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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

Primary Subject Epidemiology Heading:

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.

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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 secondline 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 20002010 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 metaanalysis 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

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 rosiglitazonecontaining 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, glucoselowering 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 19 7 several riskbenefit assessments, especially concerning cardiovascular safety . In a May 8 9 2007 metaanalysis 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 metaanalysis, 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 allcause 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 rosiglitazonecontaining

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 EMAcommissioned 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 rosiglitazonecontaining 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 postsuspension 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. Downloaded from

1 2 Methods 3 4 5 Setting and study population. This study was based on routinely collected data in Danish 6 7 and United Kingdom (UK) medical databases. In Denmark, the study population included 8 9 users of oral hypoglycaemic agents (OHAs) identified in the Aarhus University Prescription

10 15 11 Database (AUPD) . The database’s catchment area covers the North and Central Regions of 12 13 Denmark (hereafter referred to as ‘northern Denmark’), with a combined population in mid 14 15 2010 of 1,834,595For persons, peer which is about review onethird of the Danish only population. The AUPD 16 17 captures reimbursed prescriptions redeemed in the regions’ outpatient pharmacies since 1998. 18 19 In the UK, OHA users were identified from the General Practice Research Database (GPRD), 20 21 currently also known as the Clinical Practice Research Datalink. 22 23 We identified patients in each database with a prescription for any OHA between 1 24 25 January 2000 and 31 December 2010, encompassing the entire period of rosiglitazone 26 27 availability in Europe. We defined OHA users as persons who received at least one 28 29 prescription for any OHA during the study period. Prescriptions for OHAs were identified 30 31 using Anatomical Therapeutic Chemical (ATC) codes in the AUPD and Multilex codes in the 32 33 GPRD. People could have received prescriptions for multiple OHAs during the study period,

34 http://bmjopen.bmj.com/ 35 including rosiglitazone. Our use of the term ‘rosiglitazone’ includes all preparations of the 36 37 drug. 38 39 40 Start of rosiglitazone use was defined as the date of the firstrecorded prescription for a 41 42 rosiglitazonecontaining product. Patients were assumed to have discontinued rosiglitazone 43 on September 27, 2021 by guest. Protected copyright. 44 therapy in the absence of a record of a new rosiglitazone prescription during a period 45 46 encompassing the estimated length of at least two prescriptions. Prescription length was 47 48 estimated at 45 days in AUPD and 130 days in the GPRD, based on observed intervals 49 50 between prescriptions and knowledge about typical clinical practice in Denmark, as well as the 51 52 prescribing instructions in the British Monthly Index of Medications in the UK. 53 54 To describe the study population, we obtained data on participants’ clinical and 55 56 demographic characteristics, including sex, age, body mass index (BMI), smoking, medical 57 58 diagnoses, and use of other medications (lipidlowering agents, antihypertensive agents, 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 50 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 diuretics, nitrates, and antiplatelet agents). These characteristics were measured as of 1 3 4 January 2000 for patients who started an OHA before 2000 and on the date of the first OHA 5 6 prescription for those who started thereafter. We used records from routine laboratory tests to 7 8 obtain data on measured glycated haemoglobinA1c (HbA1c) and fasting plasma glucose (FPG) 9 10 levels. 11 12 Data sources. In northern Denmark, data on hospitalbased medical diagnoses, 13 14 prescription medications, and laboratory test results were obtained, respectively, from the 15 For peer review only 16 Danish National Registry of Patients (DNRP 16), from the AUPD, and from the Laboratory 17 18 Information Systems of the North and the Central Denmark Regions (LABKA 17). The 19 20 LABKA database stores results of laboratory tests performed at hospitalbased laboratories. 21 22 Patients are referred to these laboratories by hospitals, general practitioners, and specialists. 23 24 Data on smoking and BMI were obtained from the Danish National Indicator Project database 25 26 (http://www.nip.dk). All data were linked on the individual level using the universal personal 27 28 18 identifier . The GPRD is a longitudinal database that has collected data from over 450 29 30 general practices in the UK since 1987, covering a representative 6% sample of the UK 31 32 population. The GPRD captures prescriptions issued to patients by general practitioners, and it 33

34 http://bmjopen.bmj.com/ 35 also includes information on patient demographics, diagnoses, referrals, hospitalizations, and

36 1922 37 laboratory test results . 38 39 Statistical analysis. First, we examined changes in the proportion of rosiglitazone users 40 41 among all users of OHAs in the two countries between 2000 and 2010. Second, we compared 42 43 distributions of demographic and clinical characteristics between rosiglitazone users and users on September 27, 2021 by guest. Protected copyright. 44 45 of other OHAs. Third, we examined changes in HbA1c and FPG levels, comparing values 46 47 before and after discontinuation of rosiglitazone treatment. The prediscontinuation value of a 48 49 laboratory parameter was the value closest in time to the estimated discontinuation date within 50 51 24 months before that date. We defined three nonoverlapping postdiscontinuation periods as 52 53 follows: 3 months (90–179 days postdiscontinuation); 6 months (180–359 days post 54 55 discontinuation); and 12 months (360–479 days postdiscontinuation). We used the earliest 56 57 available measurement within each postdiscontinuation period. The postdiscontinuation 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 50 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 values were ascertained through 30 June 2011. Using the prediscontinuation and post 3 4 discontinuation values, we calculated the mean (with standard deviation) level for HbA1c and 5 6 FPG before and after discontinuation and the mean change for each postdiscontinuation 7 8 period. Furthermore, we calculated the proportion of patients with new postdiscontinuation 9 10 onset of loss of glycaemic control, defined as of HbA1c >7.5%, and the proportion of patients 11 12 with new postdiscontinuation onset of treatment failure, defined as FPG >10 mmol/L. To 13 14 capture new onset, these proportions first were computed among patients without evidence of 15 For peer review only 16 treatment failure/loss of glycaemic control before discontinuing rosiglitazone. We then 17 18 calculated the proportions of patients with clinically meaningful changes in HbA1c (change 19 20 >0.6%) and FPG (change >10%) after discontinuation of rosiglitazone. Finally, we examined 21

22 changes in HbA1c levels in patients who discontinued the drug on or after 23 September 2010, 23 24 presumably in response to the EMA’s suspension of the drug, and reported the first OHA 25 26 prescribed to patients who discontinued rosiglitazone after its suspension. The algorithms used 27 28 to define variables in this project are provided in the Appendix. We used SAS software 29 30 version 9.2 (SAS Inc., Cary, NC, USA) to analyse the data. 31 32 Ethical approval. This study was approved by the Danish Data Protection Agency 33

34 http://bmjopen.bmj.com/ 35 (record number 2009413866) and by the Independent Scientific Advisory Committee of the 36 37 GPRD. There was no patient contact, and informed consent was therefore not required. 38 39 40 Results 41 42 During the study period, 67,525 OHA users were recorded in the AUPD and 191,276 in on September 27, 2021 by guest. Protected copyright. 43 44 the GPRD. Of these, 2,321 (3.4%) persons in the AUPD and 25,428 (13%) persons in the 45 46 47 GPRD received at least one prescription for a rosiglitazonecontaining product. Figure 1 48 49 shows changes in the proportion of rosiglitazone users among all OHA users within the study 50 51 period. This proportion peaked at 4% in northern Denmark and at 15% in the UK in May 52 53 2007, and rapidly decreased thereafter, with virtually no rosiglizatone users remaining after 54 55 2010. 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 50 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 Table 1 compares demographic and clinical characteristics of users of rosiglitazone and 3 4 users of other OHAs. Rosiglitazone users tended to be younger, but were more likely to have 5 6 had a prescription history of lipidlowering or antihypertensive agents. Rosiglitazone users 7 8 were more likely than the other OHA users to have used OHAs other than metformin and 9 10 sulfonylurea previously. Based on data from the GPRD, users of rosiglitazonecontaining 11 12 products were slightly more likely than other OHA users to have a BMI of ≥30 kg/m2 (Table 13 14 1). 15 For peer review only 16 Glycaemic control after discontinuation of rosiglitazone. Among all rosiglitazone users in 17 18 the LABKA 1776 who discontinued the drug had HbA1c measurements available. The mean 19 20 duration of rosiglitazone use in these patients was 24.1months (standard deviation 21.1), 21 22 median 18.8. In the GPRD there were 21145 rosiglitazone users with HbA measurements. 23 1c 24 The mean duration of use in these patients was 30.3 (standard deviation 25.5), median, 24,0 . 25 26 Table 2 shows changes in HbA at three, six, and 12 months after discontinuation of 27 1c 28 rosiglitazone treatment at any time during the study period. At 12 months post 29 30 discontinuation, a change of similar magnitude in the mean HbA was observed in both the 31 1c 32 LABKA (Denmark) and Laboratory (UK) databases: –0.16% (95% confidence interval [CI]: – 33

34 http://bmjopen.bmj.com/ 35 3.4%, 3.1%) in northern Denmark, and –0.17% (95% CI: –0.21%, 0.13%) in the UK. Loss of 36 37 glycaemic control, defined by new onset of HbA1c>7.5%, was registered for up to 29% of 38 39 patients during the 12month followup period in Denmark and for up to 37% of patients in the 40 41 UK. Similar proportions of patients had HbA1c values consistent with a clinically meaningful 42 43 decrease (>0.6%) at 12 months. on September 27, 2021 by guest. Protected copyright. 44 45 Table 3 shows changes in HbA1c after discontinuation of rosiglitazonecontaining 46 47 products on or after 23 September 2010. Thus, Table 3 represents subset of patients described 48 49 in Table 2. In the UK data, mean HbA1c decreased by 1.8% at six months post 50

51 discontinuation (95% CI: –2.1%, –1.6%), but the prediscontinuation mean HbA1c in this 52 53 group was 10%. A larger proportion of patients in the UK than in Denmark had evidence of 54 55 loss of glycaemic control and a substantially larger proportion of patients in the UK 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 50 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 experienced a clinically meaningful decrease in HbA1c after discontinuation of rosiglitazone 3 4 compared with Denmark (Table 3). 5 6 Table 4 shows changes in FPG at three, six, and 12 months after discontinuation of 7 8 rosiglitazone. At 12 months postdiscontinuation, there was virtually no change seen in either 9 10 of the databases: mean change = 0.01 mmol/L (95% CI: –7.3 mmol/L; 7.3 mmol/L) in 11 12 Denmark and mean change = 0.03 mmol/L (95% CI: –0.22 mmol/L; 0.28 mmol/L) in the UK. 13 14 Treatment failure, defined by new onset of FPG >10 mmol/L during one of the followup 15 For peer review only 16 periods, was observed in a maximum of 23% of patients in Denmark and 20% in the UK. The 17 18 number of persons with available measurements for Denmark, however, was small (Table 4). 19 20 Table 5 shows the distribution of OHA prescribed to patients after terminating rosiglitazone 21 22 on 23 September 2010 or later. The majority of patients switched to another OHA (82% in 23 24 Denmark; 97% in the UK) after the last recorded pioglitazone prescription. The majority of 25 26 patients – 56.8% in Denmark and 41.7% in the UK – received a prescription for meformin. In 27 28 the UK, 23.6% of patients had a prescription for pioglitazone, and 14.5% for pioglitazone + 29 30 metformin. Pioglitazone was prescribed only to 4.4% of the patients in northern Denmark. 31 32 33 Discussion

34 http://bmjopen.bmj.com/ 35 36 We examined use of rosiglitazonecontaining products over the entire period of 37 38 availability of this drug in Europe (2000–2010) using routinely collected data in medical 39 40 databases in Denmark and the UK. Overall, the drug was more widely used in the UK than in 41 42 Denmark, with the proportion of rosiglitazone users among all users of OHA peaking at 15% on September 27, 2021 by guest. Protected copyright. 43 44 and 4% in the two countries, respectively. The timing of both peaks, which marked the 45 46 47 beginning of a steep decline in use, coincided with the May 2007 publication of the meta

48 2 49 analysis by Nissen and Wolski and subsequent regulatory warnings from the EMA. This 50 51 decline occurred three years before the regulatory decision to suspend rosiglitazone in Europe. 52 53 Similarly, a sharp decline in prescribing occurred in the United States after the FDA added a

54 23 55 boxed warning to the rosiglitazone label in May 2007 . On the patient level, discontinuation 56 57 of rosiglitazone was associated with a slight overall decrease in the mean level of glycated 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 50 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 haemoglobin. However, close to onethird of patients had evidence consistent with loss of 3 4 glycaemic control during the 12 months of followup, including patients who discontinued 5 6 rosiglitazone after the EMA decision to suspend the drug. The majority of patients who 7 8 discontinued rosiglitazone after suspension started receiving metformin. 9 10 While on the market, rosiglitazone represented a larger proportion of all OHA use in the 11 12 UK than in Denmark. This may reflect conservative recommendations issued in Denmark, 13 14 suggesting that treatment first be attempted with metformin, sulfonurea, and insulin 24. 15 For peer review only 16 Guidelines from the National Institute for Health and Clinical Excellence (NICE) in the UK 17 18 stated that rosiglitazone should only be prescribed if other classes of OHA were not effective 19 20 in lowering plasma glucose concentrations.Therefore rosiglitazone was recommended only as 21 22 second or third line therapy 25. The high prediscontinuation level of HbA in UK patients 23 1c 24 who discontinued rosiglitazone following the drug suspension is also consistent with this 25 26 guideline. Among patients terminating rosiglitazone after the drug was suspended, a larger 27 28 proportion of UK patients compared with their Danish counterparts experienced a clinically 29 30 meaningful decrease in glycated haemoglobin. The prediscontinuation values among the UK 31 32 patients were substantially higher. We thus attribute this to the result of patients with poor 33

34 http://bmjopen.bmj.com/ 35 glycaemic control coming to medical attention. 36 37 The data presented here were obtained from medical databases that provide data on 38 39 routine and independent registration of healthrelated events in two European countries. Such 40 41 data are likely to reflect typical clinical practice. The data from the two data systems are also 42 43 complementary. The AUPD records filled prescriptions, while the GPRD records prescriptions on September 27, 2021 by guest. Protected copyright. 44 45 issued by general practitioners. Furthermore, the databases draw on different health sectors for 46 47 information on patient characteristics. In Denmark data on diagnoses originate from hospital 48 49 discharge summaries, while GPRD data on diagnoses originate from generalpractitioner 50 51 records. Despite these differences and potential differences in the underlying patient 52 53 populations, the results obtained from the two data systems were generally consistent. 54 55 Because OHA are distributed by prescription only and need to be taken longterm, the 56 57 information we present on rosiglitazone utilization over calendar time is likely to be accurate. 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 50 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 The pattern of use for the two Danish regions mirrors the nationwide pattern reported by the 3 26 4 Danish Medicines Agency . However, because automated prescription records provide no 5 6 information on timing of drug intake, we had to make assumptions about timing of 7 8 rosiglitazone discontinuation and prescription length. We speculate that shortterm changes in 9 10 laboratory parameters following discontinuation of rosiglitazone are subject to more 11 12 misclassification due to errors in assigning the discontinuation status than are longterm 13 14 changes in these parameters. Therefore, our 12month estimates of postdiscontinuation 15 For peer review only 16 change in laboratory parameters may be more robust than the 3month estimates. The 17 18 information on glycated haemoglobin A1c and on fasting plasma glucose originated from 19 20 routinely collected laboratory data, although patients with laboratory measurements may differ 21 22 from the entire population of rosiglitazonetreated patients. For example, physicians may be 23 24 less likely to routinely collect laboratory data for patients with less severe diabetes. 25 26 In summary, a decline in use of rosiglitazone occurred immediately following the May 27 28 2 2007 publication of a metaanalysis describing adverse cardiac side effects of this drug . 29 30 Changes in glycaemic control after discontinuation of rosiglitazone were small on average 31 32 during the 12 month followup period, although about onethird of patients had evidence of 33

