Posts tagged statins
Articles and news from the latest research reports.
Statin Use Not Linked to a Decline in Cognitive Function
Based on the largest comprehensive systematic review to date, researchers at the Perelman School of Medicine at the University of Pennsylvania concluded that available evidence does not support an association between statins and memory loss or dementia. The new study, a collaborative effort between faculty in Penn Medicine’s Preventive Cardiovascular Program, the Penn Memory Center, and the Penn Center for Evidence-Based Practice, will be published in Annals of Internal Medicine.
“Statins are prescribed to approximately 30 million people in the United States, and these numbers may increase as a result of the national cholesterol guidelines recently released,” said senior study author Emil deGoma, MD, assistant professor of Medicine and medical director of the Preventive Cardiovascular Program at Penn. “A wealth of data supports a benefit of these cholesterol-lowering medications among individuals at risk for cardiovascular disease in terms of a reduction in the risk of heart attack and stroke; however, potential side effects of statins are less well understood. In February 2012, largely based on anecdotal reports, the U.S. Food and Drug Administration (FDA) issued a safety statement warning patients of possible adverse cognitive effects associated with statin use. Many concerned patients have asked if there is a relationship between statins and memory problems. Their concerns, along with the FDA statement, prompted us to pursue a rigorous analysis of all available evidence to better answer the question – are statins associated with changes in cognition?”
The research team conducted a systematic review of the published literature and identified 57 statin studies reporting measures of cognitive function. Dr. deGoma and colleagues found no evidence of an increased risk of dementia with statin therapy. In fact, in cohort studies, statin users had a 13 percent lower risk of dementia, a 21 percent lower risk of Alzheimer’s disease, and a 34 percent lower risk of mild cognitive impairment compared to people who did not take statins.
Most importantly, cognitive test scores were not adversely affected by statin treatment in randomized controlled trials. In these trials, roughly half of the study participants received statins and the other half received placebo. All study participants underwent formal testing of memory and other cognitive domains through tests such as the ability to recall a set of numbers. The analysis of 155 cognitive tests spanning eight categories of cognitive function, including 26 tests of memory, revealed no differences between study participants treated with statins and those provided placebo.
The research team additionally performed an analysis of the FDA post-marketing surveillance databases and found no difference in the frequency of cognitive adverse event reports between statins and two commonly prescribed cardiovascular medications that have not been associated with cognitive impairment, namely, clopidogrel and losartan.
“Overall, these findings are quite reassuring. I wouldn’t let concerns about adverse effects on cognition influence the decision to start a statin in patients suffering from atherosclerotic disease or at risk for cardiovascular disease. I also wouldn’t jump to the conclusion that statins are the culprit when an individual who is taking a statin describes forgetfulness. We may be doing more harm than good if we withhold or stop statins – medications proven to reduce the risk of heart attack and stroke – due to fears that statins might possibly cause memory loss,” said Dr. deGoma.
The team acknowledges that while their analysis is reassuring, large, high-quality randomized controlled trials are needed to confirm their findings.
“For many of the cognitive outcomes that we examined, the identified studies were small, were at risk for bias, used varying diagnostic tests to assess cognitive domains, and did not include patients on high-dose statins, which is important given the increasing use of high-dose statins for secondary prevention,” noted study co-author Craig Umscheid, MD, MSCE, assistant professor of Medicine and Epidemiology and director of the Penn Center for Evidence-based Practice. “Thus, additional trials addressing these limitations would strengthen our conclusions. Despite this, the totality of the evidence does reassure us that there’s unlikely to be a significant link between statins and cognitive impairment.”
Study finds link between commonly prescribed statin and memory impairment
New research that looked at whether two commonly prescribed statin medicines, used to lower low-density lipoprotein (LDL) or‘bad cholesterol’ levels in the blood, can adversely affect cognitive function has found that one of the drugs tested caused memory impairment in rats.
