Type 2 diabetes comorbidities and treatment challenges: rationale for DPP-4 inhibitors.

The management of type 2 diabetes is designed to reduce disease-related complications and improve long-term outcomes. Achieving glycemic control is a critical component of this process. The selection of drug therapy for reducing blood glucose is made more challenging when patients already have complications or comorbid conditions (eg, high risk for hypoglycemia, obesity, renal impairment). Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of antihyperglycemic drugs that block degradation of incretin hormones. By enhancing and prolonging incretin effects, DPP-4 inhibitors stimulate glucose-dependent insulin secretion and also reduce glucagon secretion. This results in improved glycemic control, as reflected by decreases in glycated hemoglobin (HbA1c), fasting plasma glucose, and postprandial plasma glucose. Dipeptidyl peptidase-4 inhibitors also have the potential to improve beta-cell function. In randomized clinical trials, the DPP-4 inhibitors saxagliptin and sitagliptin reduced HbA1c by 0.5% to 0.8%, compared with placebo, whether used as monotherapy or in combination with another agent. As initial combination therapy with metformin, saxagliptin and sitagliptin have demonstrated reductions in HbA1c of 2.5% and 1.9%, respectively. The efficacy of the DPP-4 inhibitors was maintained during treatment for up to 2 years, and did not differ in the elderly compared with younger adults. Dipeptidyl peptidase-4 inhibitors offer efficacy similar to other drug classes, and are well tolerated with a lower risk of hypoglycemia, weight-neutral effects, and a low propensity for drug-drug interactions. On the basis of their clinical profiles, the DPP-4 inhibitors are emerging as an attractive option for improving glycemic control in patients with type 2 diabetes. Saxagliptin and sitagliptin are approved for use as initial therapy in combination with metformin, as monotherapy, as well as in combination with metformin, a sulfonylurea, or a thiazolidinedione in patients not adequately controlled by these agents alone.