'LDL Hypothesis' More Than Just 'Hypothesis' in EAS Document

Patrice Wendling

April 25, 2017

PRAGUE, CZECH REPUBLIC — With an eye toward dispelling cholesterol skeptics, a new consensus statement from the European Atherosclerosis Society (EAS) reports that LDL cholesterol causes atherosclerotic cardiovascular disease[1].

Prof M John Chapman

"There is a dose-dependent, log-linear association between absolute LDL cholesterol and cardiovascular risk, and this association is independent of other cardiovascular risk factors and is consistent across the multiple lines of evidence," EAS consensus panel cochair Prof M John Chapman (Pitié-Salpétrière University Hospital, Paris, France) said during a late-breaking session at the European Atherosclerosis Society 2017 Annual Congress.

The consensus document, simultaneously published in the European Heart Journal, is based on more than 200 prospective epidemiologic, genetic, and Mendelian randomization studies and randomized clinical trials involving more than 2 million participants and more than 20 million person-years of follow-up.

While LDL cholesterol has long been implicated as a major modifiable CV risk factor, Chapman said an evaluation of the totality of evidence was needed because some have questioned whether LDL cholesterol is simply a biomarker.

"You might say 'why do we need a consensus panel on this topic? Do we not know enough already about HDL and LDL cholesterol?' Well, the answer is no, we don't. And even the regulatory bodies across the world are continuing to refer to LDL as a surrogate marker or as a biomarker of cardiovascular risk," he said.

Panel member Dr Christopher Packard told heartwire from Medscape the expert document is needed because there seems to be a "drifting away from the science base in writing guidelines and also in the lay and popular press."

He added, "There seems to be a disconnect between what we understood as the role of LDL cholesterol as the driver of the atherosclerotic process and what other people are perceiving; that cholesterol was not really part of the problem, it was the artery wall that was driving it all."

By gathering the evidence in one place, Packard said he hopes it will be used in discussions with payers, the media, and other expert bodies to ensure everyone is on the same page with regard to the role of LDL cholesterol.

Also, unique to the EAS consensus panel document are tables that indicate the potential clinical benefit derived from lowering plasma LDL-cholesterol levels based on the person's baseline CV risk, LDL cholesterol, and duration of lipid-lowering therapy.

One of the key implications of the paper is that lowering LDL cholesterol in those at high CV risk earlier rather than later is advisable, especially in those with familial hypercholesterolemia, Chapman said.

He noted that elevated LDL is very frequently the only risk factor accounting for accelerated atherosclerotic cardiovascular disease in FH individuals. Notably, researchers have identified a cumulative LDL-C burden threshold for coronary disease and death and that, for example, a child with homozygous FH and a plasma LDC >10 mmol/L (>400 mg/dL) will reach that threshold between the ages of 10 to 15 years, compared with age 35 years for those with heterozygous FH and lower LDL levels and typically the sixth decade for those without FH.

"It has been remarkable to witness the benefit of LDL-lowering therapy, which has allowed these patients with familial hypercholesterolemia, the commonest inherited disease worldwide, to lead longer, healthier lives," panel member Prof Frederick Raal (University of Witwatersrand, Johannesburg, South Africa) said in a statement.

The panel also reported that evidence accrued from more than 30 randomized trials, largely in statins, has consistently shown that reducing LDL cholesterol reduces the risk of CV events and that this benefit is proportional to the absolute reduction in LDL cholesterol.

They also note that all therapies that act predominantly to lower LDL, including ezetimibe (Zetia, Merck) and the newer proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors, act via the LDL-receptor pathway to upregulate LCL receptors and thus increase LDL clearance.

Commenting to heartwire , panel member Dr Kausik Ray (Charing Cross Hospital, London, UK) said, "We should actually move away from talking about hypothesis.

"We now have three different methods of lowering cholesterol—statins, ezetimibe, and PCSK9 inhibitors—that all lower LDL cholesterol but they do it through common means. So again that provides support for the fact this is a causal effect."

Travel and meeting logistics were supported by unrestricted educational grants from MSD and Amgen to the EAS. Chapman reports receiving research grants and consulting or speaker fees from Amgen, Kowa, Merck, Sanofi, Servier, Unilever, and Regeneron. Packard reports receiving research support from Roche and MSD and honoraria from MSD, Sanofi/Regeneron, Amgen, and Pfizer. Raal reports receiving grants/research support from Amgen and Sanofi and honoraria from AstraZeneca, Merck, Amgen, and Sanofi. Ray reports receiving research grants from Amgen, Sanofi/Regeneron, and Pfizer and honoraria from Aegerion, Amgen, Sanofi/Regeneron, Pfizer, AstraZeneca, Cerenis, ISIS Pharma, Medco, Resverlogix, Kowa, Novartis, Cipla, Lilly, Algorithm, Takeda, Boehringer Ingelheim, MSD, Esperion, and AbbieVie. Other member disclosures are listed in the paper.

Follow Patrice Wendling on Twitter: @pwendl. For more from theheart.org, follow us on Twitter and Facebook.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.