Statins Have Unexpected Effect On Pool Of Powerful Brain Cells

ScienceDaily (July 6, 2008) — Cholesterol-lowering drugs known as statins have a profound effect on an elite group of cells important to brain health as we age, scientists at the University of Rochester Medical Center have found. The new findings shed light on a long-debated potential role for statins in the area of dementia.

Neuroscientists found that statins, one of the most widely prescribed classes of medication ever used, have an unexpected effect on brain cells. Researchers looked at the effects of statins on glial progenitor cells, which help the brain stay healthy by serving as a crucial reservoir of cells that the brain can customize depending on its needs. The team found that the compounds spur the cells, which are very similar to stem cells, to shed their flexibility and become one particular type of cell.

The new findings come at a time of increasing awareness among neurologists and cardiologists of the possible effects of statins on the brain. Several studies have set out to show that statins provide some protection against dementia, but the evidence has been inconclusive at best. Meanwhile, there is some debate among physicians about whether statins might actually boost the risk of dementia. The new research published in the July issue of the journal Glia by Steven Goldman, M.D., Ph.D., and first author Fraser Sim, Ph.D., provides direct evidence for an effect of statins on brain cells.

"There has been a great deal of discussion about a link between statins and dementia, but evidence either way has been scant," said Goldman, a neurologist who led the team. "This new data provides a basis for further exploration.

"These findings were made through experiments done in cell culture using human brain cells and exposing them to doses of statins used widely in patients. But this research was not done in people. There are a great number of questions that need to be explored further before anyone considers changing the way statins are used," Goldman added.

Goldman's team is recognized as a leader identifying and directing the molecular signals that direct the development of stem cells and their daughter cells, known as progenitor cells. In this study, Sim ran a genomic screen to see which genes are more active in these cells compared to other brain cells. Sim and Goldman found several related to cholesterol, including the enzyme HMG-CoA reductase, which is central to making cholesterol and is the main target of statins.

"It was quite surprising that the cholesterol-signaling pathways are so active in these cells," Goldman said. "Since such signaling is blocked with compounds used literally by millions of patients every day, we decided to take a closer look."

The team measured the effects of two widely used statins, simvastatin and pravastatin, on glial progenitor cells, which can become either astrocytes or oligodendrocytes. The team looked at progenitor cells from 16 patients who had brain tissue removed during surgery to treat epilepsy, tumors, or vascular problems.

Scientists found that both compounds, when used at doses that mimic those that patients take, spur glial progenitor cells to develop into oligodendrocytes. For example, in one experiment, they found about five times as many oligodendrocytes in cultures of human progenitor cells exposed to pravastatin compared to cultures not exposed to the substance. Similarly, they found that the number of progenitor cells was just about one-sixth the level in cultures exposed to simvastatin compared to cultures not exposed to the compound.

To understand the process, think of a baseball team raising a group of great young prospects. They run fast, they throw hard, they hit well. Most teams will tailor their players to the positions the team needs -- a few pitchers, for instance, and several batters. Any team that suddenly found itself with all pitchers or all hitters would be ill prepared to compete.

The Rochester team discovered that statins essentially push most of the raw talent in one direction.

Scientists don't really know the long-term effects of such a shift. Physicians are looking at statins as a possible treatment for multiple sclerosis, where the myelin coating that covers nerve cells in the central nervous system is damaged. Myelin is produced by oligodendrocytes -- so spurring the development of oligodendrocytes might provide one way to reduce or repair the damage seen in M.S.

But the body maintains a pool of uncommitted glial progenitor cells for a reason. The body normally turns to that reservoir of cells when it needs to repair damage from a variety of causes, such as an infection, hemorrhage, a serious blow to the head, or inflammation within the brain, such as in patients with multiple sclerosis. No one knows the consequences if such cells weren't available when needed, though increased cognitive impairment might be one possibility.

"These are the cells ready to respond if you have a region of the brain that is damaged due to trauma, or lack of blood flow like a mini-stroke," said Sim, assistant professor of Neurology. "Researchers need to look very carefully at what happens if these cells have been depleted prematurely."

