NLA Safety Task Force Report:
The Nonstatins
March 19, 2007
© 2006 National Lipid Association
The NLA Safety Task Force
James M. McKenney, PharmD, Chairman
Virginia Commonwealth University
Richmond, Virginia
Harold E. Bays, MD
Louisville Metabolic and Atherosclerosis Research Center
Louisville, Kentucky
Michael H. Davidson, MD
Rush University Medical Center
Chicago, Illinois
John R. Guyton, MD
Duke University Medical Center
Durham, North Carolina
Terry A. Jacobson, MD
Emory University
Atlanta, Georgia
© 2006 National Lipid Association
Task Force Mission
• Conduct a comprehensive, rigorous,
scholarly, up-to-date, and unbiased
assessment of the safety of lipid-altering
therapies.
• Use the findings from this assessment to
educate health professionals on how to help
patients lower their cholesterol and reduce
their risk of heart attacks and strokes.
© 2006 National Lipid Association
Safety Considerations with
Fibrate Therapy
Michael H. Davidson, MD
Annemarie Armani, MD
James M. McKenney, PharmD
Terry A. Jacobson, MD
March 19, 2007
© 2006 National Lipid Association
Recommendations to healthcare professionals
regarding fibrate safety
1. Before the initiation of fibrate therapy, a measurement of serum
creatinine should be determined. If impaired renal function is present,
the patient should be prescribed gemfibrozil (unless taking a statin), or
a lower starting dose of fenofibrate (48 mg is most commonly
available) should be considered. With impaired renal function, the
periodic monitoring of renal function is recommended.
2. Routine monitoring of creatinine is not required, but if a patient has a
clinically important increase in creatinine, and other potential causes of
creatinine increase have been excluded, consideration should be given
to discontinuing fibrate therapy or reducing the dose.
3. Creatinine monitoring may be advisable if a patient is taking another
medication, such as metformin, which may need to be discontinued for
creatinine elevations 1.4 mg/dL in women and 1.5 mg/dL in men, or a
statin, which may require downward dosage adjustment.
CK creatine kinase; HDL high-density lipoprotein; INR international normalized ratio;
IV intravenous; PT prothrombin time; ULN upper limit of normal
© 2006 National Lipid Association
Recommendations to healthcare professionals
regarding fibrate safety
4. Although package inserts generally suggest using the combination of a
fibrate and a statin very carefully or not at all, there are several
circumstances in which the benefits may outweigh the risks. In these
circumstances, fenofibrate is the preferred fibrate over gemfibrozil but
still may increase the risk for myopathy or rhabdomyolysis. It is
generally recommended to get a baseline CK level before adding the
second lipid-lowering agent and to use the lowest dose of a statin or
fibrate when possible.
5. Clinicians should still use caution when prescribing the highest doses of
statins used in combination with fibrate therapy, because both classes
of drugs are independently associated with an increased risk for
myopathy. In combination with a statin, fenofibrate is the preferred
option, and gemfibrozil should be avoided unless the clinical benefits
outweigh the increased risk for myopathy. Clinicians should be aware
of the maximal statin dose allowed in combination with gemfibrozil in
the package insert.
© 2006 National Lipid Association
Recommendations to healthcare professionals
regarding fibrate safety
6. Gemfibrozil has less effect than fenofibrate on creatinine and therefore
is the National Kidney Foundation’s (NKF) fibrate of choice for renal
insufficiency. It does seem reasonable to discourage the administration
of fenofibrate to kidney transplant patients and those on dialysis,
because fenofibrate is nondialysable.
7. In patients with renal dysfunction receiving statin therapy, especially
statins with significant renal clearance (ie, simvastatin, rosuvastatin,
pravastatin, and lovastatin), combination therapy with gemfibrozil
should be avoided, and combination therapy with fenofibrate should be
initiated with caution, if at all. The dose of fenofibrate should not
exceed 48 mg (unless the benefits markedly outweigh the increased
risk for rhabdomyolysis), and the statin doses should remain below the
maximal levels.
8. Clinicians should warn patients about the possibility of myopathy on
fibrate therapy and advise the reporting of side effects of diffuse
muscle pain or weakness as soon as possible.
