All about cholesterol (Part 2)

Part 2 of 2. 8-minute read. // (Photo: The cholesterol particles circulating in blood vessels come in a variety of forms. CREDIT: DANIEL GARCIA)

continuing from a previous article...

HDL cholesterol

Just as lipoprotein(a) and LDL cholesterol are known as the baddies, HDL cholesterol has long been considered a good guy. HDL particles are thought to help by sucking cholesterol out of plaques. The HDL then takes this cholesterol to the liver for recycling or disposal. It’s the cardiovascular system’s cholesterol “garbage truck,” says Bob Eckel, a retired cardiometabolic physician and professor emeritus at the University of Colorado Anschutz Medical Campus.

If high levels of HDL cholesterol are good, scientists reasoned, then more of this cleanup crew should be even better. Exercising and weight loss can both raise HDL cholesterol. Scientists have tried to do the same with medications — but with disappointing results. The drugs did raise HDL cholesterol levels, yes, but they didn’t save lives in people already on statins, and they were weaker than statins at stopping heart attacks and strokes. “To sum it up very simplistically, approaches to raise HDL failed. Nothing really worked,” says Anatol Kontush, a lipid biochemist at the Sorbonne University in Paris.

Lifestyle changes can help to reduce the risk of heart disease.

It’s not entirely clear why raising HDL cholesterol in statin-takers bombed. It might be that the idea of boosting HDL cholesterol was simply wrong. High HDL cholesterol might be a marker for good cardiovascular health, rather than a direct cause of it, says Rohatgi. If so, artificially amplifying its levels wouldn’t help.

But the problem also might have been an overly simplistic understanding of HDL cholesterol. Scientists now know that HDL comes in many types and can do many jobs. In addition to hoovering up cholesterol from plaques, it can fight inflammation — that’s good. But sometimes, HDL can turn bad and promote inflammation instead, Cho says, though it’s not clear how. And, she adds, people who are genetically wired to make too much HDL cholesterol can have an enhanced risk for heart disease.

The problem, then, may be that various drugs meant to amplify HDL cholesterol focused on quantity over quality, and increased the wrong kind of HDL. For example, one promising category of drugs raised HDL levels by inhibiting an enzyme that transfers cholesterol away from HDL particles, giving it to LDL particles. Several studies found these inhibitors failed to improve heart health. It might be that stopping the transfer of cholesterol away from HDL particles means the particles had less capacity to pick up new cholesterol from plaques, leaving the cholesterol to languish there. In other words, these garbage trucks were already full.

So the new plan, a last-ditch effort to save lives with HDL, is to help HDL do its cholesterol-removal job better, rather than to just make more of it. Gibson, for example, is chairing a clinical trial of a medicine called CSL112. It’s made of the key protein component of HDL particles — that is, it’s the starting material for HDL particles but still empty of cholesterol. These CSL112 molecules seem to work by creating new HDL molecules primed to pack in as much cholesterol as they can possibly hold. In a preliminary study of more than 1,200 people, two-thirds of whom received CSL112 infusions, the treatment was safe. And when the scientists took blood samples for lab tests, they found that the higher the dose of CSL112 participants received, the more their blood was able to suck up cholesterol.

Depending on their composition, lipoprotein particles can be of different sizes and densities, from small and dense like HDL to large and less dense like chylomicrons and VLDL.

In another study called AEGIS-II, the researchers tested CSL112 infusions in a larger group of people who had just suffered a heart attack and could be most likely to benefit from treatment. Following 18,200 people for a year, it asked whether CSL112 prevents second heart attacks, strokes and death in this population. “That’s a really big, definitive study, and if that doesn’t work, then I suspect the field will completely abandon HDL,” said Nicholls some months back.

In mid-February, CSL of King of Prussia, Pennsylvania — CSL112’s makers — announced that the study did not achieve its main goal of reducing major cardiac events such as stroke, heart attack or death. The researchers are still analyzing the data and will present results in more depth at the American College of Cardiology conference in April.

Triglycerides

If the HDL waters seem murky, the situation with triglycerides, the fatty component of blood that’s carried around in lipoprotein particles, is muddier still. The amount a person has depends on lifestyle: diet, exercise and so on. High triglycerides are linked to a greater risk for cardiovascular disease, and very high levels can lead to inflammation of the pancreas, known as pancreatitis. Thus, it made sense to posit that getting rid of triglycerides would be a healthy thing to do, and many studies have attempted just that — with boggling results.

Lipoproteins are made up of protein, fat in the form of triglycerides, and cholesterol — both free cholesterol and a chemically modified, cholesteryl ester, form. The proportion of each varies with lipoprotein type.

One top candidate to reduce triglycerides is based on fish oil, which is high in the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Diets rich in fatty fish or omega-3s have long been linked to lower rates of cardiovascular problems. The fish or fish oil supplements are thought to work by cutting down on fat production by the liver.

