Prevalence of type 2 diabetes mellitus (T2DM) has dramatically increased worldwide, from 153 million people in 1980 to 347 million in 20081—a trend that is expected to continue, with predictions of 439 million cases by 2030.2
The goal of type 2 diabetes therapy is to achieve tight glycemic control, which reduces the microvascular complications that lead to CVD and stroke.3 However, more than half of patients treated with current therapies fail to achieve the American Diabetes Association’s recommended target of less than 7% glycated hemoglobin (HbA1C),4,5 suggesting that these therapies are inadequate. A recently published article by Basile3 reviews the role of a new class of agents—sodium glucose cotransporter 2 (SGLT2) inhibitors—in improving glycemic control and reducing diabetes-related vascular disease.
Pathogenesis of T2DM and Limitations of Current Therapies
Type 2 diabetes results from “progressive b-cell dysfunction in the presence of chronic insulin resistance, leading to a progressive decline in plasma glucose control.”3 Disruptions in signaling pathways involved in glucose homeostasis result in increased glucagon secretion, reduced incretin response, increased endogenous glucose production, and increased renal glucose reabsorption.3
Current pharmacotherapies act either by increasing insulin sensitivity or stimulating insulin secretion.3 Sulfonylurea insulin secretagogues (eg, glipizide) and nonsulfonylurea insulin secretagogues (eg, nateglinide) increase insulin secretion by closing potassium channels on the surface of pancreatic b cells.6 Metformin decreases hepatic glucose output and sensitizes peripheral tissues to insulin.6 The thiazolidinediones (pioglitazone, rosiglitazone) increase insulin sensitivity in peripheral tissue and decrease hepatic glucose production.6 The a-glucosidase inhibitors inactivate the enzyme that breaks down complex carbohydrates, slowing absorption and flattening the postglycemic curve,6 while incretin mimetics and incretin enhancers (eg, sitagliptin) stimulate glucose-dependent insulin secretion and decrease glucagon secretion.6