FDA Expands Advice on Statin Risks

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• Liver Injury Called Rare
• Reports of Memory Loss
• The Risk of Diabetes
• The Potential for Muscle Damage

If you’re one of the millions of Americans who take statins to prevent heart disease, the Food and Drug Administration (FDA) has important new safety information on these cholesterol-lowering medications.

FDA is advising consumers and health care professionals that:

• Routine monitoring of liver enzymes in the blood, once considered standard procedure for statin users, is no longer needed. Such monitoring has not been found to be effective in predicting or preventing the rare occurrences of serious liver injury associated with statin use.
• Cognitive (brain-related) impairment, such as memory loss, forgetfulness and confusion, has been reported by some statin users.
• People being treated with statins may have an increased risk of raised blood sugar levels and the development of Type 2 diabetes.
• Some medications interact with lovastatin (brand names include Mevacor) and can increase the risk of muscle damage.

This new information should not scare people off statins, says Amy G. Egan, M.D., M.P.H., deputy director for safety in FDA’s Division of Metabolism and Endocrinology Products (DMEP). “The value of statins in preventing heart disease has been clearly established,” she says. “Their benefit is indisputable, but they need to be taken with care and knowledge of their side effects.”

FDA will be changing the drug labels of popular statin products to reflect these new concerns. (These labels are not the sticker attached to a prescription drug bottle, but the package insert with details about a prescription medication, including side effects.)

The statins affected include:

• Altoprev (lovastatin extended-release)
• Crestor (rosuvastatin)
• Lescol (fluvastatin)
• Lipitor (atorvastatin)
• Livalo (pitavastatin)
• Mevacor (lovastatin)
• Pravachol (pravastatin)
• Zocor (simvastatin).

Products containing statins in combination with other drugs include:

• Advicor (lovastatin/niacin extended-release)
• Simcor (simvastatin/niacin extended-release)
• Vytorin (simvastatin/ezetimibe).

Liver Injury Called Rare

FDA has found that liver injury associated with statin use is rare but can occur. Patients are advised to consult their health care professional if they have symptoms that include unusual fatigue, loss of appetite, right upper abdominal discomfort, dark urine or yellowing of the skin or whites of the eyes.

Statins work in the liver to reduce the production of cholesterol, a waxy substance that can form plaque on the walls of the arteries and keep the heart from getting the blood it needs.

Egan explains that there had been signals in early clinical trials of possible liver damage tied to statin use, so health care professionals were advised to regularly test their patients’ liver enzyme levels. However, she says, such damage is rare, and the tests are not effective at predicting or preventing who will develop this rare side effect.

So FDA is now recommending that liver enzyme tests be performed before statin treatment begins and then as needed if there are symptoms of liver damage.

 

Reports of Memory Loss

FDA has been investigating reports of cognitive impairment from statin use for several years. The agency has reviewed databases that record reports of bad reactions to drugs and statin clinical trials that included assessments of cognitive function.

The reports about memory loss, forgetfulness and confusion span all statin products and all age groups. Egan says these experiences are rare but that those affected often report feeling “fuzzy” or unfocused in their thinking.

In general, the symptoms were not serious and were reversible within a few weeks after the patient stopped using the statin. Some people affected in this way had been taking the medicine for a day; others had been taking it for years.

What should patients do if they fear that statin use could be clouding their thinking? “Talk to your health care professional,” Egan says. “Don’t stop taking the medication; the consequences to your heart could be far greater.”

 

The Risk of Diabetes

Diabetes occurs because of defects in the body’s ability to produce or use insulin—a hormone needed to convert food into energy. If the pancreas doesn't make enough insulin or if cells do not respond appropriately to insulin, blood sugar levels in the blood get too high, which can lead to serious health problems.

A small increased risk of raised blood sugar levels and the development of Type 2 diabetes have been reported with the use of statins.

