Treatment Study for Severe High-Density Lipoprotein Deficiency

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):