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 selected markers of beta cell function and significantly reduced blood sugar levels (as measured by HbA1c) at one year and in data recently unblinded at two years.

Sitagliptin is indicated, as an adjunct to diet and exercise, to improve glycaemic control in adult patients with type 2 diabetes. It should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, and has not been studied in combination with insulin. Sitagliptin is contraindicated for patients with history of a serious hypersensitivity reaction to the product, including anaphylaxis and angioedema.

Sitagliptin is a highly selective, once-daily dipeptidyl peptidase-4 (DPP-4) inhibitor that enhances a natural body system, called the incretin system, to help regulate blood sugar. Sitagliptin 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 sitagliptin and metformin on the critical role of beta cell function in type 2 diabetes as well as to assess efficacy out to two years," said John Amatruda, M.D., senior vice president, research, Diabetes & Obesity Franchise. "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 sitagliptin 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 glycaemic control," said Priscilla Hollander, M.D., Ph.D., director of the Ruth Collins Diabetes Center at Baylor University Medical Center in Dallas, Texas.

The European Medicines Agency (EMEA) approved sitagliptin in April 2007. It was the first DPP-4 inhibitor available in Europe.

In controlled clinical studies for sitagliptin both monotherapy and combination therapy with metformin or pioglitazone, the overall incidence of adverse reactions, hypoglycaemia, and discontinuation of therapy due to clinical adverse reactions with sitagliptin were similar to placebo. In these clinical studies, the most common adverse reactions reported with (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 sulphonylurea (glimepiride), with or without metformin, sitagliptin demonstrated an overall incidence of adverse reactions higher than that seen with placebo, in part related to a higher incidence of hypoglycaemia.

Significant impact of co-administration of sitagliptin and metformin on markers of beta cell function and HbA1c levels out to two years

Initial combination therapy with sitagliptin and metformin significantly improved markers of beta cell function and significantly improved blood sugar levels compared with either metformin or sitagliptin alone at both one year and after two years of treatment. The study began with a 24-week, placebo-controlled phase (n=1,091, part A), followed by a 30-week, double-blind, active-controlled period (n=762, part B). The mean baseline HbA1c of the two populations was 8.8 for part A and 8.7 percent for part B. At the conclusion of parts A and B of the main study, 587 patients entered into a study extension for an additional fifty weeks, for a total length of two years, (including those who had initiated glycaemic rescue therapy) and 402 of those patients (mean baseline HbA1c 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 significant improvements in two of the well known endpoints to assess beta cell function for patients on the combination of sitagliptin and metformin: HOMA-β and pro-insulin-to-insulin ratio.

To assess glucose-lowering, the change from baseline HbA1c levels were measured at one year and two years. The mean HbA1c 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 sitagliptin 50 mg/metformin 1000 mg twice daily. Additionally, mean HbA1c reductions from baseline were 1.4 percent (at one year, n=147 and two years, n=96) in patients treated with sitagliptin 50 mg/metformin 500 mg twice daily, 1.3 percent (at one year, n=134 and 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 sitagliptin 100 mg once daily, there was a 0.8 percent reduction in HbA1c levels from baseline at one year (n=106) and a 1.2 percent reduction from baseline at two years (n=50).

Maintenance of combination therapy should be individualized and is left to the discretion of the health care provider.

Tolerability of sitagliptin and metformin in combination evaluated in a pooled analysis of studies up to two years duration

The longer-term tolerability of combining sitagliptin and metformin were evaluated collectively by pooling data from five completed, Phase III studies that evaluated the product 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 sitagliptin/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 hypoglycaemia in patients treated with a sulphonylurea 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 sitagliptin/metformin group and 1,392 in the placebo/active comparator group which included those treated with placebo plus metformin with or without a sulphonylurea.

Dosing of sitagliptin

The recommended dose of sitagliptin 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). Clinical study experience with sitagliptin in patients with moderate or severe renal insufficiency is limited. Therefore, use of sitagliptin is not recommended in this patient population. Sitagliptin has not been studied in patients with severe hepatic insufficiency.

Selected cautionary information for sitagliptin

Tolerability and effectiveness of sitagliptin in pediatric patients have not been established. There are no adequate and well-controlled studies in pregnant women. The product should not be used during pregnancy. It is not known whether sitagliptin is excreted in human milk therefore should not be administered to a nursing woman. There have been post-marketing reports of hypersensitivity reactions in patients treated with sitagliptin. 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 the product, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue the product, assess for other potential causes for the event and institute alternative treatment for diabetes. All adverse events should be reported to the regulatory agency or the manufacturer.

Expanding clinical development programme for sitagliptin family

Merck's clinical development programme 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.

About Merck

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