One-Year Data Showed Investigational Use of Initial Combination Therapy with JANUVIA™ (sitagliptin) and Metformin Significantly Improved Blood Sugar Control in Patients with Type 2 Diabetes Compared to Metformin Alone
Data Also Showed that Initial Combination Therapy with JANUVIA and Metformin Led to Significant Improvement in Markers of Beta Cell Function in Patients with Type 2 Diabetes
* Up to 67 percent of patients with type 2 diabetes who continued past 24 weeks in this study achieved A1C of less than seven percent with investigational use of sitagliptin and metformin as initial combination therapy, compared to 44 percent on metformin alone at 54 weeks
* In a subgroup analysis of patients grouped by severity of starting baseline A1C, mean response to treatment with JANUVIA (sitagliptin) 50 mg and metformin 1000 mg twice daily was larger for patients with higher baseline A1C
* A separate study in healthy adults showed a four-fold increase in active GLP-1 concentrations following a meal when JANUVIA and metformin were used together compared with placebo
WHITEHOUSE STATION, N.J.- Data presented at the 43rd Annual Meeting of the European Association for the Study of Diabetes (EASD) demonstrated that, when used investigationally as initial therapy in combination with metformin, JANUVIA™ (sitagliptin) provided significant and sustained improvement in blood sugar control compared to metformin alone and was generally well tolerated over a one-year period. Since metformin is administered twice daily, in this study sitagliptin was given as 50 mg twice daily to allow for co-administration of the two treatments. The approved dose for JANUVIA is 100 mg once daily.
JANUVIA is a selective, once-daily dipeptidyl peptidase-4 (DPP-4) inhibitor that enhances a natural body system, called the incretin system, which helps to regulate glucose by affecting the beta cells and alpha cells in the pancreas. JANUVIA is the first and only DPP-4 inhibitor to be approved and marketed in the United States for patients with type 2 diabetes. JANUVIA is indicated, as an adjunct to diet and exercise, to improve glycemic control in patients with type 2 diabetes mellitus. JANUVIA is also indicated to improve glycemic control, in combination with metformin or a thiazolidinedione (TZD), in patients with type 2 diabetes when the single agent alone plus diet and exercise do not provide adequate glycemic control. JANUVIA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. There are no contraindications for JANUVIA.
The study demonstrated a mean A1C reduction from baseline of 1.8 percent in patients treated with the initial combination of sitagliptin 50 mg/metformin 1000 mg twice daily for up to 54 weeks (n=153). Additionally, mean A1C reductions from baseline were 1.4 percent in patients treated with sitagliptin 50 mg/metformin 500 mg twice daily (n=147), 1.3 percent in patients treated with metformin 1000 mg twice daily (n=134), 1.0 percent in patients treated with metformin 500 mg twice daily (n=117), and 0.8 percent in patients treated with sitagliptin 100 mg once daily (n=106).
After completing an initial 24-week placebo-controlled phase (n=1091), 748 patients with a mean baseline A1C of 8.7 percent continued for an additional 30 weeks on their previously assigned active therapies: sitagliptin 50 mg/metformin 1000 mg twice daily (n=157); sitagliptin 50 mg/metformin 500 mg twice daily (n=148); metformin 1000 mg twice daily (n=137); metformin 500 mg twice daily (n=122); and sitagliptin 100 mg once-daily (n=106).
The aim of this 54-week study was to assess the longer term efficacy and safety of initial combination therapy with sitagliptin and metformin in patients with type 2 diabetes with inadequate glycemic control (A1C of 7.5 percent to 11 percent) on diet and exercise. The study found that 67 percent of patients who continued past 24 weeks in this study achieved an A1C goal of less than seven percent on sitagliptin 50 mg/metformin 1000 mg twice daily compared to 44 percent on metformin 1000 mg twice daily alone. Further, 48 percent of patients treated with sitagliptin 50 mg/metformin 500 mg twice daily, 25 percent of patients treated with metformin 500 mg twice daily, and 23 percent of patients treated with sitagliptin 100 mg once daily reached the target A1C goal.
A patient’s starting level of A1C is an important predictive factor of the magnitude of A1C reduction in response to anti-hyperglycemic therapy. In a subgroup analysis of patients grouped by severity of A1C at baseline, treatment with sitagliptin 50 mg/metformin 1000 mg twice daily demonstrated larger mean A1C reductions from baseline with higher baseline A1C. A mean reduction of 3.1 percent was seen in patients with baseline A1C of 10 percent or more (n=17), while reductions of 2.2 percent, 1.7 percent, and 1.0 percent were seen with baseline A1C values of 9 to 10 percent, 8 to 9 percent, and less than 8 percent, respectively.
