High Cholesterol Medication
Statins were linked to higher risk of acute idiopathic pancreatitis, especially during the first year of use, Finnish date suggested
Cholesterol is essential for the functioning of all human organs. Bile acids are synthesized from cholesterol in liver and are stored in the gallbladder. Gallstone disease is a common abdominal condition in developed countries. Some 80-90 % of gallstones formed within the gallbladder consist mainly of cholesterol in the western world. The prevalence of cholelithiasis is increasing. Acute pancreatitis (AP) is inflammation of the pancreas and ranges from mild symptoms to a life-threatening or life-ending process. It may progress to a chronic form leading to maldigestion and diabetes mellitus. The main causes for AP are alcohol use or small gallstone migration with obstruction of bile and pancreatic enzymes. Cholelithiasis is thus associated with pancreatitis. In up to 20% of AP the etiology is unknown. There are many possible etiologies for idiopathic pancreatitis, including drug-induced pancreatitis or microlithiasis. In animal models statins have been shown to decrease the size of gallstones. Hypercholesterolemia is a major cause of coronary heart disease and other manifestations of vascular atherosclerosis. Statins are used for the treatment of hypercholesterolemia in order to prevent cardiovascular events. In Finland there has been a 11-fold increase in statin use between 1995 and 2000 and approximately 660,000 individuals (12% of the population) purchased statins in 2012. Coinciding with the increase in statin use, there has been a notable increase in the number of patients with AP. The evidence concerning the association between statins and the risk of acute pancreatitis is inconclusive. Findings in case reports and two case–control studies have suggested that statins increase the risk of acute pancreatitis, whereas a recent meta-analysis suggested a protective association. To investigate the relationship of statins and pancreatitis, we carried out two studies in Kuopio University Hospital (461 admissions of patients with AP and 1140 patients with gallstones between 2008 - 2010) including patient cohort during (272 statin users and 272 controls). We found that statin therapy was significantly more frequent in patients with idiopathic acute pancreatitis than in other known etiologies. In patients with cholecystectomy there was no significant difference in outcome between the statin users and non-users, although statin users had more polypharmacy (including drugs that cause bleeding) and cardiovascular illnesses than non-users. The mean operation time for laparoscopic cholecystectomy was 10% shorter for the patients with statin use than for the patients without. Together with the Finnish Medicine Agency (Fimea) we carried out a large nationwide study and found that statin use was associated with an increased incidence of AP (OR 1.25, 95% CI 1.13-1.39). The incidence was elevated especially during the first year of use both among current and former statin users. Finally in a randomized study of 85 idiopathic pancreatitis patients (39 in the laparoscopic cholecystectomy and 46 in the control group) we found that 59% of operated patients had small gallstones in their gallbladder, although preoperative transabdominal ultrasonography was negative. We also found that recurrence of IAP was less common in patients undergoing LCC. Interestingly, the patients using lipid-lowering drugs had gallbladder stones in surgery less frequently than those without statins. Based on these data it is concluded that statin medication seems to affect the bile metabolisms also humans and patients who use statins have increased risk of pancreatitis. Cholecystectomy in statin-using patients is as safe as in non-users although statin users had more comorbidities than non-users. Recurrence of idiopathic pancreatitis can be prevented by laparoscopic cholecystectomy.
Source : Dissertation - Jukka Pulkkinen University of Eastern Finland
FDA probes cognitive impact of new cholesterol drugs
The Food and Drug Administration has asked Regeneron Pharmaceuticals Inc and Sanofi SA to assess potential neurocognitive side effects of their experimental cholesterol drug, Sanofi said in its annual report on Friday.
Amgen Inc, which is developing a similar drug, said it has also been in communication with the agency.
The FDA said it could not discuss specific development programs, but is "aware of concerns raised with neurocognitive adverse events and other lipid-lowering therapies, including statins, and as part of our oversight of new drug development, we are carefully monitoring these events."The new drugs are part of an experimental class known as PCSK9 inhibitors designed to block a protein that maintains "bad" LDL cholesterol in the bloodstream.
"We have not seen a neurocognitive adverse signal in the alirocumab data," Dr. Michael Aberman, Regeneron's vice president for strategy and investor relations, said in a telephone interview.
He said the alirocumab trials have been overseen by independent safety monitors.
"What the FDA asked us to do we don't expect to be difficult or time consuming," Aberman added.
Sanofi and Regeneron said they did not know how the FDA learned of the potential side effects, and they were not aware of any such side effects with alirocumab.
Pfizer Inc, also in the late stages of developing a PCSK9 drug, said in an emailed statement that it has not received a similar request from the FDA but is already assessing potential neurocognitive side effects in late-stage trials of its drug, bococizumab. "At this stage of our bococizumab development program, we are not aware of any neurocognitive safety signals," the company said.Amgen, which has said it could file for regulatory approval of PCSK9 drug evolocumab this year, said it has been proactively monitoring for cognitive impairment in its trials.
"Similar to other companies developing PCSK9 inhibitors, Amgen has been in communication with the FDA, and we will continue to investigate the potential for cognitive impairment in our program," Amgen said in an emailed statement.
The company said it has not seen any such signal so far.
Sanofi's report echoed a filing made by Regeneron last month, in which the company said the FDA advised it was aware of adverse neurocognitive effects associated with PCSK9 inhibitors.
Shares of Regeneron fell as much as 10 percent before paring losses to close down 3 percent, while shares of Amgen dropped 1.5 percent. U.S.-listed shares of France-based Sanofi fell 1 percent.
Rare side effects such as memory loss, impaired concentration, and paranoia have been associated with the use of statins for lowering LDL cholesterol, and their labels include warnings about cognitive impairment.
Statins, such as AstraZeneca PLC's Crestor and generic forms of Pfizer's Lipitor, are the most widely used cholesterol-lowering treatments and work by blocking the liver's production of LDL cholesterol."While we continue to believe the PCSK9 class has multi-billion dollar potential, we note that increased speculation on adverse events may increase the probability that the FDA could require outcomes data prior to full approval," JP Morgan analyst Geoff Meacham said in a research note.
The FDA said last year that PCSK9 drugs could get regulatory approval based on their ability to lower bad cholesterol, and may not need to show that they reduce the risk of heart attack and stroke.
In their filings, Sanofi and Regeneron said that if studies detect neurocognitive or other adverse side effects, development of alirocumab could fail or be delayed.
Source : Reuters (Mar 2014)
Cholesterol drug may block exercise benefits
Experts urge doctors to reconsider statins for obese patients after finding the cholesterol drug may block some benefits of exercise.
Statins, the most widely prescribed drugs worldwide, are often suggested to lower cholesterol and prevent heart disease in individuals with obesity, diabetes, and metabolic syndrome, which is a combination of medical disorders including excess body fat and/or high levels of blood pressure, blood sugar, and/or cholesterol.
Researchers, however, found that simvastatin, a generic type of statin previously sold under the brand name Zocor, hindered the positive effects of exercise for obese and overweight adults. The study appears in the Journal of the American College of Cardiology.
“Fitness has proven to be the most significant predictor of longevity and health because it protects people from a variety of chronic diseases,” says John Thyfault, an associate professor of nutrition and exercise physiology at the University of Missouri.
“Daily physical activity is needed to maintain or improve fitness, and thus improve health outcomes. However, if patients start exercising and taking statins at the same time, it seems that statins block the ability of exercise to improve their fitness levels.”
Thyfault says many cardiologists want to prescribe statins to all patients over a certain age regardless of whether they have metabolic syndrome; the drugs also are recommended for people with Type 2 diabetes. He recommends that cardiologists more closely weigh the benefits and risks of statins given this new data about their effect on exercise training.
“Statins have only been used for about 15-20 years, so we don’t know what the long-term effects of statins will be on aerobic fitness and overall health,” Thyfault says. “If the drugs cause complications with improving or maintaining fitness, not everyone should be prescribed statins.”
Three-month workout
Thyfault and his colleagues measured cardiorespiratory fitness in 37 previously sedentary, obese individuals ages 25-59 with low fitness levels. The participants followed the same exercise regimen for 12 weeks; 18 of the 37 people also took 40 mg of simvastatin daily. Statins significantly affected participants’ exercise outcomes.
Participants in the exercise-only group increased their cardiorespiratory fitness by an average of 10 percent compared to a 1.5 percent increase among participants also prescribed statins. Additionally, skeletal muscle mitochondrial content, the site where muscle cells turn oxygen into energy, decreased by 4.5 percent in the group taking statins while the exercise-only group had a 13 percent increase, a normal response following exercise training.
Thyfault suggests that future research determine whether lower doses of simvastatin or other types of statins similarly affect people’s exercise outcomes and thus their risk for diseases such as Type 2 diabetes. Starting a statin regimen after exercising and obtaining a higher fitness level may reduce the drugs’ effects on fitness, he says.
Source : Futurity
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Merck begins overseas recall of HDL cholesterol drug
Merck & Co said it is recalling Tredaptive, its medicine to raise "good" HDL cholesterol levels, in overseas markets where it is sold, after it failed to prevent heart problems in a large study and raised safety concerns.
The medicine is not approved in the United States but the U.S. drugmaker sells it in about 40 countries.
Merck said it would recall stocks of Tredaptive now held by wholesalers, but that pharmacies can continue to dispense their remaining supplies. Even so, the company said it plans to discourage doctors from prescribing the pill based on negative findings from the trial which were announced last month. The study followed more than 25,000 patients in Europe and China for almost four years.
The company said it will encourage doctors to consider alternative treatments to control cholesterol, but advised patients not to discontinue Tredaptive without first speaking with their physicians.
Merck spokeswoman Pam Eisele said the company expects available retail supplies of Tredaptive to be exhausted by mid-March.
Tredaptive combines an extended-release form of niacin with another drug meant to reduce facial flushing, a side effect of niacin. The medicine has annual sales of less than $20 million. That makes it a tiny product for Merck, which has global annual revenue of about $50 billion.
Merck in December said Tredaptive did no better in the study at preventing heart attacks, deaths or strokes than traditional statin drugs that lower "bad" LDL cholesterol.
Moreover, Merck said the medicine significantly raised the incidence of some types of nonfatal but serious side effects in the study. They included blood, lymph and gastrointestinal problems, as well as respiratory and skin issues.
Tredaptive was approved in the European Union in 2008, but the U.S. Food and Drug Administration was unwilling to approve the pill until Merck conducted the costly long-term study to better assess its safety and effectiveness.
Some analysts had expected Tredaptive to capture annual global sales of more than $1 billion, if it were to win approval in the United States.
Source : Reuters
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FDA Drug Safety Communication: Interactions between certain HIV or hepatitis C drugs and cholesterol-lowering statin drugs can increase the risk of muscle injury
Facts about statins and protease inhibitors
The U.S. Food and Drug Administration (FDA) is issuing updated recommendations concerning drug-drug interactions between drugs for human immunodeficiency virus (HIV) or hepatitis C virus (HCV) known as protease inhibitors and certain cholesterol-lowering drugs known as statins. Protease inhibitors and statins taken together may raise the blood levels of statins and increase the risk for muscle injury (myopathy). The most serious form of myopathy, called rhabdomyolysis, can damage the kidneys and lead to kidney failure, which can be fatal. The labels for both the HIV protease inhibitors and the affected statins have been updated to contain consistent information about the drug-drug interactions. These labels also have been updated to include dosing recommendations for those statins that may safely be co-administered with HIV or HCV protease inhibitors (see Statin Dose Limitations below).
Healthcare professionals should refer to the current drug labels for protease inhibitors and statins for the latest recommendations on prescribing these drugs.
Patients should contact their healthcare professional if they have any questions or concerns about taking protease inhibitors and statins.
Atorvastatin
The results from a drug-drug interaction study with atorvastatin and lopinavir/ritonavir that were previously in the atorvastatin label have not yet been validated. Therefore, these results have been removed from the label and the dose cap of atorvastatin 20 mg when co-administered with lopinavir/ritonavir has also been removed. Pending validation of the study, healthcare professionals should use caution when co-administering atorvastatin with lopinavir/ritonavir and use the lowest necessary dose of atorvastatin.
Lovastatin and simvastatin
Lovastatin and simvastatin are sensitive in vivo cytochrome P450 3A4 (CYP3A4) substrates. Therefore, strong CYP3A4 inhibitors are predicted to significantly increase lovastatin and simvastatin exposures. A literature review indicates that itraconazole, a strong CYP3A4 inhibitor, increases lovastatin exposure up to 20-fold, and the drug interaction appears to result in rhabdomyolysis.1 Itraconazole increases simvastatin exposure up to 13-fold. Hence, other CYP3A4 inhibitors, including ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, nefazodone, human immunodeficiency virus (HIV) protease inhibitors, and the hepatitis C virus (HCV) protease inhibitors boceprevir and telaprevir, are also expected to significantly increase lovastatin and simvastatin exposures. Therefore, concomitant administration of lovastatin and simvastatin with HIV protease inhibitors or HCV protease inhibitors (boceprevir and telaprevir) is contraindicated.
Rosuvastatin
The HIV protease inhibitor combinations lopinavir/ritonavir and atazanavir/ritonavir increase rosuvastatin exposure up to 3-fold. For these combinations, the dose of rosuvastatin should be limited to 10 mg.
Statin Dose Limitations
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Reference
Source : FDA
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FDA Drug Safety Communication: Important safety label changes to cholesterol-lowering statin drugs
The U.S. Food and Drug Administration (FDA) has approved important safety label changes for the class of cholesterol-lowering drugs known as statins. These changes were made to provide the public with more information for the safe and effective use of statins and are based on FDA’s comprehensive review of the statin class of drugs (see Data Summary below). The changes include the following: Infographic About Cholesterol and Statins
Monitoring Liver Enzymes
Labels have been revised to remove the need for routine periodic monitoring of liver enzymes in patients taking statins. The labels now recommend that liver enzyme tests should be performed before starting statin therapy and as clinically indicated thereafter. FDA has concluded that serious liver injury with statins is rare and unpredictable in individual patients, and that routine periodic monitoring of liver enzymes does not appear to be effective in detecting or preventing serious liver injury.
