Clinical Translation of “A Diabetes Outcome Progression Trial”: ADOPT Appropriate Combination Oral Therapies in Type 2 Diabetes

Thelong-termgoalsforthemanagementoftype2diabetes mellitus (T2DM) center on the prevention of its chronic micro- and macrovascular complications, which requires normalization of glycemia and control of cardiovascular risk factors (1). Growing evidence from large clinical trials supporting earlier and more aggressive therapeutic strategies to manage hyperglycemia in diabetes has been reflected in current guidelines and practice recommendations (2–5). Recent clinical trials on controlling hyperglycemia have supported moreefficacioustherapeuticapproaches,mostofwhichhave clearly shown that double or triple combinations of available and emerging pharmaceutical agents are required to achieve that elusive, but well-recognized, near-normal hemoglobin A1c goal of less than 6.5% (6). T2DM results from a combination of physiological abnormalities including systemic insulin resistance coupled with inadequate -cell insulin secretion (7). The etiology of these defects is not fully understood. Classic studies from the United Kingdom Prospective Diabetes Study (UKPDS) revealed that hyperglycemia in T2DM tends to be progressive due to persistent insulin resistance with gradual worsening of -cell insulin secretory function (8). For the majority of patients, it is well-known that maximizing doses of single oral medications does not provide a sustained normalization of glycemia and can provoke unwanted side effects (9). Moreover, diabetes results from a complex interplay among several pathophysiological mechanisms, and it seems doubtful that in the near future a therapeutic “magic bullet” will be identified to effectively “cure” the hyperglycemia of diabetes (7). Thus, successful current therapeutic approaches use early adoption of oral combination therapies, among the variety of medications that (thankfully) are currently available for use. More than 7 yr ago, before this insight into T2DM was appreciated, “A Diabetes Outcome Progression Trial” (ADOPT) was designed and initiated (10). This large (4300 patients), double-blind, randomized, controlled, clinical trial evaluated the performance of three major oral medications (rosiglitazone,metformin,andglyburide)asmonotherapyin drug naive T2DM patients who were followed for a median of 4.0 yr (11). ADOPT provides an updated view of diabetes management for several reasons. The thiazolidinediones were not available for use during the UKPDS. In addition, patients’ glucose levels that triggered an intensification of therapy in the UKPDS were much higher than modern management goals. The ADOPT investigators used a therapeutic fasting plasma glucose (FPG) goal of less than 140 mg/dl for intensifying monotherapy; the primary outcome was the timetomonotherapyfailureevidencedbyaFPGgreaterthan 180 mg/dl, a test of therapeutic “durability.” The results of ADOPT were not wholly unexpected. Considering the large number of subjects and the duration of blinded therapy in this landmark trial, however, ADOPT provides a superior level of confidence in its assessment of themonotherapyperformanceofthesedrugscomparedwith data from smaller previous studies of shorter duration. The primary results of ADOPT showed a lower failure rate at 5 yrof15%withrosiglitazonevs.21%withmetforminand34% with glyburide, a highly significant risk reduction of 32% for rosiglitazone compared with metformin, and 63% compared with glyburide. The data from ADOPT are consistent with the known mechanism of action of rosiglitazone to improve both insulin resistanceand-cellfunction(12).Interestingly,althoughthe apparent durability of the glycemic effect of rosiglitazone in prior studies has largely been attributed to its enhancement of -cell function, in ADOPT, this effect of rosiglitazone (estimatedbyhomeostasismodelassessment-Banalysis),began to wane after 1.5 yr of therapy. More accurate physio