“Clearly we think that the heart benefit of statins outweighs this small increased risk,” says Egan. But what this means for patients taking statins and the health care professionals prescribing them is that blood-sugar levels may need to be assessed after instituting statin therapy,” she says.

 

The Potential for Muscle Damage

Some drugs interact with statins in a way that increases the risk of muscle injury called myopathy, characterized by unexplained muscle weakness or pain. Egan explains that some new drugs are broken down (metabolized) through the same pathways in the body that statins follow. This increases both the amount of statin in the blood and the risk of muscle injury.

FDA is revising the drug label for Lovastatin to clarify the risk of myopathy. The label will reflect what drugs should not be taken at the same time, and the maximum lovastatin dose if it is not possible to avoid use of those other drugs.

Patients and health care professionals should report negative side effects from statin use to FDA’s MedWatch Adverse Event Reporting Program⁶.

This article appears on FDA's Consumer Update page⁷, which features the latest on all FDA-regulated products.

February 27, 2011

Cholesterol Does Not Cause Heart Disease or Any Disease - McEvoy

 

Cholesterol Does Not Cause Heart Disease or Any Disease

Michael McEvoy CNC, CMTA MARCH 31, 2010

Contrary to most people’s understanding, cholesterol is one of the most vitally important substances in the body. Cholesterol has been accused of being the culprit in many diseases, including heart disease. However, without cholesterol the body simply cannot function.

 

Cholesterol is a waxy substance in the blood that is synthesized in the liver as a necessary agent for many significant bodily functions. Cholesterol has two forms: HDL (high density lipo-protein) and LDL (low density lipo-protein). HDL cholesterol is cholesterol that is en-route back to the liver, while LDL cholesterol is cholesterol that is en-route from the liver to the bloodstream to perform its functions. LDL cholesterol is commonly called ”bad” cholesterol because it has been found inside of the arteries of the body and has been pegged as causing heart disease.

 

However as we see in bullet number four below, cholesterol serves as a metabolic nutrient. One of the many functions of cholesterol is to provide repair to damaged tissues such as the arteries. The fact that cholesterol is found in the arteries does not correlate LDL cholesterol as being “bad” or causative in any disease. It indicates, rather that LDL cholesterol is repairing damage to an area of the body.

 

The damage done to the body is linked to several patterns of degenerative processes such as: substance abuse, certain lifestyle choices, and the improper dietary habits. These patterns are causative to disease, cholesterol is not.

 

As Dr. Natasha Cambell McBride states: “Calling LDL cholesterol “bad” and HDL cholesterol “good” is like calling an ambulance travelling from the hospital to the patient a "bad ambulance," and the one travelling from the patient back to the hospital a "good ambulance."*

 

“But the situation has gotten even more ridiculous. The latest thing that our science has "discovered" is that not all LDL-cholesterol is so bad. Most of it is actually good. So, now we are told to call that part of LDL the "good bad cholesterol" and the rest of it the "bad bad cholesterol."

 

It is a fact that lower cholesterol levels correlate with an increased risk of heart attacks and memory loss more than high cholesterol levels. In fact, high cholesterol levels correlate with an increased resistance to infections, memory retention and overall better health.*

 

Another misunderstanding is that cholesterol containing foods will cause your body’s cholesterol levels to elevate. Foods that contain cholesterol, such as eggs, account for only 15-20% of your body’s total cholesterol count. For most people, cholesterol levels will actually decrease when eating cholesterol containing foods and increase when restricting cholesterol containing foods.* Many health professionals who recommend a decrease in red meats because of cholesterol content, often recommend fish. Yet fish contains on average twice as much cholesterol than red meat! Apparently these health professionals are misunderstood.

 

Cholesterol has many vital functions in the body. One of which is to repair damaged tissue such as those that exist in the arteries.