Adverse Event Information
Information about the potential for generally non-serious and reversible cognitive side effects (memory loss, confusion, etc.) and reports of increased blood sugar and glycosylated hemoglobin (HbA1c) levels has been added to the statin labels. FDA continues to believe that the cardiovascular benefits of statins outweigh these small increased risks.
Drug Interactions
The lovastatin label has been extensively updated with new contraindications (situations when the drug should not be used) and dose limitations when it is taken with certain medicines that can increase the risk for muscle injury (see Lovastatin Dose Limitations below).
Healthcare professionals should refer to the drug labels for the latest recommendations for prescribing statins (also see Additional Information for Healthcare Professionals below). Patients should contact their healthcare professional if they have any questions or concerns about statins.
Additional Information for Patients
Removal of routine monitoring of liver enzymes from drug labels
FDA reviewed current monitoring guidelines, including the National Lipid Association’s Liver Expert Panel and Statin Safety Task Force recommendations.1, 2 The Liver Expert Panel stated that the available scientific evidence does not support the routine monitoring of liver biochemistries in asymptomatic patients receiving statins. The Panel made this recommendation because (1) irreversible liver damage resulting from statins is exceptionally rare and is likely idiosyncratic in nature, and (2) no data exist to show that routine periodic monitoring of liver biochemistries is effective in identifying the very rare individual who may develop significant liver injury from ongoing statin therapy. The Panel believed that routine periodic monitoring will instead identify patients with isolated increased aminotransferase levels, which could motivate physicians to alter or discontinue statin therapy, thereby placing patients at increased risk for cardiovascular events.1 The National Lipid Association’s Statin Task Force also stated that routine monitoring of liver function tests is not supported by the available evidence.2
FDA reviewed post-marketing data to evaluate the risk of clinically serious hepatotoxicity associated with statins. FDA had conducted several post-marketing reviews of statins and hepatotoxicity between years 2000 and 2009 by searching the Agency’s Adverse Event Reporting System (AERS) database. Those reviews consistently noted that reporting of statin-associated serious liver injury to the AERS database was extremely low (reporting rate of ≤2 per one million patient-years). FDA’s updated review focused on cases of severe liver injury, defined as a 4 (severe liver injury) or a 5 (death or liver transplant) using the Drug Induced Liver Injury Network (DILIN) liver injury severity scale, which were reported to AERS from marketing of each statin through 2009. Cases meeting those criteria were further assessed for causality. Seventy-five cases (27 cases with a severity score of 4, and 48 cases with a severity score of 5 (37 deaths and 11 liver transplants) were assessed for causality. Thirty of the 75 cases (14 deaths, 7 liver transplantations, and 9 severe liver injury) were assessed as possibly or probably associated with statin therapy. No cases were assessed as highly likely or definitely associated with statin therapy. FDA concluded that, despite a rising use of statins as a class since the late 1990s, there has not been a detectable increase in the annual rates of fatal or severe liver injury cases possibly or probably causally associated with statin use.
FDA also reviewed cases from the DILIN and Acute Liver Failure Study Group (ALFSG), organizations that have been submitting reports to FDA of drug-associated liver injury in their liver injury outcome studies. As of January 1, 2011, DILIN had submitted 25 reports of statin-associated liver injury to FDA, 12 of which gave hospitalization as an outcome. A 2010 article from ALFSG included 133 prospectively identified cases of idiopathic drug-induced liver injury resulting in acute liver failure.3 Of these 133 patients, 15 were taking statins, and in six of these 15 individuals a statin was identified as the only potential drug to cause drug-induced liver injury.
Based on all available data, FDA has determined that all currently marketed statins appear to be associated with a very low risk of serious liver injury and that routine periodic monitoring of serum alanine aminotransferase (ALT) does not appear to detect or prevent serious liver injury in association with statins.
Cognitive adverse events
FDA reviewed the AERS database, the published medical literature (case reports and observational studies),4-13 and randomized clinical trials to evaluate the effect of statins on cognition.14-17
The post-marketing adverse event reports generally described individuals over the age of 50 years who experienced notable, but ill-defined memory loss or impairment that was reversible upon discontinuation of statin therapy. Time to onset of the event was highly variable, ranging from one day to years after statin exposure. The cases did not appear to be associated with fixed or progressive dementia, such as Alzheimer’s disease. The review did not reveal an association between the adverse event and the specific statin, the age of the individual, the statin dose, or concomitant medication use.
Data from the observational studies and clinical trials did not suggest that cognitive changes associated with statin use are common or lead to clinically significant cognitive decline.
Increases in glycosylated hemoglobin (HbA1c) and fasting plasma glucose
FDA’s review of the results from the Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) reported a 27% increase in investigator-reported diabetes mellitus in rosuvastatin-treated patients compared to placebo-treated patients. High-dose atorvastatin had also been associated with worsening glycemic control in the Pravastatin or Atorvastatin Evaluation and Infection Therapy – Thrombolysis In Myocardial Infarction 22 (PROVE-IT TIMI 22) substudy.18
FDA also reviewed the published medical literature.19-26 A meta-analysis by Sattar et al.,19 which included 13 statin trials with 91,140 participants, reported that statin therapy was associated with a 9% increased risk for incident diabetes (odds ratio [OR] 1.09; 95% confidence interval [CI] 1.02-1.17), with little heterogeneity (I2=11%) between trials. A meta-analysis by Rajpathak et al.,20 which included 6 statin trials with 57,593 participants, also reported a small increase in diabetes risk (relative risk [RR] 1.13; 95% CI 1.03-1.23), with no evidence of heterogeneity across trials. A recent study by Culver et al.,26 using data from the Women’s Health Initiative, reported that statin use conveys an increased risk of new-onset diabetes in postmenopausal women, and noted that the effect appears to be a medication class effect, unrelated to potency or to individual statin.
Based on clinical trial meta-analyses and epidemiological data from the published literature, information concerning an effect of statins on incident diabetes and increases in HbA1c and/or fasting plasma glucose was added to statin labels.
Lovastatin drug-drug interactions
Information regarding drug-drug interactions and contraindications and dose limitations has been added to the lovastatin label. Subsequent to the June 2011 label revisions to the simvastatin-containing products, which were based largely on the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial,27 a review of drug-drug interactions with lovastatin was conducted because the physicochemical and pharmacokinetic properties of lovastatin are comparable to those of simvastatin.
Lovastatin is a sensitive in vivo cytochrome P450 3A4 (CYP3A4) substrate. Strong CYP3A4 inhibitors are predicted to significantly increase lovastatin exposure. A literature review indicates that itraconazole, a strong CYP3A4 inhibitor, increases lovastatin exposure up to 20-fold and the drug interaction appears to result in rhabdomyolysis.28 The effect of itraconazole on lovastatin exposure can therefore be extrapolated to other strong CYP3A4 inhibitors, including ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, human immunodeficiency virus (HIV) protease inhibitors, boceprevir, telaprevir, and nefazodone.
Lovastatin Dose Limitations
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Source : FDA (February 2012)
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FDA Adds Diabetes Warning to Statin Label
The FDA said today that all statins must carry warnings about increased risks of elevated blood sugar and possible transient memory and cognition problems, but at the same time the agency removed a standing recommendation for routine liver function tests for patients taking the cholesterol-lowering drugs. The FDA said the label changes apply to atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor), lovastatin extended-release (Altoprev), pitavastatin (Livalo), pravastatin (Pravachol), rosuvastatin (Crestor), and simvastatin (Zocor).
Despite the additional warnings, the FDA said it "continues to believe that the cardiovascular benefits of statins outweigh these small increased risks."
Rather than regular monitoring of liver function, the agency said that clinicians should now simply order a liver function test before starting a patient on a statin. Although the drugs do carry a risk of liver damage, the agency has judged the risk to be "rare and unpredictable in individual patients."
The diabetes warning has been rumored as a possibility since the findings from the JUPITER trial of rosuvastatin revealed an unexpected 27% increase in new onset diabetes among patients randomized to the statin.
That finding was especially perplexing because JUPITER was a study of statins in patients who had no history of cardiovascular disease, the so-called healthy patient trial. Moreover, based on the JUPITER results, the FDA approved rosuvastatin for primary prevention.
The FDA said hyperglycemia was also observed among patients treated with 40-mg atorvastatin in a substudy of PROVE-IT TIMI 22, and a meta-analysis of data from 13 statin trials "reported that statin therapy was associated with a 9% increased risk for incident diabetes."
The cognitive data are a bit sketchier and rely mainly on post-marketing adverse event reporting. The FDA said those reports "generally described individuals over the age of 50 years who experienced notable, but ill-defined memory loss or impairment that was reversible upon discontinuation of statin therapy."
In addition to those broad label changes, the FDA added a number of restrictions to the lovastatin (Mevacor) label, including a list of 10 drugs or drug classes that are contraindicated with lovastatin.
Drugs contraindicated with lovastatin include:
In general, cardiologists contacted by ABC News/MedPage Today, applauded the FDA action -- particularly the decision to remove the requirement for liver function testing. Harlan Krumholz, MD, of Yale University, said, "Good news on liver testing -- provides no benefit and a lot of Americans are being monitored unnecessarily."
But Krumholz and others worried about patients being scared off statins by the diabetes and memory warnings.
"All drugs have side effects and rarely some patients will have an odd reaction to statins -- cognitive effects are among those -- and are usually mild and resolve with stopping the medication. The blood sugar and diabetes issue has emerged over the last couple of years -- this appears to be a side effect," Krumholz wrote in an email.
Scott Grundy, MD, of the University of Texas Southwestern Medical Center in Dallas, was dubious about the level of evidence linking diabetes and cognition problems with statins. "I do not believe there is enough hard evidence to justify information and warnings about memory loss and confusion or increase in blood sugar."
And Grundy, too, worried about the impact on patients, writing, "I also think that these warnings will cause some people who need statins to stop taking them. That would be unfortunate."
The Cleveland Clinic's Steven Nissen, MD, often a critic of the FDA, told ABC News/MedPage Today, "these are reasonable and prudent recommendations. I am pleased that FDA did not overstate the diabetes and cognitive function risks. Both problems are uncommon and don't diminish the importance of statins in cardiovascular protection. For the vast majority of patients, the benefits far outweigh the risks."
Moreover, Nissen said, the FDA's decision on liver monitoring could boost statin use because it "will help to allay public apprehension about the liver safety of statins."
Source : Medpage Today
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Statins Up Diabetes Risk in Older Women
Older women who take statins may be at an increased risk for developing type 2 diabetes, researchers found.
In an analysis of data from the Women's Health Initiative, postmenopausal women who were on a statin at study entry had almost a 50% greater risk of diabetes than those who weren't on the cholesterol-lowering drugs, Yunsheng Ma, MD, PhD, of the University of Massachusetts School of Medicine, and colleagues reported online in the Archives of Internal Medicine.
"This study urges us to further evaluate the risk-benefit profile of statins," Ma told MedPage Today, adding that the ratio will likely vary by patient population.
Recent research has suggested a potential link between statins and the development of diabetes -- most notably a meta-analysis that found a 9% increased risk of the disease with statin use (QJM 2011; 104(2): 109-124), Ma said.
Yet how the risk of diabetes with statin use varies across populations hasn't been thoroughly explored, he added. So he and colleagues looked at data from the Women's Health Initiative to assess the risk in postmenopausal women.
Data were available for 153,840 women, mean age 63, who didn't have diabetes when they were enrolled in the study in 1993. About 7% of them were on statins at that time.
Through follow-up ending in 2005, there were 10,242 cases of new-onset diabetes.
In initial analyses, Ma and colleagues found that statin use at baseline was associated with an increased risk of diabetes (HR 1.71, 95% CI 1.61 to 1.83), and that association remained significant in multivariate analyses controlling for age, race, and weight (HR 1.48, 95% CI 1.38 to 1.59).
Ma said the risk was seen with all types of statins. "It appears to be a class effect," he told MedPage Today.
Risks were increased for all ethnicities, although they did vary slightly, with the highest risks seen among Asians:
They said differences in phenotype, such as weight distribution, may explain the association.
Risk of diabetes also was similarly elevated -- by about 50% -- for women with and without heart disease, and was similar if women used either high- or low- potency statins (HR 1.45, 95% CI 1.36 to 1.61; and HR 1.48, 95% CI 1.36 to 1.61, respectively).
"The take-home message is that different populations have different risks for diabetes" associated with statin use, Annie Culver, BPharm, of the University of Massachusetts and a co-author on the study, told MedPage Today. "When a statin is indicated, it's very important to continue to monitor for diabetes as well as for the statin effects, so the dose can be adjusted along the way."
Culver added that the findings emphasize current guidelines that recommend lifestyle intervention as the primary means of treating high cholesterol.
"Too many people are put on a statin who don't have to be," Ma said. "Patients should go on a statin if they can't control [their cholesterol] through dietary intervention, but once they're on that statin they should still continue lifestyle intervention."
Suzanne Steinbaum, MD, director of women and heart disease at Lenox Hill Hospital in Bronx, N.Y., said in an email that it's not yet clear from this one study what the clinical implications are for postmenopausal women on statins.
"Due to the extensive use of statins in the aging female population, it is critical that more studies are done to help understand the association with statins and the development of diabetes," she wrote. "Women who are taking statins should be aware of the need to check their blood sugars, along with their liver function tests."
The researchers said the study was limited by its observational nature, and because individual statin analysis may be confounded by the fact that women may have changed statin type before developing diabetes.
Source : MedPage Today
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Statins Tied to Lung Damage in Smokers
Statin use appears to be associated with interstitial lung abnormalities among current and former smokers, researchers found. Among individuals with a history of at least 10 pack-years of smoking, statin use was associated with a 60% increase in the odds of having abnormalities on CT scans (OR 1.60, 95% CI 1.03 to 2.50), according to Gary Hunninghake, MD, MPH, of Brigham and Women's Hospital in Boston, and colleagues.
The findings were independent of a history of high cholesterol, coronary heart disease, or a number of other cardiovascular risk factors, the researchers reported online in the American Journal of Respiratory and Critical Care Medicine.
"Our findings suggest that statins may influence the susceptibility to, or progression of, interstitial lung disease," they wrote.
But they advised caution before applying the findings to patient care because the possible risks of statins on interstitial lung abnormalities likely do not outweigh the benefits of statin therapy in patients with cardiovascular disease.
