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June 14, 2014 12:01 pm ET

Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced results from a post-hoc analysis showing that patients with type 2 diabetes having treatment intensified with insulin glargine therapy while also being treated with JANUVIA^® (sitagliptin) 100 mg once-daily had a lower incidence of nighttime (nocturnal) hypoglycemia compared to patients also receiving placebo.  Results were presented at the American Diabetes Association 74^th Scientific Sessions.

“Type 2 diabetes is a progressive disease, so that over time many patients need to add insulin to their treatment regimens to maintain blood sugar control,” said Peter Stein, M.D., vice president, Clinical Research for diabetes and endocrinology, Merck Research Laboratories. “Insulin therapy can lead to episodes of hypoglycemia that can occur either during the day or overnight while the patient is asleep. Hypoglycemia is troubling to both the patient and to the physician, so treatment approaches that can potentially lower the occurrence of hypoglycemia—overall or overnight—may be important.”

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.

Results of the original study

The original clinical trial, “A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Study the Safety and Insulin-Sparing Efficacy of the Addition of Sitagliptin in Patients With Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control on Insulin Alone or in Combination With Metformin,” was conducted over 24 weeks in 660 insulin-treated patients, randomized to the addition of either JANUVIA (sitagliptin) 100 mg once-daily (n=329) or placebo (n=329) to their insulin regimen.  Starting two weeks after randomization, patients were to increase their dose of insulin every three days to reach a targeted fasting blood sugar level of 72-100 mg/dL.  After 24 weeks, patients randomized to JANUVIA received less additional insulin compared to patients randomized to placebo.

The study also found that patients in the group randomized to JANUVIA had better blood sugar control after 24 weeks with a significantly lower incidence of hypoglycemia.  The group randomized to JANUVIA had an A1C[1] reduction (-1.31% LS mean A1C reduction from a baseline of 8.66%) that was significantly greater than the reduction in the group randomized to placebo (-0.87% LS mean reduction from a baseline of 8.81%; difference between groups p<0.001).  The incidence of symptomatic hypoglycemia was significantly lower in the group randomized to JANUVIA compared to placebo (25% vs. 37%; p=0.001).

Results of post-hoc analysis

Nocturnal hypoglycemia results

The post-hoc analysis measured the incidence of symptomatic nocturnal hypoglycemic episodes and showed that at 24 weeks symptomatic nocturnal hypoglycemic episodes (defined as events which occurred between 11 p.m. and 7 a.m.) were lower in the group randomized to JANUVIA compared to the placebo group (14.9% vs. 20.1%; p=0.0812).  The total number of reported nocturnal events was also lower in the JANUVIA group compared to the placebo group (110 vs. 216).  The analysis also assessed nocturnal hypoglycemic episodes defined as those occurring during sleep with similar results.  

A1C results combined with nocturnal hypoglycemia

The post-hoc analysis also showed that at 24 weeks, a higher proportion of patients in the group randomized to JANUVIA achieved an A1C of less than 7.0 percent without nocturnal hypoglycemia compared to patients in the placebo group (33.9% vs. 16.6%, respectively; p<0.0001).

In a previously published separate study[i], the addition of JANUVIA 100 mg once daily to a stable dose of long-acting, intermediate-acting or premixed insulin was shown to reduce A1C by 0.6 percent compared with placebo.  A higher incidence of hypoglycemia was reported with sitagliptin (16%) compared with placebo (8%) in that study.  In contrast, the analyses being presented at ADA were in patients who underwent intensification of insulin therapy after initiation of sitagliptin.

Selected important risk information about JANUVIA (sitagliptin) 25 mg, 50 mg and 100 mg tablets (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.  It is unknown whether patients with a history of pancreatitis are at increased risk of developing pancreatitis while taking JANUVIA.

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, 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 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 healthcare through far-reaching policies, programs and partnerships.  For more information, visit www.merck.com and connect with us on Twitter, Facebook and YouTube.

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 2013 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).

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

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.