Lower LDL, Lower Risk: Early Cholesterol Reduction & Heart Health
Early, Aggressive LDL Cholesterol Lowering Key to Heart Health
Updated June 01, 2025
miami, Fla. — early and sustained reduction of low-density lipoprotein cholesterol (LDL-C) is critical in preventing atherosclerotic cardiovascular disease (ASCVD). That’s according to Kausik K. Ray, MD, speaking at the 2025 National Lipid Association (NLA) Scientific Sessions.
Ray, a professor at imperial College London, emphasized that initiating LDL-C lowering therapies early and ensuring long-term adherence leads to a greater reduction in major adverse cardiovascular events (MACE). The benefits are seen regardless of the specific lipid-lowering agent used.
while high cholesterol is often the diagnostic focus, Ray noted that the underlying issue is cholesterol retention in the arterial wall. Since LDL particles comprise about 90% of circulating apolipoprotein B (apoB)-containing particles, LDL-C remains the primary target for ASCVD prevention. Even slightly elevated LDL-C can speed up plaque formation, especially in those with diabetes, hypertension, or arterial damage from smoking.
Various strategies, including statins, ezetimibe, bempedoic acid, PCSK9 inhibitors, and siRNA agents, enhance LDL receptor activity, increasing LDL clearance. Statins and bempedoic acid reduce cholesterol synthesis in the liver, while ezetimibe and dietary changes reduce cholesterol absorption in the intestine. PCSK9 inhibitors and siRNA therapies prolong LDL receptor lifespan, allowing for sustained LDL-C clearance.
Ray highlighted the consistent benefits across different lipid-lowering therapies. Trials like ODYSSEY Outcomes and FOURIER have shown that each 1 mmol/L (38.7 mg/dL) reduction in LDL-C corresponds to a relative risk reduction in MACE. The CLEAR Outcomes trial further supported these findings, demonstrating that LDL-C reductions achieved through ATP-citrate lyase inhibition resulted in similar risk reductions to those seen in statin and PCSK9 inhibitor studies.
Data from simulation models and registry studies underscore the importance of treatment timing. Analyses from the SWEDEHEART registry indicate that initiating high-intensity statins and combination therapy within 12 weeks of an acute myocardial infarction significantly reduces MACE compared to delayed intensification. Delaying LDL-C target achievement can result in persistent excess risk, even with later intensification of therapy.
“About a month ago,we published this data from SWEDEHEART essentially trying to simulate a trial where you give statins and ezetimibe early after myocardial infarction within 12 weeks,or you give them the medication on combination therapy between 12 weeks,16 months,or never,” Ray said during the NLA presentation. “You can never ethically do a trial where you delay an intervention that you’ve already got data for.So,this is the closest we’re ever going to get to trial evidence,if you will.”
Ray explained that these findings have significant public health implications for optimizing LDL-C management. Modeling data suggest that global early combination therapy could prevent thousands of MACE events annually. These findings reinforce the need for system-level changes in care pathways and interventions focused on implementing guideline-directed therapy effectively.
“If you change your care pathway, and rather of a stepwise approach, you just [adopt a] standard of care [in which you] give people a high intensity statin and ezetimibe, for a population of 35,000, there will be 477 fewer events,” Ray said. “But for a country like the US,where there’s probably a quarter of a million myocardial infarctions per year,the number of events you’re going to get over 3 years is 17,934 events,meaning in 3 years,that policy change alone is going to prevent about 3000 MACE events.”
What’s next
future research should focus on implementing strategies for early and aggressive LDL-C lowering in routine clinical practise to improve patient outcomes and reduce the burden of ASCVD.