© 2006 National Lipid Association
Recommendations to healthcare professionals
regarding fibrate safety
9. Obtaining a pretreatment baseline CK level may be considered in
patients who are at high risk for experiencing muscle toxicity, but this is
not routinely necessary in other patients.
10. It is not necessary to measure CK levels in asymptomatic patients
during the course of fibrate therapy, because marked, clinically
important CK elevations are relatively rare. CK measurements should
be obtained in symptomatic patients to help gauge the severity of
muscle damage and facilitate a decision of whether to continue therapy
or alter doses.
11. In patients who develop intolerable muscle symptoms with or without
CK elevations, and in whom other causes have been ruled out, fibrates
should be discontinued. In patients who develop rhabdomyolysis (CK
10,000 IU/L or CK 10 ULN with an elevation in serum creatinine or
requiring IV hydration therapy), fibrate therapy should be stopped. IV
hydration therapy in a hospital setting should be instituted if indicated
for patients experiencing rhabdomyolysis. Once recovered, the risks
and benefits of fibrate therapy should be carefully monitored.
© 2006 National Lipid Association
Recommendations to healthcare professionals
regarding fibrate safety
12. Clinicians should be aware that fibrates have not been demonstrated
to significantly reduce total and cardiovascular mortality. On post hoc
analysis, certain lipid subpopulations have been shown to have greater
cardiovascular benefit (ie, elevated triglycerides and/or low HDL), but
this needs to be confirmed prospectively.
13. Fibrate therapy elevates homocysteine, however, routine monitoring of
plasma homocysteine levels on fibrate is not necesary unless further
research ascertains that this elevation is clinically relevant.
14. Caution should be exercised when anticoagulants are given in
conjunction with both fenofibrate and gemfibrozil because of the
potentiation of coumarin-type anticoagulants in prolonging PT and the
INR. Frequent PT and INR determinations are advisable, and
coumadin doses may need to be reduced to maintain PT and the INR
at the desired level to avoid bleeding complications.
© 2006 National Lipid Association
Recommendations to healthcare professionals
regarding fibrate safety
15. All fibrates have the potential to increase the cholesterol saturation
index and increase the risk for cholelithiasis; however, cases of
gallbladder disease and cholecystectomies appear to be uncommon
with gemfibrozil and fenofibrate. If cholelithiasis is suspected in a
patient receiving fibrate therapy, gallbladder studies, including
ultrasound, are indicated. If gallstones are found, consideration should
be given to stopping fibrate treatment.
Davidson M, Armani A, McKenney JM, Jacobson T. Report of the National Lipid Association’s
Safety Task Force: The Nonstatins. Am J Cardiol 2007;99(suppl):3C-18C
© 2006 National Lipid Association
Safety Considerations with
Niacin Therapy
John R Guyton, MD
Harold E. Bays, MD
March 19, 2007
© 2006 National Lipid Association
Recommendations to healthcare professionals
regarding niacin safety
1. Healthcare professionals may expect that 5%–10% of patients will not
tolerate niacin in long-term use because of flushing. Some research
clinics have been able to achieve considerably lower rates of
discontinuation because of flushing. However, the casual prescription
of any formulation of niacin without good patient education is unlikely to
achieve a goal of 90% tolerability.
2. Skin rashes associated with niacin therapy are generally not allergic but
are likely related to dermal prostaglandin release and to dry skin.
Rashes sometimes respond to moisturizing creams or to the
occasional use of steroid creams. However, withdrawal or dose
reduction of niacin may be necessary. Exacerbation of eczema may
occur, but psoriasis and most other skin disorders do not seem to be
affected by niacin administration.
