Indications

This is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both Sitagliptin and Metformin is appropriate.

Therapeutic Class

Combination Oral hypoglycemic preparations

Pharmacology

Sitagliptin: The DPP-4 inhibitors are a class of agents that act as incretin enhancers. By inhibiting the DPP-4 enzyme, Sitagliptin increases the levels of two known active incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. This mechanism is unlike the mechanism seen with sulfonylureas; sulfonylureas cause insulin release even when glucose levels are low, which can lead to sulfonylurea-induced hypoglycemia in patients with type ll diabetes and in normal subjects. Sitagliptin demonstrates high selectivity for DPP-4 and does not inhibit closely-related enzymes DPP-8 or DPP-9 at therapeutic concentrations.

Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin reduces hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis, and stimulates intracellular glycogen synthesis by acting on glycogen synthase. In muscle, it increases insulin sensitivity, improving peripheral glucose uptake and utilization. Metformin also delays intestinal glucose absorption. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and daylong plasma insulin response may actually decrease.

Dosage & Administration

The dosage of Sitagliptin & Metformin should be individualized on the basis of the patient’s current regimen, effectiveness, and tolerability while not exceeding the maximum recommended daily dose of 100 mg sitagliptin and 2000 mg metformin. Initial combination therapy or maintenance of combination therapy should be individualized and left to the discretion of the health care provider.

Sitagliptin & Metformin should generally be given twice daily with meals, with gradual dose escalation, to reduce the gastrointestinal (GI) side effects due to metformin. The starting dose of Sitagliptin & Metformin should be based on the patient’s current regimen. The recommended starting dose in patients NOT currently treated with metformin is 50 mg sitagliptin/500 mg metformin hydrochloride twice daily, with gradual dose escalation recommended to reduce gastrointestinal side effects associated with metformin.

The starting dose in patients already treated with metformin should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) and the dose of metformin already being taken. For patients taking metformin 850 mg twice daily, the recommended starting dose of Sitagliptin & Metformin is 50 mg sitagliptin/1000 mg metformin hydrochloride twice daily.

Co-administration of Sitagliptin & Metformin with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia. No studies have been performed specifically examining the safety and efficacy of Sitagliptin & Metformin in patients

previously treated with other oral antihyperglycemic agents and switched to Sitagliptin & Metformin. Any change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as changes in glycemic control can occur