Significant Glucose-Lowering Efficacy Of Sitagliptin, Investigational Drug For Type 2 Diabetes, When Taken With Metformin

Main Category: Diabetes
Also Included In: Clinical Trials / Drug Trials
Article Date: 14 Sep 2006 - 1:00 PST


New data presented for the first time today at the 42nd annual meeting of the European Association for the Study of Diabetes (EASD) in Copenhagen demonstrated in patients off therapy at randomization a significant mean placebo-subtracted reduction in HbA1c of 2.1% (primary analysis of all patients treated, p<0.001) with sitagliptin 50 mg twice daily together with metformin 1000 mg twice daily, a commonly used diabetes therapy. This study included another arm with sitagliptin and a lower dose of metformin and also monotherapy and placebo arms. Full results will be presented later this year. Sitagliptin is Merck Sharpe & Dohme's investigational oral medicine for type 2 diabetes.

In this study, simultaneous treatment of sitagliptin and metformin was generally well tolerated and showed no meaningful differences compared to metformin alone. Side effects of simultaneous treatment with sitagliptin 50 mg twice daily and metformin 1000 mg twice daily compared to metformin 1000 mg twice daily alone included diarrhoea (9% vs. 10%, respectively), nausea (6% vs. 8%, respectively), abdominal pain/discomfort (3% vs. 5%, respectively) and vomiting (3% vs. 1%, respectively). In the clinical program overall, patients receiving therapy with sitagliptin reported an overall incidence of side effects comparable to placebo and the product was generally well tolerated. The most common side effects reported with sitagliptin therapy (?3% and higher than placebo) were stuffy or runny nose and sore throat, headache, diarrhoea, upper respiratory infection, joint pain and urinary tract infection (with differences ranging from 0.1% to 1.5% vs. placebo).

Efficacy and Safety Results from New Co-Administration Study with Metformin

In clinical studies, an important predictive factor of the magnitude of HbA1c reduction in response to anti-hyperglycaemic therapy is a patient's HbA1c level at baseline; HbA1c is a measure of a person's average blood glucose.

In other Phase III non co-administration studies, sitagliptin as a monotherapy was administered once daily or as add-on treatment to other anti-hyperglycaemic therapies. In one of the arms of this new study, sitagliptin was administered 50 mg twice daily simultaneously with metformin 1000 mg twice daily. In patients with moderately elevated baseline HbA1c levels (mean: 8.8%), simultaneous treatment of sitagliptin and metformin showed significant mean placebo-subtracted reductions in HbA1c of 2.1% (primary analysis, p<0.001). In addition, simultaneous treatment with sitagliptin and metformin led to two-thirds of patients achieving goal HbA1c levels of <7% (66%) compared to patients on metformin alone (38%).

Significant HbA1c placebo-subtracted reductions (1.6%, p<0.001) and goal attainment (43% vs. 23%, p<0.001) also were seen with sitagliptin 50 mg twice daily when simultaneously administered with a lower dose of metformin (500 mg twice daily).

This 24-week, randomized, double-blind, placebo-controlled study evaluated simultaneous treatment of sitagliptin with metformin and the use of both agents as monotherapy in 1,056 untreated patients with type 2 diabetes. Analyses were performed in patients who received sitagliptin 100 mg once daily (n=175), metformin 500 mg twice daily (n=178), metformin 1000 mg twice daily (n=177), sitagliptin 50 mg twice daily and metformin 500 mg twice daily (n=183), sitagliptin 50 mg twice daily and metformin 1000 mg twice daily (n=178), and placebo (n=165).

Though not included in the analysis that addressed the study hypotheses due to the severity of their hyperglycaemia, an additional 117 patients with severely elevated baseline HbA1c (mean: 11.2%) were enrolled as an open label cohort receiving sitagliptin 50 mg twice daily and metformin 1000 mg twice daily. In this open label cohort, simultaneous treatment of sitagliptin with metformin showed a significant mean reduction of HbA1c from baseline of 2.9%.

"The significant glucose-lowering efficacy seen in this study suggests that the complementary therapeutic benefit of sitagliptin and metformin result in an additive effect when both agents are given together," said Barry Goldstein, M.D., study investigator and director, Division of Endocrinology, Diabetes and Metabolic Diseases, Thomas Jefferson University Hospital in Philadelphia, Pennsylvania. "These results demonstrated that giving sitagliptin and metformin together was well tolerated with significantly greater efficacy on HbA1c lowering than metformin alone, metformin is a mainstay of current diabetes treatment."

