US Pharm. 2012;37(9):HS17-HS20.
Dyslipidemia is a major risk factor for coronary heart
disease (CHD), and current guidelines support low-density lipoprotein
cholesterol (LDL-C) as a primary target of therapy.1 Previous
studies suggest that increasing high-density lipoprotein cholesterol
(HDL-C) and reducing triglycerides and small LDL particles may also have
a positive impact in prevention.2 These factors are
considered secondary targets of lipid management. Most lipid-altering
drugs have a sound overall safety profile and are generally well
Episodes of severe hepatotoxicity remain rare for most
drugs. The exception is high-dose, sustained-release (SR) niacin.
Overall, the incidence of drug-induced hepatotoxicity may be prevented
if both providers and patients are aware of potential contributing
Drug-induced hepatotoxicity secondary to lipid-altering
agents includes acute liver failure, hepatitis, cholestasis, and most
commonly transaminitis, an asymptomatic elevation in serum
transaminases.3 Acute liver failure is extremely rare, and
data suggest that minor asymptomatic elevations of aspartate
transaminase (AST) and alanine transaminase (ALT) do not necessarily
precede acute liver failure.3 Possible signs and symptoms of
liver problems include unusual fatigue or weakness, loss of appetite,
upper abdominal pain, dark-colored urine, and yellowing of the skin or
whites of the eyes (jaundice).4
Hepatotoxicity by Drug Class
The major classes of lipid-altering agents include the
statins, bile acid resins (BARs), fibric acid derivatives (fibrates),
cholesterol absorption inhibitors, niacin, and fish oil (TABLE 1).1,4-9 Because
reports of hepatotoxicity are extremely limited with fish oil and BARs,
these drug classes will not be a focus of this review. Additionally,
red yeast rice (RYR) is an available supplement with potential
lipid-altering properties. Reports of hepatotoxicity with this agent are
also limited and will not be discussed. However, practitioners should
be aware that RYR typically contains varying amounts of lovastatin, and
therefore should be utilized with applicable precautions.10
Cholesterol agents cause hepatotoxic effects through
various mechanisms. For instance, statins undergo hepatic metabolism
following gastrointestinal (GI) absorption, while other classes such as
BARs and the cholesterol absorption inhibitor ezetimibe primarily target
the GI tract but indirectly affect the liver.11
Statins (e.g., atorvastatin, fluvastatin, lovastatin,
pitavastatin, pravastatin, rosuvastatin, simvastatin) produce marked
reductions in LDL-C by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A
(HMG-CoA) reductase, the rate-limiting step in cholesterol synthesis.1
This inhibition decreases cholesterol production, causing an increase
in LDL-receptor expression and enhanced removal of LDL-C from the
circulation. Although statins have moderate effects on lowering
triglycerides and increasing HDL-C, they remain first-line therapy
because of their LDL-C lowering. More importantly, results from multiple
clinical trials have demonstrated that statins significantly reduce
major coronary events and overall mortality among primary and secondary
prevention populations.1,12 Statins also reduce inflammation,
improve endothelial function, and stabilize atherosclerotic plaque,
independent of their lipid effects.3,12
Clinical trial findings indicate that the overall risk of
hepatotoxicity with statins is low. The most common hepatic adverse
event involves asymptomatic increases in ALT and AST. This
dose-dependent reaction usually occurs within the first year of therapy,
but may present at any time.3,13 It has been noted that
elevations are usually reversible with a dose reduction and may
normalize with the same continued dosage.1
The National Cholesterol Education Program (NCEP) Adult
Treatment Panel III (ATP-III) guidelines provide specific
recommendations for monitoring hepatic function including transaminase
elevations (TABLE 1).1 For patients with AST/ALT ≤3
times the upper limit of normal (ULN), statin therapy can be continued.