Glial progenitor cells are distributed throughout the brain and, according to Sim, make up about 3 percent of our brain cells. While true stem cells that can become any type of cell are very rare in the brain, their progeny, progenitor cells, are much more plentiful. They are slightly more specialized than stem cells but can still develop into different cell types.

The work may be relevant to drugs commonly used by diabetics as well. That's because the team discovered that a signaling molecule called PPAR gamma is central to the effect of statins on glial progenitor cells. When PPAR gamma was blocked, the statins no longer had the effect. Since PPAR gamma is the main target of diabetes medications such as Avandia and Actos, which trigger the molecule, Goldman said it's likely that those medications have the same effect on progenitor cells. He also noted that many patients are on both diabetes drugs and statins, which could increase the effect.

"Our results suggest the need for awareness of the possible toxicities accruing to long-term statin use, and identify one such potential toxicity, the premature differentiation and attendant long-term depletion of oligodendrocyte progenitor cells of the adult brain," conclude the authors in their Glia paper.

Besides Sim and Goldman, other authors include medical student Jennifer Lang, technical associate Tracy Ali, Cornell scientist Neeta Roy, and neurosurgeons Edward Vates, M.D., and Webster Pilcher, M.D. The National Institute of Neurological Disorders and Stroke and the National Multiple Sclerosis Society funded the work.
Adapted from materials provided by University of Rochester Medical Center.

Researchers find statins slow onset of Alzheimer's

James Randerson Science correspondent
The Guardian

Tuesday August 28 2007

The cholesterol-lowering drugs statins may also slow the onset of Alzheimer's disease, according to US researchers who examined the brains of 110 elderly people after they died. They found the brains of patients who had not taken the drugs were more likely to show signs of the disease.

Previous studies have suggested that statins have a protective effect against the brain-wasting disease, but the science is contradictory. "Our study is the first to compare the brains of people who had received statins with those who had not," said Gail Li at the University of Washington.

Around 500,000 people in the UK have Alzheimer's, with around one in 20 of those aged over 65 affected. The risk increases with age and by 85 nearly half of people have developed the disease. Statins are drugs that are thought to prevent heart attacks and strokes by reducing the level of the "bad" LDL cholesterol in the blood. They have been hailed as "wonder drugs" because they have few side-effects and can be prescribed for long periods. They have even shown promising results against diseases such as rheumatoid arthritis and multiple sclerosis.

Dr Li and her colleagues took advantage of an existing study into the health of older people to investigate whether statins had an effect on Alzheimer's disease progression. More than 2,500 volunteers had originally been recruited with no health problems in 1994.

The team was given access to the brains of 110 patients who had given permission for their organs to be used in research. Of these, 36 had received at least three prescriptions for statins.

The team found after dissecting the brains that these individuals were less likely to have neurofibrillary tangles - markers of Alzheimer's progression.

"To our knowledge, this is the first study demonstrating an association between statin exposure and neuropathologic changes associated with Alzheimer's disease," the team write in the journal Neurology today.

"These results are exciting, novel, and have important implications for prevention strategies," said co-author Eric Larson, the executive director of the Group Health Centre for Health Studies. However, he stressed that the finding would need to be confirmed.

guardian.co.uk/science ...#8805;

A Risk in Cholesterol Drugs Is Detected, but Is It Real?

DOCTOR'S DILEMMA

Data Crunching Hints At Tie to Lou Gehrig's; FDA Isn't Concerned
By AVERY JOHNSON
July 3, 2007

As he examined data on a computer one day last fall, drug-safety reviewer Ralph Edwards saw something that concerned him: Of 172 people in his database who developed Lou Gehrig's disease or something similar while taking prescription medicines, 40 had been on statins, the huge-selling cholesterol drugs.

Dr. Edwards, director of the World Health Organization's drug-monitoring center, has amassed about four million reports of medical problems experienced by people taking prescription drugs. His job is to sift through these so-called adverse events, looking for "signals" of potential side effects.

The number of Lou Gehrig's cases associated with statins struck Dr. Edwards as high. He would have expected a number in the single digits, judging from how often other drugs in the database were linked to the disease. Still, the analysis didn't prove anything. Dr. Edwards hesitated to publicize his finding, wary of creating a drug scare and mindful that statins have been shown to reduce heart attacks significantly.

