ezetimibe combined with simvastatin caused a significant reduction in CIMT in FH
patients with and without a history of MI. These patients had similar mean baseline
LDL-C (301 mg/dL) to patients studied in the ENHANCE trial; however, baseline
CIMTs in this trial were much larger (1.82 mm without a history of MI, and 1.98 mm
with a history of MI) than those observed in the ENHANCE trial and were consistent
with CIMTs in patients with FH who have not been aggressively treated.
When ezetimibe was combined with simvastatin versus placebo in 1,873 patients
with mild to moderate, asymptomatic aortic stenosis and no previous history of
vascular disease, diabetes mellitus, or any other indications for cholesterol-lowering
therapy, significantly fewer patients treated with simvastatin–ezetimibe (15.7%) had
ischemic cardiovascular events compared with the placebo group (20.1%), mainly
related to a reduction in coronary artery bypass grafting (p = 0.02).
The incremental benefits of adding ezetimibe to statin therapy were evaluated in
the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial
126 This was a multicenter, randomized, double-blinded trial
involving 18,144 patients that sought to determine the clinical benefit and safety of
combination therapy with ezetimibe and simvastatin compared to simvastatin
monotherapy in high-risk patients presenting with ACS. This was the first large trial
to evaluate the clinical efficacy of adding a non-statin (ezetimibe 10 mg/day +
simvastatin 40 mg/day) to statin (simvastatin 40 mg/day) monotherapy. The primary
endpoint was cardiovascular death, nonfatal MI, rehospitalization for unstable
angina, coronary revascularization ≥30 days following randomization, or stroke.
Over a median follow-up of 57 months, the addition of ezetimibe to simvastatin 40
mg reduced the primary endpoint by 6.4% when compared with patients who
received simvastatin alone (p = 0.016). The absolute reduction in risk over 7 years
was 2.0%. The reduction in the primary endpoint was largely driven by a statistically
significant reduction in the risk of MI and ischemic stroke. Overall, there was a
significant 10% reduction in the risk of cardiovascular death, nonfatal MI, or nonfatal
stroke. However, there was no difference in all-cause mortality between the two
treatment groups. The average LDL-C during the study was 53.7 mg/dL in the
simvastatin–ezetimibe group, compared to 69.5 mg/dL in the simvastatin
PHARMACOKINETICS/PHARMACODYNAMICS
Ezetimibe is a prodrug that is rapidly conjugated to an active phenolic glucuronide
120 The drug is primarily metabolized in the small intestine
via glucuronide conjugation with subsequent renal and biliary excretion. The
elimination half-life is approximately 22 hours. Absorption is not affected by food
and ezetimibe may be administered at any time of day without regard to meals. There
are no dose adjustments necessary for patients with renal impairment or with mild
Ezetimibe is well generally well tolerated with minimal adverse effects. The adverse
effects that are the most reported include diarrhea, arthralgias, cough, fatigue,
abdominal pain, and back pain. However, the incidence is no more frequent with
ezetimibe than with placebo. Elevations in serum transaminases have also been
reported. When used as monotherapy, the incidence of consecutive elevations (≥3
times the ULN) in serum transaminases is similar between ezetimibe (0.5%) and
placebo (0.3%); however, when combined with a statin, the incidence of consecutive
elevations in serum transaminases is 1.3% and only 0.4% in patients taking a statin
alone. These elevations are usually transient and return to baseline after
discontinuation. Although very rare, cases of myopathy and rhabdomyolysis have
been reported with ezetimibe monotherapy.
Ezetimibe may be used alone or in combination with a statin or fenofibrate along
with diet for the management of dyslipidemia, specifically to lower LDL-C.
Ezetimibe reduces LDL-C by 18% to 22%, but has little effect on TG or HDL-C.
combination with a statin, it demonstrates an additive effect, enhancing LDL-C
lowering by an additional 10% to 20%. In fact, when added to a low dose of a statin,
the net LDL-C reduction can be similar to the lowering achieved with the maximal
128 When added to the maximal dose of a statin, it causes further
LDL-C reduction, an effect important in patients with very high LDL-C levels
requiring substantial reduction to achieve treatment goals.