If elevations exceed 3 times the ULN, a second liver function evaluation
should be conducted. If elevated levels persist, the statin should be
discontinued, but attempting a rechallenge or switching to a different
statin may be considered.1 Overall elevated transaminase levels ≥3 times the ULN occur in <2% of patients treated with statin monotherapy.1,3
Statin-induced transaminase elevations rarely progress to
irreversible liver damage. In 2003, a meta-analysis of 164 statin trials
reported no cases of liver failure.14 From 1987 to 2000, the
FDA recorded 30 cases of statin-induced liver failure, equal to
approximately one case per 1 million person-years of use.14
There have been isolated case reports describing statin-associated
cholestatic hepatotoxicity, autoimmune hepatitis, fulminant hepatitis,
and cirrhosis.5 If transaminase levels are elevated and
statin-induced hepatotoxicity is suspected, the National Lipid
Association’s (NLA) Liver Expert Panel recommends obtaining a
fractionated bilirubin level.15 When no biliary obstruction
is present, bilirubin is a more reliable indicator of drug-induced liver
injury. Elevated transaminase and bilirubin levels likely indicate
ongoing liver injury, prompting the need for more tests to determine
etiology.15 Hepatotoxicity may be increased with high statin
doses, concomitant administration of CYP450 enzyme inhibitors or
inducers, combination lipid-altering regimens, or impaired renal
function, and among elderly patients.13
The value of routine transaminase monitoring in treated
patients has been called into question because of the rarity of
statin-induced irreversible liver damage.16 In a 2006 report,
the NLA stated there is no evidence linking elevated AST/ALT with
subsequent serious liver injury, nor data supporting the effectiveness
of routine monitoring in identifying patients likely to progress to
liver failure.15 Concerns with frequent monitoring include
unnecessary costs and the potential of elevated transaminase levels
leading to inappropriate statin discontinuation. Statin refusal and
nonadherence are also of concern due to patients’ perception of
potential liver damage.15
In support of the NLA Liver Expert Panel, the FDA recently
revised statin labeling by removing the recommendation for routine
periodic monitoring of liver enzymes. Baseline tests are still
suggested, but follow-up monitoring is only necessary if clinically
indicated, as the FDA has determined that frequent monitoring plays
little to no role in detecting or preventing serious liver injury.4
Fibric Acid Derivatives (Fibrates)
Fibrates (e.g., clofibrate, fenofibrate, gemfibrozil,
fenofibric acid) are primarily prescribed to reduce triglycerides, with
usual reductions of 25% to 50%.1 The agents have mixed effects on LDL-C.1
With hypertriglyceridemia, fibrates typically increase LDL-C, whereas
modest reductions may be observed when triglyceride levels are normal.1
Fibrates are often used in combination with statins, but an increased
risk of myopathy and elevated transaminase levels have been observed.
This is more likely with gemfibrozil, secondary to this agent increasing
serum levels of most statins.17 However, if the concomitant statin dose remains low to moderate, adverse events including hepatotoxicity generally remain low.18 In instances of transaminase elevations, levels normalized within weeks after drug discontinuation.8
The NLA or NCEP ATP-III guidelines do not provide specific recommendations for liver function monitoring with fibrate therapy.1
However, baseline measures, periodic follow-up monitoring, and
reduction or discontinuation of therapy with transaminase levels ≥3
times the ULN is prudent. Additionally, clinicians should be cognizant
of factors that may increase risk of hepatotoxicity such as drug
interactions or pre-existing liver disease.
