Merck Statement Regarding CHMP Review of Incretin-Based Therapies for Type 2 Diabetes, Including Sitagliptin


July 26, 2013 8:15 am ET

Merck, known as MSD outside the United States and Canada, issued the
following statement regarding the conclusion of the European Medicines
Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP)
review of GLP-1, or incretin-based, therapies, including sitagliptin.
The EMA issued a news release today, “Investigation into GLP-1 based
diabetes therapies concluded: No new concerns for GLP-1 therapies
identified on the basis of available evidence.” The EMA’s full news
release is available

“Nothing is more important to us than the safety of our medicines and
the people who take them. We appreciate the important role that the EMA
and its CHMP play in monitoring the safety of medicines in Europe,” said
Michael Rosenblatt, M.D., executive vice president and chief medical
officer, Merck. “We are confident in the safety profile of sitagliptin,
an important medicine to help adults with type 2 diabetes lower their
blood sugar levels.”

Earlier this year, the U.S. Food and Drug Administration (FDA) issued a Drug
Safety Communication
on incretin-based drugs, including sitagliptin.
The statement indicated that the FDA has not reached any new conclusions
about safety risks with incretin mimetic drugs, and recommended that
patients continue to take their medicine as directed until they talk to
their health care professional, and that health care professionals
continue to follow the prescribing recommendations in the drug labels.
The FDA said “it will communicate its final conclusions and
recommendations when its review is complete or when the Agency has
additional information to report.”

The American Diabetes Association (ADA), the European Association for
the Study of Diabetes (EASD) and the International Diabetes
Federation (IDF) said that they have reviewed the data available to date
and found that there is insufficient information to modify current
treatment recommendations. On June 28, the three organizations issued a
joint statement, which is available

“The efficacy and safety profile of sitagliptin supports its use in a
wide range of adult patients with type 2 diabetes,” Rosenblatt said. “We
will continue to monitor the safety of sitagliptin in close
collaboration with regulatory agencies and scientific experts.”

About 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

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. It is
unknown whether patients with a history of pancreatitis are at increased
risk of developing pancreatitis while taking JANUVIA.

About Merck’s review of the data on the safety profile of sitagliptin

In June, Merck presented data regarding the safety profile of
sitagliptin at the National
Institutes of Health 
(NIH) Workshop on
Pancreatitis-Diabetes-Pancreatic Cancer in the United States. In that
presentation, Merck reviewed the available safety data from the
company’s non-clinical studies, data from randomized clinical trials
with sitagliptin in more than 14,000 patients, post-marketing data
including reports of pancreatic cancer, independent observational
studies, and a meta-analysis conducted by an independent academic
research group of published clinical trials with DPP-4 inhibitors
involving more than 33,000 patients1.

Safety information from randomized controlled clinical trial data

Randomized, controlled clinical trials continue to be the gold standard
for evaluation of the safety of any medicine. Merck conducted a large
pooled analysis that included data from 25 randomized controlled
clinical studies that enrolled more than 14,000 patients who were
followed for up to two years. In this analysis, which was recently
published in Diabetes
2, there were no differences in the incidence
of pancreatitis or pancreatic cancer between patients taking sitagliptin
and those who did not take sitagliptin. There were five reports of
pancreatitis/acute pancreatitis in the group treated with sitagliptin
and five reports in the group that was not treated with sitagliptin, and
there were three reports of pancreatic cancer in the group treated with
sitagliptin and three reports in the group that was not treated with
sitagliptin. Studies in the pooled analysis were not designed or powered
to identify or adjudicate events of pancreatitis or pancreatic cancer,
and do not allow for inference on the potential for long-term effects.

The Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) is
the largest randomized controlled clinical study with sitagliptin, with
more than 14,000 patients enrolled. This study, which began in 2008, is
being led by an independent academic research collaboration between the
University of Oxford Diabetes Trials Unit and the Duke University
Clinical Research Institute. TECOS continues to be monitored through an
independent Data and Safety Monitoring Board (DSMB), which has access to
unblinded safety reports. The DSMB most recently reviewed data from
TECOS in February 2013 and did not identify any safety concerns to Merck
or recommend any changes to the study.

Information from Merck non-clinical safety studies

The safety of sitagliptin is also supported by an extensive non-clinical
safety program and none of these studies has shown an association or
established a causal relationship between sitagliptin and pancreatitis
or pancreatic cancer. The non-clinical program includes FDA-requested
studies to assess for carcinogenicity in rodents. These are conducted
over the lifetime of the animals, and the absence of tumors in rodent
carcinogenicity studies is highly predictive of an absence of human
cancer risk. The carcinogenicity studies were conducted using doses that
achieved levels of sitagliptin approximately 60 to 70 times higher than
the levels of sitagliptin achieved in patients taking the maximum
recommended daily adult human dose of sitagliptin (100 mg/day). In these
studies, no adverse effects on the pancreas were observed and
sitagliptin was not associated with an increase in the incidence of
pancreatic malignancies.

About DPP-4 inhibitors

Both DPP-4 inhibitors and GLP-1 analogues are incretin-based treatments;
however, DPP-4 inhibitors and GLP-1 analogues have different mechanism
of actions. DPP-4 inhibitors enhance the body’s own ability to lower
blood sugar levels by increasing the levels of the body’s own active
incretins, called GLP-1 and glucose-dependent insulinotropic
polypeptide, or GIP. GLP-1 analogues are biological products that act as
incretin mimetics by directly stimulating the GLP-1 receptors and have
no known effect on GIP.

Selected important risk information about JANUVIA®
(sitagliptin), continued

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

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 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, 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® (sitagliptin)
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

About Merck

Today’s Merck is a global healthcare 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
consumer care 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
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Merck Forward-Looking Statement

This news release includes “forward-looking statements” within the
meaning of the safe harbor provisions of the United States Private
Securities Litigation Reform Act of 1995. These statements are based
upon the current beliefs and expectations of Merck’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; Merck’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 Merck’s patents and other protections
for innovative products; and the exposure to litigation, including
patent litigation, and/or regulatory actions.

Merck 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 Merck’s 2012 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 (

Prescribing Information and Medication Guide for JANUVIA®
(sitagliptin) are available at

JANUVIA® is a registered trademark of Merck
Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

1 Current Medical Research & Opinion Vol. 27, No.
S3, 2011, 57–64
2 Engel, S. et al. Diabetes Ther.
2013, 4:1

Pam Eisele, 908-423-5042
Mary Elizabeth Blake, 908-423-5550
Carol Ferguson, 908-423-4465

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