Ezetimibe has been evaluated in combination with several other medications. When
combined with statins or fenofibrate there is minimal impact on either drug in terms
of an alteration in metabolism and increased bioavailability that requires any
120 Post-marketing data have shown that there are some
elevations in the international normalized ratio (INR) when ezetimibe is added to
warfarin. The exact mechanism of this interaction is not fully understood and no
specific dose adjustments are necessary for either medication. However, when
ezetimibe is initiated in a patient on warfarin, closer monitoring of the INR may be
warranted. Cyclosporine in combination with ezetimibe results in increased exposure
of both medications. When used in combination, serum concentrations of
cyclosporine should be closely monitored and adjusted as clinically indicated.
Additionally, the recommended initial dose of ezetimibe when used in combination
with cyclosporine is 5 mg daily.
When cholestyramine or colestipol are in combination with ezetimibe there is an
80% reduction in the area under the curve of ezetimibe. Therefore, when these
combinations are used ezetimibe should be administered at least 2 hours prior or 4
ounces following the administration of cholestyramine or colestipol.
absorption of ezetimibe is not affected by colesevelam and this combination may be
Adding ezetimibe to a statin results in greater LDL-C reduction than increasing the
dose of the statin. Doubling the dose of any statin provides only an additional 6%
reduction in LDL-C. The addition of ezetimibe to statin therapy results in an
approximate 18% additional reduction in LDL-C. However, maximally tolerated
statin therapy is always recommended prior to consideration of the addition of nonstatin therapy.
Due to a risk of increased hepatic serum transaminases, these laboratory values
should be measured prior to the addition of ezetimibe to statin therapy and again
following 6 weeks of combination therapy.
Ezetimibe monotherapy or combination therapy with statin should be avoided in
patients with active liver disease or persistent elevations in serum transaminases that
On the basis of currently available evidence of nonefficacy and potential harms,
there are no clear indications for the routine use of niacin preparations and niacin is,
therefore, not considered in this discussion.
BP is 136/82 mm Hg; HgA1c 11.6%; Wt 132 kg; Ht 5
; fasting lipid panel TC = 250 mg/dL, HDL-C = 30
What would be the most appropriate treatment for RP and his dyslipidemia?
While RP does have elevated TGs, per the Endocrinology and AHA guidelines,
pharmacologic therapy is not indicated at this time. The most important intervention
for RP is lifestyle modifications. Controlling his diabetes and losing weight can
successfully lower his TGs as much if not more than pharmacologic therapy.
agent(s) would be the most appropriate?
All fibric acid derivatives undergo renal elimination and none of these agents are
approved for patients on hemodialysis and are therefore not a good option in RP.
Omega-3 fatty acids would be the best option to use in combination with atorvastatin
Fibrates activate peroxisome proliferator-activated receptors α (PPARα) causing
most of the beneficial effects on blood lipids.
129 PPARα are located in the nucleus of
cells and are ligand-dependent transcription factors that regulate target gene
expression. Stimulation of PPARα suppresses the gene responsible for the synthesis
of apo C-III and stimulates the gene responsible for LDL receptor synthesis.
a result, lipolysis of TGs from VLDL particles and the removal of these particles via
hepatic LDL receptors are enhanced. Stimulation of PPARα also increases fatty acid
oxidation, reducing the synthesis of TGs in the liver, reducing the TG content of
130 Stimulation of PPARα may increase the synthesis of apo
A-I, the critical building block of nascent HDL, thereby enhancing reverse
cholesterol transport. Research also suggests that fibrates stimulate the expression of
ABCA-1 transporters in macrophage cells, which are responsible for bringing
cholesterol from within the cell to the cell surface, where it can be taken up by
nascent HDL particles and removed from the cell
The results of three major primary prevention trials have raised questions about the
safety of fibrates. In the World Health Organization trial, clofibrate reduced nonfatal
MI by 25%, but caused an increase in total mortality.
