Health for life

A new study has found that many people who stopped taking cholesterol-lowering statin drugs were also taking an average of three other drugs that interfered with the normal metabolism of the statins.

The other drugs can contribute to a common side effect of taking statins - muscle pain – and often led people to discontinue use of a medication that could otherwise help save their life, researchers learned.

The interactions of many drugs with statins have been known of for some time, researchers said, but are not being adequately managed by physicians and pharmacists, who could often choose different medications or adjust dosages to retain the value of statin drugs without causing this side effect.

The research, done as part of a survey of more than 10,000 current and former statin users, found that use of medications which interfere with statin metabolism almost doubles the chance that a person will discontinue statin use due to muscle pain.

The issue is of growing importance because statin drugs are some of the most widely used medications in the world, proven to lower LDL, or “bad” cholesterol, and decrease the risk of heart attacks, heart disease, strokes and death. About 20 million people in the U.S. now take statins, and new guidelines have just been issued to further expand the types of health conditions for which statins may be of benefit. Based on those guidelines, the number of statin users could increase to more than 30 million.

The findings were published in the Journal of Clinical Lipidology by scientists from Oregon State University and four other universities or research institutes.

“We’ve known for some time of many medications that can interact with statins, but only now is it becoming clear that this is a significant contributor to the side effects, and often the reason some patients stop taking statins,” said Matt Ito, a professor in the OSU College of Pharmacy and president of the National Lipid Association, which funded this study.

“This issue is something physicians, pharmacists and patients all need to be more aware of,” Ito said. “There’s a lot we can do besides discontinue use of these valuable medications. You can change dosages, use drugs that don’t cause interactions, use different types of statins. Patients need to be proactive in understanding this issue and working with their health care providers to address it.”

Persons who have problems taking statins should discuss options with their physicians or pharmacists, Ito said, and not assume the drug has be to discontinued. A Medscape web site at http://erence.medscape.com/drug-interactionchecker also can help individuals learn more about possible interactions between statins and the full range of medications they may be taking.

Statins are usually well-tolerated, but in the recent survey, a muscle-related side effect was reported by 29 percent of participants. In former statin users, 62 percent of the people said that side effects, mostly muscle pain, were the reason they stopped taking the drugs.

There are many drugs that can interfere with statin metabolism, increase systemic exposure to the statin and raise the risk of this muscle pain, the researchers said in their report. This can include some common antibiotics, cardiovascular drugs, and others taken for treatment of cancer, mental health, HIV treatment and other conditions.

These interactions are not always adequately considered by physicians and pharmacists, however. One recent report found that as many as 20 percent of significant statin-drug interactions were missed in 64 pharmacies.

Besides drug interactions, statin side effects are also more common in women and associated with increasing age, history of cardiovascular disease, and some other conditions. Statin discontinuation has been associated with increased cardiovascular morbidity and death.

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 UK1 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 studys 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 Bristols School of Physiology and Pharmacology and the studys lead author, said: "This finding is novel and likely lects 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."

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 Medicines 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," 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 Alzheimers 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 wouldnt 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 wouldnt 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 theres unlikely to be a significant link between statins and cognitive impairment."

Statins -- the popular class of cholesterol-lowering drugs used widely to prevent recurrent heart disease or stroke as well as risk for having a first cardiac or stroke event -- appear to cause few side effects, according to new research reported in Circulation: Cardiovascular Quality and Outcomes.

Researchers conducted the largest meta-analysis on statin side effects to date, reviewing data from 135 previous drug studies to evaluate the safety of the seven statins on the market. They concluded "as a class, adverse events associated with statin therapy are not common."

Researchers noted that simvastatin and pravastatin, the generic names of the brands Zocor and Pravachol, were found to have the best safety profile in the class. This is particularly true when patients were prescribed low to moderate doses of those statins, said Huseyin Naci, M.H.S., the studys lead author and a doctoral candidate at the London School of Economics and Political Science and research fellow at Harvard Medical Schools Department of Population Medicine.

