Rosiglitazone-associated fractures in type 2 diabetes: an Analysis from A Diabetes Outcome Progression Trial (ADOPT).

OBJECTIVE: The purpose of this study was to examine possible factors associated with the increased risk of fractures observed with rosiglitazone in A Diabetes Outcome Progression Trial (ADOPT). RESEARCH DESIGN AND METHODS: Data from the 1,840 women and 2,511 men randomly assigned in ADOPT to rosiglitazone, metformin, or glyburide for a median of 4.0 years were examined with respect to time to first fracture, rates of occurrence, and sites of fractures. RESULTS: In men, fracture rates did not differ between treatment groups. In women, at least one fracture was reported with rosiglitazone in 60 patients (9.3% of patients, 2.74 per 100 patient-years), metformin in 30 patients (5.1%, 1.54 per 100 patient-years), and glyburide in 21 patients (3.5%, 1.29 per 100 patient-years). The cumulative incidence (95% CI) of fractures in women at 5 years was 15.1% (11.2-19.1) with rosiglitazone, 7.3% (4.4-10.1) with metformin, and 7.7% (3.7-11.7) with glyburide, representing hazard ratios (95% CI) of 1.81 (1.17-2.80) and 2.13 (1.30-3.51) for rosiglitazone compared with metformin and glyburide, respectively. The increase in fractures with rosiglitazone occurred in pre- and postmenopausal women, and fractures were seen predominantly in the lower and upper limbs. No particular risk factor underlying the increased fractures in female patients who received rosiglitazone therapy was identified. CONCLUSIONS: Further investigation into the risk factors and underlying pathophysiology for the increased fracture rate in women taking rosiglitazone is required to relate them to preclinical data and better understand the clinical implications of and possible interventions for these findings.

Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy.

BACKGROUND: The efficacy of thiazolidinediones, as compared with other oral glucose-lowering medications, in maintaining long-term glycemic control in type 2 diabetes is not known. METHODS: We evaluated rosiglitazone, metformin, and glyburide as initial treatment for recently diagnosed type 2 diabetes in a double-blind, randomized, controlled clinical trial involving 4360 patients. The patients were treated for a median of 4.0 years. The primary outcome was the time to monotherapy failure, which was defined as a confirmed level of fasting plasma glucose of more than 180 mg per deciliter (10.0 mmol per liter), for rosiglitazone, as compared with metformin or glyburide. Prespecified secondary outcomes were levels of fasting plasma glucose and glycated hemoglobin, insulin sensitivity, and beta-cell function. RESULTS: Kaplan-Meier analysis showed a cumulative incidence of monotherapy failure at 5 years of 15% with rosiglitazone, 21% with metformin, and 34% with glyburide. This represents a risk reduction of 32% for rosiglitazone, as compared with metformin, and 63%, as compared with glyburide (P<0.001 for both comparisons). The difference in the durability of the treatment effect was greater between rosiglitazone and glyburide than between rosiglitazone and metformin. Glyburide was associated with a lower risk of cardiovascular events (including congestive heart failure) than was rosiglitazone (P<0.05), and the risk associated with metformin was similar to that with rosiglitazone. Rosiglitazone was associated with more weight gain and edema than either metformin or glyburide but with fewer gastrointestinal events than metformin and with less hypoglycemia than glyburide (P<0.001 for all comparisons). CONCLUSIONS: The potential risks and benefits, the profile of adverse events, and the costs of these three drugs should all be considered to help inform the choice of pharmacotherapy for patients with type 2 diabetes. (ClinicalTrials.gov number, NCT00279045 [ClinicalTrials.gov].).

Rosiglitazone reduces microalbuminuria and blood pressure independently of glycemia in type 2 diabetes patients with microalbuminuria.

OBJECTIVE: To test the hypothesis that rosiglitazone combined with metformin provides a greater reduction in microalbuminuria and blood pressure than metformin and glyburide at comparable levels of glycemic control. METHODS: In a double-blind, parallel-group design 389 participants with type 2 diabetes were followed for 32 weeks. RESULTS: Urinary albumin: creatinine ratio was significantly reduced at 32 weeks compared with baseline in the rosiglitazone plus metformin group (-22.7%; P < 0.01) but not in the glyburide plus metformin comparator group (-7.1%; P = 0.32). Patients who completed the study (81.5%) demonstrated a treatment difference of -19.5% (P = 0.03), favoring the rosiglitazone group. Rosiglitazone plus metformin reduced both mean 24-h systolic (-3.4 mmHg; P = 0.01) and diastolic (-2.5 mmHg; P < 0.01) ambulatory blood pressure compared with glyburide plus metformin. Addition of rosiglitazone to metformin also reduced levels of plasminogen activator inhibitor-1 antigen and activity, C-reactive protein, von Willebrand factor and fibrinogen compared with addition of glyburide. CONCLUSIONS: Rosiglitazone added to background therapy with metformin provides greater reductions in microalbuminuria and blood pressure as compared with glyburide. These additional improvements in microalbuminuria, blood pressure and cardiovascular biomarkers were observed despite comparable improvements in glycemic control in both groups and may be related to the anti-inflammatory properties of rosiglitazone.

