A new drug lowers levels of a protein related to ‘bad’ cholesterol


Routine blood tests in the
not-too-distant future may feature a new line item: lipoprotein(a).

High levels of this fat- and
cholesterol-carrying protein increase the risk of cardiovascular disease,
research suggests. But there has been little anyone can do about it. How much
lipoprotein(a) a person produces is largely locked in by genetics, and the
level remains relatively steady throughout life. That’s in contrast to “bad”
LDL — low-density lipoprotein — cholesterol, which changes depending on diet
and exercise.

lipoprotein(a) is genetically determined, “these people who have high levels
have had it since birth, and so they can get heart disease earlier,” says Erin Michos, a preventive cardiologist at Johns
Hopkins University School of Medicine who was not involved with the clinical

Now, a therapy that specifically
targets lipoprotein(a) levels is on the horizon. In a clinical trial, the drug,
which blocks the body’s ability to make the protein, reduced people’s levels of lipoprotein(a) by as much
as 80 percent
, researchers report in
the Jan. 16 New England Journal of
. The trial also found the drug to be safe.

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Another clinical trial is now
underway to determine whether drastically lowering levels of lipoprotein(a) in
people who already have cardiovascular disease lessens their risk of heart attack
and stroke (SN: 3/15/19).

Lipoprotein(a) is
made up of a particle of LDL plus a
protein called apolipoprotein(a). The relationship between LDL cholesterol
and cardiovascular disease risk is well-established: When there is too much LDL
cholesterol in the blood, it can get into the walls of arteries, stoking an
inflammatory immune response that leads to thickened walls and narrowed
arteries (SN: 5/3/17).

But LDL doesn’t appear to be
the whole story, says cardiologist Michelle O’Donoghue of Brigham and Women’s
Hospital in Boston, who was not part of the new study. “There are people who
have very well-controlled LDL cholesterol levels who do go on to have heart
attacks.” As a result, “there’s been a tremendous amount of interest in
lipoprotein(a) and its possible role in progression of heart disease,” she says.

The LDL component is part of
the reason that cardiovascular disease risk is higher with elevated levels of lipoprotein(a).
But the apolipoprotein(a) component adds to the risk, says Sotirios Tsimikas, a
cardiologist at the University of California, San Diego School of Medicine in
La Jolla. That protein appears to provoke a stronger inflammatory reaction than
LDL does, hastening plaque development in artery walls. And apolipoprotein(a) has
the potential to prevent blood clots from breaking up — bad news if an
artery-blocking clot forms when a plaque ruptures.

in a way, it’s kind of a triple hit,” Tsimikas says. “You get all the bad
things from LDL, but then you get two other things that are not good for you.”

To directly target the
production of lipoprotein(a), Tsimikas and colleagues tested a drug called
APO(a)-LRx, developed by Ionis Pharmaceuticals in Carlsbad, Calif.,
in a phase II clinical trial designed to determine the effectiveness and best
dose of the treatment. The drug blocks the messenger RNA that provides genetic
instructions to make the protein.

The researchers tested
different drug doses in 286 patients with cardiovascular disease whose levels
of lipoprotein(a) were at least 60 milligrams per deciliter of blood. Epidemiological
data suggest that people with lipoprotein(a) levels between 50 and 100 mg per
deciliter have a modest increase in the risk of cardiovascular problems,
Tsimikas says. Those with levels above 100 mg per deciliter are at high risk.
It’s estimated that about 20 percent of the population has lipoprotein(a)
levels above 50 mg per deciliter, he says.  

At the highest dose of the drug,
injected weekly for six months, trial participants’ lipoprotein(a) levels
dropped by an average of 80 percent by the end of the experiment.

To determine if the drug is
effective at reducing the risk of heart attack and stroke, a phase III clinical
trial, run by Novartis Pharmaceuticals of Basel, Switzerland, has begun recruiting
participants. Researchers will test the drug or a placebo over about four years
in more than 7,500 people with cardiovascular disease and lipoprotein(a) levels
of 70 mg per deciliter or higher.

If that trial is successful, further research will be needed to see if the drug also helps people with high levels of lipoprotein(a) avoid developing cardiovascular disease in the first place.


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