LDL Cholesterol is the Most Important Component to Control
Low-density lipoprotein cholesterol (LDL-C) is unequivocally the primary and most important target of lipid management for reducing cardiovascular morbidity and mortality. All major guidelines consistently identify LDL-C as the principal therapeutic target based on extensive randomized controlled trial evidence demonstrating that LDL-C lowering substantially reduces major coronary events, myocardial infarction, stroke, and cardiovascular death 1, 2.
Why LDL-C is the Primary Target
LDL-C has the strongest evidence base from prospective studies showing high serum LDL-C is a major risk factor for coronary heart disease, and from numerous randomized controlled trials documenting that lowering LDL-C reduces risk for major coronary events 1.
Every 40 mg/dL (1.0 mmol/L) reduction in LDL-C produces a 20-25% reduction in cardiovascular mortality and non-fatal myocardial infarction, establishing a clear dose-response relationship 2.
The 2013 ACC/AHA guidelines explicitly state that statin therapy should be used to achieve LDL-C reduction as the primary mechanism for reducing atherosclerotic cardiovascular disease risk 1.
The PROVE-IT trial demonstrated that achieving a median LDL-C of 62 mg/dL with high-intensity statin therapy resulted in a 16% reduction in major cardiovascular events compared to achieving 95 mg/dL, proving that lower LDL-C levels translate directly to better outcomes 1, 2.
Specific LDL-C Treatment Targets
The target LDL-C level depends on cardiovascular risk stratification:
Very high-risk patients (established coronary disease, acute coronary syndrome, recurrent events): LDL-C <55 mg/dL (<1.4 mmol/L) with at least 50% reduction from baseline 2, 3.
High-risk patients (10-year risk ≥20%, diabetes, or multiple risk factors): LDL-C <100 mg/dL 1.
Moderately high-risk patients (≥2 risk factors, 10-year risk 10-20%): LDL-C <130 mg/dL, though <100 mg/dL is a therapeutic option 1.
Lower-risk patients (0-1 risk factors): LDL-C <160 mg/dL 1.
Secondary Targets: Non-HDL-C
While LDL-C is primary, non-HDL-C serves as the key secondary target, particularly when triglycerides are elevated ≥200 mg/dL 1, 3.
Non-HDL-C captures all atherogenic lipoproteins (VLDL, IDL, LDL, and remnant particles) that contribute to residual cardiovascular risk even after LDL-C optimization 3.
The non-HDL-C goal is set 30 mg/dL higher than the corresponding LDL-C goal 1, 3. For example, if the LDL-C goal is <100 mg/dL, the non-HDL-C goal is <130 mg/dL.
For very high-risk patients, the European Society of Cardiology recommends a non-HDL-C goal of <100 mg/dL 3.
Apolipoprotein B (Apo B) is an equally valid alternative secondary target, with thresholds of <80 mg/dL for very high-risk patients and <100 mg/dL for high-risk patients 1, 3.
HDL-C and Triglycerides: Not Primary Targets
HDL-C and triglycerides are not primary treatment targets because current evidence does not support setting specific goal values for HDL-C raising, and the direct link between triglyceride lowering and cardiovascular event reduction is less well-defined 1.
Optimal HDL-C levels (>40 mg/dL in men, >50 mg/dL in women) and triglycerides <150 mg/dL are considered markers of residual risk rather than primary therapeutic targets 3.
When high-risk patients have elevated triglycerides or low HDL-C, consideration can be given to combining a fibrate or nicotinic acid with LDL-lowering therapy, but only after LDL-C goals are addressed 1.
Treatment Algorithm to Achieve LDL-C Goals
Initiate high-intensity statin therapy (atorvastatin 40-80 mg or rosuvastatin 20-40 mg) to achieve ≥50% LDL-C reduction 1, 2.
If LDL-C target not achieved, add ezetimibe to statin therapy for an additional 18-25% LDL-C reduction 2, 3.
If LDL-C still >55 mg/dL in very high-risk patients, add a PCSK9 inhibitor (evolocumab, alirocumab, or inclisiran) to the statin-ezetimibe combination 2, 3.
For patients with very high baseline LDL-C, consider starting immediately with statin plus ezetimibe combination 2.
Common Pitfalls to Avoid
Do not use the Friedewald equation to calculate LDL-C in patients with levels <70 mg/dL or elevated triglycerides, as it significantly underestimates LDL-C; the Martin/Hopkins method provides more accurate calculation 2.
Do not stop at the traditional LDL-C <100 mg/dL goal for very high-risk patients—current evidence supports much lower targets of <55 mg/dL 2.
Do not prioritize HDL-C raising or triglyceride lowering before achieving LDL-C goals, as the evidence for cardiovascular benefit is strongest for LDL-C reduction 1.
Do not assume there is a lower safety threshold for LDL-C—clinical trials have shown continuous cardiovascular benefit with no lower threshold, and patients achieving LDL-C <25 mg/dL demonstrate ongoing risk reduction without safety concerns 2.