High-Density Lipoprotein (HDL) Treatment Study
Information source: McGill University Health Center
Information obtained from ClinicalTrials.gov on June 20, 2008
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Coronary Arteriosclerosis; Hypoalphalipoproteinemias; Genetic Diseases, Inborn
Intervention: Atorvastatin; Fenofibrate; Niacin (Drug)
Phase: N/A
Status: Completed
Sponsored by: McGill University Health Center Official(s) and/or principal investigator(s):
Jacques Genest, MD, Principal Investigator, Affiliation: McGill University Health Center
Summary
A low level of plasma high-density lipoprotein (HDL) cholesterol, "the good cholesterol", is
the most common lipid abnormality observed in patients with a premature atherosclerotic
cardiovascular disease. HDL carry excess cholesterol from peripheral tissues to the liver to
be metabolized or excreted, a process known as reverse cholesterol transport.
Epidemiological studies have shown an inverse correlation between plasma levels of HDL
cholesterol and the risk of cardiovascular disease. An increase in plasma HDL cholesterol
levels by 1 mg/dL may reduce the risk of cardiovascular disease by 2 to 3%. The standard care
of treatment for a low level of HDL cholesterol is: 1) lifestyle modifications including
exercise, smoking cessation, weight control, moderate alcohol intake and decreased dietary
fat intake - all patients are encouraged to follow these lifestyle modifications; 2)
medications which can raise HDL cholesterol.
Currently used medications to treat lipid disorders can increase, in some extent, HDL
cholesterol. These include niacin (vitamin B3), fibric acid derivatives (fibrates) and
statins. However there is no data on the effect of these medications on severe cases of HDL
deficiency. This project aims to determine whether currently available medications, used in
standard medical practice for the treatment of lipoprotein disorders, can substantially
increase HDL cholesterol in severe cases of HDL deficiencies.
Clinical Details
Official title: Treatment Study for Severe High-Density Lipoprotein Deficiency
Study design: Treatment, Non-Randomized, Open Label, Active Control, Single Group Assignment, Efficacy Study
Primary outcome: HDL cholesterol
Secondary outcome: apo AI
Detailed description:
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:
- Body mass index (weight and height)
- Blood pressure
- Symptoms of ischemic heart disease
- Hepatic functions
- Myopathic symptoms
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.
Eligibility
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
Criteria:
Inclusion Criteria:
- HDL deficiency (HDL-cholesterol < 5th percentile, age and gender-matched)
Exclusion Criteria:
- Triglycerides ≥ 5 mmol/L
- Diabetes
- Severe obesity (BMI ≥ 30)
- Alcohol intake > 21 drinks/week
- Untreated disease (thyroid, hepatic or renal)
Locations and Contacts
MUHC-Royal Victoria Hospital, Montreal, Quebec H3A 1A1, Canada
Additional Information
Cholesterol and your heart Treatment of high cholesterol
Related publications: McPherson R, Frohlich J, Fodor G, Genest J, Canadian Cardiovascular Society. Canadian Cardiovascular Society position statement--recommendations for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease. Can J Cardiol. 2006 Sep;22(11):913-27. Erratum in: Can J Cardiol. 2006 Oct;22(12):1077. Brewer HB Jr. High-density lipoproteins: a new potential therapeutic target for the prevention of cardiovascular disease. Arterioscler Thromb Vasc Biol. 2004 Mar;24(3):387-91. No abstract available. Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, Faas FH, Linares E, Schaefer EJ, Schectman G, Wilt TJ, Wittes J. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med. 1999 Aug 5;341(6):410-8. Schaefer JR, Schweer H, Ikewaki K, Stracke H, Seyberth HJ, Kaffarnik H, Maisch B, Steinmetz A. Metabolic basis of high density lipoproteins and apolipoprotein A-I increase by HMG-CoA reductase inhibition in healthy subjects and a patient with coronary artery disease. Atherosclerosis. 1999 May;144(1):177-84. Ashen MD, Blumenthal RS. Clinical practice. Low HDL cholesterol levels. N Engl J Med. 2005 Sep 22;353(12):1252-60. Review. No abstract available. Erratum in: N Engl J Med. 2006 Jan 12;354(2):215. Schaefer EJ, Asztalos BF. The effects of statins on high-density lipoproteins. Curr Atheroscler Rep. 2006 Jan;8(1):41-9. Review.
Starting date: November 2006
Ending date: September 2007
Last updated: June 2, 2008
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