 

Foods containing fats that have been oxidized from overheating may cause LDL cholesterol levels to elevate. But this problem can be resolved by eating the right type and quantity of fat for your individual metabolism, and by heating your fats at lower temperatures, or by not heating them at all. Regardless, the potential inflammation that may be caused by oxidized fats are nothing compared to the potential damage that can be done by the sugar molecule, trans fats (hydrogenated), alcohol and excessive grain and flour intake.

 

Here is a list of the major functions of cholesterol in the body:

 

•Cholesterol is used in all cell membrane integrity. Each and every cell of the body is comprised of cholesterol. Low cholesterol levels may correlate with enhanced cellular degeneration. Cells will literally fall apart in the blood without cholesterol.

 

•Myelin sheath development. The sheath or covering of nerve tissue is comprised of cholesterol and other fatty substances.

 

•Cholesterol is a building block for all hormone development, including the adrenal hormones and the sex hormones. Women who suffer from infertility often have very low cholesterol levels.

 

•Cholesterol is a metabolic nutrient, which repairs damaged tissues. This is why LDL cholesterol levels may rise after surgery, tooth procedures, and injuries.

 

•Cholesterol is necessary for the production of bile and bile acids. The body is not able to digest and assimilate fats without bile and bile acids. Bile is required for the absorption of vitamins A, D, K and E, all of which are vital, fat-soluble nutrients.

 

•Cholesterol is necessary to properly utilize Vitamin D. This is particularly true for the conversion of Vitamin D from sunlight. Cholesterol under the skin allows for this.

 

•Cholesterol is an anti-oxidant and scavenges free radicals. Cholesterol is required for immune system health. Being an anti-oxidant, cholesterol helps to fight infection.

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Read the complete article here.

Low Levels of Omega-3 Fatty Acids May Cause Memory Problems

Feb. 27, 2012 — A diet lacking in omega-3 fatty acids, nutrients commonly found in fish, may cause your brain to age faster and lose some of its memory and thinking abilities, according to a study published in the February 28, 2012, print issue of Neurology®, the medical journal of the American Academy of Neurology. Omega-3 fatty acids include the nutrients called docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA).

"People with lower blood levels of omega-3 fatty acids had lower brain volumes that were equivalent to about two years of structural brain aging," said study author Zaldy S. Tan, MD, MPH, of the Easton Center for Alzheimer's Disease Research and the Division of Geriatrics, University of California at Los Angeles.

For the study, 1,575 people with an average age of 67 and free of dementia underwent MRI brain scans. They were also given tests that measured mental function, body mass and the omega-3 fatty acid levels in their red blood cells.

The researchers found that people whose DHA levels were among the bottom 25 percent of the participants had lower brain volume compared to people who had higher DHA levels. Similarly, participants with levels of all omega-3 fatty acids in the bottom 25 percent also scored lower on tests of visual memory and executive function, such as problem solving and multi-tasking and abstract thinking.

The study was supported by the Framingham Heart Study's National Heart, Lung, and Blood Institute and the National Institute on Aging.

Story Source:The above story is reprinted from materials provided by American Academy of Neurology (AAN).

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Journal Reference:

1. Z. S. Tan, W. S. Harris, A. S. Beiser, R. Au, J. J. Himali, S. Debette, A. Pikula, C. DeCarli, P. A. Wolf, R. S. Vasan, S. J. Robins, S. Seshadri. Red blood cell omega-3 fatty acid levels and markers of accelerated brain aging. Neurology, 2012; 78 (9): 658 DOI: 10.1212/WNL.0b013e318249f6a9

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Read the complete article here.