34 http://bmjopen.bmj.com/ 35 loss of glycaemic control upon discontinuation. Most patients were switched to a metformin 36 37 containing regimen. 38 39 40 Acknowledgements 41 42 We thank the Pharmacovigilance Working Party (PhVWP) at the European Medicines on September 27, 2021 by guest. Protected copyright. 43 44 Agency for helpful comments. We are grateful to Hanne Kjeldahl Schlosser, Helle Vester, and 45 46 47 Kathleen Jick for outstanding administrative support. 48 49 50 Funding 51 52 This study was commissioned and funded by the European Medicines Agency (Procurement 53 54 Procedure No. EMA/2010/38/CN). The funding agency had no direct role in preparation of 55 56 this manuscript. 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12 of 50 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 Disclaimer 3 4 5 This document expresses the opinions of the authors of the paper, and may not be understood 6 7 or quoted as being made on behalf or of reflecting the position of the European Medicines 8 9 Agency or one of its committees or working parties. 10 11 12 Contribution statement 13 14 15 V. EhrensteinFor participated peer in conception review and design of the study, only led the writing, and 16 17 contributed to data analysis. R. K. Hernandez contributed to study design and data analysis in 18 19 the GPRD. S. P. Ulrichsen conducted the data analyses in Denmark, J. Rungby contributed to 20 21 study design and analysis, and provided clinical expertise, T.L. Lash participated in 22 23 conception and design of the study, A.H. Riis contributed to data analysis of the AUPD data, 24 25 L. Li contributed to data analysis of the GPRD data, H.T. Sørensen oversaw the study and 26 27 provided clinical expertise, and S. S. Jick participated in conception and design of the study. 28 29 All authors participated in revisions of the manuscript draft for intellectual content. 30 31 32 33 This study has received the ENCePP Study Seal (Reference number

34 http://bmjopen.bmj.com/ 35 ENCEPP/SDPP/1777). 36 37 38 39 Exclusive license statement 40 41 The Corresponding Author has the right to grant on behalf of all authors and does grant 42 on September 27, 2021 by guest. Protected copyright. 43 on behalf of all authors, an exclusive licence (or non exclusive for government employees) on 44 45 a worldwide basis to the BMJ Publishing Group Ltd and its Licensees to permit this article (if 46 47 accepted) to be published in BMJ editions and any other BMJPGL products and sublicences to 48 49 exploit all subsidiary rights, as set out in our licence. 50 51 52 53 Competing interest statement 54 55 All authors have completed the ICMJE uniform disclosure form at and declare: being 56 57 funded by the EMA (through institutional contracts and subcontracts) for this work; no 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 50 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 financial relationships with any organisations that might have an interest in the submitted 3 4 work in the previous three years, no other relationships or activities that could appear to have 5 6 influenced the submitted work. 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33

1 2 References 3 4 5 1. Home PD, Pocock SJ, BeckNielsen H, Gomis R, Hanefeld M, Jones NP, et al. 6 Rosiglitazone evaluated for cardiovascular outcomesan interim analysis. N Engl J 7 Med 2007;357(1):2838. 8 2. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death 9 from cardiovascular causes. N Engl J Med 2007;356(24):245771. 10 3. Psaty BM, Furberg CD. Rosiglitazone and Cardiovascular Risk. New England Journal of 11 Medicine 2007;356(24):252224. 12 4. Margolis DJ, Hoffstad O, Strom BL. Association between serious ischemic cardiac 13 outcomes and medications used to treat diabetes. Pharmacoepidemiol Drug Saf 14 2008;17(8):7539. 15 For peer review only 16 5. EMEA statement on recent publication on cardiac safety of rosiglitazone (Avandia, 17 Avandamet, Avaglim). 18 http://www.emea.europa.eu/docs/en_GB/document_library/Press_release/2009/11/W 19 C500013467.pdf. 2009. 20 6. Home PD, Pocock SJ, BeckNielsen H, Curtis PS, Gomis R, Hanefeld M, et al. 21 Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination 22 therapy for type 2 diabetes (RECORD): a multicentre, randomised, openlabel trial. 23 Lancet 2009;373(9681):212535. 24 7. Graham DJ, OuelletHellstrom R, MaCurdy TE, Ali F, Sholley C, Worrall C, et al. Risk of 25 acute myocardial infarction, stroke, heart failure, and death in elderly Medicare 26 patients treated with rosiglitazone or pioglitazone. JAMA 2010;304(4):4118. 27 28 8. Nissen SE. The rise and fall of rosiglitazone. Eur Heart J 2010;31(7):7736. 29 9. Blind E, Dunder K, de Graeff PA, Abadie E. Rosiglitazone: a European regulatory 30 perspective. Diabetologia 2011;54(2):2138. 31 10. EMEA recommends new warnings and contraindications for rosiglitazone 32 http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2009/11/WC 33 500015420.pdf. 2008.

34 http://bmjopen.bmj.com/ 11. European Medicines Agency confirms positive benefitrisk balance for rosiglitazone and 35 36 pioglitazone. 37 http://www.emea.europa.eu/docs/en_GB/document_library/Press_release/2009/11/W 38 C500011009.pdf. 2009. 39 12. Nissen SE, Wolski K. Rosiglitazone Revisited: An Updated Metaanalysis of Risk for 40 Myocardial Infarction and Cardiovascular Mortality. Arch Intern Med 2010. 41 13. European Medicines Agency recommends suspension of Avandia, Avandamet and 42

Avaglim. on September 27, 2021 by guest. Protected copyright. 43 http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2010/09/WC 44 500096996.pdf. 2010. 45 14. The European Commission. Commission Decision of 3.12.2010 suspending, under Article 46 20 of Regulation (EC) No 726/2004 of the European Parliament and of the Council, 47 the marketing authorisation, granted by Decision C(2000)1799, for "Avandia 48 Rosiglitazone" a medicinal product for human use. 2010. 49 50 15. Ehrenstein V, Antonsen S, Pedersen L. Existing data sources for clinical epidemiology: 51 Aarhus University Prescription Database. Clin Epidemiol 2010;2:2739. 52 16. Lynge E, Sandegaard JL, Rebolj M. The Danish National Patient Register. Scand J Public 53 Health 2011;39(7 Suppl):303. 54 17. Grann AF, Erichsen R, Nielsen AG, Froslev T, Thomsen RW. Existing data sources for 55 clinical epidemiology: The clinical laboratory information system (LABKA) research 56 database at Aarhus University, Denmark. Clinical epidemiology 2011;3:1338. 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 15 of 50 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 18. Pedersen CB, Gotzsche H, Moller JO, Mortensen PB. The Danish Civil Registration 3 System. A cohort of eight million persons. Dan Med Bull 2006;53(4):4419. 4 19. Jick H, Jick SS, Derby LE. Validation of information recorded on general practitioner 5 based computerised data resource in the United Kingdom. BMJ 1991;302(6779):766 6 8. 7 20. Clinical Practice Research Datalink. http://www.cprd.com. 8 9 21. Garcia Rodriguez LA, Perez Gutthann S. Use of the UK General Practice Research 10 Database for pharmacoepidemiology. Br J Clin Pharmacol 1998;45(5):41925. 11 22. Jick SS, Kaye JA, VasilakisScaramozza C, Garcia Rodriguez LA, Ruigomez A, Meier 12 CR, et al. Validity of the general practice research database. Pharmacotherapy 13 2003;23(5):6869. 14 23. Shah ND, Montori VM, Krumholz HM, Tu K, Alexander GC, Jackevicius CA. 15 RespondingFor to anpeer FDA warninggeographic review variation inonly the use of rosiglitazone. N 16 Engl J Med 2010;363(22):20814. 17 24. http://hjertedoktor.dk/content/pdf/dsams%20vejledning%20for%20type2%20diabetes.pdf. 18 19 25. National Collaborating Centre for Chronic Conditions. Type 2 diabetes: national clinical 20 guideline for management in primary and secondary care (update). London: Royal 21 College of Physicians. 2009. 22 26. The Danish Medicines Agency. Polypharmacy in diabetes care. 23 http://www.dkma.dk/1024/visUKLSArtikel.asp?artikelID=1665. 24 25 26 27 28 29 30 31 32 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 BMJ Open Page 16 of 50 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from Figure 1. Proportion of users of rosiglitazone among all users of oral hypoglycaemic agents 1 (OHA), 20002010. 2 3 4 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 Note: The maximum points of both graphs correspond to May 2007, the month of publication of 30 the initial metaanalysis by Nissen and Wolski.2 31 32 33

N N (%) agents 5,882 (3.6) 5,882 5,725 (3.5) 5,725 57,984 (35)57,984 90,682 (55)90,682 95,607 (58)95,607 9,147 (5.5) 9,358 (5.6) 14,194 (8.6)14,194 12,257 (7.4)12,257 78,772 (48)78,772 25,023 (15)25,023 (23)38,668 87,076 (53) 87,076 42,030 (25) 42,030 (17) 28,430 114,378 114,378 (69) 144,881 144,881 (87) 13,192 (8.0) 13,192 (n=165,848) hypoglycaemic hypoglycaemic Users of Users of oralother

(n=191,276)

United Kingdom N (%) 857 (3.4)857 336 336 (1.3) 589 589 (2.3) 9,297 (37)9,297 7,925 (31)7,925 2,582 (10) 2,582 2,242 (8.8) 7,661 (30)7,661 5,513 (22)5,513 6,434 (25) 6,434 22,223 (87)22,223 23,836 (94) 23,836 (77) 19,489 16,646 (65) 16,646 2,426 (9.5) 2,469 (9.7) (n=25,428) 11,259 (44)11,259 14,169 (56) 14,169 Users of rosiglitazone Users of BMJ Open

http://bmjopen.bmj.com/ N N (%) 196 196 (0.30) 3,121 (4.8)3,121 4,551 (7.0)4,551 4,149 (6.4)4,149 5,530 (8.5) 5,530 3,999 (6.1) 3,999 (7.6) 4,967 (n=65,204) 40,327 (62)40,327 30,845 (47)30,845 19,470 (30)19,470 51,022 (78) 51,022 (61) 39,931 34,359 (53) 34,359 (63) 41,183 15,724 (24) 15,724 (16) 10,423 16,751 (26)16,751 10,219 (16)10,219 Users Users of oral other hypoglycaemic agentshypoglycaemic n=67,525) n=67,525) on September 27, 2021 by guest. Protected copyright. ( Northern Northern Denmark

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml N N (%) 81 (3.5)81 9 9 (0.39) 66 (2.8)66 83 (3.6) 83 976 (42) 976 517 (22) 517 561 (24) 561 497 (21) 497 444 (19) 444 286 (12) 286 757 (33) 757 595 (26) 595 147 (6.3) 147 (n=2,321) 2,279 (98) 2,279 (74) 1,730 For peer review(58) 1,345 (73) 1,694 only Users of rosiglitazone Users of

edication use

lucose g

Baseline characteristics of patients treated with rosiglitazone and other oral hypoglycaemic agents from 1 January 2000 to 31 December 2010 in northern in 2010 northern 31to December 2000 1 January from agents hypoglycaemic other oral and rosiglitazone with treated ofpatients characteristics Baseline oral oral

74 84 44

Other agentsLipid lowering (84) 1,939 Metformin Sulfonylurea Pioglitazone lowering drugs** DPP Inhibitor 4 3+ Male 0 12 65 75 Female 5564 <35 35 4554 ≥85 Table 1. Table Denmark and the United Kingdom. Kingdom. United the and Denmark Characteristic History History of m other Charlson Charlson comorbidity index Age Age group, years History History OHA of use before baseline* Sex Page 17 of 50 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from Page 18 of 50 Page 18 of2218 Page

322 (0.19)322 623 (0.38) 623 73,225 (44)73,225 66,725 (40)66,725 43,985 (27)43,985 75,119 (45)75,119 49,463 (30)49,463 21,634 (13)21,634 27,403 (17)27,403 18,624 (11)18,624 28,120 (17)28,120 15,223 (9.2) 15,223 126,897 126,897 (77)

52 (0.20) 52 35 (0.14) 35 6,102 (24)6,102 7,458 (29)7,458 2,675 (11)2,675 4,035 (16) 4,035 3,128 (12) 3,128 2,878 (11) 2,878 (18) 4,499 13,516 (53)13,516 11,225 (44)11,225 11,699 (46)11,699 21,846 (86)21,846

. ter BMJ Open

http://bmjopen.bmj.com/

32 (0.05) 32 9,456 (14) 5,454 (8.4)5,454 3,121 (4.8)3,121 3,534 (5.4)3,534 3,257 (5.0)3,257 1,257 (1.9)1,257 2,451 (3.8) 2,451 34,650 (53)34,650 48,016 (74)48,016 55,204 (85) 55,204 56,098 (86) 56,098 33,060 (51) 33,060 on September 27, 2021 by guest. Protected copyright.

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 51 (2.2)51 2 2 (0.09) 351 (15) 351 462 (20) 462 258 (11) 258 215 (9.3)215 177 (7.6)177 175 (7.5) 175 1,404 (60)1,404 1,991 (86)1,991 1,629 (70) 1,629 1,673 (72) 1,673 1,409 (61) 1,409

For peer review only

anuary 1, anuary date 2000 first OHA or prescription,of whichever came la

gents gents Antihypertensive a Missing Missing < 18.5 <25 – 18.5 Antiplatelet agents Antiplatelet Current Former Diuretics 25 <3025 – ≥ 30 Nitrates Never

Baseline date was J * Body Body mass index category, kg/m **Other excludingglucoselowering insulinsdrugs acarbose,arerepaglinide, exenatide, liraglutide.and Smoking 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

0.13) 0.21; 0.21; 8.2 (1.8) 8.2 8.4 (1.9) 8.4 (n=8,635) 12 12 months 0.17 ( 0.17 Page 19 of 22 of 22 19 Page

0.26) 0.34; 0.34; 8.2 (1.8) 8.2 8.5 (2.1) 8.5 6 6 months 35 (34; 35 36) (35; 38) 37 28 (27; 28 28) (28; 30) 29 36 (35; 36 37) (33; 35) 34 (n=12,439) 1,641/4,672 1,246/3,408 0.30 ( 0.30 United KingdomUnited

0.53) 0.62; 0.62; 8.7 (2.2)8.7 8.1 (1.7)8.1 3 months 3 (n=9,448) 31 (30; 33)31 23 (22; 24)23 40 (39; 41)40 1,026/3,286 0.57 ( 0.57

3.4; 3.4; 3.1) 7.9 (1.7)7.9 7.7 (1.5)7.7 (n=1,162) 12 12 months 0.16 ( 0.16 mong patients with available preand postdiscontinuation measurements, in in measurements, postdiscontinuation preand available with patients mong BMJ Open

http://bmjopen.bmj.com/ 3.1; 3.1; 3.0) 7.8 (1.6)7.8 7.7 (1.5)7.7 6 months 6 (n=1,496) 0.05 ( 0.05 orthern Denmarkorthern N

on September 27, 2021 by guest. Protected copyright. 3.0; 3.0; 2.8) 160/670 160/670 228/827 179/610 7.8 (1.7)7.8 7.7 (1.5)7.7 3 months3 (n=1,242) 24 (21; 27) 24 (25; 31) 28 (26; 33) 29 26 (24; 29) 26 (26; 30) 28 (26; 31) 28 28 (25; 30) 28 (25; 29) 27 (27; 32) 30 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 0.10 ( 0.10 For peer review only

before and after discontinuation of rosiglitazone a rosiglitazone of discontinuation after and %) before

=glycated A; =glycated haemoglobin SD=standard deviation >7.5%, 1c 1c 7.5% after 7.5% baseline/N ≤7.5% ≤7.5% 1c

b level>

Glycated haemoglobin ( haemoglobin Glycated 1c

northern Denmark and in the United Kingdom, 20002011. 20002011. Kingdom, United in the and Denmark northern

