Merck (NYSE: MRK), known as MSD outside the United States and
Canada, today announced new data from the Comparative Trials with
Sitagliptin (CompoSIT) clinical trials with JANUVIA® (sitagliptin).
In the CompoSIT-I study, initiation of insulin therapy while
continuing treatment with JANUVIA resulted in greater blood glucose
reductions and more patients reaching A1C goal compared to those
who discontinued JANUVIA. In the CompoSIT-R study, among patients
with mild renal impairment inadequately controlled on metformin,
with or without a sulfonylurea, treatment with JANUVIA showed
non-inferiority and superiority in reducing A1C levels compared
with patients treated with dapagliflozin. These results were
presented at the 78th Scientific Sessions of the American Diabetes
Association (ADA) in Orlando, Florida.
“Taken together, the results offer further insight into JANUVIA
as a treatment option in these settings that impact substantial
numbers of the type 2 diabetes patient population: those initiating
insulin therapy and those with mild renal impairment,” said Dr. Sam
Engel, associate vice president, diabetes, endocrinology and
women’s health, Merck Research Laboratories. “These studies further
support the clinical profile of JANUVIA and may help to inform the
individualization of treatment, which is the cornerstone of
diabetes care.”
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. JANUVIA is
contraindicated in patients with a history of a serious
hypersensitivity reaction to sitagliptin, such as anaphylaxis or
angioedema. Selected important risk information is continued
below.
Efficacy and Safety of Continuing Sitagliptin When Initiating
Insulin Therapy in Subjects with Type 2 Diabetes Mellitus (Abstract
#112-LB; CompoSIT-I)
In this randomized, controlled double-blind study of patients
with inadequately controlled type 2 diabetes taking metformin in
dual combination therapy with JANUVIA (sitagliptin) and initiating
insulin treatment, continuing treatment with JANUVIA (n=373)
resulted in greater blood glucose reduction at week 30 compared to
discontinuing JANUVIA (n=370), with LS mean changes from baseline
A1C of -1.88 percent with JANUVIA and -1.42 percent with placebo, a
between-group difference of -0.46 percent (95 percent CI [-0.58,
-0.34], p<0.001).
More than half of the patients (54 percent) who continued
treatment with JANUVIA (n=202) achieved the ADA target A1C goal of
less than 7.0 percent, compared to 35 percent of patients who were
taking insulin alone (n=131), a between-group difference of 18.8
percent (95 percent CI [11.6, 25.7], p<0.001). Mean change from
baseline reductions in fasting plasma glucose were -84.8 mg/dL with
JANUVIA and -78.3 mg/dL with placebo, a between-group difference of
-6.5 mg/dL (95 percent CI [-11.9, -1.0]).
Furthermore, in this study, there was no increased risk of
hypoglycemia with JANUVIA; patients who continued JANUVIA had a
rate of documented symptomatic hypoglycemia of 1.55 events per
patient-year compared with 2.12 events per patient-year in the
group that discontinued JANUVIA, resulting in an event rate ratio
of 0.73, (95 percent CI [0.54, 0.98], p=0.039). Additionally,
patients continuing JANUVIA required a lower daily insulin dose
(53.2 daily units with JANUVIA compared to 61.3 daily units in
those who discontinued JANUVIA), a between-group difference of -8.0
units, (95 percent CI [-14.6, -1.5], p=0.016). The Prescribing
Information states that when JANUVIA was used in combination with a
sulfonylurea or with insulin, medications known to cause
hypoglycemia, the incidence of hypoglycemia was increased over that
of placebo used in combination with a sulfonylurea or with insulin.
Therefore, a lower dose of sulfonylurea or insulin may be required
to reduce the risk of hypoglycemia.
In this study, change in body weight was similar in the two
treatment groups after 30 weeks. The mean change in body weight was
3.3 ± 7.5 lbs with JANUVIA and 3.7 ± 8.6 lbs with placebo. Adverse
events (AEs) were also similar in the two groups (five patients
taking JANUVIA and six patients taking placebo discontinued due to
an AE; 216 patients taking JANUVIA and 222 patients taking placebo
experienced one or more AEs).
“Though continuation with oral agents upon initiation of insulin
is consistent with treatment guidelines, when insulin therapy is
initiated, physicians may still choose to discontinue the use of
oral agents,” said Dr. Ronan Roussel, Clinical Professor of
Diabetology, Université Paris Diderot, Hôpital Bichat, Centre de
Recherche des Cordeliers, Paris, France. “This study could help
physicians as they consider treatment options for patients whose
disease has progressed and require treatment with insulin.”
