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Five New Studies at Major Medical Meeting Further Demonstrate Clinical Experience for JANUVIA™ (sitagliptin)


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Study Data Show Longer Term Efficacy and Safety and Tolerability Profile of JANUVIA Up to Two Years

* JANUVIA and metformin as initial combination therapy demonstrated significant glucose-lowering efficacy over two years
* Pooled analysis of 6,139 patients showed JANUVIA was generally well tolerated in clinical trials, up to two years in duration
* Investigational study of the addition of JANUVIA to the combination of metformin and rosiglitazone significantly improved blood sugar control
* 52-week study of Japanese patients with an investigational dosing regimen demonstrated treatment with JANUVIA added to ongoing pioglitazone therapy also provided significant glucose lowering
* Additional analysis demonstrated that in patients with type 2 diabetes, JANUVIA provided glycemic control regardless of baseline characteristics of age, gender, BMI, HOMA-β and P/I ratio

WHITEHOUSE STATION, N.J.- New data analyses presented at the 44th Annual Meeting of the European Association for the Study of Diabetes (EASD) showed initial combination therapy with the dipeptidyl peptidase-4 (DPP-4) inhibitor, JANUVIA™ (sitagliptin), and metformin provided improvements in blood sugar levels (as measured by A1CI) over two years of treatment and was generally well tolerated. Also presented at the meeting was a separate, new pooled analysis of 6,139 patients that showed that JANUVIA was generally well tolerated in clinical trials up to two years in duration.

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 angiedema.

More than six million total prescriptions for JANUVIA have been dispensed worldwide since launch. JANUVIA has received approval in 80 countries and is available in every region around the world. The U.S. Food and Drug Administration approved JANUVIA in October 2006 and the European Medicines Agency (EMEA) approved JANUVIA in Europe in April 2007.

Initial combination of JANUVIA and metformin provided glycemic improvements out to two years
In a study of initial combination therapy with JANUVIA and metformin, glucose-lowering was assessed by measuring the mean change from baseline A1C levels at one year and two years. The mean A1C reductions from baseline in this study were 1.8 percent at one year (n=153) in patients treated with JANUVIA 50 mg/metformin 1000 mg twice-daily. In the extension study at two years, the mean A1C reduction was 1.7 percent (n=105; baseline A1C of 8.6 percent) for this group. Additionally, mean A1C reductions from baseline were 1.4 percent (at one year, n=147 and two years, n=96) in patients treated with JANUVIA 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 JANUVIA, 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.

Three additional studies further demonstrated the safety and efficacy profile of JANUVIA as an add-on to other oral diabetes treatments and efficacy when analyzed based on different baseline characteristics
In one 52-week investigational study, addition of JANUVIA to the combination of metformin and rosiglitazone significantly improved glycemic control in patients with type 2 diabetes. In a separate 52-week study of Japanese patients using an investigational dosing regimen, treatment with JANUVIA added to ongoing pioglitazone therapy provided effective glycemic control and was generally well tolerated with a comparable occurrence of hypoglycemia in the placebo and JANUVIA (50 mg, once daily) groups, and without clinically meaningful change in body weight. A mean change in A1C from baseline of 0.7 percent was observed; 62 percent of patients achieved A1C less than seven percent in the JANUVIA population at the end of the 52-week period.

“These data are interesting for physicians treating type 2 diabetes as they provide data regarding the clinical efficacy of JANUVIA both as initial combination therapy with metformin and also as add on therapy to other commonly used oral diabetes medications,” said Professor Bernard Charbonnel, professor of Endocrinology and Metabolic Diseases, University of Nantes and Head of the Internal Medicine, Endocrinology and Diabetes Department, Hôtel Dieu (University Hospital of Nantes). “This is important for patients and physicians because type 2 diabetes is characterized by a progressive deterioration in beta cell function over time, resulting in the disease worsening. This progression of disease leads to decreased effectiveness of all known treatments over time, with patients often requiring multiple therapies in order to achieve their glycemic goals.”

An additional analysis presented at the meeting demonstrated that in patients with type 2 diabetes, JANUVIA provided glycemic control regardless of baseline characteristics of age, gender, BMI, HOMA-β, and P/I ratio.

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 five 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.

As is typical with other anti-hyperglycemic agents used in combination with a sulfonylurea, when JANUVIA is used in combination with a sulfonylurea, a class of medications known to cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo. Therefore, a lower dose of sulfonylurea may be required to reduce the risk of hypoglycemia.

Initial combination of JANUVIA and metformin: study design and results
Initial combination therapy with JANUVIA and metformin significantly improved blood sugar levels compared with either metformin or JANUVIA alone over two years of treatment. After completing the initial, double-blind 54-week base study, 412 patients who received active treatment throughout the study were included in the all-patients-treated analysis of efficacy at two years.

The mean A1C reduction from baseline in the 1-year base study was 1.8 percent (n=153) in patients treated with JANUVIA 50 mg/metformin 1000 mg twice daily. In the extension study at two years, the mean A1C reduction from baseline was 1.7 percent (n=105) in this group of patients. Additionally, mean A1C reductions from baseline were 1.4 percent (at one year, n=147 and two years, n=96) in patients treated with JANUVIA 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 JANUVIA, 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).