Table 2. Table CI=confidenceinterval; HbA *Clinically *Clinically meaningful change defined using to European the Agency’sMedicines as definition change of thanmore 0.6% the (% is unit)test Characteristic Change from Change from baseline, (95% mean CI) Proportion with clinically a meaningful Followup mean (SD) increase, percent (95% CI) with baseline HbA Proportion Proportion with clinically a meaningful* decrease, percent (95% CI) Baseline Baseline (SD)mean glycaemic glycaemic control with HbA N with HbANwith New postdiscontinuation loss of onset of percent (95%percent CI) Page 19 of 50 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1.6)

Page 20 of 50 2.1; 2.1; 18/55 10 (2.5) 10 (n=338) 8.3 (2.1)8.3 6 months 6 69 (64; 74)69 15 (12; 19)15 33 (22; 46) 33 1.8 ( 1.8 Page 20 of 22 of 22 20 Page

United Kingdom 1.8)

2.2; 87/196 10 (2.5)10 8.0 (2.0) 8.0 3 3 months (n=1081) 44 (38;51) 44 14 (12; 14 16) 72 (69; 72 75) 2.0 ( 2.0

1.8;2.5) 94/350 (n=455) (n=455) 7.4 (1.4)7.4 7.1 (1.2)7.1 6 months6 33 (29;38)33 27 (22; 32) 27 12 (9.3; 12 15) 0.34 ( 0.34

orthern Denmarkorthern

N 1.9; 1.9; 2.7) 76/285 (n=376) 7.5 (1.5)7.5 7.1 (1.2)7.1 3 months 3 34 (29;38)34 27 (22; 32) 27 13 (9.5; 13 16) 0.40 ( 0.40 BMJ Open http://bmjopen.bmj.com/ 7.5%, percent >

HbA

≤7.5%

with 1c on September 27, 2021 by guest. Protected copyright. For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml , (95%percent CI) , percent ,(95% percent CI) a Fora peer review only of of glycaemic control

=glycated haemoglobin A; SD=standarddeviationnceinterval 1c onset of loss level>7.5% after baseline/N with baseline HbA

1c Glycated haemoglobin (%) before and after discontinuation of rosiglitazonecontaining products, among users who discontinued the drug on or after 23 23 orafter on drug the discontinued who users among products, of rosiglitazonecontaining discontinuation after and before (%) haemoglobin Glycated discontinuation

post

September 2010 (date of the EMA’s recommendation to suspend rosiglitazone), in northern Denmark and in the United Kingdom. Kingdom. United in the and Denmark northern in rosiglitazone), suspend to recommendation EMA’s the of 2010 (date September Table 3. Table Clinically Clinically meaningful change Europeandefined using to the Agency’sMedicines changedefinition as than more (% is 0.6%of testthe unit) Characteristic Proportion Proportion with a clinically meaningful decrease Change from Changebaseline, (95%CI) mean a Followup Followup mean (SD) Proportion with a clinically meaningful increase (95% CI) Baseline mean (SD) Baseline mean CI=confidence interval; CI=confidence interval; HbA N with HbA N with New 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from Page 21 of 22 of 22 21 Page (n=800) 12 12 months 6 6 months (n=1,256) United KingdomUnited 98/610 182/911 99/583 (n=820) (n=820) 8.6 (3.2)8.6 (3.2) 8.7 (3.4) 8.7 8.8 (3.2)8.8 (3.1) 8.8 (3.1) 8.7 3 months3 8/54 (n=77) 9.1 (3.5)9.1 9.1 (3.5)9.1 12 12 months 40 (30; 51)40 (27; 33) 30 (31; 33 36) (31; 38) 34 32 (23; 43)32 (36; 43) 39 (38; 40 43) (37; 44) 40 15 (7.3; 15 26) (13, 16 19) (18; 20 23) (14; 20) 17 BMJ Open http://bmjopen.bmj.com/ 18/79 (n=109) 9.3 (3.4)9.3 9.0 (3.4)9.0 6 months6 23 (15; 33)23 35 (26; 44)35 35 (26; 44)35 orthern Denmark orthern N on September 27, 2021 by guest. Protected copyright. 14/65 14/65 (n=95) 9.5 (3.6) 9.5 9.2 (3.7) 9.2 3 3 months For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 22 (13; 22 33) 39 (30; 39 49) 40 (31; 40 50) For peer review only =glycated haemoglobin A; SD=standarddeviation 1c Fasting plasma glucose (mmol/L) before and after discontinuation of rosiglitazone among patients with available preand postdiscontinuation laboratory laboratory postdiscontinuation preand withavailable patients among rosiglitazone of discontinuation after and before (mmol/L) glucose plasma Fasting discontinuation onset of

measurements, in northern Denmark and in the United Kingdom, 20002011. 20002011. Kingdom, in United the and Denmark in northern measurements, Table 4. Table Characteristic *Clinically *Clinically meaningful changeEuropean defined using to the definition Agency’sMedicines as change more of than 10 mmol/L. CI=confidence interval; HbA treatment treatment failure, mmol/L, FPG>10 with with baseline FPG ≤10 mmol/L Proportion Proportion with a clinically meaningful decrease*, (95%percent CI) Proportion Proportion with a clinically meaningful increase*, percent (95% CI) Change from Changebaseline, (95%CI) mean (9.0; 0.38 8.2) (8.2;7.6) 0.27 (7.3; 0.01 7.3) (0.04; 0.27 0.49) (0.12; 0.08 0.27) 0.03 (0.22; 0.28) Followup Followup mean (SD) Baseline mean (SD) Baseline mean percent (95%percent CI) New post New N with N with afterFPG >10 mmol/L baseline/N Page 21 of 50 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from Page 22 of 50 Page 22 of 22 of 22 22 Page

Kingdom Kingdom

2.1 (1.6; 2.1 2.7) (3.1; 3.8 4.6) (0.4; 0.6 1.0) (0.2; 0.3 0.6) (0.0; 0.1 0.3) (0.1; 0.2 0.4) (0.2; 0.3 0.6) 41.7 (39.9;41.7 43.6) (22.0;23.6 25.2) (13.2;14.5 15.9) (11.7;12.9 14.2) Percent (95% Percent (95% CI) (n=2810**)

9 2 4 9 57 16 103 641 394 351 1,136 Number GeneralPractice Research Database, United BMJ Open

http://bmjopen.bmj.com/

(0.1; 1.0) 7.4 (5.0; 7.4 9.7) (3.4; 5.5 7.5) (2.6; 4.4 6.3) (1.9; 3.6 5.3) (0.5; 1.7 2.8) (0.5; 1.7 2.8) (0.1; 0.8 1.7) (0.1; 0.8 1.7) (0.1; 0.6 1.3) (0.1; 0.6 1.3) 0.4 (0.1; 0.2 0.6) 9.5 (6.9; 9.5 12.1) 10.3 (7.6; 13.1) 56.8 (52.3; (52.3; 56.8 61.2) (14.3; 17.7 21.2) Percent (95% Percent (95% CI) on September 27, 2021 by guest. Protected copyright. (n=474*) For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

8 8 4 4 3 3 2 1 84 49 45 35 26 21 17 269

Number For peer review only Aarhus University Aarhus PrescriptionDatabase, Denmark

Oral hypoglycaemic agents (OHA) prescribed to patients after terminating rosiglitazone on 23 September 2010 or later. later. 2010 or September 23on rosiglitazone terminating after patients to prescribed (OHA) agents hypoglycaemic Oral

Table 5. Table Metformin Glimepiride Metformin+sitagliptin Sitagliptin Metformin+vildagliptin Liraglutide Pioglitazone Pioglitazone + metformin Gliclazide Glibenclamide Saxagliptin Glipizide Vildagliptin Repaglinide Exenatide Acarbose Tolbutamide *83 patients recordhad no another OHA afterlastof rosiglitazonethe prescription. **88 nopatients recordhad after of another OHA lastthe rosiglitazone prescription

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Page 23 of 50 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 STROBE Statement—checklist of items that should be included in reports of observational studies 3 4 Item 5 No Recommendation 6 Title and abstract 7 1 (a) Indicate the study’s design with a commonly used term in the title or the N/A 8 abstract 9 (b) Provide in the abstract an informative and balanced summary of what was x 10 done and what was found 11 12 Introduction 13 Background/rationale 2 Explain the scientific background and rationale for the investigation being x 14 reported 15 Objectives For3 peer State specific objectives, review including any prespecified only hypotheses x 16 17 Methods 18 Study design 4 Present key elements of study design early in the paper x 19 Setting 5 Describe the setting, locations, and relevant dates, including periods of x 20 21 recruitment, exposure, follow-up, and data collection 22 Participants 6 (a) Cohort study—Give the eligibility criteria, and the sources and methods of x 23 selection of participants. Describe methods of follow-up 24 Case-control study—Give the eligibility criteria, and the sources and methods of 25 26 case ascertainment and control selection. Give the rationale for the choice of 27 cases and controls 28 Cross-sectional study—Give the eligibility criteria, and the sources and methods 29 of selection of participants 30 (b) Cohort study—For matched studies, give matching criteria and number of N/A 31 32 exposed and unexposed 33 Case-control study—For matched studies, give matching criteria and the number

34 of controls per case http://bmjopen.bmj.com/ 35 Variables 7 Clearly define all outcomes, exposures, predictors, potential confounders, and x 36 37 effect modifiers. Give diagnostic criteria, if applicable 38 Data sources/ 8* For each variable of interest, give sources of data and details of methods of 39 measurement assessment (measurement). Describe comparability of assessment methods if 40 there is more than one group 41 Bias 9 Describe any efforts to address potential sources of bias x 42 43 Study size 10 Explain how the study size was arrived at x on September 27, 2021 by guest. Protected copyright. 44 Quantitative variables 11 Explain how quantitative variables were handled in the analyses. If applicable, x 45 describe which groupings were chosen and why 46 Statistical methods 12 (a) Describe all statistical methods, including those used to control for x 47 48 confounding 49 (b) Describe any methods used to examine subgroups and interactions x 50 (c) Explain how missing data were addressed N/A 51 (d) Cohort study—If applicable, explain how loss to follow-up was addressed N/A 52 53 Case-control study—If applicable, explain how matching of cases and controls 54 was addressed 55 Cross-sectional study—If applicable, describe analytical methods taking account 56 of sampling strategy 57 (e) Describe any sensitivity analyses N/A 58 59 Continued on next page 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml1 BMJ Open Page 24 of 50 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 Results 3 Participants 13* (a) Report numbers of individuals at each stage of study—eg numbers potentially eligible, x 4 5 examined for eligibility, confirmed eligible, included in the study, completing follow-up, 6 and analysed 7 (b) Give reasons for non-participation at each stage N/A 8 (c) Consider use of a flow diagram 9 Descriptive 14* (a) Give characteristics of study participants (eg demographic, clinical, social) and x 10 11 data information on exposures and potential confounders 12 (b) Indicate number of participants with missing data for each variable of interest x 13 (c) Cohort study—Summarise follow-up time (eg, average and total amount) x 14 Outcome data 15* Cohort study—Report numbers of outcome events or summary measures over time 15 For peer review only 16 Case-control study—Report numbers in each exposure category, or summary measures of 17 exposure 18 Cross-sectional study—Report numbers of outcome events or summary measures 19 Main results 16 (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their N/A 20 21 precision (eg, 95% confidence interval). Make clear which confounders were adjusted for 22 and why they were included 23 (b) Report category boundaries when continuous variables were categorized x 24 (c) If relevant, consider translating estimates of relative risk into absolute risk for a N/A 25 26 meaningful time period 27 Other analyses 17 Report other analyses done—eg analyses of subgroups and interactions, and sensitivity 28 analyses 29 Discussion 30 31 Key results 18 Summarise key results with reference to study objectives x 32 Limitations 19 Discuss limitations of the study, taking into account sources of potential bias or x 33 imprecision. Discuss both direction and magnitude of any potential bias

34 http://bmjopen.bmj.com/ Interpretation 20 Give a cautious overall interpretation of results considering objectives, limitations, x 35 36 multiplicity of analyses, results from similar studies, and other relevant evidence 37 Generalisability 21 Discuss the generalisability (external validity) of the study results x 38 Other information 39 40 Funding 22 Give the source of funding and the role of the funders for the present study and, if x 41 applicable, for the original study on which the present article is based 42 on September 27, 2021 by guest. Protected copyright. 43 *Give information separately for cases and controls in case-control studies and, if applicable, for exposed and 44 unexposed groups in cohort and cross-sectional studies. 45 46 47 Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and 48 published examples of transparent reporting. The STROBE checklist is best used in conjunction with this article (freely 49 available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at 50 http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is 51 52 available at www.strobe-statement.org. 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml2 Page 25 of 50 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 3 Re: bmjopen-2013-003424 - Rosiglitazone use and post-discontinuation glycaemic control in 4 two European countries, 2000-2010 5 6 11 July 2013 7 8 9 Dear Editor: 10 11 At your request, we are providing point-by-point responses to the peer review comments at 12 BMJ. Please do not hesitate to let us know if additional revision or discretional changes as 13 outlined below are necessary in your opinion. 14 15 For peer review only 16 17 With kind regards, 18 19 Vera Ehrenstein on behalf of the authors 20 21 22 Vera Ehrenstein, MPH, DSc Department of Clinical Epidemiology 23 Associate professor Aarhus University Hospital 24 Director of the PhD curriculum Olof Palmes Allé 43-45 25 Phone: +49 176 6316 9720 DK-8200 Aarhus N 26 E-mail: [email protected] http://kea.au.dk/en/home/ 27 28

29 30 31 32 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 BMJ Open Page 26 of 50 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 3 REVIEWER 1. 4 5 The data on HbA1c and FPG are of limited value. The authors do not present any information on what 6 7 proportion of patients who stopped taking rosiglitazone were switched to other oral hypoglycaemic 8 agents. It is difficult to believe that there were not such switches. Thus, a meaningful interpretation of 9 the changes in glycemic control is not possible. 10 11 12 Response: We agree that the data on post-rosiglitazone hypoglycaemic agents is important for the 13 interpretation of the changes in glycaemic control. We added Table 5 to the manuscript, whereby we 14 report the distribution of oral hypoglycaemic drugs prescribed after discontinuation of rosiglitazone. We 15 For peer review only 16 also added text to the end of the Results section to describe the findings. 17 18 19 20 REVIEWER 2. 21 22 1. It would be important addition to the paper to describe the agents that individuals switched to 23 after coming off rosiglitazone. This may be something to consider in the glycaemic control 24 25 analysis. 26 27 Response: Same response as above (REVIEWER 1) 28 29 30 31 2. It would be ideal to have minimum exposure to rosiglitazone to include in the glycaemic control 32 33 study. It is unclear what the mean median exposure time was and how it was distributed.

34 http://bmjopen.bmj.com/ 35 Response. We agree that information on median exposure to rosiglitazone is important in interpreting 36 the data on glycaemic control. We have added this information to the results section.. In the table below, 37 we provide distribution of the length of rosiglitazone treatment in the two databases. This information is 38 39 not incorporated in the current submission, but we will be happy to do so if advised by Editor/referees. 40 41 Duration of rosiglitazone treatment (in months) among patients with available baseline HbA1c measurements 42 before stopping rosiglitazone (Table 2 of the manuscript) 43 on September 27, 2021 by guest. Protected copyright. 44 25th 45 quartil 75th 46 N Mean Std Median e quartile 47 Time (in months) from start to end of 48 rosiglitazone treatment (Northern Denmark) 1776 24.09 21.11 18.77 5.72 38.12 49 50 Time (in months) from start to end of 51 rosiglitazone treatment (United Kingdom) 21145 30.16 25.50 24.00 8.00 47.00 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 27 of 50 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 3 4 3. The baseline HbA1c is also important to consider the exposure to rosiglitazone. It would be also 5 6 important to get some sense of the distribution of how far the look back was. Was it close r to 7 the 24-months or to the discontinuation date. 8 9 Response. We agree that information on recency of pre-discontinuation HbA1c measurement is 10 important to consider. In the table below, we provide distribution of time between the baseline HbA1c 11 12 measurement and the discontinuation of rosiglitazone. This information is not incorporated in the 13 current submission, but we will be happy to do so if advised by Editor/referees. 14 15 For peer review only 16 17 Time (days) from baseline HbA1c measurement until discontinuation of rosiglitazone 18 19 25th 20 quartil 75th 21 N Mean Std Median e quartile 22 23 Days from last HbA1c measurement to rosiglitazone 24 discontinuation (Northern Denmark) 1776 71.75 94.51 44.00 21.00 78.00 25 Days from last HbA1c measurement to rosiglitazone 26 discontinuation (United Kingdom) 21145 108.22 114.67 70.00 25.00 153.00 27

28 29 30 31 32 4. In the table comparing the baseline the OHA selection, it would be important to consider the 33 difference in HbA1c values between the two groups.