131,132 As a result, its use has
declined markedly in the United States. Some of these deaths may have been related
In the Helsinki Heart Study (HHS), gemfibrozil reduced fatal
and nonfatal MI by 37%, but was associated with a slight increase in non-CHD
mortality such that there was no net reduction in total mortality.
evaluations of therapies without gemfibrozil were associated with continued event
reduction. In the Veterans Affairs High Density Lipoprotein Intervention (VA-HIT)
trial, there was a significant 22% relative risk reduction in death from CHD with
gemfibrozil (p < 0.006). There was also a 24% reduction in the combined endpoint
of death from coronary revascularization, hospitalization due to angina, nonfatal MI,
and stroke (p < 0.001). However, there was no significant effect on mortality.
the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study,
fenofibrate did not significantly reduce CHD deaths and nonfatal MI compared with
placebo. In addition, more patients receiving fenofibrate had pancreatitis or a
pulmonary embolism compared with those given placebo.
evaluated versus placebo in 418 patients with diabetes and at least one visible lesion
on angiographic evaluation in the Diabetes Atherosclerosis Intervention Study
136 The trial was not powered to examine clinical endpoints, but fewer
events, including deaths, occurred in the fenofibrate group. In summary, the clinical
trial evidence for cardiovascular benefit of the fibric acid derivatives is not as robust
as for the statins. The data supporting the use of gemfibrozil in the primary and
secondary prevention setting have been established. In contrast, clear improvements
in CHD-related outcomes are still lacking for fenofibrate. Thus, these data support
the use of fibric acid derivatives as second-line agents, with the exception of use in
patients with severe hypertriglyceridemia. More recently, the incremental benefits of
adding fenofibrate to background simvastatin therapy on CHD events in patients with
diabetes were reported. Only patients with the highest tertile (≥204 mg/dL) of TGs
and the lowest tertile (≤34 mg/dL) of HDL-C showed a benefit when fenofibrate was
added to statin therapy. Overall, there was an insignificant 8% reduction in the
composite cardiovascular endpoint, and fenofibrate appeared to be harmful in
PHARMACOKINETICS/PHARMACODYNAMICS
Fenofibrate and fenofibric acids are well absorbed from the GI tract.
Fenofibrate is primarily metabolized by conjugation with peak plasma concentrations
within 6 to 8 hours after administration. It is highly bound to plasma proteins, with an
elimination half-life of 20 hours. The primary route of excretion is via the urine in the
On the other hand, gemfibrozil is completely absorbed following administration
and reaches peak plasma concentrations within 1 to 2 hours.
absorption is optimal when taken 30 minutes prior to meals as food can result in a
14% to 44% reduction in the area under the curve. It is highly bound to plasma
proteins, with an elimination half-life of 1.5 hours. It undergoes extensive hepatic
metabolism via oxidation of the ring methyl group to form carboxyl and
hydroxymethyl metabolites. Gemfibrozil relies significantly on renal excretion with
approximately 70% being eliminated by the kidneys as a glucuronide conjugate.
Dosing of fibric acid derivatives in patients with renal insufficiency is outlined in
Gemfibrozil, fenofibric acid, and fenofibrate are usually well tolerated. The most
common adverse effects associated with fibric acid derivatives include, nausea,
vomiting, dyspepsia, diarrhea, abdominal pain, flatulence, and constipation.