INTERVIEW


Read excerpts from Dr. Edwards's conversations with The Wall Street Journal.
It's an increasingly common dilemma nowadays. Sophisticated software allows health authorities to troll through huge databases looking for possible drug dangers. The data mining can detect rare side effects that didn't show up in clinical trials. But it can also raise false alarms and force regulators to divert time and money from more pressing dangers.

"People reach different judgments on when to shout and when not to shout," says Robert Temple, medical director at the Food and Drug Administration division that evaluates drugs. "It's the hardest single thing -- the value and danger to screaming early."

The issue is likely to grow as regulators expand access to their databases. The FDA and other national drug regulators used to keep a tight lid on the adverse-event reports they collected, but now the WHO can freely disseminate them. Also, since 2004, the FDA has posted its quarterly data files on the Internet, and anyone can download them free of charge. Some companies have started offering software to crunch the data for side-effect patterns.

Adverse-event reports are a major way to identify side effects after a drug is on the market, but the data can be flawed or misleading. The reports can be turned in by anyone -- patients, doctors, even plaintiffs' lawyers. Media coverage or Internet postings claiming dangers in a particular drug may lead doctors and consumers to report more problems with that drug. Meanwhile, many problems never get reported.


Determining causation is another issue. If people taking a drug are older or more overweight than usual, an adverse-events database may show more links to heart attacks. That wouldn't necessarily point to any problem with the drug -- it would just reflect the less-healthy state of the people taking it.

Clinical trials in which patients randomly receive either a drug or a placebo are usually the best way to identify side effects, because any significant difference between the two groups is likely to be a result of the drug. However, trials are often too small or too short to identify unusual side effects, and they don't necessarily reflect how patients take a drug in the real world.

Drug Monitoring

The WHO, a United Nations body, set up its collaborating center for drug monitoring in 1968 after the thalidomide scandal, in which pregnant women who took the medicine for morning sickness gave birth to children with stunted limbs and other malformities. Now based in the Swedish university town of Uppsala, the center pools adverse events from 83 countries, including the U.S.

Dr. Edwards, a 64-year-old Briton with a background in internal medicine and clinical pharmacology, took the center's helm in 1990. His first experience with puzzling side effects came during a stint at the University of Zimbabwe almost 30 years ago. There, he noticed some patients with a rare skin condition, and tracked down some antibiotics they were taking as the cause.

In the mid-1990s, Dr. Edwards's team developed a software program to mine data with the help of artificial-intelligence Ph.D.'s from a local university. The software made it easier to analyze adverse events for one drug in the context of all event reports and fish out signals of problems.

At first, Dr. Edwards needed permission to publish from the national drug regulators on whose data he relied. Then, at a conference in Hong Kong in 2002, national drug agencies including the FDA loosened their grip, allowing the WHO to publish without permission. Dr. Edwards also received the right to share his data with anyone who requested it, he says.


He gets about 200,000 new adverse-event reports and pinpoints about 60 serious signals a year. Usually he notifies national health authorities and goes no further. Only rarely does he publish his concern. One such case involved babies getting withdrawal symptoms when their mothers took certain antidepressants. That report appeared in 2005 in the Lancet.

Last fall, Dr. Edwards decided to see what his database could tell him about statins and Lou Gehrig's disease, known medically as amyotrophic lateral sclerosis or ALS. The progressive neurodegenerative disease is almost always fatal. He had heard from an American doctor about an ALS-like case that was seemingly related to statins. Dr. Edwards himself had a friend who developed another serious nerve disease, called peripheral neuropathy, after taking a statin.

With a few clicks, Dr. Edwards came upon the 40 cases of ALS in people taking statins, and his software told him the number was much higher than expected.

DATA DEBATE

• The Issue: An analysis by a drug-monitoring group suggests a link between cholesterol-lowering statins and Lou Gehrig's disease, but U.S. regulators say they don't believe there's a risk.
• The Background: Scientists are increasingly using data-mining software to sift through reports of adverse events involving drugs.
• What's Next: More studies to figure out what's happening.
Reviewing scientific literature, Dr. Edwards came up with a theory about the cases. All statins carry a warning on their label about a rare disorder that causes muscle pain or weakness, a long-known side effect of the drugs. More recently, studies have linked statins to peripheral neuropathy. Dr. Edwards speculated these diseases and ALS might be connected, since they involve some kind of neuromuscular degeneration, and he thought all might be triggered by statins in unusual instances.

