Metabolic and Mitochondrial Changes in Statin-Induced Myopathy

Measurement of Acylcarnitine Levels and Mitochondrial Functionality in Connection With Statin-Induced Skeletal Muscle Myopathy

The goal of this observational study is to learn whether statin-related muscle symptoms are linked to problems in fat metabolism in muscle cells, specifically involving acylcarnitines, in adults taking or not taking statins. The main questions it aims to answer are:

Do patients with statin-associated muscle symptoms have higher acylcarnitine levels in blood and muscle compared to statin users without symptoms and people not taking statins? Do acylcarnitine levels decrease after stopping or reducing statin treatment in affected patients?

Researchers will compare patients with statin-associated muscle symptoms, statin users without symptoms, and individuals not taking statins to see if differences in acylcarnitine levels and muscle metabolism are associated with muscle symptoms.

Participants will:

Provide blood samples for biochemical tests and acylcarnitine analysis Share information about their health, medications, and lifestyle (Optional) undergo a muscle biopsy to study muscle metabolism Some participants with muscle symptoms will have repeat blood tests and possibly a repeat muscle biopsy after statin dose reduction or discontinuation to track changes over time

Study Overview

• Status: Completed
• Conditions: Statin Adverse Reaction; Statin-induced Myopathy
• Intervention / Treatment: Other: Blood sampling and laboratory assessment; Other: Muscle biopsy

Detailed Description

Statins are widely used lipid-lowering medications that reduce cardiovascular risk, but their use may be limited by statin-associated muscle symptoms (SAMS), which range from mild myalgia to significant elevations in creatine kinase (CK). The underlying biological mechanisms of SAMS are not fully understood. One proposed mechanism involves impaired mitochondrial fatty acid metabolism, which may lead to the accumulation of acylcarnitines-intermediate metabolites involved in fatty acid transport and oxidation within mitochondria.

This study aims to investigate whether statin-associated muscle symptoms are associated with disturbances in acylcarnitine metabolism in blood and skeletal muscle tissue. Specifically, the study will assess whether patients with SAMS have higher concentrations of acylcarnitines compared to statin users without muscle symptoms and individuals not receiving statin therapy, and whether these concentrations change after discontinuation or reduction of statin therapy.

This is a single-center observational case-control study conducted at the Latvian Cardiology Center of Pauls Stradiņš Clinical University Hospital. The study population includes three groups: (1) patients with elevated CK levels with or without muscle symptoms suggestive of statin-associated myopathy, (2) patients receiving stable high-dose statin therapy without muscle symptoms, and (3) control participants not using lipid-lowering therapy and without unexplained muscle symptoms.

All participants underwent a single study visit during which demographic data, medical history, medication use (including statins and other lipid-lowering therapies), and lifestyle factors (such as smoking, alcohol consumption, and physical activity) were recorded. Blood samples were collected for routine biochemical analyses (including CK, alanine aminotransferase, creatinine, and lipid profile) and for the measurement of plasma acylcarnitine concentrations. Plasma samples were processed and stored at -80°C for current and future analyses.

Participants were assessed for statin-associated muscle symptoms using the Statin-Associated Muscle Symptom Clinical Index (SAMS-CI). In a subset of participants who provided additional informed consent, a muscle biopsy was performed under local anesthesia from the non-dominant forearm muscle. Muscle tissue samples were used to evaluate acylcarnitine concentrations and mitochondrial fatty acid metabolism.

Participants in the SAMS group (Group A) who required discontinuation or dose reduction of statin therapy as part of routine clinical care underwent prospective follow-up. Repeat blood sampling was performed approximately 4 and 8 weeks after statin discontinuation or dose adjustment, and continued at 4-week intervals (up to 24 weeks) until CK levels normalized. In selected participants, a repeat muscle biopsy was performed within 4-8 weeks after statin discontinuation or dose reduction to assess changes in mitochondrial metabolism and acylcarnitine concentrations.