Researchers also noted a 9 percent increased risk of diabetes among statin users. But according to a previous landmark study, 250 patients need to be treated with a statin for one case of diabetes to be diagnosed.

"I am concerned that patients may misunderstand this small increase in risk and stop adhering to their medications," Naci said. The proven ability of statins to significantly cut the rate of death and hospitalization in patients who have heart disease outweighs the "small increase in diabetes risk," he said.

Researchers reviewed trials published between 1985 and early 2013, which included almost 250,000 patients. On average, the trials lasted a bit longer than a year. Some compared one statin to another, while others compared a statin to an inactive placebo, which is often called a sugar pill or dummy pill.

The study also found that statins were not linked to an increase in cancer risk. However, the drugs were associated with a typically reversible increase in liver enzymes, which Naci said still resulted in a very low rate of actual liver toxicity in statin patients.

"Although the benefits of statins clearly outweigh risks at the population level, individualizing such benefits and risks is more difficult," he said. "This brings into sharp focus the importance of identifying the individuals who stand to benefit the most from statin therapy.

Although the risk of developing diabetes is low, what this risk would amount to over time is simply not known based on the existing evidence," Naci said.

A laboratory study has shown for the first time that coenzyme Q10 offsets cellular changes that may be linked to a side-effect of some statin drugs - an increased risk of adult-onset diabetes.

Statins are some of the most widely prescribed drugs in the world, able to reduce LDL, or “bad” cholesterol levels, and the risk of heart attacks or other cardiovascular events. However, their role in raising the risk of diabetes has only been observed and studied in recent years.

The possibility of thousands of statin-induced diabetics is a growing concern, and led last year to new labeling and warnings by the Food and Drug Administration about the drugs, especially when taken at higher dosage levels.

The findings of the new research were published as a rapid communication in Metabolic Syndrome and Related Disorders, and offer another clue to a possible causative mechanism of this problem.

Pharmacy researchers at Oregon State University who authored the study said the findings were made only in laboratory analysis of cells, and more work needs to be done with animal and ultimately human studies before recommending the use of coenzyme Q10 to help address this concern.

“A number of large, randomized clinical trials have now shown that use of statins can increase the risk of developing type-2 diabetes by about 9 percent,” said Matthew K. Ito, an OSU professor of pharmacy and president-elect of the National Lipid Association.

“This is fairly serious, especially if you are in the large group of patients who have not yet had a cardiovascular event, but just take statin drugs to lower your risks of heart disease,” Ito said.

A suspect in this issue has been altered levels of a protein called GLUT4, which is part of the cellular response mechanism, along with insulin, that helps to control blood sugar levels. A reduced expression of GLUT4 contributes to insulin resistance and the onset of type-2 diabetes, and can be caused by the use of some statin drugs.

The statins that reduce cholesterol production also reduce levels of coenzyme Q10, research has shown. Coenzyme Q10 is needed in cells to help create energy and perform other important functions. And this study showed in laboratory analysis that if coenzyme Q10 is supplemented to cells, it prevents the reduction in GLUT4 induced by the statins.

Not all statin drugs, however, appear to cause a reduction in GLUT4.

The problems were found with one statin, simvastatin, that is “lipophilic,” which means it can more easily move through the cell membrane. Some of the most commonly used statins are lipophilic, including simvastatin, atorvastatin, and lovastatin. All of these statins are now available as generic drugs, and high dosage levels have been most often linked with the increase in diabetes.

Tests in the new study done with a “hydrophilic” statin, in this case pravastatin, did not cause reduced levels of GLUT4. Pravastatin is also available as a generic drug.

“The concern about increasing levels of diabetes is important,” Ito said. “We need to better understand why this is happening. There’s no doubt that statins can reduce cardiovascular events, from 25-45 percent, and are very valuable drugs in the battle against heart disease. It would be significant if it turns out that use of coenzyme Q10 can help offset the concerns about statin use and diabetes.”

Before that conclusion can be reached, the researchers said, additional studies are needed on coenzyme Q10 supplementation and the pathogenesis of statin-induced diabetes.