Between six and seven million people in the UK take statins daily and the findings follow anecdotal evidence of people reporting that they feel that their newly prescribed statin is affecting their memory. Last year, the US Food and Drug Administration (FDA) insisted that all manufacturers list in their side effects that statins might affect cognitive function.
The study, led by scientists at the University of Bristol and published in the journal PLOS ONE, tested pravastatin and atorvostatin (two commonly prescribed statins) in rat learning and memory models. The findings show that while no adverse cognitive effects were observed in rat performance for simple learning and memory tasks for atorvostatin, pravastatin impaired their performance.
Rats were treated daily with pravastatin (brand name - Pravachol) or atorvostatin (brand name - Lipitor) for 18 days. The rodents were tested in a simple learning task before, during and after treatment, where they had to learn where to find a food reward. On the last day of treatment and following one week withdrawal, the rats were also tested in a task which measures their ability to recognise a previously encountered object (recognition memory).
The study’s findings showed that pravastatin tended to impair learning over the last few days of treatment although this effect was fully reversed once treatment ceased. However, in the novel object discrimination task, pravastatin impaired object recognition memory. While no effects were observed for atorvostatin in either task.
The results suggest that chronic treatment with pravastatin impairs working and recognition memory in rodents. The reversibility of the effects on stopping treatment is similar to what has been observed in patients, but the lack of effect of atorvostatin suggests that some types of statin may be more likely to cause cognitive impairment than others.
Neil Marrion, Professor of Neuroscience at Bristol’s School of Physiology and Pharmacology in the Faculty of Medical and Veterinary Sciences and the study’s lead author, said: “This finding is novel and likely reflects both the anecdotal reports and FDA advice. What is most interesting is that it is not a feature of all statins. However, in order to better understand the relationship between statin treatment and cognitive function, further studies are needed.”
(Source: bris.ac.uk)
Statins Suppress Rett Syndrome Symptoms in Mice
Statins, a class of cholesterol-lowering drugs found in millions of medicine cabinets, may help treat Rett Syndrome, according to a study published today in Nature Genetics. The Rett Syndrome Research Trust (RSRT) funded this work with generous support from the Rett Syndrome Research Trust UK and Rett Syndrome Research & Treatment Foundation.
Rett Syndrome is a neurological disorder that affects girls. A seemingly typical toddler begins to miss developmental milestones. A regression follows as young girls lose speech, mobility, and hand use. Many girls have seizures, orthopedic and severe digestive problems, as well as breathing and other autonomic impairments. Most live into adulthood and require total, round-the-clock care. Rett Syndrome affects about 1 in 10,000 girls born in the U.S. each year.
The new study screened for randomly induced mutations in genes that modify the effect of the Rett gene, MECP2 (methyl-CpG-binding protein 2), in a mouse model. MECP2 turns other genes on or off by disrupting chromatin, the DNA-protein mix that makes up chromosomes.
The challenge of treating Rett Syndrome is what drove senior author Monica Justice, Ph.D., Professor in the Departments of Molecular and Human Genetics and Molecular Physiology and Biophysics at the Baylor College of Medicine, to look beyond MECP2, hoping to find new drug targets that might improve symptoms or even reverse the course of the disease. In 2007, Adrian Bird, Ph.D., Buchanan Professor of Genetics at the Wellcome Trust Centre for Cell Biology at the University of Edinburgh, showed that symptoms in mice are reversible regardless of the age of the animal.
Exploring cholesterol metabolism in neurological diseases is an emerging area, with statin drugs being tested in fragile X syndrome, neurofibromatosis, amyotrophic lateral sclerosis, and other conditions. But it hadn’t been on the radar for Rett Syndrome. “Our screen was to see if we could suppress the symptoms to reveal alternative pathways to treatment. The cholesterol hit was a big one,” Dr. Justice said. The screen was unbiased – the researchers were looking for any gene that would interact with MECP2 in a useful way, rather than employing a candidate gene approach based on hypotheses.