Data will be analyzed to compare acylcarnitine concentrations between groups and to evaluate changes over time in the SAMS group. Quantitative variables will be summarized using means and standard deviations or medians and interquartile ranges, depending on data distribution. Between-group comparisons will be performed using parametric or non-parametric statistical tests as appropriate, and repeated measurements will be analyzed using paired statistical methods. A p-value <0.05 will be considered statistically significant.

The results of this study are expected to improve understanding of the pathophysiology of statin-associated muscle symptoms and may contribute to the development of better diagnostic and management strategies for patients experiencing statin intolerance.

• Study Type: Observational
• Enrollment (Actual): 38

Contacts and Locations

Study Locations

• Latvia
  • Riga, Latvia
    • University of Latvia (Faculty of Medicine and Institute of Cardiology and Regenerative Medicine)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

The study population consists of adult participants (≥18 years) of Caucasian ethnicity recruited at the Latvian Cardiology Center of Pauls Stradiņš Clinical University Hospital. The study includes three groups: (1) patients with elevated creatine kinase levels with or without muscle symptoms suggestive of statin-associated muscle myopathy, (2) patients receiving stable high-dose statin therapy without muscle symptoms, and (3) individuals not receiving lipid-lowering therapy and without unexplained muscle symptoms.

Participants may be hospitalized patients or outpatients, including referrals from other medical institutions. All participants must provide written informed consent, and a subset of participants may additionally consent to undergo muscle biopsy for further analysis of mitochondrial metabolism in muscle tissue.

Description

Inclusion Criteria:

1. Age at least 18 years.
2. A representative of the Caucasian race.
3. The patient agrees to participate in the study by signing an informed consent form for participation in the study. (The patient may only be included in the muscle biopsy sub-study if the relevant additional informed consent form has also been signed.)

4. Specific inclusion criteria for each of the study subgroups:

   1. Group A: patients have elevated creatine kinase levels >1.5x above the upper limit of normal (women >325 U/L and men >504 U/L) with or without muscle symptoms that have no other obvious explanation (including intense physical activity in the last 7 days).
   2. Group B: atorvastatin 40-80 mg or rosuvastatin 20-40 mg monotherapy for at least 8 weeks at a constant dose and no muscle symptoms (pain, weakness, fatigue, cramps) during this period, CK <200 U/L.
   3. Group C: no lipid-lowering agents have been used during the last year and there have been no muscle symptoms (pain, weakness, fatigue, cramps) of unknown origin lasting >1 week during this period, CK <200 U/L.

Exclusion Criteria:

1. Any disease that, in the opinion of the investigator, could also cause a significant increase in CK or muscle symptoms.

2. Use of other cholesterol-lowering agents specific to each of the study groups:

   1. Group A: use of red yeast rice extract, fibrates, or bempedoic acid within the last 8 weeks.
   2. Group B: use of other non-statin cholesterol-lowering agents (red yeast rice extract, ezetimibe, fibrates, PCSK9 inhibitors, inclisiran, bempedoic acid) in the last 8 weeks.
   3. Group C: use of any cholesterol-lowering agents (statins, red yeast rice extract, ezetimibe, fibrates, PCSK9 inhibitors, inclisiran, bempedoic acid) in the last 12 weeks.
3. Intense physical activity in the last 7 days.
4. Acute myocardial infarction or stroke in the last 4 weeks.
5. Major surgery within the last 4 weeks (invasive cardiac procedures are not an exclusion criterion).
6. Patients with severe illness that, in the investigator's opinion, may significantly affect the patient's overall metabolism (e.g., active malignancy, terminal heart failure, etc.).
7. Excessive alcohol consumption (binge drinking or >7 units of alcohol per day) within the last year.
8. Use of other substances or medications known to have direct myotoxic effects (e.g., fibrates, cyclosporins, labetalol, propofol, procainamide, interferon-alpha, hydroxyurea, zidovudine, colchicine, vincristine, amiodarone, corticosteroids) or that may affect CK elevation.
9. Use of meldonium within the last 2 months.

