Due to copyright issues, an electronic copy of the thesis must be ordered from the faculty. For the faculty to have time to process the order, the order must be received by the faculty at the latest 2 days before the public defence. Orders received later than 2 days before the defence will not be processed. After the public defence, please address any inquiries regarding the thesis to the candidate.
Trial Lecture – time and place
See Trial Lecture.
Adjudication committee
- First opponent: Professor Mikko Olavi Niemi, University of Helsinki, Finland
- Second opponent: Professor Marit Waaseth, UiT The Arctic University of Norway,
- Third member and chair of the evaluation committee: Associate Professor Per Medbøe Thorsby, University of Oslo
Chair of the Defence
Associate Professor Carola Elisabeth Henriksson, University of Oslo
Principal Supervisor
Associate Professor Nils Tore Vethe, Oslo University Hospital
Summary
Statins are central to secondary prevention of coronary heart disease, yet statin-associated muscle symptoms (SAMS) often result in discontinuation of treatment. SAMS often have non-statin causes, and no validated objective test distinguishes them from true intolerance. This thesis lies at the intersection of cardiovascular disease prevention and clinical pharmacology and sought to clarify mechanisms behind SAMS and to assess whether a simple blood test can separate atorvastatin intolerance from symptoms of other origin.
The results are based on a randomised, double-blind crossover trial in patients with SAMS (MUSE RCT) and a sub-study with paired plasma and muscle biopsies (MUSE BmS). The patients were clinically categorised as statin-tolerant or intolerant. Using LC-MS/MS, we measured mevalonate and atorvastatin acid with its metabolites in plasma and muscle. We also genotyped variants affecting statin metabolism and distribution and examined muscle histology.
Plasma- and muscle concentrations were strongly correlated, indicating plasma can proxy muscle exposure. Compared with tolerant patients, statin-intolerant patients had lower levels of active (acid) metabolites and higher lactone/acid ratios, consistent with a shift toward myotoxic metabolites. Some of the genetic variants were associated with higher lactone levels. Mevalonate and LDL-cholesterol fell with statin treatment, but less in the intolerant group, mirroring lower atorvastatin acid exposure. Biopsies were not decisive; occasional necrotic fibres on-statin did not match clinical intolerance.
In sum, a blood-based signature—low acid metabolites, elevated lactone/acid ratio, and a lesser fall in mevalonate and LDL-C—might be a tool to rule out many statin-tolerant patients and focus evaluation and follow-up on the intolerant. Validation in larger cohorts is needed; if confirmed, this approach could enable more personalised therapy, reduce unnecessary discontinuation, and improve cardiovascular outcomes.
Additional information
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