Overview of Newer Agents: Where Treatment Is Going

Impaired insulin secretion (β-cell), increased hepatic glucose production (liver), and decreased peripheral (muscle) glucose utilization constitute the traditional primary defects responsible for the development and progression of type 2 diabetes mellitus. β-Cell failure, ultimately leading to decreased insulin secretion, is now known to occur much earlier in the natural history of type 2 diabetes than originally believed. Additionally, a better understanding of the pathophysiology of type 2 diabetes reveals other etiologic mechanisms beyond the classic triad, now referred to as the ominous octet. In addition to the β-cell, liver, and muscle, other pathogenic mechanisms include adipocyte insulin resistance (increased lipolysis), reduced incretin secretion/sensitivity (gastrointestinal), increased glucagon secretion (α-cell), enhanced glucose reabsorption (kidney), and central nervous system insulin resistance resulting from neurotransmitter dysfunction (brain). Currently, the management of type 2 diabetes focuses on glucose control via lowering of blood glucose (fasting and postprandial) and hemoglobin A_1c. However, the goal of therapy should be to delay disease progression and eventual treatment failure. Treatment should target the known pathogenic disturbances of the disease (i.e., reducing the deterioration of β-cell function and improving insulin sensitivity). In recent years, treatment strategies have focused on the development of novel therapeutic options that affect many of the defects contributing to type 2 diabetes and that provide durable glucose control through a blunting of disease progression. Optimal management of type 2 diabetes should include early initiation of therapy using multiple drugs, with different mechanisms of action, in combination.