Heart Patients Warned of Using Drugs to Block ‘Flush’ from Popular Niacin Pills
Questions blocking DP1 in patients prone to cardiovascular disease, especially those taking niacin to treat cholesterol
April 9, 2012 - Niacin, or vitamin B3, is the one approved drug that increases "good" cholesterol (high density
lipoprotein, HDL) while depressing "bad" cholesterol (low density lipoprotein, LDL), and has thereby attracted much attention from patients –
seniors in particular - and physicians. Niacin keeps fat from breaking down, and so obstructs the availability of LDL building blocks.
Patients often stop taking niacin because it causes uncomfortable facial flushing, an effect caused by the release of a
fat called prostaglandin or (PG)D2. PGD2 is the primary cause of the unwanted vasodilation, the "niacin flush." The dilation occurs when blood
vessels widen from relaxed smooth muscle cells within vessel walls.
PGD2, formed by an enzyme called COX-2 and released by immune and skin cells, acts on a muscle cell-surface receptor
called DP1 to cause the flushing. In fact, a combination of a DP1- blocking drug and niacin is being evaluated in a large clinical trial to
determine its effectiveness in reducing heart attacks, as opposed to other drugs that reduce LDL cholesterol.
A work published in the Journal of Clinical Investigation this month
questions the wisdom of blocking DP1 in patients prone to cardiovascular disease, especially those taking niacin.
The first authors, Wenliang Song, MD, research assistant professor, and Jane Stubbe, PhD, postdoctoral fellow, in the
Perelman School of Medicine, University of Pennsylvania, and colleagues draw
evidence for their study from mice and humans.
They show that platelets - complicated cells circulating in the bloodstream that stick together in the first phase of
blood clotting - make PGD2, which acts as a brake via DP1 on their own activation. This is surprising as PGD2 is made in platelets by COX-1,
the target inhibited by low-dose aspirin.
What about niacin side effects, like flushing? (Mayo Clinic)
Niacin comes in a variety of forms, ranging from fast-acting forms to
those that are longer acting. Some forms of niacin, especially in high doses — 1,000 milligrams or more — do cause temporary flushing
of the skin.
The flushing can make your skin redden and possibly feel warm to the
touch. While annoying, this flushing isn't harmful. If you have flushing, talk to your doctor about taking an aspirin shortly before
you take your niacin. Aspirin can counteract this flushing effect. Also, avoiding hot drinks and alcohol can decrease flushing.
Versions of niacin with reduced flushing effects also are available by prescription.
Other possible side effects include:
…Increased blood sugar
However, your doctor may be able to find the right dose and form of
niacin that minimizes side effects. Also, taking niacin with food may help prevent side effects. Remember, don't take niacin — even in
the over-the-counter form — without discussing it with your doctor first. Niacin can cause side effects when taken in high doses.
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COX-1 in platelets also makes thromboxane (Tx)A2, another fat that activates platelets. As low-dose aspirin is
cardioprotective by thinning blood, the benefit from shutting down platelet TxA2 trumps the potential risk of suppressing platelet PGD2
To gather more information on the potential risks from blocking DP1, the Penn investigators used mice lacking the DP1
receptor. However, unlike humans, mice do not express DP1 in their platelets.
"Frankly, because of this, we did not expect to detect any
signal of cardiovascular hazard in the mice," notes senior author
Garret FitzGerald, MD, director of the
Institute for Translational Medicine and Therapeutics.
However, deletion of DP1 made mice somewhat more susceptible to hardening of the arteries, the formation of aneurysm,
thrombosis, and in some cases, high blood pressure. The researchers suggest that these findings are reflective of DP1 expression in vascular
and immune cells in mice, just as in humans, despite its absence on mouse platelet cells.
Turning back to humans, the Penn investigators discovered that niacin evoked COX-1- dependent formation of both TxA2 and
PGD2 in platelets and that a DP1 blockade enhanced the effect of TxA2 on platelet activation.
Taken together, these interwoven findings suggest that blocking the effects of PGD2 on DP1 is likely to be undesirable in
patients with heart disease, and perhaps in particular, those taking niacin. That possibility is not addressed by the design of the large
ongoing trial of the niacin/DP1 antagonist combination, say the researchers.
Should such a hazard exist, FitzGerald expects it to be confined to those patients not taking low-dose aspirin, along
"This potential hazard of blocking one aspect of PGD2 action, the one dependent on DP1, contrasts nicely with our recent
report that blocking its other receptor, DP2, may be beneficial in limiting male-pattern baldness" said FitzGerald.
Penn Medicine reports to be one of the world's leading academic medical centers, dedicated to the
related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the
Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania
(founded in 1765 as the nation's first medical school) and the
University of Pennsylvania Health System, which together form a $4.3 billion
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