*januvia™ is the proposed trademark for mk-431 (sitagliptin phosphate)
BACKGROUND INFORMATION:
About JANUVIA®
JANUVIA is a dipeptidyl peptidase-4 (DPP-4) inhibitor indicated as an adjunct to diet and
exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Important Selected Safety Information About Sitagliptin
JANUVIA is contraindicated in patients who are hypersensitive to any components of this product.
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.
"Patients with type 2 diabetes need antihyperglycemic medicines to help control their blood sugar.
Because these patients are at increased risk for cardiovascular complications, understanding the
cardiovascular safety of these medicines is important," said study co-chair Rury Holman, Professor of
Diabetic Medicine and Diabetes Trials Unit Director, University of Oxford. "The results from TECOS
showed that sitagliptin did not increase the risk of cardiovascular events in a diverse group of patients
with type 2 diabetes at high cardiovascular risk."
Additional Findings from the TECOS CV Safety Trial
TECOS was an event-driven study designed to assess the long-term CV safety of the addition of
sitagliptin to usual care, compared to usual care without sitagliptin, in patients with type 2 diabetes and
established CV disease.i In addition to showing no increased risk for the primary composite CV
endpoint, sitagliptin also met the secondary composite CV endpoint (defined as the time to the first
confirmed event of any of the following: CV-related death, nonfatal MI, or nonfatal stroke), showing non-
inferiority compared to usual care without sitagliptin (HR=0.99; 95% CI [0.89-1.11]; p<0.001 for non-
inferiority).
Erreur ! Signet non défini.
In additional secondary endpoints assessing time to first confirmed event, hospitalization for heart
failure was reported in 3.1 percent (n=228) of sitagliptin-treated patients and 3.1 percent (n=229) of
placebo-treated patients (HR=1.00; 95% CI [0.83-1.20]).
Erreur ! Signet non défini. All-cause mortality
was similar in both treatment groups, occurring in 7.5 percent (n=547) of patients in the sitagliptin group
and 7.3 percent (n=537) in the placebo group (HR=1.01; 95% CI [0.90-1.14]).
Erreur ! Signet non défini.
Acute pancreatitis was uncommon, occurring in 0.3 percent of patients in the sitagliptin group
(n=23) and 0.2 percent of patients in the placebo group (n=12); the difference was not statistically
different between groups (p=0.065).
Erreur ! Signet non défini. Pancreatic cancer was also uncommon,
occurring in 0.1 percent of patients in the sitagliptin group (n=9) and 0.2 percent of patients in the
placebo group (n=14), and was not statistically different between groups (p=0.322).
Erreur ! Signet non
défini.
In additional secondary analyses of the composite of time to first hospitalization for heart failure or
CV death, the first confirmed hospitalization for heart failure or CV death occurred in 7.3 percent (n=538)
in the sitagliptin group compared with 7.2 percent (n=525) for placebo (HR=1.02; 95% CI [0.90-
1.15]).
Erreur ! Signet non défini. The proportion of patients with CV death was 5.2 percent (n=380) in
the sitagliptin group compared with 5.0 percent (n=366) in the placebo group (HR 1.03; 95% CI [0.89-
1.19]).
Erreur ! Signet non défini.
The proportion of patients with non-CV death was 2.3 percent in both treatment groups.
Erreur !
Signet non défini. Death due to infection was 0.6 percent and 0.7 percent in the sitagliptin and placebo
groups, respectively.
Erreur ! Signet non défini. A slight reduction in eGFR (estimated glomerular
filtration rate), a measure of renal function, was observed in both treatment groups during the study: at
month 48, mean change from baseline in eGFR was -4.0 ± 18.4 mL/min/1.73m2 in the sitagliptin group
compared to -2.8 ± 18.3 mL/min/1.73m2 for placebo.
Erreur ! Signet non défini.
"We believe the results of TECOS provide important clinical information about the cardiovascular
safety profile of sitagliptin," said Dr. Roger M. Perlmutter, president, Merck Research Laboratories. "The
TECOS CV safety trial reflects the best efforts of clinical scientists at the University of Oxford, the Duke
Clinical Research Institute and MSD on behalf of patients around the world who suffer from type 2
To minimize any potential effect that differences in glucose control might have on CV outcomes,
the study aimed to achieve similar glucose control (glycemic equipoise) between treatment At
four months, mean HbA1c level was 0.4 percent lower in the sitagliptin group compared with placebo,
and this narrowed to 0.1 percent lower during patient follow-up.
