and animal experiments for assessment of rhabdomyolysis risk associated with lipid-lowering drugs. International Journal of Medical Sciences, 22(7), 1485–1492. https://doi.org/10.7150/ijms.109034 (teks lengkap: https://www.medsci.org/v22p1485.htm)
  27. Mahwal, I., Untari, E. K., & Nurmainah. (2022). Perbandingan statin terhadap kejadian efek samping terkait myalgia. Jurnal Sains dan Kesehatan, 4(2), 147–. https://jsk.ff.unmul.ac.id/index.php/JSK/article/download/368/368/1160
  28. Marsellinda, E., & Ferilda, S. (2022). Evaluasi Terapi Obat Dislipidemia Pada Pasien Diabetes Melitus Yang Mengalami Dislipidemia Yang Dirawat Di Rumah Sakit Islam Siti Rahmah. Menara Ilmu, 16(1),15–20.https://doi.org/10.31869/mi.v16i1.3406
  29. Morris, R., Bu, K., Han, W., Wood, S., Hernandez Velez, P. M., Ward, J., Crescitelli, A., Martin, M., & Cheng, F. (2025). The association between statin drugs and rhabdomyolysis: An analysis of FDA Adverse Event Reporting System (FAERS) data and transcriptomic profiles. Genes, 16(3), 248. https://doi.org/10.3390/genes16030248
  30. Niedrig, D. F., Pyra, M., Lussmann, R., Serra, A., & Russmann, S. (2024). Rosuvastatin-induced rhabdomyolysis: Case report and call for proactive multifactorial risk assessment and preventive management of statin therapy in high-risk patients. European Journal of Hospital Pharmacy, 31(3), 281–284. https://doi.org/10.1136/ejhpharm-2023-003765
  31. Permatasari, R., Suriani, E., & Kurniawan. (2022). Hubungan Kadar Kolesterol Total Dengan Tekanan Darah Pada Pasien Hipertensi pada Usia ≥ 40 Tahun. Jurnal Labora Medika, 6(2022), 16–21.
  32. Pose, E., Napoleone, L., Amin, A., Campion, D., Jimenez, C., Piano, S., Roux, O., Uschner, F. E., de Wit, K., Zaccherini, G., Alessandria, C., Angeli, P., Bernardi, M., Beuers, U., Caraceni, P., Durand, F., Mookerjee, R. P., Trebicka, J., Vargas, V., … Ginès, P. (2020). Safety of two different doses of simvastatin plus rifaximin in decompensated cirrhosis (LIVERHOPE-SAFETY): a randomised, double-blind, placebo-controlled, phase 2 trial. The Lancet Gastroenterology and Hepatology, 5(1) 31–41. https://doi.org/10.1016/S2468-1253(19) 30320-6
  33. Rahayu, A. S., Mendrofa, H. K., Bo, A., Kedokteran, P. S., Kedokteran, F., & Cenderawasih, U. (2018). Di Kampung Putali Distrik Ebungfauw Kabupaten Jayapura Hypercholesterolemia in Participants of Elderly Integrated Services
  34. Safitri, N., Alaina, M. F., Pitaloka, D. A. E., & Abdulah, R. (2021). A narrative review of statin-induced rhabdomyolysis: Molecular mechanism, risk factors, and management. Drug, Healthcare and Patient Safety, 13, 211–219. https://doi.org/10.2147/DHPS.S333738 (teks lengkap: https://pmc.ncbi.nlm.nih.gov/articles/PMC8593596)
  35. Sridharan, K., & Sivaramakrishnan, G. (2026). Genetic determinants of statin-induced myopathy: A network meta-analysis of observational studies. Current Reviews in Clinical and Experimental Pharmacology, 21(1), 75–91. https://doi.org/10.2174/0127724328356429250315163111
  36. Turongkaravee, S., Jittikoon, J., Lukkunaprasit, T., Sangroongruangsri, S., Chaikledkaew, U., & Thakkinstian, A. (2021). A systematic review and meta-analysis of genotype-based and individualized data analysis of SLCO1B1 gene and statin-induced myopathy. The Pharmacogenomics Journal, 21(3), 296-307. https://doi.org/10.1038/s41397-021-00208-w
  37. Xiao, Y., Ba, Z., Pang, S., Liu, D., Wang, H., Liang, H., Wang, Y., & Yuan, J. (2022). PCSK9 inhibitor: Safe alternative to fill the treatment gap in statin-limited conditions? Reviews in Cardiovascular Medicine, 23(11), Article 380. https://doi.org/10.31083/j.rcm2311380 (akses terbuka: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11269069/)

Downloads

PDF

Statistic

Abstract Views
: 41 times
PDF
: 44 times