Effect of Gemfibrozil on Serum Glycosylphosphatidylinositol (GPI) Phospholipase D and Triglycerides
Information source: Department of Veterans Affairs
Information obtained from ClinicalTrials.gov on June 20, 2008
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Hypertriglyceridemia
Intervention: Gemfibrozil (Drug)
Phase: Phase 1
Status: Completed
Sponsored by: Department of Veterans Affairs
Summary
The purpose of this study is to examine the role of glycosylphosphatidylinositol-specific
phospholipase D (GPI-PLD) in triglyceride metabolism.
Clinical Details
Official title: Effect of Gemfibrozil on Serum GPI Phospholipase D and Triglycerides
Study design: Treatment, Randomized, Double-Blind, Placebo Control, Factorial Assignment, Pharmacokinetics/Dynamics Study
Detailed description:
Increased fasting serum triglyceride levels are associated with an increased risk of coronary
artery disease. However, triglyceride levels in the postprandial state are a more sensitive
marker of coronary artery disease. Postprandial elevations in triglycerides result from a
decrease in the catabolism of triglyceride-rich lipoproteins, i. e. chylomicrons and very low
density lipoproteins (VLDL). This leads to an accumulation of atherogenic remnants of
triglyceride-rich lipoproteins. Although fasting triglycerides are the best predictors of
postprandial triglycerides, differences in fasting triglycerides only partially account for
the variation in magnitude of postprandial triglycerides. Recently, we have identified a new
protein involved in triglyceride-rich lipoprotein catabolism,
glycosylphosphatidylinositol-specific phospholipase D (GPI-PLD). We have shown that elevated
levels of GPI-PLD are associated with increased fasting triglyceride levels. Serum GPI-PLD is
associated with high density lipoproteins (HDL) in the fasting state and exchange onto VLDL
in the postprandial state. Hepatic GPI-PLD decreases triglyceride-rich lipoprotein catabolism
in the liver. Hepatic and serum GPI-PLD levels are decreased by peroxisome proliferator
receptor (PPAR) alpha agonist treatment, which also reduces fasting and postprandial
triglycerides. The central hypothesis of this application is that variations in GPI-PLD
expression account for a portion of the differences in fasting and postprandial triglycerides
among humans.
The objective of this proposal is to determine the role of GPI-PLD in regulating fasting
triglycerides and post-prandial hypertriglyceridemia in humans. This will be accomplished by
conducting a double blind, placebo controlled study in humans examining the effect of
gemfibrozil on fasting and postprandial triglycerides in relationship to the variation and
changes in GPI-PLD before and after gemfibrozil.
Our specific objectives are:
- 1a) Determine the extent to which variations in GPI-PLD account for differences in
fasting and postprandial triglycerides
- 1b) Establish the degree to which the lowering of fasting and postprandial triglycerides
by gemfibrozil is accounted for by changes in GPI-PLD.
- 2) Quantify the changes in serum GPI-PLD and distribution of GPI-PLD among lipoproteins
in the postprandial state.
This will be the first prospective bench-to-bedside study examining the role of GPI-PLD in
triglyceride metabolism. This proposal will be the first in humans examining 1) the role of a
novel protein, GPI-PLD, in triglyceride metabolism, and 2) the effect of gemfibrozil, a drug
currently used clinically to lower triglyceride levels, on GPI-PLD levels in humans. It is
expected that the results from this study will increase our understanding of triglyceride
metabolism and develop new information in understanding the regulation of GPI-PLD and its
relationship to triglyceride metabolism.
Eligibility
Minimum age: 19 Years.
Maximum age: 74 Years.
Gender(s): Both.
Criteria:
Inclusion Criteria:
- Age >18 and <75
- Fasting triglycerides >150 mg/dl
Exclusion Criteria:
- Fasting triglycerides >600 mg/dl
- LDL >130 mg/dl
- Concurrent lipid lowering therapy
- Known hypersensitivity to gemfibrozil
- Alcohol intake >30 gm/day (2 drinks/day)
- Fasting glucose >125 mg/dl or known type 2 diabetes
- AST or ALT > 2. 0 x upper limit of normal
- Creatinine: men >1. 4 mg/dl, women >1. 3 mg/dl
- Cancer treatment in the past 5 years (unless cured)
- Infectious diseases including HIV or tuberculosis
- Significant cardiac disease in the past 6 months (myocardial infarction, coronary
artery bypass graph, angioplasty, class 3 or 4 congestive heart failure, left bundle
branch block, third degree AV block)
- Uncontrolled hypertension (systolic blood pressure [SBP] >180 or diastolic blood
pressure [DBP] > 105 mm Hg)
- Anemia (hematocrit <40% men, <35% women)
- Any other significant systemic disease or medication that could interfere with
tolerance of medication or outcome
- Any indication that a participant will be unable to adhere to the protocol
- Unable to give informed consent
- Pregnant or breastfeeding females or a female who plans to become pregnant while
participating in the study
Locations and Contacts
Roudebush VA Medical Center, Indianapolis, Indiana 46202, United States
Additional Information
Starting date: October 2004
Ending date: September 2007
Last updated: March 27, 2008
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