Objective and rationale. We have collected, in the past 15 years, a large group of patients
with familial HDL cholesterol deficiency. In approximately 25% of index probands in our
family studies, the genetic basis of HDL deficiency is identified at the molecular level.
Approximately 20% of our severe HDL cholesterol deficient patients have mutations within the
ABCA1 gene, while mutations at the apoA-I and SMPD1 genes have also been identified. In the
present study, we wish to determine whether conventional lipid-regulating medication can
substantially increase HDL cholesterol in patients with severe HDL deficiency. Anecdotal
reports from our clinic suggest that patients with ABCA1 mutations do not respond to
currently available medication; this will be more thoroughly ascertain in this protocol. In
addition, examining patients with other genetic HDL deficiencies and familial forms (gene not
yet identified) will provide insight on the treatment options for these patients. We feel it
is important first whether currently recommended medication can effectively raise HDL
cholesterol in these patients.
Study subjects. The subjects will include patients with familial HDL deficiency (HDL
cholesterol < 5th percentile for age and gender, with at least one degree relative affected)
and HDL deficiency with well-defined genetic mutation. We expect approximately 20-25 patients
to enter the study.
Patients will be excluded if at least one of the following criteria is present:
Triglycerides ≥ 5 mmol/L
Diabetes
Severe obesity (BMI ≥ 30)
Alcohol intake > 21 drinks/week
Untreated disease (thyroid, hepatic or renal)
Study procedure. Patients will be treated according to current lipid treatment guidelines
(McPherson R, Frohlich J, Fodor G, Genest J. Canadian Cardiovascular Society position
statement: recommendations for the diagnosis and treatment of dyslipidemias and prevention of
cardiovascular disease. Can J Cardiol 2006; 22:913-927) and the use of the three following
medications (separately or in combination):
Lipitor 20 mg
Lipidil 200 mg
Niaspan 2 g
It should be noted that all three medications are currently used to treat patients with
dyslipidemia and represent the current "standard of care".
Statistics. The null hypothesis expects that no treatment effect increases HDL cholesterol by
10% in the study sample (α = 0.05 and β = 0.8). Using this study design, each patient will
serve as his/her own control. Differences between baseline (B) and treatment (T) periods for
each medication will be examined by sudent's t-test.
Protocol. Each treatment period will last 8 weeks; wash-out periods will last 4 weeks.
Baseline values (B1-3) will be taken at the beginning of each treatment period. On-treatment
values (T1-3) will be drawn at the end of each medication period. At each time B (baseline)
and T (after a treatment) patient will be examined for:
The following blood test will be performed:
Total cholesterol
Triglycerides
HDL cholesterol
LDL cholesterol
ApoA-I, apoB
ALT, CK
At time B1 blood will also be collected for the determination of:
TSH
Creatinine
ALT
Blood glucose
In addition, blood will be used to examine the ability of the patient's HDL and plasma to
promote cellular cholesterol efflux, using an in vitro model which is well established in our
laboratory. Cellular cholesterol efflux tests the efficiency of apoA-I lipidation from cells
for the formation of HDL particles. This will provide a general index of the functional
status of HDL particles in the body.