"In addition, our findings do not rule out the possibility that statin use could benefit some patients with respiratory disease," they wrote. "Instead, we believe that clinicians should be aware that radiographic evidence of interstitial lung disease, much like myopathy, can occur in some patients on statins."
Previous studies have provided conflicting evidence on the relationship between statins and interstitial lung disease, so Hunninghake and colleagues examined data from the COPDGene study to further explore the issue.
The current analysis included 2,115 current and former smokers who underwent chest CT scans.
By definition, interstitial lung abnormalities affected more than 5% of any lung zone and included non-dependent ground-glass or reticular abnormalities, diffuse centrilobular nodularity, nonemphysematous cysts, honeycombing, or traction bronchiectasis.
The percentage of patients with such abnormalities was greater among patients taking statins (38% versus 27%, P=0.04).
The relationship between statins and lung abnormalities was stronger with more hydrophilic statins and with older patient age (P<0.05 for both trends). Pravastatin (a hydrophilic statin, brand name Pravachol) was most strongly associated with abnormalities (OR 4.61, 95% CI 1.99 to 10.70).
Hunninghake and colleagues explored the potential mechanism underlying the association between statins and lung damage using mice and cell cultures.
They found that pretreating mice with pravastatin enhanced the lung inflammation and fibrosis induced by bleomycin.
Also, in vitro studies revealed that statins increased the generation of mitochondrial reactive oxygen species in macrophages, which increased NLRP3-inflammasome activation.
The experimental findings conflict with two previous studies in which statins reduced bleomycin-induced lung injury. Hunninghake noted that those studies differed based on the type of statin, the dose of bleomycin, and the timing of statin administration.
But they acknowledged some limitations of the current analysis, including the lack of data to correlate the experimental findings in mice to humans, the lack of biopsies in the human participants, the lack of information on the duration of statin use or dose for most patients, and the possibility that the findings apply only to current and former smokers.
Despite the potential negative association of statins with interstitial lung damage, recent studies have shown that statins might confer protective benefits for those hospitalized with the flu and for those who suffered a head trauma.
Source : MedPage Today
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FDA Drug Safety Communication:Review update of Trilipix (fenofibric acid) and the ACCORD Lipid trial
Facts about Trilipix (fenofibric acid)
The U.S. Food and Drug Administration (FDA) is informing the public that the cholesterol-lowering medicine Trilipix (fenofibric acid) may not lower a patient's risk of having a heart attack or stroke. This is based on data from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid trial, which evaluated the efficacy and safety of fenofibrate plus simvastatin combination therapy versus simvastatin alone in patients with type 2 diabetes mellitus (see Data Summary below). FDA reviewed this trial as part of its ongoing investigation of the safety and efficacy of Trilipix.
nformation from the trial has been added to the Important Limitations of Use and Warnings and Precautions sections of the Trilipix physician label and to the patient Medication Guide. Healthcare professionals should consider the benefits and risks of Trilipix when deciding to prescribe the drug to patients. Patients should contact their healthcare professional if they have any questions or concerns about Trilipix.
In the ACCORD Lipid trial, there was no significant difference in the risk of experiencing a major adverse cardiac event between the group treated with fenofibrate plus simvastatin compared with simvastatin alone. In addition, a subgroup analysis showed that relative to treatment in men, there was an increase in the risk for major adverse cardiac events in women receiving the combination therapy versus simvastatin alone. The clinical significance of this subgroup finding is unclear, as this finding was not observed in a separate large randomized controlled clinical trial of fenofibrate versus placebo.
Based on results from the ACCORD Lipid trial and other clinical trials of drugs similar to Trilipix, FDA is requiring the manufacturer of Trilipix to conduct a clinical trial to evaluate the cardiovascular effects of Trilipix in patients at high risk for cardiovascular disease who are already taking statins.
FDA had previously communicated to the public about the ACCORD Lipid trial in a Statement to Healthcare Professionals on March 15, 2010. The results of this trial were later discussed at the FDA Endocrinologic and Metabolic Drugs Advisory Committee meeting, held on May 19, 2011.
Additional Information for Patients
The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid trial was a randomized, double-blind, placebo-controlled add-on trial which evaluated the efficacy and safety of adding fenofibrate therapy to treatment with simvastatin in patients with type 2 diabetes mellitus. Patients were randomized to receive simvastatin plus fenofibrate (n=2765) or simvastatin plus placebo (n=2753). All patients received open-label simvastatin therapy for four weeks prior to initiation of blinded therapy with fenofibrate or placebo. The primary outcome was major adverse cardiovascular events (MACE), a composite of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular disease death.
The mean duration of follow-up was 4.7 years. The results showed that fenofibrate plus simvastatin combination therapy was associated with a non-significant 8% relative risk reduction in the primary outcome of MACE (hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.79-1.08; p=0.32) as compared to simvastatin plus placebo. In a prespecified subgroup analysis of the primary efficacy outcome, the HR for MACE in men receiving combination therapy versus simvastatin monotherapy was 0.82 (95% CI 0.69-0.99), and the HR for MACE in women receiving combination therapy versus simvastatin monotherapy was 1.38 (95% CI 0.98-1.94) (interaction p=0.01). The clinical significance of this subgroup finding is unclear, as this finding was not observed in a separate large randomized controlled clinical trial of fenofibrate versus placebo.
However, the study results also raised the hypothesis that a subgroup of patients with high triglycerides and low high-density lipoprotein (HDL) cholesterol may experience some reduction in the risk of MACE from the combination therapy versus simvastatin monotherapy.
The results of the ACCORD Lipid trial were discussed at the FDA Endocrinologic and Metabolic Drugs Advisory Committee meeting, held on May 19, 2011 (for complete reviews and background information discussed at this meeting see: May 19, 2011 AC meeting).
Based on the results from the ACCORD Lipid trial and other clinical trials of drugs similar to Trilipix, FDA is requiring the manufacturer of Trilipix to conduct a randomized, double-blind, placebo-controlled clinical trial to test the hypothesis that Trilipix in combination with a statin versus statin alone significantly reduces the incidence of major adverse cardiovascular events in high-risk men and women who are at their low-density lipoprotein (LDL) cholesterol goal on statin therapy, but have residually high triglycerides and low HDL cholesterol.
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FDA announces new safety recommendations for high-dose simvastatin
Increased risk of muscle injury cited
Simvastatin is sold under the brand-name Zocor and as a single-ingredient generic product. It is also sold in combination with ezetimibe as Vytorin and in combination with Niacin as Simcor.
The U.S. Food and Drug Administration today is announcing safety label changes for the cholesterol-lowering medication simvastatin because the highest approved dose--80 milligram (mg)--has been associated with an elevated risk of muscle injury or myopathy, particularly during the first 12 months of use.
The agency is recommending that simvastatin 80 mg be used only in patients who have been taking this dose for 12 months or more and have not experienced any muscle toxicity. It should not be prescribed to new patients. There are also new contraindications and dose limitations for when simvastatin is taken with certain other medications.
The changes to the label for simvastatin-containing medications are based on the FDA's review of the results of the seven-year Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine clinical trial, other clinical trial data, and analyses of adverse events submitted to the FDA's Adverse Event Reporting System. All showed that patients taking simvastatin 80 mg daily had an increased risk of muscle injury compared to patients taking lower doses of simvastatin or other statin drugs. The risk of muscle injury is highest during the first year of treatment with the 80 mg dose of simvastatin, is often the result of interactions with certain other medicines, and is frequently associated with a genetic predisposition for simvastatin-related muscle injury.
Simvastatin is sold under the brand-name Zocor and as a single-ingredient generic product. It is also sold in combination with ezetimibe as Vytorin and in combination with Niacin as Simcor.
The FDA has revised the drug labels for simvastatin and Vytorin to include the new 80 mg dosing restrictions. The agency also revised the labels for simvastatin, Vytorin and Simcor to include new dosing recommendations when these drugs are used with certain medications that interact to increase the level of simvastatin in the body, which can increase the risk for myopathy. Patients who are unable to adequately lower their level of LDL-C on simvastatin 40 mg should not be given the higher 80 mg dose of simvastatin; instead, they should be placed on an alternative LDL-C lowering treatment(s).
Source : FDA (June 2011)
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Statin drugs cause liver damage, kidney failure and cataracts, says BMJ
Cholesterol-lowering statin drugs significantly increase a person's risk of cataracts, muscle weakness, liver dysfunction and kidney failure, according to a study in the British Medical Journal.
The study also confirmed that the drugs lower the risk of heart disease and esophageal cancer, but claims of other health benefits were unsupported.
Researchers from Nottingham University in the United Kingdom examined data on more than 2 million patients between the ages of 30 and 84, seen at 38 different general practices, who had been prescribed the cholesterol-lowering drugs. More than 70 percent were taking simvastatin (Zocor), 22.3 percent were taking atorvastatin (Lipitor), 3.6 percent were taking pravastatin (Pravachol, Selektine), 1.9 percent were taking rosuvastatin (Crestor) and 1.4 percent were taking fluvastatin (Canef, Lescol, Lochol, Vastin).
The researchers confirmed prior data suggesting that statins increase patients' risk of cataracts, liver dysfunction, kidney failure and a form of muscle weakness known as myopathy. They found that for every 10,000 women treated with the drugs, 23 would develop acute kidney (renal) failure, 39 would develop myopathy, 74 would develop liver dysfunction and 309 would develop cataracts. Men suffered an even higher risk of myopathy, but their risks of the other three conditions were similar to those suffered by women.
Putting it in different terms, the researchers found that only 434 people would need to be treated with the drugs for five years for one case of acute renal failure to develop. It would take only 136 treated for each case of liver dysfunction and 33 for each case of cataracts. Among women, 259 would need to be treated for each case of myopathy; among men, the number was only 91.
The risk of developing all conditions was highest during the first year of treatment, but continued throughout the course of the study. Risk of liver and kidney problems increased proportionally with the dose of statins being taken.
All drugs appeared to pose a similar risk of all conditions, with the exception of fluvastatin, which increased the risk of liver dysfunction more than its competitors. Men taking fluvastatin were twice as likely to develop liver dysfunction as those not taking statins, while women's risk increased by 2.5 times.
The researchers did find, however, that the risk of cataracts returned to normal within one year of stopping statin treatment, while the risk of liver and kidney problems returned to normal within one to three years. Additionally, they found no connection between statin use and the risk of dementia, osteoporotic fracture, Parkinson's disease, rheumatoid arthritis or venous thromboembolism.
Examining the purported benefits of the drugs, researchers found that they did in fact lower the risk of heart disease, averting 271 cases for every 10,000 high-risk patients treated. Put another way, 33 high-risk men or 37 high-risk women would need to be treated with the drugs to avert one case of the disease.
Although advocates of the drugs have claimed that they may also reduce the risk cancer, the researchers found almost no data supporting these claims. The study "largely confirmed other studies that reported no clear association between statins and risk of cancers," the researchers wrote.
The only cancer-fighting effect uncovered in the study was a slightly lower risk of esophageal cancer, with eight cases averted for every 10,000 high-risk women treated. In other words, 1,266 high-risk women or 1,082 high-risk men would need to be treated with the drugs to prevent one case of esophageal cancer.
Although sales of the blockbuster drugs are unlikely to be reduced as a result of the study, the researchers encouraged closer monitoring of patients for side effects and said their findings "would tend to support a policy of using lower doses of statins in people at high risk of the adverse event."
Source : Natural News 7/11/2010
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Statins and Myoglobin: How Muscle Pain and Weakness Progress to Heart, Lung and Kidney Failure Part 1
Statin drug use has steadily increased over the last several decades, due to the widespread belief that cholesterol reduction is an important step in preventing heart disease. It is undeniable that statins are effective: they can decrease serum cholesterol levels from over 300 db/ml to well within the normal range in a matter of weeks. For a person who already has normal cholesterol levels, statins can drive their cholesterol down to levels not seen in nature. Statins have also been shown to reduce the relative risk of heart attacks in men in their 50's by as much as 30%, but, because heart attacks are relatively rare for this segment of the population, the absolute risk reduction is only on the order of 2%, a point that is often missed by the person being treated.
All drugs have potential side effects, and with any drug it's a matter of weighing the risk/benefit factors to decide whether the drug is warranted. Statin drugs have a remarkably diverse set of side effects, including cognitive and memory impairment, reduced libido, and muscle pain and weakness. The drug manufacturers claim that the incidence of side effects is relatively rare, but often side effects don't appear until after several months or even years into treatment. In many of these cases, it may not be obvious that the statin drug is the cause of the problem. This is especially true because these side effects can easily be attributed to increasing age. In fact, as I will show later, statin side effects can best be interpreted as an acceleration of the aging process.
In my view, statin drugs are never worth the risk of their side effects. Cholesterol is a vital nutrient, without which mammalian cells can not survive, and it is inconceivable to me that crippling the body's ability to synthesize cholesterol can ever be a good idea. In an excellent and highly informative review article published in 2009, Wainwright et al. [43] developed a strong argument that statin drugs, by depleting cholesterol, lead to a destabilization of cell membranes "from head to toe." This problem, in turn, increases risk to a long list of serious health conditions and diseases, including diabetes, multiple sclerosis, cognitive problems, hemorrhagic stroke, cancer, and even ALS (amyotrophic lateral sclerosis, also known commonly as Lou Gehrig's disease). Their arguments are backed up by references to 85 peer-reviewed journal publications. I have argued in previous essays that statins may increase the risk to Alzheimer's disease, as well as to sepsis, cancer, and heart failure.
The most commonly reported side effects to statin therapy are muscle pain and weakness. If left unchecked, these symptoms can progress to rhabdomyolysis (severe muscle damage) and kidney failure. Muscle weakness in the lungs can lead to breathing difficulties; in the heart it leads to heart failure. Statin users are reassured by their doctors that they can halt statin therapy if their liver and muscle enzymes rise too high. In practice, however, it's possible to suffer irreversible muscle damage (the problem does not go away after the statin therapy is stopped), and this can happen even when the enzyme levels are not above the normal range.