Erreur ! Signet non défini. This resulted
in an overall difference of -0.29 percent in patients treated with sitagliptin versus placebo.
Erreur ! Signet
non défini. Compared with patients treated with placebo, fewer patients treated with sitagliptin received
additional antihyperglycemic agents during the study period (1,591 vs. 2,046 patients, respectively;
p<0.001) and were less likely to start chronic insulin therapy (542 vs. 744 patients, respectively;
p<0.001).
Erreur ! Signet non défini.
Study Methods and Design
TECOS was led by an independent academic research collaboration between the University of
Oxford Diabetes Trials Unit (DTU) and the Duke University Clinical Research Institute (DCRI), and was
sponsored by MSDA total of 14,735 patients from 38 countries were randomized between December
2008 and July 2012.
Erreur ! Signet non défini. Of these, 14,671 were included in the ITT analysis
population, with 7,332 assigned to sitagliptin and 7,339 to placebo, in addition to existing therapy. The
median patient follow-up was three years, with a maximum follow-up of 5.7 years.
Erreur ! Signet non
défini.
Patients enrolled in the trial had type 2 diabetes with established CV disease in the coronary,
cerebral, or peripheral arteries.
Erreur ! Signet non défini. Patients were at least 50 years of age, had a
baseline HbA1c between 6.5 and 8.0 percent, and were dose-stable for at least three months on either:
monotherapy or dual combination therapy with metformin, pioglitazone or a sulfonylurea; or
insulin as monotherapy or in combination with a stable dose of metformin.
Erreur ! Signet non défini.
Participants were randomly assigned to treatment with sitagliptin 100 mg daily (50 mg daily if baseline
eGFR was ≥30 and <50 mL/min/1.73m2) or matching placebo.
Erreur ! Signet non défini.
The primary non-inferiority hypothesis was assessed by determining whether the upper bound of
the 95 percent confidence interval for the hazard ratio for the risk of the primary composite CV endpoint
(time to first event) between the sitagliptin and placebo groups in the PP population did not exceed 1.3,
with a key supporting analysis in the ITT population.
Erreur ! Signet non défini. If non-inferiority on the
primary composite CV endpoint was met, superiority was to be evaluated in the ITT population.
Erreur !
Signet non défini.
Important Selected Safety Information About Sitagliptin (continued)
• There have been post-marketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic
or necrotizing pancreatitis. If pancreatitis is suspected, promptly discontinue JANUVIA.
• There have been postmarketing reports of acute renal failure, sometimes requiring dialysis. Dosage
adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with
ESRD. Assessment of renal function is recommended prior to initiating JANUVIA and periodically
• There is an increased risk of hypoglycemia when JANUVIA is added to an insulin secretagogue (e.g.,
sulfonylurea) or insulin therapy. Consider lowering the dose of the sulfonylurea or insulin to reduce the
risk of hypoglycemia.
• There have been post-marketing reports of serious allergic and hypersensitivity reactions in patients
treated with JANUVIA such as anaphylaxis, angioedema, and exfoliative skin conditions including
Stevens-Johnson syndrome. In such cases, promptly stop JANUVIA, assess for other potential causes,
institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes.
• There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction
with JANUVIA or any other anti-diabetic drug.
• Adverse reactions reported in 5% of patients treated with JANUVIA and more commonly than in
patients treated with placebo are: upper respiratory tract infection nasopharyngitis and headache. In the
add-on to sulfonylurea and add-on to insulin studies, hypoglycemia was also more commonly reported in
patients treated with JANUVIA compared to placebo.
About MSD
Today's MSD is a global healthcare leader working to help the world be well. MSD is a tradename of Merck
& Co., Inc., with headquarters in Kenilworth, N.J., U.S.A. 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 healthcare through far-reaching policies, programs and partnerships.
MSD 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 MSD'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; MSD'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 MSD/Merck patents and other protections for innovative
products; and the exposure to litigation, including patent litigation, and/or regulatory actions.
MSD/Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result
of new information, future events or otherwise except as required by applicable law. Additional factors that could
cause results to differ materially from those described in the forward-looking statements can be found in
MSD's/Merck'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 JANUVIA® (sitagliptin) at and Medication Guide for JANUVIA at
Green JB et al. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. New England Journal of Medicine. 2015 June.
