It’s well established that lowering LDL cholesterol reduces cardiovascular risk, but the story of HDL is much less certain, according to a review series on lipidology published in The Lancet ahead of the European Society of Cardiology meeting.

Still, several questions about LDL remain, according to Paul Ridker, MD, of Brigham and Women’s Hospital in Boston: Can other LDL-lowering drugs besides statins reduce cardiovascular risk? Are treatment targets needed? Is aggressive lowering safe?

The three papers and an editorial delve into the knowns and unknowns of LDL, HDL, and triglycerides.

Latest on LDL

There’s “extensive evidence” that LDL predicts vascular risk and is a causal factor in atherosclerosis, but there’s still plenty of controversy with regard to specific issues within cholesterol management, Ridker wrote — particularly in light of recent U.S. guidelines that remove treatment targets for LDL levels.

Treating to target is a mainstay of therapy for most other nations, Ridker wrote, but the U.S. guidelines instead advocate for the use of higher-intensity statins in patients with higher absolute risk of cardiovascular events.

Other questions include how and when lipid fractions should be measured, whether population-based screening is useful, why certain drugs that lower LDL have not shown the same benefits as statins, and whether aggressive LDL lowering is safe.

Ridker also characterizes the landscape of new pharmacological strategies for LDL lowering, noting the recent lack of success with CETP inhibitors torcetrapib and dalcetrapib, which reduced LDL cholesterol but didn’t diminish vascular event rates in trials.

Other approaches are under investigation, including two drugs which were approved for homozygous familial hypercholesterolemia in 2013: mipomersen and lomitapide. Mipomersen is an antisense oligonucleotide that interferes with apolipoprotein transcription; lomitapide inhibits microsomal triglyceride transport protein (MTP).

But the “most promising” new drugs for additional LDL lowering are the PCSK9 inhibitors, which block a protein secreted by hepatocytes that impairs the action of the LDL receptor, Ridker said.

“Efficacy and safety data from hard-endpoint trials will be available soon for several novel therapeutic approaches that reduce LDL cholesterol well below the concentrations that are currently achievable with statins alone,” he wrote.

What Happened to HDL?

Although there’s solid evidence that HDL is a key component of predicting cardiovascular risk, there’s no clear causal relationship between HDL and atherosclerosis, according toDaniel Rader, MD, of the University of Pennsylvania, and Kees Hovingh, MD, of the University of Amsterdam.

Now, the “HDL hypothesis” has been recast as a “more subtle concept” — the HDL function hypothesis, which posits that it may not be HDL cholesterol itself that has a causal relationship to atheroprotection, but instead HDL’s function that is protective.

“The classic HDL hypothesis — defined as the concept that intervention to raise HDL cholesterol concentrations will reduce cardiovascular risk — is questionable and is increasingly difficult to defend in its simplest form,” they wrote, noting, however, that it is “important to emphasize that its value as a predictor of cardiovascular risk remains largely unchallenged.”

The methods for measuring HDL function are in the early stages and are vastly more complex than the current standard of measuring HDL mass, and new tests should be “reproducible, straightforward to measure, and show an association with coronary heart disease outcome measures,” they wrote.

Attention Back on Triglycerides

Before statins stole the spotlight with their focus on LDL lowering, high triglycerides were once treated with the aim of preventing cardiovascular disease.

“As time went by, the randomized evidence for treating raised triglycerides to prevent cardiovascular disease seemed weaker and weaker,” wrote Borge Nordestgaard, MD, DMSc, and Anette Varbo, MD, PhD, of the University of Copenhagen.

But now that HDL research has painted an uncertain picture, there’s a renewed interest in triglycerides — which are strongly inversely linked with HDL levels, the researchers said.

Randomized trials showing the cardiovascular benefits of triglyceride reduction are scarce, they wrote, but that may be remedied by upcoming studies of new triglyceride-lowering drugs, which will “hopefully provide conclusive evidence as to whether lowering triglycerides reduces the risk of cardiovascular disease.”

In an accompanying editorial, John Kastelein, MD, PhD, of the University of Amsterdam, echoed the researchers’ sentiments that “few clinicians have any doubt about [LDL’s] causal role in heart disease,” while answers about HDL are still “very far away.”

“Fortunately, all three lipoproteins (LDL, HDL, and triglycerides) share the fact that new therapies to address them are under investigation in outcome trials,” he wrote, hoping that these trials will answer some of the most important questions in the specialty over the next 5 years:

• Will LDL cholesterol reduction by modalities other than statins yield similar outcome benefits?
• Will lowering of triglyceride-rich lipoproteins and remnant cholesterol result in a reduction of major adverse cardiovascular events?
• Will infusion of pre-beta-like HDL particles to promote reverse cholesterol transport from macrophage to circulation lead to an improvement in coronary artery disease risk?

“After a wait of 20 years,” he wrote, “we will have to hold our breath a little longer.”