Cardiovascular Benefit of Lowering Low-Density Lipoprotein Cholesterol Below 40 mg/dL

Marston NA, Giugliano RP, Park JG, et al.



First published: August 27, 2021  DOI: 10.1161/CIRCULATIONAHA.121.056536


The American College of Cardiology/American Heart Association/Multisociety cholesterol guidelines recommend adding a nonstatin if the low-density lipoprotein cholesterol (LDL-C) remains ≥70 mg/dL in patients with high-risk atherosclerotic cardiovascular disease ASCVD,1 effectively creating a target of <70 mg/dL. The 2019 European Society of Cardiology/European Atherosclerosis Society Dyslipidemia Guidelines go further and recommend an LDL-C goal of <55 mg/dL for patients with very high-risk ASCVD and to consider an even lower goal of <40 mg/dL for patients with multiple cardiovascular events within 2 years despite optimal statin therapy.2 The advent of PCSK9 inhibition allows many patients to achieve even lower LDL-C levels. For example, evolocumab lowered LDL-C by 59% when added to statin therapy in the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk), reducing LDL-C from a median of 93 mg/dL to 30 mg/dL.3 Nevertheless, a key question is whether there is evidence of continued clinical benefit with lowering LDL-C below 40 mg/dL.

An analysis from FOURIER showed no significant heterogeneity in clinical benefit of evolocumab between patients with a baseline LDL-C less than versus greater than or equal to 70 mg/dL, but this analysis did not address the fraction of LDL-C lowering below subsequently published targets.4 Another analysis demonstrated a strong relationship between achieved LDL-C at 1 month and adjusted risk of cardiovascular events.5 However, this was a postrandomization association analysis, which carries the risk of confounding. Therefore, in the current analysis, we aimed to determine whether there is continued cardiovascular benefit from lowering LDL-C to <40 mg/dL using comparisons of randomized groups and analyzing in the context of the magnitude of LDL-C lowering below the most recent recommended targets.

To achieve this aim, we performed an exploratory analysis in FOURIER, a cardiovascular outcomes trial comparing evolocumab with placebo in patients with stable ASCVD on optimized statin therapy.3 Major adverse cardiovascular events were defined as cardiovascular death, myocardial infarction, or stroke. Median follow-up was 2.2 years. We used a Cox proportional hazard regression model to determine the hazard ratio for major adverse cardiovascular events for evolocumab versus placebo (normalized per 39 mg/dL [1 mmol/L] reduction in LDL-C) across the range of baseline LDL-C. When LDL-C was <40 mg/dL, ultracentrifugation was performed. Nonetheless, we also performed analogous analyses using apolipoprotein B and non–high-density lipoprotein cholesterol given they are metrics of all atherogenic lipoproteins and there are no analytic concerns. Each site’s ethics committee approved the trial protocol, and all subjects provided informed consent. Data will not be made publicly available; however, interested parties can contact the corresponding authors.

Among 27 564 patients with ASCVD enrolled in FOURIER (mean age, 63 years; 75% men), 81% had previous myocardial infarction, 19% previous ischemic stroke, and 13% peripheral artery disease. A total of 80% had hypertension, 37% had diabetes, and 28% were smokers. The median baseline LDL-C was 93 mg/dL (interquartile range, 80–109 mg/dL) with 99% on a moderate- or high-intensity statin regimen. Of subjects randomized to evolocumab, 65% achieved an LDL-C <40 mg/dL.


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3. Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, Kuder JF, Wang H, Liu T, Wasserman SM, et al.; FOURIER Steering Committee and Investigators. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017; 376:1713–1722. doi: 10.1056/NEJMoa1615664 

4. Giugliano RP, Keech A, Murphy SA, Huber K, Tokgozoglu SL, Lewis BS, Ferreira J, Pineda AL, Somaratne R, Sever PS, et al.. Clinical efficacy and safety of evolocumab in high-risk patients receiving a statin: secondary analysis of patients with low LDL cholesterol levels and in those already receiving a maximal-potency statin in a randomized clinical trial. JAMA Cardiol. 2017; 2:1385–1391. doi: 10.1001/jamacardio.2017.3944

5. Giugliano RP, Pedersen TR, Park JG, De Ferrari GM, Gaciong ZA, Ceska R, Toth K, Gouni-Berthold I, Lopez-Miranda J, Schiele F, et al.; FOURIER Investigators. Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. Lancet. 2017; 390:1962–1971. doi: 10.1016/S0140-6736(17)32290-0

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