1 Green JB et al. Rationale, design, and organization of a randomized, controlled Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) in patients with type 2 diabetes and established cardiovascular disease. American Heart Journal. 2013 Dec;166(6):983-989.e7.
Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS)
Background and Timeline
TECOS is an event-driven safety study conducted in adults with type 2 diabetes and a history of cardiovascular
(CV) disease, which is designed to assess the CV safety of long-term treatment with JANUVIA® (sitagliptin) as part
of usual diabetes carea compared with usual care without JANUVIA. The primary hypothesis of the TECOS CV
safety trial is to confirm that JANUVIA plus usual care shows no increased risk (non-inferiority) for the primary
endpoint of time to first significant confirmed CV event, or MACE+ (a composite of CV-related death, nonfatal
myocardial infarction (MI), nonfatal stroke, and unstable angina requiring hospitalization)b compared to placebo plus
usual care. If JANUVIA plus usual care is found to be non-inferior to placebo plus usual care with respect to CV
outcomes, the superiority of JANUVIA compared to placebo with respect to CV outcomes will be evaluated.ii
Achieving similar glucose control (glycemic equipoise) between treatment groups is a design element of the
TECOS CV safety trial that is intended to minimize any effect that differences in glucose control might have on CV results.
The TECOS CV safety trial enrolled 14,724 participants from 38 countries between December 2008 and July
2012. The median patient follow-up for TECOS is expected to be approximately three years.iii
The TECOS CV safety trial is being led by an independent academic research collaboration between the University of Oxford Diabetes Trials Unit (DTU) and the Duke University Clinical Research Institute (DCRI) and is being sponsored by MSDThe study's academic leaders are:iv Rury Holman, FMedSci FRCP, Professor and Director, Diabetes Trials Unit, University of Oxford (study co-
Eric Peterson, M.D., MPH, Executive Director of the Duke Clinical Research Institute, Professor of Medicine,
Division of Cardiology, Duke University (study co-chair as of March 25; replaced Robert Califf M.D., Vice Chancellor for Clinical and Translational Research, Professor of Medicine, Division of Cardiology, Duke University)
Paul Armstrong, M.D., Professor of Medicine, Division of Cardiology, University of Alberta
John Buse, M.D., Ph.D., Professor of Medicine, Chief of Division of Endocrinology, Executive Associate Dean
for Clinical Research, University of North Carolina Chapel Hill
Robert Josse, M.D., Professor, Department of Medicine, University of Toronto
John Lachin, Sc.D., Research Professor of Biostatistics and Epidemiology, and Statistics, The Biostatistics
Center, The George Washington University
Darren McGuire, M.D., Professor of Internal Medicine and Director, Cardiology Clinical Trials Unit, University of
Texas Southwestern Medical Center
Eberhard Standl, M.D., Professor of Medicine, Munich Diabetes Research Group/Diabetes Research Institute Frans Van de Werf, M.D., Ph.D., Professor of Cardiology, Chair of the Division of Cardiology, Catholic
University of Leuven
About JANUVIA® (sitagliptin)
JANUVIA is a dipeptidyl peptidase-4 (DPP-4) inhibitor indicated as an adjunct to diet and exercise to improve
glycemic control in adults with type 2 diabetes mellitus.
Important Selected Safety Information About Sitagliptin
JANUVIA is contraindicated in patients who are hypersensitive to any components of this product. 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.
Please see Prescribing Information for JANUVIA (sitagliptin) at
and Medication Guide for
JANUVIA at
a)Additional oral antihyperglycemic agents or insulin were to be added to target A1C goals based on current guidelines.
b) MACE is defined as Major Adverse Cardiac Events (a composite of CV-related death, nonfatal myocardial infarction (MI),
nonfatal stroke, and unstable angina requiring hospitalization)
DIAB-1144241-0003, 04/15
Copyright 2015 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved
TECOS CV Safety Trial Designi
Primary hypothesis: Confirm no increased risk (non-
inferiority) for the primary endpoint of time to first
significant confirmed CV event, or MACE+.b
Study population: Patients aged ≥50 years with type
2 diabetes; documented vascular disease in the
TECOS Timeline
coronary, cerebral, or peripheral arteries; and
baseline A1C1c between 6.5 and 8.0 percent and
dose-stable for at least 3 months on:
JANUVIA approved in the U.S. and Mexico.v,vi
o Monotherapy or dual combination therapy with
metformin, pioglitazone, and/or a sulfonylurea, or
Additional regulatory approvals of JANUVIA begin
Insulin as monotherapy or in combination with
stable dose of metformin
Treatment arms: JANUVIA + usual carea vs. placebo TECOS CV safety trial protocol is established by
MSD, in partnership with an academic research
collaboration between the University of Oxford
Event-driven study: Study completion based upon
Diabetes Trials Unit and the Duke University Clinical
attainment of 1,300 patients with a confirmed primary
Research Institute.viii
outcome of CV events.