Dangers of Statin Drugs - Seneff

Drug Side Effect Discovery from Online Patient-Submitted Reviews: Dangers of Statin Drugs

 

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by Jingjing Liu, Alice Li and Stephanie Seneff MIT Computer Science & Artificial Intelligence Laboratory

Abstract—In recent years, consumers have become empowered to share personal experiences regarding prescription drugs via Web page discussion groups. This paper describes our recent research involving automatically identifying adverse reactions from patient-provided drug reviews on health-related web sites. We focus on the statin class of cholesterol-lowering drugs. We extract a complete set of side effect expressions from patient-submitted drug reviews, and construct a hierarchical ontology of side effects. We use log-likely ratio estimation to detect biases in word distributions when comparing reviews of statin drugs with age-matched reviews of a broad spectrum of other drugs. We find a highly significant correlation between statins and a wide range of disorders and conditions, including diabetes, amyotrophic lateral sclerosis (ALS), rhabdomyolysis, neuropathy, Parkinson’s disease, arthritis, memory loss, and heart failure. A review of the research literature on statin side effects corroborates many of our findings.

I. INTRODUCTION

The last few decades have witnessed a steady increase in drug prescriptions for the treatment of biometric markers rather than overt physiological symptoms. Today, people regularly take multiple drugs in order to normalize serum levels of biomarkers such as cholesterol or glucose, or to reduce blood pressure. All drugs have side effects, which are sometimes debilitating or even life-threatening. When a person taking multiple drugs experiences a new symptom, it is not always clear which, if any, of the drugs or drug combinations are responsible.

 

Increasingly, consumers are turning to the Web to seek information, and, increasingly, this information comes in the form of consumer-provided comments in discussion groups or chat rooms. User reviews of products and services have empowered consumers to obtain valuable data to guide their decision process. Recently, statistical and linguistic methods have been applied to large datasets of reviews to extract summary and/or rating information in various domains ([9] [22]).

 

Health care and prescription drugs are a growing topic of discussion online, not surprising given that almost half of all Americans take prescription drugs each month, costing over $200 billion in 2008 alone ([5]). Though drugs are subject to clinical trials before reaching market, these trials are often too short, and may involve too few people to give conclusive results. A large study recently conducted on the heart failure drug, nesiritude, invalidated the findings of the smaller study that had led to the drug’s approval [11]. While regulatory agencies do attempt to monitor the safety of approved medical treatments, surveillance programs such as the U.S. Food and Drug Administration’s (FDA’s) and Adverse Event Reporting System (AERS) are often difficult for patients to use.

 

In addition, the large language gap between medical documents and patient vocabulary can cause confusion and misunderstanding ([23]). We hope to take advantage of the vast amount of information available in patient anecdotes posted online to address the dual problems of insufficient clinical studies and mismatched terminology.

 

We envision a system that increases patient awareness of drug-related side effects by enabling consumers of prescription drugs to easily browse a large consolidated database of posts from health-related web sites. Beyond aggregating data from drug review and health discussion sites, we plan to support spoken queries, which would be answered via a set of succinctly summarized hits that best match the query, based on sophisticated statistical and linguistic techniques. The user could then click on any one of these displayed summaries to read the associated post.

 

This paper describes our preliminary efforts to detect associations between a drug class and its side effects. We use statistics and heuristic methods to build up a hierarchical ontology of side effects by aggregating patient-submitted drug reviews. We use log-likelihood ratios to extract summary information derived from biases in word and phrase distributions, and to quantify associations between drugs and symptoms. For the scope of this paper, we focus on statin drugs, which are among the most costly and commonly prescribed drugs in the United States. The methods described are applicable to all drug classes.

 

In the remainder of this paper, we will first review the research literature reflecting known or suspected side effects associated with statin drugs. After explaining our data collection and side-effect ontology construction, we describe our methodology and verify that many of our extracted associations align with observations from the literature.

II. BRIEF LITERATURE REVIEW

A. Side Effects of Statin drugs

Statins (Hydroxy methyl glutaryl coenzyme A reductase inhibitors) have become increasingly popular as very effective agents to normalize serum cholesterol levels. The most popular of these, atorvastatin, marketed under the trade name, Lipitor, has been the highest revenue branded pharmaceutical for the past 6 years. The official Lipitor web site lists as potential side effects mainly muscle pain and weakness and digestive problems. However, several practitioners and researchers have identified suspected side effects in other more alarming areas, such as heart failure, cognition and memory problems, and even severe

neurological diseases such as Parkinson’s disease and ALS (Lou Gehrig’s disease). [21] provides compelling arguments for the diverse side effects of statins, attributing them mainly to cholesterol depletion in cell membranes.

