Statins: The Story Behind the Label Changes

An Expert Interview With the FDA's Amy G. Egan, MD, MPH

Laurie Scudder, DNP, NP; Amy G. Egan, MD, MPH

|Disclosures|March 06, 2012

Statins, the Liver, and the Brain

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:

Table. Statin Dose Limitations

Statin Interacting Protease
Prescribing Recommendation
  • Tipranavir + ritonavir

  • Telaprevir

Avoid atorvastatin
  • Lopinavir + ritonavir

Use with caution and use with the lowest atorvastatin dose necessary
  • Darunavir + ritonavir

  • Fosamprenavir

  • Fosamprenavir + ritonavir

  • Saquinavir + ritonavir

Do not exceed 20 mg atorvastatin daily
  • Nelfinavir

Do not exceed 40 mg atorvastatin daily
Fluvastatin   No data available
  • HIV protease inhibitors

  • Boceprevir

  • Telaprevir

  • Atazanavir ± ritonavir

  • Darunavir + ritonavir

  • Lopinavir + ritonavir

No dose limitations
  • Darunavir + ritonavir

  • Lopinavir + ritonavir

No dose limitations
  • Atazanavir ± ritonavir

  • Lopinavir + ritonavir

Limit rosuvastatin dose to 10 mg once daily
  • HIV protease inhibitors

  • Boceprevir

  • Telaprevir


FDA Drug Safety Communication.[2]

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.

2 of 2
Latest in Cardiology


  1. U.S. Food and Drug Administration. FDA Drug Safety Communication: Important safety label changes to cholesterol-lowering statin drugs. 2012. Accessed March 5, 2012.

  2. 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. Accessed March 5, 2012.

  3. 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

  4. 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

  5. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative metaanalysis of randomized statin trials. Lancet. 2010;375:735-742. Abstract

  6. 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

  7. 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

  8. Koh KK, Quon MJ, Han SH, Lee Y, Kim SJ, Shin EK. Atorvastatin causes insulin resistance and increases ambient glycemia in hypercholesterolemic patients. J Am Coll Cardiol. 2010;55:1209-1216. Abstract

  9. Thongtang N, Ai M, Otokozawa S, et al. Effects of maximal atorvastatin and rosuvastatin treatment on markers of glucose homeostasis and inflammation. Am J Cardiol. 2011;107:387-392. Abstract

  10. Kostapanos MS, Liamis GL, Milionis HJ, Elisaf MS. Do statins beneficially or adversely affect glucose homeostasis? Curr Vasc Pharmacol. 2010;8:612-631. Abstract

  11. 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

  12. 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

  13. 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

  14. 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

Authors and Disclosures


Laurie Scudder, DNP, NP

Clinical Editor, Medscape from WebMD

Disclosure: Laurie Scudder, DNP, NP, has disclosed no relevant financial relationships.


Amy G. Egan, MD, MPH

Deputy Director for Safety, US Food and Drug Administration, Division of Metabolism and Endocrinology Products, Silver Spring, Maryland

Disclosure: Amy G. Egan, MD, MPH, has disclosed no relevant financial relationships.

Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as:


All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.