Additional Real-World Analyses from DYSIS
and DYSIS II Assessing the Treatment of Dyslipidemia to be
Presented
Merck (NYSE:MRK), known as MSD outside the United States and
Canada, announced today that new analyses from the investigational
IMPROVE-IT (IMProved Reduction of Outcomes: VYTORIN Efficacy
International Trial) study of VYTORIN® (ezetimibe and simvastatin),
the TECOS (Trial Evaluating Cardiovascular Outcomes with
Sitagliptin) cardiovascular safety trial of JANUVIA® (sitagliptin),
and real-world data from the Dyslipidemia International Study
(DYSIS I and DYSIS II) will be presented at the upcoming European
Society of Cardiology (ESC) Congress 2015, held Aug. 29 to Sept. 2,
2015. IMPROVE-IT was designed to evaluate the cardiovascular
benefit of the combination of ezetimibe and simvastatin compared to
simvastatin alone. The TECOS cardiovascular safety trial was
designed to assess the cardiovascular safety of Merck’s DPP-4
inhibitor, JANUVIA. In all, Merck has 13 data presentations at this
year’s ESC.
“At this year’s European Society of Cardiology Congress,
we are pleased to share new data from two important studies –
IMPROVE-IT and the TECOS cardiovascular safety
trial – which have already added substantially to our
knowledge of cardiovascular disease and the
cardiovascular safety profile
of sitagliptin, respectively,” said Dr. Roy Baynes,
senior vice president, global clinical development, Merck Research
Laboratories.
The primary results from IMPROVE-IT, which enrolled 18,144
high-risk patients presenting with acute coronary syndromes (ACS),
were presented in November 2014 at the American Heart Association
Scientific Sessions and published in The New England Journal of
Medicine in June 2015. VYTORIN and ZETIA® (ezetimibe) are indicated
for use along with a healthy diet to reduce elevated LDL
cholesterol in patients with hyperlipidemia. The current U.S.
Prescribing Information for VYTORIN and ZETIA 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 IMPROVE-IT to regulatory
authorities in the U.S. and European Union to support a new
indication for reduction of major cardiovascular events for
VYTORIN® and ZETIA®.
TECOS was an event-driven study of more than 14,000 patients
that evaluated the long-term cardiovascular safety of the addition
of JANUVIA to usual care, compared to usual care without JANUVIA,
in patients with type 2 diabetes and established cardiovascular
disease. The primary results of the TECOS cardiovascular safety
trial were presented at the 75th Scientific Sessions of the
American Diabetes Association and published simultaneously in the
New England Journal of Medicine in June 2015.
Indications and Limitations of Use for JANUVIA®
(sitagliptin) 25 mg, 50 mg and 100 mg tablets
JANUVIA is indicated, as an adjunct to diet and exercise, to
improve glycemic control in adults with type 2 diabetes mellitus.
JANUVIA should not be used in patients with type 1 diabetes or for
the treatment of diabetic ketoacidosis. JANUVIA has not been
studied in patients with a history of pancreatitis. It is unknown
whether patients with a history of pancreatitis are at increased
risk of developing pancreatitis while taking JANUVIA.
Selected Important Risk Information about JANUVIA
JANUVIA is contraindicated in patients with a history of a
serious hypersensitivity reaction to sitagliptin, such as
anaphylaxis or angioedema.
There have been no clinical studies establishing conclusive
evidence of macrovascular risk reduction with JANUVIA or with any
other antidiabetic drug.
Analysis of DYSIS and DYSIS II
The cross-sectional, observational study DYSIS examined lipid
goal attainment among statin-treated patients including patients
suffering from coronary heart disease (CHD), diabetes, chronic
kidney disease or peripheral atherosclerotic disease. DYSIS
enrolled approximately 60,000 patients from 30 countries from
regular clinical practice such as physicians’ offices and hospital
outpatient wards between 2008 and 2012. DYSIS II, a continuation of
DYSIS study evaluating lipid goal attainment, enrolled
approximately 4,000 ACS patients and 7,000 CHD patients globally
between 2012 and 2014.
The following data will be presented at ESC Congress 2015:
TECOS Cardiovascular Safety Trial Data Analysis
- (Oral Presentation) Trial Evaluating
Cardiovascular Outcomes with Sitagliptin in Patients with Type 2
Diabetes: TECOS
- Monday, Aug. 31: 11:00AM – 12:30PM GMT;
Presentation 11:00AM – 11:10AM GMT. Location: London – Main
Auditorium, Hot Line III – Diabetes Mellitus/Pharmacology
IMPROVE-IT Data Analysis
- (Oral Presentation) Safety and
Efficacy of Long-term Very Low Achieved LDL-C in the IMPROVE-IT
Trial
- Saturday, Aug. 29: 11:00AM – 12:30PM
GMT; Presentation 11:20AM – 11:37AM GMT. Location: San Marino –
Village 2, Low-Density Lipoprotein Cholesterol: How Low and How to
Lower?