CK creatine kinase; ER extended release; HDL high-density lipoprotein; IR immediate
release; PCP phencyclidine; SR sustained release; ULN upper limit of normal
© 2006 National Lipid Association
Recommendations to healthcare professionals
regarding niacin safety
3. Serious hepatic toxicity can occur with niacin therapy, but it is almost
entirely associated with the use of slow-release formulations. IR
(regular or crystalline) niacin or ER niacin generally should be used
rather than SR niacin. Nevertheless, slow-release niacin in doses up to
1,000 mg twice daily can be used safely with liver function test
monitoring (1) in exceptional cases in which only slow-release niacin is
tolerated or (2) in clinics that have developed experience with a highquality brand of slow-release niacin. If patients are taking concomitant
statin therapy, then even mild liver toxicity from SR niacin might lead to
decreased hepatic clearance of statins and potentially to serious
myopathy. Therefore, in statin-treated patients, SR niacin doses should
be limited to 1,500 mg total daily dose.
4. Hepatic transaminase levels should be monitored every 6–12 week
during the first 6–12 month of treatment with niacin and periodically
thereafter (eg, at 6-mo intervals). Withdrawal of niacin therapy or
dosage reduction should be undertaken if persistent and substantial
transaminase increases are found, especially if (1) they are 3 the ULN,
(2) they are accompanied by elevated bilirubin or prothrombin time, or
(3) they are accompanied by symptoms of nausea, malaise, or fever.
© 2006 National Lipid Association
Recommendations to healthcare professionals
regarding niacin safety
5. Isolated increases of serum bilirubin remaining 3 mg/dL, without other
signs of hepatic toxicity, may represent niacin interference with specific
bilirubin transport and should not necessarily lead to dosage reduction
or withdrawal.
6. Unexplained increases in prothrombin time with only minor
transaminase increases may rarely be a niacin side effect.
Nevertheless, because of the rarity of this effect and the lack of a drug
interaction with warfarin, niacin can be safely used in patients
anticoagulated with warfarin.
7. Niacin is useful for the treatment of the dyslipidemia of diabetes
mellitus, especially low HDL cholesterol. Minor increases (4%–5% on
average) in glucose levels result from niacin-induced insulin resistance,
but these increases are often clinically insignificant or readily treated.
Glycemic control in diabetes should be monitored following niacin
initiation or dosage increase.
© 2006 National Lipid Association
Recommendations to healthcare professionals
regarding niacin safety
8. In some patients with impaired fasting glucose or impaired glucose
tolerance, especially with fasting glucose levels of 110–125 mg/dL, the
possibility of inducing clinical diabetes may outweigh the
cardiovascular benefit of niacin therapy. It is reasonable to defer niacin
therapy while attempting to improve glycemic status with lifestyle and
dietary measures, or alternatively, niacin may be administered with
careful monitoring as lifestyle and dietary measures are instituted.
9. In patients who have increased risk for developing type 2 diabetes (eg,
patients with familial or ethnic predisposition), but who do not have
impaired fasting glucose or impaired glucose tolerance, the
cardiovascular protection afforded by niacin will often outweigh the
presumed increase in the risk for developing diabetes. No increase in
the risk for new-onset diabetes or hyperglycemia was evident in a longterm placebo-controlled clinical trial, in which 853 men took an average
dose of approximately 2,000 mg regular niacin over 5 years.
© 2006 National Lipid Association
Recommendations to healthcare professionals
regarding niacin safety
10. The onset of type 2 diabetes (multiple fasting glucose levels 125
mg/dL or postprandial glucose levels 200 mg/dL) in a patient taking
niacin should prompt consideration of niacin withdrawal or dosage
reduction. Niacin-associated insulin resistance is reversible. In a few
cases (such as in patients with very low HDL responding well to niacin
or patients with progressive atherosclerotic disease), cardiovascular
benefits might be judged to outweigh the role of niacin in inducing and
perpetuating the diabetic state. In any case, if diabetes is persistent
and requires medication or insulin after niacin withdrawal, the
reinitiation of niacin should be considered. The reinitiation of niacin
likely will require no, or only minor, changes in antidiabetic therapy.
11. On the basis of almost 2 decades of clinical evidence, niacin
coadministration with a statin does not potentiate statin-related
myopathic reactions. Isolated case reports of myopathy, including
rhabdomyolysis, with niacin-statin combination therapy appeared early
after the clinical introduction of lovastatin. These cases might have
been related to other drug interactions (polypharmacy) or possibly to
hepatic toxicity from earlier forms of niacin with subsequent decreased
hepatic extraction of statins and increased peripheral blood statin
levels.