“Initial therapy with one agent is often unsuccessful at getting patients to blood sugar goals. Many patients may require initial combination therapy, and this study provides important and useful information about the use of sitagliptin and metformin, in addition to diet and exercise, in order to achieve and maintain blood sugar control,” said John Amatruda, M.D., vice president, clinical research, Merck & Co., Inc. “This study examines the clinical effect of initial combination therapy with JANUVIA and metformin over one year.”
Investigational use of JANUVIA (sitagliptin) and metformin as initial combination therapy led to improvement in markers of beta cell function in patients with type 2 diabetes
The effects of sitagliptin and metformin on beta cell function were examined in patients with type 2 diabetes who participated in the 24-week, placebo-controlled phase of the above investigational study, in which 1,091 patients were randomized in a balanced manner to receive one of six treatments. Pancreatic islet beta cell function determines the ability of the body to produce insulin and suppress glucagon, hormones which play a central role in the regulation of blood sugar levels. Of the 1,091 patients randomized, a subset of 500 patients underwent frequently-sampled meal tolerance tests. Beta cell function was measured using a computer model-based evaluation. Parameters of beta cell function from this model allowed for the estimation of the insulin secretion rate (ISR) and the characterization of the ISR into static (beta cell responsiveness to above-basal glucose following a meal) and dynamic (beta cell responsiveness to the rate of increase in above-basal glucose following a meal) components.
After 24 weeks, the changes in static and dynamic beta cell responsiveness and insulin sensitivity were increased across all active treatments relative to placebo, and appeared to be increased in an approximately additive fashion with co-administration with sitagliptin and high dose metformin in comparison to each as monotherapy. The results of the beta cell modeling analysis showed that initial combination therapy with sitagliptin and metformin resulted in a 49 percent increase in measured change in static beta cell responsiveness compared with metformin alone (20.1, sitagliptin 50 mg/metformin 1000 mg twice daily vs. 13.5, metformin 1000 mg twice daily). Further, the initial combination therapy with sitagliptin and metformin resulted in a 114 percent increase in measured change in dynamic beta cell responsiveness compared with metformin alone (151.0, sitagliptin 50 mg/metformin 1000 mg twice daily vs. 70.7, metformin 1000 mg twice daily).
JANUVIA (sitagliptin) and metformin together increase active GLP-1 levels in healthy adults by more than four-fold compared to placebo
Data from a separate pharmacologic study suggest that the different mechanisms of action of sitagliptin and metformin, when used in combination in healthy adults, may have a complementary effect on levels of glucagon-like peptide-1 (GLP-1), another hormone that is an important regulator of blood sugar levels. This aspect of the mechanism of action of metformin used in combination with sitagliptin was previously unknown. GLP-1 acts, in part, by enhancing insulin production and secretion by the pancreatic beta cell.
A randomized, placebo-controlled, double-blind, crossover study was conducted in 16 healthy adults to assess the potential complementary effects of sitagliptin and metformin on GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). In each 2-day treatment period, subjects received one of four treatments: sitagliptin, metformin, the co-administration of sitagliptin and metformin, or placebo.
In this study, sitagliptin and metformin, when taken separately, increased overall, post-meal, active GLP-1 levels by 1.95- and 1.76-fold, respectively , compared with placebo. When administered together, sitagliptin and metformin increased active GLP-1 levels by 4.12-fold compared with placebo. In contrast to active GLP-1 levels that were increased by both drugs, the levels of total GLP-1 (which includes both active and inactive GLP-1) were increased by metformin only and not by sitagliptin. Active GIP concentrations increased with sitagliptin, but were unchanged with metformin. Measurement of the enzymatic activity of DPP-4 in this study demonstrated that sitagliptin, but not metformin, inhibited DPP-4 activity. These observations are consistent with the effect of sitagliptin to raise active GLP-1 levels by reducing its clearance, and suggest that metformin acts in a different manner to increase active GLP-1 levels.
GLP-1 plays an important role in regulating the body’s blood sugar levels. When food is consumed, GLP-1 is released by the gastrointestinal tract to stimulate the pancreatic beta cells to secrete insulin, a hormone that helps the body to use glucose for energy. GLP-1 also suppresses the release of glucagon from the pancreatic alpha cells, which, in turn, signals the liver to reduce its production of sugar.
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 . 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 , the dose of JANUVIA is 50 mg once daily. For those with severe renal insufficiency 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. Caution should be exercised when JANUVIA is administered to a nursing woman. In clinical trials, JANUVIA demonstrated an overall incidence of side effects comparable to placebo. The most common side effects reported with JANUVIA (5 percent and higher than placebo) were stuffy or runny nose and sore throat, upper respiratory infection, and headache.
Expanding clinical development program for sitagliptin family
Merck’s clinical development program for sitagliptin is robust and continues to expand with 49 studies completed or underway and five more studies set to begin this year. There have been more than 9,400 patients in the Company’s clinical studies, with about 6,000 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 400 patients have been treated for at least two years.
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