What is the clinical significance of elevated Very Low Density Lipoprotein (VLDL) in the setting of low Low Density Lipoprotein (LDL) cholesterol?

From the Guidelines

Elevated VLDL with low LDL cholesterol is clinically significant and requires attention to reduce the risk of atherosclerotic cardiovascular disease (ASCVD), as VLDL particles are atherogenic, similar to LDL, and can contribute to cardiovascular risk despite normal or low LDL levels. This pattern may indicate hypertriglyceridemia, insulin resistance, or metabolic syndrome, and treatment should focus on lifestyle modifications, including weight reduction, limiting alcohol intake, reducing simple carbohydrates, and increasing physical activity 1.

Key Considerations

• Elevated VLDL levels are associated with an increased risk of ASCVD, and reducing their levels is reasonable to decrease this risk 1.
• The management of elevated VLDL should address excesses in both VLDL and other lipoproteins, such as chylomicrons, especially in cases of severe hypertriglyceridemia 1.
• For patients with significantly elevated triglycerides (>500 mg/dL), medications such as fibrates, omega-3 fatty acids, or niacin may be indicated to reduce triglyceride levels and VLDL, in addition to lifestyle modifications 1.

Treatment Approach

• Lifestyle modifications are the first line of treatment and should include dietary changes, increased physical activity, and weight reduction.
• Medications such as fibrates (e.g., gemfibrozil 600mg twice daily or fenofibrate 145mg daily), omega-3 fatty acids (2-4g daily), or niacin (1-2g daily) may be considered for patients with significantly elevated triglycerides.
• Statins may be less effective for VLDL reduction but can be considered in patients with concurrent cardiovascular risk factors, as they are primarily used to lower LDL cholesterol levels 1.

Monitoring and Management

• Regular monitoring of the complete lipid panel, liver function, and blood glucose is essential, as elevated VLDL often correlates with insulin resistance, fatty liver disease, or other metabolic disorders that require comprehensive management 1.
• A comprehensive approach to managing elevated VLDL and low LDL cholesterol should consider the patient's overall cardiovascular risk profile and include strategies to address all modifiable risk factors.

From the FDA Drug Label

In patients with hypertriglyceridemia and normal cholesterolemia with or without hyperchylomicronemia, treatment with fenofibrate at dosages equivalent to fenofibrate 160 mg per day decreased primarily very low density lipoprotein (VLDL) triglycerides and VLDL cholesterol.

The clinical significance of an elevated VLDL in the setting of low LDL cholesterol is that it may still pose a risk for cardiovascular disease, as VLDL is also an atherogenic lipid. Although LDL cholesterol is low, elevated VLDL can contribute to the development of atherosclerosis. Treatment with fenofibrate can decrease VLDL triglycerides and VLDL cholesterol, which may help reduce this risk 2.

• Key points:
  • Elevated VLDL can contribute to cardiovascular disease risk
  • Fenofibrate can decrease VLDL triglycerides and VLDL cholesterol
  • Low LDL cholesterol does not necessarily eliminate the risk associated with elevated VLDL
• Clinical decision: Monitor and manage elevated VLDL levels, even in the presence of low LDL cholesterol, to reduce cardiovascular disease risk 2.

From the Research

Clinical Significance of Elevated VLDL

The clinical significance of elevated Very Low Density Lipoprotein (VLDL) in the setting of low Low Density Lipoprotein (LDL) cholesterol is a complex issue.

• Elevated VLDL levels are associated with increased cardiovascular risk, particularly in patients with type 2 diabetes and mild-to-moderate hypertriglyceridemia 3.
• However, the relationship between VLDL-cholesterol and cardiovascular risk is not entirely clear, with some studies suggesting that VLDL-C is not associated with risk of major adverse cardiovascular events (MACE) or all-cause mortality, but may be associated with an increased risk of major adverse limb events (MALE) 4.
• Triglyceride lowering, which is often accompanied by a reduction in VLDL, has been associated with a lower risk of major vascular events, although the effect is less than that for LDL-C lowering 5.
• Certain therapies, such as fish oil supplements, have been shown to lower VLDL and triglyceride levels, and may have utility as triglyceride-lowering agents 6.

Therapeutic Targets

• Raising low levels of high-density lipoprotein (HDL) cholesterol is an important target of therapy, particularly in patients with low HDL and normal levels of LDL cholesterol and triglycerides 7.
• Decreasing elevated levels of LDL cholesterol and increasing low levels of HDL cholesterol should comprise dual targets of pharmacotherapy in patients with dyslipidemia.
• The clinical significance of elevated VLDL in the setting of low LDL cholesterol highlights the importance of considering multiple lipid parameters when assessing cardiovascular risk and guiding therapy.