Heidelberg, Germany - A new study appears to have uncovered the reason nicotinic acid causes flushing in most people taking the HDL-raising therapy [1]. Using various mouse models, researchers have identified a G-protein-coupled receptor that, when activated by niacin, produces the characteristic "hot flashes," a common side effect that, depending on the location of the receptor in the body, can strongly affect patient compliance.

The results are published in the December 1, 2005 issue of the Journal of Clinical Investigation. Senior investigator Dr Stefan Offermanns (University of Heidelberg, Germany) told heartwire that the G-protein-coupled receptor, known as GPR109A, has recently been shown to mediate the nicotinic-acid-induced antilipolytic effects in fat cells. The purpose of the study was to determine whether the same receptor mediated the flushing response commonly seen in patients.

"While there is no other drug quite like niacin, especially for raising HDL-cholesterol levels, it is a difficult agent to get patients to comply with, mainly because of the strong flushing response," said Offermanns.

Using various mouse models, Offermanns and his colleagues first showed that mice lacking the murine form of GPR109A, known as PUMA-G, did not respond to nicotinic acid with any measurable change in cutaneous blood flow. Offermanns said that the G-protein-coupled receptor in the skin activated by niacin responds by increasing intracellular calcium, activating phospholipase A2, and eventually producing arachidonic acid. This is converted to prostaglandins, resulting in the characteristic vasodilatory response. Experiments conducted by the investigators confirmed that the nicotinic-acid-induced flushing response involves prostaglandin D₂ and prostaglandin E₂; mice lacking both these prostanoids had reduced flushing responses.

Offermanns explained that PUMA-G is expressed in adipose cells and in various immune cells, including macrophages. To test whether immune cells mediated nicotinic-acid-induced flushing, investigators transplanted wild-type bone marrow into irradiated PUMA-G-deficient mice. In this experiment, the bone marrow restored the nicotinic-acid-induced flushing response, indicating that bone-marrow-deficient cells expressing PUMA-G mediate the flushing reaction. Based on these animal models, Offermanns said the data indicate that GPR109A mediates the flushing response and that this effect involves the release of prostaglandins, most likely from immune cells in the skin.

Upon discovering that the receptor that triggers the flushing response is the same receptor that mediates the antilipolytic effects, such as raising HDL cholesterol and lowering vLDL- and LDL-cholesterol levels, Offermanns said it will be difficult to separate the vasodilatory response from niacin's effects on lipids.

"The bad news is that it is the same receptor that results in the good and negative effects of niacin," Offermanns told heartwire. "It will be hard to dissociate the wanted from the unwanted effects, although it might be possible to reduce flushing if we are able to target the response further downstream from the identified receptor."

In an editorial accompanying the published study [2], Dr Nicholas Pike (GlaxoSmithKline, Hertfordshire, UK) said that GPR109A continues to represent an exciting target. However, the confirmation that nicotinic-acid-induced flushing is mediated by GPR109A raises questions about whether agonists can be developed to produce the beneficial effects of niacin without the flushing response. Pike suspects that as the chemical diversity of future GPR109A ligands increases, it is possible that future agents will produce less flushing.

"Further examination of this receptor may facilitate our understanding of the mechanism of action of nicotinic acid and thereby aid the development of improved therapeutic options for the treatment of cardiovascular disease," Pike writes.