Dr. Justice and her team injected healthy male mice with a chemical called ENU (a form of nitrosourea) that mutates sperm stem cells randomly, then mated the males to Rett females. The researchers then looked for offspring that should have developed the syndrome (according to their genes), but didn’t (according to their good health).
Key to the investigation was being able to tell sick mice from healthy ones. Fortunately this turned out to be easy. The rescued mice didn’t develop the characteristic tremor, trouble breathing, poor limb-clasping, and general scruffiness of their affected cage-mates. They moved around more, performed better on mobility tests and lived longer.
Once the rescued mice had been identified the random gene mutations from the 24,000 genes that make up the mouse genome had to be pinpointed. “With next generation DNA sequencing, we are finding mutations so easily and quickly. It’s amazing,” said Dr. Justice, compared to the old days of setting up many more generations of crosses to narrow down a part of the genome harboring a gene of interest.
“We are only15% of the way through the screen, and so far we have identified 5 modifiers. The most drug-targetable is a gene called squalene epoxidase (Sqle), which encodes a rate-limiting enzyme in the cholesterol biosynthetic pathway. Frankly, this discovery was a surprise,” Dr. Justice said. It’s important to note that this enzyme is different from the rate-limiting enzyme (HMG CoA reductase) influenced by statin drugs.
Cholesterol is of course best known for its negative effects on the cardiovascular system, but the lipid has multiple roles in the brain: it helps to form the myelin insulation on neurons and takes part in membrane trafficking, dendrite remodeling, synapse formation, signal transduction, and neuropeptide synthesis.
The next step was to test several statins (fluvastatin and lovastatin) on Rett mice. Like the Sqle mutation, the drugs improved symptoms. Treated mice performed well on mobility and gross motor tests, had better overall health scores and lived longer. The drugs didn’t, however, improve breathing.
“When we saw the mutation in a cholesterol pathway enzyme, we immediately thought of statin drugs. Now that our eyes have opened to what is going on, we have a multitude of drugs that modulate lipid metabolism that we can try in addition to statins,” said first author Christie Buchovecky, graduate student in the Justice lab.
With additional RSRT funding, pediatric neurologist and Director of the Tri-State Rett Syndrome Center in the Bronx Dr. Sasha Djukic undertook a detailed review of lipid data in girls with Rett Syndrome. She found that a subset have elevated cholesterol levels which normalize as they age. These data are not included in the Nature Genetics publication but will be part of a subsequent paper. Dr. Djukic is now planning a clinical trial.
Drs. Justice and Djukic caution that carefully designed and rigorously executed clinical trials are essential to test whether what works in mice will also work in girls with Rett Syndrome. Clinical trials should also determine the most effective timeframe for treatment, ways to identify which girls are most likely to respond, (for example, will statins help girls with Rett who do not have elevated cholesterol?), which drugs to trial and what dosages are effective but not toxic.
“Although statins are blockbuster drugs taken by a large percentage of the population they are not without risks and side-effects, and data on statins in the general pediatric population are quite limited. One of the key objectives of the clinical trial will be to determine correct dosages for Rett symptoms. It’s important to note that the mice in Dr. Justice’s study received very low doses of statins. I urge parents to resist any temptation to medicate their children with off-label statins,” cautions Dr Djukic. “The only way to know if this class of drugs will be efficacious in Rett is through controlled trials. Working with Dr. Justice and RSRT we will be bringing families additional information as soon as possible.”
“The biggest finding is the discovery that this pathway is so important to the pathology of the disorder; it suggests new directions for trying to learn more about Rett Syndrome,” Dr. Justice explains. “Emerging evidence from both mice and humans suggest that Rett Syndrome may have a component of disease that is metabolic. Certainly, this study will further clarify our data, and may suggest avenues for treatment that were previously unexplored.”
