How low should LDL be lowered?
Title: [Paper Review] Should LDL cholesterol be lowered to 'below 55'? Decoding the Ez-PAVE trial published in NEJM
Introduction In secondary prevention of atherosclerotic cardiovascular disease (ASCVD), how low should LDL (bad) cholesterol be lowered? In recent years, Western guidelines have begun to recommend stricter target values for patients at high risk of recurrence, moving from the conventional 'below 70 mg/dL' to 'below 55 mg/dL'. However, evidence from randomized controlled trials (RCTs) supporting this strict numerical value has actually been limited.
In this article, we will discuss the Ez-PAVE trial and explain whether this 'below 55' target setting is truly useful for preventing cardiovascular events, as well as the challenges in actual clinical practice.
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1. What is the Ez-PAVE trial? (Study Overview) The Ez-PAVE trial was a multicenter, open-label, randomized controlled trial conducted at 17 institutions in South Korea.
Participants: 3,048 patients aged 19–80 with ASCVD (those who have had a myocardial infarction, angina, stroke, etc. in the past).
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Methods: Patients were divided 1:1 into the following two groups.
Intensive treatment group: LDL target value <55 mg/dL
Standard treatment group: LDL target value <70 mg/dL
Evaluation items (primary endpoint): 3-year composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, revascularization, and hospitalization for unstable angina.
Adjustment of therapeutic drugs was left to the attending physician, but a step-wise approach was recommended, starting with high-intensity statins (rosuvastatin or atorvastatin), adding ezetimibe if necessary, and further considering PCSK9 inhibitors.
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2. Results: Does lowering it aggressively reduce events? In conclusion, the group that strictly controlled LDL to below 55 mg/dL showed a significant reduction in the risk of cardiovascular events.
With a median follow-up period of 3.0 years, the median LDL cholesterol levels during the trial were 56 mg/dL in the intensive treatment group and 66 mg/dL in the standard treatment group, showing a clear difference. The incidence rates of the primary endpoint events were as follows.
Intensive treatment group: 6.6% (100 patients)
Standard treatment group: 9.7% (147 patients)
Hazard ratio: 0.67 (P = 0.002)
Looking at subgroup analyses (age, sex, presence of diabetes, etc.), consistent results are shown across almost all groups, indicating that the "intensive treatment group" is superior.
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3. Safety: Is it okay to lower it too much? Some may have concerns that "lowering cholesterol excessively might have negative effects on the body." In particular, the onset of new-onset diabetes and effects on muscles due to high-intensity statins are frequently discussed.
However, in this study,no significant differences were observed between the two groups regarding new-onset diabetes, worsening of glycemic control, statin-associated muscle symptoms, or the incidence of cancer.
Interestingly, regarding the increase in creatinine levels (a sign of worsening renal function), the result was that it was significantly lower in the intensive treatment group (1.2%) than in the standard treatment group (2.7%) (P=0.004). While further long-term investigation is needed on how powerful LDL lowering affects renal function, it can be said that at least short- to medium-term safety has been confirmed.
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4. Real-world challenges: The difficulty of achieving goals Another important point highlighted by this study is "the difficulty of achieving a target of less than 55 mg/dL."
Even three years after the start of the study,approximately 39% of patients in the intensive treatment group had not reached the target (less than 55). In the intensive treatment group, 48.4% of patients took high-intensity statins and 66.6% used ezetimibe in combination. Even so, there were many cases that did not reach the target.
The background for this is cited as the use of "PCSK9 inhibitors," the most powerful drugs, remaining at only 2.3% due to constraints such as the insurance system (and other new drugs were not yet approved in South Korea).
In real-world data, it is said that less than 25% of ASCVD patients are able to achieve less than 55 mg/dL. The authors emphasize that in order to achieve this strict target, it is necessary touse ezetimibe in combination from the early stages of treatment and to actively utilize non-statin drugs such as PCSK9 inhibitorsrather than relying on statin monotherapy.
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Summary Through the Ez-PAVE trial, the validity of the strict target setting of "LDL less than 55 mg/dL" for patients with atherosclerotic cardiovascular disease was strongly supported as evidence from an RCT.
Going forward, the question is how to safely and reliably achieve this target value. Early multi-drug combination therapy (statin + ezetimibe, etc.) may become the standard for secondary prevention.
(Reference: Intensive LDL Cholesterol Targeting in Atherosclerotic Cardiovascular Disease. N Engl J Med 2026; 394: 1365-75.)
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