ARTICLE IN BRIEF
✓ ALS experts said that there are flaws in an analysis of findings from a World Health Organization database that found an association between statins and amyotrophic lateral sclerosis. Nevertheless, some investigators are exploring that link and an additional association with coenzyme Q10.
Sifting through millions of reports of problems linked to prescription drugs, I. Ralph Edwards, MD, director of the World Health Organization's (WHO) drug monitoring center in Uppsala, Sweden, uncovered a faint link between statins, used to control cholesterol levels, and amyotrophic lateral sclerosis (ALS): Of 172 people with ALS similar disorder, 40 had been taking statins.
“In 34 of the 40 reports, a statin was the sole reported suspected drug,” Dr. Edwards reported (Drug Saf 2007; 30(6):515–525). “Seven of the statin cases also had features of peripheral neuropathy.”
Of 5,534 individual case safety reports of peripheral neuropathy related to any drug in Vigibase, the database of the WHO Programme for International Drug Monitoring, 547 were on statins.
“The disproportional reporting of statins and upper motor neurone lesion persisted after age stratification, and such disproportionality was not seen for statins, Parkinson disease, Alzheimer disease, extrapyramidal disorders, or multiple sclerosis-like syndromes,” Dr. Edwards stated in the paper.
The risk posed by this association is small. Each year, ALS strikes only about two people in 100,000, with the incidence increasing with age to as high as one in 10,000 each year for people over 70. Even if statins doubled or tripled the number of cases of ALS, few people would be affected. Moreover, statins are credited for reducing the risk of heart disease, a leading cause of death and disability.
The study itself has major flaws, according to Edward Kasarskis, MD, PhD, professor of neurology at the University of Kentucky Medical School in Louisville, and chief of the neurology service at the VA Medical Center there.
“First of all, we're not even sure these people have ALS,” Dr. Kasarskis said. “They have ‘ALS-like’ syndromes. ALS can be incredibly difficult to diagnose.”
In addition, 25 of those with an ALS-like syndrome had static disease, “which is not at all like ALS,” said Dr. Kasarskis, and six of those 25 recovered. “Also, these are all self-reported cases, so there's reporting bias.”
Carmel Armon, MD, considers the type of “data mining” that produced this result inherently unreliable. A database containing self-reported events can be useful for a problem that has never been seen, such as birth defects in children born to women taking thalidomide, or for a problem that emerges in connection with a drug, such as compulsive gambling in some people taking pramipexole (Mirapex).
Figure. Dr. Carmel A...Image Tools
“Neither of these circumstances applies to ALS,” said Dr. Armon, professor of neurology at Tufts University School of Medicine and chief of the Division of Neurology at Baystate Medical Center in Springfield, MA. To detect an increase in ALS occurrence due to exposure to a medication you'd need a good comparison group, which this analysis cannot provide. For all we know, untreated hyperlipidemia may be a greater risk factor for ALS than hyperlipidemia treated with statins, but the Vigibase dataset would capture only reports of patients on statins who developed ALS.
“When we spin theories, we can easily get carried away, so I would strongly caution against making any kind of inference or speculation about why statins might be implicated in triggering ALS based on such limited data.”
Walter A. Rocca, MD, MPH, professor of epidemiology and neurology at the Mayo Clinic College of Medicine in Rochester, MN, agrees. “Data mining may be useful to detect rare side effects or unexpected events,” he said. “However, there is an important risk of false positives or chance findings. At this point, the evidence for a link (between statins and ALS) is minimal but sufficient to prompt some additional exploration of the issue.”
ALS, STATINS, AND COQ10
Some researchers are engaging in such explorations. Lorene Nelson, PhD, chief of the Stanford University Division of Epidemiology, has been investigating whether the statins use increases the risk of developing ALS, or if the rate of disease progression is altered among ALS patients treated with statins. Her study will be completed in about 18 months.
“One of our goals is to determine if the rate of disease progression is faster among those treated with statins,” Dr. Nelson said.
Figure. Dr. Edward K...Image Tools
Statins reduce cholesterol by inhibiting the enzyme HMG-CoA reductase in the liver, thereby stimulating LDL receptors to remove more low-density lipoprotein from the bloodstream. However, HMG-CoA also promotes the synthesis of mevalonate, a precursor to coenzyme Q10, an antioxidant that promotes the ability of mitochondria to produce energy.
In theory, if statins suppressed the synthesis of mevalonate so much that the body became deficient in CoQ10, mitochondrial energy production could become depressed, triggering or accelerating neuropathies such as ALS.
Some researchers, such as Merit E. Cudkowicz, MD, associate professor of neurology at Harvard Medical School, are finding evidence that seems to support this theory.
“One mechanistic hypothesis is that statins lower CoQ10 levels in tissue,” Dr. Cudkowicz said. “In some people with ALS, it is possible that lowering CoQ10 levels could be a trigger for ALS, or could accelerate existing ALS. However, to date there are no completed studies that address these possibilities.”
Dr. Cudkowicz and colleagues recently looked at whether people taking statins had a faster rate of disease progression than those who did not take the drug. In May, they reported at the AAN annual meeting that in a group of 700 patients with ALS, they did not find any difference in the rate of disease progression with statin use.
CoQ10 is considered a possible therapeutic agent for ALS and other degenerative diseases. In a paper published in June (Mitochondrion 2007;7(supplement 1):S146-S153), Dr. Cudkowicz and Wendy L. Galpern, MD, PhD, of the NINDS, point out that mitochondrial dysfunction and oxidative stress contribute to several neurodegenerative disorders, and that CoQ10 has been considered beneficial in animal models of ALS, Huntington disease, and Parkinson disease.
M. Flint Beal, MD, chair of neurology and neuroscience at New York Presbyterian Hospital-Weill Medical College of Cornell University, has been investigating CoQ10 as a possible treatment for neurodegenerative diseases. In a 2002 paper he found that CoQ10 “significantly extended survival in a transgenic mouse model of ALS” (Free Radic Res 2002;36(4):455–460).
Statins sometimes cause muscle pain and a breakdown of muscle fibers that can progress to full-blown muscle necrosis and myoglobinuria, which may lead to renal failure. This problem also could be linked to the inhibition of CoQ10, some researchers suspect.
Figure. Dr. Walter A...Image Tools
In a review of this problem, Leo Marcoff, MD, of the Yale University School of Medicine, and Paul D. Thompson, MD, of the University of Connecticut, found insufficient evidence to link CoQ10 deficiency to statin-associated myopathy, and called for clinical trials to study the connection (J Am Coll Cardiol 2007;49:2231–2237).
However, they also pointed out that anecdotal and preliminary trial evidence suggests that CoQ10 supplements may be beneficial for people taking statins. “Consequently, CoQ10 can be tested in patients requiring statin treatment who develop statin myalgia, and who cannot be satisfactorily treated with other agents,” they concluded.
In reporting the link between statin use and ALS, Dr. Edwards emphasized that the dangers posed by this correlation is small, but the use of statins is so widespread that more study is urgently needed.
“In the meantime,” he concluded, “it seems wise for patients using statins with severe neuron muscular symptoms to consider stopping the drug, under medical supervision, and in the absence of an urgent clinical need for continuation.”