 

It is widely acknowledged that statin drugs cause muscle pain, weakness and damage ([7] [12]), likely due in part to their interference with the synthesis of the potent antioxidant Coenzyme Q10 (CoQ10) ([10]). CoQ10 plays an essential role in mitochondrial function to produce energy. Congestive heart failure is a condition in which the heart can no longer pump enough blood to the rest of the body, essentially because it is too weak. Because the heart is a muscle, it is
plausible that heart muscle weakness could arise from longterm statin usage. Indeed, atorvastatin has been shown to impair ventricular diastolic heart performance ([14]). Furthermore, CoQ10 supplementation has been shown to improve cardiac function ([13] [20]).

 

The research literature provides plausible biological explanations for a possible association between statin drugs and neuropathy ([15] [24]). A recent evidence-based article ([1]) found that statin drug users had a high incidence of neurological disorders, especially neuropathy, parasthesia and neuralgia, and appeared to be at higher risk to the debilitating neurological diseases, ALS and Parkinson’s disease. The evidence was based on careful manual labeling of a set of self-reported accounts from 351 patients. A mechanism for such damage could involve interference with the ability of oligodendrocytes, specialized glial cells in the nervous system, to supply sufficient cholesterol to the myelin sheath surrounding nerve axons. Genetically-engineered mice with defective oligodendrocytes exhibit visible pathologies in the myelin sheath which manifest as muscle twitches and tremors ([16]).

 

Cholesterol depletion in the brain would be expected to lead to pathologies in neuron signal transport, due not only to defective myelin sheath but also to interference with signal transport across synapses ([17]). Cognitive impairment, memory loss, mental confusion, and depression were significantly present in Cable’s patient population ([1]). Wagstaff et al. ([19]) conducted a survey of cognitive dysfunction from AERS data, and found evidence of both short-term memory loss and amnesia associated with statin usage. Golomb et al. ([6]) conducted a study to evaluate evidence of statin-induced cognitive, mood or behavioral

changes in patients. She concluded with a plea for studies that “more clearly establish the impact of hydrophilic and lipophilic statins on cognition, aggression, and serotonin.”

B. Relationship between Cholesterol and Health

ALS and heart failure are both conditions for which published literature suggests an increased risk associated with statin therapy ([1] [10]). Indeed, for both of these conditions, a survival benefit is associated with elevated cholesterol levels. A statistically significant inverse correlation was found in a study on mortality in heart failure. For 181 patients with heart disease and heart failure, half of those whose serum cholesterol was below 200 mg/dl were dead three years after diagnosis, whereas only 28% of the patients whose serum cholesterol was above 200 mg/dl had died. In another study on a group of 488 patients diagnosed with ALS, serum levels of triglycerides and fasting cholesterol were measured at the time of diagnosis ([2]). High values for both lipids were associated with improved survival, with a p-value <0 .05.=".05." p="p">

 

A very recent study on the relationship between various measures of cholesterol status and health in the elderly came up with some surprising results, strongly suggesting that elevated cholesterol is beneficial for this segment of the population [18]. A study population initially over 75 years old was followed over a 17 year period beginning in 1990. In addition to serum cholesterol, a biometric associated with the ability to synthesize cholesterol (lathosterol) and a biometric associated with the ability to absorb cholesterol through the gut (sitosterol) were measured. For all three measures of cholesterol, low values were associated with a poorer prognosis for frailty, mental decline and early death. A reduced ability to synthesize cholesterol showed the strongest correlation with poor outcome. Individuals with high measures of all three biometrics enjoyed a 4.3 year extension in life span, compared to those for whom all measures were low.

