Knowns and Unknowns: Lancet Reviews Role of Lipids in CVD

August 20, 2014

LONDON, UK — In anticipation of the European Society of Cardiology (ESC) 2014 Congress, clinical experts have turned their attention to LDL cholesterol, HDL cholesterol, and triglycerides in an attempt to address the relationship between these lipids and cardiovascular disease. Three papers, which are published in the August 16, 2014 issue of the Lancet, cast an eye on what is known about the relationship between the lipids and coronary heart disease risk, but equally important, on what remains controversial or unknown.

For the first paper in the series, Dr Paul Ridker (Brigham and Women's Hospital, Boston, MA) takes on controversies with LDL cholesterol[1]. Despite consistent biological, genetic, and epidemiologic studies showing the benefit of lowering LDL-cholesterol levels, the field is far from settled, according to Ridker.

The controversy partly stems from the new cholesterol guidelines, which recently abandoned LDL-cholesterol targets in favor of treating patients with either a moderate- or high-dose statin depending on baseline risk. Since the publication of the guidelines, there has been continued debate about how low LDL cholesterol should be reduced and the value of cholesterol targets following statin therapy, Ridker told heartwire .

The review also examines whether or not nonstatin therapies should be used for reducing LDL cholesterol. For now, until more evidence is in, these nonstatin drugs, including ezetimibe (Zetia, Merck/Schering-Plough), should be restricted in most general practice settings, just as the guidelines recommend, says Ridker.

"What is clear is that statins—powerful agents that inhibit cholesterol production and have anti-inflammatory effects—dramatically reduce vascular event rates and must be more widely used as an adjunct to diet, exercise, and smoking cessation," said Ridker.

In terms of future directions, the approval of lomitapide (Juxtapid, Aegerion Pharmaceuticals) and mipomersen (Kynamro, Genzyme) provide the first drug-therapy options to LDL apheresis for patients with homozygous hypercholesterolemia. Ridker notes that three major outcomes studies have been launched testing new monoclonal antibodies targeting PCSK9, "the most promising novel target for additional LDL-cholesterol reduction." These outcomes trials, which will test alirocumab (Sanofi/Regeneron), bococizumab (Pfizer), and evolocumab (Amgen), will expose more than 60 000 patients to the PCSK9 inhibitors for a period ranging from two to four years, notes Ridker. (The ESC meeting has an entire hot-line session on August 31 dedicated to coronary artery disease and lipids, which includes new results using alirocumab.)

"The evolving LDL story provides clear evidence that novel concepts from genetics and genomics can be rapidly translated into clinical practice," he told heartwire .

What to Do About HDL?

In the second paper, Dr Daniel Rader (University of Pennsylvania, Philadelphia) and Dr Kees Hovingh (University of Amsterdam, the Netherlands) tackle the HDL question, a field that has suffered a number of setbacks in recent years[2]. For example, two major studies, AIM-HIGH and HPS2-THRIVE , failed to show that raising HDL cholesterol with niacin provided any benefit, while the cholesteryl-ester-transfer-protein (CETP) inhibitors torcetrapib and dalcetrapib have also disappointed.

In their review of the HDL hypothesis—the concept that raising HDL-cholesterol levels would lower the risk of coronary heart disease—Rader and Hovingh note that while the cholesterol within HDL has been shown to be inversely associated with coronary heart disease risk and is a predictor of cardiovascular risk, genetic studies of Mendelian disorders challenge the concept. In people with genetic mutations resulting in low–HDL-cholesterol concentrations, there does not appear to be an increased risk of coronary disease.

"Although each of these trials have their caveats, taken together they contribute to the perception that raising HDL-cholesterol concentrations per se does not necessarily confer a cardiovascular benefit or result in a beneficial effect on coronary heart disease outcome measures."

The reviewers turn their attention to the HDL "function" hypothesis, the idea that HDL cholesterol itself does not protect from atherosclerosis, but rather it is the function, such as the ability to promote cholesterol efflux and reverse cholesterol transport, that is most critical.

Beyond LDL and HDL cholesterol

And finally, in a third paper, Drs Børge Nordestgaard and Anette Varbo (University of Copenhagen, Denmark) examine the role of triglycerides in cardiovascular disease[3]. They point out that clinical trials examining the cardiovascular benefit of lowering triglycerides are scarce, but despite this, new clinical trials testing novel agents are ongoing. This renewed interest is driven by epidemiologic and genetic studies showing that raised triglycerides, remnant cholesterol, or triglyceride-rich lipoproteins can pose an additional risk for cardiovascular disease.

In an editorial accompanying the three papers[4], Dr John Kastelein (Academic Medical Center, Amsterdam, the Netherlands) says there is still much to learn. For example, the precise role of inflammation in atherosclerosis is still not fully understood, and several anti-inflammatory drugs have failed in phase 3 studies despite promising results in earlier studies.

Also, it remains to be seen just how safely LDL cholesterol can be lowered with the novel agents and whether this translates into improved clinical outcomes. Kastelein suspects that lowering LDL cholesterol to as low as 25 mg/dL—"the true physiological LDL-cholesterol concentration"—might result in a reduction in clinical events.

Ridker reports investigator-initiated research grants from the National Heart Lung and Blood Institute, the American Heart Association, the Leducq Foundation, the Reynolds Foundation, AstraZeneca, Novartis, Amgen, and Pfizer. He has served as a consultant to Pfizer, ISIS Pharmaceuticals, Amgen, Vascular Biogenics, and Boston Heart. Rader reports grants from AstraZeneca, Bristol-Myers Squibb, and the National Institutes of Health. He is a founder of Vascular Strategies, which performs assays of HDL function, and is an inventor on a patent method for reverse cholesterol transport in humans. Nordestgaard has received honoraria from Omthera, Sanofi, Regeneron, Aegerion Pharmaceuticals, AstraZeneca, Merck, Fresenius, and ISIS Pharmaceuticals. Disclosures for the coauthors are listed in the articles. Kastelein is a consultant to and receives honoraria from Dezima Pharmaceuticals, Merck, Cerenis, the Medicines Company, CSL Behring, Amgen, Sanofi, Regeneron, Eli Lilly, Genzyme, ISIS Pharmaceuticals, Aegerion, Esperion, AstraZeneca, Omthera, Pronova, Vascular Biogenics, Boehringer Ingelheim, Catabasis, Atheronova, UniQure, and Novartis.


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