Study shows how COX-2 inhibitors cause cardiovascular problems

A promising discovery: Unlike coxibs, an mPGES-1 inhibitor may mitigate clotting and hypertension risks.

Research into the biochemical factors behind the cardiovascular problems associated with COX-2 inhibitor has yielded results that may aid risk management strategies and help patients with arthritis.

In an animal study involving mice, researcher found that many factors — disrupting COX-2’s genetic qualities, inhibiting the enzyme with other substances and removing a prostacyclin (PGI2) receptor — predisposed the mice to the blood clotting and high blood pressure associated with COX-2 inhibitors. The researchers also confirmed that adding aspirin reduced clotting and hypertension, and may be similarly effective in humans.

Yan Cheng, PhD, Garret A. FitzGerald, MD, and colleagues at the Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, conducted the study, which involved genetically manipulated mice that mimicked the effects of prostaglandin G/H synthase-2 (PGHS-2) inhibitors or low doses of aspirin. The results were published online ahead of print on The Journal of Clinical Investigation’s Web site. The study is scheduled for print publication in May.

PGHS-2 inhibitors are more commonly known as COX-2 inhibitors — the active components of popular pain medications, such as Celebrex. The researchers compared the genetically modified mice to healthy mice administered the COX-2 inhibitor Celebrex (celecoxib, Pfizer) and to mice administered a PGHS-inhibitor. They then fed the mice normal and high-salt diets and measured blood flow to exposed carotid arteries.

In addition to confirming the mechanisms contributing to increased cardiovascular risks, the researchers found that another enzyme may mitigate the adverse cardiovascular effects associated with COX-2 inhibitors. They found that inhibiting microsomal PGE synthase-1 (mPGES-1), as opposed to inhibiting the COX-2 enzyme, did not increase thrombosis risk or raise blood pressure in the mice. Further, mPGES-1 inhibitors may keep their anti-inflammatory values while avoiding the adverse cardiovascular events associated with PGI2 suppression, according to the study.

“These observations raise the possibility that inhibitors of mPGES-1 may be less prone to adverse effects involving the cardiovascular system than are specific inhibitors of PGHS-2,” the authors said in the study.

The discovery of mPGES-1 inhibition’s positive effects is encouraging. Because mPGES-1 inhibitors are as effective as traditional NSAIDs they may someday substitute for COX-2 inhibitors in patients with high cardiovascular risks, the authors said.

“The demonstration that mPGES-1 deletion is as effective as (traditional) NSAIDs in models of pain and inflammation, including collagen-induced arthritis, suggests that such inhibitors might represent alternatives to coxibs, potentially devoid of their cardiovascular hazard,” they said.

(FitzGerald receives financial support from Bayer, Merck and Boehringer Ingelheim, which make COX-targeting drugs. He also serves as a consultant for Johnson & Johnson, Bayer, Merck, GlaxoSmithKline, Novartis, Boehringer Ingelheim and NiCox..)

For more information:
Cheng Y, Wang M, Yu Y, et al. Cyclooxygenases, microsomal prostaglandin E sythase-1, and cardiovascular function. J Clin Invest. Published online ahead of print April 13, 2006. Accessed April 19, 2006. Available at: jci.org.