Gemfibrozil causes mild GI symptoms (nausea, dyspepsia, abdominal pain) in about
one-third of patients. Fenofibrate causes a rash in 2% to 4% of patients. Fibrate
therapy can also cause muscle side effects, including myositis and
138–143 Most cases of muscle toxicity have been reported with
gemfibrozil, especially when it is used in combination with a statin. Recent studies
reveal that the area under the blood concentration curve of most statins is increased
twofold to fourfold when given concurrently with gemfibrozil. These effects have not
been observed with fenofibrate. The mechanism causing this interaction appears to
be related to inhibition of glucuronidation by gemfibrozil, which is a metabolic
pathway for statins, thereby reducing clearance of statins from the systemic
Fibric acid derivatives have also been associated with abnormalities in liver
function tests including bilirubin and alkaline phosphatase.
elevations are often not worrisome and usually return to baseline levels upon
discontinuation. Fenofibrate has been shown to cause a reversible increase in serum
138–145 Although also observed with gemfibrozil, the incidence is lower.
Despite this increase, there does not appear to be a resultant decrease in GFR and the
mechanism for this effect has not been clearly defined. Gemfibrozil also increases
biliary secretion of cholesterol, which increases the lithogenicity of bile and results
in the development of cholesterol gallstones. Presumably, the same effect occurs with
Gemfibrozil, fenofibric acid, and fenofibrate are all indicated for the reduction of TG
levels in patients with hypertriglyceridemia.
138–146 The NLA recommends a fibric
acid derivative as one of several agents that may be initiated in patients who have
TG levels > 1,000 mg/dL and are at risk for experiencing pancreatitis.
AHA/ACC define hypertriglyceridemia at a TG level >500 mg/dL and make no
formal recommendations on the use of fibric acid derivatives in this setting.
Similarly, in patients with familial dysbetalipoproteinemia, fibric acid derivatives
are highly effective and are considered the drugs of choice. Fibrates also have a
place in the management of combined or mixed hyperlipidemia. Support for this
comes primarily from the results of the HHS and the VA-HIT trials, in which
gemfibrozil combined with diet therapy was associated with a reduction in CHD
133,134 These positive outcomes are attributed to significant
reductions in serum TGs (and, therefore, a reduction in TG-rich VLDL remnants and
in small, dense LDL) and an increase in HDL-C. Persons most likely to benefit are
those with diabetes or the lipid triad found in patients with the metabolic syndrome.
Dosing of Fibric Acid and Fenofibric Acid Derivatives in Renal Insufficiency
Gemfibrozil 600 mg twice daily No specific
40–120 mg daily Start at lowest dose
Fenofibrate (Tricor) 48–145 mg daily Start at lowest dose
35–105 mg daily Start at lowest dose
50–150 mg daily Start at lowest dose
Fenofibrate (Antara) 43–130 mg daily Start at lowest dose
54–160 mg daily Start at lowest dose
67–200 mg daily Start at lowest dose
160 mg daily Avoid use Contraindicated
Fenofibrate (Trilipix) 45–135 mg daily Start at lowest dose
Drug interactions associated with fibric acid derivatives are fairly well known and
several of these drug interactions can be managed by careful monitoring. The most
clinically significant interactions occur with statins, warfarin, repaglinide,
cholestyramine, and colestipol. The combination of statins and gemfibrozil increases
systemic concentrations of the statin and raises the risk for the development of
myopathy and rhabdomyolysis. As previously mentioned, data suggest that there is
less risk of a significant drug interaction with fenofibrate, and subsequently a lower
risk of myopathy and rhabdomyolysis. The combination of gemfibrozil should be
avoided with lovastatin, pravastatin, and simvastatin. The maximum dose of
rosuvastatin should be 10 mg daily when combined with gemfibrozil. Although
gemfibrozil does interact with atorvastatin and pitavastatin, the increase in statin
concentrations is minor and the combination may be utilized if clinically indicated.
However, there are no data demonstrating that adding a fibrate to a statin will reduce
CHD risk. The co-administration of gemfibrozil with ezetimibe may cause increased
cholesterol excretion into the bile, increasing the risk of cholelithiasis.
does not appear to be a concern with fenofibrate and ezetimibe combination.
TG 1,872 mg/dL, LDL-C was unable to be calculated, amylase 325 U/L, and lipase 3,265 U/L.
