Is there evidence that the lower the LDL-C is, the better?

12th April 2026, A/Prof Chee L Khoo

When we think about ischaemic heart disease (IHD), we think about obstructive coronary artery disease. Until recently, the aim of management of patients with coronary artery disease (CAD) was to treat the obstructions which cause ischaemia which is essentially what we call unstable angina. The Lancet Commission on rethinking coronary artery disease (CAD) (2025) reminded us that CAD (or should be called atherosclerotic CAD (ACAD)) starts years or decades prior to any symptoms of ischaemia (1). We should be intervening or treating at the start of the disease and not when it is obstructive. We should be treating CAD and not IHD.

The efficacy of treatment should not depend on when it is treated but how aggressive the treatment of the CV risk factors is depending on the overall CV risk. The more CV risk factors someone has, the higher risk of CV events there is. Patients who have had previous events are obviously that group that we need to target aggressively in the secondary prevention effort. But there are many other patients who have not have events but are at equally high risk of future CV events. These are patients with known ACAD.

We have seen many trials demonstrating the effect of intensive lipid lowering on reducing plaque size or plaque progression (2). Some studies compared one lipid lowering agent with another and their differential effects on plaque progression. Based on many of these studies, the LDL-C targets for secondary prevention have been revised in Europe (3) and the US  (4) in 2021/2022 and in Australia in 2025 (5).

There really haven’t been any trials looking at the effects of differing LDL-C targets on cardiovascular event. Until now. The Ez-PAVE trial (Effects of Ezetimibe Combination Therapy for Patients with Atherosclerotic Cardiovascular Disease — Randomized Comparison of LDL Cholesterol Targeting <70mg/dl vs <55mg/dl was designed to investigate whether targeting an LDL cholesterol level of < 1.4mmol/L is superior to targeting a level of <1.8mmol/L for preventing recurrent major cardiovascular events in patients with atherosclerotic cardiovascular disease (6).

This trial recruited participants between January 2021 and July 2022 whence the target LDL-C for secondary prevention was < 1.8mmol/L. 3048 patients underwent randomisation at 17 sites in South Korea – 1526 were assigned to the intensive targeting group and 1522 to the conventional targeting group.

Participants were randomised to either the intensive group where the target LDL-C was < 1.4 mmol/L (intensive-targeting group) or the conventional group where the target LDL-C was < 1.8mmol/L (conventional-targeting group). Lipid lowering agents used were statins (rosuvastatin or atorvastatin), ezetimibe and PCSK9 inhibitors. Once the participants were randomised to their specific groups, it was up to the digression of the investigating physician to use whatever agents they see fit to achieve those LDL-C targets. Follow-up assessments were performed at base line, at 1 month, and at 1, 2, and 3 years after randomisation. The primary objective of the trial was to evaluate the hypothesis that intensive targeting of LDL cholesterol levels would be superior to conventional targeting with respect to the primary end point.

At baseline, 1694 (55.6%) had previous acute coronary syndrome, 1474 (48.4%) had stable angina with imaging or functional studies, 2049 (67.2%) had had coronary revascularisation or other arterial revascularization, 117 (3.8%) had had a stroke or transient ischemic attack, and 266 (8.7%) had peripheral artery disease. See Table 1 below.

Table 1. Baseline characteristics
Prev ACS55.60%
Stsble angina48.40%
Prev revascularisation67.20%
Prev CV/TIA3.80%
Periphera artery disease8.70%

The mean (±SD) age of the patients was 64.4±9.0 years, 638 patients (20.9%) were women. The median LDL cholesterol level was 1.96 mmol/L.

The median follow up period was 3.0 years. The median LDL-C level during the trial was 1.4 mmol/L (range, 1.2 to 1.7) in the intensive-targeting group and 1.7 mmol/L (range 1.5 to 2.0) in the conventional-targeting group.

Obviously, not everyone reached their target LDL-C. In the intensive-targeting group, at 1, 2, and 3 years, the percentages of patients reaching their target LDL-F were 42.9%, 53.3%, and 60.8%, respectively while in the conventional-targeting group they were 67.2%, 67.7%, and 68.1% respectively.

The primary end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, any revascularization, or hospitalization for unstable angina at 3 years after randomisation. Secondary end points included efficacy and safety measures.

A primary end-point event occurred in 100 patients (6.6%) in the intensive-targeting group and in 147 patients (9.7%) in the conventional-targeting group which translate to a hazard ratio of 0.67 (p=0.002). Most of the benefit came from reduction in revascularisation rate (hazard ratio 0.63) and reduction in non-fatal myocardial infarction (hazard ratio 0.46). The other endpoints did not differ significantly. In particular, there were no difference in CV and all cause death between the groups.

As impressive as the results are, it goes against previous clinical trial results though. The Cholesterol Treatment Trialists’ Collaboration meta-analysis of more than 170,000 patients tells us to expect an approximate 22% relative risk reduction per 1 mmol/L drop in LDL-C. A difference of 0.4 mmol/L between the groups should yield 5%-6% relative reduction at best — not 33% difference between the groups (7).

A further criticism of the trial was that the duration was only 3 years. It wasn’t a blinded trial either. The investigators were aware of which target group the participants were in and perhaps, it might be a confounding factor. Further, these were primarily Asian participants and perhaps, their sensitivity to statins might be different. Perhaps, there are other pleiotrophic effects of the lipid lowering agents such as anti-inflammatory effects or plaque regression. As the trials were conducted in 2021/2022, the availability of PCSK9 inhibitors were limited and were only in use in up to 2.3% of patients in the intensive-targeting group by year 3.

Nonetheless, the Ez-PAVE trial reminds of the importance of getting the LDL-C to guideline mandated targets.

References:

  1. Zaman S, Wasfy J, Kapil V et al. The Lancet Commission on rethinking coronary artery disease: moving from ischaemia to atheroma The Lancet, 2025; 405, 1264-1312
  2. Di Giovanni G, Nicholls SJ. Intensive lipid lowering agents and coronary atherosclerosis: Insights from intravascular imaging. Am J Prev Cardiol. 2022 Jul 1;11:100366.
  3. Byrne RA, Rossello X, Coughlan JJ, et al. ESC Scientific Document Group. 2023 ESC Guidelines for the management of acute coronary syndromes. Eur Heart J. 2023 Oct 12;44(38):3720-3826. doi: 10.1093/eurheartj/ehad191. Erratum in: Eur Heart J. 2024 Apr 1;45(13):1145.
  4. Heidenreich PA, Bozkurt B, Aguilar D, et al. ACC/AHA Joint Committee Members. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022 May 3;145(18):e895-e1032.
  5. https://www.heartfoundation.org.au/for-professionals/acs-guideline. Accessed 11th April 2026.
  6. Cholesterol Treatment Trialists’ (CTT) Collaboration Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials. The Lancet, 2010; 376, 1670-1681