New Analyses from the IMPROVE-IT Study with VYTORIN® (ezetimibe and simvastatin)
September 1, 2015 8:00 am ET
Further Analyses on the Long-Term Safety and Efficacy of VYTORIN® from the IMPROVE-IT Study Presented at the European Society of Cardiology (ESC) Meeting
Merck (NYSE:MRK), known as MSD in the United States and Canada, today
announced results from new analyses from the IMPROVE-IT study.
“IMPROVE-IT presents us with the opportunity to look at cardiovascular
outcomes data for patients treated with the combination of simvastatin
and ezetimibe (VYTORIN) and allows us to look at the important aspect of
long-term safety and efficacy under controlled conditions,” said Dr.
Michael A. Blazing, Duke Department of Medicine.
VYTORIN (ezetimibe and simvastatin) and ZETIA (ezetimibe) are currently
indicated for use along with a healthy diet to reduce elevated LDL
cholesterol in patients with hyperlipidemia. The current U.S.
Prescribing Information for both products states that the effect of
ezetimibe on cardiovascular morbidity and mortality, alone or
incremental to statin therapy, has not been determined. Merck has
submitted the data from the IMPROVE-IT study to the U.S. Food and Drug
Administration to support a new indication for reduction of
cardiovascular events for ZETIA and VYTORIN.
Incidence of New Onset Diabetes in the IMPROVE-IT Trial: Does Adding
Ezetimibe to Simvastatin Increase Risk Compared to Simvastatin Alone?
The results of one of the analyses presented at ESC showed that patients
treated with VYTORIN® – which combines simvastatin with the non-statin
ZETIA® – showed a similar risk of new onset diabetes mellitus (DM)
compared to simvastatin alone over a period of >5.5 years median
follow-up. During the trial, 1,414 patients (13.3% of those without
diabetes at enrollment) developed new onset DM defined as initiation of
a diabetes medication or two consecutive fasting glucose levels ≥7
mmol/L (126 mg/dL). Of the new onset DM cases, 50.9% occurred in the
VYTORIN (ezetimibe and simvastatin) arm and 49.1% in the simvastatin arm
(hazard ratio 1.04; 95% CI 0.94-1.15).
Safety and Efficacy of Long-term Very Low Achieved LDL-C in the
This post-hoc analysis compared safety and efficacy data during the
median six years follow-up in patients stratified by achieved LDL-C at
month one of the trial. This analysis assessed patients achieving LDL-C
levels <30 mg/dL, 30 – <50 mg/dL, 50 – <70 mg/dL and ≥70 mg/dL at month
one of the trial. The nine selected safety events of special interest,
which included hemorrhagic stroke and adverse events leading to
treatment discontinuation, showed similar rates in patients with LDL-C
<30 mg/dL at month one (achieved by 6% of patients) compared with
patients with higher achieved LDL-C levels. For a complete list of all
the safety parameters analyzed please visit the ESC website. In
addition, this analysis concluded that cardiovascular events occurred
less frequently in patients who achieved an LDL-C level <70 mg/dL at
month 1 of the trial compared with LDL-C levels ≥70 mg/dL.
Achievement of Dual LDL-C (<70 mg/dL) and hs-CRP (<2 mg/L) Goals More
Frequent with Addition of Ezetimibe and Associated with Better Outcomes
Additional evidence relating to the efficacy of VYTORIN comes from
another IMPROVE-IT analysis, which assessed outcomes in subjects
achieving specific levels of LDL-C and high sensitivity C-reactive
protein (hs-CRP). CRP levels, a marker of inflammation, are associated
with a higher cardiovascular risk in some settings. This analysis showed
that patients achieving both LDL-C <70 mg/dL and hs-CRP <2 mg/L at one
month had a lower rate of the primary composite endpoint of major CV
events over the course of the trial compared with patients not achieving
either level. Significantly more patients treated with VYTORIN met these
specified dual levels at month one compared to patients treated with
simvastatin alone (50% vs 29%, p<0.001).