© 2006 National Lipid Association
Recommendations to healthcare professionals
regarding niacin safety
12. In patients with myopathic reactions or clinically significant myalgia
(enough to limit statin doses) while taking niacin-statin combination
therapy, other contributors to myopathy should be considered, such as
hypothyroidism, excessive alcohol ingestion, increased physical activity,
infections, polymyositis, dermatomyositis, trauma, and drug abuse
(cocaine, amphetamines, heroin, or PCP). Otherwise, recommendations
for the evaluation of myopathic reactions in patients on statin
monotherapy should be followed (eg, the National Lipid Association
[NLA] recommendations described in Am J Cardiol 2006;97[suppl]:88C–
94C).
13. In patients predisposed to statin-induced myopathy, such as those with
chronic kidney disease, elderly patients, or those engaging in extreme
physical activity, one may consider obtaining pretreatment CK levels
before the addition of niacin to an established statin regimen. The level
of pretreatment CK can be used to judge whether and how frequently to
monitor on-treatment CK levels.
14. Blurred vision due to cystoid macular edema or other ocular effects can
be a dose-related side effect caused by niacin administration, requiring
niacin withdrawal and perhaps retitration to a lower dose. This side
© 2006 National Lipid Association
effect is very rare when niacin doses 3,000 mg/day are used.
Recommendations to healthcare professionals
regarding niacin safety
15. Niacin should not be used in the presence of active peptic ulcer disease,
but a remote history of peptic ulcer is not a contraindication to niacin
use. Gastroesophageal reflux disease is generally not affected by
niacin.
16. Nausea and vomiting have occurred in association with higher doses of
niacin but are very uncommon at doses up to 2,000 mg/day.
17. Palpitations and tachycardia are potential adverse experiences with
niacin. In rare cases, this may relate to the increased incidence of
“definite or suspected” atrial fibrillation found in a single large,
randomized trial of high-dose, IR niacin, given in doses of 2–3 g/day.
Theoretically, niacin may thus be relatively contraindicated in patients
with paroxysmal atrial fibrillation. However, postoperative atrial fibrillation
occurring after cardiothoracic surgery is not a contraindication to the
subsequent clinical use of niacin. Furthermore, established atrial
fibrillation is not a contraindication to niacin use, because the ventricular
response rate is not affected by niacin.
© 2006 National Lipid Association
Recommendations to healthcare professionals
regarding niacin safety
18. Active gout is a relative contraindication to niacin use, because niacin
(nicotinic acid) competes with uric acid for secretion by kidney tubules
and raises serum uric acid levels by 5%–15%.
19. Laboratory abnormalities occurring with niacin may include small
reductions in platelet count (mean 11% with ER niacin 2,000 mg) and
serum phosphorus (mean 10% at the same dose). These abnormalities
are not large enough to require monitoring and generally do not require
dosage adjustment.
Guyton G, Bays H. Report of the National Lipid Association’s Safety Task Force: The
Nonstatins. Am J Cardiol 2007;99(suppl):22C-31C
© 2006 National Lipid Association
Safety Considerations with
Omega-3 Fatty Acid Therapy
Harold E. Bays, MD
March 19, 2007
© 2006 National Lipid Association
Recommendations to healthcare professionals
regarding fish oil therapy safety
● The clinical trial evidence does not support an increased bleeding risk
with fish oil therapy, even when used in combination with other agents
that may increase bleeding (such as aspirin and warfarin).
● It is reasonable to monitor patients treated with fish oils and
anticoagulants for potential bleeding adverse experiences; however, it
is unclear if more monitoring is required than what would otherwise be
done with patients administered anticoagulants alone.
● Fish oils should probably be discontinued during acute bleeding
episodes, such as hemorrhagic stroke.
● The decision to discontinue fish oils days before an invasive procedure
at high risk for bleeding complications should be based on weighing
the unproved potential increase in bleeding risk versus the potential
reduction in atrial fibrillation before certain procedures, such as
coronary artery bypass surgery.
