Paul D. Thompson - Statin-Associated Muscle Symptoms

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Lovastatin was approved by the FDA in July 1987, over 30 years ago. Since then, multiple clinical outcome trials have so consistently demonstrated their ability to reduce cardiovascular disease (CVD) events that the question with statins is often not who should be treated but who should not receive these life-saving drugs. Some authorities have recommended that statins be added to the water supply.

Statins benefit most patients, but they cause side effects that limit effectiveness in some individuals. The most frequently reported side effect is statin-associated muscle symptoms (SAMS), a loosely defined set of symptoms that includes muscle pain, cramping, aching, and stiffness that are attributed to the statin. These are labeled statin-associated because there is ongoing debate as to whether or not statins actually cause these symptoms. Part of the debate is due to the fact that the mechanism or mechanisms for SAMS are unknown but could involve altered calcium flux, oxidative stress, mitochondrial function, cell membrane integrity, and apoptotic signaling, since all are implicated in the etiology of SAMS.

We have had a long and interesting journey in studying how statins affect skeletal muscle. Paul distinctly remembers hearing a lecture on lovastatin in the late 1980s which mentioned that lovastatin could increase blood creatine kinase (CK) levels. Paul noted that comment because he had an interest in exercise-related rhabdomyolysis since medical school. At about the same time, Paul was involved in an industry-sponsored trial comparing the effects of lovastatin and fluvastatin on lipid levels. Several of the subjects had demonstrated an increase CK levels soon after exercise. One subject had a CK of 21,400 U/L, 5 days after a weight-lifting session. Paul subsequently embarked on a double-blind, placebo-controlled study which demonstrated that lovastatin-treated subjects experience a 40% higher increase in CK the day after 45 minutes of downhill walking.

Beth, an exercise physiologist, joined Paul in Hartford 10 years ago, and we have continued studies on how statins affect skeletal muscle. These studies have combined our personal interests in exercise and human performance with our interest in lipid metabolism. The mix is even more complex, however, because Pauls interest in lipid metabolism came from his attempts to explain how exercise increases HDL since muscle neither secretes nor directly catabolizes lipoproteins. Many others have been involved in these statin studies. Evan Stein, MD, is a well-known statin researcher who delivered the lecture that mentioned CK levels. Peter Herbert, MD, was an internationally known lipid expert and Pauls mentor at Brown. Eileen Cullinane, DVM; Linda Bausserman, PhD; and Stan Sady, MD, PhD, were Pauls collaborators at Brown. John Guyton, MD, at Duke obtained the funding for the lovastatin downhill walking study. John was approached by a pharmaceutical company to perform studies and included Paul. Joe Zmuda, PhD, and Richard Zimet, PhD, helped perform that study. Neil Moyna, PhD; Amanda Zaleski, PhD; Gregory Panza, MS; and C. Michael White, PharmD, have been invaluable collaborators at Hartford Hospital.

But, why this book? It has been our experience that patients report SAMS, clinicians treat SAMS, and researchers study SAMS, but often in very disparate settings. We know of no comprehensive textbook that combines the three worlds of patient experience, clinician insight, and investigator knowledge. Indeed, one of our conclusions after reading and editing each chapter was that the study of SAMS requires a collaborative, multidisciplinary approach that has been lacking. The lack of such cohesive clinical and scientific collaborations may contribute to the continuing uncertainty surrounding SAMS, despite it being the most frequently reported side effect of one of the most commonly prescribed classes of drugs.

To create this book, we compiled a list of all the unsolved problems surrounding SAMS. We identified the experts in the field who could best present these topics in a way that might elicit new ideas and solutions. To our surprise, almost every author we asked agreed to contribute. We are ever grateful to them for showcasing their collective expertise within these pages.

Several facts are undeniable: CVD is still the leading cause of death in the United States and the world, and statins are an incredibly powerful drug for reducing CV risk. To improve statin use and effectiveness, SAMS need to be better studied, defined, and treated, and this textbook represents what we believe to be a step in that direction.