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ADOPT (A Diabetes Outcome Progression Trial) demonstrated that initial monotherapy with rosiglitazone provided superior durability of glycemic control compared with metformin and glyburide in patients with recently diagnosed type 2 diabetes. Herein, we examine measures of β-cell function and insulin sensitivity from an oral glucose tolerance test (OGTT) over a 4-year period among the three treatments. Recently diagnosed, drug-naïve patients with type 2 diabetes (4,360 total) were treated for a median of 4.0 years with rosiglitazone, metformin, or glyburide and were examined with periodic metabolic testing using an OGTT. Measures of β-cell function and insulin sensitivity from an OGTT showed more favorable changes over time with rosiglitazone versus metformin or glyburide. Persistent improvements were seen in those who completed 4 years of monotherapy and marked deterioration of β-cell function in those who failed to maintain adequate glucose control with initial monotherapy. The favorable combined changes in β-cell function and insulin sensitivity over time with rosiglitazone appear to be responsible for its superior glycemic durability over metformin and glyburide as initial monotherapy in type 2 diabetes.

To the Editor: The Sounding Board article by Swedberg and colleagues, 1 now published in the Journal, describes the experience of the data monitoring committee of the Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure (ATMOSPHERE) as data from other trials of aliskiren raised questions regarding a possible risk to participants in ATMOSPHERE. 2 Novartis, as the sponsor of ATMOSPHERE, had engaged the independent data monitoring committee, which was composed of respected experts, to oversee the participants’ safety in this trial through periodic reviews of unblinded safety and efficacy data. During the course of the trial, the data monitoring committee, . . .

Abstract Context Glucocorticoids (GCs) prescribed for chronic pediatric illnesses are associated with osteoporotic fractures. Objective This study aims to determine the efficacy and safety of intravenous (IV) zoledronic acid (ZA) compared with placebo to treat pediatric GC-induced osteoporosis (GIO). Methods Children aged 5 to 17 years with GIO were enrolled in this multinational, randomized, double-blind, placebo-controlled phase 3 trial (ClinicalTrials.gov NCT 00799266). Eligible children were randomly assigned 1:1 to 6 monthly IV ZA 0.05 mg/kg or IV placebo. The primary end point was the change in lumbar spine bone mineral density z score (LSBMDZ) from baseline to month 12. Incident fractures and safety were assessed. Results Thirty-four children were enrolled (mean age 12.6 ± 3.4 years [18 on ZA, 16 on placebo]), all with low-trauma vertebral fractures (VFs). LSBMDZ increased from −2.13 ± 0.79 to −1.49 ± 1.05 on ZA, compared with −2.38 ± 0.90 to −2.27 ± 1.03 on placebo (least squares means difference 0.41 [95% CI, 0.02-0.81; P = .04]); when corrected for height z score, the least squares means difference in LBMDZ was 0.75 [95% CI, 0.27-1.22; P = .004]. Two children on placebo had new low-trauma VF vs none on ZA. Adverse events (AEs) were reported in 15 of 18 children (83%) on ZA, and in 12 of 16 (75%) on placebo, most frequently within 10 days after the first infusion. There were no deaths or treatment discontinuations due to treatment-emergent AEs. Conclusion LSBMDZ increased significantly on ZA compared with placebo over 1 year in children with GIO. Most AEs occurred after the first infusion.

