Research suggests statins may cause muscle pain by disrupting calcium balance — Evidence Review

Scientists have uncovered how some statins may trigger muscle pain by disrupting calcium balance in muscle cells. Most previous research supports a link between statins and muscle-related side effects, though the new findings from Columbia University provide more precise molecular detail on the mechanism involved.

• Several large-scale reviews and meta-analyses confirm that statin-associated muscle symptoms (SAMS) are a principal cause of discontinuation, but most cases are mild and the absolute risk remains small relative to the drugs’ cardiovascular benefits 1 3 14.
• Previous mechanistic studies have pointed to mitochondrial dysfunction, cellular stress, and genetic predisposition as contributors to statin-induced myopathy; the new research adds evidence of direct statin interaction with calcium-handling proteins in muscle 5 9.
• While the new study identifies a specific protein interaction as a potential cause of muscle symptoms in certain patients, related studies suggest that multiple mechanisms—including altered mitochondrial function and membrane stability—may underlie these side effects 1 4 5 8.

Study Overview and Key Findings

Muscle pain and weakness are the leading reasons individuals stop taking statins, despite these medications’ proven value in reducing cardiovascular risk. Understanding the biological mechanisms behind these side effects is critical to improving patient adherence and developing safer therapies. The current study is significant because it pinpoints a precise molecular interaction—between statins and the ryanodine receptor in muscle cells—that could explain muscle symptoms in a subset of patients, potentially opening new avenues for “muscle-friendly” statin design or adjunct therapies.

Property	Value
Study Year	2025
Organization	Columbia University
Journal Name	The Journal of Clinical Investigation
Authors	Gunnar Weninger, Haikel Dridi, Steven Reiken, Qi Yuan, Nan Zhao, Linda Groom, Jennifer Leigh, Yang Liu, Carl Tchagou, Jiayi Kang, Alexander Chang, Estefania Luna-Figueroa, Marco C. Miotto, Anetta Wronska, Robert T. Dirksen, Andrew R. Marks
Population	Patients experiencing muscle pain from statins
Methods	In Vitro Study
Outcome	Muscle pain and calcium balance disruption
Results	Statins may cause muscle pain by disrupting calcium balance.

Literature Review: Related Studies

We searched the Consensus paper database, which contains over 200 million research papers, to identify relevant studies on statin-induced muscle effects and underlying mechanisms. The following search queries were used:

1. statins muscle pain mechanisms
2. calcium balance statins effects
3. statins side effects population studies

Below, we summarize the major themes and findings from these related studies.

Topic	Key Findings
How common and severe are muscle side effects from statins?	- Muscle symptoms are a leading cause for discontinuation, affecting up to 10% of statin users; most cases are mild and serious muscle injury is rare 1 3 14. - Adverse muscle effects often appear in the first year and are usually reversible 12 13.
What are the molecular and cellular mechanisms of statin-induced muscle symptoms?	- Proposed mechanisms include mitochondrial dysfunction, membrane disruption, altered calcium handling, and genetic susceptibility 1 4 5 8 9. - Statins can impair calcium balance and chloride conductance in muscle cells 8 9.
Are the cardiovascular benefits of statins outweighed by their muscle-related risks?	- The cardiovascular benefits of statins far outweigh the small absolute risks of muscle symptoms 3 13 14. - Most muscle complaints are not causally related to the drug in blinded trials, suggesting a strong nocebo effect 3 15.
Can genetic or molecular markers help identify patients at higher risk for muscle symptoms?	- Genetic variants (e.g., SLCO1B1, RYR2) are linked to increased susceptibility to statin-induced myopathy 5. - Some subpopulations may have unique molecular or gene expression profiles after statin exposure 5.

How common and severe are muscle side effects from statins?

Related studies confirm that muscle symptoms are the most frequent side effect leading to statin discontinuation, but severe muscle injury (myopathy or rhabdomyolysis) is rare. The new study’s findings are consistent with this body of evidence, particularly regarding the prevalence and impact of statin-associated muscle symptoms (SAMS).

• Observational and registry studies estimate that up to 10% of statin users report muscle symptoms, with most cases being mild and reversible 1 12 13.
• Serious muscle injury (e.g., rhabdomyolysis) occurs in approximately 1 per 10,000 to 100,000 person-years 1 11.
• The risk of muscle symptoms is highest in the first year of therapy and decreases after discontinuation 12.
• Meta-analyses of randomized controlled trials (RCTs) show a small excess of muscle complaints in statin users compared to placebo, but most reports are not causally due to the statin 3 14.
• The incidence of muscle symptoms is similar across different statins and doses, except for a slight increase with higher-intensity regimens 3.

