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

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.

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.