FDA reviewed current guidelines and data on monitoring liver enzymes in asymptomatic statin users. The available evidence does not support routine monitoring, as it rarely identifies serious liver issues and could motivate stopping statin therapy prematurely. FDA analysis of post-marketing reports found that serious liver injury from statins is very rare, with no detectable increase in rates of fatal or severe cases associated with statin use. Routine monitoring does not appear to detect or prevent serious liver injury. FDA also reviewed data on cognitive effects and risk of diabetes from statins, finding a small increased risk of diabetes but no evidence of common or clinically significant cognitive impacts.

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2. 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 evidenc

3. 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

4. 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

5. • 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

6. 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.
• 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

7. 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