ADA 2009: Proton-Pump Inhibitors Blunt Efficacy of Clopidogrel in Diabetics With Coronary Stents

Diabetics with coronary stents who require antiplatelet therapy with clopidogrel have a 44% higher risk for cardiovascular events if they are also taking a proton pump inhibitor (PPI) than if they are taking clopidogrel without a PPI, investigators announced here at the American Diabetes Association (ADA) 69th Scientific Sessions.

A retrospective cohort study of 4005 diabetic patients who had undergone percutaneous coronary intervention with stenting and who were taking clopidogrel was conducted by Eric J. Stanek, PharmD, senior director of personalized medicine and associate at Medco Health Solutions in Franklin Lakes, New Jersey. Last month, Dr. Stanek presented a clopidogrel/PPI analysis from the entire Medco Health Solutions pharmacy and medical claims database. In his ADA presentation addressing diabetic patients only, 1767 patients were taking a PPI and 2238 were not.

More patients taking PPIs were women, and they were older and generally had greater baseline comorbidity than those not taking PPIs.

During the 12-month period following stenting, patients were evaluated for the incidence of a composite primary end point of cardiovascular death or hospitalization for myocardial infarction, unstable angina, stroke/transient ischemic attack, or repeat percutaneous coronary intervention or coronary artery bypass grafting.

The primary end point rate was 19.7% in patients not taking a PPI and 26.7% in patients taking both clopidogrel and a PPI (hazard ratio [HR], 1.44; 95% confidence interval [CI], 1.22 - 1.69; P < .0001). Risk for cardiovascular events in the nondiabetic patients taking clopidogrel was 17.9%, Dr. Stanek said.

Excess risk with PPIs was primarily due to myocardial infarction or unstable angina (10.2% without and 16.8% with PPI therapy; HR, 1.66; 95% CI,1.34 - 2.06; P < .0001).

Evidence Comes Together

"In our study, 2 pieces of evidence come together," Dr. Stanek told Medscape Diabetes & Endocrinology after his presentation. "It is known that PPIs inhibit cytochrome P450 2C19 and impair the efficacy of clopidogrel. And diabetics are at increased risk of cardiovascular events. Diabetics on clopidogrel have a compounded risk of events with PPI therapy."

"Clopidogrel is very strongly recommended in stenting, so diabetics really need to be given this drug," Dr. Stanek said. "The question is what to do about PPI therapy. Physicians need to consider the risks and benefits of PPIs, and whether or not an H₂ antagonist is a reasonable alternative. For a diabetic on clopidogrel with a high risk of gastrointestinal bleeding, PPI therapy may, in fact, be indicated and necessary to minimize that risk."

"Type 2 diabetes is a heterogeneous disease, affecting multiple systems," ADA's president of medicine and science, F. Paul Robertson, MD, told Medscape Diabetes & Endocrinology. "It can be a balancing act, minimizing risk factors and maximizing drug therapy." Dr. Robertson is an endocrinologist at the Swedish Medical Center in Seattle, Washington.

"We know that PPIs compete with the P450 enzyme," he said. "And we know these diabetics need clopidogrel. We have to make sure that they also need PPI therapy."

He continued: "Diabetics need a large number of drugs. Physicians need to carefully consider the risks and benefits of each and any possible drug interactions."