In this study, 746 patients with a mean A1C of 8.8 percent and
disease duration of 10.6 years were randomized to continuing or
discontinuing JANUVIA (sitagliptin), with both groups initiating
insulin glargine. Eligible patients had inadequately controlled
type 2 diabetes taking metformin greater or equal to 1500 mg/day in
dual or triple combination therapy with a DPP-4 inhibitor with or
without a sulfonylurea. Those taking metformin and JANUVIA 100
mg/day directly entered the trial; all others were switched to
metformin and JANUVIA and stabilized during a run-in period.
Safety and Efficacy of Sitagliptin Compared with
Dapagliflozin in Subjects with Type 2 Diabetes, Mild Renal
Impairment and Inadequate Glycemic Control on Metformin ± a
Sulfonylurea (Abstract #1142-P; CompoSIT-R)
In this randomized, double-blind, active comparator-controlled
clinical study of patients with mild renal impairment taking
metformin with or without a sulfonylurea, LS mean changes from
baseline A1C were -0.51 percent with the addition of JANUVIA
(n=307) and -0.36 percent with the addition of dapagliflozin
(n=306), a between-group difference of -0.15 percent (95 percent CI
[-0.26, -0.04], p=0.006), meeting both non-inferiority and
superiority criteria for JANUVIA at week 24. The ADA-recommended
A1C goal of less than 7.0 percent was met by 43 percent of patients
with JANUVIA (n=116) and 27 percent with dapagliflozin (n=71), a
between-group difference of 16 percent (95 percent CI [7.7, 23.2]),
a secondary outcome.
The pre-specified analysis of two-hour post-prandial glucose
showed no significant difference between groups (mean change from
baseline -42.9 mg/dL with JANUVIA and -39.3 mg/dL with
dapagliflozin, a between-group difference of -3.6 mg/dL (95 percent
CI [-12.3, 5.0]). Mean reductions from baseline in fasting plasma
glucose were -16.5 mg/dL with JANUVIA and -20.1 mg/dL with
dapagliflozin, a between-group difference of 3.5 mg/dL (95 percent
CI [-1.2, 8.3]). Mean change from baseline in systolic blood
pressure was -0.6 ± 0.8 mm Hg with JANUVIA and -3.3 ± 0.7 mm Hg
with dapagliflozin. Mean reduction from baseline in body weight was
0.9 ± 0.4 lbs with JANUVIA and 5.3± 0.4 lbs with dapagliflozin.
There were significantly fewer patients with drug-related AEs
with JANUVIA than with dapagliflozin (24 vs. 42 patients). Summary
AE profiles were generally similar: discontinuation due to an AE,
10 patients taking JANUVIA (sitagliptin) and 10 patients taking
dapagliflozin; one or more events of hypoglycemia, seven patients
taking JANUVIA and metformin and eight patients taking
dapagliflozin and metformin, and 15 patients taking JANUVIA,
metformin and a sulfonylurea and 13 patients taking dapagliflozin,
metformin and a sulfonylurea.
The study assessed the safety and efficacy of adding JANUVIA
(sitagliptin) 100 mg once-daily or dapagliflozin 10 mg once-daily
to treatment of patients with mild renal impairment (eGFR ≥60 and
<90 mL/min/1.73 m2) and A1C between 7.0 and 9.5 percent while on
metformin with or without a sulfonylurea. Patients initiated
dapagliflozin 5 mg once-daily at randomization and were up-titrated
to dapagliflozin 10 mg once-daily at week 4. The primary efficacy
endpoint was change from baseline A1C at week 24, with a primary
hypothesis of non-inferiority of JANUVIA to dapagliflozin based on
the pre-specified criterion of the upper bound of the
between-treatment difference 95 percent CI (JANUVIA minus
dapagliflozin) of less than 0.3 percent; if the upper bound was
less than 0.0 percent, JANUVIA would be declared superior.
Treatment groups were well-balanced at baseline (n=307 and 306,
mean A1C of 7.7 and 7.8 percent, mean eGFR [mL/min/1.73 m2] of 79.4
and 76.9 for JANUVIA and dapagliflozin, respectively).
“Approximately 38 percent of patients with type 2 diabetes in
the U.S. have mild renal impairment,i,ii” said Dr. Russell Scott,
clinical professor, University of Otago, and director, Lipid and
Diabetes Research, Christchurch Hospital, Christchurch, New
Zealand. “These data from the study of sitagliptin and
dapagliflozin in those with mild renal impairment may help
physicians to evaluate how to individualize diabetes treatment for
their patients.”
Selected Important Risk Information about JANUVIA
(sitagliptin) (continued)
JANUVIA is contraindicated in patients with a history of a
serious hypersensitivity reaction to sitagliptin, such as
anaphylaxis or angioedema.
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.
An association between dipeptidyl peptidase-4 (DPP-4) inhibitor
treatment and heart failure has been observed in cardiovascular
outcomes trials for two other members of the DPP-4 inhibitor class.