What are the molecular and cellular mechanisms of statin-induced muscle symptoms?

The new research provides direct molecular evidence that statins can bind to and activate the ryanodine receptor in muscle cells, causing abnormal calcium release. This aligns with and adds to previous studies that have implicated altered calcium handling, mitochondrial dysfunction, and membrane disruption in statin-induced myopathy.

• Earlier studies suggested that statins may impair muscle mitochondrial function and energy production, contributing to muscle symptoms 1 9.
• Muscle biopsies from statin-treated patients show ultrastructural damage, including disruption of the T-tubular system and changes linked to cholesterol depletion 4.
• Statins and related drugs can reduce chloride conductance and increase cytosolic calcium in muscle fibers, supporting a role for disrupted ion balance 8 9.
• Gene expression studies in patients with statin myalgia reveal upregulation of cellular stress and calcium-handling pathways, as well as genetic variants associated with higher susceptibility 5.
• The new study’s identification of direct statin-ryanodine receptor binding provides a mechanistic link between drug exposure and calcium dysregulation in muscle 8 9.

Are the cardiovascular benefits of statins outweighed by their muscle-related risks?

Multiple large-scale studies and reviews agree that the benefits of statins in reducing cardiovascular events greatly outweigh the small risk of muscle-related side effects. The new findings do not alter this risk-benefit profile but may inform strategies to improve statin tolerability.

• Meta-analyses indicate that the absolute excess risk of muscle symptoms due to statins is small compared to the reduction in major cardiovascular events 3 13 14.
• Many muscle complaints reported by statin users are not actually caused by the drug, as shown in blinded RCTs versus open-label studies (highlighting the nocebo effect) 3 15.
• Systematic reviews and scientific statements reinforce that statins are generally safe, with the risk of serious muscle injury below 0.1% 11 14.
• Tailored approaches, such as using the lowest effective dose and combining statins with non-statin therapies, are recommended for patients with muscle symptoms 1.

Can genetic or molecular markers help identify patients at higher risk for muscle symptoms?

There is growing evidence that genetic and molecular markers may help identify individuals who are more susceptible to statin-induced muscle side effects. The current study’s focus on the ryanodine receptor, and prior genetic associations, support the value of personalized approaches.

• Single nucleotide polymorphisms (SNPs) in genes such as SLCO1B1 and RYR2 have been associated with increased risk of statin-induced myopathy 5.
• Patients with statin-induced myalgia have distinct gene expression profiles in skeletal muscle, suggesting underlying biological differences 5.
• The identification of a specific statin interaction with the ryanodine receptor could inform screening for at-risk patients or guide the design of muscle-sparing statins 5.
• Further research is needed to validate and implement genetic and molecular markers in clinical practice.

Future Research Questions

While the new study offers important insights into the molecular basis of statin-induced muscle pain, several questions remain. Further research is necessary to determine which patients are most at risk, how these findings translate to clinical practice, and whether new therapies can effectively prevent or treat muscle symptoms without compromising cardiovascular protection.

Research Question	Relevance
Which genetic variants predict statin-induced muscle pain?	Identifying genetic risk factors such as SLCO1B1 and RYR2 variants could enable personalized statin therapy and reduce the risk of muscle symptoms 5.
Can statins be redesigned to avoid muscle side effects?	The current study suggests that modifying statins to prevent ryanodine receptor binding could preserve cardiovascular benefits while minimizing muscle risks 8 9.
What are the long-term outcomes of patients with statin-associated muscle symptoms?	Longitudinal data are needed to assess whether muscle symptoms have lasting health impacts or affect cardiovascular outcomes if statin therapy is discontinued 12 13.
Do calcium channel regulators prevent statin-induced myopathy?	Experimental drugs targeting calcium channels may offer new approaches for preventing or treating statin-induced muscle pain, but clinical studies are required to assess efficacy 8 9.
What is the role of the nocebo effect in statin-associated muscle symptoms?	There is evidence that patient expectations contribute to reported muscle symptoms, highlighting the need for strategies to minimize nocebo effects and improve adherence 3 15.