BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from Rosiglitazone use and post-discontinuation glycaemic control in two European countries, 2000-2010 ForJournal: peerBMJ Open review only Manuscript ID: bmjopen-2013-003424 Article Type: Research Date Submitted by the Author: 17-Jun-2013 Complete List of Authors: Ehrenstein, Vera; Aarhus University Hospital, Department of Clinical Epidemiology Hernandez, Rohini; Amgen, Inc., Center for Observational Research Ulrichsen, Sinna; Aarhus University Hospital, Department of Clinical Epidemiology Rungby, Jørgen; Aarhus University Hospital, Department of Biomedicine - Pharmacology Lash, Timothy; Emory University Rollins School of Public Health, Department of Epidemiology Riis, Anders; Aarhus University Hospital, Department of Clinical Epidemiology Li, Lin; Boston University School of Medicine, Boston Collaborative Drug Surveillance Program Toft Sørensen, Henrik; Aarhus University Hospital, Department of Clinical Epidemiology http://bmjopen.bmj.com/ Jick, Sn; Boston University, ; Boston University School of Medicine, Boston http://bmjopen.bmj.com/ Collaborative Drug Surveillance Program <b>Primary Subject Epidemiology Heading</b>: Secondary Subject Heading: Pharmacology and therapeutics, Public health diabetes mellitus, drug safety, glucose-lowering drugs, rosiglitazone, Keywords: on September 27, 2021 by guest. Protected copyright. thiazolidinediones on September 27, 2021 by guest. Protected copyright. For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 50 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from 1 2 Rosiglitazone use and post-discontinuation glycaemic control in two European countries, 3 4 2000-2010 5 6 7 8 9 10 1* 2,3** 1 4 1,5 1 11 V. Ehrenstein, R. K. Hernandez, S. P. Ulrichsen, J. Rungby, T. L. Lash, A.H. Riis, L. 12 13 Li,2 H. T. Sørensen,1 S. S. Jick2 14 15 For peer review only 16 17 1Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark 18 19 2 20 Boston Collaborative Drug Surveillance Program (BCDSP), Boston University School of 21 22 Public Health, Lexington, MA, USA 23 24 3Amgen, Inc., Thousand Oaks, CA, USA 25 26 4Department of Biomedicine - Pharmacology, Aarhus University, Aarhus, Denmark 27 28 5 29 Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, 30 31 GA, USA 32 33 34 http://bmjopen.bmj.com/ 35 *Correspondence to: V. Ehrenstein [email protected] 36 37 **Dr. Hernandez was affiliated with BCDSP at the time the work for this project was 38 39 conducted. 40 41 42 43 on September 27, 2021 by guest. Protected copyright. 44 45 46 Words: abstract 241, main text 2,553 47 48 49 1 Figure, 5 Tables 50 51 52 53 54 55 56 57 Page 1 of 22 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 50 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from 1 2 Article summary 3 4 5 Article focus (up to three bullet points on the research questions or hypotheses addressed); 6 • Rosiglitazone is a second-line oral hypoglycaemic agent, which was sold in the 7 European Union starting in 2000; in a series of regulatory decision, its use was 8 restricted and ultimately suspended in Europe in September 2010 9 • This article examines utilization of rosiglitazone in Denmark and the United 10 Kingdom, in 2000-2010 11 • On the patient level, this article explores changes in glycaemic control following 12 discontinuation of rosiglitazone 13 14 15 Key messagesFor (up to three peer bullet points showingreview the key messages only or significance of the 16 study) 17 • Following a 2007 publication of a meta-analysis showing increased cardiovascular 18 morbidity associated with rosiglitazone, use of the drug declined sharply and 19 irreversibly in Denmark and in the UK; this predated the official suspension of the 20 drug by the European Medicines Agency in 2010 21 • On the patient level, observed mean changes in fasting plasma glucose and glycated 22 haemoglobin A1c were slight in patients who discontinued rosiglitazone 23 24 25 Strengths and limitations of this study 26 • The study makes use of population based routine medical databases in two European 27 countries, which are likely to reflect typical clinical practice 28 • Despite differences in record generation mechanisms in the two databases, results 29 were overall concordant 30 31 • Automated prescription and dispensation data may have imprecisely measured 32 initiation and discontinuation of medication intake 33 34 http://bmjopen.bmj.com/ 35 36 37 38 39 40 41 42 43 on September 27, 2021 by guest. Protected copyright. 