The importance of LDL-C lowering in atherosclerotic cardiovascular disease prevention: Lower for longer is better

• Published in: American journal of preventive cardiology 2024-06, Vol.18, p.100649-100649, Article 100649
• Main Authors: Mhaimeed, Omar, Burney, Zain A, Schott, Stacey L, Kohli, Payal, Marvel, Francoise A, Martin, Seth S
• Format: Article
• Language: English
• Subjects: Atherosclerotic cardiovascular disease; LDL cholesterol; Lipid lowering; Non-statin; Primary prevention; Secondary prevention; Statins; VSI: Therapies for Dyslipidemia
• ISSN: 2666-6677; 2666-6677
• DOI: 10.1016/j.ajpc.2024.100649

Cumulative exposure to low-density lipoprotein cholesterol (LDL-C) is a key driver of atherosclerotic cardiovascular disease (ASCVD) risk. An armamentarium of therapies to achieve robust and sustained reduction in LDL-C can reduce ASCVD risk. The gold standard for LDL-C assessment is ultracentrifugation but in routine clinical practice LDL-C is usually calculated and the most accurate calculation is the Martin/Hopkins equation. For primary prevention, consideration of estimated ASCVD risk frames decision making regarding use of statins and other therapies, and tools such as risk enhancing factors and coronary artery calcium enable tailoring of risk assessment and decision making. In patients with diabetes, lipid lowering therapy is recommended in most patients to reduce ASCVD risk with an opportunity to tailor therapy based on other risk factors. Patients with primary hypercholesterolemia and familial hypercholesterolemia (FH) with baseline LDL-C greater than or equal to 190 mg/dL are at elevated risk, and LDL-C lowering with high-intensity statin therapy is often combined with non-statin therapies to prevent ASCVD. Secondary prevention of ASCVD, including in patients with prior myocardial infarction or stroke, requires intensive lipid lowering therapy and lifestyle modification approaches. There is no established LDL-C level below which benefit ceases or safety concerns arise. When further LDL-C lowering is required beyond lifestyle modifications and statin therapy, additional medications include oral ezetimibe and bempedoic acid, or injectables such as PCSK9 monoclonal antibodies or siRNA therapy. A novel agent that acts independently of hepatic LDL receptors is evinacumab, which is approved for patients with homozygous FH. Other emerging agents are targeted at Lp(a) and CETP. In light of the expanding lipid treatment landscape, this manuscript reviews the importance of early, intensive, and sustained LDL-C-lowering for primary and secondary prevention of ASCVD. Lower LDL-C for Longer is Better. The illustration includes a Mendelian analysis showing that prolonged LDL-C reductions of similar magnitude provide greater ASCVD risk benefit than late reductions, and data from FOURIER-OLE demonstrating that intensive lowering of LDL-C yields optimal ASCVD risk reduction without any apparent increase in the risk of adverse events. Collectively, the data in the central illustration emphasize that LDL-C lowering for longer durations is safe and associated with be