Pooled analysis of safety and tolerability of JANUVIA: study design and results
In a pooled analysis of clinical studies up to two years in duration, treatment with JANUVIA was found to be generally well tolerated, with generally similar incidence of adverse experiences in patients treated with JANUVIA relative to those not exposed to JANUVIA.

The safety and tolerability of JANUVIA were evaluated by pooling data from 12 large, double-blind, randomized, completed Phase IIb and III studies of 18-weeks to two years duration that included 6,139 patients receiving either JANUVIA once-daily (n=3,415) or placebo or an active comparator (n=2,724; non-exposed group). The studies assessed JANUVIA as monotherapy, initial combination therapy with metformin or add-on therapy to oral antihyperglycemic agents (metformin, pioglitazone, a sulfonylurea, a sulfonylurea plus metformin or metformin plus rosiglitazone). Patients not receiving JANUVIA received a range of treatments, including placebo, pioglitazone, metformin, a sulfonylurea, a sulfonylurea plus metformin, or metformin plus rosiglitazone. This comparison group, patients not receiving JANUVIA, is referred to as the “non-exposed” group.

For clinical adverse experiences (AEs), the incidence of AEs overall, serious AEs and discontinuations due to AEs were similar between the JANUVIA and non-exposed groups. The incidence of drug-related AEs and discontinuations due to drug-related AEs were higher in the non-exposed group primarily due to events of hypoglycemia in sulfonylurea-treated patients.

Clinical AEs that occurred at a higher incidence in the sitagliptin group and for which the 95 percent confidence intervals around the between-group difference excluded zero were as follows: atrial fibrillation, asthenia, chest discomfort, tooth abscess, osteoarthritis, acne and contact dermatitis. Eleven AEs occurred at a higher incidence in the non-exposed group for which the 95 percent confidence intervals around the between-group difference excluded zero and were as follows: bradycardia, goiter, change in bowel habit, blood glucose decreased, blood glucose increased, weight increased, hypoglycemia, sinus headache, prostatitis, balanitis and hyperkeratosis.

Investigational use of combination therapy with JANUVIA, metformin, and rosiglitazone: study design and results
In this study, 262 patients (mean baseline A1C 8.8 percent) taking metformin (greater than or equal to 1500 mg/day) and rosiglitazone (greater than or equal to 4 mg/day) were randomized in a 2:1 ratio to the addition of JANUVIA (n=170) or placebo (n=92). After 18 weeks, the addition of JANUVIA significantly (p0.001) reduced mean A1C by 0.7 percent relative to placebo (mean change from baseline -1.0 percent with JANUVIA vs. -0.3 percent with placebo). From the mean baseline A1C of 8.8 percent, the proportion of patients with an A1C less than seven at week 18 percent was significantly (p=0.005) greater with the addition of JANUVIA (22 percent) compared with placebo (9 percent). In addition, measures related to ?-cell function were significantly (p?0.05) improved with JANUVIA compared with placebo. After 18 weeks of treatment, nasopharyngitis and upper respiratory tract infection were reported more frequently in patients treated with JANUVIA (5 percent and 6 percent, respectively) than in patients treated with placebo (4 percent and 5 percent, respectively).

In the continuation of this study out to 54-weeks, the addition of JANUVIA to the combination of metformin and rosiglitazone was generally well tolerated and continued to show significant (p0.001) mean reductions in A1C of 0.8 percent relative to placebo. Clinical adverse events occurring at an incidence rate greater than or equal to three percent and higher in the JANUVIA group included in the 54 week study were: upper respiratory tract infection, nasopharyngitis, peripheral edema, headache, urinary tract infection, back pain, dizziness and cough.

Treatment with an investigational dosing regimen of JANUVIA (50 mg once daily) added to ongoing pioglitazone therapy in Japanese patients with type 2 diabetes over 52 weeks: study design and results
A 12-week double-blind period where patients (n=134) on a stable dose of pioglitazone were randomized to the addition of JANUVIA 50 mg (n=66) or placebo (n=68) was followed by a 40-week open-label extension period where patients on placebo were reallocated to JANUVIA 50 mg and JANUVIA could be titrated from 50 mg to 100 mg. In the double-blind period, JANUVIA significantly reduced mean A1C from baseline relative to placebo at week 12 by 0.8 percent. In the open-label extension period of 66 patients allocated to JANUVIA treatment, 50 patients completed 52-weeks of treatment. In this patient population, efficacy at week 52 was observed with a sustained change in A1C from baseline of 0.7 percent and with 62 percent of patients at an A1C goal of less than seven percent. Treatment with JANUVIA was generally well tolerated compared to placebo with a low occurrence of hypoglycemia (3.0 percent vs. 2.9 percent) and edema (1.5 percent vs. 0.0 percent) and without clinically meaningful change in body weight.

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, angiedema 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.

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JANUVIA or any other anti-diabetic drug.



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