Abnormal Lipids - Causes and Effects

Hypertriglyceridaemia: Therapeutic Targets, Genetic Causes, and Associated Neuropathy

1. At target LDL-C levels, apoB100 concentrations will be higher than recommended levels in the following populations:

   1. Tertiary centre lipid clinic patients with raised TG treated with statins.
   2. Patients with type 2 diabetes treated with statins.
   3. Patients with Chronic Kidney disease (CKD) stages 4 and 5 treated with statins.
2. Despite achieving LDL-C and non-HDL-C targets, a significant number of statin-treated patients have residual cardiovascular risk related to raised hsCRP. The relationship between hsCRP and Lp-PLA2 (markers of inflammation) and LDL particle number measured by apoB100 is stronger than that of measured and calculated LDL and non-HDL. In statin treated patients there will be higher levels of hs-CRP and Lp-PLA2 in patients achieving LDL targets but not apo B targets.
3. We hypothesise that non-diabetic patients with severe hypertriglyceridaemia (fasting serum triglyceride >5.5 mmol/l) have evidence of greater nerve damage compared with matched controls.
4. LAL deficiency is underdiagnosed in patients with severe hypertriglyceridaemia, low HDL-C, hyperlipidaemias, non alcoholic fatty liver disease and idiopathic high liver enzymes.

Study Overview

• Status: Recruiting
• Conditions: Hypertriglyceridaemia

Detailed Description

Fats are present in the body in the form of lipid particles containing cholesterol and triglycerides. Lipid particles can deposit in blood vessels, forming atheromas, blocking blood vessels and leading to heart attacks and strokes. These harmful particles are termed 'atherogenic' particles. Low density lipoprotein (LDL) is the major atherogenic particle. Each atherogenic particle has a protein associated with it called apolipoprotein B (apoB). Cholesterol, triglycerides, and apoB levels can be measured in the laboratory. In this study we focus on patients with raised levels of triglycerides (hypertriglyceridaemia).

We will recruit patients with hypertriglyceridaemia to look at (1) therapeutic targets, (2) genetic causes, and (3) associated neuropathy in these patients.

1. Therapeutic target arm:

   LDL-cholesterol (LDL-C) is the primary target for lipid-lowering drugs. A drug (commonly a statin) is effective when it lowers LDL-C. Patients with diabetes, chronic kidney disease and hypertriglyceridaemia on statins may have normal levels of LDL-C; but because the size of LDL particles in these patients is smaller, they may in fact have raised levels of apoB and therefore remain at cardiovascular risk. Thus, measurement of apoB may be a better target for treatment because it measures 'atherogenic' particle numbers. Since atheromatous disease is an inflammatory disease, we will also investigate if residual risk may be correlated with inflammatory markers, such as hsCRP and Lp-PLA2.

2. Hypertriglyceridaemia and nerve function arm:

   We aim to demonstrate that severe hypertriglyceridaemia is associated with more significant nerve damage.

3. Genetic screening arm:

Several genetic mutations have been identified to cause hypertriglyceridaemia. Deficiency of the enzyme lysosomal acid lipase (LAL) results in Cholesterol Ester Storage Disease (CESD) and hypercholesterolaemia, hypertriglyceridaemia, and abnormal lipid deposition in organs. We wish to identify genetic mutations associated with severe hypertriglyceridemia and the prevalence of LAL deficiency in patients attending our tertiary referral centre.

• Study Type: Observational
• Enrollment (Estimated): 1396

Contacts and Locations

• Study Contact: Name: See Kwok, MD FRCGP; Phone Number: 01612768863; Email: sk7@doctors.org.uk

Study Locations

• United Kingdom
  • Manchester, United Kingdom, M13 9WL
    • Recruiting
    • Cardiovascular Trials Unit
    • Sub-Investigator: See Kwok, MD FRCGP
    • Contact: See Kwok, MD FRCGP; Phone Number: 01612768863; Email: sk7@doctors.org.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients are recruited from secondary and tertiary care hospital clinics.

Description

Inclusion Criteria:

• Therapeutic target arm

  • Statin treated patients with and without hypertriglyceridemia.
  • Statin treated patients with type 2 diabetes.
  • Statin treated patients with CKD stages 4 and 5.

• Nerve function arm

  •Patients known to have severe hypertriglyceridaemia (defined as triglyceride >5.5 mmol/l) but not known to have diabetes and matched controls.

• Genetic screening arm

  • Patients with a documented triglyceride level of more than 10 mmol/l at any time.
  • Criteria for screening for FH and LAL deficiency include non-obese patients (BMI <30) with low HDL-C (<1.0 mmol/l male and <1.3 mmol female), high triglycerides >1.7 mmol/l, high total cholesterol >6.2 or LDL cholesterol >4.7 mmol/l; patients with raised liver alanine aminotransferase (ALT) (1.5 x above ULN) but no metabolic or viral disease or alcohol excess and patients diagnosed with NAFLD with or without hyperlipidaemia.

Exclusion Criteria:

• Pregnant and/or breast-feeding women.
• Significant liver impairment.
• Patients known to have active malignant disease.
• Patients treated with medications that could affect lipoprotein metabolism significantly (like atypical antipsychotics, chemotherapy).
• Untreated hypothyroid and hyperthyroidism (if treated and TFT normal could be recruited).

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
Therapeutic target arm; Statin treated patients with and without raised triglycerides who do not have diabetes or dysglycemia. Statin treated patients with type 2 diabetes.Statin treated patients with CKD stages 4 and 5 (eGFR ≤30mL/min).
Nerve function arm; Patients with severe hypertriglyceridaemia (fasting TG > 5.5mmol/l.) are recruited for nerve function assessment and corneal confocal microscopy.
Genetic screening arm; For LAL deficiency screening, patients will be recruited over a 5 year period with a documented triglyceride level of more than 10 mmol/l at any time, low HDLC, raised ALT, combined hyperlipidaemia, or non-alcoholic fatty liver disease. Patients recruited from Manchester will be offered additional genetic testing for familial hypercholesterolaemia.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measurement of ApoB in specified patient populations to gauge cardiovascular risk.	Residual risk due to the presence of sd-LDL and reflected in a discrepancy between apoB and cholesterol indices is correlated with hs-CRP.	1 day.

Collaborators and Investigators

• Sponsor: Manchester University NHS Foundation Trust
• Investigators: Principal Investigator: Handrean Soran, MD FRCP, Manchester University NHS Foundation Trust

Study record dates

Study Major Dates

• Study Start (Actual): January 23, 2014
• Primary Completion (Estimated): December 1, 2030
• Study Completion (Estimated): December 1, 2030

Study Registration Dates

• First Submitted: July 10, 2014
• First Submitted That Met QC Criteria: July 17, 2014
• First Posted (Estimated): July 21, 2014

Study Record Updates

• Last Update Posted (Actual): May 31, 2023
• Last Update Submitted That Met QC Criteria: May 30, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Lipid Metabolism Disorders; Hyperlipidemias; Dyslipidemias; Hypertriglyceridemia
• Other Study ID Numbers: APOB2012; R03301 (Other Identifier: Manchester University NHS Foundation Trust)