III. SIDE-EFFECT DISCOVERY

A. Data Collection

To learn the underlying associations between side effects and drug usage from patient-provided reviews, we collected drug reviews from three drug discussion forums (“AskPatient.com,” “Medications.com” and “WebDB.com”) which allow users to post reviews on specific drugs and share their experiences. Table 1 gives the statistics on the review data collection. A total of 8,515 statin reviews were collected from the three data sources. We also collected 105K drug reviews from the AskPatient.com, on drugs to treat a broad range of problems such as depression, acid reflux disease, high blood pressure, diabetes, etc. This set includes reviews for non-statin cholesterol lowering drugs.

 

Continue Reading the Research Study Here: http://people.csail.mit.edu/seneff/IMMM.pdf

Important safety label changes to cholesterol-lowering statin drugs

FDA Drug Safety Communication: Important safety label changes to cholesterol-lowering statin drugs

Facts about statins

A class of prescription drugs used together with diet and exercise to reduce blood levels of low-density lipoprotein (LDL) cholesterol (“bad cholesterol”) Marketed as single-ingredient products, including Lipitor (atorvastatin), Lescol (fluvastatin), Mevacor (lovastatin), Altoprev (lovastatin extended-release), Livalo (pitavastatin), Pravachol (pravastatin), Crestor (rosuvastatin), and Zocor (simvastatin) Also marketed as combination products, including Advicor (lovastatin/niacin extended-release), Simcor (simvastatin/niacin extended-release), and Vytorin (simvastatin/ezetimibe)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Safety Announcement

[2-28-2012] 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 Statins1 2

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.
  

Additional Information for Healthcare Professionals

• 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.
  

Data Summary

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

Previous lovastatin label	New lovastatin label
Avoid lovastatin with: Itraconazole Ketoconazole Erythromycin Clarithromycin Telithromycin HIV protease inhibitors Nefazodone	Contraindicated with lovastatin: Itraconazole Ketoconazole Posaconazole Erythromycin Clarithromycin Telithromycin HIV protease inhibitors Boceprevir Telaprevir Nefazodone
Do not exceed 20 mg lovastatin daily with: Gemfibrozil Other fibrates Lipid-lowering doses (≥1 g/day) of niacin Cyclosporine Danazol	Avoid with lovastatin: Cyclosporine Gemfibrozil
	Do not exceed 20 mg lovastatin daily with: Danazol Diltiazem Verapamil
Do not exceed 40 mg lovastatin daily with: Amiodarone Verapamil	Do not exceed 40 mg lovastatin daily with: Amiodarone
Avoid large quantities of grapefruit juice (>1 quart daily)	Avoid large quantities of grapefruit juice (>1 quart daily)

References

1. Cohen DE, Anania FA, Chalasani N; for the National Lipid Association Statin Safety Task Force Liver Expert Panel. An assessment of statin safety by hepatologists. Am J Cardiol. 2006;97(8A):77C-81C.
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Read the complete article here.

FDA Expands Advice on Statin Risks

If you’re one of the millions of Americans who take statins to prevent heart disease, the Food and Drug Administration (FDA) has important new safety information on these cholesterol-lowering medications.

FDA is advising consumers and health care professionals that:

• Routine monitoring of liver enzymes in the blood, once considered standard procedure for statin users, is no longer needed. Such monitoring has not been found to be effective in predicting or preventing the rare occurrences of serious liver injury associated with statin use.
• Cognitive (brain-related) impairment, such as memory loss, forgetfulness and confusion, has been reported by some statin users.
• People being treated with statins may have an increased risk of raised blood sugar levels and the development of Type 2 diabetes.
• Some medications interact with lovastatin (brand names include Mevacor) and can increase the risk of muscle damage.

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Read the rest of the FDA article here.