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Atherosclerosis begins early and progresses silently. Patients requiring secondary prevention have already accumulated decades of low-density lipoprotein cholesterol (LDL-C) exposure resulting in some potentially irreversible arterial aging and injury. LDL-C should be conceived of as a marker of cumulative risk rather than a single assessment at a point in time. As Shapiro and Bhatt described, cumulative exposure to LDL-C functions much like pack-years for smoking, predicting not only the likelihood but also the timing and severity of atherosclerotic cardiovascular disease (ASCVD).¹ For true primary prevention of ASCVD, when it comes to LDL-C levels, lower is better for longer.

Decades of genetic, epidemiologic, and clinical evidence summarized in recent meta-analyses and guidelines demonstrate a linear, causal, and cumulative relationship between lifelong elevated LDL-C levels and ASCVD risk.^1,2 Recent data reveal that timing of elevated LDL-C exposure matters as much as the degree of elevation. Domanski et al. demonstrated that both total cumulative LDL-C exposure and the time-weighted mean LDL-C levels were independently predictive of future cardiovascular (CV) events.³ Specifically, exposure prior to 50 years of age may increase risk of CV events more than exposure later in life—a concept consistent with the life-course framework, which emphasizes the ways timing of exposure shapes long-term disease trajectories.⁴ Specifically, lowering LDL-C levels in young adults has a more potent effect in reducing ASCVD incidence than does starting later.

These findings complement recent findings from Wilkins et al. that a single LDL-C or non–high-density lipoprotein cholesterol (HDL-C) measurement obtained between 18 and 30 years of age predicts an individual’s cumulative exposure through 40 years of age with excellent precision.⁵ Participants in the top quartile of early-life non–HDL-C levels >135 mg/dL had a 4.5-fold greater risk of ASCVD after 40 years of age than did those in the lowest quartile. Thus, a single lipid panel in young adulthood can predict decades of risk. For many adults who are open to preventive statin therapy, the questions should be how early and how intensively to start. The 2025 Focused Update of the 2019 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) Guidelines for the Management of Dyslipidaemias reinforces a proactive approach that calls for consideration of earlier, more aggressive LDL-C lowering in primary prevention rather than waiting for the disease to manifest.²

If cumulative exposure to atherogenic lipoproteins drives ASCVD, it would make sense that earlier LDL-C reduction would yield greater benefit than waiting until moderate atherosclerosis is present. Every 1 mmol/L LDL-C reduction yields approximately 20-25% relative major adverse CV events reduction over 5 years, with absolute risk reduction dependent on baseline risk.² Long-term follow-up of the WOSCOPS (The West of Scotland Coronary Prevention Study) participants demonstrated a persistent legacy benefit of early statin therapy and lower coronary and CV mortality up to 20 years later despite similar LDL-C levels in follow-up.^6,7 A similar legacy effect was observed in the FOURIER-OLE (FOURIER Open-Label Extension) study, an open label extension of the FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) trial. These findings highlight that earlier LDL-C control forestalls atheroma formation and reduce risk of recurrent events, and, thereby, highlight how preventive pharmacotherapy supports healthy vascular aging.

Traditionally, lipid management followed a sequential, stepwise approach. Most patients would start a statin, LDL-C levels would be rechecked months later, and, if targets were unmet despite concomitant efforts at lifestyle improvement, ezetimibe or, more rarely, a proprotein convertase subtilisin/kexin type 9 inhibitor was considered. In contrast, both the 2025 ESC/EAS focused update on dyslipidemia and the 2022 American College of Cardiology (ACC) Expert Consensus Decision Pathway on the Role of Nonstatin Therapies for LDL-C Lowering in the Management of ASCVD Risk now recommend consideration of more rapid, intensive lipid-lowering strategies from the start, especially for patients with CV risk–enhancing factors such as elevated lipoprotein(a) levels, elevated high-sensitivity C-reactive protein levels, and health-related social needs.^2,8 Implementation of such guidelines may help overcome the low use of combination lipid-lowering therapy in both Europe and the United States (US).