This essay will develop an argument for why, over time, a statin user may become increasingly weak, in some cases to the point of major disability. A key message is that muscles are forced to cannibalize themselves to acquire sufficient energy. But another factor is oxidative damage to muscle tissue, with subsequent disintegration of the cell walls. This is true not only for the skeletal muscles, but also for the respiratory muscles controlling breathing and the heart muscle. With continued abuse, the muscle cells disintegrate, and the debris travels in the blood stream to the kidneys, which can lead to kidney failure.
The rest of this essay will unfold as follows. In the next section, I will explain how statin drugs work, which will also show why they interfere with the synthesis not only of cholesterol but also of other essential biological substances involved in cell metabolism. The following section will present evidence that statins damage muscle cells. Sections 4 and 5 describe the biochemical pathways involved in assuring that muscles have enough energy to effect movement, especially during situations of stress such as extreme exercise. Section 6 describes the condition known as rhabdomyolysis, caused by extreme exercise but also by statin drugs, and the subsequent risk to kidney failure. Section 7 describes the role that myoglobin, a key protein found in muscle cells, plays in the disease process. After a section explaining how cholesterol protects cell membranes from oxidative damage, the four subsequent sections (sections 9-12) will be devoted to the repercussions of statin damage to the muscles, the heart, the lungs, and the pancreas, respectively. Finally, the conclusion section will summarize the essay and provide hints about my upcoming essay on ALS, a physically disabling neurodegenerative disease that is due not to muscle damage per se but to damage of the motor neurons in the spinal cord that transmit signals from the brain to the skeletal muscles.
2. The Biological Mechanism of Statin Drugs
Why do statins cause so many side effects? To answer this question requires explaining all the crucial roles that cholesterol plays in maintaining the integrity and functioning of the body's cells. However, statins interfere not only with the synthesis of cholesterol, but also with the synthesis of an enzyme, coenzyme Q10, that plays a critical role in energy metabolism in all cells. A deficiency in both cholesterol and coenzyme Q10, over time, leads to a huge list of potential health problems. Exactly how an individual responds depends upon their genetic make-up: faced with a deficiency, the body will decide to sacrifice certain cell types in order to safeguard certain other cell types. So, one person may develop Alzheimer's because the brain's neurons are sacrificed, while another succumbs to heart failure or rhabdomyolysis (skeletal muscle wasting).
Statins suppress a critical early step in the multi-step biological pathway that leads to cholesterol synthesis. This is why statins are able to dramatically reduce the blood serum levels of cholesterol. Specifically, statins interfere with the production of the enzyme, HMG-Coenzyme A Reductase, which catalyzes production of mevalonate from its precursor, HMG-Coenzyme A. Several more steps produce cholesterol from mevalonate. Mevalonate is also the precursor to a large number of other biologically active molecules that are important for proper cell function. These include the antioxidants, coenzyme Q10 and the dolichols, as shown in the figure to the right.
The so-called "bad" cholesterol, LDL, delivers cholesterol, fats, and antioxidants from the liver to all the cells of the body. All cells need both fats and cholesterol to maintain healthy membranes, not only in the outer cell wall, but also in the membranes encasing the nucleus, the mitochondria (energy producing units), and the lysosomes (the cell's digestive system). Antioxidants are critical for neutralizing the damaging effects of oxygen exposure, always an issue whenever energy is generated in the mitochondria through a chemical reaction between food sources and oxygen.
In a double-blind placebo controlled study [18], it has been shown that statins can reduce serum levels of coenzyme Q10 by as much as 40%. Coenzyme Q10 is not only a powerful antioxidant, but it also plays a crucial role in the process that breaks down glucose in the presence of oxygen to yield carbon dioxide and water. This metabolic pathway, which is essentially the burning of glucose as fuel, takes place in the mitochondria via the well-known citric acid, or Kreb's cycle. The energy that is released through this process is packaged up in the form of ATP (Adenosine Triphosphate), the currency that all cells use to store their energy reserves.
The dolichols play a special role for the lysosomes [20]. The lysosomes are walled off "rooms" that contain digestive enzymes to break down debris from damaged cell parts so that they can be recycled into useful materials. Lysosomes must maintain a highly acidic internal environment in order for the digestive enzymes to work properly. The dolichols are responsible for pumping hydrogen ions into the lysosomes to keep them highly acidic.
A final way that statins can damage cells is through their entry mechanism. Statins belong to a class of drugs called "amphiphilic" drugs [2] that manage to break through the cell wall in spite of being relatively large. They act like a soap by essentially dissolving a section of the cell membrane. This leaves behind a hole in the wall, which needs to be patched up, as well as debris which must be cleaned up and recycled by the lysosomes. To patch the hole requires new sources of both fats and cholesterol, which come from the LDL particles, whose supply is greatly reduced due to the statin drug. So it becomes increasingly difficult over time for the cell to repair all the holes introduced by the statin drug molecules. As the cell wall becomes more permeable due to previous exposure to an amphiphilic drug, the amount of drug that successfully enters the cell steadily increases over time, leading to ever greater internal concentrations of the drug.
3. Statins, Muscle Pain and Weakness, and Rhabdomyolysis
Muscle cells have tremendous energy needs, particularly if the person has been put on an exercise regimen as part of their treatment program. The heart, in particular, never rests. It has to keep on beating 24x7 at the rate of at least once every second. Hence the heart is especially dependent on coenzyme Q10 to replenish the ATP consumed every time it contracts and pushes blood from one chamber to another and out the aorta.
The pharmaceutical industry readily admits that statin therapy may cause muscle pain and/or muscle weakness in some cases, but they claim that the incidence of these side effects is small, on the order of 2%. However, observational studies have shown that at least 10% to 15% of statin users complain of muscle pain [6][40]. The actual number who experience pain or weakness is likely to be much larger, however, because many people are unaware that this is a potential side effect. Furthermore, it sometimes takes several years of cumulative statin damage before the symptoms become intolerable. People are often willing to believe that their aches and pains and generally weakening condition are simply due to getting older.
The reaction by the general community to a relatively benign article posted by WebMD on muscle pain suggests that the problem is much worse than is generally acknowledged. Over 200 often lengthy comments describe many very sad stories; often the doctor was also misinformed, and denied that the pain could be due to the statin drug. A case in point is described in this New York Times article. A woman in Kansas had been taking a statin for years to reduce her cholesterol. Over that same time period, she experienced chronic muscle pain which neither she nor her doctor attributed to the statin therapy. It even led to a useless shoulder operation. Her problem eventually escalated into skin lesions caused by a reaction to toxic protein by-products released by her disintegrating muscles. She was given an antifungal to treat the skin lesions, another misdiagnosis. But the antifungal interacted with the statins [25] to further increase the severity of her muscle disorders. Three months later, she could barely stand, and her pulmonary muscles were so weak she couldn't breathe. She died shortly thereafter.
Rhabdomyolysis is a condition where the muscles rapidly disintegrate due to an injury, often, for example, physical trauma following an accident. But Rhabdomyolysis is also a rare side effect of statins -- essentially where the muscle pain and weakness are extreme. Some people react immediately to statin therapy with severe rhabdomyolysis, and it is often fatal, due to acute renal failure (ARF). Myoglobin is sloughed off from the muscle cells in large amounts, and it overloads the kidneys and causes them to shut down completely. Initiating statin therapy is therefore a bit like Russian roulette -- there is even a known case where a single statin dose caused rhabdomyolysis [21]. One of the statins, Baycol, was abruptly taken off the market in 2001, after 31 people died from subsequent rhabdomyolysis.
Source: The (Skeptic's) Health Journal Club
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FDA Warns about Increased Risk of Muscle Injury with Zocor
Highest approved dose of cholesterol-lowering medication could cause harm to muscles
The U.S. Food and Drug Administration today warned patients and healthcare providers about the potential for increased risk of muscle injury from the cholesterol-lowering medication Zocor (simvastatin) 80 mg. Although muscle injury (called myopathy) is a known side effect with all statins, today’s warning highlights the greater risk of developing muscle injury, including rhabdomyolysis, for patients when they are prescribed and use higher doses of this drug. Rhabdomyolysis is the most serious form of myopathy and can lead to severe kidney damage, kidney failure, and sometimes death.
“Review of simvastatin is part of an ongoing FDA effort to evaluate the risk of statin-associated muscle injury and to provide that information to the public as it becomes available,” said Eric Colman, M.D., Deputy Director of FDA’s Division of Metabolism and Endocrinology Products (DMEP). “It’s important for patients and healthcare professionals to consider all the potential risks and known benefits of any drug before deciding on any one therapy or dose of therapy.”
Simvastatin is sold as a single-ingredient generic medication and as the brand-name Zocor. It also is sold in combination with ezetimibe as Vytorin, and in combination with niacin as Simcor.
FDA’s review of new information on the risk of muscle injury is derived from clinical trials, observational studies, adverse event reports, and prescription use data. The agency also is reviewing data from the SEARCH (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine) trial, which evaluated major cardiovascular events, such as heart attack, revascularization and cardiovascular death, in patients taking 80 mg compared to 20 mg of simvastatin. SEARCH also included data on muscle injury in patients taking simvastatin.
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Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials
Naveed Sattar, David Preiss, Heather M Murray, Paul Welsh, Brendan M Buckley, Anton J M de Craen, Sreenivasa Rao Kondapally Seshasai, John J McMurray, Dilys J Freeman, J Wouter Jukema, Peter W Macfarlane, Chris J Packard, David J Stott, Rudi G Westendorp, James Shepherd, Barry R Davis, Sara L Pressel, Roberto Marchioli, Rosa Maria Marfisi, Aldo P Maggioni, Luigi Tavazzi, Gianni Tognoni, John Kjekshus, Terje R Pedersen,
Thomas J Cook, Antonio M Gotto, Michael B Clearfield, John R Downs, Haruo Nakamura, Yasuo Ohashi, Kyoichi Mizuno, Kausik K Ray, Ian Ford
Summary
Background Trials of statin therapy have had conflicting findings on the risk of development of diabetes mellitus in patients given statins. We aimed to establish by a meta-analysis of published and unpublished data whether any relation exists between statin use and development of diabetes.
Methods
We searched Medline, Embase, and the Cochrane Central Register of Controlled Trials from 1994 to 2009,
for randomised controlled endpoint trials of statins. We included only trials with more than 1000 patients, with
identical follow-up in both groups and duration of more than 1 year. We excluded trials of patients with organ
transplants or who needed haemodialysis. We used the I² statistic to measure heterogeneity between trials and
calculated risk estimates for incident diabetes with random-effect meta-analysis.
Findings
We identified 13 statin trials with 91 140 participants, of whom 4278 (2226 assigned statins and 2052 assigned control treatment) developed diabetes during a mean of 4 years. Statin therapy was associated with a 9% increased risk for incident diabetes (odds ratio [OR] 1·09; 95% CI 1·02–1·17), with little heterogeneity (I²=11%) between trials. Meta-regression showed that risk of development of diabetes with statins was highest in trials with older participants, but neither baseline body-mass index nor change in LDL-cholesterol concentrations accounted for residual variation in risk. Treatment of 255 (95% CI 150–852) patients with statins for 4 years resulted in one extra case of diabetes.
Interpretation
Statin therapy is associated with a slightly increased risk of development of diabetes, but the risk is low
both in absolute terms and when compared with the reduction in coronary events. Clinical practice in patients with moderate or high cardiovascular risk or existing cardiovascular disease should not change.
LINK TO FULL ARTICLE
Cholesterol is essential for the functioning of all human organs. Bile acids are synthesized from cholesterol in liver and are stored in the gallbladder. Gallstone disease is a common abdominal condition in developed countries. Some 80-90 % of gallstones formed within the gallbladder consist mainly of cholesterol in the western world. The prevalence of cholelithiasis is increasing. Acute pancreatitis (AP) is inflammation of the pancreas and ranges from mild symptoms to a life-threatening or life-ending process. It may progress to a chronic form leading to maldigestion and diabetes mellitus. The main causes for AP are alcohol use or small gallstone migration with obstruction of bile and pancreatic enzymes. Cholelithiasis is thus associated with pancreatitis. In up to 20% of AP the etiology is unknown. There are many possible etiologies for idiopathic pancreatitis, including drug-induced pancreatitis or microlithiasis. In animal models statins have been shown to decrease the size of gallstones. Hypercholesterolemia is a major cause of coronary heart disease and other manifestations of vascular atherosclerosis. Statins are used for the treatment of hypercholesterolemia in order to prevent cardiovascular events. In Finland there has been a 11-fold increase in statin use between 1995 and 2000 and approximately 660,000 individuals (12% of the population) purchased statins in 2012. Coinciding with the increase in statin use, there has been a notable increase in the number of patients with AP. The evidence concerning the association between statins and the risk of acute pancreatitis is inconclusive. Findings in case reports and two case–control studies have suggested that statins increase the risk of acute pancreatitis, whereas a recent meta-analysis suggested a protective association. To investigate the relationship of statins and pancreatitis, we carried out two studies in Kuopio University Hospital (461 admissions of patients with AP and 1140 patients with gallstones between 2008 - 2010) including patient cohort during (272 statin users and 272 controls). We found that statin therapy was significantly more frequent in patients with idiopathic acute pancreatitis than in other known etiologies. In patients with cholecystectomy there was no significant difference in outcome between the statin users and non-users, although statin users had more polypharmacy (including drugs that cause bleeding) and cardiovascular illnesses than non-users. The mean operation time for laparoscopic cholecystectomy was 10% shorter for the patients with statin use than for the patients without. Together with the Finnish Medicine Agency (Fimea) we carried out a large nationwide study and found that statin use was associated with an increased incidence of AP (OR 1.25, 95% CI 1.13-1.39). The incidence was elevated especially during the first year of use both among current and former statin users. Finally in a randomized study of 85 idiopathic pancreatitis patients (39 in the laparoscopic cholecystectomy and 46 in the control group) we found that 59% of operated patients had small gallstones in their gallbladder, although preoperative transabdominal ultrasonography was negative. We also found that recurrence of IAP was less common in patients undergoing LCC. Interestingly, the patients using lipid-lowering drugs had gallbladder stones in surgery less frequently than those without statins. Based on these data it is concluded that statin medication seems to affect the bile metabolisms also humans and patients who use statins have increased risk of pancreatitis. Cholecystectomy in statin-using patients is as safe as in non-users although statin users had more comorbidities than non-users. Recurrence of idiopathic pancreatitis can be prevented by laparoscopic cholecystectomy.