34 http://bmjopen.bmj.com/ 35 Response. It was not the goal of the study to compare HbA1c in the 2 groups thus Table 1 provides no 36 inferential comparison, only distribution of patient characteristics with and without use of rosiglitazone. 37 38 We included all users of OHA during the study period to show characteristics of medicinally treated 39 diabetic patients in the two countries. 40 41 5. It is unclear how the other OHA group is identified. It looks like a bulk of this group had prior 42 43 OHA use. What is this population. on September 27, 2021 by guest. Protected copyright. 44 45 Response. We identified all users of other OHAs within each database during the study time period. See 46 the second paragraph in the Methods section for details. We have added additional text to clarify who 47 the OHA users were. 48 49 50 51 6. What is Table 2. Are these all users who ever discontinued rosiglitazone? The discontinuation 52 prior to 2007 is for different reasons compared to after 2007. This is not addressed in the 53 54 manuscript. The analysis also needs to be done here. 55 56 Response. Table 2 shows all those who ever discontinued rosiglitazone. Table 3 shows patients who 57 discontinued rosiglitazone post-suspension. We agree with the reviewer that reasons for discontinuation 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 28 of 50 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 3 are different before and after 2007, and especially before and after 2010. After the suspension of 4 5 rosiglitazone, in September 2010, the patients had to be taken off the drug. 6 7 8 7. While the specific warnings and restrictions went into effect in September 2010 the decrease in 9 use started in May 2007. This needs to be considered and addressed in the manuscript. 10 11 12 Response. There were several warnings: some went in effect shortly after the publication of the 2007 13 analysis. In September 2010 rosiglitazone was suspended in Europe. Please see Discussion, first 14 paragraph for relevant text. 15 For peer review only 16 8. The authors do a nice job of looking at glycaemic control in many different ways. While the 17 18 HbA1c of 7.5% may be a guideline driven threshold, there isn’t strong evidence based for this 19 cut-point. Would it be better to look at poor glycaemic control cutpoint of 9%? 20 21 Response: We used the guideline-driven threshold to make our results comparable to results of other 22 23 studies. Furthermore, decisions relevant to pioglitazone were most likely driven by the guidelines’ values. 24 We therefore respectfully retain current analyses in the manuscript. 25 26 Result 27 28 The results section can be much stronger. There needs to be some information on what individuals 29 30 switched to. The comparison group for other OHA is still not clear…. Is it truly everyone else. If so, a large 31 amount was on previous OHAs. If so, are incident cases included? Thou should most likely be removed as 32 incident case typically would not get rosiglitazone and thus would be an inappropriate comparison 33 group.

34 http://bmjopen.bmj.com/ 35 36 Response: See response above to Reviewer #1 and Reviewer #2 comment 1. We have added a table to 37 the manuscript. Assuming that by ‘comparison group’ the reviewer means persons exposed to OHAs 38 other than rosiglitazone in Table 1, we reported characteristics of new and prevalent users of oral 39 40 hypoglycaemic agents who had at least one prescription of rosiglitazone vs. another OHA during the 41 study period (2000-2010). No inferential comparison is intended in Table 1.We have clarified this in the 42 Methods section. on September 27, 2021 by guest. Protected copyright. 43 44 45 Interpretation and conclusion 46 47 The discussion for this manuscript can be much stronger. Given the real contribution here, there is 48 relatively little on the impact of these changes on the surrogate outcomes. Ideally the discussion would 49 focus around rates of use, agents that were changed to, and glycaemic control. 50 51 52 Response: Rates of rosiglitazone use are presented in the Figure. Conclusion about the glycaemic control 53 has been provided at the end of the Discussion section. 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 29 of 50 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

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 2,471553 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 30 of 50 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

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 rosiglitazonecontaining 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, glucoselowering 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 32 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 19 7 several riskbenefit assessments, especially concerning cardiovascular safety . In a May 8 9 2007 metaanalysis published in the New England Journal of Medicine, Nissen and Wolski

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 EMAcommissioned 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 rosiglitazonecontaining 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 postsuspension 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 33 of 50 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

10 15 11 Database (AUPD) . The database’s catchment area covers the North and Central Regions of 12 13 Denmark (hereafter referred to as ‘northern Denmark’), with a combined population in mid 14 15 2010 of 1,834,595For persons, peer which is about review onethird of the Danish only population. The AUPD 16 17 captures reimbursed prescriptions redeemed in the regions’ outpatient pharmacies since 1998. 18 19 In the UK, OHA users were identified from the General Practice Research Database (GPRD), 20 21 currently also known as the Clinical Practice Research Datalink. 22 23 We identified patients in each database with a prescription for any OHA between 1 24 25 January 2000 and 31 December 2010, encompassing the entire period of rosiglitazone 26 27 availability in Europe. We defined OHA users as persons with who received at least one OHA 28 29 prescription for any OHA during the study period. Prescriptions for OHAs , including 30 31 rosiglitazone, were identified using Anatomical Therapeutic Chemical (ATC) codes in the 32 33 AUPD and Multilex codes in the GPRD. . People could have received prescriptions for

34 http://bmjopen.bmj.com/ 35 multiple OHAs during the study period, including rosiglitazone. Our use of the term 36 37 ‘rosiglitazone’ includes all preparations of the drug. 38 39 40 Start of rosiglitazone use was defined as the date of the firstrecorded prescription for a 41 42 rosiglitazonecontaining product. Patients were assumed to have discontinued rosiglitazone 43 on September 27, 2021 by guest. Protected copyright. 44 therapy in the absence of a record of a new rosiglitazone prescription during a period 45 46 encompassing the estimated length of at least two prescriptions. Prescription length was 47 48 estimated at 45 days in AUPD and 130 days in the GPRD, based on observed intervals 49 50 between prescriptions and knowledge about typical clinical practice in Denmark, as well as the 51 52 prescribing instructions in the British Monthly Index of Medications in the UK. 53 54 To describe the study population, we obtained data on participants’ clinical and 55 56 demographic characteristics, including sex, age, body mass index (BMI), smoking, medical 57 58 diagnoses, and use of other medications (lipidlowering agents, antihypertensive agents, 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 34 of 50 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

34 http://bmjopen.bmj.com/ 35 also includes information on patient demographics, diagnoses, referrals, hospitalizations, and

36 1922 37 laboratory test results . 38 39 Statistical analysis. First, we examined changes in the proportion of rosiglitazone users 40 41 among all users of OHAs in the two countries between 2000 and 2010. Second, we compared 42 43 distributions of demographic and clinical characteristics between rosiglitazone users and users on September 27, 2021 by guest. Protected copyright. 44 45 of other OHAs. Third, we examined changes in HbA1c and FPG levels, comparing values 46 47 before and after discontinuation of rosiglitazone treatment. The prediscontinuation value of a 48 49 laboratory parameter was the value closest in time to the estimated discontinuation date within 50 51 24 months before that date. We defined three nonoverlapping postdiscontinuation periods as 52 53 follows: 3 months (90–179 days postdiscontinuation); 6 months (180–359 days post 54 55 discontinuation); and 12 months (360–479 days postdiscontinuation). We used the earliest 56 57 available measurement within each postdiscontinuation period. The postdiscontinuation 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 35 of 50 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

34 http://bmjopen.bmj.com/ 35 (record number 2009413866) and by the Independent Scientific Advisory Committee of the 36 37 GPRD. There was no patient contact, and informed consent was therefore not required. 38 39 40 Results 41 42 During the study period, 67,525 OHA users were recorded in the AUPD and 191,276 in on September 27, 2021 by guest. Protected copyright. 43 44 the GPRD. Of these, 2,321 (3.4%) persons in the AUPD and 25,428 (13%) persons in the 45 46 47 GPRD received at least one prescription for a rosiglitazonecontaining product. Figure 1 48 49 shows changes in the proportion of rosiglitazone users among all OHA users within the study 50 51 period. This proportion peaked at 4% in northern Denmark and at 15% in the UK in May 52 53 2007, and rapidly decreased thereafter, with virtually no rosiglizatone users remaining after 54 55 2010. 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 36 of 50 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

51 discontinuation (95% CI: –2.1%, –1.6%), but the prediscontinuation mean HbA1c in this 52 53 group was 10%. A larger proportion of patients in the UK than in Denmark had evidence of 54 55 loss of glycaemic control and a substantially larger proportion of patients in the UK 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 37 of 50 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

54 23 55 boxed warning to the rosiglitazone label in May 2007 . On the patient level, discontinuation 56 57 of rosiglitazone was associated with a slight overall decrease in the mean level of glycated 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 38 of 50 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

34 http://bmjopen.bmj.com/ 35 glycaemic control coming to medical attention. 36 37 The data presented here were obtained from medical databases that provide data on 38 39 routine and independent registration of healthrelated events in two European countries. Such 40 41 data are likely to reflect typical clinical practice. The data from the two data systems are also 42 43 complementary. The AUPD records filled prescriptions, while the GPRD records prescriptions on September 27, 2021 by guest. Protected copyright. 44 45 issued by general practitioners. Furthermore, the databases draw on different health sectors for 46 47 information on patient characteristics. In Denmark data on diagnoses originate from hospital 48 49 discharge summaries, while GPRD data on diagnoses originate from generalpractitioner 50 51 records. Despite these differences and potential differences in the underlying patient 52 53 populations, the results obtained from the two data systems were generally consistent. 54 55 Because OHA are distributed by prescription only and need to be taken longterm, the 56 57 information we present on rosiglitazone utilization over calendar time is likely to be accurate. 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 39 of 50 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

34 http://bmjopen.bmj.com/ 35 loss of glycaemic control upon discontinuation. Most patients were switched to a metformin 36 37 containing regimen. 38 39 40 Acknowledgements 41 42 We thank the Pharmacovigilance Working Party (PhVWP) at the European Medicines on September 27, 2021 by guest. Protected copyright. 43 44 Agency for helpful comments. We are grateful to Hanne Kjeldahl Schlosser, Helle Vester, and 45 46 47 Kathleen Jick for outstanding administrative support. 48 49 50 Funding 51 52 This study was commissioned and funded by the European Medicines Agency (Procurement 53 54 Procedure No. EMA/2010/38/CN). The funding agency had no direct role in preparation of 55 56 this manuscript. 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 40 of 50 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

34 http://bmjopen.bmj.com/ 35 ENCEPP/SDPP/1777). 36 37 38 39 Exclusive license statement 40 41 The Corresponding Author has the right to grant on behalf of all authors and does grant 42 on September 27, 2021 by guest. Protected copyright. 43 on behalf of all authors, an exclusive licence (or non exclusive for government employees) on 44 45 a worldwide basis to the BMJ Publishing Group Ltd and its Licensees to permit this article (if 46 47 accepted) to be published in BMJ editions and any other BMJPGL products and sublicences to 48 49 exploit all subsidiary rights, as set out in our licence. 50 51 52 53 Competing interest statement 54 55 All authors have completed the ICMJE uniform disclosure form at and declare: being 56 57 funded by the EMA (through institutional contracts and subcontracts) for this work; no 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 41 of 50 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

Avaglim. on September 27, 2021 by guest. Protected copyright. 43 http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2010/09/WC 44 500096996.pdf. 2010. 45 14. The European Commission. Commission Decision of 3.12.2010 suspending, under Article 46 20 of Regulation (EC) No 726/2004 of the European Parliament and of the Council, 47 the marketing authorisation, granted by Decision C(2000)1799, for "Avandia 48 Rosiglitazone" a medicinal product for human use. 2010. 49 50 15. Ehrenstein V, Antonsen S, Pedersen L. Existing data sources for clinical epidemiology: 51 Aarhus University Prescription Database. Clin Epidemiol 2010;2:2739. 52 16. Lynge E, Sandegaard JL, Rebolj M. The Danish National Patient Register. Scand J Public 53 Health 2011;39(7 Suppl):303. 54 17. Grann AF, Erichsen R, Nielsen AG, Froslev T, Thomsen RW. Existing data sources for 55 clinical epidemiology: The clinical laboratory information system (LABKA) research 56 database at Aarhus University, Denmark. Clinical epidemiology 2011;3:1338. 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 43 of 50 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

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 BMJ Open Page 44 of 50 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from Figure 1. Proportion of users of rosiglitazone among all users of oral hypoglycaemic agents 1 (OHA), 20002010. 2 3 4 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 Note: The maximum points of both graphs correspond to May 2007, the month of publication of 30 the initial metaanalysis by Nissen and Wolski.2 31 32 33

(n=191,276)

United Kingdom (9.5) N (%) 857 (3.4)857 336 336 (1.3) 589 589 (2.3) 9,297 (37)9,297 7,925 (31)7,925 2,582 (10) 2,582 2,242 (8.8) 7,661 (30)7,661 5,513 (22)5,513 6,434 (25) 6,434 22,223 (87)22,223 23,836 (94) 23,836 (77) 19,489 16,646 (65) 16,646 2,426 2,469 (9.7) (n=25,428) 11,259 (44)11,259 14,169 (56) 14,169 Users of rosiglitazone Users of BMJ Open

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51 (2.2)51 2 2 (0.09) 351 (15) 351 462 (20) 462 258 (11) 258 215 (9.3)215 177 (7.6)177 175 (7.5) 175 1,404 (60)1,404 1,991 (86)1,991 1,629 (70) 1,629 1,673 (72) 1,673 1,409

For peer review only

anuary 1, anuary date 2000 first OHA or prescription,of whichever came la

gents gents Antihypertensive a Missing Missing < 18.5 <25 – 18.5 Antiplatelet agents Antiplatelet Current Former Diuretics 25 <3025 – ≥ 30 Nitrates Never

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0.53) 0.62; 0.62; 8.7 (2.2)8.7 8.1 (1.7)8.1 3 months 3 (n=9,448) 31 (30; 33)31 23 (22; 24)23 40 (39; 41)40 1,026/3,286 0.57 ( 0.57

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Table 2. Table CI=confidenceinterval; HbA *Clinically *Clinically meaningful change defined using to European the Agency’sMedicines as definition change of thanmore 0.6% the (% is unit)test Characteristic Change from Change from baseline, (95% mean CI) Proportion with clinically a meaningful Followup mean (SD) increase, percent (95% CI) with baseline HbA Proportion Proportion with clinically a meaningful* decrease, percent (95% CI) Baseline Baseline (SD)mean glycaemic glycaemic control with HbA N with HbANwith New postdiscontinuation loss of onset of percent (95%percent CI) Page 47 of 50 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1.6)

Page 48 of 50 2.1; 2.1; 18/55 10 (2.5) 10 (n=338) 8.3 (2.1)8.3 6 months 6 69 (64; 74)69 15 (12; 19)15 33 (22; 46) 33 1.8 ( 1.8 Page 20 of 22 of 22 20 Page

United Kingdom 1.8)

2.2; 87/196 10 (2.5)10 8.0 (2.0) 8.0 3 3 months (n=1081) 44 (38;51) 44 14 (12; 14 16) 72 (69; 72 75) 2.0 ( 2.0

1.8;2.5) 94/350 (n=455) (n=455) 7.4 (1.4)7.4 7.1 (1.2)7.1 6 months6 33 (29;38)33 27 (22; 32) 27 12 (9.3; 12 15) 0.34 ( 0.34

orthern Denmarkorthern

N 1.9; 1.9; 2.7) 76/285 (n=376) 7.5 (1.5)7.5 7.1 (1.2)7.1 3 months 3 34 (29;38)34 27 (22; 32) 27 13 (9.5; 13 16) 0.40 ( 0.40 BMJ Open http://bmjopen.bmj.com/ >7.5%, percent