About the IMPROVE-IT Trial
IMPROVE-IT (IMProved Reduction of Outcomes: VYTORIN Efficacy
International Trial) was led by the Thrombolysis In Myocardial
Infarction (TIMI) Study Group of Brigham and Women’s Hospital and the
Duke Clinical Research Institute (DCRI) and was sponsored by Merck.
IMPROVE-IT was an international, multi-center, randomized, double-blind,
active comparator trial of 18,144 high-risk patients presenting with
acute coronary syndromes (ACS), including unstable angina (UA),
non-ST-segment elevation acute myocardial infarction (NSTEMI) and
ST-segment elevation acute myocardial infarction (STEMI). The study
assessed the incidence of major CV events, as measured by a composite of
CV death, non-fatal MI, non-fatal stroke, re-hospitalization for ACS or
coronary revascularization (occurring 30 days or more after the initial
event), in patients treated with ezetimibe/simvastatin (VYTORIN)
compared with patients treated with simvastatin alone.
All patients in the trial were started at doses of ezetimibe and
simvastatin 10/40 mg or simvastatin 40 mg. Prior to a 2011 protocol
amendment, the dose could be titrated to ezetimibe/simvastatin 10/80 mg
or simvastatin 80 mg if successive LDL-C values exceeded 79 mg/dL. The
study enrolled patients within 10 days of ACS hospitalization who had
sufficient risk as defined in the protocol and who had an initial LDL-C
of ≤125 mg/dL if lipid-lowering drug naïve or <100 mg/dL if on a prior
prescription lipid-lowering therapy identified as no more potent than
simvastatin 40 mg/day. The LDL-C entry limitations were designed to
enroll patients reasonably anticipated to achieve LDL-C levels of 70
mg/dL or less in the simvastatin only cohort, which was the optional
recommended target set in the 2004 update to the Adult Treatment Panel
(ATP) III guidelines.
About VYTORIN® (ezetimibe and simvastatin)
VYTORIN contains ezetimibe and simvastatin. VYTORIN is indicated as
adjunctive therapy to diet for the reduction of elevated total
cholesterol, LDL cholesterol, apolipoprotein B, triglycerides, and
non–HDL cholesterol, and to increase HDL cholesterol in patients with
primary (heterozygous familial and nonfamilial) hyperlipidemia or mixed
hyperlipidemia when diet alone is not enough.
The Prescribing Information for VYTORIN states that no incremental
benefit of VYTORIN on cardiovascular morbidity and mortality over and
above that demonstrated for simvastatin has been established. VYTORIN is
not indicated to reduce cardiovascular events in patients who have
presented with acute coronary syndromes.
VYTORIN (ezetimibe and simvastatin) should not be taken with strong
CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole,
voriconazole, HIV protease inhibitors, boceprevir, telaprevir,
erythromycin, clarithromycin, telithromycin, nefazodone, and
cobicistat-containing products); or with gemfibrozil, cyclosporine, or
danazol. VYTORIN also should not be taken by anyone with active liver
disease, unexplained persistent elevations of hepatic transaminase
levels, or hypersensitivity to the product; or by women who are
pregnant, nursing or may become pregnant.
Selected Cautionary Information About VYTORIN (ezetimibe and
All patients starting therapy with VYTORIN, or whose dose of VYTORIN is
being increased, should be advised of the risk of myopathy, including
rhabdomyolysis, and told to promptly report any unexplained muscle pain,
tenderness, or weakness particularly if accompanied by malaise or fever
or if muscle signs and symptoms persist after discontinuing VYTORIN.
VYTORIN should be discontinued immediately if markedly elevated creatine
kinase (CK) levels occur or myopathy is diagnosed or suspected. VYTORIN
contains simvastatin, which occasionally causes myopathy manifested as
muscle pain, tenderness, or weakness with CK levels above 10 times ULN.
