Hyperlipidemia and Treatment

Study Notes

Abnormally elevated levels of lipids (cholesterol, triglyceride) or lipoproteins (VLDL, LDL) in the blood.
Divided into two subtypes:
- Primary Hyperlipidemia: Genetic causes, like mutations in receptor proteins.
- Secondary Hyperlipidemia: Other underlying causes, often diabetes.
A modifiable risk factor for cardiovascular disease due to its influence on atherosclerosis.
Some forms may be associated with acute pancreatitis.

Lifestyle changes: Diet, exercise, and weight reduction can modestly decrease LDL and increase HDL.
Drug therapy often required for significant LDL reduction:
- HMG-CoA Reductase Inhibitors (Statins): Primary treatment option for hypercholesterolemia.
  - Contraindications: Pregnancy, nursing mothers, children and teenagers.

Effective for increasing HDL and lowering LDL and triglycerides.
Can be used in combination with statins.
Mechanism of action: At gram doses, inhibits lipolysis in adipose tissue, reducing free fatty acid production. This decreases hepatic VLDL production, further leading to lower LDL plasma concentrations.
Pharmacokinetics: Administered orally, converted to nicotinamide. Excreted in urine.
Therapeutic uses: Useful for treating familial hyperlipidemias and severe hypercholesterolemias, often in combination with other agents.
Adverse effects:
- Intense cutaneous flush and pruritus (can be reduced with aspirin).
- Nausea and abdominal pain.
- Inhibits tubular secretion of uric acid, predisposing to hyperuricemia and gout.
- Impaired glucose tolerance and hepatotoxicity have been reported.

Derivatives of fibric acid, lowering serum triglycerides and increasing HDL levels.
- Fenofibrate is more effective than gemfibrozil in lowering LDL cholesterol and triglyceride levels.
Mechanism of action: Activate peroxisome proliferator-activated receptors (PPARs), which regulate lipid metabolism. This leads to decreased triglyceride concentrations through increased expression of lipoprotein lipase and decreased apo CII concentration. Fibrates also increase HDL cholesterol by increasing the expression of apo AI and apo AII.
Therapeutic uses: Treat hypertriglyceridemias, particularly type III hyperlipidemia (dysbetalipoproteinemia).
Adverse effects:
- Gastrointestinal effects: Mild gastrointestinal disturbances that lessen over time.
- Lithiasis: Predisposition to gallstone formation due to increased biliary cholesterol excretion.
- Muscle: Myositis can occur. Muscle weakness or tenderness should be evaluated, especially in patients with renal insufficiency.
  - Myopathy and rhabdomyolysis have been reported in patients taking gemfibrozil and lovastatin together.

Lower LDL cholesterol, but benefits are less than those observed with statins.
Mechanism of action:
- Bind negatively charged bile acids and bile salts in the small intestine.
- Resin/bile acid complex is excreted in the feces, leading to lower bile acid concentration in intestines.
- Hepatocytes increase conversion of cholesterol to bile acids, leading to decreased intracellular cholesterol concentrations. This stimulates increased hepatic uptake of LDL particles, resulting in a decrease in plasma LDL-C.
Therapeutic uses: Useful for treating hyperlipidemias, often in combination with diet or niacin.

Over-the-counter or prescription fish oil capsules (EPA/DHA) can be valuable as dietary consumption alone is often insufficient.
Icosapent ethyl: A prescription product containing only EPA. Unlike other fish oil supplements, it does not significantly raise LDL-C.
Efficacy: May be considered as an adjunct to other lipid-lowering therapies for individuals with significantly elevated triglycerides (≥500mg/dl). However, does not consistently reduce cardiovascular morbidity and mortality.
Adverse effects: GI effects (abdominal pain, nausea, diarrhea), fishy aftertaste, increased bleeding risk when used concurrently with anticoagulants or antiplatelets.

Often required to achieve desired plasma lipid levels.
HMG CoA reductase inhibitor and bile acid-binding agent combination is effective in lowering LDL-C levels.
Simvastatin and ezetimibe, and simvastatin and niacin are available in combination products.
Longer-term benefits of combination therapy require further investigation.
Many experts recommend maximizing statin dosages and adding niacin or fibrates only in cases of persistently elevated triglycerides (greater than 500 mg/dL) or low HDL cholesterol levels (less than 40 mg/dL).
Increased risk of liver and muscle toxicity with combination therapy.