Source : Dissertation - Jukka Pulkkinen University of Eastern Finland
FDA probes cognitive impact of new cholesterol drugs
The Food and Drug Administration has asked Regeneron Pharmaceuticals Inc and Sanofi SA to assess potential neurocognitive side effects of their experimental cholesterol drug, Sanofi said in its annual report on Friday.
Amgen Inc, which is developing a similar drug, said it has also been in communication with the agency.
The FDA said it could not discuss specific development programs, but is "aware of concerns raised with neurocognitive adverse events and other lipid-lowering therapies, including statins, and as part of our oversight of new drug development, we are carefully monitoring these events."The new drugs are part of an experimental class known as PCSK9 inhibitors designed to block a protein that maintains "bad" LDL cholesterol in the bloodstream.
"We have not seen a neurocognitive adverse signal in the alirocumab data," Dr. Michael Aberman, Regeneron's vice president for strategy and investor relations, said in a telephone interview.
He said the alirocumab trials have been overseen by independent safety monitors.
"What the FDA asked us to do we don't expect to be difficult or time consuming," Aberman added.
Sanofi and Regeneron said they did not know how the FDA learned of the potential side effects, and they were not aware of any such side effects with alirocumab.
Pfizer Inc, also in the late stages of developing a PCSK9 drug, said in an emailed statement that it has not received a similar request from the FDA but is already assessing potential neurocognitive side effects in late-stage trials of its drug, bococizumab. "At this stage of our bococizumab development program, we are not aware of any neurocognitive safety signals," the company said.Amgen, which has said it could file for regulatory approval of PCSK9 drug evolocumab this year, said it has been proactively monitoring for cognitive impairment in its trials.
"Similar to other companies developing PCSK9 inhibitors, Amgen has been in communication with the FDA, and we will continue to investigate the potential for cognitive impairment in our program," Amgen said in an emailed statement.
The company said it has not seen any such signal so far.
Sanofi's report echoed a filing made by Regeneron last month, in which the company said the FDA advised it was aware of adverse neurocognitive effects associated with PCSK9 inhibitors.
Shares of Regeneron fell as much as 10 percent before paring losses to close down 3 percent, while shares of Amgen dropped 1.5 percent. U.S.-listed shares of France-based Sanofi fell 1 percent.
Rare side effects such as memory loss, impaired concentration, and paranoia have been associated with the use of statins for lowering LDL cholesterol, and their labels include warnings about cognitive impairment.
Statins, such as AstraZeneca PLC's Crestor and generic forms of Pfizer's Lipitor, are the most widely used cholesterol-lowering treatments and work by blocking the liver's production of LDL cholesterol."While we continue to believe the PCSK9 class has multi-billion dollar potential, we note that increased speculation on adverse events may increase the probability that the FDA could require outcomes data prior to full approval," JP Morgan analyst Geoff Meacham said in a research note.
The FDA said last year that PCSK9 drugs could get regulatory approval based on their ability to lower bad cholesterol, and may not need to show that they reduce the risk of heart attack and stroke.
In their filings, Sanofi and Regeneron said that if studies detect neurocognitive or other adverse side effects, development of alirocumab could fail or be delayed.
Source : Reuters (Mar 2014)
Cholesterol drug may block exercise benefits
Experts urge doctors to reconsider statins for obese patients after finding the cholesterol drug may block some benefits of exercise.
Statins, the most widely prescribed drugs worldwide, are often suggested to lower cholesterol and prevent heart disease in individuals with obesity, diabetes, and metabolic syndrome, which is a combination of medical disorders including excess body fat and/or high levels of blood pressure, blood sugar, and/or cholesterol.
Researchers, however, found that simvastatin, a generic type of statin previously sold under the brand name Zocor, hindered the positive effects of exercise for obese and overweight adults. The study appears in the Journal of the American College of Cardiology.
“Fitness has proven to be the most significant predictor of longevity and health because it protects people from a variety of chronic diseases,” says John Thyfault, an associate professor of nutrition and exercise physiology at the University of Missouri.
“Daily physical activity is needed to maintain or improve fitness, and thus improve health outcomes. However, if patients start exercising and taking statins at the same time, it seems that statins block the ability of exercise to improve their fitness levels.”
Thyfault says many cardiologists want to prescribe statins to all patients over a certain age regardless of whether they have metabolic syndrome; the drugs also are recommended for people with Type 2 diabetes. He recommends that cardiologists more closely weigh the benefits and risks of statins given this new data about their effect on exercise training.
“Statins have only been used for about 15-20 years, so we don’t know what the long-term effects of statins will be on aerobic fitness and overall health,” Thyfault says. “If the drugs cause complications with improving or maintaining fitness, not everyone should be prescribed statins.”
Three-month workout
Thyfault and his colleagues measured cardiorespiratory fitness in 37 previously sedentary, obese individuals ages 25-59 with low fitness levels. The participants followed the same exercise regimen for 12 weeks; 18 of the 37 people also took 40 mg of simvastatin daily. Statins significantly affected participants’ exercise outcomes.
Participants in the exercise-only group increased their cardiorespiratory fitness by an average of 10 percent compared to a 1.5 percent increase among participants also prescribed statins. Additionally, skeletal muscle mitochondrial content, the site where muscle cells turn oxygen into energy, decreased by 4.5 percent in the group taking statins while the exercise-only group had a 13 percent increase, a normal response following exercise training.
Thyfault suggests that future research determine whether lower doses of simvastatin or other types of statins similarly affect people’s exercise outcomes and thus their risk for diseases such as Type 2 diabetes. Starting a statin regimen after exercising and obtaining a higher fitness level may reduce the drugs’ effects on fitness, he says.
Source : Futurity
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Merck begins overseas recall of HDL cholesterol drug
Merck & Co said it is recalling Tredaptive, its medicine to raise "good" HDL cholesterol levels, in overseas markets where it is sold, after it failed to prevent heart problems in a large study and raised safety concerns.
The medicine is not approved in the United States but the U.S. drugmaker sells it in about 40 countries.
Merck said it would recall stocks of Tredaptive now held by wholesalers, but that pharmacies can continue to dispense their remaining supplies. Even so, the company said it plans to discourage doctors from prescribing the pill based on negative findings from the trial which were announced last month. The study followed more than 25,000 patients in Europe and China for almost four years.
The company said it will encourage doctors to consider alternative treatments to control cholesterol, but advised patients not to discontinue Tredaptive without first speaking with their physicians.
Merck spokeswoman Pam Eisele said the company expects available retail supplies of Tredaptive to be exhausted by mid-March.
Tredaptive combines an extended-release form of niacin with another drug meant to reduce facial flushing, a side effect of niacin. The medicine has annual sales of less than $20 million. That makes it a tiny product for Merck, which has global annual revenue of about $50 billion.
Merck in December said Tredaptive did no better in the study at preventing heart attacks, deaths or strokes than traditional statin drugs that lower "bad" LDL cholesterol.
Moreover, Merck said the medicine significantly raised the incidence of some types of nonfatal but serious side effects in the study. They included blood, lymph and gastrointestinal problems, as well as respiratory and skin issues.
Tredaptive was approved in the European Union in 2008, but the U.S. Food and Drug Administration was unwilling to approve the pill until Merck conducted the costly long-term study to better assess its safety and effectiveness.
Some analysts had expected Tredaptive to capture annual global sales of more than $1 billion, if it were to win approval in the United States.
Source : Reuters
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FDA Drug Safety Communication: Interactions between certain HIV or hepatitis C drugs and cholesterol-lowering statin drugs can increase the risk of muscle injury
Facts about statins and protease inhibitors
- Statins are a class of prescription drugs used together with diet and exercise to reduce blood levels of low-density lipoprotein (LDL) cholesterol (“bad cholesterol”).
- HIV protease inhibitors are a class of prescription anti-viral drugs used to treat HIV.
- HCV protease inhibitors are a class of prescription anti-viral drugs used to treat hepatitis C infection.
- A side effect of taking HIV protease inhibitors is increased cholesterol and triglyceride (fat) levels. Therefore, some patients taking HIV protease inhibitors may need to take cholesterol-lowering medicines such as statins.
The U.S. Food and Drug Administration (FDA) is issuing updated recommendations concerning drug-drug interactions between drugs for human immunodeficiency virus (HIV) or hepatitis C virus (HCV) known as protease inhibitors and certain cholesterol-lowering drugs known as statins. Protease inhibitors and statins taken together may raise the blood levels of statins and increase the risk for muscle injury (myopathy). The most serious form of myopathy, called rhabdomyolysis, can damage the kidneys and lead to kidney failure, which can be fatal. The labels for both the HIV protease inhibitors and the affected statins have been updated to contain consistent information about the drug-drug interactions. These labels also have been updated to include dosing recommendations for those statins that may safely be co-administered with HIV or HCV protease inhibitors (see Statin Dose Limitations below).
Healthcare professionals should refer to the current drug labels for protease inhibitors and statins for the latest recommendations on prescribing these drugs.
Patients should contact their healthcare professional if they have any questions or concerns about taking protease inhibitors and statins.
- Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) protease inhibitors can interact with cholesterol-lowering statins to increase the risk of muscle injury.
- Patients should inform their healthcare professional about all medicines that they are taking or plan to take prior to starting an HIV or HCV protease inhibitor or statin.
- HIV and HCV protease inhibitors should never be taken (are contraindicated) with lovastatin (Mevacor) and simvastatin (Zocor) (see Statin Dose Limitations below).
- Patients should contact their healthcare professional if they have any questions or concerns about HIV or HCV protease inhibitors or statins.
- Patients should report side effects from the use of HIV or HCV protease inhibitors and/or statins to the FDA MedWatch program, using the information in the "Contact FDA" box at the bottom of the page.
- Co-administration of human immunodeficiency virus (HIV) or hepatitis C virus (HCV) protease inhibitors with certain statins can increase the risk of myopathy/rhabdomyolysis.
- Healthcare professionals should follow the recommendations in the drug labels when prescribing HIV or HCV protease inhibitors with statins (also see Statin Dose Limitations below).
- Healthcare professionals should report adverse events involving HIV or HCV protease inhibitors and/or statins to the FDA MedWatch program using the information in the "Contact FDA" box at the bottom of this page.
Atorvastatin
The results from a drug-drug interaction study with atorvastatin and lopinavir/ritonavir that were previously in the atorvastatin label have not yet been validated. Therefore, these results have been removed from the label and the dose cap of atorvastatin 20 mg when co-administered with lopinavir/ritonavir has also been removed. Pending validation of the study, healthcare professionals should use caution when co-administering atorvastatin with lopinavir/ritonavir and use the lowest necessary dose of atorvastatin.
Lovastatin and simvastatin
Lovastatin and simvastatin are sensitive in vivo cytochrome P450 3A4 (CYP3A4) substrates. Therefore, strong CYP3A4 inhibitors are predicted to significantly increase lovastatin and simvastatin exposures. A literature review indicates that itraconazole, a strong CYP3A4 inhibitor, increases lovastatin exposure up to 20-fold, and the drug interaction appears to result in rhabdomyolysis.1 Itraconazole increases simvastatin exposure up to 13-fold. Hence, other CYP3A4 inhibitors, including ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, nefazodone, human immunodeficiency virus (HIV) protease inhibitors, and the hepatitis C virus (HCV) protease inhibitors boceprevir and telaprevir, are also expected to significantly increase lovastatin and simvastatin exposures. Therefore, concomitant administration of lovastatin and simvastatin with HIV protease inhibitors or HCV protease inhibitors (boceprevir and telaprevir) is contraindicated.
Rosuvastatin
The HIV protease inhibitor combinations lopinavir/ritonavir and atazanavir/ritonavir increase rosuvastatin exposure up to 3-fold. For these combinations, the dose of rosuvastatin should be limited to 10 mg.
Statin Dose Limitations
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Reference
- Lees RS, Lees AM. Rhabdomyolysis from the coadministration of lovastatin and the antifungal agent itraconazole. N Engl J Med. 1995;333:664-5.
Source : FDA
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FDA Drug Safety Communication: Important safety label changes to cholesterol-lowering statin drugs
The U.S. Food and Drug Administration (FDA) has approved important safety label changes for the class of cholesterol-lowering drugs known as statins. These changes were made to provide the public with more information for the safe and effective use of statins and are based on FDA’s comprehensive review of the statin class of drugs (see Data Summary below). The changes include the following: Infographic About Cholesterol and Statins
Monitoring Liver Enzymes
Labels have been revised to remove the need for routine periodic monitoring of liver enzymes in patients taking statins. The labels now recommend that liver enzyme tests should be performed before starting statin therapy and as clinically indicated thereafter. FDA has concluded that serious liver injury with statins is rare and unpredictable in individual patients, and that routine periodic monitoring of liver enzymes does not appear to be effective in detecting or preventing serious liver injury.
Adverse Event Information
Information about the potential for generally non-serious and reversible cognitive side effects (memory loss, confusion, etc.) and reports of increased blood sugar and glycosylated hemoglobin (HbA1c) levels has been added to the statin labels. FDA continues to believe that the cardiovascular benefits of statins outweigh these small increased risks.
Drug Interactions
The lovastatin label has been extensively updated with new contraindications (situations when the drug should not be used) and dose limitations when it is taken with certain medicines that can increase the risk for muscle injury (see Lovastatin Dose Limitations below).
Healthcare professionals should refer to the drug labels for the latest recommendations for prescribing statins (also see Additional Information for Healthcare Professionals below). Patients should contact their healthcare professional if they have any questions or concerns about statins.
Additional Information for Patients
- The statin drug labels have been revised to provide patients with more information on the safe and effective use of statins. Patients should be aware of the following information:
- There have been rare reports of serious liver problems in patients taking statins. Patients should notify their healthcare professional right away if they have the following symptoms: unusual fatigue or weakness; loss of appetite; upper belly pain; dark-colored urine; or yellowing of the skin or the whites of the eyes.
- Memory loss and confusion have been reported with statin use. These reported events were generally not serious and went away once the drug was no longer being taken.
- Increases in blood sugar levels have been reported with statin use.
