Yes folks, those pills that everyone is taking, the lipid-lowering statins, have now become toxicologically controversial. Efficacy is now in question, risk/benefit analyses are shifting, and cardiologists and toxicologists are re-evaluating value. I came across this interesting interview with the FDA's Amy Egan, MD, MPH who discusses the story behind statin label changes. In late February 2012, the FDA issued new labeling changes for the entire statin drug class. First, all statins must now carry a warming noting that there have been reports of increased blood sugar and hemoglobin A1c levels with statin use. Second, labels must now warm about interactions between statins and protease inhibitors for HIV and Hepatitis C patients, because the interaction of the two could cause myopathy and acute renal failure. Read the interview:
Do Statins Cause Diabetes?
Medscape: Recent studies of popular statins showed a significant increase in the risk for diabetes associated with statin therapy. The Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial showed an increase in the incidence of diabetes mellitus in patients taking rosuvastatin compared with placebo.[3] Also, in the Pravastatin or Atorvastatin Evaluation and Infection Therapy - - Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) substudy, worsening glycemic control occurred more frequently in the intensive lipid-lowering therapy (atorvastatin) arm than in the moderate lipid-lowering therapy (pravastatin) arm.[4] Were these trials the primary bases for the changes made by the FDA? Did the recent results from the Women's Health Initiative (WHI), which showed a 48% increased risk for diabetes in women taking statins, also play a role in these changes? Can you describe the strengths and limitations of these studies?
Dr. Egan: This labeling change, with regard to an increase in A1c and fasting plasma glucose, was added to the rosuvastatin (Crestor®; AstraZeneca Pharmaceuticals; Wilmington, Delaware) label in February 2010 subsequent to our review of data from the JUPITER trial that showed a 27% increase in investigator-reported diabetes in rosuvastatin- exposed patients vs placebo-exposed patients. We were also aware of the results of the substudy of the PROVE IT-TIMI 22 trial, which reported worsening glycemic control in patients receiving intensive lipid-lowering therapy with atorvastatin relative to moderate lipid-lowering therapy with pravastatin. At the time of our review of the JUPITER trial, there were already meta-analyses appearing in the medical literature that showed an effect of statins on fasting plasma glucose and incident diabetes.[5-12] During the course of our labeling negotiations with the statin sponsors, we became aware of the publication of the results of the WHI study.[13] The WHI study was provocative though there were methodological flaws that limited the interpretability of the findings. While we certainly do acknowledge the results of the study, they did not provide the most robust data leading to the labeling change.
Medscape: Were there differences between statins in the effect on A1c?
Dr. Egan: While we don't have as much data on the most recently approved statin, pitavastatin, we know tha
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pharmacokinetically it is quite similar to rosuvastatin. While there are no large cardiovascular outcome trials for pitavastatin, we did not consider the absence of data to be evidence of an absence of the signal, so pitavastatin was required to make the same labeling change with regard to an effect on A1c and fasting plasma glucose. We did not require this labeling change for pravastatin. Our reasoning was based on the results of the West of Scotland Coronary Prevention Study (WOSCOPS) which reported a 30% decrease in the incidence of diabetes in pravastatin- exposed patients vs unexposed patients.[14] We found it difficult to consider the data from the meta-analyses as more compelling than data from this clinical trial. You will see from the Website and from the posted labels that all of the statins have the language regarding increases in A1c and fasting plasma glucose with the exception of pravastatin. Medscape: The labeling change did not indicate that avoidance of these agents in prediabetic persons or newly diagnosed diabetics was warranted. Dr. Egan: We do know from our review of the JUPITER data that many of the patients who went on to develop investigator-diagnosed diabetes mellitus had impaired glucose tolerance at baseline so they do seem to be more susceptible. However, again, we did not make any specific recommendations as to particular groups because we also see impaired tolerance in patients who do not have impaired fasting glucose at baseline; we see it in nondiabetic patients, prediabetic patients, and diabetic patients. However, keep in mind that we consider these changes, and the resultant risk, to be very small. We do not know whether discontinuation of the statin results in a reduction of fasting plasma glucose back to pretherapy levels because this was not a discontinuation criterion in the trials -- ie, if a patient's fasting plasma glucose went up or that individual was diagnosed with diabetes, statins were not discontinued in that person. That is the same message that we want to convey: We are not recommending that patients be discontinued from their statin therapy based on a small increase in blood sugar levels. Rather, elevations in blood sugar levels should be treated with dietary and lifestyle management and/or adjustment or initiation of antidiabetic therapies. We do not consider this a reason to not continue or not initiate statins, particularly in the diabetic population where patients are at increased risk for major adverse cardiovascular events and statin therapy has been shown to reduce that risk. Medscape: Do the label changes apply to any specific populations, such as women? that there is a gender effect for the development of this adverse effect. Statins, the Liver, and the Brain |