Rosiglitazone-Associated Fractures in Type 2 Diabetes An analysis from A Diabetes Outcome Progression Trial (ADOPT) Steven E. Kahn , MB, CHB 1 , Bernard Zinman , MD 2 , John M. Lachin , SCD 3 , Steven M. Haffner , MD 4 , William H. Herman , MD 5 , Rury R. Holman , MD 6 , Barbara G. Kravitz , MS 7 , Dahong Yu , PHD 7 , Mark A. Heise , PHD 7 , R. Paul Aftring , MD, PHD 7 , Giancarlo Viberti , MD 8 and for the A Diabetes Outcome Progression Trial (ADOPT) Study Group * 1 Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle, Washington 2 Samuel Lunenfeld Research Institute, Mount Sinai Hospital and University of Toronto, Toronto, Ontario, Canada 3 Biostatistics Center, George Washington University, Rockville, Maryland 4 University of Texas Health Science Center at San Antonio, San Antonio, Texas 5 Departments of Internal Medicine and Epidemiology, University of Michigan, Ann Arbor, Michigan 6 Diabetes Trials Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford, U.K. 7 GlaxoSmithKline, King of Prussia, Pennsylvania 8 King's College London School of Medicine, King's College London, London, U.K. Corresponding author: Steven E. Kahn, MB, ChB, VA Puget Sound Health Care System (151), 1660 S. Columbian Way, Seattle, WA 98108. E-mail: skahn{at}u.washington.edu Abstract 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. ADOPT, A Diabetes Outcome Progression Trial Footnotes Published ahead of print at http://care.diabetesjournals.org on 5 February 2008. DOI: 10.2337/dc07-2270. Clinical trial reg. no. NCT00279045, clinicaltrials.gov. * ↵ * A list of members of the ADOPT Study Group can be found in ref. 11 . ADOPT was overseen by a steering committee comprising Steven Kahn and Giancarlo Viberti (cochairs), Steven Haffner, William Herman, Rury Holman, Paul Aftring, Nigel Jones, John Lachin, Colleen O'Neill, and Bernard Zinman. S.E.K., B.Z., J.M.L., S.M.H., W.H.H., R.R.H., and G.V. have received honoraria, consulting fees, and/or grant support from GlaxoSmithKline. G.V. holds stock in GlaxoSmithKline. B.G.K., D.Y., M.A.H., and R.P.A. are employees of GlaxoSmithKline and hold equity interest in the company. Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/dc07-2270 . The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C Section 1734 solely to indicate this fact. Accepted January 22, 2008. Received November 30, 2007. DIABETES CARE

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). 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. 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. 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.

OBJECTIVE--ADOPT (A Diabetes Outcome Progression Trial) demonstrated that initial monotherapy with rosiglitazone provided superior durability of glycemic control compared with metformin and glyburide in patients with recently diagnosed type 2 diabetes. Herein, we examine measures of [beta]-cell function and insulin sensitivity from an oral glucose tolerance test (OGTT) over a 4-year period among the three treatments. RESEARCH DESIGN AND METHODS--Recently diagnosed, drug-naive patients with type 2 diabetes (4,360 total) were treated for a median of 4.0 years with rosiglitazone, metformin, or glyburide and were examined with periodic metabolic testing using an OGTT. RESULTS--Measures of [beta]-cell function and insulin sensitivity from an OGTT showed more favorable changes over time with rosiglitazone versus metformin or glyburide. Persistent improvements were seen in those who completed 4 years of monotherapy and marked deterioration of [beta]-cell function in those who failed to maintain adequate glucose control with initial monotherapy. CONCLUSIONS--The favorable combined changes in [beta]-cell function and insulin sensitivity over time with rosiglitazone appear to be responsible for its superior glycemic durability over metformin and glyburide as initial monotherapy in type 2 diabetes. Diabetes 60:1552-1560, 2011

Six patients from the phase 3 trials of zoledronic acid in Paget's disease, who had received zoledronic acid initially and had subsequently relapsed, were entered into an open re-treatment study. Following re-treatment, each patient reached similar absolute nadirs of serum alkaline phosphatase to those recorded after their first dose. No significant adverse events were reported. It is concluded that, while re-treatment of Paget's disease with zoledronic acid is rarely needed, it is safe and effective, with no evidence of treatment resistance based on this small cohort.

The label for the diabetes drug Avandia already contained information about congestive heart failure at the time a Maryland physician raised concerns (\"Doctors Claim Glaxo Dismissed Worries on...