Were Low-Density Lipoprotein (LDL) levels lowered below 50 mg/dL in any studies?

From the Guidelines

Yes, there have been studies where LDL cholesterol was lowered below 50 mg/dL, with the most recent and highest quality study being the FOURIER trial, which used evolocumab (140 mg every 2 weeks or 420 mg monthly) plus statin therapy to achieve median LDL levels of 30 mg/dL 1. Several large clinical trials have achieved LDL levels below 50 mg/dL using high-intensity statin therapy combined with PCSK9 inhibitors. For example:

• The FOURIER trial used evolocumab (140 mg every 2 weeks or 420 mg monthly) plus statin therapy to achieve median LDL levels of 30 mg/dL.
• The ODYSSEY OUTCOMES trial used alirocumab (75-150 mg every 2 weeks) plus statin therapy to achieve mean LDL levels of 38 mg/dL. To achieve such low LDL levels in practice:

1. Start with high-intensity statin therapy (e.g., atorvastatin 40-80 mg daily or rosuvastatin 20-40 mg daily)
2. Add ezetimibe 10 mg daily if needed
3. Consider adding a PCSK9 inhibitor (evolocumab or alirocumab) for further LDL reduction These very low LDL levels appear to be safe and well-tolerated in studies, with no increase in adverse events compared to higher LDL levels. The rationale for achieving such low levels is based on the concept that lower LDL correlates with reduced cardiovascular risk, even at these extremely low levels. However, it's essential to note that while these studies demonstrate the feasibility of achieving very low LDL levels, current guidelines typically recommend LDL targets based on individual risk factors rather than universally aiming for levels below 50 mg/dL for all patients. Key points to consider:

• The FOURIER trial demonstrated a statistically significant reduction in the composite of cardiovascular death, myocardial infarction, ischemic stroke, coronary revascularization, and unstable angina compared to patients with LDL-C values >30 mg/dL 1.
• The ODYSSEY OUTCOMES trial showed that alirocumab reduced all-cause death [hazard ratio (HR), 0.78; 95% CI, 0.65–0.94; P = 0.01] 1.
• A post hoc spline analysis from the ODYSSEY OUTCOMES trial showed that in the alirocumab group, all-cause mortality declines with lower achieved LDL-C levels, down to an LDL-C level of 30 mg/dL (adjusted P-value for model = 0.017 for linear trend) 1.

From the FDA Drug Label

On stable background lipid-lowering therapy, the median [Q1, Q3] LDL-C at baseline was 92 80, 109 mg/dL; the mean (SD) was 98 (28) mg/dL.

The FDA drug label does not provide information on whether LDL levels were lowered below 50 mg/dL in any studies.

From the Research

LDL Levels Below 50 mg/dL

• There is evidence to suggest that LDL levels can be lowered below 50 mg/dL in some studies.
• For example, one study found that patients with achieved LDL cholesterol below 30 mg/dL had no increase in adverse events compared to patients with LDL cholesterol levels above 30 mg/dL 2.
• Another study found that the median LDL-C levels achieved in the lower LDL-C group were 62 mg/dL, which is below 70 mg/dL but not below 50 mg/dL 3.
• However, there is no direct evidence in the provided studies to suggest that LDL levels were lowered below 50 mg/dL in any of the studies.

Achievement of Low LDL Levels

• The attainment of LDL-C goal of less than 70 mg/dL was significantly associated with a lower major adverse cardiac and cerebrovascular events (MACCE) or target-vessel revascularization (TVR) rate in very high-risk patients treated with drug-eluting stents 4.
• Treatment to achieve LDL-C levels below 70 mg/dL using intensive lipid-lowering therapy can safely reduce the risk of mortality and major adverse cardiovascular events (MACE) 3.
• However, there is limited evidence to suggest that lowering LDL levels below 50 mg/dL is beneficial or safe.

Measurement of LDL Cholesterol

• Accurate assessment of LDL-C levels at very low levels is required for the current therapeutic goal of LDL-C values below 70 mg/dL in high-risk patients 5.
• Martin's method for estimating LDL-C has been shown to better correlate with β-quantification or homogeneous assays compared with the Friedewald equation, especially with values of triglycerides at least 150 mg/dl and/or LDL-C less than 70 mg/dl 5.