SAN FRANCISCO, June 7, 2008 -
New data presented at the American Diabetes Association (ADA) 68th Annual Scientific Sessions showed initial combination therapy with JANUVIA™ (sitagliptin), a diabetes medicine from Merck & Co., Inc., and metformin substantially improved markers of beta cell function and significantly reduced blood sugar levels (as measured by A1Ci) at one year and two years.
JANUVIA is indicated, as an adjunct to diet and exercise, to improve glycemic control in adult patients with type 2 diabetes. JANUVIA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. JANUVIA has not been studied in combination with insulin. JANUVIA is contraindicated for patients with history of a serious hypersensitivity reaction to sitagliptin, including anaphylaxis and angioedema.
JANUVIA is a selective, once-daily dipeptidyl peptidase-4 (DPP-4) inhibitor that enhances a natural body system, called the incretin system, to help regulate blood sugar. JANUVIA and metformin act in different ways to increase blood levels of active GLP-1 (glucagon-like peptide-1), a hormone that, when blood sugar is higher than normal, enhances the production and secretion of insulin from beta cells in the pancreas. Insulin lowers blood sugar.
"We wanted to evaluate the combined and complementary effects of JANUVIA and metformin on the critical role of beta cell function in type 2 diabetes as well as to assess efficacy out two years," said John Amatruda, M.D., senior vice president, clinical research, Diabetes & Obesity, Merck & Co., Inc. "The improvements in markers of beta cell function we saw in this study may contribute to the significant lowering of blood sugar levels that was observed during two years of therapy with the initial combination of JANUVIA and metformin."
"These two-year data on initial therapy with sitagliptin and metformin are interesting, particularly to the many physicians who over time need to treat their patients with combination therapy to help achieve and maintain glycemic control," said Priscilla Hollander, M.D., Ph.D., director, Ruth Collins Diabetes Center, Baylor University Medical Center, Dallas.
The U.S. Food and Drug Administration approved JANUVIA in October 2006. JANUVIA is the first and only DPP-4 inhibitor available in the United States.
In controlled clinical studies for JANUVIA as both monotherapy and combination therapy with metformin or pioglitazone, the overall incidence of adverse reactions, hypoglycemia, and discontinuation of therapy due to clinical adverse reactions with JANUVIA were similar to placebo. In these clinical studies, the most common adverse reactions reported with JANUVIA (greater than or equal to 5 percent and higher than placebo) were stuffy or runny nose and sore throat, upper respiratory infection and headache. In clinical trials in combination with a sulfonylurea (glimepiride), with or without metformin, JANUVIA demonstrated an overall incidence of adverse reactions higher than that seen with placebo, in part related to a higher incidence of hypoglycemia.
Significant impact of co-administration of JANUVIA and metformin on markers of beta cell function and A1C levels out to two years
Initial combination therapy with JANUVIA and metformin significantly improved markers of beta cell function and significantly improved blood sugar levels compared with either metformin or JANUVIA alone at both one year and after two years of treatment. The study began with a 24-week, placebo-controlled phase (n=1,091), followed by a 30-week, double-blind, active-controlled period (n=762). The mean baseline A1C of the two populations was 8.8 and 8.7 percent, respectively. Five-hundred-eighty-seven patients entered into a study extension out to two years (including those who had initiated glycemic rescue therapy) and 402 of those patients (mean baseline A1C of 8.6 percent) were included in the all-patients-treated analysis of efficacy at two years.
To assess beta cell function, a self-selected subset of patients underwent a frequently-sampled meal tolerance test at baseline and at week 54 (n=203) and/or week 104 (n=125). Patients ingested a standard meal (one nutrition bar and one nutrition drink within 15 minutes), followed by blood collection at different time points relative to the start of meal. At both one year and two years, there were substantial improvements on two well known endpoints to assess beta cell function for patients on the combination of JANUVIA and metformin: HOMA-β and pro-insulin-to-insulin ratio.
To assess glucose-lowering, the change from baseline A1C levels were measured at one year and two years. The mean A1C reductions from baseline in this study were 1.8 percent (at one year, n=153) and 1.7 percent (at two years, n=105) in patients treated with JANUVIA 50 mg/metformin 1000 mg twice daily. Additionally, mean A1C reductions from baseline were 1.4 percent (at one year, n=147; at two years, n=96) in patients treated with JANUVIA 50 mg/metformin 500 mg twice daily, 1.3 percent (at one year, n=134; at two years, n=87) in patients treated with metformin 1000 mg twice daily, 1.0 percent (at one year, n=117) and 1.1 percent (at two years, n=64) in patients treated with metformin 500 mg twice daily. For patients treated with JANUVIA 100 mg once daily, there was a 0.8 percent reduction in A1C levels from baseline at one year (n=106) and a 1.2 percent reduction from baseline at two years (n=50).
