Late-breaking observational data show patients with type 2 diabetes taking JANUVIA® (sitagliptin) and metformin initiated insulin therapy at a slower rate compared to patients taking a sulfonylurea an

(Press-News.org) WHITEHOUSE STATION, N.J., June 14, 2014 – Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced results from a late-breaking observational study that assessed the differences in time to initiation of insulin use and the proportion of the population initiating insulin among patients with type 2 diabetes taking the combination of JANUVIA® (sitagliptin) and metformin, and patients taking the combination of a sulfonylurea and metformin. In this study, patients treated with a combination of JANUVIA and metformin initiated insulin therapy at a slower rate during the period of observation than patients treated with a combination of sulfonylurea and metformin.

"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. "This study provides insight about different oral treatment regimens and their possible effect on initiation of insulin under real-world conditions. Real-world research is an important complement to clinical trials as we seek to improve patient health outcomes."

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 from "Assessing time to insulin use among type 2 diabetes patients treated with sitagliptin or sulfonylurea plus metformin dual therapy" (169-LB)

This late-breaking observational study showed that patients with type 2 diabetes treated with a combination of JANUVIA and metformin initiated insulin therapy at a slower rate during the period of observation than patients treated with a combination of sulfonylurea and metformin. The retrospective cohort study used a propensity score matched sample from the GE Centricity Electronic Medical Record database, initially including 7,728 patients with type 2 diabetes who used JANUVIA (n=3,864) or a sulfonylurea (n=3,864) as dual therapy with metformin for at least 90 days after starting JANUVIA or the sulfonylurea in 2006 to 2013.

The objectives of the study were to assess the differences in time to initiation of insulin use and the proportion of the population initiating insulin among patients taking the combination of JANUVIA and metformin, and patients taking the combination of a sulfonylurea and metformin. Differences in known baseline characteristics, including demographics, clinical and laboratory measures, and comorbidities, were balanced using propensity score matching.

The Kaplan-Meier estimator was utilized to assess the cumulative progression to insulin use between the groups using JANUVIA and metformin, and sulfonylurea and metformin. The Cox proportional hazards regression model was utilized to assess the progression to insulin use by year between the two groups.

In the study, the percentages of patients initiating insulin by years one through six were 3.6, 8.4, 12.9, 17.7, 22.4, 26.6 for patients taking JANUVIA; and 4.1, 9.4, 14.6, 21.0, 27.1, 34.1 for patients taking a sulfonylurea. An analysis of the data overall (Kaplan-Meier method) showed that patients taking JANUVIA progressed more slowly to insulin use than patients taking a sulfonylurea (p=0.0034). The Cox proportional hazard regression analysis indicated that by year six, patients in the JANUVIA group were 24 percent less likely to initiate insulin during the period of observation compared to patients taking a sulfonylurea (HR = 0.76; p = 0.0011). Similar results were observed in the sub-group of patients with a baseline A1C of less than 9 percent (HR = 0.77; p = 0.0128]; however there was no statistically significant difference in time to insulin initiation in the sub-group with a baseline A1C of greater than or equal to 9 percent (HR = 0.75; p = 0.1818). Results of this observational study need to be confirmed through a randomized clinical trial, the gold standard of clinical research.

There were a number of limitations for this study. Day-of-supply for prescription and stopping dates of medications were unavailable for a considerable number of patients. Treatment sequences were primarily estimated based on the prescription dates. While the database captured prescription and medication information, it could not be ascertained that patients adequately followed the prescribing physicians' instructions in filling their prescriptions or taking the medications. It is possible that patients never or only partially filled the prescription. Due to the absence of prescription refill data, the prescription data alone could not fully account for treatment adherence and therapy type (i.e., dual therapy versus triple therapy). The Cox proportional hazard regression analysis does not account for changes in concomitant therapies and/or comorbidities that may have occurred after initiation of sitagliptin or sulfonylurea. Although propensity score matching creates balanced treatment groups based on observed baseline characteristics, the possibility of potential imbalances between matched groups with regard to unobserved characteristics cannot be excluded. Due to the methods employed in this analysis, the time period in which an outcome can be observed must be pre-specified and patients without complete data needed to be excluded.

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. I f 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.

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[1] A1C is a measure of a person's average blood glucose over a two- to three-month period.

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.