By Georgirene D. Vladutiu, Ph.D.

The age of personalized medicine is fast becoming a reality. Personalized medicine is defined as the ability to use an individual's genetic makeup to tailor medical care to unique and specific needs of the individual patient. An example would be the prescribing of certain medications at selected dosages that an individual could tolerate without significant side effects. One person's tolerance may be different from that of another.

In August 2007, the FDA recognized the fact that individuals respond differently to a blood-thinning drug named warfarin, also known as coumadin, depending on genetic variation in 2 genes that alter an individual's response to the drug [1]. The FDA added new information to the drug's label stating that genetic variants exist that alter an individual's response to the drug and genetic testing is available to aide physicians in prescribing the proper dosages of the drug to their patients. Even though this genetic testing is now available for warfarin, physicians must learn how to use the results from the testing in terms of what they mean for warfarin dosing in individual patients.

The story of warfarin is just the tip of the iceberg with respect to genetic influence on drug response. The debilitating and sometimes lethal consequences of adverse drug reactions (ADRs) rank as one of the top 10 leading causes of serious illness and even mortality with direct medical costs in the range of $137 to $177 billion annually in the U.S. [2].

There is increasing evidence that genetic variants influence susceptibility to serious side effects in muscle with the use of cholesterol-lowering drugs such as statins. In 2006, our laboratory reported a pilot study of biochemical and molecular effects in severely affected patients with myopathic symptoms that developed during statin therapy. Some of these patients recovered as soon as the drug therapy was terminated and others did not. Some people with long-term effects actually suffered increased severity of symptoms post-therapy as though some process had been unleashed that would not stop and they have never recovered.

In our study, mutation screening was performed for 3 relatively common metabolic myopathies in statin myopathy patients. We found that 10% of patients either had one of these diseases or had carrier status for one mutation causing a disease (see Genetic Predisposition to Statin Myopathy for details) [3].

We realized from these findings that underlying hereditary forms of muscle disease, or carrier status for them, may underlie at least 10% of cases of severe statin myopathy and, more likely, upwards of 25% of cases when all is said and done. Therefore, we are in the process of trying to verify our findings by seeking out carriers for muscle disease who are taking statins and determining whether they have a greater risk to develop muscle disease with statin therapy than non-carrier statin takers in the general population. 

We are also expanding our screening studies to include more mutations causative for these disorders as well as expanding the number of metabolic muscle disorders included in the testing. At the same time, we are performing genomewide association studies searching for other genetic determinants across the entire human genome that may play a role in the risk to develop statin myopathy.

Many questions remain as we go forward in studying risk for statin myopathy. It is important to define the severity of symptoms in each affected patient.  In other words, what is statin myopathy exactly? What are the key features? Are there different levels of severity? These are all important questions as we begin to realize that there exists a range of adverse responses to statins from individuals who suffer no muscle side effects (approximately 95% of statin takers), to those who have mild reversible symptoms (5-7% of statin takers), to those who have severe incapacitating symptoms but eventually return to normal with time post-therapy (perhaps 0.3-0.4% of statin takers) and finally, to those who become seriously ill and never recover from muscle side effects even though they may no longer take any statins.

Altogether we have estimated that approximately 38 million people will be taking statins in the U.S. by the end of 2008 and that as many as 0.5% of these individuals or nearly 200,000 people, will have experienced serious muscle side effects during therapy [4]. We predict that up to 25% of these individuals (50,000) may have carrier status or, in rare cases, affected status for underlying hereditary muscle disease that contributes to their risk. They may have never had symptoms of their muscle disorder, especially if they are only carriers, until triggered by statins.

We believe it is very important to evaluate or score the disease level in each individual with a statin myopathy based on the presence of key symptoms and features, including muscle biopsy results, if available. We should then be able to associate genetic liability or risk with the presence of key features. It is no longer adequate to simply describe an individual as having a "statin myopathy" without stating exactly what the features are and the degree of their severity in that individual. Recently, small but significant numbers of individuals have been identified with neurologic features as well as muscle symptoms as a part of their adverse response to statins. These reports must be taken into account and used to determine whether statin myopathy is actually a collection of disorders based on underlying risk factors for a whole host of disorders ranging from myopathy to neuropathy.

The key features of statin myopathy vary but there are certain characteristics that are more prevalent than others. Muscle pain or cramps with or without muscle weakness is a common scenario. Not infrequently, muscle weakness is the predominant feature. Some affected individuals have exercise intolerance and develop something called rhabdomyolysis defined as severe muscle breakdown that often leads to a release of a muscle protein called myoglobin into the blood stream and ultimately into the urine. The urine turns dark brown similar to the color of coca cola. This can be a very serious finding and may require hospitalization with IV fluid therapy to prevent kidney damage.

