Genome library, blood test aim to minimize statin side effects, maximize benefits
With more than 200 million global users of statins, these medications are the very definition of ‘blockbuster.’ By stopping a substance the body uses to make cholesterol, statins can help stave off heart attacks and strokes — the top two causes of death worldwide. But in a significant percent of patients — up to 30 percent by some reports — statins can also eat away muscle tissue, causing weakness, muscle pain and in rare cases, potentially deadly kidney and liver damage.
And the problem could grow larger. Under the most recent heart disease prevention guidelines issued by the American Heart Association and American College of Cardiology, the potential number of candidates for statin therapy in the US jumped from 43 million to 56 million.
‘As doctors follow the current guidelines, we expect that nearly half of Americans ages 40 to 75 and most men over 60 may be prescribed a statin,’ said Joseph Kitzmiller, MD, PhD an associate director of the Center for Pharmacogenomics at The Ohio State University Wexner Medical Center. ‘We currently have a limited ability to predict clinical outcomes and potential side effects for any of those individual patients — many of whom will be on a statin for the rest of their lives. In general and for most patients, statins are largely beneficial. Unfortunately, not all patients benefit and some are harmed by statins.’
Kitzmiller, who has devoted his career to untangling the many ways that genetics influence how patients respond to their medications, thinks that statin dosage recommendations need also to consider common genetic variants the affect drug exposure.
‘The muscle toxicity associated with statins is largely about exposure, and exposure is significantly affected by a patient’s genetics,’ Kitzmiller explained. ‘If you give two people 20 milligrams of a statin, and one of them has a polymorphism, or gene variation that changes the way the body processes that statin, it may be as though you’ve given them two or three times as much medication.’
Kitzmiller is team, which is primarily studying simvastatin, have already identified a gene variation that decreases statin metabolism — making people more susceptible to adverse events.
‘For our patients carrying this genetic variant, simvastatin doesn’t break down as much in the liver. This means more of the drug is in their bloodstream, increasing their exposure and potential for muscle toxicity,’ said Kitzmiller. ‘For these people, a lower dose of simvastatin could potentially deliver the same benefits while causing fewer side effects.’
Kitzmiller also found that a patient’s likelihood for carrying a genetic polymorphism depends on their race. Recent work by his research team suggests that the effect size also varies significantly across racial groups. One genetic variant resulted in a nearly 3-fold increase in simvastatin concentrations for African-Americans but only a modest increase for Caucasians.
‘That can have incredible clinical significance, especially since African-Americans often suffer higher rates of drug adverse outcomes and higher disease mortality rates despite receiving similar or even identical treatment,’ said Kitzmiller, who is also an associate professor in the Department of Pharmacology at Ohio State’s College of Medicine.
His team has also recently developed a blood test that can simultaneously measure the quantities of three different types of statins and their metabolites, which indicates how much of a medication the body has metabolized. This type of tool is essential to help scientists establish connections between genetic profiles and the variation in how statins are absorbed, transported, distributed and excreted. Kitzmiller is in the process of developing a multigene test that could tell clinicians if their patients have any of the genetic culprits that are likely to lead to muscle problems or other side effects from statins. He hopes to bring this test to clinical trials later this year. Science Daily