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measurements, in northern Denmark and in the United Kingdom, 20002011. 20002011. Kingdom, in United the and Denmark in northern measurements, Table 4. Table Characteristic *Clinically *Clinically meaningful changeEuropean defined using to the definition Agency’sMedicines as change more of than 10 mmol/L. CI=confidence interval; HbA treatment treatment failure, mmol/L, FPG>10 with with baseline FPG ≤10 mmol/L Proportion Proportion with a clinically meaningful decrease*, (95%percent CI) Proportion Proportion with a clinically meaningful increase*, percent (95% CI) Change from Changebaseline, (95%CI) mean (9.0; 0.38 8.2) (8.2;7.6) 0.27 (7.3; 0.01 7.3) (0.04; 0.27 0.49) (0.12; 0.08 0.27) 0.03 (0.22; 0.28) Followup Followup mean (SD) Baseline mean (SD) Baseline mean percent (95%percent CI) New post New N with N with afterFPG >10 mmol/L baseline/N Page 49 of 50 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from Page 50 of Page 22 of 22 of 22 22 Page

0.4)

2.1 (1.6; 2.1 2.7) (3.1; 3.8 4.6) (0.4; 0.6 1.0) (0.2; 0.3 0.6) (0.0; 0.1 0.3) (0.1; 0.2 (0.2; 0.3 0.6) 41.7 (39.9;41.7 43.6) (22.0;23.6 25.2) (13.2;14.5 15.9) (11.7;12.9 14.2) Percent (95% Percent (95% CI) (n=2810**)

9 2 4 9 57 16 103 641 394 351 1,136 Number GeneralPractice Research Database, United Kingdom BMJ Open

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(0.5; 2.8) 7.4 (5.0; 7.4 9.7) (3.4; 5.5 7.5) (2.6; 4.4 6.3) (1.9; 3.6 5.3) 1.7 (0.5; 1.7 2.8) (0.1; 0.8 1.7) (0.1; 0.8 1.7) (0.1; 0.6 1.3) (0.1; 0.6 1.3) (0.1; 0.4 1.0) (0.1; 0.2 0.6) 9.5 (6.9; 9.5 12.1) 10.3 (7.6; 13.1) 56.8 (52.3; (52.3; 56.8 61.2) (14.3; 17.7 21.2) Percent (95% Percent (95% CI) on September 27, 2021 by guest. Protected copyright. (n=474*) For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

8 8 4 4 3 3 2 1 84 49 45 35 26 21 17 269

Number For peer review only Aarhus University Aarhus PrescriptionDatabase, Denmark

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open 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.R1

Article Type: Research

Date Submitted by the Author: 08-Aug-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 Jick, Sn; Boston University, ; Boston University School of Medicine, Boston http://bmjopen.bmj.com/ Collaborative Drug Surveillance Program

Primary Subject Epidemiology Heading:

Secondary Subject Heading: Pharmacology and therapeutics, Public health

diabetes mellitus, drug safety, glucose-lowering drugs, rosiglitazone, Keywords:

thiazolidinediones on September 27, 2021 by guest. Protected copyright.

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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 Key words: diabetes mellitus, drug safety, glucoselowering drugs, rosiglitazone, 45 46 thiazolidinediones 47 48 49 50 51 Words: abstract 258, main text 2,622 52 53 1 Figure, 5 Tables 54 55 56 57 Page 1 of 23 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 82 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 3 4 5 6 Article summary 7 8 Article focus 9 • Rosiglitazone is a secondline oral hypoglycaemic agent, which was sold in the 10 European Union starting in 2000; after a series of regulatory decisions, its use was 11 first restricted and ultimately suspended in Europe, in September of 2010 12 • This study examines utilization of rosiglitazone in Denmark and the United Kingdom 13 (UK) in 20002010 14 • On the patient level, this study explores changes in glycaemic control following 15 discontinuationFor peerof rosiglitazone review only 16 17 18 19 Key messages 20 • Following a 2007 publication of a metaanalysis showing increased cardiovascular 21 morbidity associated with rosiglitazone, use of the drug declined sharply and 22 irreversibly in Denmark and in the UK; this predated the official suspension of the 23 drug by the European Medicines Agency, in 2010 24 • On the patient level, observed mean changes in fasting plasma glucose and glycated 25 haemoglobin A1c were slight in patients who discontinued rosiglitazone 26 27 28 Strengths and limitations of this study 29 • The study makes use of populationbased routine medical databases in two European 30 countries, which are likely to reflect typical clinical practice 31 • Despite differences in record generation mechanisms in the two databases, results 32 were overall concordant 33 • Automated prescription and dispensation data may have imprecisely measured time of

34 initiation and discontinuation of medication intake 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 82 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 3 4 Abstract 5 6 7 Objectives To evaluate the impact of risk minimisation policies on use of rosiglitazone 8 9 containing products and on glycaemic control among patients in Denmark and the United 10 11 Kingdom (UK). 12 13 Design, setting and participants We used populationbased data from the Aarhus University 14 15 PrescriptionFor Database (AUPD),peer in northern review Denmark and from the only General Practice Research 16 17 Database (GPRD), in the UK. 18 19 20 Main outcome measures We examined use of rosiglitazone during its entire period of 21 22 availability on the European market (2000–2010) and evaluated changes in glycated 23 24 haemoglobinA1c (HbA1c) and fasting plasma glucose (FPG) levels among patients 25 26 discontinuing this drug. 27 28 Results During 2000–2010, 2321 patients with records in the AUPD used rosiglitazone in 29 30 northern Denmark and 25,428 patients with records in the GPRD used it in the UK. The 31 32 proportion of rosiglitazone users among all users of oral hypoglycaemic agents (OHA) peaked 33

34 at 4% in the AUPD and at 15% in the GPRD, in May 2007, the month of publication of a http://bmjopen.bmj.com/ 35 36 metaanalysis showing increased cardiovascular morbidity associated with rosiglitazone use. 37 38 Twelve months after discontinuation of rosiglitazonecontaining products, the mean change in 39 40 HbA1c was –0.16% (95% confidence interval [CI]: –3.4%, 3.1%) in northern Denmark and – 41 42

0.17% (95% CI: –0.21%, 0.13%) in the UK. Corresponding mean changes in FPG were 0.01 on September 27, 2021 by guest. Protected copyright. 43 44 mmol/L (95% CI: –7.3 mmol/L, 7.3 mmol/L) and 0.03 mmol/L (95% CI: –0.22 mmol/L, 0.28 45 46 mmol/L). 47 48 49 Conclusions Publication of evidence concerning potential cardiovascular risks of rosiglitazone 50 51 was associated with an irreversible decline in use of rosiglitazonecontaining products in 52 53 Denmark and the UK. Mean changes in HbA1c and FPG after drug discontinuation were slight. 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 82 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 3 4 5 INTRODUCTION 6 7 8 Since first marketed in the European Union, in 2000, rosiglitazone has been subject to

9 19 10 several riskbenefit assessments, especially concerning cardiovascular safety. In a May 2007 11 12 metaanalysis published in the New England Journal of Medicine, Nissen and Wolski reported

13 2 14 increased cardiovascular morbidity associated with rosiglitazone use . In 2008, the European 15 For peer review only 16 Medicines Agency (EMA) amended the rosiglitazone product label, adding coronary 17 18 syndrome to the list of contraindications and inserting a warning about potentially increased 19 10 20 risk of ischemic events. At the time of this label amendment, EMA concluded “that the 21 22 benefits of [...] rosiglitazone [...] in the treatment of type 2 diabetes continue to outweigh their 23 24 risks”.11 In June 2010, Nissen and Wolski updated their metaanalysis, confirming the finding 25 26 of an increased risk of myocardial infarction (but not the original finding of increased all 27 28 cause mortality) in association with rosiglitazone use12. In July 2010, Graham and colleagues 29 30 published a paper in JAMA, based on data from US Medicare beneficiaries, showing increased 31 32 risks of several cardiovascular events, as well as allcause mortality, in a comparison of 33 7

34 rosiglitazone users with pioglitazone users. Following these two publications, on 22 http://bmjopen.bmj.com/ 35 36 September 2010, the EMA recommended suspension of use of all rosiglitazonecontaining 37 38 products in the European Union.13 The European Commission subsequently mandated 39 40 suspension of the drug, citing absence of unique therapeutic benefits outweighing its risks.14 41 42 Here we report results of an EMAcommissioned study on the impact of labelling on September 27, 2021 by guest. Protected copyright. 43 44 changes and findings reported in scientific publications on utilisation of rosiglitazone 45 46 47 containing products in Europe. On the population level, we examined changes in use of 48 49 rosiglitazonecontaining products over the entire period when rosiglitazone was available on 50 51 the European market. On the patient level, we assessed the impact of rosiglitazone 52 53 discontinuation on glycaemic control and reported oral hypoglycaemic agents prescribed after 54 55 postsuspension discontinuation of rosiglitazone. 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 82 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 METHODS 3 4 5 Setting and study population 6 7 This study was based on routinely collected data in medical databases in Denmark and in 8 9 the United Kingdom (UK). In Denmark, the study population included users of oral 10 11 hypoglycaemic agents (OHAs) identified in the Aarhus University Prescription Database 12 13 (AUPD).15 The database’s catchment area covers the North and Central Regions of Denmark 14 15 (hereafter referredFor to as ‘northernpeer Denmark’), review with a combined population only in mid2010 of 1.8 16 17 million persons, which is about onethird of the Danish population. The AUPD captures 18 19 reimbursed prescriptions redeemed in the regions’ outpatient pharmacies since 1998. In the 20 21 UK, OHA users were identified from the General Practice Research Database (GPRD), 22 23 currently also known as the Clinical Practice Research Datalink.16 24 25 We identified patients in each database with a prescription for any OHA between 1 26 27 January 2000 and 31 December 2010, encompassing the entire period of rosiglitazone 28 29 availability in Europe. We defined OHA users as persons who received at least one 30 31 32 prescription for any OHA during the study period. Prescriptions for OHAs were identified 33 using Anatomical Therapeutic Chemical (ATC) codes in the AUPD and Multilex codes in the

34 http://bmjopen.bmj.com/ 35 36 GPRD. People could receive prescriptions for multiple OHAs, including rosiglitazone, during 37 38 the study period. Our use of the term ‘rosiglitazone’ includes all preparations of the drug. 39 40 Start of rosiglitazone use was defined as the date of the firstrecorded prescription for a 41 42 rosiglitazonecontaining product. Patients were assumed to have discontinued rosiglitazone 43 on September 27, 2021 by guest. Protected copyright. 44 therapy in the absence of a record of a rosiglitazone prescription refill during a period 45 46 encompassing the estimated length of at least two prescriptions. Prescription length was 47 48 estimated at 45 days in AUPD and 130 days in the GPRD, based on observed intervals 49 50 between prescriptions and knowledge about typical prescribing practice in Denmark, as well 51 52 as on the prescribing instructions in the British Monthly Index of Medications in the UK. 53 54 To describe the study population, we obtained data on participants’ clinical and 55 56 demographic characteristics, including sex, age, body mass index (BMI), smoking, medical 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 82 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 diagnoses, and use of other medications (lipidlowering agents, antihypertensive agents, 3 4 diuretics, nitrates, and antiplatelet agents). These characteristics were measured as of 1 5 6 January 2000 for patients who started an OHA before 2000 and on the date of the first OHA 7 8 prescription for those who started thereafter. We used records from routine laboratory tests to 9 10 obtain data on measured glycated haemoglobinA1c (HbA1c) and fasting plasma glucose (FPG) 11 12 levels. 13 14 Data sources 15 For peer review only 16 In northern Denmark, data on hospitalbased medical diagnoses, prescription 17 18 medications, and laboratory test results were obtained, respectively, from the Danish National 19 20 Registry of Patients (DNRP17), from the AUPD, and from the Laboratory Information Systems 21

22 18 23 of the North and the Central Denmark Regions (the LABKA database ). The LABKA 24 25 database stores results of laboratory tests performed at hospitalbased laboratories. Patients are 26 27 referred to these laboratories by hospitals, general practitioners, and specialists. Data on 28 29 smoking and BMI were obtained from the Danish National Indicator Project diabetes 30 19 31 database. All data were linked on the individual level using the universal personal 32 20 33 identifier. In the UK all data were obtained from the GPRD. The GPRD is a longitudinal

34 http://bmjopen.bmj.com/ 35 database that has collected data from over 450 general practices in the UK since 1987, 36 37 covering a representative 6% sample of the UK population. The GPRD captures prescriptions 38 39 issued to patients by general practitioners, and it also includes information on patient 40 41 demographics, diagnoses, referrals, hospitalizations, and laboratory test results.16 2123 42 on September 27, 2021 by guest. Protected copyright. 43 Statistical analysis 44 45 First, we examined changes in the proportion of rosiglitazone users among all users of 46 47 OHAs in the two countries between 2000 and 2010. Second, we compared distributions of 48 49 50 demographic and clinical characteristics between rosiglitazone users and users of other OHAs. 51 52 Third, we examined changes in HbA1c and FPG levels, comparing values before and after 53 54 discontinuation of rosiglitazone treatment. The prediscontinuation value of a laboratory 55 56 parameter was the value closest in time to the estimated discontinuation date within 24 months 57 58 before that date. We defined three nonoverlapping postdiscontinuation periods as follows: 3 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 82 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 months (90–179 days); 6 months (180–359 days); and 12 months (360–479 days). We used 3 4 the earliest available measurement within each postdiscontinuation period. The post 5 6 discontinuation values were ascertained through 30 June 2011. We calculated the mean (with 7 8 standard deviation) level for HbA1c and FPG before and after discontinuation and the mean 9 10 change for each postdiscontinuation period. Furthermore, we calculated the proportion of 11 12 patients with new postdiscontinuation onset of loss of glycaemic control, defined as HbA1c 13 14 >7.5%; and the proportion of patients with new postdiscontinuation onset of treatment failure, 15 For peer review only 16 defined as FPG >10 mmol/L. To capture new onset, these proportions were computed among 17 18 patients without evidence of treatment failure/loss of glycaemic control before discontinuing 19 20 rosiglitazone. We then calculated the proportions of patients with clinically meaningful 21

22 changes in HbA1c (change >0.6%) and FPG (change >10%) after discontinuation of 23

24 rosiglitazone. Finally, we examined changes in HbA1c levels in patients who discontinued the 25 26 drug on or after 23 September 2010, presumably in response to the EMA’s suspension of the 27 28 drug. We also reported the distribution of the first OHA prescribed after rosiglitazone 29 30 suspension. The algorithms used to define variables in this project are provided in the 31 32 Appendix. We used SAS software version 9.2 (SAS Inc., Cary, NC, USA) to analyse the data. 33

34 http://bmjopen.bmj.com/ 35 Ethical approval 36 37 This study was approved by the Danish Data Protection Agency (record number 200941 38 39 3866) and by the Independent Scientific Advisory Committee of the GPRD. There was no 40 41 patient contact, and informed consent was therefore not required. 42 43 on September 27, 2021 by guest. Protected copyright. 44 RESULTS 45 46 47 Utilisation of rosiglitazone and patient characteristics 48 49 During the study period, 67,525 OHA users were recorded in the AUPD and 191,276 in 50 51 the GPRD. Of these, 2,321 (3.4%) persons in the AUPD and 25,428 (13%) persons in the 52 53 GPRD received at least one prescription for a rosiglitazonecontaining product. Figure 1 54 55 shows changes in the proportion of rosiglitazone users among all OHA users during the study 56 57 period. This proportion peaked at 4% in northern Denmark and at 15% in the UK in May 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 82 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 2007, and rapidly decreased thereafter, with virtually no rosiglitazone users remaining after 3 4 2010. 5 6 Table 1 compares demographic and clinical characteristics of users of rosiglitazone with 7 8 users of other OHAs. Rosiglitazone users tended to be younger, but were more likely to have 9 10 had a prescription history of lipidlowering or antihypertensive agents. Rosiglitazone users 11 12 were more likely than the other OHA users to have used OHAs other than metformin and 13 14 sulfonylurea before starting rosiglitazone. Based on data from the GPRD, users of 15 For peer review only 16 rosiglitazonecontaining products were slightly more likely than other OHA users to have a 17 18 BMI of ≥30 kg/m2. BMI data for patients in Denmark were sparse (Table 1). 19 20 21 Glycaemic control after discontinuation of rosiglitazone 22 23 Among all rosiglitazone users in the AUPD, 1776 patients who discontinued the drug had 24 25 HbA1c measurements. Among these patients, the median duration of rosiglitazone use was 19 26 27 months (quartiles, 6–38 months), and the median time from the last prediscontinuation HbA1c 28 29 measurement until discontinuation of rosiglitazone was 44 days (quartiles, 21–78 days). In the 30 31 GPRD, there were 21,145 rosiglitazone users with HbA1c measurements. Among these 32 33 patients, the median duration of rosiglitazone use was 24 months (quartiles, 8–47 months) and

