What should the ratio of High-Density Lipoprotein (HDL) to Low-Density Lipoprotein (LDL) be?

HDL to LDL Ratio: Not a Treatment Target

The HDL/LDL ratio should be used only for cardiovascular risk assessment, not as a treatment target—LDL cholesterol remains the primary therapeutic goal with specific absolute targets based on risk category. 1, 2

Primary Treatment Target: LDL Cholesterol Alone

• LDL cholesterol is the primary target for treatment because nearly all lipid-lowering trials have used LDL-C as the indicator of treatment response, with robust evidence that LDL reduction improves cardiovascular outcomes. 1, 2

• Every 1.0 mmol/L (40 mg/dL) reduction in LDL-C produces dose-dependent reductions in cardiovascular disease, as confirmed by meta-analysis involving over 170,000 patients. 2

• The European Society of Cardiology explicitly states that "TC and LDL-C remain the primary targets recommended in these guidelines" because most risk estimation systems and virtually all drug trials are based on these traditional measures. 2

LDL Treatment Goals by Risk Category

Very High-Risk Patients:

• Target LDL-C <1.8 mmol/L (70 mg/dL), or at least 50% reduction if baseline LDL-C is between 1.8-3.5 mmol/L (70-135 mg/dL). 1
• Very high-risk includes documented CVD, diabetes with target organ damage, severe CKD, or calculated very high SCORE risk. 1

High-Risk Patients:

• Target LDL-C <2.6 mmol/L (100 mg/dL), or at least 50% reduction if baseline LDL-C is between 2.6-5.1 mmol/L (100-200 mg/dL). 1

Moderately High-Risk Patients (≥1 risk factor, 10-20% 10-year risk):

• Target LDL-C <3.4 mmol/L (130 mg/dL), with consideration of <2.6 mmol/L (100 mg/dL) as a therapeutic option based on recent trial evidence. 1

Role of HDL/LDL Ratio in Risk Assessment Only

• The LDL/HDL ratio provides additional risk stratification beyond LDL alone, particularly for identifying patients who may be at higher risk despite seemingly acceptable LDL levels. 2

• The ratio makes intuitive sense by combining an atherogenic lipoprotein (LDL) with a protective one (HDL), and has been well-supported by observational epidemiology. 2, 3

• Critical limitation: The LDL/HDL ratio should be used as a marker of increased risk rather than as an index of treatment success or a therapeutic goal. 2

• European guidelines acknowledge that ratios are "useful for risk estimation, but for diagnosis and as treatment targets the components of the ratio have to be considered separately." 2

Practical Clinical Algorithm

For Initial Risk Assessment:

1. Measure total cholesterol, HDL cholesterol, and triglycerides (fasting). 1, 2
2. Calculate LDL cholesterol using validated equations (Friedewald if TG <4.5 mmol/L, or Sampson-NIH2 equation if TG up to 9 mmol/L). 4
3. Calculate total cholesterol/HDL ratio or LDL/HDL ratio for additional risk stratification. 1, 2
4. Perform Framingham risk scoring or SCORE risk estimation to determine 10-year cardiovascular risk. 1

For Treatment Decisions:

1. Categorize patient into risk category (very high, high, moderate, or low risk). 1
2. Set absolute LDL-C target based on risk category—ignore the HDL/LDL ratio for treatment goals. 1, 2
3. Initiate statin therapy at appropriate intensity to achieve LDL-C goal. 1
4. Titrate statin to highest tolerable dose to reach target, adding ezetimibe or PCSK9 inhibitor if needed. 1

Common Pitfalls to Avoid

• Do not use the HDL/LDL ratio as a treatment endpoint—this lacks evidence from randomized controlled trials and is explicitly discouraged by European guidelines. 2

• Even with a favorable HDL/LDL ratio, elevated absolute LDL cholesterol levels still warrant aggressive management according to risk category. 2

• The ratio must be interpreted as part of a complete lipid profile and overall cardiovascular risk assessment, not in isolation. 2

• While low HDL cholesterol may rival high LDL cholesterol as a risk factor, there is insufficient evidence to use HDL as a therapeutic target. 2

Additional Considerations for High Triglycerides

• If triglycerides are ≥150 mg/dL (1.70 mmol/L) or HDL-C is <40 mg/dL (1.05 mmol/L), emphasize weight management, physical activity, and smoking cessation. 1

• If triglycerides are 200-499 mg/dL (2.26-5.64 mmol/L), target non-HDL cholesterol <130 mg/dL, with consideration of <100 mg/dL. 1

• Consider adding fibrate or niacin therapy after optimizing LDL-lowering therapy in patients with persistently elevated triglycerides and low HDL. 1