Background: Aggressive management of type 2 diabetes is necessary to achieve glycemic and nonglycemic treatment goals. Attainment of treatment goals is associated with a decreased risk of diabetes-related complications, costs, and health care utilization.

Objective: To review the advantages and disadvantages of different glucose-lowering agents, with an emphasis on the role of thiazolidinediones (TZDs).

Summary: Diabetes has become increasingly prevalent, particularly among younger age groups in the United States, accounting for approximately 15% of health care expenditures by managed care organizations. Reducing a patient's glycated hemoglobin (A1C) has been shown to decrease the risk of diabetes-related complications, as well as reduce medical costs and health care utilization. Despite this knowledge, achievement of the American Diabetes Association (ADA) goal A1C of < 7% is suboptimal, and < 1 in 10 patients also reach the ADA _targets for cholesterol (low-density lipoprotein < 100 mg per dL) and blood pressure (< 130/80 mm Hg). To ensure that all ADA treatment goals are met, clinicians need to closely monitor patients and adjust therapy as needed, taking into consideration both a drug's glycemic and nonglycemic effects when selecting medication therapy. Four basic defects contribute to type 2 diabetes: insulin resistance, decreased insulin secretion, increased hepatic glucose production, and reduced glucagon-like peptide-1 levels. Unlike metformin, sulfonylureas, and insulin that address only 1 or 2 physiologic defects, TZDs uniquely address 3 of these defects at the adipocyte. Metformin is recommended for initial drug therapy; TZDs, sulfonylureas, and insulin are useful options as add-on therapy for patients whose A1C levels remain >or= 7% despite treatment with metformin and lifestyle interventions. It has been suggested that TZDs, when used either as add-on therapy or when appropriate as monotherapy, may conserve pancreatic beta-cell function over an observed 3- to 5-year period of time and sustain a decrease in A1C ranging from 0.5%-1.5%. Although rarely associated with hypoglycemia, TZDs may cause total body weight gain that is most commonly caused by volume expansion, which may manifest as new or worsened heart failure in susceptible individuals. Pioglitazone and rosiglitazone, the 2 TZDs available in the United States, contain black box label warnings about their potential to cause or exacerbate congestive heart failure; additional data have suggested a link to ischemic cardiac events. Recent data also suggest that TZDs may reduce bone density. Conversely, pioglitazone may have some vasculoprotective effect related to elevation of high-density lipoprotein and lessened progression of carotid intima-media thickness; however, any effect on macrovascular clinical outcomes is unknown. Other drug options are available for the treatment of type 2 diabetes, such as incretin-based therapies. Yet despite their favorable effects on glycemia, they have not been included to date in the ADA treatment algorithm.

Conclusions: Proper glycemic control and attainment of other nonglycemic management _targets (e.g., blood pressure, lipids, body weight) are essential to the prevention of long-term complications of diabetes and to reduction of overall disease management costs. Therefore, patients with diabetes should be followed closely to ensure that they achieve and maintain both glycemic and nonglycemic treatment goals. Most patients will not sustain an adequate level of control using nondrug or single-drug therapeutic approaches. When choosing among treatment options, consideration should be given to the nonglycemic as well as glycemic effects of various glucose-lowering agents.