CRN council for responsible nutrition; DHA docosahexaenoic acid; EPA eicosapentaenoic
acid; FDA US food and drug administration; USP United States pharmacopeia
© 2006 National Lipid Association
Recommendations to healthcare professionals
regarding fish oil therapy safety
● Rigorous purification processes involved in fish oil manufacturing reduce
the risk of fatty acid oxidation, hypervitaminosis, and exposure to
environmental toxins.
● Clinicians and patients should be aware of the variance in the
purification processes among different fish oil manufacturers.
● Because fish oil supplements are generally regarded as safe, they are
not subject to FDA premarket and approval requirements.
● If a product has the “USP-Verified” mark on its label, the manufacturer
has met voluntary USP standards, which include initial and ongoing
determinations to ensure that (1) what is on the label is in fact in the
bottle (all the listed ingredients in the declared amounts), (2) the
supplement does not contain harmful levels of contaminants, (3) the
supplement will break down and release ingredients in the body, and
(4) the supplement has been made under current good manufacturing
practices.
© 2006 National Lipid Association
Recommendations to healthcare professionals
regarding fish oil therapy safety
● Some fish oil manufacturers advertise voluntary compliance with the
standards set by the CRN, which suggests that the fish oil
manufacturers are adhering to a voluntary monograph developed by an
association of manufacturers in the dietary supplement industry that
specifies quality standards for fish oil supplements marketed in the
United States.
● Claims of a fish oil supplement being “pharmaceutical grade” have little
meaning regarding safety and have even less meaning with regard to
efficacy, unless the fish oil preparation has been approved by the FDA
as a prescription pharmaceutical.
● Prescription fish oil preparations undergo the same rigorous FDA
regulatory requirements as other prescription pharmaceuticals, with
regard to both efficacy and safety.
© 2006 National Lipid Association
Recommendations to healthcare professionals
regarding fish oil therapy safety
● One of the most common pitfalls in the day-to-day, clinical use of fish oil
therapy is the sense among patients that all fish oil therapies are the
same. Clinicians need to educate patients of the wide variance in fish
oil therapies regarding efficacy, tolerability, and perhaps even safety.
For example, the efficacy of fish oil therapy is most dependent on the
amount of omega-3 fatty acids (such as EPA and DHA) in each
capsule, not the total amount of fish oil concentrate. Thus, to achieve
the same level of omega-3 fatty acid intake, patients may have to take
as many as 11 capsules of some fish oil supplements to match the
same amount of omega-3 fatty acid intake as 4 fish oil capsules of
prescription fish oil.
Bays H. Report of the National Lipid Association’s Safety Task Force: The Nonstatins. Am J
Cardiol 2007;99(suppl):35C-43C
© 2006 National Lipid Association
Safety Considerations with
Gastrointestinally Active
Lipid-Lowering Drugs
Terry A. Jacobson, MD
Annemarie Armani, MD
James M. McKenney, PharmD
John R. Guyton, MD
March 19, 2007
© 2006 National Lipid Association
Recommendations to healthcare
professionals regarding ezetimibe safety
Ezetimibe and muscle safety
1. Obtaining a pretreatment baseline CK level is not routinely necessary
before initiating ezetimibe therapy. It may be considered in patients
who are at high risk for experiencing muscle toxicity (eg, in older
individuals or when combining ezetimibe and a statin with other
agents known to increase myotoxicity), but this is not routinely
necessary in other patients.
2. It is not necessary to measure CK levels in asymptomatic patients
during the course of ezetimibe therapy because marked, clinically
important CK elevations are rare and are usually related to physical
exertion or other causes. CK measurements should be obtained in
symptomatic patients to help gauge the severity of muscle damage
and facilitate a decision of whether to continue therapy or alter doses.