Yet Dr. Edwards also learned that pharmaceutical companies and other researchers are studying statins as potential treatments for brain or nervous-system diseases such as Alzheimer's, multiple sclerosis and even ALS. Some believe the anti-inflammatory effects of statins may be useful in these diseases.

As Dr. Edwards reflected on whether to publish his findings, one point weighed heavily. ALS is rare -- it strikes about five in 100,000 people and affects some 350,000 people world-wide. By contrast, heart attacks are a leading cause of death, and statins have helped millions of people reduce their heart risk. Dr. Edwards didn't want to raise unwarranted fears about drugs whose value is well-documented.

"We were on the horns of a dilemma and it wasn't easy to resolve," Dr. Edwards says.

Behind the scenes at the FDA, officials were facing a similar dilemma. Ana Szarfman, an agency official who pioneered statistical analyses of adverse events, had noticed the ALS-statin signal in March 2006, about six months before it caught Dr. Edwards's attention. She was using the FDA's database, which overlaps with the WHO's but isn't identical. The FDA says that through the end of last year, about one-third of the ALS adverse-event reports in its database -- 99 of 298 -- involved people on statins.

Dr. Szarfman was known at the FDA for her sleuthing into unexpected side effects, such as the odd link between a Parkinson's-disease medicine, Mirapex, and isolated cases of compulsive gambling. She also helped confirm in 2001 that Baycol, a Bayer AG statin later withdrawn from the market, was linked to an especially high number of muscle-disease cases.

Dr. Szarfman took the ALS signal seriously and considered publishing an article about it. But she held off while the FDA took a closer look. The agency didn't want to jump to any conclusions about a life-saving class of drugs, officials say. Unlike the WHO, the FDA has the ability to press drug companies for more information. That's what it did in this case, asking Pfizer and other statin makers for all their clinical-trial data.

Statin Trials

Taken together, the long-term statin trials involved 120,000 patients. The number of ALS cases came to 20, spread equally between statin takers and those on placebo.

"The result of the analysis was very reassuring," says Dr. Temple, who takes a statin himself. "I personally was relieved because I like my statins."

Dr. Temple says a close look at the FDA's adverse-event data suggested some reports might be unreliable. Slightly more than half of the adverse-event reports in the FDA's database about statins and ALS were submitted by consumers, which is unusual because doctors usually account for the lion's share. Also, some of the ALS cases were reported soon after the patients had started taking statins, raising doubts about whether the drug could have been the cause. Officials noted that the incidence of ALS in the general population hasn't risen since statins became popular.

The FDA plans to publish an academic paper about its statistical findings soon, says an agency official. But based on the analysis of clinical trials, it decided it didn't need to issue any caution about statins.

Dr. Edwards came to a different conclusion. He talked the issue over with his staff and P. Murali Doraiswamy, an expert in neurodegenerative diseases at Duke University who has done research on statins and the brain. Dr. Doraiswamy agreed that the ALS signal was worrisome and should be investigated.

After months of hesitation, Dr. Edwards came across a study by Greek researchers that helped make up his mind. Typically, ALS leads to death within three to five years, usually because the lungs fail when the neurons that send instructions to the respiratory system stop working. But in some rare cases, ALS-like symptoms could be halted or even reversed, the study said. Dr. Edwards decided his finding might help some patients prevent their disease from deteriorating. He wrote a paper and submitted it to two prestigious journals.

Both journals, the British Medical Journal and the Lancet, rejected it, he says. Fiona Godlee, the BMJ's editor, says she can't comment on specific papers, but she calls adverse events hard to interpret. "You only have a record of the people who developed problems, without knowing how many people took the drug and didn't develop problems," she says. The Lancet declined to comment.

Dr. Edwards pitched his paper to Drug Safety, a little-known journal based in New Zealand, which rushed it into print last month.

