Fenofibrate Treatment in SCI

Although considered a modifiable risk factor for coronary artery disease (CAD) in the general
population, the magnitude of physical activity required to promote cardiorespiratory fitness
and a clinically meaningful change in blood-derived biomarkers of CAD is not achievable in
those with a severe physical disability, such as with immobilizing paralysis from spinal cord
injury (SCI). During the chronic phase of SCI, a characteristic dyslipidemia emerges, with
mean serum high density lipoprotein cholesterol (HDL-C) concentrations <40 mg/dl, a threshold
level for HDL-C that is appreciated to be an independent risk factor for CAD, elevations in
triglycerides (TG) to concentrations at, or near, target values for the general population
that trigger clinical intervention, and low density lipoprotein cholesterol (LDL-C)
concentrations that are within the normal range. It should not be a surprise that
cardiovascular disease (CVD)-related morbidity in persons with SCI occurs earlier in life, at
a greater prevalence than that of the general population, and is the primary cause of death
after the first year of injury. Population-based epidemiological studies are unavailable for
clinical guidance because of the relatively low incidence rates for SCI. Clinical target
values used to initiate treatment in the general population may be inappropriate in those
with SCI because of their unique pathophysiology. In the absence of significant physical
activity and lifestyle modifications, it would seem that appropriate pharmaceutical options
are needed to properly manage markers of CVD-related risk in persons with SCI. To date, there
is limited empirical evidence to support the use of lipid-lowering treatments in persons with
SCI.

Fenofibrate is a fibric acid derivate that activates peroxisome proliferator-activated
receptor and lipoprotein lipase, leading to enhanced elimination of TG from plasma. In
clinical trials where fenofibrate was used as a monotherapy, serum TG concentrations fell
41-53%, very low density lipoprotein (VLDL) fell 38-52%, LDL-C decreased 6-20%, and HDL-C
improved by as much as 20%. In consideration for the nature of dyslipidemia in persons with
SCI, fenofibrate appears to be an appropriate first-line agent for treatment in this cohort,
especially because most of those with SCI have LDL values that are within the clinically
acceptable range. In the general population, standard clinical practice for lipid-lowering
treatment with fenofibrate monotherapy follows a known and clinically accepted timeline to
monitor safety and to determine therapeutic efficacy. It is recommended that, if after 2
months of continuous therapy there are no beneficial changes to the lipoprotein profile, that
treatment be discontinued (i.e., non-responders). Similarly, several large clinical trials
have demonstrated that the peak therapeutic effects of fenofibrate are observed after 12-16
weeks of treatment (i.e., responders). The proposed study will test the efficacy of
administering fenofibrate to persons with SCI, a severely immobilized cohort that does not
have established clinical practice guidelines to treat dyslipidemia and appears to have
unique considerations that may be hypothesized to call for a more disease-specific approach
for care. If successful, the treatment will reduce clinical markers of CVD-related risk by
modifying the concentration and number of particles that are known to contribute to incident
cardiac events and mortality. It is anticipated that the insight gained from this
investigation will provide clinicians with a proof-of-concept for instituting appropriate use
of lipid lowering agents to treat the dyslipidemia that has been well described in persons
with SCI.

Inclusion Criteria:

- Male or female, age 21 to 69;

- Chronic (e.g., duration of injury at least 6 months), stable SCI (regardless of level
of neurological lesion);

- American Spinal Injury Association Impairment Scale (AIS) designation of A, B or C;
and

- TG concentration 135 mg/dl (paraplegia) or 115 mg/dl (tetraplegia).

Exclusion Criteria:

- Acute illness or infection;

- Reduced kidney function (by glomerular filtration rate (GFR <60 ml/min) or liver
function tests (LFTs 2.5 standard deviations above the upper limit of normal);

- Current pharmacological treatment with: HMG-CoA reductase inhibitors (statins), or any
other hypolipidemic agent; anti-coagulant therapy; cyclosporine; or any other
medications known to effect the TG concentration (i.e., -blockers, thiazides or
estrogen);

- Hypersensitivity to fenofibrate;

- Existing diagnosis of atherosclerosis, congestive heart failure, or recent history of
myocardial infarction (i.e., 12 months);

- Pregnancy or women who may become pregnant during the course of the study, or those
who are nursing;

- Diminished mental capacity; and

- Inability or unwillingness of subject to provide informed consent.

- Existing diagnosis of diabetes mellitus, or the results from screening blood tests
indicate that diabetes mellitus is present (and perhaps undiagnosed); laboratory
thresholds for exclusion will be as follows: HbA1C 6.5% and fasting plasma glucose is
>126 mg/dl.