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35 the median time from the last prediscontinuation HbA1c measurement until discontinuation of 36

37 rosiglitazone was 70 days (quartiles, 25–153 days). Table 2 shows changes in HbA1c at three, 38 39 six, and 12 months after discontinuation of rosiglitazone treatment at any time during the 40 41 study period. At 12 months postdiscontinuation, a change of similar magnitude in the mean 42 43 on September 27, 2021 by guest. Protected copyright. HbA1c was observed in both databases: –0.16% (95% confidence interval [CI]: –3.4%, 3.1%) 44 45 in northern Denmark, and –0.17% (95% CI: –0.21%, 0.13%) in the UK. Loss of glycaemic 46 47 control, defined by new onset of HbA1c>7.5%, was registered for up to 29% of patients during 48 49 the 12month followup period in Denmark and for up to 37% of patients in the UK. Similar 50 51 proportions of patients had HbA values consistent with a clinically meaningful decrease 52 1c 53 (>0.6%) at 12 months postdiscontinuation. 54 55 56 Table 3 shows changes in HbA1c among patients who discontinued rosiglitazone 57 58 containing products on or after 23 September 2010. Thus, Table 3 represents subset of patients 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 82 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 described in Table 2. In the UK data, mean HbA1c decreased by 1.8% (95% CI: –2.1%, –1.6%) 3 4 at six months postdiscontinuation, but the prediscontinuation mean HbA1c in this group was 5 6 10%. A larger proportion of patients in the UK than in Denmark had evidence of loss of 7 8 glycaemic control and a substantially larger proportion of patients in the UK experienced a 9 10 clinically meaningful decrease in HbA1c after discontinuation of rosiglitazone compared with 11 12 Denmark (Table 3). 13 14 Table 4 shows changes in FPG at three, six, and 12 months after discontinuation of 15 For peer review only 16 rosiglitazone. At 12 months, there was virtually no change seen in either of the databases: 17 18 mean change of 0.01 mmol/L (95% CI: –7.3 mmol/L; 7.3 mmol/L) in northern Denmark, and 19 20 mean change of 0.03 mmol/L (95% CI: –0.22 mmol/L; 0.28 mmol/L) in the UK. Treatment 21 22 failure, defined by new onset of FPG >10 mmol/L during one of the followup periods, was 23 24 observed in a maximum of 23% of patients in northern Denmark and 20% in the UK. The 25 26 number of persons with available measurements for northern Denmark, however, was small 27 28 (Table 4). Table 5 shows the distribution of OHA prescribed to patients who discontinued 29 30 rosiglitazone on 23 September 2010 or later. The majority of the patients switched to another 31 32 OHA (82% in northern Denmark; 97% in the UK) after the last recorded rosiglitazone 33

34 http://bmjopen.bmj.com/ 35 prescription. The majority of patients – 56.8% in Denmark and 41.7% in the UK – received a 36 37 prescription for metformin. In the UK, 23.6% of patients had a prescription for pioglitazone, 38 39 and 14.5% for pioglitazone and metformin. Pioglitazone was prescribed only to 4.4% of the 40 41 patients in northern Denmark. 42 43 on September 27, 2021 by guest. Protected copyright. 44 DISCUSSION 45 46 47 We examined use of rosiglitazonecontaining products over the entire period of 48 49 availability of this drug in Europe (2000–2010) using routinely collected data in medical 50 51 databases in Denmark and in the United Kingdom. Overall, the drug was more widely used in 52 53 the UK than in Denmark, with the proportion of rosiglitazone users among all users of OHA 54 55 peaking at 15% and 4% in the two countries, respectively. The timing of both peaks, which 56 57 marked the beginning of a steep decline in use, coincided with the May 2007 publication of 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 82 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 2 the metaanalysis by Nissen and Wolski and subsequent regulatory warnings from the EMA. 3 4 This decline occurred three years before the regulatory decision to suspend rosiglitazone in 5 6 Europe. Similarly, a sharp decline in prescribing occurred in the United States after the FDA 7 24 8 added a boxed warning to the rosiglitazone label in May 2007. On the patient level, 9 10 discontinuation of rosiglitazone was associated with a slight overall decrease in the mean level 11 12 of glycated haemoglobin. However, close to onethird of patients had evidence consistent with 13 14 loss of glycaemic control during the 12 months of followup, including patients who 15 For peer review only 16 discontinued rosiglitazone after the EMA decision to suspend the drug. Most patients who 17 18 discontinued rosiglitazone after the EMAmandated suspension started receiving metformin. 19 20 Meaning of the findings 21 22 23 While on the market, rosiglitazone represented a larger proportion of all OHA use in the 24 25 UK than in Denmark. This may reflect conservative recommendations issued in Denmark,

26 25 27 suggesting that treatment first be attempted with metformin, sulfonurea, and insulin. 28 29 Guidelines from the National Institute for Health and Clinical Excellence (NICE) in the UK 30 31 stated that rosiglitazone should only be prescribed if other classes of OHA were not effective 32 33 in lowering plasma glucose concentrations. Therefore rosiglitazone was recommended only as

34 http://bmjopen.bmj.com/ 26 35 second or third line therapy. The high prediscontinuation level of HbA1c in UK patients who 36 37 discontinued rosiglitazone following the drug suspension is also consistent with this guideline. 38 39 Among patients terminating rosiglitazone after the drug was suspended, a larger proportion of 40 41 UK patients compared with their Danish counterparts experienced a clinically meaningful 42 43 decrease in glycated haemoglobin. The prediscontinuation values among the UK patients on September 27, 2021 by guest. Protected copyright. 44 45 were substantially higher, probably reflecting heightened medical attention drawn to patients 46 47 with poor glycaemic control. 48 49 Strengths and weaknesses 50 51 52 The data presented here were obtained from medical databases containing data on routine 53 54 and independent registration of healthrelated events in two European countries. Such data are 55 56 therefore likely to reflect typical clinical practice. The data from the two data systems are also 57 58 complementary. The AUPD records purchased prescriptions, while the GPRD records 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 82 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 prescriptions issued by general practitioners. Furthermore, the databases draw on different 3 4 health sectors for information on patient characteristics: in Denmark data on diagnoses 5 6 originate from hospital discharge summaries, while in the GPRD, data on diagnoses originate 7 8 from generalpractitioner records. Despite these differences and potential differences in the 9 10 underlying patient populations, the results obtained from the two countries were generally 11 12 consistent. 13 14 Because OHA are distributed by prescription only and need to be taken longterm, the 15 For peer review only 16 information we present on rosiglitazone utilization over calendar time is likely to be accurate. 17 18 The pattern of use for the two Danish regions included here mirrors the nationwide pattern 19 20 reported by the Danish Medicines Agency.27 However, because automated prescription records 21 22 provide no information on the exact timing of drug intake, we had to make assumptions about 23 24 timing of rosiglitazone discontinuation and prescription length. We speculate that shortterm 25 26 changes in laboratory parameters following discontinuation of rosiglitazone are subject to 27 28 more misclassification due to errors in assigning the discontinuation status than are longterm 29 30 changes in these parameters. Therefore, our 12month estimates of postdiscontinuation 31 32 change in laboratory parameters may be more robust than the 3month estimates. The 33

34 http://bmjopen.bmj.com/ 35 information on glycated haemoglobin A1c and on fasting plasma glucose originated from 36 37 routinely collected laboratory data, although patients with laboratory measurements may differ 38 39 from the entire population of rosiglitazonetreated patients. For example, physicians may be 40 41 less likely to routinely collect laboratory data for patients with less severe diabetes. 42 43 Conclusion on September 27, 2021 by guest. Protected copyright. 44 45 In summary, a decline in use of rosiglitazone occurred immediately following the May 46 47 2007 publication of a metaanalysis describing adverse cardiac side effects of this drug. 48 49 Changes in glycaemic control were, on average, small during 12 months after discontinuation 50 51 of rosiglitazone, although about onethird of patients had evidence of loss of glycaemic control 52 53 upon discontinuation. Most patients who discontinued rosiglitazone after EMAmandated 54 55 suspension were switched to a metformincontaining regimen. 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12 of 82 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 ACKNOWLEDGMENTS 3 4 5 We thank the Pharmacovigilance Working Party (PhVWP) at the European Medicines 6 7 Agency for helpful comments. We are grateful to Hanne Kjeldahl Schlosser, Helle Vester, and 8 9 Kathleen Jick for outstanding administrative support. 10 11 12 FUNDING 13 14 15 This study Forwas commissioned peer and funded review by the European Medicines only Agency (Procurement 16 17 Procedure No. EMA/2010/38/CN). The funding agency had no direct role in preparation of 18 19 this manuscript. 20 21 22 DISCLAIMER 23 24 This document expresses the opinions of the authors of the paper, and may not be understood 25 26 27 or quoted as being made on behalf or of reflecting the position of the European Medicines 28 29 Agency or one of its committees or working parties. 30 31 32 CONTRIBUTION STATEMENT 33

34 http://bmjopen.bmj.com/ V. Ehrenstein participated in conception and design of the study, led the writing, and 35 36 37 contributed to data analysis. R. K. Hernandez contributed to study design and data analysis in 38 39 the GPRD. S. P. Ulrichsen conducted the data analyses in Denmark, J. Rungby contributed to 40 41 study design and analysis, and provided clinical expertise, T.L. Lash participated in 42 43 conception and design of the study, A.H. Riis contributed to data analysis of the AUPD data, on September 27, 2021 by guest. Protected copyright. 44 45 L. Li contributed to data analysis of the GPRD data, H.T. Sørensen oversaw the study and 46 47 provided clinical expertise, and S. S. Jick participated in conception and design of the study. 48 49 All authors participated in revisions of the manuscript draft for intellectual content. 50 51 52 53 This study has received the ENCePP Study Seal (Reference number ENCEPP/SDPP/1777). 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 82 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 Exclusive license statement 3 4 5 The Corresponding Author has the right to grant on behalf of all authors and does grant 6 7 on behalf of all authors, an exclusive licence (or nonexclusive for government employees) on a 8 9 worldwide basis to the BMJ Publishing Group Ltd and its Licensees to permit this article (if 10 11 accepted) to be published in BMJ editions and any other BMJPGL products and sublicenses to 12 13 exploit all subsidiary rights, as set out in our licence. 14 15 For peer review only 16 Competing interest statement 17 18 19 All authors have completed the ICMJE uniform disclosure form at and declare: being 20 21 funded by the EMA (through institutional contracts and subcontracts) for this work; no 22 23 financial relationships with any organisations that might have an interest in the submitted 24 25 work in the previous three years, no other relationships or activities that could appear to have 26 27 influenced the submitted work. 28 29 Data Sharing 30 31 32 Additional unpublished data from the study relate to changes in glycaemic control before 33

34 suspension of rosiglitazone in the EU. The data are available to the investigators and from the http://bmjopen.bmj.com/ 35 36 investigators, upon request. 37 38 39 REFERENCES 40 41 42 1. Home PD, Pocock SJ, BeckNielsen H, et al. Rosiglitazone evaluated for 43 cardiovascular outcomesan interim analysis. N Engl J Med 2007;357:2838. on September 27, 2021 by guest. Protected copyright. 44 2. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial 45 infarction and death from cardiovascular causes. N Engl J Med 2007;356:245771. 46 3. Psaty BM, Furberg CD. Rosiglitazone and Cardiovascular Risk. New England 47 Journal of Medicine 2007;356:252224. 48 49 4. Margolis DJ, Hoffstad O, Strom BL. Association between serious ischemic 50 cardiac outcomes and medications used to treat diabetes. Pharmacoepidemiol Drug Saf 51 2008;17:7539. 52 5. EMEA statement on recent publication on cardiac safety of rosiglitazone 53 (Avandia, Avandamet, Avaglim). 2009. 54 http://www.emea.europa.eu/docs/en_GB/document_library/Press_release/2009/11/WC500013 55 467.pdf (accessed August 2013). 56 6. Home PD, Pocock SJ, BeckNielsen H, et al. Rosiglitazone evaluated for 57 cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a 58 multicentre, randomised, openlabel trial. Lancet 2009;373:212535. 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14 of 82 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 7. Graham DJ, OuelletHellstrom R, MaCurdy TE, et al. Risk of acute myocardial 3 infarction, stroke, heart failure, and death in elderly Medicare patients treated with 4 rosiglitazone or pioglitazone. JAMA 2010;304:4118. 5 8. Nissen SE. The rise and fall of rosiglitazone. Eur Heart J 2010;31:7736. 6 9. Blind E, Dunder K, de Graeff PA, et al: a European regulatory perspective. 7 Diabetologia 2011;54:2138. 8 9 10. EMEA recommends new warnings and contraindications for rosiglitazone 10 2009. 11 http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2009/11/WC5000154 12 20.pdf (accessed August 2013). 13 11. European Medicines Agency confirms positive benefitrisk balance for 14 rosiglitazone and pioglitazone. 2009 15 http://www.emea.europa.eu/docs/en_GB/document_library/Press_release/2009/11/WC500011For peer review only 16 009.pdf (accessed August 2013). 17 12. Nissen SE, Wolski K. Rosiglitazone Revisited: An Updated Metaanalysis of 18 Risk for Myocardial Infarction and Cardiovascular Mortality. Arch Intern Med 2010. 19 13. European Medicines Agency recommends suspension of Avandia, Avandamet 20 and Avaglim. 2010 21 http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2010/09/WC5000969 22 96.pdf (accessed August 2013). 23 24 14. The European Commission. Commission Decision of 3.12.2010 suspending, 25 under Article 20 of Regulation (EC) No 726/2004 of the European Parliament and of the 26 Council, the marketing authorisation, granted by Decision C(2000)1799, for "Avandia 27 Rosiglitazone" a medicinal product for human use. 28 15. Ehrenstein V, Antonsen S, Pedersen L. Existing data sources for clinical 29 epidemiology: Aarhus University Prescription Database. Clin Epidemiol 2010;2:2739. 30 16. Clinical Practice Research Datalink. http://www.cprd.com (accessed August 31 2013). 32 33 17. Lynge E, Sandegaard JL, Rebolj M. The Danish National Patient Register. Scand J Public Health 2011;39:303.