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Do Statins Cause Cognitive Changes? Medscape: The cognitive side effects noted with statins include memory loss and confusion. Was this labeling change based on anecdotal reports or trial data? Some earlier studies have suggested that statins may protect against memory loss and even Alzheimer disease. Although there was no evidence to support this benefit, are there any clinical studies under way now that are looking at these effects in statins vs placebo? Dr. Egan: We did look at clinical trial data. There were several statin sponsors who had conducted clinical trials in which some form of neurocognitive assessment had been performed as part of the study protocol. We looked at those study results; there was no difference in neurocognitive functioning observed between patients exposed to statin therapy vs those unexposed, including in executive function (attention and speed) and memory, both immediate and delayed. There were trials conducted with statins to see if they could improve cognitive functioning in patients with mild to moderate Alzheimer disease. We reviewed the results of one such study, which showed neither evidence of benefit nor harm in cognitive functioning associated with statin therapy. What we were left with were these reports in our Adverse Event Reporting System (AERS) that were largely anecdotal and really ran the spectrum from very mild deficits to quite profound reports of patients saying that they felt like they "lost their minds." We were very unsure about how to put this in the label, or whether to label it at all, because we were concerned that patients would experience "benign forgetfulness," such as forgetting where they put their car keys or what level they parked their car on at the shopping mall, and would blame it on their statin and stop taking their statin. It is far more likely that these episodes are just the forgetfulness that we all experience from time to time and are not related to their statin therapy. The data we reviewed did not allow us to establish a causal relationship between these events and statin therapy. We did, however, want patients and clinicians to be aware that these reports exist, and if patients experience persistent alteration in their thinking or cognitive functioning, then they should report that to their healthcare provider. |
Medscape: Am I correct that these anecdotal reports indicate that most of these effects were reversible? Dr. Egan: Yes, that's correct. These changes did reverse upon discontinuation of the statin.
Liver Function With Statins
Medscape: The FDA is no longer requiring periodic liver function tests for patients using statins over the long term. What was the basis for this change?
Dr. Egan: The National Lipid Association's liver expert panel and statin safety taskforce had been recommending that FDA reconsider the recommendation for routine periodic monitoring of liver enzyme tests that is contained in statin labeling. In that context, we went back and submitted information request letters to the statin sponsors, trying to gauge their level of interest in removing this recommendation from their labels. We then undertook a comprehensive review of the AERS database, pulling out cases of severe liver injury and then having those cases adjudicated by a panel of clinicians from the Office of Surveillance and Epidemiology and the Office of New Drugs so that we could determine whether there was a causal relationship between the severe liver injury cases and the statin therapy. FDA had conducted 5 previous postmarket reviews of statins and hepatotoxicity between 2000 and 2009. Those reviews had consistently noted that reporting of statin-associated serious liver injury to AERS was extremely low. We looked at this one last time for any evidence of causality, and what we can conclude is that statin-associated severe liver injury is an extremely rare event and appears to be largely idiosyncratic. We do not find evidence that periodic monitoring of liver enzyme tests is helpful in terms of detecting or preventing these rare cases. It was therefore determined that the recommendation would be removed from the label and replaced with a recommendation to perform liver enzyme tests before the initiation of statin therapy (as a baseline) and as clinically indicated thereafter -- ie, if signs or symptoms of liver injury occur during therapy.
Medscape: On March 1, the FDA announced an additional change to statin labeling. The labels of certain statins as well as protease inhibitors (PIs) for HIV and hepatitis C virus will now warn about interactions between the 2 sets of drugs that could increase the risk for myopathy and kidney failure. Can you discuss the current understanding of the increase in risk for myopathy?