November: MSD announces TECOS CV safety trial to
evaluate the cardiovascular (CV) safety of JANUVIA.ix
Primary outcome: Time from randomization to first
December: First patient enrolled
confirmed MACE+ event.
September: Protocol amended to permit insulin use at
Key secondary outcomes: Composite of time to first
confirmed CV-related death, nonfatal MI, nonfatal
stroke (MACE); time to occurrence of the individual
components of the primary endpoint; time to all-cause July: TECOS reached full patient enrollment.x
mortality; time to hospital admission for adjudicated
congestive heart failure (CHF).b
October: "Rationale, design, and organization of a
randomized, controlled Trial Evaluating
Cardiovascular Outcomes with Sitagliptin (TECOS) in
patients with type 2 diabetes and established
cardiovascular disease," published online by the
American Heart Journal (published in print in
January: "Regional, age, and sex differences in
a Additional oral antihyperglycemic agents or insulin were to be added
baseline characteristics of patients enrolled in the
to target A1C goals based on current guidelines.
Trial Evaluating Cardiovascular Outcomes with
MACE is defined as Major Adverse Cardiac Events (a composite of
CV-related death, nonfatal myocardial infarction (MI), nonfatal stroke,
Sitagliptin (TECOS)," published online in Diabetes,
and unstable angina requiring hospitalization)
Obesity and Metabolism in January 2015
c A1C is an estimate of a person's average blood glucose over a two- to
three-month period.
March 31: Study completexi (ClinicalTrials.gov
d CV events will be adjudicated by an independent committee, blinded
to study therapy.
June: The primary results of TECOS will be
American Diabetes Association in Boston on June 8,
presented at the 75th Scientific Sessions of the
ii Green JB et al. Rationale, design, and organization of a randomized, controlled Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) in patients with type 2 diabetes and established cardiovascular disease. American Heart Journal. 2013 Dec;166(6):983-989.e7.
iii Bethel MA et al. Regional, age and sex differences in baseline characteristics of patients enrolled in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). Diabetes, Obesity and Metabolism. 2015 Apr;17(4):395-402.
iv University of Oxford. Trial Evaluating Cardiovascular Outcomes With Sitagliptin – Organisation - Executive Committee (EC).Accessed March 17, 2015.
v U.S. Food and Drug Administration. FDA Approves New Treatment for Diabetes – First in a New Class of Diabetes Drugs.Accessed February 24, 2015.
vi Merck. JANUVIA Receives Approval in Mexico. ccessed February 25, 2015.
vii Merck. JANUVIA Approved in the European Union for the Treatment of Type 2 Diabetes. ccessed February 25, 2015.
viii Merck. Clinical Trials: Update on Cardiovascular Outcomes Study with JANUVIA. ccessed February 13, 2015.
ix University of Oxford. Trial Evaluating Cardiovascular Outcomes With Sitagliptin - News. ccessed January 12, 2015.
x University of Oxford. Trial Evaluating Cardiovascular Outcomes With Sitagliptin - Protocol. Accessed February 25, 2015.
xi Duke Clinical Research Institute; Oxford Diabetes Trials Unit. Sitagliptin Cardiovascular Outcome Study (TECOS). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Accessed January 12, 2015. Copyright 2015 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, USA. All rights reserved. 15-Jun-2016 GULF-DIAB-1152951-0001 In case you need any update or you have an inquiry, you can contact: Tel: +971 426 9100 Fax: +971 426 9204 Em
DIAB-1144241-0003, 04/15
Copyright 2015 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved.
Source: http://www.apo-mail.org/150630.pdf
Wiri Wai Care Wonders! Students from Wiri Central School proudly sign W after completing work on the Puhinui stream. Learning goes beyond the classroom Drury School drain painting Wai Care Fieldtrip to Hunua Brendon with a longfin eel found during fish monitoring Drury School's Wai Care club recently painted up a Papakura Normal School's middle and senior
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