The paper acknowledges that some Internet sites have been discussing an ALS-statin link for at least a year, raising the possibility of skewed reporting of adverse events. But it notes that the number of events was also high earlier in the decade, before the majority of the Internet postings. The paper calls on patients using statins to talk to their doctor about stopping if they experience severe neuromuscular symptoms.

Pfizer, which brings in nearly $13 billion a year from Lipitor, says it too noticed the ALS signal last year in adverse-event reports, but concluded there was nothing to it after examining all its data. The company says Dr. Edwards has the right to publish what he found, but signals derived from adverse events can unnecessarily alarm the public and create needless headaches for drug companies.

Manfred Hauben, a Pfizer medical director, has long specialized in analyzing adverse events, and several years ago started using sophisticated software adopted by Pfizer. A math junkie who jokes that he suffers from an impulse-control disorder and stays awake at night studying statistics, Dr. Hauben says his enthusiasm for data mining has cooled.

He says with so many drugs and diseases, mere coincidence will create some worrisome-looking links. "Especially when you're looking for rare events, most positive results are going to be false positives," he says. Also, data mining presents "a lot of opportunities to retrofit an analysis to pre-existing expectations," he says. "Two different vendors' software can give two different results."

Prompting Research

Dr. Edwards says his paper is merely intended to prompt more research into the matter -- not cause millions of heart patients on statins to panic and stop the drugs.

But he hopes it will be useful to some patients. "Suppose you started to get symptoms and your doctor said, 'Now you have two years to live,' " he says. "Wouldn't you want to know that there's some possibility that the disease is linked to the drug so you could stop taking the drug?"

Dr. Edwards isn't persuaded by the clinical-trial data collected by the FDA. The signal wouldn't necessarily show up there, he says, because ALS is so rare.

Sheila O'Donovan, a 62-year-old retired journalist who lives in Delray Beach, Fla., wishes the signal had been publicized sooner. Ms. O'Donovan was on Lipitor when she started losing control of her right thumb in 2005. Soon, she was limping and slurring her words. After going off the drug in April of last year, she suddenly felt "brighter," her muscle cramps stopped and she was able to swallow more easily, she wrote in an email. But the improvement was short-lived. Her neurologist diagnosed her with ALS last September and she's gone downhill since. Her voice is now almost gone and she needs a wheelchair to get around.

More evidence could be available in a year or two. Beatrice Golomb, an associate professor of medicine at the University of California, San Diego, is analyzing case reports of people who developed ALS-like symptoms after taking statins. And researchers at Stanford University are looking at patient records in Northern California kept by Kaiser Permanente, a big health-maintenance organization, to see whether people who developed ALS were more likely than control subjects to have used statins.

Write to Avery Johnson at avery.johnson@wsj.com

Lipid-Lowering Drugs Protect Against Peripheral Diabetic Neuropathy

A major epidemiological study conducted over eight years in Australia has shown that two classes of lipid- lowering drugs -- statins and fibrates -- significantly lower the risk of developing nerve damage known as peripheral sensory diabetic neuropathy, according to a report presented today at the American Diabetes Association's 67th Annual Scientific Sessions.

"Statins and fibrates, drugs already highly recommended for people with type 2 diabetes to help prevent heart attacks, now also appear to help prevent one form of diabetic nerve damage called 'peripheral neuropathy,' a common complication of diabetes," said Timothy Davis, MD, PhD, Professor of Medicine, at the University of Western Australia, and principal investigator of the study, in a recent interview. "Statins or fibrates reduced the risk of developing peripheral neuropathy by 35% or 48%, respectively, although these should be considered comparable risk reductions because of the wide confidence intervals." A correct estimate falls into a statistical range called a confidence interval, and the range in this instance means that the two estimates are indistinguishable, statistically speaking.

Peripheral neuropathy is the most common form of nerve damage caused by diabetes, affecting approximately 50% of those with diabetes. Damaged nerves can cause stinging or burning sensations, tingling, pain, numbness or weakness in the hands and feet. Although many medications have been used to treat the condition's symptoms, many fail, and preventing the condition by means other than controlling blood glucose levels, has also proven difficult. The project was essentially two studies in one: a large cross-sectional snapshot and a longitudinal five-year study of a subsection of the larger group.

