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Rosiglitazone-Associated Fractures in Type 2 Diabetes an Analysis from a Diabetes Outcome Progression Trial (ADOPT)

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Rosiglitazone-Associated Fractures in Type 2 Diabetes an Analysis from a Diabetes Outcome Progression Trial (ADOPT) Clinical Care/Education/Nutrition/Psychosocial Research ORIGINAL ARTICLE Rosiglitazone-Associated Fractures in Type 2 Diabetes An analysis from A Diabetes Outcome Progression Trial (ADOPT) 1 7 STEVEN E. KAHN, MB, CHB DAHONG YU, PHD preclinical data and better understand the 2 7 BERNARD ZINMAN, MD MARK A. HEISE, PHD clinical implications of and possible interven- 3 7 JOHN M. LACHIN, SCD R. PAUL AFTRING, MD, PHD tions for these findings. 4 8 STEVEN M. HAFFNER, MD GIANCARLO VIBERTI, MD 5 WILLIAM H. HERMAN, MD FOR THE ADIABETES OUTCOME Diabetes Care 31:845–851, 2008 6 RURY R. HOLMAN, MD PROGRESSION TRIAL (ADOPT) STUDY 7 BARBARA G. KRAVITZ, MS GROUP* ype 2 diabetes is associated with an increased risk of fractures, with the risk increasing with longer duration OBJECTIVE — The purpose of this study was to examine possible factors associated with the T increased risk of fractures observed with rosiglitazone in A Diabetes Outcome Progression Trial of disease (1,2). These fractures affect pre- (ADOPT). dominantly the hip, arm, and foot (1–5) and occur despite the fact that bone min- RESEARCH DESIGN AND METHODS — Data from the 1,840 women and 2,511 men eral density is either normal or even in- randomly assigned in ADOPT to rosiglitazone, metformin, or glyburide for a median of 4.0 years creased in patients with type 2 diabetes were examined with respect to time to first fracture, rates of occurrence, and sites of fractures. compared with those who are not hyper- glycemic (5–7). Although the reason for RESULTS — In men, fracture rates did not differ between treatment groups. In women, at this increased risk is unclear, it has been least one fracture was reported with rosiglitazone in 60 patients (9.3% of patients, 2.74 per 100 postulated that in older patients some of patient-years), metformin in 30 patients (5.1%, 1.54 per 100 patient-years), and glyburide in 21 the risk may be related to disability and patients (3.5%, 1.29 per 100 patient-years). The cumulative incidence (95% CI) of fractures in falls (8). In the context of specific diabetes women at 5 years was 15.1% (11.2–19.1) with rosiglitazone, 7.3% (4.4–10.1) with metformin, therapy, a recent report from the Health, and 7.7% (3.7–11.7) with glyburide, representing hazard ratios (95% CI) of 1.81 (1.17–2.80) Aging and Body Composition Study—an and 2.13 (1.30–3.51) for rosiglitazone compared with metformin and glyburide, respectively. observational study—noted that older The increase in fractures with rosiglitazone occurred in pre- and postmenopausal women, and women with type 2 diabetes who were 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 taking thiazolidinediones experienced in- identified. creased bone loss compared with control subjects, whereas no differences were CONCLUSIONS — Further investigation into the risk factors and underlying pathophysi- seen in men (9). However, a recent retro- ology for the increased fracture rate in women taking rosiglitazone is required to relate them to spective study suggested a greater loss of bone mineral density in men taking ros- iglitazone (10). ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● A Diabetes Outcome Progression Trial (ADOPT) was a randomized, con- 1 From the Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, VA Puget Sound trolled clinical trial comparing the effect Health Care System and University of Washington, Seattle, Washington; the 2Samuel Lunenfeld Research Institute, Mount Sinai Hospital and University of Toronto, Toronto, Ontario, Canada; the 3Biostatistics of the thiazolidinedione rosiglitazone, the Center, George Washington University, Rockville, Maryland; the 4University of Texas Health Science Center biguanide metformin, and the sulfonyl- at San Antonio, San Antonio, Texas; the 5Departments of Internal Medicine and Epidemiology, University of urea glyburide on glucose control in Michigan, Ann Arbor, Michigan; the 6Diabetes Trials Unit, Oxford Centre for Diabetes, Endocrinology and drug-naive patients recently diagnosed Metabolism, Oxford, U.K.; 7GlaxoSmithKline, King of Prussia, Pennsylvania; and 8King’s College London Ͻ School of Medicine, King’s College London, London, U.K. ( 3 years) with type 2 diabetes (11). In Corresponding author: Steven E. Kahn, MB, ChB, VA Puget Sound Health Care System (151), 1660 S. the study it was shown that treatment Columbian Way, Seattle, WA 98108. E-mail: [email protected]. with rosiglitazone produced more dura- Received for publication 30 November 2007 and accepted in revised form 22 January 2008. ble glycemic control than metformin or 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. glyburide