CK creatine kinase; FDA US food and drug administration; IV intravenous; NLA National
Lipid Association; ULN upper limit of normal
© 2006 National Lipid Association
Recommendations to healthcare
professionals regarding ezetimibe safety
3. Whenever muscle symptoms or an increased CK level is encountered in
a patient receiving ezetimibe therapy, health professionals should
attempt to rule out other causes because these are most likely to
explain the findings. Other common causes include increased
physical activity, trauma, falls, accidents, seizures, shaking chills,
hypothyroidism, infections, drug abuse (alcohol, cocaine,
amphetamines, etc), or statin therapy. If other causes have been ruled
out, ezetimibe should be discontinued. When the patient becomes
asymptomatic, ezetimibe should be restarted to test the reproducibility
of symptoms. The recurrence of symptoms requires consideration of
other lipid-altering agents.
4. Obtaining a pretreatment baseline CK level is not routinely necessary
before initiating ezetimibe therapy with a 3-hydroxy-3-methylglutaryl
coenzyme A reductase inhibitor (statin). It may be considered in
patients who are at high risk for experiencing muscle toxicity (eg, in
older individuals or when combining ezetimibe and a statin with other
agents known to increase myotoxicity).
5. In patients taking ezetimibe and statins who develop tolerable muscle
complaints or are asymptomatic with CK elevations 10 ULN, the
© 2006 National Lipid Association
statin
Recommendations to healthcare
professionals regarding ezetimibe safety
5. In patients taking ezetimibe and statins who develop tolerable muscle
complaints or are asymptomatic with CK elevations 10 ULN, the statin
portion of the therapy may be continued at the same or a reduced dose,
and symptoms may be used as the clinical guide to stop or continue
therapy.
6. In patients taking ezetimibe and statins who develop intolerable muscle
symptoms with CK elevations 10 ULN and in whom other causes have
been ruled out, the statins can be discontinued or reduced first. Once
asymptomatic, the same or different statins, at the same or lower
doses, can be restarted to test the reproducibility of symptoms. The
recurrence of symptoms with multiple statins and doses requires
consideration of other lipid-altering therapy.
7. A small number of cases of myopathy have been reported regardless of
causality with ezetimibe monotherapy or with the addition of ezetimibe
to agents associated with increased risk for myopathy, such as statins.
Physicians should tell patients to promptly report muscle pain,
tenderness, or weakness. Discontinue ezetimibe and any statin or
fibrate if myopathy is diagnosed or suspected.
© 2006 National Lipid Association
Recommendations to healthcare
professionals regarding ezetimibe safety
8. In patients taking ezetimibe and statins who develop rhabdomyolysis
(CK elevation 10,000 IU/L or CK elevation 10 ULN with an elevation
in serum creatinine or requiring IV hydration therapy), both ezetimibe
and the statin therapy should be stopped. IV hydration therapy in a
hospital setting should be instituted if indicated for patients
experiencing rhabdomyolysis. Once recovered, the risk and benefits
of statin therapy should be carefully reconsidered.
Ezetimibe and liver safety
9. Because ezetimibe monotherapy has not been associated with a
significant impact on liver enzymes, liver function tests are not
required before initiating therapy or in follow-up. However, during the
routine general evaluation of patients being considered for any type of
lipid-lowering therapy, it is always advisable to obtain liver
transaminase levels. If these test results are found to be abnormal,
further investigation should be performed to determine the cause of
the abnormal test results.
© 2006 National Lipid Association
Recommendations to healthcare
professionals regarding ezetimibe safety
10. Ezetimibe in combination therapy with statins produces slightly higher
levels of liver transaminase levels than with statin therapy alone, but
these elevations are mild, transient, reversible, and without apparent
clinical significance. The effect is considered to be due to the statins
and is dose related.
11. The routine monitoring of liver function tests for ezetimibe in
combination with a statin is not supported by the available evidence.
However, until there is a change in the FDA-approved prescribing
information for statins, or for the combination of statins plus ezetimibe,
transaminase levels should be measured before starting therapy, and
periodically thereafter.
12. Because of the unknown effects of the increased exposure to
ezetimibe in patients with moderate or severe hepatic insufficiency,
ezetimibe is not recommended for these patients. No dosage
adjustment is necessary in patients with mild hepatic insufficiency.
Jacobson TA, Armani A, McKenney JM, Guyton GR. Report of the National Lipid
Association’s Safety Task Force: The Nonstatins. Am J Cardiol 2007;99(suppl):47C-55C
© 2006 National Lipid Association