- Certain medicines should never be taken (are contraindicated) with lovastatin (Mevacor) (see Lovastatin Dose Limitations below).
- Patients should contact their healthcare professional if they have any questions or concerns about statins.
- Patients should report side effects from the use of statins to the FDA MedWatch program, using the information in the "Contact FDA" box at the bottom of the page.
- Healthcare professionals should perform liver enzyme tests before initiating statin therapy in patients and as clinically indicated thereafter. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment, therapy should be interrupted. If an alternate etiology is not found, the statin should not be restarted.
- There have been rare post-marketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These reported symptoms are generally not serious and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).
- Increases in glycosylated hemoglobin (HbA1c) and fasting serum glucose levels have been reported with statin use.
- Healthcare professionals should follow the recommendations in the lovastatin label regarding drugs that may increase the risk of myopathy/rhabdomyolysis when used with lovastatin (see Lovastatin Dose Limitations below).
- Healthcare professionals should report adverse events involving statins to the FDA MedWatch program using the information in the "Contact FDA" box at the bottom of this page.
Removal of routine monitoring of liver enzymes from drug labels
FDA reviewed current monitoring guidelines, including the National Lipid Association’s Liver Expert Panel and Statin Safety Task Force recommendations.1, 2 The Liver Expert Panel stated that the available scientific evidence does not support the routine monitoring of liver biochemistries in asymptomatic patients receiving statins. The Panel made this recommendation because (1) irreversible liver damage resulting from statins is exceptionally rare and is likely idiosyncratic in nature, and (2) no data exist to show that routine periodic monitoring of liver biochemistries is effective in identifying the very rare individual who may develop significant liver injury from ongoing statin therapy. The Panel believed that routine periodic monitoring will instead identify patients with isolated increased aminotransferase levels, which could motivate physicians to alter or discontinue statin therapy, thereby placing patients at increased risk for cardiovascular events.1 The National Lipid Association’s Statin Task Force also stated that routine monitoring of liver function tests is not supported by the available evidence.2
FDA reviewed post-marketing data to evaluate the risk of clinically serious hepatotoxicity associated with statins. FDA had conducted several post-marketing reviews of statins and hepatotoxicity between years 2000 and 2009 by searching the Agency’s Adverse Event Reporting System (AERS) database. Those reviews consistently noted that reporting of statin-associated serious liver injury to the AERS database was extremely low (reporting rate of ≤2 per one million patient-years). FDA’s updated review focused on cases of severe liver injury, defined as a 4 (severe liver injury) or a 5 (death or liver transplant) using the Drug Induced Liver Injury Network (DILIN) liver injury severity scale, which were reported to AERS from marketing of each statin through 2009. Cases meeting those criteria were further assessed for causality. Seventy-five cases (27 cases with a severity score of 4, and 48 cases with a severity score of 5 (37 deaths and 11 liver transplants) were assessed for causality. Thirty of the 75 cases (14 deaths, 7 liver transplantations, and 9 severe liver injury) were assessed as possibly or probably associated with statin therapy. No cases were assessed as highly likely or definitely associated with statin therapy. FDA concluded that, despite a rising use of statins as a class since the late 1990s, there has not been a detectable increase in the annual rates of fatal or severe liver injury cases possibly or probably causally associated with statin use.
FDA also reviewed cases from the DILIN and Acute Liver Failure Study Group (ALFSG), organizations that have been submitting reports to FDA of drug-associated liver injury in their liver injury outcome studies. As of January 1, 2011, DILIN had submitted 25 reports of statin-associated liver injury to FDA, 12 of which gave hospitalization as an outcome. A 2010 article from ALFSG included 133 prospectively identified cases of idiopathic drug-induced liver injury resulting in acute liver failure.3 Of these 133 patients, 15 were taking statins, and in six of these 15 individuals a statin was identified as the only potential drug to cause drug-induced liver injury.
Based on all available data, FDA has determined that all currently marketed statins appear to be associated with a very low risk of serious liver injury and that routine periodic monitoring of serum alanine aminotransferase (ALT) does not appear to detect or prevent serious liver injury in association with statins.
Cognitive adverse events
FDA reviewed the AERS database, the published medical literature (case reports and observational studies),4-13 and randomized clinical trials to evaluate the effect of statins on cognition.14-17
The post-marketing adverse event reports generally described individuals over the age of 50 years who experienced notable, but ill-defined memory loss or impairment that was reversible upon discontinuation of statin therapy. Time to onset of the event was highly variable, ranging from one day to years after statin exposure. The cases did not appear to be associated with fixed or progressive dementia, such as Alzheimer’s disease. The review did not reveal an association between the adverse event and the specific statin, the age of the individual, the statin dose, or concomitant medication use.
Data from the observational studies and clinical trials did not suggest that cognitive changes associated with statin use are common or lead to clinically significant cognitive decline.
Increases in glycosylated hemoglobin (HbA1c) and fasting plasma glucose
FDA’s review of the results from the Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) reported a 27% increase in investigator-reported diabetes mellitus in rosuvastatin-treated patients compared to placebo-treated patients. High-dose atorvastatin had also been associated with worsening glycemic control in the Pravastatin or Atorvastatin Evaluation and Infection Therapy – Thrombolysis In Myocardial Infarction 22 (PROVE-IT TIMI 22) substudy.18
FDA also reviewed the published medical literature.19-26 A meta-analysis by Sattar et al.,19 which included 13 statin trials with 91,140 participants, reported that statin therapy was associated with a 9% increased risk for incident diabetes (odds ratio [OR] 1.09; 95% confidence interval [CI] 1.02-1.17), with little heterogeneity (I2=11%) between trials. A meta-analysis by Rajpathak et al.,20 which included 6 statin trials with 57,593 participants, also reported a small increase in diabetes risk (relative risk [RR] 1.13; 95% CI 1.03-1.23), with no evidence of heterogeneity across trials. A recent study by Culver et al.,26 using data from the Women’s Health Initiative, reported that statin use conveys an increased risk of new-onset diabetes in postmenopausal women, and noted that the effect appears to be a medication class effect, unrelated to potency or to individual statin.
Based on clinical trial meta-analyses and epidemiological data from the published literature, information concerning an effect of statins on incident diabetes and increases in HbA1c and/or fasting plasma glucose was added to statin labels.
Lovastatin drug-drug interactions
Information regarding drug-drug interactions and contraindications and dose limitations has been added to the lovastatin label. Subsequent to the June 2011 label revisions to the simvastatin-containing products, which were based largely on the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial,27 a review of drug-drug interactions with lovastatin was conducted because the physicochemical and pharmacokinetic properties of lovastatin are comparable to those of simvastatin.
Lovastatin is a sensitive in vivo cytochrome P450 3A4 (CYP3A4) substrate. Strong CYP3A4 inhibitors are predicted to significantly increase lovastatin exposure. A literature review indicates that itraconazole, a strong CYP3A4 inhibitor, increases lovastatin exposure up to 20-fold and the drug interaction appears to result in rhabdomyolysis.28 The effect of itraconazole on lovastatin exposure can therefore be extrapolated to other strong CYP3A4 inhibitors, including ketoconazole, posaconazole, erythromycin, clarithromycin, telithromycin, human immunodeficiency virus (HIV) protease inhibitors, boceprevir, telaprevir, and nefazodone.
Lovastatin Dose Limitations
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Source : FDA (February 2012)
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FDA Adds Diabetes Warning to Statin Label
The FDA said today that all statins must carry warnings about increased risks of elevated blood sugar and possible transient memory and cognition problems, but at the same time the agency removed a standing recommendation for routine liver function tests for patients taking the cholesterol-lowering drugs. The FDA said the label changes apply to atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor), lovastatin extended-release (Altoprev), pitavastatin (Livalo), pravastatin (Pravachol), rosuvastatin (Crestor), and simvastatin (Zocor).
Despite the additional warnings, the FDA said it "continues to believe that the cardiovascular benefits of statins outweigh these small increased risks."
Rather than regular monitoring of liver function, the agency said that clinicians should now simply order a liver function test before starting a patient on a statin. Although the drugs do carry a risk of liver damage, the agency has judged the risk to be "rare and unpredictable in individual patients."
The diabetes warning has been rumored as a possibility since the findings from the JUPITER trial of rosuvastatin revealed an unexpected 27% increase in new onset diabetes among patients randomized to the statin.
That finding was especially perplexing because JUPITER was a study of statins in patients who had no history of cardiovascular disease, the so-called healthy patient trial. Moreover, based on the JUPITER results, the FDA approved rosuvastatin for primary prevention.
The FDA said hyperglycemia was also observed among patients treated with 40-mg atorvastatin in a substudy of PROVE-IT TIMI 22, and a meta-analysis of data from 13 statin trials "reported that statin therapy was associated with a 9% increased risk for incident diabetes."
The cognitive data are a bit sketchier and rely mainly on post-marketing adverse event reporting. The FDA said those reports "generally described individuals over the age of 50 years who experienced notable, but ill-defined memory loss or impairment that was reversible upon discontinuation of statin therapy."
In addition to those broad label changes, the FDA added a number of restrictions to the lovastatin (Mevacor) label, including a list of 10 drugs or drug classes that are contraindicated with lovastatin.
Drugs contraindicated with lovastatin include:
- Itraconazole
- Ketoconazole
- Posaconazole
- Erythromycin
- Clarithromycin
- Telithromycin
- HIV protease inhibitors
- Boceprevir
- Telaprevir
- Nefazodone
In general, cardiologists contacted by ABC News/MedPage Today, applauded the FDA action -- particularly the decision to remove the requirement for liver function testing. Harlan Krumholz, MD, of Yale University, said, "Good news on liver testing -- provides no benefit and a lot of Americans are being monitored unnecessarily."
But Krumholz and others worried about patients being scared off statins by the diabetes and memory warnings.
"All drugs have side effects and rarely some patients will have an odd reaction to statins -- cognitive effects are among those -- and are usually mild and resolve with stopping the medication. The blood sugar and diabetes issue has emerged over the last couple of years -- this appears to be a side effect," Krumholz wrote in an email.
Scott Grundy, MD, of the University of Texas Southwestern Medical Center in Dallas, was dubious about the level of evidence linking diabetes and cognition problems with statins. "I do not believe there is enough hard evidence to justify information and warnings about memory loss and confusion or increase in blood sugar."
And Grundy, too, worried about the impact on patients, writing, "I also think that these warnings will cause some people who need statins to stop taking them. That would be unfortunate."
The Cleveland Clinic's Steven Nissen, MD, often a critic of the FDA, told ABC News/MedPage Today, "these are reasonable and prudent recommendations. I am pleased that FDA did not overstate the diabetes and cognitive function risks. Both problems are uncommon and don't diminish the importance of statins in cardiovascular protection. For the vast majority of patients, the benefits far outweigh the risks."
Moreover, Nissen said, the FDA's decision on liver monitoring could boost statin use because it "will help to allay public apprehension about the liver safety of statins."
Source : Medpage Today
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Statins Up Diabetes Risk in Older Women
Older women who take statins may be at an increased risk for developing type 2 diabetes, researchers found.
In an analysis of data from the Women's Health Initiative, postmenopausal women who were on a statin at study entry had almost a 50% greater risk of diabetes than those who weren't on the cholesterol-lowering drugs, Yunsheng Ma, MD, PhD, of the University of Massachusetts School of Medicine, and colleagues reported online in the Archives of Internal Medicine.
"This study urges us to further evaluate the risk-benefit profile of statins," Ma told MedPage Today, adding that the ratio will likely vary by patient population.
Recent research has suggested a potential link between statins and the development of diabetes -- most notably a meta-analysis that found a 9% increased risk of the disease with statin use (QJM 2011; 104(2): 109-124), Ma said.
Yet how the risk of diabetes with statin use varies across populations hasn't been thoroughly explored, he added. So he and colleagues looked at data from the Women's Health Initiative to assess the risk in postmenopausal women.
Data were available for 153,840 women, mean age 63, who didn't have diabetes when they were enrolled in the study in 1993. About 7% of them were on statins at that time.
Through follow-up ending in 2005, there were 10,242 cases of new-onset diabetes.
In initial analyses, Ma and colleagues found that statin use at baseline was associated with an increased risk of diabetes (HR 1.71, 95% CI 1.61 to 1.83), and that association remained significant in multivariate analyses controlling for age, race, and weight (HR 1.48, 95% CI 1.38 to 1.59).
Ma said the risk was seen with all types of statins. "It appears to be a class effect," he told MedPage Today.
Risks were increased for all ethnicities, although they did vary slightly, with the highest risks seen among Asians:
- White: HR 1.49, 95% CI 1.38 to 1.62
- African American: HR 1.18, 95% CI 0.96 to 1.45
- Hispanic: 1.57, 95% CI 1.14 to 2.17
- Asian: HR 1.78, 95% CI 1.32 to 2.40
They said differences in phenotype, such as weight distribution, may explain the association.
Risk of diabetes also was similarly elevated -- by about 50% -- for women with and without heart disease, and was similar if women used either high- or low- potency statins (HR 1.45, 95% CI 1.36 to 1.61; and HR 1.48, 95% CI 1.36 to 1.61, respectively).
"The take-home message is that different populations have different risks for diabetes" associated with statin use, Annie Culver, BPharm, of the University of Massachusetts and a co-author on the study, told MedPage Today. "When a statin is indicated, it's very important to continue to monitor for diabetes as well as for the statin effects, so the dose can be adjusted along the way."
Culver added that the findings emphasize current guidelines that recommend lifestyle intervention as the primary means of treating high cholesterol.
"Too many people are put on a statin who don't have to be," Ma said. "Patients should go on a statin if they can't control [their cholesterol] through dietary intervention, but once they're on that statin they should still continue lifestyle intervention."
Suzanne Steinbaum, MD, director of women and heart disease at Lenox Hill Hospital in Bronx, N.Y., said in an email that it's not yet clear from this one study what the clinical implications are for postmenopausal women on statins.
"Due to the extensive use of statins in the aging female population, it is critical that more studies are done to help understand the association with statins and the development of diabetes," she wrote. "Women who are taking statins should be aware of the need to check their blood sugars, along with their liver function tests."
The researchers said the study was limited by its observational nature, and because individual statin analysis may be confounded by the fact that women may have changed statin type before developing diabetes.
