Debate on LDL Role in Heart Disease Reignited Out of the Blue

Patrice Wendling

May 09, 2017

LONDON, UK — A recent editorial asserting that coronary artery disease is a chronic inflammatory condition best reduced by simple lifestyle choices rather than focusing on LDL cholesterol continues to reverberate among cardiologists[1].

The opening salvo is that the conceptual model of coronary arteries as kitchen pipes clogged with dietary saturated fat is "just plain wrong."

The argument, however, is hardly new. Editorial coauthor Dr Aseem Malhotra (Lister Hospital, Stevenage, UK) took the clogged-pipe analogy to task in a 2013 editorial, as did Dr Michael Rothberg (Cleveland Clinic, OH) in a second editorial published that year[2].

So why pen yet another editorial?

There is sufficient evidence now against lowering LDL cholesterol and consumption of dietary saturated fat as the primary means to prevent heart disease, Malhotra told heartwire from Medscape.

"It's important that the mainstream narrative changes. This is an inflammatory condition, a chronic inflammatory disease," he said.

The provocative editorial has kept the Twittersphere buzzing since it hit just as the European Atherosclerosis Society released its consensus statement declaring that LDL cholesterol causes atherosclerotic CVD.

Lead author of that document, Dr Brian Ference (Wayne State University School of Medicine, Detroit, MI), told heartwire that a systematic review in elderly patients cited by the editorialists was "neither systematic nor quantitatively literate, but instead was based on a highly selected group of studies with no quantitative synthesis of the presented evidence."

The editorial, published April 25, 2017 in the British Journal of Sports Medicine, contains no new data, but Malhotra and coauthors Dr Rita Redberg (University of California, San Francisco) and Dr Pascal Meier (University College London, UK) highlight several studies to support their position. They include:

  • The 2014 PREDIMED study, in which a Mediterranean-style diet high in fat from sources such as extra virgin oil and nuts reduced the risk of CVD by 30% in high-risk patients compared with following a low-fat diet.

  • A 2015 systematic review/meta-analysis by De Souza et al finding no association between saturated-fat consumption and all-cause mortality, CHD, CHD mortality, ischemic stroke, or type 2 diabetes in healthy adults[3].

  • A 2016 systematic review by Ravnskov et al concluding that LDL cholesterol is not associated with CVD and is inversely associated with all-cause mortality in the elderly[4].

The editorialists suggest "selective reporting" may partly explain this misconception and cite a reanalysis of unpublished data from the Minnesota Coronary Experiment reporting that replacing saturated fat with vegetable oils rich in linoleic acid increased the risk of death, despite significant reductions in LDL and total cholesterol[5].

Ference argues that the new EAS consensus statement on LDL causality was designed specifically to avoid the type of "selective reporting of the evidence" contained in the review by Ravnskov et al by focusing on the "totality of the evidence" from more than 200 studies with more than 2 million participants and over 200 million person-years of follow-up.

"These studies demonstrate a remarkably consistent dose-dependent log-linear association between the absolute magnitude of exposure of the vasculature to LDL-C and the risk of atherosclerotic cardiovascular disease," Ference said.

Conflating Dietary Fat with LDL-C

Furthermore, Ference said the editorialists "appear to conflate dietary fat with plasma LDL-cholesterol levels" and that the EAS consensus statement clearly points out that the efficacy of any intervention that attempts to reduce the risk of atherosclerotic CVD by lowering plasma LDL-C, such as a low-fat diet, will depend on both the absolute magnitude and achieved LDL-C reduction and the total duration of exposure to lower LDL-C.

He added, "The interpretation of the dietary trials has been limited by the fact that data on the effect of low-fat diets on circulating plasma LDL-C over the 3 to 5 years of follow-up that would be needed to demonstrate a clinical benefit are not sufficient to make quantitatively reliable inferences of the potential efficacy of low-fat diets to reduce the risk of cardiovascular events by lowering LDL-C."

In statement to heartwire , prepared for the American Heart Association and reported elsewhere, Dr Frank Sacks (Harvard School of Public Health, Boston, MA) assails the De Souza paper for using "obsolete methodology" that didn't take into account the replacement of macronutrients for saturated fat.

Sacks adds, "The editorial is misleading, ignoring a large database of highest-quality evidence that saturated fat does cause atherosclerosis and does so in large part because it increases LDL cholesterol."

Cone of Silence

Of special note, heartwire contacted at least a dozen cardiologists regarding the editorial,  alternately called "worthy of coverage" and "deplorable." One cardiologist laughed it off, another noted its appearance in a "low-impact sports-medicine journal," and still others punted the request to their colleagues.

Malhotra said accusations of cherry-picking the data or being extremists are nothing new and reflect a larger issue in healthcare of stifling debate that contradicts the status quo or powerful competing interests.

"Science doesn't progress when you try to stifle debate and there are legitimate questions being asked," he said. "It's a system failure."

Mutually Exclusive Approaches to Prevention?

The editorialists conclude that the way to combat heart disease is to decrease insulin resistance and inflammation through stress reduction, brisk walking for 22 minutes a day, and eating real food.

"There's no business model or market to help spread this simple yet powerful intervention," they write.

Sacks remarked, "This 'real-food' recommendation is not a scientific approach."

Dr Neil J Stone (Northwestern Memorial Hospital, Chicago, IL) told heartwire in an email that the key point to the editorial "is that the two approaches are not mutually exclusive. Lowering LDL and inflammation (cutting down on sugar especially) are both important."

It's unlikely the debate will die down any time soon, with The Telegraph just reporting that a coalition of physicians, which includes Malhotra, is calling for patients to be warned that the "hugely expensive" PCSK9-inhibitor evolocumab (Repatha, Amgen) does not provide a cardiovascular or all-cause survival benefit, despite lowering LDL cholesterol by some 59%.

Malhotra reports being the coproducer of the documentary The Big Fat Fix. Redberg reports having served as a consultant for one day in 2015 for Amgen. Meier reports no relevant financial relationships. Ference reports consulting for or serving on advisory boards of Merck, Ionis, the American College of Cardiology, Amgen, and Esperion Therapeutics; speaker honoraria and fellowship/travel grants from Merck; and research grants from Merck, Esperion Therapeutics, and Amgen. Sacks reports being a coinventor of a patent held by Harvard University for the measurement of HDL subspecies by apoC-III. Stone reports being the lead author for the 2013 American College of Cardiology/American Heart Association cholesterol guidelines.

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