What makes one group different from another in the extent of side effects experienced with statins? There are likely many factors, in addition to subgroups with underlying muscle disease, which contribute to the differences. These may include the co-existence of other complex disorders in some patients such as heart disease, diabetes, or hypothyroidism. Body mass and levels of activity may vary, as well as nutritional status. There is also the fact that some patients take multiple medications for various indications having to do with co-existing conditions and it is very difficult to determine how these drugs may interact with each other.

All drugs are cleared from the body at various rates, called drug turnover, and a large part of this turnover occurs via specific receptor-mediated processes in the liver.  If a combination of different drugs is cleared by the same mechanism in the liver, they will compete for clearance and may stay in the body's circulation longer than if they existed alone in the clearance process. This could cause higher effective doses of certain drugs for longer periods of time in the body than originally intended and possibly lead to side effects that are dose-dependent. There are even genetic determinants that control the drug clearance process and we all vary in terms of our ability to clear drugs from our circulation.

So how can all of this varied information be put together in a manageable way to develop a personalized approach to the treatment of each individual? It is a work in progress that will not be as straightforward as the genetic testing mentioned above for warfarin. I believe that a large part of the answer will be based on relevant genetic factors and this will include underlying hereditary disease risk as well as genetic determinants for drug clearance and genetic determinants for complex disorders such as heart disease and diabetes. In addition there is the interaction of hereditary factors with so-called environmental factors, that is, those factors that impact our health over which we have some control, such as what we eat, how much exercise we get, whether we smoke or drink alcohol, the dosage of drugs, such as statins, etc. There are also things in our environment, such as stress, over which we have little control that can also impact our risk for heart disease or stroke and subsequently our response to drugs such as statins.

Down the road, I expect that we each will carry a bar-coded plastic card that our family physicians will be able to place in a card reader during a routine visit that will tell the doctor just what drugs and dosages and combinations of drugs we can individually tolerate without side effects. The card should also contain information that takes into account some of the environmental factors that will impact on drug response, such as body mass, but these will change over time and the information will have to be periodically updated. Will personalized medicine be good news for drug companies? I think the answer is yes, because it will make clear the fact that we each possess factors beyond a drug company's power to control or predict that will impact on how we respond to certain medications.

Eventually it may be important for drug companies to add to their drug labels all the definitive factors, both hereditary and environmental, that interact in a specific manner to contribute to risk for an adverse reaction. The truth is, however, that this level of personalized medicine for statin use, at least, will take time to evaluate and score the impact of all the contributing factors. In the meantime, we will continue to search for contributing genetic factors toward the development of a genetic screening test for statin myopathy risk. It is important to accomplish at least this much soon because more and more uses for statins as anti-inflammatory agents are being found which means potentially millions of additional people will be treated, a portion of which will have adverse reactions.

It is particularly important for physicians, as well as their patients, to realize that stopping the medication or changing the dosage does not always reverse the side effects once they have occurred and this is an important consideration in our collective efforts in the medical and research communities to make statin use safe for everyone who absolutely needs this therapy as part of their effective medical care.

References

[1] Press-Release. FDA approves updated warfarin (Coumadin) prescribing information. In: Food and Drug Administration, Rockville, MD, August 16, 2007. Accessed February 14, 2008, at http://www.fda.gov/bbs/topics/NEWS/2007/NEW01701.html.

[2] Ross CJ, Carleton B, Warn DG et al. Genotypic approaches to therapy in children: a national active surveillance network (GATC) to study the pharmacogenomics of severe adverse drug reactions in children. Ann NY Acad Sci 2007; 1110:177-192.

[3] Vladutiu,GD, Simmons Z, Isackson PJ, et al.  Genetic risk factors associated with
 lipid-lowering drug-induced myopathies.  Muscle Nerve 2006; 34(2):153-62

[4] Vladutiu GD. Genetic predisposition to statin myopathy. Curr Opin Rheumatol 2008; 20:648-655.

Georgirene D. Vladutiu, Ph.D.
Professor of Pediatrics, Neurology and Pathology & Anatomical Sciences
School of Medicine & Biomedical Sciences
The University at Buffalo, Buffalo, NY

November 24, 2008
 

Dr. Georgirene Vladutiu is a Professor of Pediatrics, Neurology, and Pathology & Anatomical Sciences in the School of Medicine and Biomedical Sciences, University at Buffalo.
She is also Director of the Robert Guthrie Biochemical & Molecular Genetics Laboratory, at the Buffalo General Hospital, Kaleida Health System in Buffalo, NY.

Dr. Vladutiu is a Board-Certified Clinical Biochemical Geneticist with 37 years of experience in research and diagnostic laboratory testing for inborn errors of metabolism.
She has published more than 70 papers on metabolic disorders with a special interest in metabolic muscle diseases. Her current NIH-funded research interests are in the area of genetic susceptibility to statin-induced myopathies.