Clinical trial NCT04227678: Postprandial Fatty Acid Metabolism in Subjects With Lipoprotein Lipase Deficiency
Official title: Postprandial Fatty Acid Metabolism in Subjects With Lipoprotein Lipase Deficiency
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Lipoprotein Lipase Deficiency
Lead sponsor: Université de Sherbrooke
Sponsor class: OTHER
Collaborators: name: Institut de Recherches Cliniques de Montreal
First posted: 2020-01-14
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: Lipoprotein lipase (LPL) is an enzyme that plays an important role in removing triglycerides (TG) (molecules that transport dietary fat) from the blood. Patients with LPL deficiency (LPLD) display during their whole life very high plasma TG levels often associated with episodes of postprandial abdominal pain, malaise, blurred vision, dizziness (hyperchylomicronemia syndrome) that may lead to recurrent pancreatitis episodes. Because of their very slow clearance in blood of their chylomicron-TG, these patients need to severely restrict their dietary fat intake to avoid these complications. Fortunately, novel treatments are being developed to circumvent LPL deficiency (LPLD) metabolic effect on chylomicron-TG clearance. However, there is no data on how LPLD affect organ-specific dietary fatty acid metabolism nor how the novel therapeutic agents may change this metabolism. For example, it is currently not understood how subjects with LPLD store their DFA into adipose tissues and whether they are able to use DFA as a fuel to sustain their cardiac metabolism, as healthy individuals do. This study aims to better understand theses two questions.

Detailed description: The study protocol includes 3 visits: the screening visit and 2 postprandial metabolic studies performed in random order at an interval of 7 to 14 days, and performed with (A1) and without (A0) an intravenous (i.v.) heparin bolus followed by 250 IU/h i.v during 6 hours. Each metabolic study will last 9 hours (with 6 hours postprandial) and will include PET and stable isotopic tracer methods. At time 0, a low fat liquid meal will be ingested over 20 minutes.

Eligibility criteria: Inclusion Criteria:

* 8 healthy LPL-deficient individuals (LPLD subjects) with history of fasting TG \> 5 mmol/l and homozygote or compound heterozygote for a LPL-gene mutation;
* 8 control subjects (fasting glucose \< 5.6, 2-hour post 75g OGTT glucose \< 7.8 mmol/l and HbA1c \< 5.8%; fasting TG \< 1.5 mmol/l);
* age 18 to 75 yo;
* To be willing and able to adhere to the specifications of the protocol;
* To have signed an informed consent document indicating that they understood the purpose

Exclusion Criteria:

* age \< 18 yo;
* overt cardiovascular disease as assessed by medical history, physical exam, and abnormal ECG
* Treatment with a fibrate, thiazolidinedione, beta-blocker or other drug known to affect lipid or carbohydrate metabolism (except statins, metformin, and other antihypertensive agents that can be safely interrupted);
* Treatment with anti-hypertensive medication (only for LPL-deficient individuals);
* presence of liver or renal disease; uncontrolled thyroid disorder;
* previous diagnosis of heparin-induced thrombocytopenia;
* Treatment with oral anticoagulation medication or platelet aggregation inhibiting drugs;
* A history of major hemorrhagic event;
* smoking (\>1 cigarette/day) and/or consumption of \>2 alcoholic beverages per day;;
* Female of child-bearing potential who is pregnant, breast feeding or intends to become pregnant or pre-menopausal female with a positive serum pregnancy test at the time of enrollment.

Primary outcomes:
measure: Organ-specific Dietary Fatty Acid (DFA) partitioning
timeFrame: 2 months
measure: Myocardial DFA uptake
timeFrame: 2 months
Secondary outcomes:
measure: Myocardial nonesterified fatty acids (NEFA) metabolism
timeFrame: 2 months
measure: Dietary fatty acid oxidation rate
timeFrame: 6 months
measure: Total oxidation rate
timeFrame: 2 months
measure: postprandial plasma NEFA turnover
timeFrame: 6 months
measure: postprandial plasma glucose turnover
timeFrame: 6 months
measure: Left ventricular function by Positron Emitting Positron (PET) ventriculography
timeFrame: 2 months
measure: Myocardial oxidative metabolism
timeFrame: 2 months
measure: Insulin sensitivity
timeFrame: 6 months
measure: Liver nonesterified fatty acids (NEFA) metabolism
timeFrame: 2 months
measure: Metabolites distribution in plasma
timeFrame: 2 months
Other outcomes:
Locations:
city: Sherbrooke
country: Canada
facility: Centre de recherche du CHUS
state: Quebec
Study officials:
affiliation: Université de Sherbrooke
name: André Carpentier
role: PRINCIPAL_INVESTIGATOR
References: