Dr. Greg Burns (not his real name) is a 72-year-old retired radiologist living in Connecticut. Until early last year, he ran with his dog at canine agility meets, skied, ice skated and played 18 holes of golf. He is now unable to walk and is taking a course of medication that will postpone, by a few months, his death.
Burns' rapid decline began in December 2007 when he suffered a short-acting stroke from which he fully recovered.
His cholesterol level was elevated and so as a preventative measure his doctor prescribed a 20mg daily dose of Crestor, a cholesterol-lowering drug in the "statin" class. Statin drugs are designed to inhibit cholesterol synthesis, and about 20 million people are taking statins, most for life.
A few months after beginning Crestor, Burns developed muscle cramps. He was assured by his doctors that these were not serious side effects of taking the drug. But in December 2008 when tests showed that his creatine phosphokinase — an enzyme that is released into the blood stream when muscle cells are damaged — was elevated, Dr. Burns stopped taking Crestor. When his enzyme levels returned to normal, he began taking Pravachol, another statin drug. He quickly developed weakness in his lower legs and a right foot drop. In January 2010, following an extensive neurological exam, Dr. Kevin Felice at The Hospital for Special Care in New Britain, Conn., diagnosed Burns as having amyotrophic lateral sclerosis or ALS, commonly known as Lou Gehrig's Disease.
ALS is a fatal, progressive neurodegenerative disease that affects lower motor nerve cells in the brain and the spinal cord. Muscular paralysis ultimately reaches the respiratory system and, when that happens, the patient will die if not placed on a respirator. This, however, is only an interim measure. The average life expectancy from the time of diagnosis is two to five years.
Burns attributes his condition to the statin drugs. Mayo Clinic cardiologists acknowledge that the side effects of statin drugs can include muscle pain, extreme fatigue, liver damage, digestive problems and neurological damage including memory loss. While a connection between ALS or ALS-like illnesses and the cholesterol-reducing medication seems increasingly plausible, the debate is fierce — in large part because the stakes are high.
The drugs account for a significant percent of all cardiovascular medications, and are the largest-selling class of prescription drugs (and are available over-the-counter in the United Kingdom). Crestor, made by AstraZeneca, ranks second to Pfizer's Lipitor, the biggest seller.
The FDA has expanded the consumer base for drug companies that are marketing statins. In March 2010, the agency revised its guidelines for prescribing statins based on evidence of inflammation in the body, this despite debate over whether inflammation is indicative of high cholesterol. The criteria also factors in the presence of at least one risk factor like smoking or high blood pressure for people older than 50. This expansive criteria, which FDA approved for Crestor, makes about 6.5 million people who have no cholesterol problems or evident heart problems candidates for taking statins.
A small but urgent chorus has long wondered if statins are overused.
This week, new research from the London School of Hygiene & Tropical Medicine suggests that the research underlying statin drugs may have been "cherry-picked" to present the best possible outcomes, and that statin drugs may be inappropriate for low-risk patients.
A significant relationship between muscle toxicity and statin drugs was confirmed in a study published in the American Academy of Neurology in 2002. Danish epidemiologist David Gaist found that "long-term exposure to statins may substantially increase the risk of polyneuropathy," a neurological disorder that occurs when peripheral nerves throughout the body malfunction simultaneously. Gaist cautioned against throwing the baby out with the bathwater, however, noting "the substantial protective effect of statins, particularly on coronary artery disease, is well documented and by far outweighs the potential risk of statin-induced polyneuropathy."
Sometimes the negative side effects of statins are downplayed, and conclusions can be skewed by the limited parameters of the trials. As a 2007 Scripps Mercy Hospital study noted: "The incidence of statin-induced rhabdomyolysis (acute breakdown of skeletal muscles) is higher in practice than in controlled trials because of the exclusion of potentially susceptible subjects."
Also complicating matters is how ALS is defined. Dr. Ralph Edwards, director of the World Health Organization's drug-monitoring center, told me that U.S. Food and Drug Administration's definition is too limiting. "The FDA uses a classic description of ALS which may not pick up all the cases, despite our emphasis that any study ought to think more widely about a condition that is seriously disabling and may also lead to death."
In 2007, the year of the Scripps study, Edwards found evidence that statins may be linked to an illness not typically defined as ALS: "It was an odd condition that was a mix of muscle and neurological damage which did not fit the classic ALS definition but could result in mortality."
This side effect alarmed Edwards so much that he made his suspicions known to the FDA. The government responded by asking the drug companies to examine their pre-marketing clinical data relating to statin and ALS. The FDA also reviewed the outcomes of 41 pre-marketing trials conducted by the drug companies. It concluded that the data was "reassuring" about statin safety.
Edwards was not reassured. He conducted his own research, but both The British Medical Journal and the Lancet rejected his paper. It was published in 2007 in the specialty journal, Drug Safety.
In 2008, the American Journal of Cardiovascular Drugs published a metastudy citing nearly 900 studies of statins' wide-ranging adverse side effects. The next year, the lead author of that piece, Dr. Beatrice A. Golomb, published her own research from the University of California, San Diego, on "Amyotrophic Lateral Sclerosis-Like Conditions in Possible Association with Cholesterol-Lowering Drugs." She noted: "An excess reporting of ALS in apparent association with lipid-lowering drug use was identified in our patient-targeted AE (adverse effect) surveillance study, prior to the corroborating reports of others, providing independent affirmation of elevated reporting."
While falling short of making the direct link between statins and ALS, Golomb raised significant questions. Do statins increase ALS overall? Do statins accelerate ALS, hastening its clinical presentation or progression in general or only in individuals where statins have oxidant effects? She suggested the "testable possibility of an identifiable vulnerable subgroup, an observation of high potential importance."
University of Oxford researchers funded by the British Heart Association took up the challenge. Their study represents the first time the complete human genome has been scanned to locate the genetic culprit of a drug's side effect. The culprit turned out to be a mutation, a sort of rogue gene that boosts the risk of myopathy caused by taking statins. The Oxford team determined that this variation in the DNA code of a gene called SLC01B1, which helps the liver regulate statin uptake, was responsible for 60 percent of the myopathy in people taking high-dose statin therapy. Patients on high statin doses who carry one copy of the rogue gene were at least four times more likely to develop myopathy than those without the gene. Patients who carried two copies of the rogue gene were 16 times more likely to develop ALS. Astonishingly, 1 in 4 people carries one or two copies of this rogue gene.
"This is very exciting," Edwards said. "They made that link between statins and myopathy and ALS, two critical conditions that are definitely related to each other."
The classic definition of ALS excludes illnesses and symptoms linked to taking statins, making an exact count of who has the disease — based on symptoms alone — difficult.
More than 5,000 individuals in the U.S. are diagnosed with classic ALS annually, and at least 30,000 may be now living with ALS. With the recent establishment of a National ALS Registry, those figures may prove low.
There is no cure for ALS. Rilutec, the only FDA-approved medication for treatment, simply postpones death by a few months. Recently a drug tested by Cytokinetics showed some favorable results in small-scale trials. However, like Rilutec, it does not reverse the illness nor cure the nerve damage, and it is not yet on the market.
Nine months after his diagnosis, Greg Burns' speech became slurred. By year end 2010, paralysis set in. He has begun taking Rilutec.