(Source: rsrt.org)
Research Reveals Possible Reason for Cholesterol-Drug Side Effects
The U.S. Food and Drug Administration and physicians continue to document that some patients experience fuzzy thinking and memory loss while taking statins, a class of global top-selling cholesterol-lowering drugs.
A University of Arizona research team has made a novel discovery in brain cells being treated with statin drugs: unusual swellings within neurons, which the team has termed the “beads-on-a-string” effect.
The team is not entirely sure why the beads form, said UA neuroscientist Linda L. Restifo, who leads the investigation. However, the team believes that further investigation of the beads will help inform why some people experience cognitive declines while taking statins.
"What we think we’ve found is a laboratory demonstration of a problem in the neuron that is a more severe version for what is happening in some peoples’ brains when they take statins," said Restifo, a UA professor of neuroscience, neurology and cellular and molecular medicine, and principal investigator on the project.
Restifo and her team’s co-authored study and findings recently were published in Disease Models & Mechanisms, a peer-reviewed journal. Robert Kraft, a former research associate in the department of neuroscience, is lead author on the article.
Restifo and Kraft cite clinical reports noting that statin users often are told by physicians that cognitive disturbances experienced while taking statins were likely due to aging or other effects. However, the UA team’s research offers additional evidence that the cause for such declines in cognition is likely due to a negative response to statins.
The team also has found that removing statins results in a disappearance of the beads-on-a-string, and also a restoration of normal growth.
With research continuing, the UA team intends to investigate how genetics may be involved in the bead formation and, thus, could cause hypersensitivity to the drugs in people. Team members believe that genetic differences could involve neurons directly, or the statin interaction with the blood-brain barrier.
"This is a great first step on the road toward more personalized medication and therapy," said David M. Labiner, who heads the UA department of neurology. "If we can figure out a way to identify patients who will have certain side effects, we can improve therapeutic outcomes."
For now, the UA team has multiple external grants pending, and researchers carry the hope that future research will greatly inform the medical community and patients.
"If we are able to do genetic studies, the goal will be to come up with a predictive test so that a patient with high cholesterol could be tested first to determine whether they have a sensitivity to statins," Restifo said.
Detecting, Understanding a Drugs’ Side Effects
Restifo used the analogy of traffic to explain what she and her colleagues theorize.
The beads indicate a sort of traffic jam, she described. In the presence of statins, neurons undergo a “dramatic change in their morphology,” said Restifo, also a BIO5 Institute member.
"Those very, very dramatic and obvious swellings are inside the neurons and act like a traffic pileup that is so bad that it disrupts the function of the neurons," she said.
It was Kraft’s observations that led to team’s novel discovery.
Restifo, Kraft and their colleagues had long been investigating mutations in genes, largely for the benefit of advancing discoveries toward the improved treatment of autism and other cognitive disorders.
At the time, and using a blind-screened library of 1,040 drug compounds, the team ran tests on fruit fly neurons, investigating the reduction of defects caused by a mutation when neurons were exposed to different drugs.
The team had shown that one mutation caused the neuron branches to be curly instead of straight, but certain drugs corrected this. The research findings were published in 2006 in the Journal of Neuroscience.
Then, something serendipitous occurred: Kraft observed that one compound, then another and then two more all created the same reaction – “these bulges, which we called beads-on-a-string,’” Kraft said. “And they were the only drugs causing this effect.”
At the end of the earlier investigation, the team decoded the library and found that the four compounds that resulted in the beads-on-a-string were, in fact, statins.
"The ‘beads’ effect of the statins was like a bonus prize from the earlier experiment," Restifo said. "It was so striking, we couldn’t ignore it."
In addition to detecting the beads effect, the team came upon yet another major finding: when statins are removed, the beads-on-a-string effect disappears, offering great promise to those being treated with the drugs.
"For some patients, just as much as statins work to save their lives, they can cause impairments," said Monica Chaung, who has been part of the team and is a UA undergraduate researcher studying molecular and cellular biology and physiology.