34 http://bmjopen.bmj.com/ 35 18. Grann AF, Erichsen R, Nielsen AG, et al. Existing data sources for clinical 36 epidemiology: The clinical laboratory information system (LABKA) research database at 37 Aarhus University, Denmark. Clinical epidemiology 2011;3:1338. 38 19. Danish National Indicator Project. http://www.nip.dk (accessed August 2013). 39 20. Pedersen CB, Gotzsche H, Moller JO, et al. The Danish Civil Registration 40 System. A cohort of eight million persons. Dan Med Bull 2006;53:4419. 41 42 21. Jick H, Jick SS, Derby LE. Validation of information recorded on general 43 practitioner based computerised data resource in the United Kingdom. BMJ 1991;302:7668. on September 27, 2021 by guest. Protected copyright. 44 22. Garcia Rodriguez LA, Perez Gutthann S. Use of the UK General Practice 45 Research Database for pharmacoepidemiology. Br J Clin Pharmacol 1998;45:41925. 46 23. Jick SS, Kaye JA, VasilakisScaramozza C, et al. Validity of the general 47 practice research database. Pharmacotherapy 2003;23:6869. 48 49 24. Shah ND, Montori VM, Krumholz HM, et al. Responding to an FDA warning 50 geographic variation in the use of rosiglitazone. N Engl J Med 2010;363:20814. 51 25. 52 http://hjertedoktor.dk/content/pdf/dsams%20vejledning%20for%20type2%20di 53 abetes.pdf (accessed August 2013). 54 26. National Collaborating Centre for Chronic Conditions. Type 2 diabetes: 55 national clinical guideline for management in primary and secondary care (update). 2009 56 London: Royal College of Physicians. 57 27. The Danish Medicines Agency. Polypharmacy in diabetes care. 58 http://www.dkma.dk/1024/visUKLSArtikel.asp?artikelID=1665 (accessed May 2013). 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 15 of 82 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 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 BMJ Open Page 16 of 82 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from FIGURE LEGEND 1 Figure 1. Proportion of users of rosiglitazone among all users of oral hypoglycaemic agents 2 (OHA), 20002010 in northern Denmark and in the United Kingdom The maximum points of 3 both graphs correspond to May 2007, the month of publication of the initial metaanalysis by 4 Nissen and Wolski.2 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33

N N (%) agents 5882 5882 (3.6) 5725 5725 (3.5) 9358 9358 (5.6) 9147 9147 (5.5) 90,682 (55)90,682 95,607 (58)95,607 57,984 (35)57,984 12,257 (7.4)12,257 14,194 (8.6) 14,194 78,772 (48)78,772 87,076 (53)87,076 28,430 (17)28,430 38,668 (23)38,668 42,030 (25)42,030 25,023 (15) 25,023 144,881 144,881 (87) 114,378 114,378 (69) 13,192 (8.0)13,192 (n=165,848)

hypoglycaemic hypoglycaemic Users of Users of oralother

(n=191,276)

United Kingdom N (%) 857 (3.4)857 2582 2582 (10) 9297 9297 (37) 7925 7925 (31) 589 589 (2.3) 336 336 (1.3) 2242 2242 (8.8) 7661 7661 (30) 6434 (25) 5513 5513 (22) 2426 (9.5) 2426 2469 (9.7) 2469 23,836 (94)23,836 19,489 (77)19,489 16,646 (65)16,646 22,223 (87) 22,223 (n=25,428) 11,259 (44)11,259 14,169 (56)14,169 Users of rosiglitazone Users of BMJ Open

http://bmjopen.bmj.com/ 219 219 (16) N N (%) , 4551 4551 (7.0) 4149 4149 (6.4) 3999 3999 (6.1) 196 196 (0.30) 3121 3121 (4.8) 4967 4967 (7.6) 5530 5530 (8.5)

(n=65,204) 30,845 (47)30,845 51,022 (78)51,022 39,931 (61)39,931 34,359 (53)34,359 41,183 (63)41,183 10,423 (16)10,423 40,327 (62) 40,327 19,470 (30) 19,470 10 16,751 (26)16,751 (24)15,724 Users Users of oral other hypoglycaemic agentshypoglycaemic on September 27, 2021 by guest. Protected copyright. (n=67,525)

Northern Northern Denmark

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml N N (%) 66 (2.8)66 83 (3.6)83 81 (3.5) 81 9 9 (0.39) 976 (42) 976 517 (22) 517 561 (24) 561 595 (26) 595 757 (33) 757 (19) 444 286 (12) 286 497 (21) 497 147 (6.3)147 2279 2279 (98) 1730 1730 (74) 1345 1345 (58) 1694 1694 (73) 1939 1939 (84) For(n=2,321) peer review only Users of rosiglitazone Users of

54 2

Other oral Other glucose oral lowering drugs** Pioglitazone agentsLipid lowering Sulfonylurea 1 Metformin DPP Inhibitor 4 0 3+ 45 ≥85 Female Male <35 <35 5564 6574 3544 7584 TABLES TABLES 1. Table Denmark and the United Kingdom. Kingdom. United the and Denmark Sex Age Age group, years Characteristic History History of medication other use History History OHA of use before baseline* Charlson Charlson comorbidity index Page 17 of 82 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from Page 18 of 82 Page 18 of2318 Page

322 (0.19)322 623 (0.38) 623 73,225 (44)73,225 66,725 (40)66,725 75,119 (45)75,119 43,985 (27)43,985 49,463 (30)49,463 21,634 (13)21,634 27,403 (17)27,403 18,624 (11)18,624 28,120 (17)28,120 15,223 (9.2) 15,223 126,897 126,897 (77)

52 (0.20) 52 35 (0.14) 35 6102 6102 (24) 7458 7458 (29) 2675 2675 (11) 4035 4035 (16) 3128 3128 (12) 2878 2878 (11) 4499 (18) 13,516 (53)13,516 11,225 (44)11,225 11,699 (46)11,699 21,846 (86)21,846

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32 (0.05) 32 9456 (14) 9456 5454 5454 (8.4) 3534 3534 (5.4) 3121 3121 (4.8) 3257 3257 (5.0) 1257 1257 (1.9) 2451 2451 (3.8) 34,650 (53)34,650 48,016 (74)48,016 55,204 (85) 55,204 56,098 (86) 56,098 33,060 (51) 33,060 on September 27, 2021 by guest. Protected copyright.

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 51 (2.2)51 2 2 (0.09) 351 (15) 351 462 (20) 462 258 (11) 258 215 (9.3)215 177 (7.6)177 175 (7.5) 175 1404 1404 (60) 1991 1991 (86) 1629 1629 (70) 1673 1673 (72) 1409 1409 (61) For peer review only

anuary 1, anuary date 2000 first OHA or prescription,of whichever came la

gents gents Antihypertensive a ≥ 30 Missing Missing < 18.5 <25 – 18.5 25 <3025 – Antiplatelet agents Antiplatelet Current Former Diuretics Never Nitrates Baseline date was J * Body Body mass index category, kg/m **Other excludingglucoselowering insulinsdrugs acarbose,arerepaglinide, exenatide, liraglutide.and Smoking 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from Page 19 of2319 Page BMJ Open http://bmjopen.bmj.com/ on September 27, 2021 by guest. Protected copyright. For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml For peer review only

Page 19 of 82 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

0.13) Page 20 of 82 0.21; 0.21; 8.2 (1.8) 8.2 8.4 (1.9) 8.4 (n=8635) 12 12 months 0.17 ( 0.17 Page 20 of 23 of 23 20 Page

0.53) 0.62; 0.62; 8.7 (2.2)8.7 8.1 (1.7)8.1 3 months 3 (n=9448) 31 (30; 33)31 23 (22; 24)23 40 (39; 41)40 1,026/3,286 0.57 ( 0.57

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on September 27, 2021 by guest. Protected copyright. 3.0; 3.0; 2.8) 160/670 160/670 228/827 179/610 7.8 (1.7)7.8 7.7 (1.5)7.7 3 months3 (n=1242) 24 (21; 27) 24 (25; 31) 28 (26; 33) 29 26 (24; 29) 26 (26; 30) 28 (26; 31) 28 28 (25; 30) 28 (25; 29) 27 (27; 32) 30 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 0.10 ( 0.10 For peer review only

before and after discontinuation of rosiglitazone a rosiglitazone of discontinuation after and %) before *

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northern Denmark and in the United Kingdom, 20002011. 20002011. Kingdom, United in the and Denmark northern Table 2. Table with HbA with CI, confidenceCI, HbAinterval; *Clinically *Clinically meaningful change defined using to European the Agency’sMedicines as definition change of thanmore 0.6% the (% is unit)test Characteristic Change from Change from baseline, (95% mean CI) Proportion with clinicallya Followup mean (SD) increase, percent (95% CI) with baseline HbA Proportion Proportion with clinically a meaningful* decrease, percent (95% CI) Baseline Baseline (SD)mean glycaemic glycaemic control with HbA N New postdiscontinuation loss of onset of percent (95%percent CI) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

18/55 .3 (2.1).3 10 (2.5) 10 (n=338) 8 6 months 6 33 (22; 46)33 15 (12; 19)15 69 (64; 74) 69 Page 21 of 23 of 23 21 Page

United Kingdom

87/196 10 (2.5) 10 8.0 (2.0) 8.0 3 3 months (n=1081) 44 (38;51) 44 14 (12; 14 16) 72 (69; 72 75)

94/350 (n=455) (n=455) 7.1 (1.2)7.1 (1.4)7.4 6 months6 33 (29;38)33 27 (22; 32) 27 12 (9.3; 12 15)

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1c on September 27, 2021 by guest. Protected copyright. For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml For peer review only decrease, (95%percent CI)

increase, percent(95% CI) * * , glycated haemoglobinglycated , SD, A; standard deviation 1c ally ally meaningful

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Page 22 of 23 of 23 22 Page (n=800) 8.7 (3.4)8.7 (3.1)8.7 12 12 months

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98/610 182/911 99/583 (n=820) (n=820) 8.6 (3.2)8.6 (3.2)8.8 3 months 3

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18/79 (n=109) 9.3 (3.4)9.3 (3.4)9.0 6 months 6 23 (15; 33)23 35 (26; 44)35 (26; 44)35 Northern Northern Denmark

on September 27, 2021 by guest. Protected copyright.

14/65 14/65 (n=95) 9.5 (3.6) 9.5 (3.7) 9.2 3 3 months For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 22 (13; 22 33) 40 (31; 40 50) (30; 39 49) For peer review only

* , glycated haemoglobinglycated , SD, A; standard deviation 1c

Fasting plasma glucose (mmol/L) before and after discontinuation of rosiglitazone among patients with available preand postdiscontinuation laboratory laboratory postdiscontinuation preand withavailable patients among rosiglitazone of discontinuation after and before (mmol/L) glucose plasma Fasting discontinuation onset of up up mean (SD)

ow measurements, in northern Denmark and in the United Kingdom, 20002011. 20002011. Kingdom, in United the and Denmark in northern measurements, Table 4. Table Characteristic Proportion Proportion with a clinically meaningful Baseline mean (SD) Baseline mean Foll from Changebaseline, (95%CI) mean Proportion with a clinically meaningful* percent increase, (95% CI) (9.0; 0.38 8.2) percentdecrease,(95% CI) (8.2;7.6) 0.27 treatment failure, mmol/L, FPG>10 (7.3; 0.01 7.3) (0.04; 0.27 0.49) (0.12; 0.08 0.27) 0.03 (0.22; 0.28) with with baseline FPG ≤10 mmol/L *Clinically *Clinically meaningful changeEuropean defined using to the definition Agency’sMedicines as change more of than 10 mmol/L. confidenceCI, interval;HbA percent (95%percent CI) New post New N with N with afterFPG >10 mmol/L baseline/N 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from Page 23 of 23 of 23 23 Page

0.2; 0.2; 0.6) ent (95% (95% ent CI) 0.6 (0.4; 0.6 1.0) 0.1 (0.0; 0.1 0.3) 2.1 (1.6; 2.1 2.7) 3.8 (3.1; 3.8 4.6) (0.2; 0.3 0.6) (0.1; 0.2 0.4) ( 0.3 23.6 (22.0;23.6 25.2) 14.5 (13.2;14.5 15.9) (11.7;12.9 14.2) 41.7 (39.9;41.7 43.6) Perc ) + (n=2810

2 9 4 9 16 16 57 57 136 641 641 103 394 351 1 Number GeneralPractice Research Database, United Kingdom BMJ Open

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1.7 (0.5; 1.7 2.8) 5.5 (3.4; 5.5 7.5) 0.6 (0.1; 0.6 1.3) 0.6 (0.1; 0.6 1.3) 4.4 (2.6; 4.4 6.3) 1.7 (0.5; 1.7 2.8) 7.4 (5.0; 7.4 9. (1.9; 3.6 5.3) (0.1; 0.8 1.7) (0.1; 0.8 1.7) (0.1; 0.4 1.0) (0.1; 0.2 0.6) 9.5 (6.9; 9.5 12.1) 10.3 (7.6; 13.1) 17.7 (14.3; (14.3; 17.7 21.2) 56.8 (52.3; (52.3; 56.8 61.2) Percent (95% Percent (95% CI) on September 27, 2021 by guest. Protected copyright. enmark enmark (n=474*) D

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8 3 3 8 4 4 2 1 49 49 26 26 21 21 84 84 45 35 17 269

ForNumber peer review only Aarhus University AarhusPrescription Database, northern

5. Table 88 record 88 patients had another no of OHA afterlastthe rosiglitazone prescription

Sitagliptin Metformin+vildagliptin Pioglitazone + metformin Gliclazide Glipizide Vildagliptin Acarbose Tolbutamide *83 patients recordhad no another OHA afterlastof rosiglitazonethe prescription. Saxagliptin Metformin Glimepiride Liraglutide Glibenclamide Repaglinide + Pioglitazone Metformin+sitagliptin Exenatide Page 23 of 82 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open Page 24 of 82 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 260x161mm (100 x 100 DPI) 30 31 32 33

1 2 3 Appendix: Algorithms used to identify variables in the study titled: 4 5 6 Rosiglitazone use and post-discontinuation glycaemic control in two European countries, 7 2000-2010 8 9 Diagnostic codes used to Abstract the Danish National Registry of Patients 10 11 Disease/condition ICD-8 code ICD-10 code 12 13 Diabetes type 1 249.00; 249.06; 249.07; 249.09 E10.0, E10.1; E10.9 14 Diabetes type 2 250.00; 250.06; 250.07; 250.09 E11.0; E11.1; E11.9 15 Acute myocardialFor infarction peer410 review onlyI21, I22, I23 16 Ischemic heart disease (acute 411-414 I20, I24, I25 17 and chronic) 18 19 Congestive heart failure 427.09, 427.10, 427.11, I50, I11.0, I13.0, I13.2 20 427.19, 428.99, 782.49; 21 Other cardiac disease 393–398, 400–404 I05–I09 22 Peripheral vascular disease 440, 441, 442, 443, 444, 445 I70, I71, I72, I73, I74, I77 23 24 Ischemic stroke 430-438 (cerebrovascular I63-64 25 disease) 26 Alcoholism 291, 303, 577.10, 571.09, F10.1-F10.9, G31.2, G62.1, 27 571.10 G72.1, I42.6, K29.2, K86.0, 28 Z72.1 29 30 Obesity 277.99 E65-E66 31 Mild liver disease 571, 573.01, 573.04 B18, K70.0–K70.3, K70.9, 32 K71, K73, K74, K76.0 33 Moderate to severe liver 070.00, 070.02, 070.04, B15.0, B16.0, B16.2, B19.0,

34 disease 070.06, 070.08, 573.00, K70.4, K72, K76.6, I85 http://bmjopen.bmj.com/ 35 36 456.00–456.09 37 Deep vein thrombosis 451.00 I81, I82 38 Pulmonary embolism 450.99 I26 39 ICD-8: http://www.sst.dk/Indberetning%20og%20statistik/Klassifikationer/SKS_download.aspx 40 ICD-10: http://apps.who.int/classifications/apps/icd/icd10online/ 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 Page 1 of 33 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 26 of 82 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 3 Diagnostic codes used to compute Charlson Comorbidity Index 4 5 Disease ICD-8 code ICD-10 code 6 Myocardial infarction 410 I21;I22;I23 7 Congestive heart failure 427.09; 427.10; 427.11; I50; I11.0; I13.0; I13.2 8 427.19; 428.99; 782.49 9 Peripheral vascular 440; 441; 442; 443; 444; 445 I70; I71; I72; I73; I74; I77 10 11 disease 12 Cerebrovascular disease 430-438 I60-I69; G45; G46 13 Dementia 290.09-290.19; 293.09 F00-F03; F05.1; G30 14 Chronic pulmonary 490-493; 515-518 J40-J47; J60-J67; J68.4; J70.1; 15 disease For peer review J70.3;only J84.1; J92.0; J96.1; 16 17 J98.2; J98.3 18 Connective tissue disease 712; 716; 734; 446; 135.99 M05; M06; M08; 19 M09;M30;M31; 20 M32; M33; M34; M35; M36; 21 D86 22 23 Ulcer disease 530.91; 530.98; 531-534 K22.1; K25-K28 24 Mild liver disease 571; 573.01; 573.04 B18; K70.0-K70.3; K70.9; 25 K71; K73; K74; K76.0 26 Diabetes type1 249.00; 249.06; 249.07; E10.0, E10.1; E10.9 27 249.09 28 29 Diabetes type2 250.00; 250.06; 250.07; E11.0; E11.1; E11.9 30 250.09 31 Hemiplegia 344 G81; G82 32 Moderate to severe renal 403; 404; 580-583; 584; I12; I13; N00-N05; N07; N11; 33 disease 590.09; 593.19; 753.10- N14; N17-N19; Q61