Source : MedPage Today
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Statins Tied to Lung Damage in Smokers
Statin use appears to be associated with interstitial lung abnormalities among current and former smokers, researchers found. Among individuals with a history of at least 10 pack-years of smoking, statin use was associated with a 60% increase in the odds of having abnormalities on CT scans (OR 1.60, 95% CI 1.03 to 2.50), according to Gary Hunninghake, MD, MPH, of Brigham and Women's Hospital in Boston, and colleagues.
The findings were independent of a history of high cholesterol, coronary heart disease, or a number of other cardiovascular risk factors, the researchers reported online in the American Journal of Respiratory and Critical Care Medicine.
"Our findings suggest that statins may influence the susceptibility to, or progression of, interstitial lung disease," they wrote.
But they advised caution before applying the findings to patient care because the possible risks of statins on interstitial lung abnormalities likely do not outweigh the benefits of statin therapy in patients with cardiovascular disease.
"In addition, our findings do not rule out the possibility that statin use could benefit some patients with respiratory disease," they wrote. "Instead, we believe that clinicians should be aware that radiographic evidence of interstitial lung disease, much like myopathy, can occur in some patients on statins."
Previous studies have provided conflicting evidence on the relationship between statins and interstitial lung disease, so Hunninghake and colleagues examined data from the COPDGene study to further explore the issue.
The current analysis included 2,115 current and former smokers who underwent chest CT scans.
By definition, interstitial lung abnormalities affected more than 5% of any lung zone and included non-dependent ground-glass or reticular abnormalities, diffuse centrilobular nodularity, nonemphysematous cysts, honeycombing, or traction bronchiectasis.
The percentage of patients with such abnormalities was greater among patients taking statins (38% versus 27%, P=0.04).
The relationship between statins and lung abnormalities was stronger with more hydrophilic statins and with older patient age (P<0.05 for both trends). Pravastatin (a hydrophilic statin, brand name Pravachol) was most strongly associated with abnormalities (OR 4.61, 95% CI 1.99 to 10.70).
Hunninghake and colleagues explored the potential mechanism underlying the association between statins and lung damage using mice and cell cultures.
They found that pretreating mice with pravastatin enhanced the lung inflammation and fibrosis induced by bleomycin.
Also, in vitro studies revealed that statins increased the generation of mitochondrial reactive oxygen species in macrophages, which increased NLRP3-inflammasome activation.
The experimental findings conflict with two previous studies in which statins reduced bleomycin-induced lung injury. Hunninghake noted that those studies differed based on the type of statin, the dose of bleomycin, and the timing of statin administration.
But they acknowledged some limitations of the current analysis, including the lack of data to correlate the experimental findings in mice to humans, the lack of biopsies in the human participants, the lack of information on the duration of statin use or dose for most patients, and the possibility that the findings apply only to current and former smokers.
Despite the potential negative association of statins with interstitial lung damage, recent studies have shown that statins might confer protective benefits for those hospitalized with the flu and for those who suffered a head trauma.
Source : MedPage Today
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FDA Drug Safety Communication:Review update of Trilipix (fenofibric acid) and the ACCORD Lipid trial
Facts about Trilipix (fenofibric acid)
- A prescription medicine used to treat cholesterol in the blood by lowering low-density lipoprotein (LDL) cholesterol ("bad cholesterol"), and increasing the high-density lipoprotein (HDL) cholesterol ("good cholesterol").
- Can be used to lower very high levels of fat (triglycerides) in the blood to help reduce the risk for pancreatitis.
- Can be used in combination with other cholesterol-lowering medicines called statins in patients at high risk for cardiovascular disease.
The U.S. Food and Drug Administration (FDA) is informing the public that the cholesterol-lowering medicine Trilipix (fenofibric acid) may not lower a patient's risk of having a heart attack or stroke. This is based on data from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid trial, which evaluated the efficacy and safety of fenofibrate plus simvastatin combination therapy versus simvastatin alone in patients with type 2 diabetes mellitus (see Data Summary below). FDA reviewed this trial as part of its ongoing investigation of the safety and efficacy of Trilipix.
nformation from the trial has been added to the Important Limitations of Use and Warnings and Precautions sections of the Trilipix physician label and to the patient Medication Guide. Healthcare professionals should consider the benefits and risks of Trilipix when deciding to prescribe the drug to patients. Patients should contact their healthcare professional if they have any questions or concerns about Trilipix.
In the ACCORD Lipid trial, there was no significant difference in the risk of experiencing a major adverse cardiac event between the group treated with fenofibrate plus simvastatin compared with simvastatin alone. In addition, a subgroup analysis showed that relative to treatment in men, there was an increase in the risk for major adverse cardiac events in women receiving the combination therapy versus simvastatin alone. The clinical significance of this subgroup finding is unclear, as this finding was not observed in a separate large randomized controlled clinical trial of fenofibrate versus placebo.
Based on results from the ACCORD Lipid trial and other clinical trials of drugs similar to Trilipix, FDA is requiring the manufacturer of Trilipix to conduct a clinical trial to evaluate the cardiovascular effects of Trilipix in patients at high risk for cardiovascular disease who are already taking statins.
FDA had previously communicated to the public about the ACCORD Lipid trial in a Statement to Healthcare Professionals on March 15, 2010. The results of this trial were later discussed at the FDA Endocrinologic and Metabolic Drugs Advisory Committee meeting, held on May 19, 2011.
Additional Information for Patients
- Trilipix has not been shown to lower patients' risk of having a heart attack or a stroke.
- Patients should not stop taking their Trilipix medicine without first consulting with their healthcare professional.
- Patients should discuss the benefits and risks of taking Trilipix with their healthcare professional.
- Patients should read the Medication Guide that they get along with their Trilipix prescription.
- Patients should talk to their healthcare professional if they have any questions or concerns about Trilipix.
- Patients should report serious side effects from the use of Trilipix to the FDA MedWatch program, using the information in the "Contact Us" box at the bottom of this page.
- Fenofibrate at a dose equivalent to 135 mg of Trilipix was not shown to reduce coronary heart disease morbidity and mortality in patients in two large randomized controlled trials of patients with type 2 diabetes mellitus.
- Healthcare professionals should consider the benefits and risks of Trilipix when deciding to prescribe the drug to patients, and counsel patients about those benefits and risks.
- Healthcare professionals should encourage patients to read the Medication Guide they receive along with their Trilipix prescription.
- Healthcare professionals should report adverse events involving Trilipix to the FDA MedWatch program using the information in the "Contact Us" box at the bottom of this page.
The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid trial was a randomized, double-blind, placebo-controlled add-on trial which evaluated the efficacy and safety of adding fenofibrate therapy to treatment with simvastatin in patients with type 2 diabetes mellitus. Patients were randomized to receive simvastatin plus fenofibrate (n=2765) or simvastatin plus placebo (n=2753). All patients received open-label simvastatin therapy for four weeks prior to initiation of blinded therapy with fenofibrate or placebo. The primary outcome was major adverse cardiovascular events (MACE), a composite of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular disease death.
The mean duration of follow-up was 4.7 years. The results showed that fenofibrate plus simvastatin combination therapy was associated with a non-significant 8% relative risk reduction in the primary outcome of MACE (hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.79-1.08; p=0.32) as compared to simvastatin plus placebo. In a prespecified subgroup analysis of the primary efficacy outcome, the HR for MACE in men receiving combination therapy versus simvastatin monotherapy was 0.82 (95% CI 0.69-0.99), and the HR for MACE in women receiving combination therapy versus simvastatin monotherapy was 1.38 (95% CI 0.98-1.94) (interaction p=0.01). The clinical significance of this subgroup finding is unclear, as this finding was not observed in a separate large randomized controlled clinical trial of fenofibrate versus placebo.
However, the study results also raised the hypothesis that a subgroup of patients with high triglycerides and low high-density lipoprotein (HDL) cholesterol may experience some reduction in the risk of MACE from the combination therapy versus simvastatin monotherapy.
The results of the ACCORD Lipid trial were discussed at the FDA Endocrinologic and Metabolic Drugs Advisory Committee meeting, held on May 19, 2011 (for complete reviews and background information discussed at this meeting see: May 19, 2011 AC meeting).
Based on the results from the ACCORD Lipid trial and other clinical trials of drugs similar to Trilipix, FDA is requiring the manufacturer of Trilipix to conduct a randomized, double-blind, placebo-controlled clinical trial to test the hypothesis that Trilipix in combination with a statin versus statin alone significantly reduces the incidence of major adverse cardiovascular events in high-risk men and women who are at their low-density lipoprotein (LDL) cholesterol goal on statin therapy, but have residually high triglycerides and low HDL cholesterol.
-Related Information
- Statement to Healthcare Professionals on the ACCORD Lipid Trial from the FDA’s Center for Drug Evaluation and Research
3/15/2010 - 2011 Meeting Materials, Endocrinologic and Metabolic Drugs Advisory Committee
5/19/2011 - Information on Fenofibric Acid (marketed as Trilipix)
- FDA Drug Safety Podcast for Healthcare Professsionals: Review update of Trilipix (fenofibric acid) and the ACCORD Lipid trial
11/9/2011
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FDA announces new safety recommendations for high-dose simvastatin
Increased risk of muscle injury cited
Simvastatin is sold under the brand-name Zocor and as a single-ingredient generic product. It is also sold in combination with ezetimibe as Vytorin and in combination with Niacin as Simcor.
The U.S. Food and Drug Administration today is announcing safety label changes for the cholesterol-lowering medication simvastatin because the highest approved dose--80 milligram (mg)--has been associated with an elevated risk of muscle injury or myopathy, particularly during the first 12 months of use.
The agency is recommending that simvastatin 80 mg be used only in patients who have been taking this dose for 12 months or more and have not experienced any muscle toxicity. It should not be prescribed to new patients. There are also new contraindications and dose limitations for when simvastatin is taken with certain other medications.
The changes to the label for simvastatin-containing medications are based on the FDA's review of the results of the seven-year Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine clinical trial, other clinical trial data, and analyses of adverse events submitted to the FDA's Adverse Event Reporting System. All showed that patients taking simvastatin 80 mg daily had an increased risk of muscle injury compared to patients taking lower doses of simvastatin or other statin drugs. The risk of muscle injury is highest during the first year of treatment with the 80 mg dose of simvastatin, is often the result of interactions with certain other medicines, and is frequently associated with a genetic predisposition for simvastatin-related muscle injury.
Simvastatin is sold under the brand-name Zocor and as a single-ingredient generic product. It is also sold in combination with ezetimibe as Vytorin and in combination with Niacin as Simcor.
The FDA has revised the drug labels for simvastatin and Vytorin to include the new 80 mg dosing restrictions. The agency also revised the labels for simvastatin, Vytorin and Simcor to include new dosing recommendations when these drugs are used with certain medications that interact to increase the level of simvastatin in the body, which can increase the risk for myopathy. Patients who are unable to adequately lower their level of LDL-C on simvastatin 40 mg should not be given the higher 80 mg dose of simvastatin; instead, they should be placed on an alternative LDL-C lowering treatment(s).
Source : FDA (June 2011)
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Statin drugs cause liver damage, kidney failure and cataracts, says BMJ
Cholesterol-lowering statin drugs significantly increase a person's risk of cataracts, muscle weakness, liver dysfunction and kidney failure, according to a study in the British Medical Journal.
The study also confirmed that the drugs lower the risk of heart disease and esophageal cancer, but claims of other health benefits were unsupported.
Researchers from Nottingham University in the United Kingdom examined data on more than 2 million patients between the ages of 30 and 84, seen at 38 different general practices, who had been prescribed the cholesterol-lowering drugs. More than 70 percent were taking simvastatin (Zocor), 22.3 percent were taking atorvastatin (Lipitor), 3.6 percent were taking pravastatin (Pravachol, Selektine), 1.9 percent were taking rosuvastatin (Crestor) and 1.4 percent were taking fluvastatin (Canef, Lescol, Lochol, Vastin).
The researchers confirmed prior data suggesting that statins increase patients' risk of cataracts, liver dysfunction, kidney failure and a form of muscle weakness known as myopathy. They found that for every 10,000 women treated with the drugs, 23 would develop acute kidney (renal) failure, 39 would develop myopathy, 74 would develop liver dysfunction and 309 would develop cataracts. Men suffered an even higher risk of myopathy, but their risks of the other three conditions were similar to those suffered by women.
Putting it in different terms, the researchers found that only 434 people would need to be treated with the drugs for five years for one case of acute renal failure to develop. It would take only 136 treated for each case of liver dysfunction and 33 for each case of cataracts. Among women, 259 would need to be treated for each case of myopathy; among men, the number was only 91.
The risk of developing all conditions was highest during the first year of treatment, but continued throughout the course of the study. Risk of liver and kidney problems increased proportionally with the dose of statins being taken.
All drugs appeared to pose a similar risk of all conditions, with the exception of fluvastatin, which increased the risk of liver dysfunction more than its competitors. Men taking fluvastatin were twice as likely to develop liver dysfunction as those not taking statins, while women's risk increased by 2.5 times.
The researchers did find, however, that the risk of cataracts returned to normal within one year of stopping statin treatment, while the risk of liver and kidney problems returned to normal within one to three years. Additionally, they found no connection between statin use and the risk of dementia, osteoporotic fracture, Parkinson's disease, rheumatoid arthritis or venous thromboembolism.
Examining the purported benefits of the drugs, researchers found that they did in fact lower the risk of heart disease, averting 271 cases for every 10,000 high-risk patients treated. Put another way, 33 high-risk men or 37 high-risk women would need to be treated with the drugs to avert one case of the disease.
Although advocates of the drugs have claimed that they may also reduce the risk cancer, the researchers found almost no data supporting these claims. The study "largely confirmed other studies that reported no clear association between statins and risk of cancers," the researchers wrote.
The only cancer-fighting effect uncovered in the study was a slightly lower risk of esophageal cancer, with eight cases averted for every 10,000 high-risk women treated. In other words, 1,266 high-risk women or 1,082 high-risk men would need to be treated with the drugs to prevent one case of esophageal cancer.
