What is the significance and management of a high triglyceride (TG) to high-density lipoprotein (HDL) ratio?

Triglyceride to HDL Ratio: Clinical Significance and Management

Clinical Significance as a Risk Marker

The triglyceride to HDL cholesterol (TG/HDL-C) ratio serves as a simple, clinically useful marker of insulin resistance and cardiovascular risk, with elevated ratios (>3.5 in men, >2.5 in women) identifying individuals at increased cardiometabolic risk who warrant aggressive intervention. 1, 2

Risk Prediction and Thresholds

• The TG/HDL-C ratio correlates strongly with insulin resistance, with approximately one-third of individuals exceeding threshold values demonstrating insulin resistance by HOMA index 2
• Elevated ratios are associated with increased odds ratios for metabolic complications: 9.3 for overweight, 27.5 for obesity, and 4.41 for abdominal obesity 1
• In diabetic patients with coronary artery disease on statin therapy, higher TG/HDL-C ratios predict both all-cause mortality and cardiovascular death, with significant improvements in risk stratification (C-statistic improvement from 0.799 to 0.812 for all-cause mortality) 3

Mechanistic Associations

• The ratio integrates information about triglyceride-rich lipoproteins, remnant cholesterol, and small dense LDL particles—all atherogenic lipid components 4
• It correlates with glycemic control, particularly in obese patients with type 2 diabetes, making it a dual marker of metabolic dysfunction 4
• Conversely, low TG-high HDL-C levels (TG ≤97 mg/dL and HDL-C ≥57 mg/dL) confer protection, with 35% of ischemic heart disease potentially preventable if all individuals achieved these favorable levels 5

Management Approach Based on Ratio Findings

Step 1: Identify Secondary Causes

• Screen for hypothyroidism, poorly controlled diabetes (check HbA1c), and chronic kidney disease as these conditions elevate triglycerides 6, 7
• Review medications that raise triglycerides: thiazide diuretics, beta-blockers (except carvedilol), oral estrogens, atypical antipsychotics, steroids, and bile acid resins 6
• Assess alcohol intake and mandate complete abstinence if excessive, as alcohol significantly elevates triglycerides especially with high saturated fat intake 6, 7

Step 2: Implement Aggressive Lifestyle Modifications

• Restrict total dietary fat to 20-25% of total calories and eliminate added sugars and refined carbohydrates 7
• Target 5-10% body weight reduction in overweight/obese individuals, which can reduce triglycerides by approximately 20% 8
• Prescribe at least 150 minutes weekly of moderate-intensity aerobic activity 7, 8
• Limit saturated fat intake and eliminate trans fats while increasing omega-3 fatty acids from marine sources 7

Step 3: Risk Stratification for Pharmacotherapy

For moderate hypertriglyceridemia (150-499 mg/dL) with low HDL-C:

• Initiate fenofibrate 54-160 mg daily as first-line therapy, which reduces triglycerides by 30-50% and increases HDL cholesterol 8, 9, 10
• Consider adding moderate-intensity statin therapy if LDL-C remains elevated, but monitor carefully for myopathy with combination therapy 8, 9
• The 2021 ACC Expert Consensus recommends using elevated triglycerides as a risk-enhancing factor in primary prevention to guide statin initiation 6

For severe hypertriglyceridemia (≥500 mg/dL):

• Initiate fenofibrate immediately at 54-160 mg daily to prevent acute pancreatitis, which becomes a significant risk above 500 mg/dL and especially above 1,000 mg/dL 7, 10
• Do not delay pharmacotherapy while attempting lifestyle modifications alone at these levels 7
• After 4-8 weeks, add prescription omega-3 fatty acids (icosapent ethyl) if triglycerides remain elevated despite fibrate therapy 7
• In patients with established ASCVD or diabetes plus additional risk factors and persistent elevation (median TG ~216 mg/dL), icosapent ethyl added to statin therapy significantly reduces cardiovascular events and mortality 6

Step 4: Treatment Goals and Monitoring

• Target triglycerides <150 mg/dL (ideally <100 mg/dL for optimal metabolic health) 7, 8, 9
• Target HDL-C >40 mg/dL in men and >50 mg/dL in women 9
• Recheck fasting lipid panel in 4-8 weeks after initiating therapy 7, 8
• Monitor liver function tests and creatine kinase at baseline and during treatment with fibrates or combination therapy 7, 8
• Once goals achieved, monitor every 6-12 months 9

Critical Clinical Pitfalls

• Do not use bile acid resins when triglycerides exceed 200 mg/dL, as they paradoxically increase triglyceride levels 8
• Avoid gemfibrozil with statins due to increased myopathy risk; fenofibrate is the preferred fibrate for combination therapy 7
• Do not substitute over-the-counter fish oil for prescription omega-3 fatty acids, as dosing and purity differ substantially 7
• Do not ignore glycemic control in diabetic patients, as optimizing glucose control can dramatically reduce triglycerides and may obviate need for additional pharmacotherapy 7, 9
• While the 2018 AHA/ACC cholesterol guideline emphasizes LDL-C as the primary target, non-HDL-C provides better risk estimation in patients with elevated triglycerides, diabetes, or metabolic syndrome 6
• The TG/HDL-C ratio identifies more at-risk individuals than metabolic syndrome criteria alone, though metabolic syndrome identifies those with more accentuated risk profiles 2