Phase III studies demonstrated that Sitagliptin ( Januvia ), an investigational oral, once-daily medicine for type 2 diabetes, significantly reduced blood glucose levels when used as monotherapy or as an add-on treatment to two commonly used therapies ( Metformin or Pioglitazone ).
Additionally, treatment with Sitagliptin improved measures of beta cell function.

Sitagliptin, if approved, would potentially be the first in a new class of oral drugs ( dipeptidyl peptidase-4 -DPP-4- inhibitors ).
DPP-4 inhibitors inhibit the DPP-4 enzyme that inactivates the incretin gut hormones GLP-1 and GIP.
Sitagliptin is expected to lower blood glucose levels by increasing the level of active incretin hormones which increase insulin from pancreatic beta-cells and decrease glucagon from pancreatic alpha cells in a glucose-dependent manner ( when blood glucose is elevated and not when blood glucose is low ).

In three monotherapy studies in patients with mildly to moderately elevated A1C levels ( mean baseline A1C levels ranged from 7.5% to 8.1% ), Sitagliptin 100 mg once daily showed significant mean placebo-subtracted reductions in A1C ranging from 0.60% to 1.05%.
In these studies, the mean effect of Sitagliptin on A1C levels was greater with higher baseline A1C levels.
Sitagliptin demonstrated significant mean placebo-subtracted A1C reductions that ranged from 1.20% to 1.50% in patients with higher baseline A1C levels .
In patients in the lowest baseline A1C ( less than 8% ), the mean placebo-subtracted A1C reductions ranged from 0.44% to 0.57%.
The monotherapy studies also showed Sitagliptin substantially reduced both fasting plasma glucose and postprandial, or post-meal, glucose levels.

In two Phase III add-on studies in patients whose blood glucose levels were inadequately controlled on either Metformin or Pioglitazone with mildly to moderately elevated baseline A1C levels ( mean baseline A1C approximately 8% ), Sitagliptin 100 mg once daily showed significant additional mean placebo-subtracted A1C reductions of 0.65% and 0.70% respectively ( both p less than 0.001 vs. placebo ). Approximately twice as many patients achieved goal A1C of less than 7% with the addition of Sitagliptin vs. placebo ( 47 percent vs. 18 percent and 45 percent vs. 23 percent in the Metformin add-on study and Pioglitazone add-on study, respectively ).

In the monotherapy studies, Sitagliptin produced significant improvements in measures of beta cell function: HOMA-Beta and the fasting proinsulin/insulin ratio.

The safety and tolerability of Sitagliptin at once-daily doses of 100 mg and 200 mg ( twice the proposed registration dose ) were assessed by pooling data from two monotherapy and two add-on studies.
The overall incidence of clinical and laboratory adverse experiences was similar between Sitagliptin and placebo.
The incidence of hypoglycemia was similar between Sitagliptin and placebo ( 1.2% in 100 mg, 0.9% in 200 mg and 0.9% in placebo ) and no clinically meaningful changes compared to placebo were observed in body weight with Sitagliptin in these studies.
The most common side effects ( greater than or equal to 3% and greater than placebo ) reported with Sitagliptin were stuffy or runny nose and sore throat; headache; diarrhea; upper respiratory infection; joint pain; and urinary tract infection ( with differences ranging from 0.1% to 1.5% vs. placebo ).

For laboratory assessments, no clinically meaningful differences in the occurrence of pre-defined changes in laboratory values were noted. Although not clinically meaningful, small increases in uric acid, in white cell blood count ( due to a small increase in neutrophil count ), and a small decrease in alkaline phosphatase were observed with Sitagliptin compared with placebo.
In these studies, no significant changes in vital signs or in ECG including in QTc intervals were observed.

Source: 66th Annual Scientific Sessions - American Diabetes Association ( ADA ), 2006


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