What is the best management approach for a 45-year-old patient with severe hypertriglyceridemia, hyponatremia, hyperproteinemia, and hyperglycemia, with lab results showing triglycerides (TG) of 6000, sodium (Na) of 125, protein of 15.9, globulin of 11, negative amylase, and a high hemoglobin A1c (HbA1c)?

Management of Severe Hypertriglyceridemia with Multiple Metabolic Derangements

This patient requires immediate fenofibrate therapy to prevent acute pancreatitis, aggressive correction of hyperglycemia which is likely the primary driver of the severe hypertriglyceridemia, and urgent evaluation for the cause of hyponatremia and hyperproteinemia which may indicate an underlying monoclonal gammopathy or other serious condition. 1, 2, 3

Immediate Priorities: Prevent Pancreatitis

Triglycerides at 6000 mg/dL place this patient at extreme risk for acute pancreatitis and require emergency intervention. 1, 3, 4

• Initiate fenofibrate 54-160 mg daily immediately as first-line therapy to rapidly reduce triglycerides below the critical 1000 mg/dL threshold, providing 30-50% triglyceride reduction. 1, 2, 3, 5
• Dose fenofibrate based on renal function: if eGFR ≥60 mL/min/1.73 m², start at 54 mg and titrate to 160 mg; if eGFR 30-59, use 54 mg maximum; contraindicated if eGFR <30. 1
• Implement extreme dietary fat restriction to <5% of total calories immediately until triglycerides fall below 1000 mg/dL, as medications have limited effectiveness at this level. 1, 3
• Eliminate all added sugars and alcohol completely—sugar directly increases hepatic triglyceride production, and alcohol can precipitate hypertriglyceridemic pancreatitis. 1, 2, 3

Address the Primary Driver: Uncontrolled Diabetes

The high A1c indicates poor glycemic control, which is often the primary cause of severe hypertriglyceridemia and may be more effective to treat than adding additional lipid medications. 6, 1, 2

• Initiate or intensify diabetes therapy immediately, targeting HbA1c <7%, as optimizing glucose control can reduce triglycerides by 20-50% independent of lipid medications. 2, 3
• Consider insulin therapy for acute management given the severity of hypertriglyceridemia and hyperglycemia. 3
• Metformin should be part of the regimen if renal function permits, as it improves insulin sensitivity and helps lower triglycerides. 1

Urgent Diagnostic Evaluation

The constellation of severe hyponatremia (Na 125), markedly elevated protein (15.9), and elevated globulin (11) raises serious concern for a plasma cell dyscrasia or other monoclonal gammopathy that could be contributing to the metabolic derangements. 1

• Obtain serum protein electrophoresis (SPEP) with immunofixation immediately to evaluate for multiple myeloma or monoclonal gammopathy of undetermined significance. 1
• Check serum free light chains and quantitative immunoglobulins. 1
• Measure serum osmolality to determine if hyponatremia is true or pseudohyponatremia from severe hyperlipidemia or hyperproteinemia. 1
• Check TSH to rule out hypothyroidism as a secondary cause of hypertriglyceridemia. 1, 7, 4
• Assess renal function (BUN, creatinine, eGFR) as chronic kidney disease contributes to hypertriglyceridemia and affects fenofibrate dosing. 1, 5
• Measure liver function tests (AST, ALT) before initiating fenofibrate. 1

Monitoring Strategy

• Reassess fasting lipid panel in 4-8 weeks after initiating fenofibrate and optimizing glycemic control. 1, 2
• Monitor for myopathy with baseline and follow-up creatine kinase (CPK) levels, especially given the metabolic complexity. 1, 5
• Check renal function within 3 months after fenofibrate initiation and every 6 months thereafter; discontinue if eGFR falls below 30. 1
• Obtain complete blood count periodically during the first 12 months, as fibrates can rarely cause hematologic changes. 5

Treatment Goals

• Primary goal: Reduce triglycerides to <500 mg/dL urgently to eliminate acute pancreatitis risk. 1, 2, 3
• Secondary goal: Further reduce to <200 mg/dL (ideally <150 mg/dL) to reduce cardiovascular risk. 1, 3
• Target non-HDL-C <130 mg/dL once triglycerides are controlled. 1, 3
• Achieve HbA1c <7% to address the underlying metabolic dysfunction. 2

Statin Therapy: Defer Until Triglycerides Controlled

Do not start statin therapy when triglycerides are ≥500 mg/dL, as statins provide only 10-30% triglyceride reduction and are insufficient for preventing pancreatitis at this level. 1, 3

• Once triglycerides fall below 500 mg/dL with fenofibrate and glycemic optimization, reassess LDL-C and consider adding moderate-intensity statin therapy (atorvastatin 10-20 mg or rosuvastatin 5-10 mg). 1, 2
• If combining fenofibrate with a statin, use lower statin doses to minimize myopathy risk, particularly given the patient's age and metabolic complexity. 1, 3
• Fenofibrate has a better safety profile than gemfibrozil when combined with statins—never use gemfibrozil. 1, 3

Adjunctive Therapy Considerations

• Consider adding prescription omega-3 fatty acids (icosapent ethyl 2-4 g daily) as adjunctive therapy if triglycerides remain >200 mg/dL after 3 months of fenofibrate plus optimized lifestyle and glycemic control. 1, 2, 3
• Monitor for increased risk of atrial fibrillation with high-dose omega-3 therapy. 1

Critical Pitfalls to Avoid

• Do not delay fenofibrate initiation while attempting lifestyle modifications alone—pharmacologic therapy is mandatory at this triglyceride level. 1, 3
• Do not overlook the hyponatremia and hyperproteinemia—these require urgent evaluation as they may indicate a serious underlying condition affecting prognosis and treatment approach. 1
• Do not ignore the importance of glycemic control—this can be more effective than additional medications in reducing triglycerides. 6, 2
• Do not use over-the-counter fish oil supplements as substitutes for prescription omega-3 formulations—they are not equivalent. 1