Reduction in use of healthcare services with combination sulfonylurea and rosiglitazone: findings from the Rosiglitazone Early vs SULfonylurea Titration (RESULT) study.

OBJECTIVE: To assess and compare healthcare utilization and costs over a 2-year period in older patients (> or = 60 years) with type 2 diabetes receiving combination therapy with rosiglitazone plus a sulfonylurea (glipizide) or progressive up-titration of glipizide monotherapy. STUDY DESIGN: Two-year, randomized, double-blind, parallel-group clinical trial. PATIENTS AND METHODS: Older type 2 diabetic patients initially receiving submaximal doses of a sulfonylurea were randomized to receive rosiglitazone plus glipizide (n = 115) or up-titrated glipizide monotherapy (n = 110). Information on patient self-reported healthcare utilization (hospitalizations, emergency department [ED] visits, physician office visits) was collected prospectively for the duration of the trial. National average healthcare costs per unit were applied to calculate direct medical costs. RESULTS: Demographic characteristics of the 2 groups were similar. At the study's end, glycemic values were better in the rosiglitazone-plus-glipizide group. Compared with the glipizide group, patients receiving rosiglitazone plus glipizide had significantly fewer ED visits (P = .0006) and hospitalizations (P = .0263). Although the glipizide group had more unscheduled physician office visits, the difference was not statistically significant. Estimated treatment costs per patient per month were significantly lower for the rosiglitazone-plus-glipizide group than for the glipizide group (480 dollars vs 645 dollars; P < .05). CONCLUSION: Addition of rosiglitazone to sulfonylurea therapy was associated with decreased use of medical resources, in particular hospitalizations and ED visits, compared with progressive sulfonylurea up-titration. Although causality could not be established, this therapeutic approach could improve clinical outcomes in patients with type 2 diabetes and reduce healthcare utilization and costs.

Phenotypic characteristics of GAD antibody-positive recently diagnosed patients with type 2 diabetes in North America and Europe.

A number of patients with type 2 diabetes are GAD antibody positive. A Diabetes Outcome Progression Trial (ADOPT) is a randomized, double-blind clinical trial in recently diagnosed drug-naive patients with type 2 diabetes that allows for the evaluation of GAD positivity in the context of anthropometric and biochemical characteristics. Of the 4,134 subjects enrolled in ADOPT for whom GAD status was obtained, 174 (4.2%) were GAD positive, with the prevalence of GAD antibodies being similar in North America (4.7%) and Europe (3.7%). Although BMI and age were similar, GAD-positive patients had a lower fasting insulin level, compatible with them being more insulin sensitive. The lower fasting insulin concentration was accompanied by a decreased early insulin response to oral glucose. However, when this insulin response was corrected for the degree of insulin sensitivity, GAD-positive and -negative patients had similar beta-cell function. Consistent with the difference in insulin sensitivity, GAD-positive patients had higher HDL cholesterol and lower triglyceride levels. In the GAD-positive individuals, the prevalence of the metabolic syndrome as defined by NCEP ATP III (National Cholesterol Education Program Adult Treatment Panel III) was also lower (74.1 vs. 83.7%, P = 0.0009). These phenotypic differences may underlie a potential difference in the natural history of hyperglycemia and its clinical outcomes.

A diabetes outcome progression trial (ADOPT): an international multicenter study of the comparative efficacy of rosiglitazone, glyburide, and metformin in recently diagnosed type 2 diabetes.

OBJECTIVE: Therapies with metformin, sulfonylureas, or insulin improve glycemic control in the short term but do not prevent progressive islet beta-cell failure or long-term deterioration in glycemia. Our goal was to evaluate, in patients recently diagnosed with type 2 diabetes (<3 years), the long-term efficacy of monotherapy with rosiglitazone on glycemic control and on the progression of pathophysiological abnormalities associated with type 2 diabetes as compared with metformin or glyburide monotherapy. RESEARCH DESIGN AND METHODS: A Diabetes Outcome Progression Trial (ADOPT) is a randomized, double-blind, parallel-group study consisting of a screening visit, a 4-week placebo run-in, a 4-year treatment period, and an observational follow-up of approximately 3,600 drug-naïve patients with type 2 diabetes diagnosed within the previous 3 years. After run-in, patients will be randomized to rosiglitazone, glyburide, or metformin titrated to the maximum effective daily doses (8 mg rosiglitazone, 15 mg glyburide, or 2 g metformin). The primary outcome is time to monotherapy failure, defined as the time following titration to the maximal effective or tolerated dose when fasting plasma glucose exceeds 180 mg/dl (10 mmol/l). Secondary outcomes include measures of islet beta-cell function, insulin sensitivity, dyslipidemia, changes in urinary albumin excretion, plasminogen activator inhibitor-1 antigen, fibrinogen, and C-reactive protein. Safety and tolerability will also be evaluated. Patient-reported outcomes and resource utilization data will be collected and analyzed. CONCLUSIONS: ADOPT will provide data on the effect of mechanistically differing treatment options on metabolic control, beta-cell function, and markers of macrovascular disease risk in type 2 diabetes.