Friday, September 22, 2023
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Professor, Department of Medicine, Division of Clinical Epidemiology, University of Texas Health Science Center, San Antonio, Texas
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The United Kingdom Prospective Diabetes Study (UKPDS), a landmark outcome study released in 1998, demonstrated that increasing glucose levels in patients with type 2 diabetes result from increasing insulin resistance and decreased beta-cell function and lead to both micro- and macrovascular complications.[1] Until recently, no other large randomized studies have compared currently available oral antidiabetic agents. ADOPT (A Diabetes Outcome Progression Trial) provides a much-needed update to the UKPDS, which preceded the availability of thiazolidinediones (TZDs) and included only 2 of the 3 oral agents evaluated in ADOPT -- metformin and sulfonylurea.[2]
ADOPT is the first large, multicenter, randomized, double-blind, controlled clinical trial designed to compare the durability of glycemic control of the TZD rosiglitazone with that of metformin or the sulfonylurea glyburide as monotherapy, based on factors related to disease progression in patients with newly diagnosed (< 3 years) type 2 diabetes.[2] ADOPT assessed the time interval of loss of glycemic control once a participant reached the maximum effective dose of each therapy and allowed investigation of the effects of beta-cell function and insulin resistance on disease progression and long-term glycemic control, among other outcomes. This international study included 4360 patients who were followed for 4 to 6 years.
The primary outcome measure was the time to monotherapy failure, defined as hyperglycemia confirmed by fasting plasma glucose (FPG) level greater than 180 mg/dL for subjects at the maximum-dictated or maximum-tolerated dose after at least 6 weeks of therapy.[2] As patients reached the defined action point level of confirmed FPG of 140 mg/dL, they were further uptitrated to the next highest dose level based on the respective study arm. Secondary measures included the effects of monotherapy in delaying the progressive loss of glycemic control based on cumulative incidence of FPG greater than 140 mg/dL and the percentage of patients remaining on monotherapy (A1C < 7%).
Results from ADOPT demonstrated that initial treatment with rosiglitazone significantly reduced the risk of monotherapy failure by 32% compared with metformin (P < .001), and by 63% compared with glyburide (P < .001) at 5 years.[2] Similarly, rosiglitazone was significantly more effective in delaying the progressive loss of glycemic control as measured by FPG and A1C levels. Risk reduction of decreasing glycemic control was 34% compared with metformin (P = .002) and 62% compared with glyburide (P < .001). Additionally, mean A1C levels of less than 7% were maintained at 60 months with rosiglitazone compared with only 45 months for metformin and 33 months for glyburide (Figures 1, 2, and 3).
Figure 1. Cumulative incidence of monotherapy failure (FPG > 180 mg/dL).[2]
Figure 2. Cumulative incidence of FPG > 140 mg/dL among patients with baseline FPG ≤ 140 mg/dL.[2]
Figure 3. Durability of glycemic control: time to mean A1C > 7%.[2]
This study also demonstrated that rosiglitazone significantly improved insulin sensitivity vs metformin or glyburide (P < .001 at 4 years) and reduced the loss of beta-cell function vs metformin (P = .02) and glyburide (P < .001). These were not unexpected findings based on the superior efficacy results of rosiglitazone vs comparators and consistent long-term support of these effects (beta-cell preservation and improved insulin sensitivity) with TZDs.[2]
Safety assessments were followed for 6 years in ADOPT, with no unanticipated results. Commonly reported adverse events across the treatment groups for rosiglitazone, metformin, and glyburide, respectively, were edema (14.1%, 7.2%, 8.5%); weight gain (6.9%, 1.2%, 3.3%); gastrointestinal events (23%, 38.3%, 21.9%); and hypoglycemia (9.8%, 11.6%, 38.7%). Similar rates of discontinuation were reported in the rosiglitazone and metformin groups (37% and 38%, respectively) and were highest in the glyburide group (44%) due to an increase in hypoglycemia. Similarly, low rates of congestive heart failure (CHF) serious adverse events were reported with rosiglitazone (0.8%) and metformin (0.8%), while fewer such events were reported with glyburide (0.2%).[2] Of these serious events, an independent cardiology review found 21 of 51 to be true CHF, involving 9 patients with no deaths in the rosiglitazone group, 8 patients with 1 death in the metformin group, and 4 patients with 1 death in the glyburide group. For all investigator-reported CHF events, there was a slight difference observed with rosiglitazone compared with metformin (1.5% vs 1.3%, respectively), with fewer events reported for glyburide (0.6%; P = .05).
Further examination of the data showed an increased fracture rate, most commonly involving fractures of the foot and upper limb, in women treated with rosiglitazone compared with metformin or glyburide. Fractures occurred in all treatment arms of ADOPT; however, the fractures were of the upper limbs and not the hip. The fracture rates observed appear to be within the range that has been noted in literature-based reviews of observational studies, in addition to an analysis of databases at a large managed care organization.[3] Editor's Note: As this column posted, the FDA and GlaxoSmithKline issued a warning about the risk for fracture with rosiglitazone.[4] The warning notes that further evaluations are ongoing and that "in the interim, the risk for fracture should be considered when initiating or continuing rosiglitazone therapy, particularly in women."[5]
ADOPT is the first long-term study to demonstrate that progressive loss of glycemic control can be delayed and that durable control of targeted glycemic levels can be maintained for a longer duration with rosiglitazone than with metformin or glyburide. Therefore, these results provide evidence that suggest earlier treatment with a TZD in the management of type 2 diabetes may be warranted. In addition, this study provides the rationale that when combination therapy is required to maintain glycemic control, a TZD should be considered for use with other agents. These results, along with the potential risks and benefits, adverse events profile, and costs, must be considered by healthcare providers in choosing optimal management strategies for patients with type 2 diabetes.
