Findings Published in the New England
Journal of Medicine and Presented at the American Diabetes
Association Scientific Sessions
Treatment with Sitagliptin Did Not Increase
the Risk of Major Adverse Cardiovascular Events in the Primary
Composite Endpoint, or Hospitalization for Heart Failure, Compared
with Placebo
KIRKLAND, QC, June 10, 2015 /CNW Telbec/ - Merck (NYSE: MRK)
known as MSD outside Canada and
the United States, announced the
primary results of the Trial Evaluating Cardiovascular Outcomes
with Sitagliptin (TECOS), a placebo-controlled study of the
cardiovascular (CV) safety of MSD's DPP-4 inhibitor,
JANUVIA® (sitagliptin), added to usual care in more than
14,000 patients.i The study achieved its primary
composite CV endpoint of non-inferiority (defined as the time to
the first confirmed event of any of the following: CV-related
death, nonfatal myocardial infarction (MI), nonfatal stroke, or
hospitalization for unstable angina) compared to usual care without
sitagliptin.i Overall, the primary endpoint
occurred in 11.4 percent (n=839) of sitagliptin-treated patients
compared with 11.6 percent (n=851) of placebo-treated patients in
the Intention-to-Treat (ITT) analysis (HR=0.98; 95% CI
[0.89-1.08]), and in 9.6 percent (n=695) of patients in both the
sitagliptin and placebo groups in the Per Protocol (PP) analysis
(HR=0.98; 95% CI [0.88-1.09]; p<0.001 for
non-inferiority).1,i
In addition, there was no increase in hospitalization for heart
failure, and rates of all-cause mortality were similar in both
treatment groups, which were two key secondary
endpoints.i These data were presented on
June 8 at the 75th
Scientific Sessions of the American Diabetes Association and were
also published in the New England Journal of
Medicine.
"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."
"TECOS contains a robust and rich data set derived from over
14,000 diabetic patients followed for almost approximately 3
years," explained Dr. Paul
Armstrong, Distinguished University Professor, Department of
Medicine (Cardiology), University of
Alberta. "With TECOS, we have learned that when sitagliptin
is added to usual care it did not increase the risk of
cardiovascular events and there was no increase in heart
failure."
"The TECOS study provides important new information highlighting
the cardiovascular and safety profile of sitagliptin," added Dr.
Lawrence Leiter, Endocrinologist at
St. Michael's Hospital in
Toronto.
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.ii 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).i
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]).i 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]).i
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).i
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).i
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]).i 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]).i
The proportion of patients with non-CV death was 2.3 percent in
both treatment groups.i Death due to infection was
0.6 percent and 0.7 percent in the sitagliptin and placebo groups,
respectively.i 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.i
"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 Merck on behalf of
patients around the world who suffer from type 2 diabetes."
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
groups.ii 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.i This resulted in an overall difference of
-0.29 percent in patients treated with sitagliptin versus
placebo.i 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).i
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 MSD.ii A total of 14,735 patients
from 38 countries were randomized between December 2008 and July
2012.i 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.i
Patients enrolled in the trial had type 2 diabetes with
established CV disease in the coronary, cerebral, or peripheral
arteries.i 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.i 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.i
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.i If
non-inferiority on the primary composite CV endpoint was met,
superiority was to be evaluated in the ITT
population.i
About JANUVIA
In Canada, JANUVIA is indicated
as an adjunct to diet and exercise to improve glycemic control in
adult patients with type 2 diabetes mellitus as monotherapy when
metformin is inappropriate due to contraindications or intolerance
or in combination with metformin, a sulfonylurea, or pioglitazone,
or as an add-on to sulfonylurea + metformin or pioglitazone +
metformin when the current regimen, with diet and exercise does not
provide adequate glycemic control. JANUVIA is also indicated as
add-on to premixed or long/intermediate acting insulin (with or
without metformin) when diet and exercise plus insulin do not
provide adequate glycemic control.
Important Selected Safety Information About
Sitagliptin
There have been reports of acute pancreatitis, including fatal
and non-fatal hemorrhagic or necrotizing pancreatitis, in patients
taking JANUVIA. After initiation of JANUVIA, patients should be
observed carefully for signs and symptoms of pancreatitis. If
pancreatitis is suspected, JANUVIA should promptly be discontinued
and appropriate management should be initiated. Risk factors for
pancreatitis include a history of: pancreatitis, gallstones,
alcoholism, or hypertriglyceridemia.
A limited number of patients with congestive heart failure
participated in clinical studies of sitagliptin. In studies of
sitagliptin in combination with metformin, patients with congestive
heart failure requiring pharmacological therapy or NYHA Class III
or IV congestive heart failure were excluded. Patients with Classes
I and II were included in small number. Use in this population is
not recommended.
A dosage adjustment is recommended in patients with moderate or
severe renal insufficiency or with end-stage renal disease
requiring hemodialysis or peritoneal dialysis. .
For additional adverse experience information, consult the
product monograph at www.merck.ca.
About Merck
Today's Merck is a global healthcare leader working to help the
world be well. Merck is known as MSD outside Canada and the
United States. 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 healthcare through far-reaching
policies, programs and partnerships. For more information about our
operations in Canada, visit
www.merck.ca.
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at www.merck.ca
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1 The primary hypothesis of non-inferiority of
sitagliptin vs. placebo for the composite CV endpoint was based on
the Per Protocol (PP) analysis.
i Green JB et al. Effect of Sitagliptin on
Cardiovascular Outcomes in Type 2 Diabetes. New England Journal of
Medicine. 2015 June.
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.
SOURCE Merck Canada Inc.