These trials evaluated patients with type 2 diabetes mellitus and
atherosclerotic cardiovascular disease. Consider the risks and
benefits of JANUVIA prior to initiating treatment in patients at
risk for heart failure, such as those with a prior history of heart
failure and a history of renal impairment, and observe these
patients for signs and symptoms of heart failure during therapy.
Advise patients of the characteristic symptoms of heart failure and
to immediately report such symptoms. If heart failure develops,
evaluate and manage according to current standards of care and
consider discontinuation of JANUVIA (sitagliptin).
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 impairment
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
impairment, 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/patient-year) for JANUVIA 100 mg in combination with
glimepiride (with or without metformin), 1.8 percent (0.24
episodes/patient-year) for placebo in combination with glimepiride
(with or without metformin), 15.5 percent (1.06
episodes/patient-year) for JANUVIA 100 mg in combination with
insulin (with or without metformin), and 7.8 percent (0.51
episodes/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 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 postmarketing reports of severe and disabling
arthralgia in patients taking DPP-4 inhibitors. The time to onset
of symptoms following initiation of drug therapy varied from one
day to years. Patients experienced relief of symptoms upon
discontinuation of the medication. A subset of patients experienced
a recurrence of symptoms when restarting the same drug or a
different DPP-4 inhibitor. Consider DPP-4 inhibitors as a possible
cause for severe joint pain and discontinue drug if
appropriate.
Postmarketing cases of bullous pemphigoid requiring
hospitalization have been reported with DPP-4 inhibitor use. In
reported cases, patients typically recovered with topical or
systemic immunosuppressive treatment and discontinuation of the
DPP-4 inhibitor. Tell patients to report development of blisters or
erosions while receiving JANUVIA (sitagliptin). If bullous
pemphigoid is suspected, JANUVIA should be discontinued and
referral to a dermatologist should be considered for diagnosis and
appropriate treatment.
There have been no clinical studies establishing conclusive
evidence of macrovascular risk reduction with JANUVIA.
In clinical studies, the adverse reactions reported, regardless
of investigator assessment of causality, in ≥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 the Comparative Trials with Sitagliptin (CompoSIT)
Clinical Trial Program
Merck has continued to invest in the sitagliptin clinical
development program. The objective of the Comparative Trials with
Sitagliptin (CompoSIT) Clinical Trial Program is to better
understand the use of JANUVIA in certain patient populations,
specifically in patients already on JANUVIA who are initiating
insulin (CompoSIT-I), patients with mild renal impairment
(CompoSIT-R), and patients not at A1C goal on a submaximal dose of
metformin (CompoSIT-M). For more information about these studies,
visit https://clinicaltrials.gov/.
Our Commitment to Diabetes
At Merck, we’re committed to scientific innovation, and we
believe it’s our responsibility to help address the global diabetes
epidemic, one community and one patient at a time.iii
Our legacy in diabetes is rooted in research, which led to the
first FDA approval in 2006 of a DPP-4 inhibitor in the U.S.,
JANUVIA (sitagliptin), but our work didn’t stop there.iv We
continue to invest our resources and capabilities and collaborate
with others to develop and deliver a range of treatments and
educational tools for patients and healthcare providers to help
address this public health challenge.iii
For more information about our commitment to diabetes, visit
www.merck.com/about/our-work/diabetes.html.
About Merck
For more than a century, Merck, a leading global
biopharmaceutical company known as MSD outside of the United States
and Canada, has been inventing for life, bringing forward medicines
and vaccines for many of the world's most challenging diseases.
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. Today,
Merck continues to be at the forefront of research to advance the
prevention and treatment of diseases that threaten people and
communities around the world - including cancer, cardio-metabolic
diseases, emerging animal diseases, Alzheimer's disease and
infectious diseases including HIV and Ebola. For more information,
visit www.merck.com and connect with us
on Twitter, Facebook, Instagram, YouTube
and LinkedIn.
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 2017
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
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
i Bailey RA, et al. Chronic kidney disease in US adults with
type 2 diabetes: an updated national estimate of prevalence based
on Kidney Disease: Improving Global Outcomes (KDIGO) staging. BMC
Research Notes. 2014; 7:415.ii Wang T, et al. Chronic kidney
disease in US adults with type 2 diabetes and cardiovascular
diseases: a national estimate of prevalence by KDIGO 2012
classification. Presented at the American Diabetes Association
(ADA) 78th Annual Scientific Sessions; June 22-26, 2018; Orlando,
FL.iii International Diabetes Federation. Diabetes Atlas. 8th ed.
Brussels, Belgium. International Diabetes Federation. 2018.1-150.iv
Sitagliptin U.S. PI. Pages 1-23. Accessed: June 2018.
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