"It’s not a one drug fits all," said Chaung, a UA junior who is also in the Honors College. "We suspect different gene mutations alter how people respond to statins."
Having been trained by Kraft in techniques to investigate cultured neurons, Chuang was testing gene mutations and found variation in sensitivity to statins. It was through the work of Chuang and Kraft that the team would later determine that, after removing the statins, the cells were able to repair themselves; the neurotoxicity was not permanent, Restifo said.
"In the clinical literature, you can read reports on fuzzy thinking, which stops when a patient stops taking statins. So, that was a very important demonstration of a parallel between the clinical reports and the laboratory phenomena," Restifo said.
The finding led the team to further investigate the neurotoxicity of statins.
"There is no question that these are very important and very useful drugs," Restifo said. Statins have been shown to lower cholesterol and prevent heart attacks and strokes.
But too much remains unknown about how the drugs’ effects may contribute to muscular, cognitive and behavioral changes.
"We don’t know the implications of the beads, but we have a number of hypotheses to test," Restifo said, adding that further studies should reveal exactly what happens when the transportation system within neurons is disrupted.
Also, given the move toward prescribing statins to children, the need to have an expanded understanding of the effects of statins on cognitive development is critical, Kraft said.
"If statins have an effect on how the nervous system matures, that could be devastating," Kraft said. "Memory loss or any sort of disruption of your memory and cognition can have quite severe effects and negative consequences."
Restifo and her colleagues have multiple grants pending that would enable the team to continue investigating several facets related to the neurotoxicity of statins. Among the major questions is, to what extent does genetics contribute to a person’s sensitivity to statins?
"We have no idea who is at risk. That makes us think that we can use this genetic laboratory assay to infer which of the genes make people susceptible," Restifo said.
"This dramatic change in the morphology of the neurons is something we can now use to ask questions and experiment in the laboratory," she said. "Our contribution is to find a way to ask about genetics and what the genetic vulnerability factors are."
The Possibility for Future Research, Advice
The team’s findings and future research could have important implications for the medical field and for patients with regard to treatment, communication and improved personalized medicine.
"It’s important to look into this to see if people may have some sort of predisposition to the beads effect, and that’s where we want to go with this research," Kraft said. "There must be more research into what effects these drugs have other than just controlling a person’s elevated cholesterol levels."
And even as additional research is ongoing, suggestions already exist for physicians, patients and families.
"Most physicians assume that if a patient doesn’t report side effects, there are no side effects," Labiner said.
"The paternalistic days of medication are hopefully behind us. They should be," Labiner said.
"We can treat lots of things, but the problem is if there are side effects that worsen the treatment, the patient is more likely to shy away from the medication. That’s a bad outcome," he said. "There’s got to be a give and take between the patient and physician."
Patients should feel empowered to ask questions, and deeper questions, about their health and treatment and physicians should be very attentive to any reports of cognitive decline for those patients on statins, she said.
For some, it starts early after starting statins; for others, it takes time. And the signs vary. People may begin losing track of dates, the time or their keys.
"These are not trivial things. This could have a significant impact on your daily life, your interpersonal relationships, your ability to hold a job," Restifo said.
"This is the part of the brain that allows us to think clearly, to plan, to hold onto memories," she said. "If people are concerned that they are having this problem, patients should ask their physicians."
Restifo said open and direct patient-physician communication is even more important for those on statins who have a family history of side effects from statins.
Also, physicians could work more closely with patients to investigate family history and determine a better dosage plan. Even placing additional questions on the family history questionnaire could be useful, she said.
"There is good clinical data that every-other-day dosing give you most of the benefits, and maybe even prevents some of the accumulation of things that result in side effects," Restifo said, suggesting that physicians should try and get a better longitudinal picture on how people react while on statins.
"Statins have been around now for long enough and are widely prescribed to so many people," she said. "But increased awareness could be very helpful."