Do statins (HMG-CoA reductase inhibitors) have a role in primary prevention of cardiovascular events in individuals with Coronary Artery Disease (CAD) who have optimal Low-Density Lipoprotein (LDL) levels, specifically less than 1.5 mmol/L, without statin therapy?

From the Guidelines

Statins are recommended for individuals with coronary artery disease (CAD) regardless of their LDL levels, due to their pleiotropic effects beyond cholesterol lowering, as stated in the 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA guideline for the management of patients with chronic coronary disease 1. When considering primary risk prevention in patients with CAD and excellent LDL levels (< 1.5 mmol/L or < 58 mg/dL) without statin use, it's essential to weigh the benefits and risks of statin therapy. The 2023 guideline emphasizes the importance of team-based, patient-centered care, considering social determinants of health and associated costs, while incorporating shared decision-making in risk assessment, testing, and treatment 1. Some key points to consider include:

• Nonpharmacologic therapies, such as healthy dietary habits and exercise, are recommended for all patients with chronic coronary disease (CCD) 1.
• Statins remain first-line therapy for lipid lowering in patients with CCD, with several adjunctive therapies available for select populations 1.
• The goal of treatment is to lower LDL-C to <1.4 mmol/L (<55 mg/dL) and to reduce it by at least 50% if the baseline LDL-C level is 1.8-3.5 mmol/L (70-135 mg/dL), as stated in the 2020 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation 1. However, the most recent and highest quality study, the 2023 AHA/ACC/ACCP/ASPC/NLA/PCNA guideline, takes precedence in guiding clinical decision-making 1. Therefore, statins should be considered for primary risk prevention in patients with CAD, even with excellent LDL levels, due to their potential benefits beyond cholesterol lowering, as recommended by the 2023 guideline 1.

From the FDA Drug Label

The JUPITER study was stopped early by the Data Safety Monitoring Board due to meeting predefined stopping rules for efficacy in rosuvastatin-treated subjects The primary end point was a composite end point consisting of the time-to-first occurrence of any of the following major CV events: CV death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina or an arterial revascularization procedure. Rosuvastatin significantly reduced the risk of major CV events (252 events in the placebo group vs. 142 events in the rosuvastatin group) with a statistically significant (p<0. 001) relative risk reduction of 44% and absolute risk reduction of 1. 2% In a post-hoc subgroup analysis of JUPITER subjects (rosuvastatin=725, placebo=680) with a hsCRP ≥2 mg/L and no other traditional risk factors (smoking, BP ≥140/90 or taking antihypertensives, low HDL-C) other than age, after adjustment for high HDL-C, there was no significant treatment benefit with rosuvastatin treatment.

The use of statins, such as rosuvastatin, in primary prevention for someone with CAD and excellent LDL levels (< 1.5) without statin treatment is not directly supported by the provided drug label information.

• The JUPITER study included patients with LDL-C levels <130 mg/dL, which is higher than the specified LDL level of < 1.5.
• There is no direct evidence to support the use of statins for primary risk prevention in patients with CAD and excellent LDL levels. 2

From the Research

Statin Use in Primary Risk Prevention for CAD with Excellent LDL Levels

• The use of statins for primary risk prevention in individuals with coronary artery disease (CAD) and excellent LDL levels (< 1.5 mmol/L) without statin therapy is a topic of interest.
• According to the study by 3, current guidelines recommend the use of statins to lower LDL-C levels for the primary prevention of CAD based on an individual's risk factor profile and baseline LDL-C level.
• However, the study by 4 proposed a new "extreme-risk" category of patients, for whom a low-density lipoprotein cholesterol (LDL-C) level < 55 mg/dL (1.4 mmol/L) is advised, which may be relevant for individuals with CAD and excellent LDL levels.

Benefits of Statin Therapy in CAD Patients with Low LDL Levels

• The study by 5 found that lower levels of low-density lipoprotein cholesterol are associated with a lower prevalence of thin-cap fibroatheroma in statin-treated patients with coronary artery disease.
• This suggests that statin therapy may still be beneficial for CAD patients with low LDL levels, as it can help reduce the risk of cardiovascular events.
• Additionally, the study by 6 found that many high-risk patients have elevated levels of triglycerides or low levels of HDL cholesterol despite treatment, highlighting the importance of combination lipid-lowering therapy.

Lipid Control in Patients with Premature CAD

• The study by 7 found that lipid control is suboptimal in patients with premature CAD, with only 23.0% and 8.9% of patients achieving non-strict and strict lipid control, respectively.
• This highlights the need for more aggressive pharmacological intervention and novel preventive programs to reduce the burden of premature CAD.
• The study by 4 also found that more than half of all patients with stable CAD are at extreme CV risk and very few (∼5%) achieve LDL-C levels < 55 mg/dL, emphasizing the importance of intensive lipid-lowering therapy in high-risk patients.