Although sales of the blockbuster drugs are unlikely to be reduced as a result of the study, the researchers encouraged closer monitoring of patients for side effects and said their findings "would tend to support a policy of using lower doses of statins in people at high risk of the adverse event."
Source : Natural News 7/11/2010
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Statins and Myoglobin: How Muscle Pain and Weakness Progress to Heart, Lung and Kidney Failure Part 1
Statin drug use has steadily increased over the last several decades, due to the widespread belief that cholesterol reduction is an important step in preventing heart disease. It is undeniable that statins are effective: they can decrease serum cholesterol levels from over 300 db/ml to well within the normal range in a matter of weeks. For a person who already has normal cholesterol levels, statins can drive their cholesterol down to levels not seen in nature. Statins have also been shown to reduce the relative risk of heart attacks in men in their 50's by as much as 30%, but, because heart attacks are relatively rare for this segment of the population, the absolute risk reduction is only on the order of 2%, a point that is often missed by the person being treated.
All drugs have potential side effects, and with any drug it's a matter of weighing the risk/benefit factors to decide whether the drug is warranted. Statin drugs have a remarkably diverse set of side effects, including cognitive and memory impairment, reduced libido, and muscle pain and weakness. The drug manufacturers claim that the incidence of side effects is relatively rare, but often side effects don't appear until after several months or even years into treatment. In many of these cases, it may not be obvious that the statin drug is the cause of the problem. This is especially true because these side effects can easily be attributed to increasing age. In fact, as I will show later, statin side effects can best be interpreted as an acceleration of the aging process.
In my view, statin drugs are never worth the risk of their side effects. Cholesterol is a vital nutrient, without which mammalian cells can not survive, and it is inconceivable to me that crippling the body's ability to synthesize cholesterol can ever be a good idea. In an excellent and highly informative review article published in 2009, Wainwright et al. [43] developed a strong argument that statin drugs, by depleting cholesterol, lead to a destabilization of cell membranes "from head to toe." This problem, in turn, increases risk to a long list of serious health conditions and diseases, including diabetes, multiple sclerosis, cognitive problems, hemorrhagic stroke, cancer, and even ALS (amyotrophic lateral sclerosis, also known commonly as Lou Gehrig's disease). Their arguments are backed up by references to 85 peer-reviewed journal publications. I have argued in previous essays that statins may increase the risk to Alzheimer's disease, as well as to sepsis, cancer, and heart failure.
The most commonly reported side effects to statin therapy are muscle pain and weakness. If left unchecked, these symptoms can progress to rhabdomyolysis (severe muscle damage) and kidney failure. Muscle weakness in the lungs can lead to breathing difficulties; in the heart it leads to heart failure. Statin users are reassured by their doctors that they can halt statin therapy if their liver and muscle enzymes rise too high. In practice, however, it's possible to suffer irreversible muscle damage (the problem does not go away after the statin therapy is stopped), and this can happen even when the enzyme levels are not above the normal range.
This essay will develop an argument for why, over time, a statin user may become increasingly weak, in some cases to the point of major disability. A key message is that muscles are forced to cannibalize themselves to acquire sufficient energy. But another factor is oxidative damage to muscle tissue, with subsequent disintegration of the cell walls. This is true not only for the skeletal muscles, but also for the respiratory muscles controlling breathing and the heart muscle. With continued abuse, the muscle cells disintegrate, and the debris travels in the blood stream to the kidneys, which can lead to kidney failure.
The rest of this essay will unfold as follows. In the next section, I will explain how statin drugs work, which will also show why they interfere with the synthesis not only of cholesterol but also of other essential biological substances involved in cell metabolism. The following section will present evidence that statins damage muscle cells. Sections 4 and 5 describe the biochemical pathways involved in assuring that muscles have enough energy to effect movement, especially during situations of stress such as extreme exercise. Section 6 describes the condition known as rhabdomyolysis, caused by extreme exercise but also by statin drugs, and the subsequent risk to kidney failure. Section 7 describes the role that myoglobin, a key protein found in muscle cells, plays in the disease process. After a section explaining how cholesterol protects cell membranes from oxidative damage, the four subsequent sections (sections 9-12) will be devoted to the repercussions of statin damage to the muscles, the heart, the lungs, and the pancreas, respectively. Finally, the conclusion section will summarize the essay and provide hints about my upcoming essay on ALS, a physically disabling neurodegenerative disease that is due not to muscle damage per se but to damage of the motor neurons in the spinal cord that transmit signals from the brain to the skeletal muscles.
2. The Biological Mechanism of Statin Drugs
Why do statins cause so many side effects? To answer this question requires explaining all the crucial roles that cholesterol plays in maintaining the integrity and functioning of the body's cells. However, statins interfere not only with the synthesis of cholesterol, but also with the synthesis of an enzyme, coenzyme Q10, that plays a critical role in energy metabolism in all cells. A deficiency in both cholesterol and coenzyme Q10, over time, leads to a huge list of potential health problems. Exactly how an individual responds depends upon their genetic make-up: faced with a deficiency, the body will decide to sacrifice certain cell types in order to safeguard certain other cell types. So, one person may develop Alzheimer's because the brain's neurons are sacrificed, while another succumbs to heart failure or rhabdomyolysis (skeletal muscle wasting).
Statins suppress a critical early step in the multi-step biological pathway that leads to cholesterol synthesis. This is why statins are able to dramatically reduce the blood serum levels of cholesterol. Specifically, statins interfere with the production of the enzyme, HMG-Coenzyme A Reductase, which catalyzes production of mevalonate from its precursor, HMG-Coenzyme A. Several more steps produce cholesterol from mevalonate. Mevalonate is also the precursor to a large number of other biologically active molecules that are important for proper cell function. These include the antioxidants, coenzyme Q10 and the dolichols, as shown in the figure to the right.
The so-called "bad" cholesterol, LDL, delivers cholesterol, fats, and antioxidants from the liver to all the cells of the body. All cells need both fats and cholesterol to maintain healthy membranes, not only in the outer cell wall, but also in the membranes encasing the nucleus, the mitochondria (energy producing units), and the lysosomes (the cell's digestive system). Antioxidants are critical for neutralizing the damaging effects of oxygen exposure, always an issue whenever energy is generated in the mitochondria through a chemical reaction between food sources and oxygen.
In a double-blind placebo controlled study [18], it has been shown that statins can reduce serum levels of coenzyme Q10 by as much as 40%. Coenzyme Q10 is not only a powerful antioxidant, but it also plays a crucial role in the process that breaks down glucose in the presence of oxygen to yield carbon dioxide and water. This metabolic pathway, which is essentially the burning of glucose as fuel, takes place in the mitochondria via the well-known citric acid, or Kreb's cycle. The energy that is released through this process is packaged up in the form of ATP (Adenosine Triphosphate), the currency that all cells use to store their energy reserves.
The dolichols play a special role for the lysosomes [20]. The lysosomes are walled off "rooms" that contain digestive enzymes to break down debris from damaged cell parts so that they can be recycled into useful materials. Lysosomes must maintain a highly acidic internal environment in order for the digestive enzymes to work properly. The dolichols are responsible for pumping hydrogen ions into the lysosomes to keep them highly acidic.
A final way that statins can damage cells is through their entry mechanism. Statins belong to a class of drugs called "amphiphilic" drugs [2] that manage to break through the cell wall in spite of being relatively large. They act like a soap by essentially dissolving a section of the cell membrane. This leaves behind a hole in the wall, which needs to be patched up, as well as debris which must be cleaned up and recycled by the lysosomes. To patch the hole requires new sources of both fats and cholesterol, which come from the LDL particles, whose supply is greatly reduced due to the statin drug. So it becomes increasingly difficult over time for the cell to repair all the holes introduced by the statin drug molecules. As the cell wall becomes more permeable due to previous exposure to an amphiphilic drug, the amount of drug that successfully enters the cell steadily increases over time, leading to ever greater internal concentrations of the drug.
3. Statins, Muscle Pain and Weakness, and Rhabdomyolysis
Muscle cells have tremendous energy needs, particularly if the person has been put on an exercise regimen as part of their treatment program. The heart, in particular, never rests. It has to keep on beating 24x7 at the rate of at least once every second. Hence the heart is especially dependent on coenzyme Q10 to replenish the ATP consumed every time it contracts and pushes blood from one chamber to another and out the aorta.
The pharmaceutical industry readily admits that statin therapy may cause muscle pain and/or muscle weakness in some cases, but they claim that the incidence of these side effects is small, on the order of 2%. However, observational studies have shown that at least 10% to 15% of statin users complain of muscle pain [6][40]. The actual number who experience pain or weakness is likely to be much larger, however, because many people are unaware that this is a potential side effect. Furthermore, it sometimes takes several years of cumulative statin damage before the symptoms become intolerable. People are often willing to believe that their aches and pains and generally weakening condition are simply due to getting older.
The reaction by the general community to a relatively benign article posted by WebMD on muscle pain suggests that the problem is much worse than is generally acknowledged. Over 200 often lengthy comments describe many very sad stories; often the doctor was also misinformed, and denied that the pain could be due to the statin drug. A case in point is described in this New York Times article. A woman in Kansas had been taking a statin for years to reduce her cholesterol. Over that same time period, she experienced chronic muscle pain which neither she nor her doctor attributed to the statin therapy. It even led to a useless shoulder operation. Her problem eventually escalated into skin lesions caused by a reaction to toxic protein by-products released by her disintegrating muscles. She was given an antifungal to treat the skin lesions, another misdiagnosis. But the antifungal interacted with the statins [25] to further increase the severity of her muscle disorders. Three months later, she could barely stand, and her pulmonary muscles were so weak she couldn't breathe. She died shortly thereafter.
Rhabdomyolysis is a condition where the muscles rapidly disintegrate due to an injury, often, for example, physical trauma following an accident. But Rhabdomyolysis is also a rare side effect of statins -- essentially where the muscle pain and weakness are extreme. Some people react immediately to statin therapy with severe rhabdomyolysis, and it is often fatal, due to acute renal failure (ARF). Myoglobin is sloughed off from the muscle cells in large amounts, and it overloads the kidneys and causes them to shut down completely. Initiating statin therapy is therefore a bit like Russian roulette -- there is even a known case where a single statin dose caused rhabdomyolysis [21]. One of the statins, Baycol, was abruptly taken off the market in 2001, after 31 people died from subsequent rhabdomyolysis.
Source: The (Skeptic's) Health Journal Club
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FDA Warns about Increased Risk of Muscle Injury with Zocor
Highest approved dose of cholesterol-lowering medication could cause harm to muscles
The U.S. Food and Drug Administration today warned patients and healthcare providers about the potential for increased risk of muscle injury from the cholesterol-lowering medication Zocor (simvastatin) 80 mg. Although muscle injury (called myopathy) is a known side effect with all statins, today’s warning highlights the greater risk of developing muscle injury, including rhabdomyolysis, for patients when they are prescribed and use higher doses of this drug. Rhabdomyolysis is the most serious form of myopathy and can lead to severe kidney damage, kidney failure, and sometimes death.
“Review of simvastatin is part of an ongoing FDA effort to evaluate the risk of statin-associated muscle injury and to provide that information to the public as it becomes available,” said Eric Colman, M.D., Deputy Director of FDA’s Division of Metabolism and Endocrinology Products (DMEP). “It’s important for patients and healthcare professionals to consider all the potential risks and known benefits of any drug before deciding on any one therapy or dose of therapy.”
Simvastatin is sold as a single-ingredient generic medication and as the brand-name Zocor. It also is sold in combination with ezetimibe as Vytorin, and in combination with niacin as Simcor.
FDA’s review of new information on the risk of muscle injury is derived from clinical trials, observational studies, adverse event reports, and prescription use data. The agency also is reviewing data from the SEARCH (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine) trial, which evaluated major cardiovascular events, such as heart attack, revascularization and cardiovascular death, in patients taking 80 mg compared to 20 mg of simvastatin. SEARCH also included data on muscle injury in patients taking simvastatin.
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Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials
Naveed Sattar, David Preiss, Heather M Murray, Paul Welsh, Brendan M Buckley, Anton J M de Craen, Sreenivasa Rao Kondapally Seshasai, John J McMurray, Dilys J Freeman, J Wouter Jukema, Peter W Macfarlane, Chris J Packard, David J Stott, Rudi G Westendorp, James Shepherd, Barry R Davis, Sara L Pressel, Roberto Marchioli, Rosa Maria Marfisi, Aldo P Maggioni, Luigi Tavazzi, Gianni Tognoni, John Kjekshus, Terje R Pedersen,
Thomas J Cook, Antonio M Gotto, Michael B Clearfield, John R Downs, Haruo Nakamura, Yasuo Ohashi, Kyoichi Mizuno, Kausik K Ray, Ian Ford
Summary
Background Trials of statin therapy have had conflicting findings on the risk of development of diabetes mellitus in patients given statins. We aimed to establish by a meta-analysis of published and unpublished data whether any relation exists between statin use and development of diabetes.
Methods
We searched Medline, Embase, and the Cochrane Central Register of Controlled Trials from 1994 to 2009,
for randomised controlled endpoint trials of statins. We included only trials with more than 1000 patients, with
identical follow-up in both groups and duration of more than 1 year. We excluded trials of patients with organ
transplants or who needed haemodialysis. We used the I² statistic to measure heterogeneity between trials and
calculated risk estimates for incident diabetes with random-effect meta-analysis.
Findings
We identified 13 statin trials with 91 140 participants, of whom 4278 (2226 assigned statins and 2052 assigned control treatment) developed diabetes during a mean of 4 years. Statin therapy was associated with a 9% increased risk for incident diabetes (odds ratio [OR] 1·09; 95% CI 1·02–1·17), with little heterogeneity (I²=11%) between trials. Meta-regression showed that risk of development of diabetes with statins was highest in trials with older participants, but neither baseline body-mass index nor change in LDL-cholesterol concentrations accounted for residual variation in risk. Treatment of 255 (95% CI 150–852) patients with statins for 4 years resulted in one extra case of diabetes.
Interpretation
Statin therapy is associated with a slightly increased risk of development of diabetes, but the risk is low
both in absolute terms and when compared with the reduction in coronary events. Clinical practice in patients with moderate or high cardiovascular risk or existing cardiovascular disease should not change.
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