This is an individual that is high risk for pancreatitis as well as ASCVD. His risk
score using the new risk calculator based on recent guidelines reveals a 10-year risk
of about 18.6% and a statin is indicated. Additionally, the endocrinology guidelines
define a triglyceride level of ≥1,000 mg/dL as severe and the AHA guidelines define
a level ≥500 mg/dL as very high and that pharmacologic therapy should be initiated.
J.S. should be initiated on a statin and a fibric acid derivative, or two different agents
to lower TGs first such as omega-3 fatty acids plus fibric acid derivative to get TGs
down and then consider the addition of a statin.
CASE 8-6, QUESTION 2: What are some considerations when using fibric acid derivatives in combination
The risk of adverse effects of statin–fibrate combination therapy is dependent on
pharmacokinetic interactions that alter statin metabolism and clearance. One of the
most significant drug interactions with statins and a fibric acid derivative is the
combination of a statin with gemfibrozil. Gemfibrozil inhibits glucuronidation which
is an elimination pathway of all statins with the exception of fluvastatin. This
interaction can lead to increased concentrations of these statins, increasing the risk of
toxicity. In contrast, fenofibrate appears to have a minimal effect and is considered a
safer alternative. The use of gemfibrozil with simvastatin, pravastatin, or lovastatin
should be avoided. The combination gemfibrozil with atorvastatin, pitavastatin, and
rosuvastatin may be considered if fenofibrate is not an option.
doses of statins should be used to minimize adverse effects. Labeling for rosuvastatin
suggests limiting the daily dose of rosuvastatin to 10 mg daily when used with
Many different formulations of fenofibrate are available with the dose ranging from
130 to 200 mg. All products are dosed once daily. For the treatment of
hypertriglyceridemia, the initial dose may be at the lower end of the dosing range. If
the initial dose chosen is lower than the maximum dose, it should be titrated upwards
at 4- to 8-week intervals based on patient response up to the maximum dose.
Obtain a baseline serum creatinine prior to the initiation of therapy.
Gemfibrozil is preferred in renal insufficiency.
Consider discontinuation of fibric acid derivative or a dose reduction in the setting of
otherwise unexplained increases in serum creatinine.
Fenofibrate is the preferred agent to use when combination with a statin is warranted.
Obtain a baseline CK prior to adding a fibrate to statin therapy and in those patients
Patients who receive any fibric acid derivative therapy alone or in combination
with a statin should be monitored for symptoms of muscle soreness and pain. If these
symptoms emerge, a CK level should be obtained. CK level ≥10 times the ULN in
combination with muscle symptoms supports a diagnosis of myositis. If other
possible causes are not apparent, such as increased physical exercise or a recent
trauma or fall, the presence of myositis is an indication to withdraw fibrate therapy.
The exact mechanism by which the omega-3 fatty acids, dicosohexanoic acid (DHA)
and eicosopentanoic acid (EPA), lower TGs is not fully understood. There are
currently three prescription fish oil formulations available: combined EPA and DHA
in ethyl ester form, EPA ethyl ester only, and EPA and DHA in carboxylic acid
148–150 The ethyl ester formulation may possibly work thru inhibition of acyl
CoA:1,2-diacylglycerol acyltransferase and increased peroxisomal B oxidation.
However, DHA and EPA inhibit the esterification of other fatty acids, and
triglyceride lowering may be due to a reduction in hepatic TG synthesis.
active metabolite of icosapent ethyl ester reduces hepatic VLDL-TG synthesis and/or
secretion and increases TG clearance from circulating VLDL particles.
potential mechanisms of action for the carboxylic acid formulation include inhibition
of acyl-CoA:1,2-diacylglycerol acyltransferase, increased mitochondrial and
peroxisomal oxidation in the liver, decreased lipogenesis in the liver, and increased
plasma lipoprotein lipase activity. This agent may reduce the synthesis of TGs in the
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