By Pat Anson, PNN Editor

Health experts have known for over a decade that diclofenac, a non-steroidal anti-inflammatory drug (NSAID), raises the risk of heart failure, stroke and other cardiovascular problems. Because of that, oral formulations of diclofenac are only available by prescription in the U.S. and some European nations, although the drug is still widely available as an over-the-counter pain reliever in Asia, Africa and the Middle East.

“Most patients who are using diclofenac have arthritis, and many of them are at risk of heart disease,” says Bhagwat Prasad, PharmD, an associate professor in the Washington State University College of Pharmacy and Pharmaceutical Sciences. “So there is a concern that taking diclofenac may be putting them at even greater risk of cardiovascular events such as heart attack and stroke.”

Prasad is senior author of a study, recently published in the journal Clinical Pharmacology & Therapeutics, that found women, children and some ethnic groups are more at risk from diclofenac because they have low levels of an enzyme that helps metabolize the drug in their intestines.

The enzyme – known as UGT2B17 – is present at much lower levels in women than in men, which helps explain why there are more reports of women suffering heart damage after taking diclofenac. UGT2B17 is mostly absent in children under the age of nine.

Ethnic differences also play a role. In studies on human liver and intestinal samples, WSU researchers found that up to 90% of people of Japanese descent lack the gene for the enzyme, compared to just 20% of Caucasian people.

“No one knew why this heart toxicity is happening in some individuals,” said first author Deepak Ahire, a graduate student in the WSU College of Pharmacy and Pharmaceutical Sciences. “Our study showed, for the first time, that UGT2B17 is important in diclofenac metabolism and suggests that differences in UGT2B17 expression are what makes people’s response to diclofenac so variable, leading to toxicity in some whereas for others the drug simply does not work.”

Ahire and his colleagues hope to confirm their findings in a clinical trial. They also want to work with large hospitals to further study the connection between diclofenac and patients with heart problems. One way they suggest to reduce the risk of cardiovascular problems is to use genetic testing to screen patients who may have problems metabolizing diclofenac.

According to the FDA’s Adverse Events Reporting System, there have been over 27,000 serious medical cases involving diclofenac since 2010, including 2,827 deaths. The number of U.S. cases has tripled in recent years, with women involved in nearly twice as many adverse events as men.

In 2020, the FDA approved the use of diclofenac in Voltaren, a topical OTC gel that contains a small dose of diclofenac absorbed through the skin. The WSU study involved higher dose diclofenac tablets that are taken orally and absorbed in the digestive system. About half the prescriptions written for diclofenac in the U.S. are for tablets.

A large 2018 study in Denmark found that people who used diclofenac were 50 percent more likely to have cardiovascular problems within 30 days of taking the drug than those who took nothing. The risk of gastrointestinal bleeding was also higher. The authors of that study recommended that diclofenac not be available OTC and should only be prescribed with prominent warning labels.