Effect of simvastatin on myocardial triglyceride accumulation, cardiac function and al vessel wall thickness in patients with type 2 diabetes mellitus

Patients with type 2 diabetes mellitus (DM2) have a considerably higher risk to
develop heart failure than can be accounted for by hypertension and coronary
artery disease. Diabetes-related alterations in cardiac metabolism are thought
to play a causal role in the development of non-ischemic cardiomyopathy.
In DM2, insulin resistance and central obesity lead to increased lipolysis with
high flux of free fatty acids (FFA) from adipose tissue and elevated production
of triglyceride (TG)-rich particles. Exposure to high levels of FFA causes
accumulation of TG in non-adipose tissues such as pancreas, liver and the
myocardium. Animal studies have provided consistent evidence that access
accumulation of TG within cardiomyocytes is associated with contractile
dysfunction. This excessive accumulation of TG and its by-product ceramide
induces activation of nonoxidative metabolic pathways that leads to cell
dysfunction and accelerated cell death (apoptosis). In this way, lipid
accumulation in the myocardium could be directly cardiotoxic.
Recently, ¹H-magnetic resonance spectroscopy (MRS) has been developed and
validated for measuring intracellular lipid content in humans in vivo. Recent
studies in healthy individuals and patients with heart failure reveal that
myocardial lipid content is associated with body mass index (BMI) and age and
may contribute to adverse structural and functional cardiac adaptations.
Large clinical trials showed that statin therapy was effective for the
prevention of cardiovascular events in patients with diabetes mellitus.
Although these studies proved that there was a linear relation between lowering
LDL cholesterol and cardiovascular events, the effect of statins on
cardiovascular mortality is greater than expected from the changes in serum
lipids, leading to the proposal that statins have pleiotropic effects. In a
recent cross sectional study we observed that patients with DM2 who were taking
statins had lower myocardial triglyceride contents compared to patients without
a statin.

To study the possible beneficial effect of simvastatin on accumulation of
triglycerides in the myocardium of patients with DM2 and the effect on vessel
wall thickness using magnetic resonance imaging and spectroscopy

Double blind randomized placebo controlled intervention study

Study procedure:

All patients will be screened in our outpatient clinic. If the patient meets
all the inclusion criteria, and gives signed informed consent, he/she will be
included. All patients will be asked not to make any changes in their usual
diets and physical activities during the whole study. Patients will have three
study days. At day 0, an intravenous (iv) cannula will be inserted for
gadoteric acid (Gd) contrast and bloodsampling. Subsequently, a baseline MRI
with spectroscopy will be performed on a 1.5 Tesla (T) scanner to measure
cardiac function and myocardial/ hepatic triglyceride content. Gd-contrast will
be given iv for delayed enhancement scans. Vessel wall imaging will be
performed during a separate session using a 3T scanner. Afterwards each patient
will start with simvastatin 40 mg or placebo once daily. All participants will
undergo safety and efficacy measurements during follow up visits after 2 and 6
weeks. During the follow up visits, tolerance, safety measures and compliance
with therapy will be assessed.
After 12 weeks, blood sampling, MR imaging and MR spectroscopy will be repeated
as described above except for the delayed enhancement scans. Afterwards (at 12
weeks of treatment) the randomization code will be broken. In the placebo arm,
the placebo will be replaced by simvastatin 40 mg and the simvastatin arm will
continue medication at the same dose.
A follow up MRI assessment will be performed as described above in both groups
one year after starting simvastatin.

treatment with simvastatin 40 mg or placebo for 12 weeks, followed by
simvastatin 40 mg for 1 year (in total)

The risks associated with participation are small; simvastatin is a safe and
efficacious drug which is widely used. Placebo is a capsule of wich no side
effects are expected to occur, since it does not contain any active substances.
Contrast nephropathy and nephrogenic systemic fibrosis induced by Gadoteric
acid contrast are very rare and predominantly occur in patients with
pre-existing renal insufficiency, who will be excluded from this study.
There are no known hazards from MRI/MR spectroscopy when MR exclusion criteria
have been checked.
Six visits, including screening, follow up visits, begin and endpoint
assessments are applicable to all subjects. At screening and before each MRI
scan blood samples will be taken via venous puncture or iv cannula. Total
amount of blood taken from the patient for the entire protocol is maximally 150
ml.
Total examination time for MRI may be 120 and subsequently 90 minutes at
maximum. During that time period patients have to lie still inside the small
bore of the MRI machine. This may cause some discomfort.
Participants will benefit from this study, since the will be screened for
cardiac dysfunction using MRI and the will use simvastatin which will reduce
the risk on cardiovascular disease.