Initial combination therapy or maintenance of combination therapy should be individualized and are left to the discretion of the health care provider.
Safety of JANUVIA and metformin in combination evaluated in a pooled analysis of studies up to two years duration
The longer-term safety and tolerability of combining JANUVIA and metformin were evaluated by pooling data from five completed, Phase III studies that evaluated sitaglipin as add-on therapy to metformin or as initial co-administration therapy with metformin for durations of 30 weeks up to two years. For clinical adverse experiences (AEs), there were no notable differences in the overall incidence of AEs (73 percent vs. 73 percent), serious AEs (8.5 percent vs. 8.0 percent) and discontinuation due to AEs (3.4 percent vs. 4.0 percent) between the JANUVIA/metformin and comparator groups, respectively. The incidence of drug-related AEs was lower with sitagliptin/metformin compared with the comparator group (15.5 percent vs. 23.1 percent). This difference was mainly due to the increased incidence of hypoglycemia in patients treated with a sulfonylurea in the comparator group.
Of the approximately 1,000 specific clinical AEs reported in this analysis, a total of 16 specific clinical AEs occurred more frequently in one or the other group, with six AEs occurring more frequently in the sitagliptin/metformin group and 10 AEs in the comparator group.
This pooled safety analysis included 3,028 patients of which 1,636 were in the JANUVIA/metformin group and 1,392 in the placebo/active comparator group which included those treated with placebo plus metformin with or without a sulfonylurea.
Dosing of JANUVIA
The recommended dose of JANUVIA is 100 mg once daily, with or without food, for all approved indications. No dosage adjustment is needed for patients with mild to moderate hepatic insufficiency or in patients with mild renal insufficiency (CrCl >50 mL/min). To achieve plasma concentrations of JANUVIA similar to those in patients with normal renal function, lower dosages are recommended in patients with moderate and severe renal insufficiency as well as in end-stage renal disease (ESRD) patients requiring hemodialysis. For patients with moderate renal insufficiency (CrCl >30 to <50 mL/min), the dose of JANUVIA is 50 mg once daily. For those with severe renal insufficiency (CrCl <30 mL/min) or with ESRD requiring dialysis, the dose of JANUVIA is 25 mg once daily. Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter.
Selected cautionary information for JANUVIA
Because JANUVIA is renally eliminated, and to achieve plasma concentrations of JANUVIA similar to those in patients with normal renal function, a dosage adjustment is recommended in patients with moderate renal insufficiency and in patients with severe renal insufficiency or with ESRD requiring hemodialysis or peritoneal dialysis. Safety and effectiveness of JANUVIA in pediatric patients have not been established. There are no adequate and well-controlled studies in pregnant women. JANUVIA should be used during pregnancy only if clearly needed. It is not known whether sitagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when JANUVIA is administered to a nursing woman. There have been post-marketing reports of hypersensitivity reactions in patients treated with JANUVIA. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Onset of these reactions occurred within the first three 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.
Expanding clinical development program for sitagliptin family
Merck's clinical development program for sitagliptin is robust and continues to expand with 55 studies completed or underway. Approximately 12,000 patients have participated in the Company's clinical studies of sitagliptin, with about 7,400 of these patients being treated with sitagliptin. Additionally, about 2,300 patients have been treated with sitagliptin for more than a year and, of these, approximately 500 patients have been treated for at least two years.
Merck's commitment to patient education
Journey for Control™ is Merck's comprehensive educational program designed to enlighten and empower patients by giving them the information and tools they need to make the lifestyle changes that lead to improved self-management. The Merck Journey for Control Program is proud to sponsor the U.S. Diabetes Conversation Map® Program, which was developed by Healthy Interactions in collaboration with the American Diabetes Association. The U.S. Diabetes Conversation Map Program is an innovative teaching method which provides participants with a process by which they can plan changes in their decision making and behaviors. For more information, visit www.JourneyforControl.com.
About Merck
Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck currently discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs. The Company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them. Merck also publishes unbiased health information as a not-for-profit service. For more information, visit www.merck.com.
Forward Looking Statement
This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the risk factors and cautionary statements in Item 1A of Merck's Form 10-K for the year ended Dec. 31, 2007, and in any risk factors or cautionary statements contained in the Company's periodic reports on Form 10-Q or current reports on Form 8-K, which the Company incorporates by reference.
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