- (Moderated Poster) Prospective
Evaluation of Cancer in 18,144 Patients Randomized to Ezetimibe vs
Placebo: a Prespecified Analysis from the IMPROVE-IT Trial
- Sunday, Aug. 30: 10:00AM – 11:00AM GMT;
Presentation 10:51AM – 11:00AM GMT. Location: Poster Area, Managing
Lipids – Statins and Beyond
- (Poster Session) Muscle Related
Complaints, Serious Adverse Events and Drug Discontinuations in
17,706 Subjects Randomized to Simvastatin or Ezetimibe/Simvastatin
in the IMPROVE-IT Study
- Tuesday, Sept. 1: 2:00PM – 4:00PM GMT.
Location: Poster Area, Surveillance of Risk Factors and
Interventions
- (Best Posters) 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 In
IMPROVE-IT
- Tuesday, Sept. 1: 2:00PM – 4:00PM GMT.
Location: Poster Area, Best Posters in Medical Therapy of Stable
Coronary Artery Disease
- (Oral Presentation) Incidence of New
Onset Diabetes in the IMPROVE-IT Trial: Does Adding Ezetimibe to
Simvastatin Increase Risk Compared to Simvastatin Alone?
- Tuesday, Sept. 1: 2:00PM – 3:30PM GMT;
Presentation 2:30PM-2:45PM GMT. Location: Hyde Park – The Hub,
Clinical Trial Update III - Pharmacology & Therapy.
- (Oral Presentation) Benefit Of
Adding Ezetimibe To Statin Therapy On Cardiovascular Outcomes And
Safety In Patients With Vs. Without Diabetes: The IMPROVE-IT
Trial
- Sunday, Aug. 30: 2:00PM – 3:30PM GMT;
Presentation 2:15PM – 2:30PM GMT. Location: Hyde Park – The Hub,
Clinical Trial Update I - Cardiovascular Diseases: Prevention,
Outcomes, Quality.
DYSIS & DYSIS II Data Analysis
- (Poster Session) High Prevalence of
Persistent Lipid Abnormalities Among Coronary Patients: The
Dyslipidemia International Study (DYSIS) II Global Results
- Sunday, Aug. 30: 8:30AM – 12:30PM GMT.
Location: Poster Area, Treatment Strategies and Adherence: Can We
Decrease Risk?
- (Poster Session) Are Coronary
Patients on Lipid-lowering Therapy in Europe Achieving the
Recommended LDL-C Target? Results from the Dyslipidemia
International Study (DYSIS) II Europe
- Sunday, Aug. 30: 8:30AM – 12:30PM GMT.
Location: Poster Area, Strategies and Adherence: Can We Decrease
Risk?
- (Poster Session) Prevalence of Lipid
Abnormalities Among Coronary Patients Remains High in the Middle
East/Africa Region: The Dyslipidemia International Study (DYSIS) II
MEA results
- Sunday, Aug.30: 8:30AM – 12:30PM GMT.
Location: Poster Area, Strategies and Adherence: Can We Decrease
Risk?
- (Poster Session) LDL-C Target
Attainment Remains Low Among Treated Coronary Patients in
Asia-Pacific: The Dyslipidemia International Study (DYSIS) II AP
Results
- Sunday, Aug. 30: 8:30AM – 12:30PM GMT.
Location: Poster Area, Strategies and Adherence: Can We Decrease
Risk?
- (Poster Session) Unexpected High
Prevalence of Possible and Probable FH in Clinical Practice -
Results of DYSIS I
- Sunday, Aug. 30: 8:30AM – 12:30PM GMT.
Location: Poster Area, Classical and New Risk Factors for
Cardiovascular Disease
- (Oral Presentation) Low
LDL-cholesterol Target Achievement in Statin-treated Patients in
Clinical Practice in China and Europe: Results of the Dyslipidemia
International Study (DYSIS)
- Saturday, Aug. 29: 11:00AM - 12:30PM
GMT; Presentation 11:37AM – 11:54 AM GMT. Location: San Marino -
Village 2 - Low-Density Lipoprotein Cholesterol: How Low and How to
Lower?
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
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 related.
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 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 statin.
Selected cautionary information about ZETIA
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 impairment.
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 percent).
Selected Important Risk Information about JANUVIA®
(continued)
There have been postmarketing reports of acute pancreatitis,
including fatal and nonfatal hemorrhagic or necrotizing
pancreatitis, in patients taking JANUVIA. After initiating JANUVIA,
observe patients carefully for signs and symptoms of pancreatitis.
If pancreatitis is suspected, promptly discontinue JANUVIA and
initiate appropriate management.
