How do cyclosporine, thiazide (diuretics) and steroids cause hypertriglyceridemia?

Mechanisms of Hypertriglyceridemia Induced by Cyclosporine, Thiazides, and Steroids

Cyclosporine, thiazide diuretics, and steroids each cause hypertriglyceridemia through distinct mechanisms that disrupt lipid metabolism, with cyclosporine having the most pronounced effect on triglyceride levels.

Cyclosporine-Induced Hypertriglyceridemia

Cyclosporine causes significant elevation of triglycerides through several mechanisms:

• Dose-dependent effect: Triglyceride elevations are directly related to cyclosporine dosage and occur rapidly (within 2 weeks) of starting treatment 1
• Persistent elevation: The increase persists throughout treatment duration and is reversible upon dose reduction or discontinuation 1
• Severity: Elevations of triglycerides >750 mg/dL occur in approximately 15% of psoriasis patients on cyclosporine 2
• Primary mechanism: Cyclosporine impairs triglyceride clearance by:
  • Inhibiting lipoprotein lipase activity
  • Increasing hepatic triglyceride synthesis
  • Altering apolipoprotein metabolism 1, 3

Patients with pre-existing hypertriglyceridemia or prior history of lipid abnormalities with other medications (like etretinate) are at particularly high risk for severe triglyceride elevations on cyclosporine 4.

Thiazide Diuretic-Induced Hypertriglyceridemia

Thiazide diuretics cause more modest elevations in triglycerides through:

• Potassium depletion: Thiazide-induced hypokalemia impairs insulin secretion, leading to:
  • Impaired glucose tolerance
  • Increased peripheral insulin resistance
  • Elevated insulin levels that promote triglyceride synthesis 5
• Insulin resistance: Thiazides increase peripheral resistance to insulin action, which:
  • Enhances lipolysis in adipose tissue
  • Increases free fatty acid flux to the liver
  • Promotes hepatic triglyceride synthesis 1, 5
• Direct metabolic effects: Thiazides increase triglyceride, total cholesterol and LDL cholesterol levels without changing HDL cholesterol 6

The combination of thiazides with cyclosporine can exacerbate nephrotoxicity and potentially worsen lipid abnormalities 1.

Steroid-Induced Hypertriglyceridemia

Corticosteroids cause hypertriglyceridemia through:

• Increased VLDL production: Steroids enhance hepatic VLDL synthesis and secretion 1, 7
• Altered lipoprotein composition: Steroids increase VLDL-cholesterol and total cholesterol along with triglycerides 7
• Insulin resistance: Steroids promote insulin resistance and hyperinsulinemia, which:
  • Increases hepatic triglyceride synthesis
  • Reduces triglyceride clearance 1, 7
• Lipolysis stimulation: Steroids enhance adipose tissue lipolysis, increasing free fatty acid flux to the liver for triglyceride synthesis 7

Clinical Implications and Monitoring

• Baseline assessment: Check serum lipid levels before initiating any of these medications, particularly in high-risk patients (diabetes, pre-existing hyperlipidemia) 1
• Regular monitoring: Monitor lipid levels throughout treatment, with special attention after 1-2 months of therapy when triglyceride elevations often peak 1, 4
• Management strategies:
  • Dietary restriction of cholesterol and saturated fat is first-line for clinically significant hyperlipidemia 1
  • Consider dose reduction or medication alternatives when possible
  • For severe hypertriglyceridemia (>500 mg/dL), consider fibrates or statins with caution due to potential drug interactions 1

Special Considerations

• Patients receiving multiple medications that affect lipid metabolism (e.g., transplant recipients on cyclosporine, steroids, and thiazides) are at particularly high risk for severe hypertriglyceridemia 1
• The risk of pancreatitis increases significantly when triglyceride levels exceed 1000 mg/dL 1
• Drug interactions must be carefully considered when treating medication-induced hypertriglyceridemia, especially with cyclosporine which interacts with many lipid-lowering medications 1