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 50 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from 1 2 Abstract 3 4 5 Objectives To evaluate the impact of risk minimisation policies on use of rosiglitazone- 6 7 containing products and on glycaemic control among patients in Denmark and the United 8 9 Kingdom (UK). 10 11 Design, setting and participants We used population-based data from the Aarhus University 12 13 Prescription Database (AUPD) in northern Denmark and the General Practice Research 14 15 Database (GPRD)For in the peer UK. review only 16 17 Main outcome measures We examined use of rosiglitazone during its entire period of 18 19 availability on the European market (2000–2010) and evaluated changes in glycated 20 21 haemoglobin-A (HbA ) and fasting plasma glucose (FPG) levels among patients 22 1c 1c 23 discontinuing this drug. 24 25 26 Results During 2000–2010, 2,321 patients with records in the AUPD used rosiglitazone in 27 28 northern Denmark and 25,428 patients with records in the GPRD used it in the UK. The 29 30 proportion of rosiglitazone users among all users of oral hypoglycaemic agents (OHA) peaked 31 32 at 4% in the AUPD and 15% in the GPRD in May 2007. Twelve months after discontinuation 33 of rosiglitazone-containing products, the mean change in HbA1c was –0.16% (95% confidence 34 http://bmjopen.bmj.com/ 35 36 interval [CI]: –3.4%, 3.1%) in northern Denmark and –0.17% (95% CI: –0.21%, 0.13%) in the 37 38 UK. Corresponding mean changes in FPG were 0.01 mmol/L (95% CI: –7.3 mmol/L, 7.3 39 40 mmol/L) and 0.03 mmol/L (95% CI: –0.22 mmol/L, 0.28 mmol/L). 41 42 Conclusions Publication of evidence concerning potential cardiovascular risks of rosiglitazone on September 27, 2021 by guest. Protected copyright. 43 44 was associated with a irreversible decline in use of rosiglitazone-containing products in 45 46 Denmark and the UK. Mean changes in HbA1c and FPG after drug discontinuation were slight. 47 48 49 Key words: diabetes mellitus, drug safety, glucose-lowering drugs, rosiglitazone, 50 51 thiazolidinediones 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 50 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from 1 2 Introduction 3 4 5 Since first marketed in the European Union in 2000, rosiglitazone has been subject to 6 1-9 7 several risk-benefit assessments, especially concerning cardiovascular safety . In a May 8 9 2007 meta-analysis published in the New England Journal of Medicine, Nissen and Wolski 10 2 11 reported increased cardiovascular morbidity associated with rosiglitazone use . In 2008, the 12 13 European Medicines Agency (EMA) amended the rosiglitazone product label, adding coronary 14 15 syndrome toFor the list of contraindicationspeer andreview inserting a warning aboutonly potentially increased 16 10 17 risk of ischemic events . At the time of this label amendment, EMA concluded “that the 18 19 benefits of [...] rosiglitazone [...] in the treatment of type 2 diabetes continue to outweigh their 20 21 risks” 11. In June 2010, Nissen and Wolski updated their meta-analysis, confirming the finding 22 23 of an increased risk of myocardial infarction (but not the original finding of increased all- 24 25 cause mortality) in association with rosiglitazone use 12. In July 2010, Graham and colleagues 26 27 published a paper in JAMA, based on data from US Medicare beneficiaries, showing increased 28 29 risks of several cardiovascular events, as well as all-cause mortality, in a comparison of 30 31 rosiglitazone users with pioglitazone users 7. Following these two publications, on 22 32 33 September 2010, the EMA recommended suspension of use of all rosiglitazone-containing 34 http://bmjopen.bmj.com/ 35 products in the European Union 13. The European Commission subsequently mandated 36 37 suspension of the drug, citing absence of unique therapeutic benefits outweighing its risks 14. 38 39 Here we report results of an EMA-commissioned study on the impact of labelling 40 41 changes and findings reported in scientific publications on utilisation of rosiglitazone- 42 43 on September 27, 2021 by guest. Protected copyright. 44 containing products in Europe. On the population level, we examined changes in use of 45 46 rosiglitazone-containing products over the entire period when rosiglitazone was available on 47 48 the market. On the patient level, we assessed the impact of rosiglitazone discontinuation on 49 50 glycaemic control and reported oral hypoglycaemic agents prescribed after post-suspension 51 52 discontinuation of rosiglitazone. 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 50 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013.