Is the LDL (Low-Density Lipoprotein)/HDL (High-Density Lipoprotein) ratio more important than LDL or HDL levels alone in assessing cardiovascular risk?

LDL/HDL Ratio vs. Individual LDL and HDL Levels

LDL cholesterol alone remains the primary target for cardiovascular risk assessment and treatment, while the LDL/HDL ratio serves as a useful supplementary risk marker but should not replace absolute LDL targets in clinical decision-making. 1, 2

Primary Treatment Target: LDL Cholesterol

• LDL cholesterol is the established primary target because nearly all lipid-lowering trials have used LDL-C as the indicator of treatment response, and the evidence base for LDL reduction improving cardiovascular outcomes is robust and proven across multiple clinical trials. 1

• Every 1.0 mmol/L (40 mg/dL) reduction in LDL-C produces dose-dependent reductions in cardiovascular disease, as confirmed by the Cholesterol Treatment Trialists' Collaboration meta-analysis involving over 170,000 patients. 1

• European Society of Cardiology/European Atherosclerosis Society guidelines explicitly state 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. 1

Role of the LDL/HDL Ratio in Risk Assessment

• The LDL/HDL ratio (or total cholesterol/HDL ratio) provides additional risk stratification beyond LDL alone, particularly for identifying patients who may be at higher risk despite seemingly acceptable LDL levels. 1, 2, 3

• The ratio makes intuitive sense by combining an atherogenic lipoprotein variable (LDL) with a protective one (HDL), and has been well-supported by observational epidemiology. 1, 4

• In the ARIC study of 14,403 participants, individuals with LDL cholesterol below the median but discordant TC/HDL-cholesterol at or above the median had 24-29% greater risk of atherosclerotic cardiovascular disease events, demonstrating that the ratio captures additional risk information. 3

Critical Limitation: Not a Treatment Target

• 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. 1, 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." 1

• The problem with using ratios as treatment targets is that it's unclear whether lowering the ratio by decreasing LDL (strong evidence of benefit) provides the same benefit as increasing HDL (insufficient evidence to support HDL as a therapeutic target). 1, 2

HDL Cholesterol: Protective But Not a Treatment Goal

• Low HDL cholesterol (<40 mg/dL in men, <45 mg/dL in women) indicates increased cardiovascular risk and may rival high LDL as a risk factor. 2, 5

• Even among patients with very low LDL cholesterol levels (<70 mg/dL) achieved with statin therapy, those in the highest HDL quintile had significantly lower cardiovascular event rates than those in the lowest HDL quintile (P=0.03). 6

• However, there is insufficient evidence to use HDL as a therapeutic goal despite its strong inverse association with cardiovascular events. 2, 5

Practical Clinical Algorithm

For risk assessment:

1. Measure total cholesterol and HDL cholesterol (can be done non-fasting). 1
2. Calculate LDL cholesterol (requires fasting sample for accuracy). 1
3. Calculate the LDL/HDL or TC/HDL ratio for additional risk stratification. 1, 2
4. Use the ratio to identify patients who may be at higher risk despite acceptable LDL levels, particularly those with diabetes or metabolic syndrome. 3

For treatment decisions:

1. Set LDL cholesterol targets based on overall cardiovascular risk category: <70 mg/dL for very high-risk, <100 mg/dL for high-risk, <130 mg/dL for moderate-risk patients. 2
2. Use the LDL/HDL ratio to inform intensity of risk factor modification, but do not use it as a treatment target. 2
3. Focus therapeutic interventions on lowering LDL cholesterol, as this has the strongest evidence for reducing cardiovascular events. 1

Common Pitfalls to Avoid

• Do not rely on the ratio alone—even with a favorable LDL/HDL ratio, elevated absolute LDL cholesterol levels still warrant appropriate management according to risk category. 2, 5

• Do not attempt to improve the ratio by focusing on raising HDL cholesterol, as drug therapy to increase HDL without lowering LDL has not been proven to reduce cardiovascular events. 1

• Discordance between the ratio and absolute LDL levels is particularly common in patients with diabetes (48% prevalence), so pay special attention to both measures in this population. 3

• The ratio must be interpreted as part of a complete lipid profile including consideration of triglycerides, non-HDL cholesterol, and other cardiovascular risk factors such as hypertension, diabetes, smoking, and family history. 2, 5