The effects of statins on skeletal muscle mitochondria:a pilot study?

Statins are among the most widely prescribed medications in developed
countries. They markedly reduce the incidence of ischemic heart disease and
stroke by lowering low-density lipoprotein (LDL) cholesterol. Although statins
have demonstrated remarkable clinical safety, muscle toxicity is a frequent
limiting factor in the administration of statin therapy. Statin-associated
muscle symptoms (SAMS) exist in a spectrum from mild muscle symptoms (e.g.
fatigue, myalgia, cramps, weakness, reported in 9-27% of patients) to rare
life-threatening rhabdomyolysis. The occurrence of diffuse muscle aches
significantly limits quality of life and prompts many patients to quit this
life-saving medication. As lipid-lowering treatments are intended for long-term
use, statin non-adherence has a marked impact on cardiovascular risk management
an increases mortality risk.

The mechanisms underlying statin-induced muscular side effects remain
incompletely understood. Both in vivo and ex vivo evidence is present for an
impaired mitochondrial oxidative capacity in skeletal muscle of patients on
statin therapy. Recently, Prof. Frans Russel from the department of
Pharmacology and Toxicology at the Radboudumc examined muscle biopsies of
subjects with SAMS and found that statins can in fact accumulate in skeletal
muscle and specifically bind to and inhibit the activity of complex III of the
mitochondrial respiratory chain (Schirris, Smeitink, Russel, Cell Metabolism
accepted). These novel data strongly support an inhibitory role of statins on
mitochondrial function. Unfortunately no comparison was made with individuals
on statins without complaints nor with subjects that do not use statins.
Therefore, the first aim of this study is to investigate whether we can detect
differences in the mitochondrial energy generating capacity of skeletal muscle
between 1. statin users with SAMS compared to 2. statin users without SAMS and
compared to 3. controls (non-statin users). The three groups will be matched
for age and sex.

Statin-induced effects on skeletal muscle cause a decrease in aerobic capacity.
The fact that aerobic fitness is a strong predictor for all-cause mortality but
also diabetes risk - which has recently been coupled to statin use-, emphasizes
the need to clarify the interaction between statins and skeletal muscle
function. There are only a limited number of studies that examined the effects
of statins on muscle performance, muscle function and on aerobic capacity.
Therefore, the secondary aim of this study is (A). to investigate if statin
users with SAMS have an altered muscle function and cardiorespiratory fitness
compared to statin users without SAMS and controls (non-statin users) and (B).
if this relates to the mitochondrial energy generating capacity of the muscle.

Primary Objectives:
To investigate whether differences exist in the mitochondrial energy generating
capacity of skeletal muscle of statin users with SAMS compared to statin users
without SAMS and controls (non-statin users).

Secondary objectives:
2A. To investigate if statin users with SAMS have an altered muscle function
and cardiorespiratory fitness compared to statin users without SAMS and
controls (non-statin users)

2B To investigate if altered muscle function and cardiorespiratory fitness in
statin users relates to the mitochondrial energy generating capacity of the
muscle.

A cross-sectional study will allow comparison of the energy generating capacity
of the mitochondria, muscle function and cardiorespiratory fitness between the
different study groups.

symptomatic + asymptomatic statin users
placebo intake for a period of 12 weeks in a singleblind fashion

During this study, patients using statins will not be exposed to a major risk,
as standard care will not be withheld, as patients will not be taken of their
medication and will carefully screened.
Performance of a muscle biopsy is not associated with an important health risk.
Complications include infection, bleeding and hematoma formation (<2%), whilst
these complications will resolve within 2 weeks. The biopsy procedures do not
induce discomfort and/or functional impairment. The contra-indications for a
muscle biopsy (e.g. use of anticoagulants) will be carefully checked by an
experienced physician during the medical screening procedure. After the muscle
biopsy, participants will receive written instructions (Sectie E.4
voorlichtingsmateriaal) to which they should adhere and pay attention to (e.g.
not perform any exercise of heavy labour immediately after the biopsy, not to
take a both for 48h, etc.). Venous blood withdrawal can induce a local hematoma
(<5%). However, this is completely reversible within 2 weeks and will not
induce permanent damage. Taken together, the nature and extent of burden and
risks associated with the different measurements are modest.