Kinetic Study of Lp(a) and PCSK9 in Humans (HuLaUP)

Nantes University Hospital (NUH)

Status: Completed

Conditions: Cholesterol; Metabolic Disorder; Lipoproteinemia

Treatments: Other: infusion of tracer [5,5,5-2H3] -L-leucine

Study type: Interventional

Funder types: Other

Identifiers

NCT04247048

RC18_0281

Details and patient eligibility

About

The aim is to study the relationship between lipoprotein(a) [Lp(a)] and PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9) in humans with a kinetic study of lipoproteins in patients with dramatic increase of Lp(a) and controls.

Full description

Elevated plasma levels of lipoprotein(a) [Lp(a)] are independently associated with an increased risk of cardiovascular diseases (CVD). Recently an unexpected and significant 15 to 30 % reduction of Lp(a) was reported with PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9) inhibitors. The relation between Lp(a) and PCSK9 are unclear and debated.

Kinetic studies of lipoprotein are an important tool to decipher the complexity of apolipoprotein metabolism in human. The comparison of apoprotein(a) and PCSK9 kinetic parameters of patients with extreme lipid disorder link to PCSK9 and apo(a) will allow to better understand the impact of PCSK9 on apo(a). From one previous in vitro study, the hypothesize is that PCSK9 increases the production rate and the assembly of Lp(a).

The objectives are to explore the relationship between the plasma concentration of PCSK9 and apo(a) production rate as well as the impact on the catabolic rate. Patients with extreme Lp(a) levels and healthy controls will be explored by performing a continuous infusion of deuterated leucine for 14 hours. LC/MS-MS will be used to analyze the samples and kinetic data of apo(a) and PCSK9 will be generated from a compartmental model. Tracer enrichment analysis could be complicated for proteins with low plasma concentrations as PCSK9. This issue will be solved with SPE and/or immune affinity concentration techniques. Non-parametrical test and multivariate analysis will be use to describe the relationship between these two variables.

This study will provide new knowledge on Lp(a) and PCSK9 metabolism and their interactions in humans.

Enrollment: 21 patients

Sex: All

Ages: 18 to 75 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• age: 18 to 75 years
• For subjects in the "Control" group: Patients with no major LDL-cholesterol deficiency (patients eligible for LDL-apheresis, eg LDL-C> 200 mg / dL for secondary prevention and 300 mg / dl in primary prevention)) and a level of Lp (a) <50 mg / dl or
• For subjects in the "high-dose" group: Patients with no major LDL-cholesterol abnormalities (LDL-apheresis eligible patients, eg LDL-C> 200 mg / dL for secondary prevention and 300 mg / dl in primary prevention)) and a level of Lp (a)> 80 mg / dl Whenever possible, groups will be balanced for age, sex, familial forms of hypercholesterolemia and their major groups of mutations.

Exclusion criteria

• Patients treated with PCSK9 antibodies.
• Patients with acute illness and considered incompatible by the investigator
• Uncontrolled diabetes (HbA1c> 8.5%)
• Severe hepatic insufficiency
• Creatinine clearance <30 ml / min
• Patients not covered by a social security scheme or beneficiary of such a scheme
• Patients unable to understand and / or sign consent
• Pregnant or lactating women
• Minors
• Majors under guardianship or trusteeship or safeguard of justice

Trial design

Primary purpose: Other

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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21 participants in 2 patient groups

Control group

Experimental group

Description:

Patients with no major LDL cholesterol abnormalities (patients eligible for LDL-apheresis, eg LDL-C\> 200 mg / dL for secondary prevention and 300 mg / LDL-C) dl in primary prevention)) and a level of Lp (a) \<50 mg / dl

Treatment:

Other: infusion of tracer [5,5,5-2H3] -L-leucine

High-dose group

Experimental group

Description:

Patients with no major LDL-cholesterol abnormalities (LDL-apheresis eligible patients, eg LDL-C\> 200 mg / dL for secondary prevention and 300 mg / dl in primary prevention)) and a level of Lp (a)\> 80 mg / dl

Treatment:

Other: infusion of tracer [5,5,5-2H3] -L-leucine