Myopathy sometimes takes the form of rhabdomyolysis with or without
acute renal failure secondary to myoglobinuria, and rare fatalities have
occurred. Predisposing factors for myopathy include advanced age (≥65
years), female gender, uncontrolled hypothyroidism, and renal
impairment. The risk of myopathy, including rhabdomyolysis, is dose
The 10/80 mg dose of VYTORIN should not be started in new patients. The
risk of myopathy, including rhabdomyolysis, is greater in patients
taking simvastatin 80 mg compared with other statin therapies with
similar or greater LDL cholesterol lowering efficacy, and with lower
doses of simvastatin. The 10/80 mg dose of VYTORIN should be used only
in patients who have been taking that dose chronically (e.g., for 12
months or more) without evidence of muscle toxicity. If a patient who is
currently tolerating the 10/80 mg dose needs to be initiated on an
interacting drug that is contraindicated or is associated with a dose
cap for simvastatin, that patient should be switched to an alternative
statin or statin-based regimen with less potential for the drug-drug
interaction. Please read Warnings and Precautions in the Prescribing
Information for additional information.
In addition to drugs that are contraindicated because of an increased
risk of myopathy/rhabdomyolysis, grapefruit juice should be avoided. Use
caution when prescribing VYTORIN with a fenofibrate, and immediately
discontinue both drugs if myopathy is diagnosed or suspected. Cases of
myopathy, including rhabdomyolysis, have been reported with simvastatin
coadministered with colchicine, and caution should be used when
prescribing VYTORIN (ezetimibe and simvastatin) with colchicine.
The dose of VYTORIN should not exceed 10/10 mg daily in patients
receiving verapamil, diltiazem or dronedarone, and 10/20 mg daily in
patients receiving amiodarone, amlodipine or ranolazine. For patients
with homozygous familial hypercholesterolemia (HoFH) taking lomitapide,
the dose should not exceed 10/20 mg/day (or 10/40 mg/day for patients
who have previously taken simvastatin 80 mg/day chronically, e.g., for
12 months or more, without evidence of muscle toxicity); patients
initiating lomitapide should have their dose of VYTORIN (ezetimibe and
simvastatin) reduced by 50%. The benefits of combined use of VYTORIN
with these drugs, other fenofibrates, or niacin (≥1 g/day) should be
carefully weighed against the potential risk of myopathy/rhabdomyolysis.
Caution should be used when Chinese patients taking niacin (≥1 g/day)
are coadministered doses of VYTORIN exceeding 10/20 mg/day; Chinese
patients should not receive VYTORIN 10/80 mg with niacin.
Persistent elevations in hepatic transaminase can occur. Liver function
tests should be performed at treatment initiation and thereafter when
clinically indicated. If serious liver injury with clinical symptoms
and/or hyperbilirubinemia or jaundice occurs during treatment, therapy
should be interrupted promptly and not restarted unless an alternate
etiology is found.
Increases in HbA1c and fasting serum glucose levels have been reported
with statins, including simvastatin.
In clinical trials, the most commonly reported side effects, regardless
of cause, included headache (5.8 percent), increased ALT (3.7 percent),
myalgia (3.6 percent), upper respiratory tract infection (3.6 percent),
and diarrhea (2.8 percent).
VYTORIN tablets contain ezetimibe and simvastatin: 10 mg of ezetimibe
and 10, 20, 40, or 80 mg of simvastatin (VYTORIN 10/10, 10/20, 10/40, or
10/80 mg, respectively). The usual dosage range is 10/10 mg/day to 10/40
mg/day; patients should not be titrated to the restricted 10/80-mg dose.
About ZETIA® (ezetimibe)
ZETIA, administered alone or in combination with a statin, is indicated
as adjunctive therapy to diet for the reduction of elevated total
cholesterol, LDL cholesterol, apolipoprotein B, and non-HDL cholesterol
in patients with primary (heterozygous familial and non-familial)
hyperlipidemia when diet alone is not enough.
The Prescribing Information for ZETIA states that the effect of ZETIA on
cardiovascular morbidity and mortality has not been determined. ZETIA is
not indicated for use with a statin to further reduce cardiovascular
events in patients who have presented with acute coronary syndromes.