Assessment of renal function is recommended prior to initiating
JANUVIA and periodically thereafter. A dosage adjustment is
recommended in patients with moderate or severe renal insufficiency
and in patients with end-stage renal disease requiring hemodialysis
or peritoneal dialysis. Caution should be used to ensure that the
correct dose of JANUVIA is prescribed.
There have been postmarketing reports of worsening renal
function, including acute renal failure, sometimes requiring
dialysis. A subset of these reports involved patients with renal
insufficiency, some of whom were prescribed inappropriate doses of
sitagliptin.
When JANUVIA was used in combination with a sulfonylurea or
insulin, medications known to cause hypoglycemia, the incidence of
hypoglycemia was increased over that of placebo. Therefore, a lower
dose of sulfonylurea or insulin may be required to reduce the risk
of hypoglycemia.
The incidence (and rate) of hypoglycemia based on all reports of
symptomatic hypoglycemia were: 12.2 percent (0.59 episodes per
patient-year) for JANUVIA 100 mg in combination with glimepiride
(with or without metformin), 1.8 percent (0.24 episodes per
patient-year) for placebo in combination with glimepiride (with or
without metformin), 15.5 percent (1.06 episodes per patient-year)
for JANUVIA (sitagliptin) 100 mg in combination with insulin (with
or without metformin), and 7.8 percent (0.51 episodes per
patient-year) for placebo in combination with insulin (with or
without metformin).
There have been postmarketing reports of serious
hypersensitivity reactions in patients treated with JANUVIA
(sitagliptin), such as anaphylaxis, angioedema and exfoliative skin
conditions including Stevens-Johnson syndrome. Onset of these
reactions occurred within the first 3 months after initiation of
treatment with JANUVIA®, with some reports occurring after the
first dose. If a hypersensitivity reaction is suspected,
discontinue JANUVIA, assess for other potential causes for the
event, and institute alternative treatment for diabetes.
Angioedema has also been reported with other dipeptidyl
peptidase-4 (DPP-4) inhibitors. Use caution in a patient with a
history of angioedema with another DPP-4 inhibitor because it is
unknown whether such patients will be predisposed to angioedema
with JANUVIA.
There have been no clinical studies establishing conclusive
evidence of macrovascular risk reduction with JANUVIA or with any
other antidiabetic drug. In clinical studies, the adverse reactions
reported, regardless of investigator assessment of causality, in
greater than or equal to 5 percent of patients treated with JANUVIA
as monotherapy and in combination therapy, and more commonly than
in patients treated with placebo, were upper respiratory tract
infection, nasopharyngitis and headache.
About Merck
Today’s Merck is a global health care leader working to help the
world be well. Merck is known as MSD outside the United States and
Canada. Through our prescription medicines, vaccines, biologic
therapies and animal health products, we work with customers and
operate in more than 140 countries to deliver innovative health
solutions. We also demonstrate our commitment to increasing access
to health care through far-reaching policies, programs and
partnerships. For more information, visit www.merck.com and connect
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Forward-Looking Statement of Merck & Co., Inc.,
Kenilworth, N.J., USA
This news release of Merck & Co., Inc., Kenilworth, N.J.,
USA (the “company”) includes “forward-looking statements” within
the meaning of the safe harbor provisions of the U.S. Private
Securities Litigation Reform Act of 1995. These statements are
based upon the current beliefs and expectations of the company’s
management and are subject to significant risks and uncertainties.
If underlying assumptions prove inaccurate or risks or
uncertainties materialize, actual results may differ materially
from those set forth in the forward-looking statements.
Risks and uncertainties include but are not limited to, general
industry conditions and competition; general economic factors,
including interest rate and currency exchange rate fluctuations;
the impact of pharmaceutical industry regulation and health care
legislation in the United States and internationally; global trends
toward health care cost containment; technological advances, new
products and patents attained by competitors; challenges inherent
in new product development, including obtaining regulatory
approval; the company’s ability to accurately predict future market
conditions; manufacturing difficulties or delays; financial
instability of international economies and sovereign risk;
dependence on the effectiveness of the company’s patents and other
protections for innovative products; and the exposure to
litigation, including patent litigation, and/or regulatory
actions.
The company undertakes no obligation to publicly update any
forward-looking statement, whether as a result of new information,
future events or otherwise. Additional factors that could cause
results to differ materially from those described in the
forward-looking statements can be found in the company’s 2014
Annual Report on Form 10-K and the company’s other filings with the
Securities and Exchange Commission (SEC) available at the SEC’s
Internet site (www.sec.gov).
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.
Please see Prescribing Information for JANUVIA®
(sitagliptin) at
http://www.merck.com/product/usa/pi_circulars/j/januvia/januvia_pi.pdf
and Medication Guide for JANUVIA at
http://www.merck.com/product/usa/pi_circulars/j/januvia/januvia_mg.pdf.
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