Nearly 21 million Americans have diabetes, a group of serious diseases characterized by high blood glucose levels that result from defects in the body's ability to produce and/or use insulin. Diabetes can lead to severely debilitating or fatal complications, such as heart disease, blindness, kidney disease, nerve damage, and amputations. It is the fifth leading cause of death by disease in the U.S.

All of the study participants had type 2 diabetes, which involves insulin resistance -- the body's inability to properly use its own insulin. Type 2 used to occur mainly in adults who were overweight and ages 40 and older. Now, as more children and adolescents become overweight and inactive, type 2 diabetes is occurring more often in young people.

METHODOLOGY AND FINDINGS

The researchers assessed the relationship between lipid-lowering therapy and the prevalence and incidence of peripheral neuropathy, based on scoring on the Michigan Neuropathy Screening Instrument -- one of the most sensitive and specific tools for screening for the condition -- in a large representative cohort of adults. Prevalence measures how much of a disease or condition there is in a population at a particular point in time. Incidence measures the rate of occurrence of new cases of a disease or condition.

The cross-sectional sample was comprised of all 1,294 of those recruited to the Fremantle Diabetes Study between 1993 and 1996.

At their entrance into the study, the participants average age was 64 years, with their diabetes diagnosed four years previously, 48.8% were male, and 30.9% had neuropathy. Fibrates and statins were used by 3.5% and 6.8%, respectively.

Older age, longer diabetes duration, central adiposity, increasing height, higher fasting plasma glucose, higher systolic blood pressure, higher urinary albumin to creatinine ratios, and indigenous racial background were all independently associated with prevalent peripheral neuropathy at baseline, while use of fibrates was associated with a 70% reduction in neuropathy prevalence.

The longitudinal sub-group was comprised of 531 people who had attended six comprehensive annual health assessments by November 2001. Use of fibrates and statins increased to 10.4% and 36.5%, respectively, during the five years of follow-up. The results were controlled for potential confounding variables, including changes in A1C levels, a measure of long-term blood glucose control.

Time to development of newly diagnosed peripheral neuropathy in the longitudinal sub-group showed that fibrates and statins reduced neuropathy risk by 48% and 35% respectively. Further, they may have independent action. "In our analysis, the beneficial effects of the drugs were independent of each other and they may work through different mechanisms," said Dr. Davis. "It's just a hypothesis, but taking both drugs may yield greater benefit than taking either drug alone."

At the outset, in the cross-sectional study, the fibrate participants were using gemfibrozil, and the statins in use were atorvastatin, simvastatin and pravastatin. At the end of the longitudinal study, gemfibrozil continued to be the primary fibrate used, although some had begun to use fenofibrate. By then atorvastatin was the predominant statin, although simvastatin and pravastatin also continued to be in use.

"We believe these benefits are class effects of these drugs," said Dr. Davis. While many mechanisms have been proposed, their mechanism of action in neuropathy remains unknown. The leading theory for statins seems to be a reduction of both inflammation and oxidative stress.

RECOMMENDATIONS

Although laboratory and animal studies have provided evidence that both statins and fibrates may protect against nerve damage, anecdotal clinical reports have associated their use with a reversible clinical neuropathy. In light of the new findings, Dr. Davis suggested that such reports may have been coincidence -- the individuals were developing neuropathy anyway -- or perhaps that there may be a small number of people who were sensitive to the drug but, he emphasized, with greater numbers who may benefit from taking it.

"People with diabetes should not shy away from taking these drugs for both heart and neuropathy benefits," he said. "Whether a fibrate or statin should be taken is never an easy choice, but a statin is usually the first line drug because of the strong evidence of cardiovascular disease prevention benefits."

Co-authors with Dr. Davis were Bu Yeap, MD, PhD, David G. Bruce, MD, PhD, and Wendy A. Davis, PhD, all of the University of Western Australia.

The American Diabetes Association is the nation's leading voluntary health organization supporting diabetes research, information and advocacy. Founded in 1940, the Association has offices in every region of the country, providing services to hundreds of communities.

American Diabetes Association
http://www.diabetes.org