Researchers explore drug combinations that reduce adverse effects

Researchers using data from the FDA’s Adverse Event Reporting System (FAERS) have hypothesized that certain drug combinations can be used to mitigate serious adverse events. They have tested their hypothesis with an animal model to determine the mechanisms of action by which these drugs interact. According to a study published in October in the journal Science Translational Medicine, this could be the starting point for the development of clinical trials to investigate safer drug combinations.

Lead author Ravi Iyengar, PhD, professor in the Department of Pharmacology and Systems Therapeutics, and director of the Systems Biology Center, Icahn School of Medicine at Mount Sinai, New York, explained that after studying different drug combinations in FAERS, the researchers noticed that the first drug had different levels of adversity when combined with different second drugs.

Rosiglitazone plus exenatide

One combination that stood out was that of rosiglitazone and exenatide, used to treat type 2 diabetes. Patients who were prescribed both rosiglitazone and exenatide had a low rate of myocardial infarction (MI), 2%, compared to other second drugs used in combination with rosiglitazone: Rosiglitazone and metformin had a 21% rate of MI, rosiglitazone and aspirin had a 17% rate of MI, and rosiglitazone and warfarin had a 13% rate of MI.

“As biologists, we were trying to figure out the molecular mechanisms in which these drugs interact,” Iyengar said. “The rosiglitazone and exenatide combination was easy to work on because it was a mouse model of diabetes using spontaneously diabetic mice.”

The researchers decided to study the clotting mechanism because rosiglitazone has been associated with increased risk of MI and stroke in patients with type 2 diabetes. Because of the drug’s cardiovascular effects, its use was restricted in this population in the United States in 2010.

“We found that this protein plasminogen activator inhibitor-1 (PAI-1) - which is a known risk factor in humans for clotting disorders - could be a point of convergence for the two drugs,” Iyengar said. “In the mouse model, we were able to show that rosiglitazone increases the PAI-1 levels in diabetic mice, but not in normal mice. Exenatide suppresses the increased PAI-1 levels induced by rosiglitazone.”

“This type of analysis will lead to many currently used drugs being repurposed for mitigation of serious adverse events in individual patients,” the researchers wrote.

Collaboration with clinicians

To follow up on these potentially beneficial drug combinations, Iyengar said, he wants to collaborate with clinicians. Clinical trials should be conducted to test these hypotheses to see whether the drug combinations could be useful in human beings.

The study identified other potential drug combinations from the FAERS that might result in mitigation of serious adverse events. Another potentially useful combination would be the addition of an H2 antagonist, such as ranitidine, to a selective serotonin reuptake inhibitor (SSRI) to mitigate the risk of suicides, Iyengar said.

The data from the FAERS demonstrated a 3.1% suicide rate for patients taking an SSRI. With the addition of an H2 antagonist, the rate of suicide dropped to 0.6% in this patient population.

“It would be interesting to see if some patients on SSRIs are having suicidal ideation and a clinical trial undertaken to see if the H2 antagonist might decrease the chances of suicide. This would be something useful,” Iyengar said.