Cholesterol Absorption Inhibitor (Ezetimibe)
Ezetimibe decreases LDL-C by inhibiting cholesterol absorption at the brush border of the intestine.5
This agent is not metabolized by the CYP450 enzyme system and does not
interact with CYP3A4 inhibitors. Following absorption, ezetimibe is
glucuronidated to produce an active metabolite that undergoes
Clinical trial data indicate that the incidence of
asymptomatic elevated transaminase levels ≥3 times the ULN is 0.7%,
which is similar to placebo.7 Because of the infrequency, no
specific recommendations are available for monitoring hepatic function
with ezetimibe monotherapy.19 Transaminase levels may be slightly higher with combination ezetimibe-simvastatin compared to simvastatin alone.20
Safety results from a trial involving atorvastatin monotherapy versus
atorvastatin-ezetimibe showed no significant difference in transaminase
elevations.21 The value of monitoring liver function among
patients receiving a statin-ezetimibe regimen is similar to that of
statin therapy; obtain measures at baseline and thereafter when
clinically indicated, such as in dose titration.19
Niacin, also known as vitamin B3 or nicotinic acid,
has positive effects on all major lipid parameters including LDL-C,
non-HDL, and triglycerides, when given at appropriate therapeutic doses.1 It is also the most efficacious drug for raising HDL-C.22
Niacin therapy may lead to regression in mean carotid intima-media
thickness in patients with CHD whose LDL-C is at goal with statin
therapy.23 However, findings from a recent clinical trial
indicate that niacin did not produce further reductions in vascular
events when added to statin therapy.24
There are primarily three different formulations of
niacin: immediate-release (IR) or crystalline, extended-release (ER),
and SR, with approximate absorption rates of 1 hour, 8 hours, and 12
hours, respectively.22 A considerable amount of confusion
exists regarding the various dosages, drug-delivery systems, effects on
the lipid profile, and potential adverse events, including
hepatotoxicity. IR niacin is available as a supplement and as
prescription Niacor. Niacin is also available as a prescription ER
product, Niaspan. Various long-acting formulations are available as
supplements and marketed as “time-released” or “sustained-release.”
Monitoring hepatic function is recommended for all niacin formulations (TABLE 1).
Adverse events for IR niacin include flushing, chills, pruritus, and GI upset, with a very low incidence of hepatotoxicity.22
Extended-release niacin is associated with lower flushing rates and a
low incidence of hepatotoxicity at doses ≤2,000 mg/day. Conversely, SR
is commonly associated with more dose-dependent transaminase elevations.22
A comparative study indicated that approximately 50% of those receiving
SR niacin experienced hepatotoxicity, especially with doses >2,000
mg/day, compared to none in the IR niacin group.25
The differences in hepatotoxicity among formulations are likely explained by two metabolic pathways.22
Conjugation of niacin with glycine to form nicotinuric acid is a
low-affinity, high-capacity system, which leads to flushing. The second
nonconjugative pathway involves multiple reactions that convert niacin
to nicotinamide, and is a high-affinity, low-capacity system with
greater potential for hepatotoxicity. IR products will quickly saturate
the nonconjugative pathway, with most of the drug being metabolized by
conjugation, resulting in increased flushing and a low incidence of
hepatotoxicity. Slowly absorbed preparations (e.g., SR niacin) are
metabolized primarily by the high-affinity nonconjugative pathway,
resulting in less flushing but increased hepatotoxicity.
Pharmacists must inform patients that maximum dosages vary
among formulations and dose-dependent hepatotoxicity is possible,
especially when patients choose SR formulations in an effort to avoid
flushing, reduce cost, or self-treat. Additionally, products may not be
interchangeable. For example, if a patient has been maintained on IR
niacin at a dose >2,000 mg/day, switching to an equivalent dose of SR
niacin would likely result in hepatotoxicity. Lastly, “flush-free” and
“no flush” formulations contain very little to no active niacin but list
ingredients such as inositol hexanicotinate. These products have not
shown the same cardiovascular and lipid-lowering benefits as niacin.22
Severe drug-induced hepatotoxicity is rare for most
lipid-altering agents. However, the incidence increases with certain
agents and in the presence of other contributing factors. Appropriate
monitoring may limit hepatotoxic events. Asking pertinent questions and
gathering needed information will help determine the risk for
hepatotoxicity with lipid-altering therapy. Key information includes
identifying disease states that may predispose the patient to increased
risk for liver damage and obtaining a complete medication and supplement
list to check for potential interactions. Pharmacists may also educate
patients on the importance of reporting any unusual signs or symptoms of
hepatotoxicity and adhering to laboratory and clinic appointments.
The pharmacist in the community setting has the
opportunity to identify patients who self-treat with supplements and OTC
medications. Education on appropriate use is essential. Specific
opportunities include those patients on statins who self-treat with RYR,
and patients switching from IR or ER niacin to equivalent doses of SR
niacin. For a provider, it is important to be vigilant in identifying
patients who may be at increased risk of hepatotoxicity secondary to
In such cases the pharmacist may recommend a dose reduction, discontinuation of therapy, or selection of an alternative agent.
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