Sitagliptin, part of a new class of oral treatments known as dipeptidyl peptidase-4 (DPP-4) inhibitors that enhance the body's own ability to lower blood sugar (glucose) when it is elevated, became the first approved DPP-4 inhibitor in the world when it received regulatory approval in Mexico in August. In controlled clinical development studies sitagliptin was generally not associated with weight gain from baseline, and the overall incidence of hypoglycaemia (when blood sugar becomes to low) was similar to placebo.

MSD's Commitment to Diabetes

MSD's clinical development program for sitagliptin is robust and continues to expand with 43 studies completed or under way, and four more studies set to begin this year. There are about 6,700 patients in the Company's clinical studies with about 4,700 of these patients being treated with sitagliptin. Additionally, about 1,100 patients have been treated with sitagliptin for more than a year.

MSD is committed to developing innovative therapies that offer advances in the treatment of serious diseases - including diabetes. As part of MSD's commitment to diabetes research and education, the Company continues to support EASD through unrestricted educational grants and other funding.

About Sitagliptin

Sitagliptin is part of a new class of oral treatments known as dipeptidyl peptidase-4 (DPP-4) inhibitors that enhance the body's own ability to lower blood sugar (glucose) when it is elevated, became the first approved DPP-4 inhibitor in the world when it received regulatory approval in Mexico in August. In controlled clinical development studies sitagliptin was generally not associated with weight gain from baseline, and the overall incidence of hypoglycaemia (when blood sugar becomes to low) was similar to placebo.

Sitagliptin is a potent and highly selective DPP-4 inhibitor. DPP-4 inhibitors work by enhancing a natural body process that lowers blood sugar, the incretin system. When blood sugar is elevated, incretins work in two ways to help the body regulate high blood sugar levels: they trigger the pancreas to increase the release of insulin and signal the liver to stop producing glucose. DPP-4 inhibitors enhance the body's own ability to better control blood sugar levels by increasing the active levels of these incretin hormones in the body, helping to decrease blood sugar levels in patients with type 2 diabetes.

Sitagliptin is also being investigated as part of MSD's single tablet combination with metformin (MK-0431A). The mechanism of action of DPP-4 inhibitors is distinct from that of oral metformin and all other drugs in the currently available classes of glucose-lowering agents. MK-0431A has been accepted for standard review by the United States Food and Drug Administration (FDA). FDA action is expected on the New Drug Application by the end of March 2007. The Company is also moving forward as planned with regulatory filings in countries outside the United States.

About Type 2 Diabetes

Type 2 diabetes is a condition in which the body has elevated blood sugar or glucose. With type 2 diabetes, the body may not make enough insulin (which helps the body use glucose), the insulin that the body produces may not work as well as it should, or the body may release too much glucose from stored sources. Patients with diabetes can develop heart disease, kidney disease, blindness, vascular or neurological problems that can lead to amputation, and they can suffer increased mortality.

Diabetes is one of the most significant diseases affecting the modern age. Diabetes is the fifth leading cause of death globally. Currently, more than 230 million people, almost 6% of the world's population, now live with diabetes. The number is expected to grow to 350 million in less than 20 years if action is not taken. In 2000, the number of excess deaths attributable to diabetes was similar in magnitude to numbers reported for HIV/AIDS. Every 10 seconds a person dies from diabetes-related causes and death rates are expected to rise by 25% over the next decade. The devastating complications of diabetes, such as blindness, kidney failure and heart disease, are a huge burden to healthcare services, accounting for an estimated 5-10 percent of a nation's health budget.

About Merck

Merck & Co., Inc., which operates in many countries as MSD (Merck Sharp & Dohme) is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, MSD 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 MSD medicines but help deliver them to the people who need them. MSD also publishes unbiased health information as a not-for-profit service.

http://www.merck.com
MSD is proud to be a platinum sponsor of the Unite for Diabetes campaign. The Unite for Diabetes Campaign aims to highlight the alarming rise of diabetes worldwide and to encourage government support for a United Nations resolution on diabetes. The International Diabetes Federation (IDF) is leading the local diabetes community in a concerted effort to secure the resolution on or around World Diabetes Day (November 14th) 2007.

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. MSD 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 MSD's business, particularly those mentioned in the cautionary statements in Item 1 of MSD's Form 10-K for the year ended Dec. 31, 2005, and in its periodic reports on Form 10-Q and Form 8-K, which the company incorporates by reference.

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