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Genome library, blood test aim to minimize statin side effects, maximize benefits

Date:
May 1, 2015
Source:
Ohio State University Center for Clinical and Translational Science
Summary:
In the midst of the growing and often conflicting data around the benefits of statins, researchers are developing gene-based resources to help improve statin efficacy and cost-effectiveness and to reduce the incidence of adverse effects -- some of which can be fatal.
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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."

While the Food and Drug Administration (FDA) provides guidelines on preventing simvastatin (the most prescribed statin in the US) induced muscle toxicity -- the guidance is based on reducing the maximum dose in relation to interactions with other medications that slow down the metabolism of simvastatin.

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."

In 2012, Kitzmiller was awarded a five-year, $1 million grant from the National Institutes of Health (NIH) to identify key genes involved in statin metabolism in order to develop a multi-gene test that can predict how individuals respond to statin therapy. His team, which is primarily studying simvastatin, has 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.

Ultimately, Kitzmiller aims to put all of these findings into a resource library that clinicians could use to help manage statin therapy in their patients and insure the best possible outcomes. The library would include a list of polymorphisms that impact statin metabolism and action as well as details about how these variations may play out differently in men and women of different races and ethnicities. This library may also help inform FDA guidelines for statin dosing.

The statin library could have even greater significance in the future. As studies continue to uncover new benefits of statins and guidelines continue to expand their indications and use, Kitzmiller says that the number of people using statins is also likely to grow.

"First of all, many people who may likely benefit from statins are not prescribed them or are not taking them. Patients and some prescribers may be less than enthusiastic of statin use due to the uncertainty of the risks of side effects, so hopefully as our ability to predict outcomes improves, we'll see more patients benefitting from their use," said Kitzmiller. "I can also see a future where people are taking statins to prevent other inflammation-related diseases that we haven't explored yet. Having this genomic database and a multi-gene test will be critical to helping us understand which patients are the best candidates for statin therapy."


Story Source:

Materials provided by Ohio State University Center for Clinical and Translational Science. Note: Content may be edited for style and length.


Journal Reference:

  1. Jiang Wang, Jasmine A. Luzum, Mitch A. Phelps, Joseph P. Kitzmiller. Liquid chromatography–tandem mass spectrometry assay for the simultaneous quantification of simvastatin, lovastatin, atorvastatin, and their major metabolites in human plasma. Journal of Chromatography B, 2015; 983-984: 18 DOI: 10.1016/j.jchromb.2014.12.029

Cite This Page:

Ohio State University Center for Clinical and Translational Science. "Genome library, blood test aim to minimize statin side effects, maximize benefits." ScienceDaily. ScienceDaily, 1 May 2015. <www.sciencedaily.com/releases/2015/05/150501095756.htm>.
Ohio State University Center for Clinical and Translational Science. (2015, May 1). Genome library, blood test aim to minimize statin side effects, maximize benefits. ScienceDaily. Retrieved May 8, 2017 from www.sciencedaily.com/releases/2015/05/150501095756.htm
Ohio State University Center for Clinical and Translational Science. "Genome library, blood test aim to minimize statin side effects, maximize benefits." ScienceDaily. www.sciencedaily.com/releases/2015/05/150501095756.htm (accessed May 8, 2017).