New combination treatments in the management of diabetes: focus on sitagliptin – metformin

Jennifer Green, Mark Feinglos

Duke University Medical Center, Department of Medicine, Division of Endocrinology, Durham, North Carolina, USA

Abstract: Type 2 diabetes mellitus is an increasingly prevalent condition worldwide. The complications of this disease are known to significantly increase the morbidity and mortality of those affected, resulting in substantial direct and indirect costs. Although good glycemic control has been shown to reduce the incidence and progression of diabetes-related microvascular complications, blood glucose levels are not adequately controlled in most individuals with diabetes. The reasons for this are many, and include issues such as poor adherence to complex medication regimes; costs of prescribed therapies; and the failure of traditionally prescribed medications to preserve beta cell function over time. However, our armamentarium of glucose-lowering drugs has expanded recently with the development of medications that act via the incretin pathway. Sitagliptin, the first commercially available dipeptidyl peptidase-4 inhibitor, inhibits the metabolism and inactivation of the incretin hormones GLP-1 and GIP. The subsequent elevation in levels of these hormones and associated prolongation of their actions has been shown to increase insulin secretion and suppress glucagon secretion in a glucoseappropriate fashion. Sitagliptin therapy in individuals with type 2 diabetes has been found to lower significantly hemoglobin A1c (Hb1c) levels with a minimum of adverse side effects such as weight gain or hypoglycemia. Use of sitagliptin in conjunction with the insulin-sensitizing medication metformin has been shown to decrease HbA1c levels more significantly than does either drug alone. This combination of medications is generally well tolerated, with no adverse effects on weight and a very low likelihood of treatment-related hypoglycemia. Use of both drugs will positively affect many of the underlying metabolic abnormalities associated with type 2 diabetes, including the disordered secretion of insulin and glucagon as well as impaired sensitivity to insulin which are known to accompany this disease. Animal studies also suggest that dipeptidyl peptidase-4 inhibitor treatment may help to preserve beta cell mass; however, it is unclear at present whether or not this will prove to be the case in humans.

Keywords: diabetes, DPP-4, sitagliptin, metformin