Statins and Personalized Medicine

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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 U.S. Food and Drug Administration (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 impact and management of adverse drug reactions (ADRs) may cost up to $30 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 an early report, we described a pilot study of biochemical and molecular effects in severely affected patients with muscle 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 that early study, mutation screening was performed for 3 relatively common metabolic muscle diseases 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 so we went on to study more muscle disorders that could underlie risk for developing statin-induced 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 90% of statin takers), to those who have mild reversible symptoms (approximately 10% of statin takers), to those who have severe incapacitating symptoms (as many as 0.5% of statin takers) and who may or may not recover after stopping the drugs.

Altogether it is estimated that at least 40 million people take statins in the U.S. and as many as 0.5% of these individuals or nearly 200,000 people, will have experienced serious muscle side effects during therapy [4].

In additional studies of genes causing 12 hereditary muscle diseases, we found that 17% of patients with severe statin myopathy had underlying disease-causing mutations compared to 4.5% of statin-tolerant controls [5].  

In more recent studies using whole genome sequencing of DNA from 50 severe statin myopathy patients we have found more than 27 genes with mutations that may be causative for muscle disease (unpublished studies).

One of those disorders is malignant hyperthermia (MH), a disorder usually associated with adverse reactions to anesthesia during surgery. In more recent years, mutations causing MH have been associated with exertional rhabdomyolysis (“muscle breakdown”), heat stroke and in our previous studies, statin myopathy [6].

We believe it is very important to evaluate 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.

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 rhabdomyolysis 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 or family history of 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, including statins, 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 genetically in terms of our ability to clear drugs from our circulation.

So how can all of this 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.

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 exposure to extremes in temperature, dehydration, anesthesia, sleep deprivation and even stress, over which we have little control; these can all impact our risk for disease and our response to drugs such as statins.

There is international interest among physicians worldwide to provide optimal medical management of statin therapy and to also manage statin intolerance. In 2014, I participated in an international consensus panel within the European Atherosclerosis Society and had the opportunity to stress the impact of genetic factors on risk for statin myopathy at meetings of the panel held in Europe. The consensus was published incorporating a vast array of factors, including genetic factors, to consider in the management of statin therapy and statin intolerance [7].

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 genetic factors and have recently developed a 20-gene screening test containing genes that impact on susceptibility to statin-induced myopathy. This test has been approved by the New York State Department of Health and will be on our menu of tests soon for screening individuals who have statin myopathy, exertional rhabdomyolyisis, heat stroke and MH.

It is particularly important for physicians, as well as their patients, to realize that stopping statin therapy 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] Sultana, J. Cutroneo, P. and  Trifirò, G. J Pharmacol Pharmacother 2013; 4(Suppl1): S73–S77.

[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.

[5] Vladutiu GD, Tarnopolsky M, Baker S, Christopher-Stine L, Peltier W, Weisman M,

Isackson PJ. Inborn errors of muscle metabolism implicated in risk for statin induced

myopathy. Molec Genet Metab 2014;111:264–265.

[6] Vladutiu GD, Isackson PJ, Kaufman K, Harley JB, Cobb B, Christopher-Stine L, Wortmann RL. Genetic risk for malignant hyperthermia in non-anesthesia-induced myopathies. Mol Genet Metab. 2011 Sep-Oct;104(1-2):167-73

[7] Stroes ES, Thompson PD, Corsini A, Vladutiu GD, Raal FJ, Ray KK, Roden M, Stein E, Tokgözoğlu L, Nordestgaard BG, Bruckert E, De Backer G, Krauss RM, Laufs U, Santos RD, Hegele RA, Hovingh GK, Leiter LA, Mach F, März W, Newman CB, Wiklund O, Jacobson TA, Catapano AL, Chapman MJ, Ginsberg HN; European Atherosclerosis Society Consensus Panel. Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J. 2015 May 1;36(17):1012-22

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

Website: www.rgbmgl.org

Updated December, 2016
 

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