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Group A: Statin-Associated Muscle Symptoms (SAM); Adults with elevated creatine kinase (CK >1.5× upper limit of normal) with or without muscle symptoms that cannot be explained by other causes. Participants may continue using statins or may require statin discontinuation or dose reduction.	Other: Blood sampling and laboratory assessment; Collection of blood samples for measurement of acylcarnitine concentrations and routine biochemistry, including creatine kinase and lipid profile.; Other: Muscle biopsy; Optional muscle tissue sampling under local anesthesia from the non-dominant forearm muscle for assessment of acylcarnitine concentrations and mitochondrial fatty acid metabolism.
Group B: Statin Users Without Muscle Symptoms; Adults receiving stable high-dose statin monotherapy (atorvastatin 40-80 mg or rosuvastatin 20-40 mg) for at least 8 weeks, without muscle symptoms and with normal CK levels (<200 U/L).	Other: Blood sampling and laboratory assessment; Collection of blood samples for measurement of acylcarnitine concentrations and routine biochemistry, including creatine kinase and lipid profile.; Other: Muscle biopsy; Optional muscle tissue sampling under local anesthesia from the non-dominant forearm muscle for assessment of acylcarnitine concentrations and mitochondrial fatty acid metabolism.
Group C: Control Group (No Statin Use); Adults who have not used any lipid-lowering therapy in the past year, have no unexplained muscle symptoms, and have normal CK levels (<200 U/L).	Other: Blood sampling and laboratory assessment; Collection of blood samples for measurement of acylcarnitine concentrations and routine biochemistry, including creatine kinase and lipid profile.; Other: Muscle biopsy; Optional muscle tissue sampling under local anesthesia from the non-dominant forearm muscle for assessment of acylcarnitine concentrations and mitochondrial fatty acid metabolism.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Acylcarnitine concentrations in blood	Comparison of plasma acylcarnitine levels between patients with statin-associated muscle symptoms, statin users without symptoms, and controls not using statins.	At baseline (single visit)
Acylcarnitine concentrations in muscle tissue	Comparison of acylcarnitine levels in muscle biopsy samples between study groups to assess differences in mitochondrial fatty acid metabolism.	At baseline (muscle biopsy visit)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in acylcarnitine concentrations after statin discontinuation or dose reduction	Evaluation of changes in plasma acylcarnitine levels in patients with statin-associated muscle symptoms after stopping or reducing statin therapy.	Approximately 4 weeks and 8 weeks after statin discontinuation or dose reduction (up to 24 weeks if needed)
Changes in muscle acylcarnitine concentrations (subset of participants)	Evaluation of changes in muscle acylcarnitine levels in patients undergoing repeat muscle biopsy after statin discontinuation or dose reduction.	4-8 weeks after statin discontinuation or dose reduction (up to 24 weeks)

Collaborators and Investigators

• Sponsor: Riga Stradins University
• Collaborators: Latvian Institute of Organic Synthesis; University of Latvia
• Investigators: Study Chair: Gustavs Latkovskis, PhD, MD, Faculty of Medicine, University of Latvia

Study record dates

Study Major Dates

• Study Start (Actual): August 22, 2023
• Primary Completion (Actual): October 9, 2024
• Study Completion (Actual): October 9, 2024

Study Registration Dates

• First Submitted: March 30, 2026
• First Submitted That Met QC Criteria: March 30, 2026
• First Posted (Actual): April 6, 2026

Study Record Updates

• Last Update Posted (Actual): April 6, 2026
• Last Update Submitted That Met QC Criteria: March 30, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: statins; myopathy; acylcarnitines; statin-induced myopathy
• Additional Relevant MeSH Terms: Musculoskeletal Diseases; Nervous System Diseases; Neuromuscular Diseases; Muscular Diseases; Investigative Techniques; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Blood Specimen Collection
• Other Study ID Numbers: VPP-EM-BIOMEDICĪNA-2022/1-0001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: We will deposit individual original measurement results, but not anthropometric data.
• IPD Sharing Time Frame: Available immediately following completion of the statistical analysis of the study. Study data will be stored indefinitely in accordance with institutional and regulatory requirements on an open repository https://zenodo.org/
• IPD Sharing Access Criteria: Data will be provided to researchers on request. We will evaluate whether their purpose comply with the consent and ethics approval.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No