Is there a lower limit for low-density lipoprotein (LDL) levels in secondary prevention?

From the Guidelines

There is no established lower limit for LDL cholesterol levels in secondary prevention, and current guidelines recommend intensive LDL lowering for patients with established cardiovascular disease, with a general target of LDL below 55 mg/dL for very high-risk patients, as recommended by the 2025 guidelines 1.

Key Considerations

• The 2025 guidelines recommend using lifestyle and high-intensity statin therapy to reduce LDL cholesterol by ≥50% from baseline to a goal of <55 mg/dL, and adding ezetimibe or a PCSK9-directed therapy if LDL cholesterol goals are not met on maximum tolerated statin therapy 1.
• High-intensity statins like atorvastatin 40-80 mg or rosuvastatin 20-40 mg daily are typically first-line therapy, and if targets aren't achieved with statins alone, ezetimibe 10 mg daily can be added, followed by PCSK9 inhibitors (evolocumab 140 mg every 2 weeks or alirocumab 75-150 mg every 2 weeks) if needed.
• Clinical trials have shown cardiovascular benefits with LDL levels as low as 20-30 mg/dL without significant safety concerns, as noted in the 2021 study 1.
• The body can synthesize cholesterol when dietary intake is low, so very low LDL levels from medication don't typically cause adverse effects.
• Individual patient factors, including side effect profiles, cost considerations, and comorbidities, should guide treatment decisions, with regular monitoring of liver function and muscle symptoms recommended during intensive lipid-lowering therapy.

Treatment Approach

• The 2024 International Lipid Expert Panel (ILEP) recommendations suggest using upfront lipid-lowering combination therapy, including double or even triple therapy in the case of extremely high-CVD-risk patients, to improve access and adherence to LLT 1.
• The use of bempedoic acid and monoclonal antibody/small interference RNA (siRNA) targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) can provide an additional opportunity to significantly reduce LDL-C levels and consequently reduce the risk of ASCVD.
• It is essential to emphasize that most of the disease burden is modifiable, particularly by effective lipid-lowering therapy (LLT), and that guideline-directed LLT should be prescribed to all ASCVD/ACS patients to ensure those individuals at greatest risk of recurrent events can access the most efficacious LLT without delay.

From the FDA Drug Label

The FDA drug label does not answer the question.

From the Research

LDL Levels in Secondary Prevention

The question of whether there is a lower limit for low-density lipoprotein (LDL) levels in secondary prevention is addressed in several studies.

• The general consensus is that lowering LDL cholesterol levels leads to a progressively lower risk of cardiovascular disease (CVD) events 2.
• Studies have shown that achieving extremely low LDL-C levels through the combination of PCSK9 inhibitors and statins results in additional reduction of CVD events in secondary prevention 2, 3, 4.
• However, there is ongoing discussion on whether very low LDL-C might result in some non-CVD adverse events, although serious adverse events associated with achieving very low LDL-C levels have not been noted 2.
• Current guidelines, such as the ESC/EAS Guidelines (2019) for dyslipidaemia management, recommend LDL-C lowering to levels achieved in trials of PCSK9 inhibitors 2, 4, 5.
• The European guidelines set a goal of <1.4 mmol/L (<55 mg/dL) in patients with very high-risk cardiovascular disease 5.

Safety and Efficacy of LDL Lowering

• The safety and efficacy of aggressive LDL-C lowering have been evaluated in several studies, including those on PCSK9 inhibitors and ezetimibe 3, 4, 6.
• These studies have shown that LDL-C lowering with these agents can reduce cardiovascular events and all-cause mortality in patients with clinical ASCVD 3, 4.
• However, the cost-effectiveness of PCSK9 inhibitor therapy is limited to secondary prevention in high-risk patients 4.
• The use of PCSK9 inhibitors and other lipid-lowering agents should be guided by current guidelines and individual patient risk factors 5.