What medications can cause elevated triglycerides in patients, particularly those with a history of cardiovascular disease?

Medications That Cause Elevated Triglycerides

Multiple medication classes can significantly elevate triglycerides, with protease inhibitors (particularly ritonavir and lopinavir), atypical antipsychotics (especially clozapine and olanzapine), oral estrogens, thiazide diuretics, beta-blockers, corticosteroids, and immunosuppressants being the most common culprits. 1

High-Risk Medication Classes

Protease Inhibitors (HIV Antiretrovirals)

• Ritonavir causes the most severe hypertriglyceridemia among protease inhibitors, with significantly higher frequency and severity compared to other agents, and can cause substantial increases in total cholesterol and triglycerides. 1, 2, 3
• Lopinavir/ritonavir combination therapy causes hypertriglyceridemia in approximately 40% of antiretroviral-naive patients after 12 months, with mean triglyceride increases of 73.3 mg/dL, and marked triglyceride elevations are a risk factor for pancreatitis. 4, 5
• Indinavir causes significantly more hypertriglyceridemia than saquinavir, NRTI-NNRTI combinations, or no antiretroviral therapy, though less severe than ritonavir. 1, 3
• Atazanavir-ritonavir–containing regimens have more favorable lipid profiles compared to other protease inhibitor regimens. 1
• Switching from ritonavir-boosted protease inhibitors to dolutegravir-based regimens results in 7.7% LDL-C reduction while maintaining viral suppression. 1

Atypical Antipsychotics

• Clozapine and olanzapine carry the highest risk of hypertriglyceridemia among psychiatric medications, followed by quetiapine and risperidone. 6, 7
• Aripiprazole and ziprasidone have lower metabolic risk and minimal effects on lipid metabolism compared to other atypical antipsychotics. 7
• Severe hypertriglyceridemia (>500 mg/dL) from antipsychotics increases risk of acute pancreatitis. 7

Hormonal Agents

• Oral estrogens (including oral contraceptives and postmenopausal hormone therapy) greatly influence triglyceride levels, with oral preparations increasing triglycerides more than transdermal formulations. 1, 6
• Tamoxifen and raloxifene can raise triglyceride levels. 1, 6

Cardiovascular Medications

• Thiazide diuretics are commonly prescribed antihypertensives that can increase triglycerides. 1, 6
• Beta-blockers, particularly atenolol, can increase triglycerides, though carvedilol is preferred in diabetic patients and those with hypertriglyceridemia. 1, 6

Immunosuppressive Agents

• Cyclosporine, sirolimus, and tacrolimus elevate triglyceride levels. 1, 6
• Corticosteroids affect lipid metabolism and can raise triglycerides. 1, 6

Other Medication Classes

• Bile acid sequestrants (resins) can significantly raise triglycerides in predisposed individuals and should not be used with preexisting hypertriglyceridemia >200 mg/dL. 1, 8
• Retinoic acid drugs (retinoids) affect lipid metabolism. 1, 6
• Interferon can elevate triglycerides. 1
• L-asparaginase raises triglyceride levels. 1
• Cyclophosphamide can increase triglycerides. 1
• Rosiglitazone may elevate triglycerides. 1

Mood Stabilizers and Antidepressants

• Valproic acid can cause weight gain that may contribute to elevated triglycerides. 7
• Carbamazepine has been associated with weight gain affecting lipid profiles. 7
• Lithium can cause weight gain that may indirectly affect triglyceride levels. 7
• Mirtazapine is associated with weight gain that could indirectly affect triglycerides. 7
• Most SSRIs are generally weight-neutral or may cause initial weight loss. 7

Critical Clinical Considerations

Risk Factors for Medication-Induced Hypertriglyceridemia

• Baseline cholesterol >200 mg/dL and triglycerides >150 mg/dL are independent risk factors for developing dyslipidemia when starting protease inhibitors like lopinavir/ritonavir. 5
• Patients with preexisting hypertriglyceridemia are especially concerning when exposed to triglyceride-raising medications. 1
• The risk of developing hyperlipidemia increases with duration of protease inhibitor treatment, with >50% developing hypercholesterolemia and hypertriglyceridemia after 2 years. 9

Management Approach

• When possible, discontinue or substitute triglyceride-raising medications, particularly in patients with severe hypertriglyceridemia (≥500 mg/dL). 8
• Select antipsychotics with lower metabolic risk (aripiprazole or ziprasidone) in patients with pre-existing dyslipidemia or metabolic syndrome. 7
• Consider switching abacavir-containing antiretroviral regimens in patients with HIV and cardiovascular disease due to possible association with increased cardiovascular events. 1
• Avoid lovastatin and simvastatin with protease inhibitors due to CYP3A4 metabolism and increased rhabdomyolysis risk; use pravastatin, pitavastatin, rosuvastatin, or atorvastatin instead. 1, 9

Monitoring Requirements

• Careful monitoring of serum lipid profile is needed during antiretroviral therapy including protease inhibitors to identify need for diet and/or hypolipidemic treatment. 3
• Hepatitis C coinfection appears protective against developing hyperlipidemia after starting lopinavir/ritonavir. 5

Common Pitfalls to Avoid

• Do not overlook medication-induced hypertriglyceridemia as a secondary cause before initiating pharmacologic lipid-lowering therapy. 8
• Do not use bile acid resins when triglycerides are >200 mg/dL as they are relatively contraindicated and can worsen hypertriglyceridemia. 1, 8
• Do not combine gemfibrozil with statins when treating protease inhibitor-induced dyslipidemia; use fenofibrate instead due to better safety profile. 9
• Protease inhibitors like nelfinavir and ritonavir induce enzymes that metabolize fibric acid derivatives, potentially reducing lipid-lowering efficacy of gemfibrozil or fenofibrate. 9