What is the appropriate workup and treatment approach for an adult patient with hypertriglyceridemia, possibly with a history of obesity, diabetes, or other metabolic disorders, and a potential family history of cardiovascular disease?

Hypertriglyceridemia Workup

Begin with a fasting lipid panel to classify severity, then systematically evaluate for secondary causes (uncontrolled diabetes, hypothyroidism, excessive alcohol, medications) while simultaneously assessing cardiovascular risk and pancreatitis risk to guide treatment intensity. 1, 2

Classification and Risk Stratification

Measure fasting serum triglycerides and classify severity: 1, 2

• Normal: <150 mg/dL
• Mild: 150-199 mg/dL
• Moderate: 200-499 mg/dL
• Severe: 500-999 mg/dL (14% risk of pancreatitis) 2
• Very severe: ≥1,000 mg/dL (markedly increased pancreatitis risk) 1, 3

Mild to moderate hypertriglyceridemia primarily increases cardiovascular disease risk, while severe and very severe levels dramatically increase acute pancreatitis risk. 1, 2

Initial Laboratory Workup

Order the following tests to identify secondary causes and assess metabolic status: 1, 2

• Complete fasting lipid panel: Total cholesterol, LDL-C, HDL-C, triglycerides, calculated non-HDL-C 2
• Hemoglobin A1c and fasting glucose: Uncontrolled diabetes is often the primary driver of severe hypertriglyceridemia 1, 2
• TSH: Hypothyroidism commonly elevates triglycerides 1, 2
• Comprehensive metabolic panel: Assess renal function (creatinine, eGFR) and liver function (AST, ALT) 1, 2
• Urinalysis: Screen for proteinuria suggesting nephrotic syndrome 1

Calculate non-HDL cholesterol (total cholesterol minus HDL-C) with a target goal of <130 mg/dL for moderate hypertriglyceridemia, as this becomes an important secondary lipid target when triglycerides are 200-499 mg/dL. 2

Clinical History Assessment

Systematically evaluate for secondary causes that must be addressed before or concurrent with pharmacotherapy: 1, 2

Lifestyle and Dietary Factors

• Alcohol consumption: Even 1 ounce daily increases triglycerides by 5-10%; excessive intake can precipitate levels ≥250 mg/dL and trigger hypertriglyceridemic pancreatitis 2
• Dietary patterns: Excessive intake of simple sugars, refined carbohydrates, and saturated fats 1, 2
• Physical inactivity: Sedentary lifestyle strongly associated with elevated triglycerides 2
• Body weight: Excess weight and visceral adiposity reduce fatty acid oxidation 2, 4

Medical Conditions

• Diabetes mellitus: Poor glycemic control dramatically increases triglyceride production 1, 2
• Hypothyroidism: Common endocrine cause 1, 2
• Chronic kidney disease or nephrotic syndrome: Elevate triglyceride levels 1, 2
• Chronic liver disease: Contributes to disordered triglyceride metabolism 1, 2
• Pregnancy: Physiologic cause of elevation 1
• Autoimmune disorders: Can contribute to dyslipidemia 1

Medications That Raise Triglycerides

Review and consider discontinuing or substituting the following medications if possible: 1, 2

• Thiazide diuretics and beta-blockers 1, 2
• Estrogen therapy: Oral contraceptives and postmenopausal hormone preparations (oral > transdermal) 1, 2
• Isotretinoin (Accutane) 1
• Corticosteroids 1, 2
• Bile acid-binding resins 1
• Antiretroviral protease inhibitors 1, 2
• Immunosuppressants 1
• Antipsychotics 1, 2

Family History and Genetic Evaluation

Assess for primary genetic causes, particularly if triglycerides are markedly elevated without obvious secondary causes: 1, 2

• Family history of dyslipidemia and premature cardiovascular disease 1
• Familial hypertriglyceridemia 1
• Familial combined hyperlipidemia 1
• Familial dysbetalipoproteinemia 1
• Familial chylomicronemia syndrome: Very rare, requires specialized outpatient clinic management 5

Consider genetic testing in cases of severe primary hypertriglyceridemia (especially ≥1,000 mg/dL) without identifiable secondary causes to personalize management. 2

Cardiovascular Risk Assessment

For patients with mild to moderate hypertriglyceridemia, calculate 10-year ASCVD risk to determine need for statin therapy: 2, 6

• Persistently elevated nonfasting triglycerides ≥175 mg/dL constitute a cardiovascular risk-enhancing factor 2
• Assess for additional cardiovascular risk factors: Central obesity, hypertension, abnormal glucose metabolism, family history of premature cardiovascular disease 1, 2
• Evaluate for established ASCVD or diabetes with ≥2 additional risk factors (relevant for icosapent ethyl consideration) 2

Additional Assessments Based on Severity

For Severe to Very Severe Hypertriglyceridemia (≥500 mg/dL)

Immediate priorities to prevent acute pancreatitis: 2, 3

• Assess for symptoms of pancreatitis: Abdominal pain, nausea, vomiting 2
• Evaluate glycemic control urgently: Check A1c and fasting glucose, as poor control is often the primary driver 2
• Screen for excessive alcohol use: Mandatory complete abstinence at these levels 2

For Patients with Diabetes

Optimize glycemic control as the highest priority, as this can be more effective than additional lipid medications in some cases. 2, 7

Monitoring Strategy

Establish baseline and follow-up schedule: 2

• Reassess fasting lipid panel in 6-12 weeks after implementing lifestyle modifications 2
• Reassess lipids 4-8 weeks after initiating or adjusting pharmacotherapy 2
• Monitor transaminases (AST/ALT) at diagnosis and annually to screen for non-alcoholic fatty liver disease 2
• If fibrates are initiated, monitor creatine kinase (CK) and muscle symptoms at baseline and follow-up, especially in patients >65 years or with renal disease 2

Common Pitfalls to Avoid

Do not overlook secondary causes: Uncontrolled diabetes, hypothyroidism, or certain medications can lead to unnecessary medication treatment when addressing the underlying cause would suffice. 2

Do not delay fibrate therapy while attempting lifestyle modifications alone in patients with triglycerides ≥500 mg/dL: Pharmacologic therapy is mandatory to prevent pancreatitis. 2

Do not start with statin monotherapy when triglycerides are ≥500 mg/dL: Statins provide only 10-30% triglyceride reduction and are insufficient for preventing pancreatitis at this level; initiate fibrates or niacin before LDL-lowering therapy. 2

Do not ignore the importance of glycemic control in diabetic patients: Poor glucose control is often more important than additional lipid medications for severe hypertriglyceridemia. 2