ZETIA (ezetimibe) should not be taken by people with hypersensitivity to
any component of the medication. Statin contraindications also apply
when ZETIA is used with these drugs: statins are contraindicated in
patients with active liver disease, unexplained persistent elevations in
hepatic transaminase levels and in pregnant and nursing women. Refer to
individual statin labels for details about who should not take that
Selected Cautionary Information About ZETIA (ezetimibe)
When using ZETIA with a statin, also follow the label recommendations
for that specific statin.
When ZETIA was coadministered with a statin, consecutive elevations in
hepatic transaminase levels (greater than or equal to 3 times ULN) were
slightly higher (1.3 percent) than those of statins alone (0.4 percent).
Liver function tests should be performed when ZETIA is added to statin
therapy and according to statin recommendations. Should an increase in
ALT or AST greater than or equal to 3 times ULN persist, consider
withdrawal of ZETIA and/or the statin.
Patients should be advised to promptly report muscle pain, tenderness,
or weakness. Risk for skeletal muscle toxicity increases with higher
statin doses, advanced age (>65), hypothyroidism, renal impairment, and
depending on the statin used, concomitant use of other drugs.
Discontinue drug if myopathy is diagnosed or suspected.
ZETIA is not recommended in patients with moderate to severe hepatic
The coadministration of ZETIA with fibrates other than fenofibrate is
not recommended until use in patients is adequately studied. Exercise
caution when using ZETIA and cyclosporine concomitantly because exposure
to both drugs is increased. Cyclosporine concentrations should be
monitored in these patients.
ZETIA should be used in pregnant or nursing women only if the benefit
outweighs the risk.
In clinical trials, regardless of causality assessment, the most
frequent side effects for ZETIA coadministered with a statin versus a
statin alone included nasopharyngitis (3.7 percent vs 3.3 percent),
myalgia (3.2 percent vs 2.7 percent), upper respiratory tract infection
(2.9 percent vs 2.8 percent), arthralgia (2.6 percent vs 2.4 percent),
and diarrhea (2.5 percent vs 2.2 percent); for ZETIA administered alone
vs placebo: upper respiratory tract infection (4.3 percent vs 2.5
percent), diarrhea (4.1 percent vs 3.7 percent), arthralgia (3.0 percent
vs 2.2 percent), sinusitis (2.8 percent vs 2.2 percent), pain in
extremity (2.7 percent vs 2.5 percent), and fatigue (2.4 percent vs 1.5
Additional Information About the IMPROVE-IT Trial
IMPROVE-IT was a multi-center, randomized, double-blind active
comparator trial of 18,144 high-risk patients presenting with acute
coronary syndromes (ACS), including unstable angina (UA), non-ST-segment
elevation acute myocardial infarction (NSTEMI) and ST-segment elevation
acute myocardial infarction (STEMI). Patients were randomized to receive
ezetimibe and simvastatin (VYTORIN) or simvastatin alone, and were
followed for up to nine years, with a median clinical follow-up of
approximately six years. The primary efficacy endpoint was the composite
of cardiovascular death, non-fatal MI, non-fatal stroke,
re-hospitalization for ACS or coronary revascularization (occurring 30
days or more after the initial event).
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Please see Prescribing Information for VYTORIN®
(ezetimibe and simvastatin) at http://www.merck.com/product/usa/pi_circulars/v/vytorin/vytorin_pi.pdf
and the Patient Information for VYTORIN at http://www.merck.com/product/usa/pi_circulars/v/vytorin/vytorin_ppi.pdf.
Please see Prescribing Information for ZETIA®
(ezetimibe) at http://www.merck.com/product/usa/pi_circulars/z/zetia/zetia_pi.pdf
and the Patient Information for ZETIA at http://www.merck.com/product/usa/pi_circulars/z/zetia/zetia_ppi.pdf.
Pamela Eisele, 267-305-3558
Michael Close, 267-305-1211
Justin Holko, 908-740-1879