Under the European model, treatment initiation should be considered when LDL-C levels exceed 100 mg/dL in individuals at moderate risk and 70 mg/dL in those at high risk, with targets of <70 mg/dL for those at moderate risk and <55 mg/dL for those at high risk.² The 2025 ESC/EAS focused update on dyslipidemia elevates bempedoic acid to a class I recommendation on the basis of the CLEAR Outcomes (Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen) trial results and recognizes inclisiran as an alternative.²

Similarly, the 2022 ACC expert consensus decision pathway on LDL-C lowering recommends reassessment within 6 weeks and immediate addition of nonstatin lipid-lowering therapy if LDL-C targets are unmet (<70 mg/dL for individuals at high risk, <55 mg/dL for those at very high risk).⁸ This guidance encourages clinicians to anticipate the need for combination therapy from initiation in patients at high risk.

Beyond clinical benefit, earlier LDL-C lowering is economically optimal. Cost-effectiveness analyses support earlier initiation of lipid-lowering therapy: Statins are cost-effective in adults <40 years of age with LDL-C levels ≥130-160 mg/dL, and starting 10 years earlier likely prevents more events than intensifying therapy later.⁹ In an accompanying editorial, Heidenreich et al. urged the US societies to relax the 40-years-old age threshold and to adopt lifetime risk-guided pharmacologic LDL-C lowering to align with the European prevention principles.¹⁰ Early testing enables earlier treatment rather than delayed reaction. Even modest LDL-C reduction begun early yields exponential economic benefit, which may be thought of as a legacy effect.

Atherogenesis is a cumulative vascular aging process. Every decade of elevated LDL-C levels compounds lifetime risk, whereas each year of earlier LDL-C lowering confers protection. The 2025 ESC/EAS focused update on dyslipidemia emphasizes early prevention by lowering initiation thresholds to 100 mg/dL in groups at moderate risk and to 70 mg/dL those at high risk. By reframing lipid management as lifelong exposure reduction to promote healthy vascular aging rather than reactive correction, clinicians can shift from managing disease to effectively preventing it.

References

1. Shapiro MD, Bhatt DL. “Cholesterol-years” for ASCVD risk prediction and treatment. J Am Coll Cardiol. 2020;76(13):1517-1520. doi:10.1016/j.jacc.2020.08.004
2. Mach F, Koskinas KC, Roeters van Lennep JE, et al. 2025 focused update of the 2019 ESC/EAS guidelines for the management of dyslipidaemias. Eur Heart J. 2025;46(42):4359-4378. doi:10.1093/eurheartj/ehaf190
3. Domanski MJ, Tian X, Wu CO, et al. Time course of LDL cholesterol exposure and cardiovascular disease event risk. J Am Coll Cardiol. 2020;76(13):1507-1516. doi:10.1016/j.jacc.2020.07.059
4. Zheutlin AR, Handoo F, Luebbe S, et al. Cumulative exposure to atherogenic lipoprotein particles in young adults and subsequent incident atherosclerotic cardiovascular disease. Eur Heart J. 2025;46(41):4302-4312. doi:10.1093/eurheartj/ehaf472
5. Wilkins JT, Ning H, Allen NB, et al. Prediction of cumulative exposure to atherogenic lipids during early adulthood. J Am Coll Cardiol. 2024;84(11):961-973. doi:10.1016/j.jacc.2024.05.070
6. Mhaimeed O, Burney ZA, Schott SL, Kohli P, Marvel FA, Martin SS. The importance of LDL-C lowering in atherosclerotic cardiovascular disease prevention: lower for longer is better. Am J Prev Cardiol. 2024;18:100649. Published 2024 Mar 18. doi:10.1016/j.ajpc.2024.100649
7. Ford I, Murray H, McCowan C, Packard CJ. Long-term safety and efficacy of lowering low-density lipoprotein cholesterol with statin therapy: 20-year follow-up of West of Scotland coronary prevention study. Circulation. 2016;133(11):1073-1080. doi:10.1161/CIRCULATIONAHA.115.019014
8. Writing Committee, Lloyd-Jones DM, Morris PB, et al. 2022 ACC expert consensus decision pathway on the role of nonstatin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2022;80(14):1366-1418. doi:10.1016/j.jacc.2022.07.006
9. Kohli-Lynch CN, Bellows BK, Zhang Y, et al. Cost-effectiveness of lipid-lowering treatments in young adults. J Am Coll Cardiol. 2021;78(20):1954-1964. doi:10.1016/j.jacc.2021.08.065
10. Heidenreich PA, Clarke SL, Maron DJ. Time to relax the 40-year age threshold for pharmacologic cholesterol lowering. J Am Coll Cardiol. 2021;78(20):1965-1967. doi:10.1016/j.jacc.2021.08.072