Dr. Egan: We continuously modify drug labels based on ongoing information we receive about drug-drug interactions or other adverse effects. Many drugs are metabolized by the CYP3A4 enzyme, and simvastatin and lovastatin are sensitive CYP3A4 substrates. Therefore, when a new drug application is submitted, the sponsors will frequently have conducted drug-drug interaction studies with simvastatin to test the new agent against a sensitive CYP3A4 substrate, especially if the drug is a known CYP3A4 inhibitor. So, we are continually receiving data on drug-drug interactions with statins, which we try to get into the labels as quickly as possible. In the case of the PIs, we had received some drug-drug interaction studies from the published literature for one of the statins, and the manufacturer had requested that this information be put in the label. At the time of that review, we looked across all of the PI labels and all of the statin labels, and we found discrepancies between what the PI labels were recommending and what the statin labels were recommending. We formed a group to look across the labels in both of those divisions, review the relevant literature and drug-drug interaction studies, and align the labels so that we were giving consistent recommendations to pharmacists and clinicians. The alert includes a table noting more specific information.
Bottom Line With Statins
Medscape: Are there any other issues that you wish to emphasize for our readers today?
Dr. Egan: The bottom line is, as we've already discussed, that these were fairly routine labeling changes for us. However, because statins are so widely used, there is a heightened awareness by the public when we make any safety-related labeling changes to this class of drugs. These changes do not in any way alter the risk-benefit calculus for this class of
drugs. We continue to believe that the benefits of statins far outweigh their risks, but we do want clinicians and patients to be aware of their side effects so that they can be used in the most safe and effective manner possible.
Full text of the FDA Safety Communication regarding labeling changes and information about drug-drug interactions with statins can be found on the FDA Website.
References
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U.S. Food and Drug Administration. FDA Drug Safety Communication: Important safety label changes to cholesterol-lowering statin drugs. 2012. http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm Accessed March 5, 2012.
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U.S. Food and Drug Administration. DA Drug Safety Communication: Interactions between certain HIV or hepatitis C drugs and cholesterol-lowering statin drugs can increase the risk of muscle injury. 2012. http://www.fda.gov/Drugs/DrugSafety/ucm293877.htm Accessed March 5, 2012.
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Ridker PM, Danielson E, Fonseca FA, et al. JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195-2207. Abstract
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Gibson CM, Pride YB, Hochberg CP, Sloan S, Sabatine MS, Cannon CP; TIMI Study Group. Effect of intensive statin therapy on clinical outcomes among patients undergoing percutaneous coronary intervention for acute coronary syndrome. PCI-PROVE IT: A PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22) Substudy. J Am Coll Cardiol. 2009;54:2290-2295. Abstract
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Sukhija R, Prayaga S, Marashdeh M, et al. Effect of Statins on Fasting Plasma Glucose in Diabetic and Nondiabetic Patients. J Investig Med. 2009;57:495-499. Abstract
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Rajpathak SN, Kumbhani DJ, Crandall J, Barzilai N, Alderman M, Ridker PM. Statin therapy and risk of developing type 2 diabetes: a meta-analysis. Diabetes Care. 2009;32:1924-1929. Abstract
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Kostapanos MS, Liamis GL, Milionis HJ, Elisaf MS. Do statins beneficially or adversely affect glucose homeostasis? Curr Vasc Pharmacol. 2010;8:612-631. Abstract
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Mills EJ, Wu P, Chong G, et al. Efficacy and safety of statin treatment for cardiovascular disease: a network meta- analysis of 170255 patients from 76 randomized trials. QJM. 2011;104:109-124. Abstract
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Culver AL, Ockene IS, Balasubramanian R, et al. Statin Use and risk of diabetes mellitus in postmenopausal women in the Women's Health Initiative. Arch Intern Med. 2012;172:144-152. Abstract
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Culver AL, Ockene IS, Balasubramanian R, et al. Statin use and risk of diabetes mellitus in postmenopausal women in the Women's Health Initiative. Arch Intern Med. 2012;172:144-152. Abstract
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Freeman DJ, Norrie J, Sattar N, et al. Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study. Circulation. 2001;103:357-362. Abstract