as measured by fasting glucose *A list of members of the ADOPT Study Group can be found in ref. 11. ADOPT was overseen by a steering and A1C. This effect resulted from a committee comprising Steven Kahn and Giancarlo Viberti (cochairs), Steven Haffner, William Herman, Rury greater preservation of ␤-cell function Holman, Paul Aftring, Nigel Jones, John Lachin, Colleen O’Neill, and Bernard Zinman. with rosiglitazone. After unblinding and 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 completion of the prespecified statistical 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. analysis plan, a review of adverse events of Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/ special interest uncovered an increase in dc07-2270. the number of fractures in women taking Abbreviations: ADOPT, A Diabetes Outcome Progression Trial. rosiglitazone; a brief description of the © 2008 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby finding was added as a postscript to the marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. primary manuscript then in press (11). In DIABETES CARE, VOLUME 31, NUMBER 5, MAY 2008 845 Rosiglitazone and fractures in type 2 diabetes women we observed an increased occur- was defined as fasting plasma glucose considered statistically significant. Analy- rence of bone fractures in the upper and Ͼ180 mg/dl on two successive occasions ses were conducted using SAS (SAS Insti- lower limbs, but an increase in hip or ver- or by independent adjudication (11). tute, Cary, NC). tebral fractures was not noted. An in- creased fracture risk was subsequently Concomitant medication use and reported in women receiving pioglitazone adverse event reporting RESULTS (12), the other thiazolidinedione cur- Site investigators recorded all concomi- rently in clinical use. We now report in tant prescription medication use at base- Demographic and clinical variables greater detail the ADOPT findings related line and at each clinic visit. Medications at baseline and follow-up to fractures. were classified using a validated coding Women and men randomly assigned to system (GSKDrug). Site investigators re- the three treatment arms were well ported adverse events during the treat- matched at baseline (Table 1). As antici- RESEARCH DESIGN AND ment portion of the study, and these were pated, the majority of women in the study METHODS — In ADOPT, 4,360 indi- categorized using the Medical Dictionary were aged Ͼ50 years (71%) and post- viduals with type 2 diabetes whose diabe- for Regulatory Activities (MedDRA). Frac- menopausal by self-report (77%). The tes had been diagnosed within 3 years and tures included any preferred term with proportions of patients at baseline using who were naive to oral hypoglycemic the text “fracture” within the higher-level selected categories of medications re- drugs were randomly assigned. Nine of group term of “bone and joint injuries.” In lated to bone health did not differ among the randomly assigned subjects never re- the case of fractures, the site of the frac- the treatment groups within each sex ceived study medication; 1,456 subjects tures was as reported to or determined by (Table 1), although generally more were assigned to rosiglitazone, 1,454 to the investigators with no adjudication or women than men were using medications metformin, and 1,441 to glyburide ther- subsequent directed assessment per- associated with better bone health (estro- apy. The study was performed in 488 cen- formed as part of the study protocol. gen-containing hormones, calcium sup- ters in 17 countries in North America and plements, and bisphosphonates). Europe. The protocol was reviewed and Methods, assays, and calculations The median duration of follow-up approved by institutional review boards Fasting blood samples were drawn for was 4.0 years for the rosiglitazone and for each center, and all subjects gave writ- measurement of fasting plasma glucose, metformin groups and 3.3 years for the ten, informed consent. The study was a A1C, and immunoreactive insulin levels. glyburide group. The proportions of pa- registered clinical trial. All assays were performed at a central lab- tients completing the study were 63, 62, The study protocol has been pub- oratory (13). and 56% for the rosiglitazone, metformin, lished previously (13). In brief, ADOPT and glyburide groups, respectively. Thus, was a randomized, double-blind, parallel- Statistical methods the number of patient-years of medica- group trial. Eligible patients with diabetes The cumulative incidence of time-to- tion exposure was 4,953.8 for the rosigli- were aged 30–75 and had a fasting plasma event variables was estimated by the tazone group, 4,905.6 for the metformin glucose concentration between 126 and Kaplan-Meier method (14), with with- cohort, and 4,243.6 for the glyburide 180 mg/dl with lifestyle therapy.
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