So, in a study called REDUCE-IT, researchers tested a highly purified derivative of EPA in more than 4,000 people with cardiovascular disease or diabetes. They compared these patients to a similar number of people who received inert mineral oil as a placebo.

At first glance, the results reported in 2019 looked “really spectacular,” says Nicholls, who wasn’t involved in the trial. In the group that had taken the EPA for about five years, risk of major cardiovascular problems or death dropped by 25 percent or more compared to those getting a placebo. But oddly, this benefit came without a big reduction in the triglycerides themselves.

In other words, “if EPA is working, it’s doing something other than lowering triglycerides,” says Kenneth Feingold, an endocrinologist and emeritus professor of medicine at the University of California, San Francisco. EPA might counter inflammation, for example, or stabilize the membranes of heart cells.

Based on the REDUCE-IT results, the US Food and Drug Administration approved the purified EPA derivative in 2019 as a medicine for people with high triglycerides and other cardiovascular risk factors. But things got more confusing in 2020, when Nicholls, Nissen and colleagues published another trial, called STRENGTH. This study also aimed to lower triglycerides in high-risk patients, about 6,500 of them, using EPA plus DHA. The researchers compared these patients to people who received a corn oil placebo. But the team halted their study early because, although triglyceride levels did fall, EPA plus DHA didn’t seem to have any beneficial effect on the rate of heart attack, stroke, hospitalization for heart problems, or death.

Researchers are still debating why REDUCE-IT hit paydirt but STRENGTH faltered. Looking back at REDUCE-IT, some experts see a problem with the mineral oil placebo that was used. LDL cholesterol levels and signs of inflammation went up in that group — and if the control participants were worse off than if they’d received nothing at all, then their data would make the experimental treatment look better than it really is.

But Gibson, who was part of the REDUCE-IT team, argues for a different explanation: that pure EPA is better than the EPA/DHA combo. And supporting REDUCE-IT’s conclusions, he points to an older, 1990s study that compared people taking EPA plus statins with people taking statins alone and also found fewer major coronary events in the EPA group.

Then, in 2022, came the latest blow to the once-promising idea of lowering triglycerides: the PROMINENT trial, in which Eckel and colleagues tested a drug called pemafibrate that reduces blood triglycerides. The 10,000-plus study participants had type 2 diabetes, high triglycerides and low HDL, and were at risk for cardiovascular events. But even though triglyceride levels fell by about 26 percent, on average, in the group receiving the drug, this made no difference to the rate of cardiovascular events.

Taken together, the results suggest that triglycerides indicate poor cardiovascular health without being the reason behind the problem. “Triglycerides were just innocent bystanders,” concludes Eckel. The exception, he adds, might be people with very high triglycerides who are at risk of pancreatitis and might still benefit from triglyceride-lowering treatment.

Remnant cholesterol

This is a loosely used term, with science still to be settled. In the doctor’s office, physicians assume that any cholesterol that isn’t HDL or LDL is a leftover or “remnant” fraction. From a molecular point of view, remnant cholesterol is a fat-delivering lipoprotein in an intermediate state: It left the liver, loaded with fat and cholesterol, and has dropped off some of its triglycerides in the body’s tissues, but not so much of its cargo that it’s become an LDL lipoprotein. Chylomicrons from the gut, once depleted of fats, also become remnant particles.

In people with healthy metabolisms, the body quickly disposes of remnant particles. But if a person has a problem such as diabetes or obesity, these fatty remnants might stick around. Remnant cholesterol may accumulate in atherosclerotic plaques, potentially making it as dangerous as the classic bad LDL cholesterol. Indeed, high levels of remnant cholesterol have been linked to cardiovascular disease in some studies, quite independently of patients’ LDL cholesterol measurements. That suggests that getting rid of those remnants could be beneficial.

The substances remain a bit of a black box, though. “We still don’t know precisely how to define them, we don’t know precisely how to measure them, so it’s kind of difficult to be precise about remnants,” says Feingold. Nonetheless, some researchers are interested in treatments that might target remnants in addition to, or instead of, triglycerides. For example, Nicholas Marston, a cardiologist at Brigham and Women’s, and colleagues are testing a medication called olezarsen that, he says, appears to promote clearance of the cholesterol-carrying particles. But it will take more study to learn if that translates into fewer cardiovascular problems.

Remnant cholesterol is “probably important,” says Nissen — so even though the science is still nascent, he says he feels hopeful about the potential of treatments targeting it.

In sum, the emerging picture is one in which certain forms of HDL cholesterol are good and all the other lipoproteins are bad. The best approach, experts suggest, may be to reduce all the non-HDL cholesterol — whether by diet and exercise or some of these new medicines, should they prove effective.

“If it’s not HDL, we should minimize it,” says Feingold. “The lower, the better.”