34 http://bmjopen.bmj.com/ 35 753.19; 792 36 Diabetes with end organ 37 damage type1 249.01-249.05; 249.08 E10.2-E10.8 38 type2 250.01-250.05; 250.08 E11.2-E11.8 39 Any tumor 140-194 C00-C75 40 41 Leukemia 204-207 C91-C95 42 Lymphoma 200-203; 275.59 C81-C85; C88; C90; C96 on September 27, 2021 by guest. Protected copyright. 43 Moderate to severe liver 070.00; 070.02; 070.04; B15.0; B16.0; B16.2; B19.0; 44 disease 070.06; 070.08; 573.00; K70.4; K72; K76.6; I85 45 46 456.00-456.09 47 Metastatic solid tumor 195-198; 199 C76-C80 48 AIDS 079.83 B21-B24 49 50 51 52 53 54 55 56 57 58 Page 2 of 33 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 27 of 82 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 3 Anatomical Therapeutic Chemical (ATC) codes used to abstract the Aarhus University 4 5 Prescription Database 6 Drug ATC code 7 Drugs used in diabetes A10 8 Insulins and analogues for injection, fast-acting A10AB 9 Insulins and analogues for injection, intermediate-acting A10AC 10 11 Insulins and analogues for injection, intermediate-acting A10AD 12 combined with fast-acting 13 Insulins and analogues for injection, long-acting A10AE 14 Insulins and analogues for inhalation A10AF 15 For peer review only 16 Rosiglitazone preparations A10BG02 rosiglitazone 17 A10BD03 rosiglitazone+metformin 18 A10BD04 19 rosiglitazone+glimepiride 20 Biguanides A10BA 21 22 Sulfonamides, urea derivatives A10BB 23 Sulfonamides (heterocyclic) A10BC 24 Combinations of oral blood glucose lowering drugs A10BD (except A10BD03 and 25 A10BD04) 26 Thiazolidinediones other than rosiglitazone A10BG03 (pioglitazone) 27 28 Alpha glucosidase inhibitors A10BF 29 Dipeptidyl peptidase 4 (DPP-4) inhibitors A10BH 30 Other blood glucose lowering drugs, excl. insulins A10BX 31 Lipid-lowering drugs including statins C10A 32 Antihypertensive agents C07 (beta blockers) 33 C08 (calcium channel blockers)

34 http://bmjopen.bmj.com/ 35 C09, C09 (ACE-inhibitors and 36 angiotensin blockers) 37 Diuretics (loop, potassium sparing, thiazide) C03 38 Nitrates C01DA 39 40 Antiplatelet agents (anti-thrombotic) B01A 41 ATC classification: http://www.whocc.no/atc_ddd_index/ 42 on September 27, 2021 by guest. Protected copyright. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 Page 3 of 33 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 28 of 82 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 3 Codes used to identify laboratory tests accodring to the International Union of Pure and 4 5 Applied Chemistry (IUPAC) 6 7 Test IUPAC codes 8 Fasting blood glucose ASS00203, ASS00204, DNK35842, 9 NPU02193, NPU02195, NPU08509, 10 11 NPU08972, NPU22069 12 HbA1c NPU02307,NPU03835 13 Haemoglobin (anaemia) NPU02319, AAA00359, AAA00137, 14 AAA00115 15 AlanintransaminaseFor peer reviewDNK05051,NPU19651 only 16 17 Albumin/creatinine ratio (urine) ASS00023, ASS00024, ASS00194, 18 AAA00760,DNK05289, NPU03918, 19 NPU03929, 10913 20 Serum creatinine NPU18016, NPU01807 21 Total cholesterol NPU01566 22 23 LDL cholesterol NPU01568, NPU10171 24 HDL cholesterol NPU01567, NPU10157 25 Triglycerides NPU03620 26 IUPAC codes: http://www.sst.dk/NPU 27 28 29 30 31 32 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 Page 4 of 33 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 29 of 82 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 3 4 5 Diagnostic codes used to abstract the General Practice Research Database 6 7 Diabetes (includes both non-specific and Type II) 8 9 13AB.00 DIABETIC LIPID LOWERING DIET 10 13AC.00 DIABETIC WEIGHT REDUCING DIET 11 2BBF.00 RETINAL ABNORMALITY - DIABETES RELATED 12 2G51000 FOOT ABNORMALITY - DIABETES RELATED 13 14 2G5A.00 O/E - RIGHT DIABETIC FOOT AT RISK 15 2G5B.00 O/E -For LEFT DIABETIC peer FOOT reviewAT RISK only 16 3882.00 DIABETES WELL BEING QUESTIONNAIRE 17 3883.00 DIABETES TREATMENT SATISFACTION QUESTIONNAIRE 18 42W..00 HB. A1C - DIABETIC CONTROL 19 20 42WZ.00 HB. A1C - DIABETIC CONTROL NOS 21 42c..00 HBA1 - DIABETIC CONTROL 22 66A..00 DIABETIC MONITORING 23 66A2.00 FOLLOW-UP DIABETIC ASSESSMENT 24 66A3.00 DIABETIC ON DIET ONLY 25 26 66A4.00 DIABETIC ON ORAL TREATMENT 27 66A8.00 HAS SEEN DIETICIAN - DIABETES 28 66A9.00 UNDERSTANDS DIET - DIABETES 29 66AD.00 FUNDOSCOPY - DIABETIC CHECK 30 66AG.00 DIABETIC DRUG SIDE EFFECTS 31 66AH.00 DIABETIC TREATMENT CHANGED 32 33 66AH000 CONVERSION TO INSULIN 66AI.00 DIABETIC - GOOD CONTROL

34 http://bmjopen.bmj.com/ 35 66AJ.00 DIABETIC - POOR CONTROL 36 66AJ.11 UNSTABLE DIABETES 37 66AJ100 BRITTLE DIABETES 38 39 66AJz00 DIABETIC - POOR CONTROL NOS 40 66AK.00 DIABETIC - COOPERATIVE PATIENT 41 66AL.00 DIABETIC-UNCOOPERATIVE PATIENT 42 66AM.00 DIABETIC - FOLLOW-UP DEFAULT on September 27, 2021 by guest. Protected copyright. 43 66AN.00 DATE DIABETIC TREATMENT START 44 66AO.00 DATE DIABETIC TREATMENT STOPP. 45 46 66AP.00 DIABETES: PRACTICE PROGRAMME 47 66AQ.00 DIABETES: SHARED CARE PROGRAMME 48 66AR.00 DIABETES MANAGEMENT PLAN GIVEN 49 66AS.00 DIABETIC ANNUAL REVIEW 50 66AT.00 ANNUAL DIABETIC BLOOD TEST 51 52 889A.00 DIAB MELLIT INSULIN-GLUCOSE INFUS ACUTE MYOCARDIAL INFARCT 53 8A12.00 DIABETIC CRISIS MONITORING 54 8A13.00 DIABETIC STABILISATION 55 8CA4100 PT ADVISED RE DIABETIC DIET 56 8H2J.00 ADMIT DIABETIC EMERGENCY 57 58 Page 5 of 33 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 30 of 82 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 3 C10..00 DIABETES MELLITUS 4 5 C100.00 DIABETES MELLITUS WITH NO MENTION OF COMPLICATION 6 C100100 DIABETES MELLITUS, ADULT ONSET, NO MENTION OF COMPLICATION 7 C100111 MATURITY ONSET DIABETES 8 C100112 NON-INSULIN DEPENDENT DIABETES MELLITUS 9 C100z00 DIABETES MELLITUS NOS WITH NO MENTION OF COMPLICATION 10 C101.00 DIABETES MELLITUS WITH KETOACIDOSIS 11 12 C101100 DIABETES MELLITUS, ADULT ONSET, WITH KETOACIDOSIS 13 C101y00 OTHER SPECIFIED DIABETES MELLITUS WITH KETOACIDOSIS 14 C101z00 DIABETES MELLITUS NOS WITH KETOACIDOSIS 15 C102.00 DIABETESFor MELLITUS peer WITH reviewHYPEROSMOLAR onlyCOMA 16 C102100 DIABETES MELLITUS, ADULT ONSET, WITH HYPEROSMOLAR COMA 17 18 C102z00 DIABETES MELLITUS NOS WITH HYPEROSMOLAR COMA 19 C103.00 DIABETES MELLITUS WITH KETOACIDOTIC COMA 20 C103100 DIABETES MELLITUS, ADULT ONSET, WITH KETOACIDOTIC COMA 21 C104.00 DIABETES MELLITUS WITH RENAL MANIFESTATION 22 C104.11 DIABETIC NEPHROPATHY 23 C104100 DIABETES MELLITUS, ADULT ONSET, WITH RENAL MANIFESTATION 24 25 C104y00 OTHER SPECIFIED DIABETES MELLITUS WITH RENAL COMPLICATIONS 26 C104z00 DIABETES MELLITIS WITH NEPHROPATHY NOS 27 C105.00 DIABETES MELLITUS WITH OPHTHALMIC MANIFESTATION 28 C105100 DIABETES MELLITUS, ADULT ONSET, + OPHTHALMIC MANIFESTATION 29 C105y00 OTHER SPECIFIED DIABETES MELLITUS WITH OPHTHALMIC 30 31 COMPLICATN 32 C105z00 DIABETES MELLITUS NOS WITH OPHTHALMIC MANIFESTATION 33 C106.00 DIABETES MELLITUS WITH NEUROLOGICAL MANIFESTATION

34 C106.11 DIABETIC AMYOTROPHY http://bmjopen.bmj.com/ 35 C106.12 DIABETES MELLITUS WITH NEUROPATHY 36 C106.13 DIABETES MELLITUS WITH POLYNEUROPATHY 37 38 C106100 DIABETES MELLITUS, ADULT ONSET, + NEUROLOGICAL 39 MANIFESTATION 40 C106y00 OTHER SPECIFIED DIABETES MELLITUS WITH NEUROLOGICAL COMPS 41 C106z00 DIABETES MELLITUS NOS WITH NEUROLOGICAL MANIFESTATION 42 C107.00 DIABETES MELLITUS WITH PERIPHERAL CIRCULATORY DISORDER on September 27, 2021 by guest. Protected copyright. 43 44 C107.11 DIABETES MELLITUS WITH GANGRENE 45 C107.12 DIABETES WITH GANGRENE 46 C107100 DIABETES MELLITUS, ADULT, + PERIPHERAL CIRCULATORY DISORDER 47 C107200 DIABETES MELLITUS, ADULT WITH GANGRENE 48 C107z00 DIABETES MELLITUS NOS WITH PERIPHERAL CIRCULATORY DISORDER 49 C108y00 OTHER SPECIFIED DIABETES MELLITUS WITH MULTIPLE COMPS 50 51 C108z00 UNSPECIFIED DIABETES MELLITUS WITH MULTIPLE COMPLICATIONS 52 C109.00 NON-INSULIN-DEPENDENT DIABETES MELLITUS 53 C109.11 NIDDM - NON-INSULIN DEPENDENT DIABETES MELLITUS 54 C109.12 TYPE 2 DIABETES MELLITUS 55 C109.13 TYPE II DIABETES MELLITUS 56 57 58 Page 6 of 33 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 31 of 82 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 3 C109000 NON-INSULIN-DEPENDENT DIABETES MELLITUS WITH RENAL COMPS 4 5 C109011 TYPE II DIABETES MELLITUS WITH RENAL COMPLICATIONS 6 C109100 NON-INSULIN-DEPENDENT DIABETES MELLITUS WITH OPHTHALM 7 COMPS 8 C109111 TYPE II DIABETES MELLITUS WITH OPHTHALMIC COMPLICATIONS 9 C109200 NON-INSULIN-DEPENDENT DIABETES MELLITUS WITH NEURO COMPS 10 C109211 TYPE II DIABETES MELLITUS WITH NEUROLOGICAL COMPLICATIONS 11 12 C109300 NON-INSULIN-DEPENDENT DIABETES MELLITUS WITH MULTIPLE COMPS 13 C109400 NON-INSULIN DEPENDENT DIABETES MELLITUS WITH ULCER 14 C109411 TYPE II DIABETES MELLITUS WITH ULCER 15 C109500 NON-INSULINFor DEPENDENTpeer reviewDIABETES MELLITUS only WITH GANGRENE 16 C109511 TYPE II DIABETES MELLITUS WITH GANGRENE 17 18 C109600 NON-INSULIN-DEPENDENT DIABETES MELLITUS WITH RETINOPATHY 19 C109611 TYPE II DIABETES MELLITUS WITH RETINOPATHY 20 C109700 NON-INSULIN DEPENDANT DIABETES MELLITUS - POOR CONTROL 21 C109711 TYPE II DIABETES MELLITUS - POOR CONTROL 22 C109900 NON-INSULIN-DEPENDENT DIABETES MELLITUS WITHOUT 23 COMPLICATION 24 25 C109A00 NON-INSULIN DEPENDENT DIABETES MELLITUS WITH 26 MONONEUROPATHY 27 C109A11 TYPE II DIABETES MELLITUS WITH MONONEUROPATHY 28 C109B00 NON-INSULIN DEPENDENT DIABETES MELLITUS WITH 29 POLYNEUROPATHY 30 31 C109B11 TYPE II DIABETES MELLITUS WITH POLYNEUROPATHY 32 C109C00 NON-INSULIN DEPENDENT DIABETES MELLITUS WITH NEPHROPATHY 33 C109C11 TYPE II DIABETES MELLITUS WITH NEPHROPATHY

34 C109D00 NON-INSULIN DEPENDENT DIABETES MELLITUS WITH HYPOGLYCA http://bmjopen.bmj.com/ 35 COMA 36 C109D11 TYPE II DIABETES MELLITUS WITH HYPOGLYCAEMIC COMA 37 38 C109E00 NON-INSULIN DEPEND DIABETES MELLITUS WITH DIABETIC CATARACT 39 C109E11 TYPE II DIABETES MELLITUS WITH DIABETIC CATARACT 40 C109F00 NON-INSULIN-DEPENDENT D M WITH PERIPHERAL ANGIOPATH 41 C109F11 TYPE II DIABETES MELLITUS WITH PERIPHERAL ANGIOPATHY 42 C109G00 NON-INSULIN DEPENDENT DIABETES MELLITUS WITH ARTHROPATHY on September 27, 2021 by guest. Protected copyright. 43 44 C109G11 TYPE II DIABETES MELLITUS WITH ARTHROPATHY 45 C109H00 NON-INSULIN DEPENDENT D M WITH NEUROPATHIC ARTHROPATHY 46 C109H11 TYPE II DIABETES MELLITUS WITH NEUROPATHIC ARTHROPATHY 47 C10A.00 MALNUTRITION-RELATED DIABETES MELLITUS 48 C10A000 MALNUTRITION-RELATED DIABETES MELLITUS WITH COMA 49 C10A100 MALNUTRITION-RELATED DIABETES MELLITUS WITH KETOACIDOSIS 50 51 C10B.00 DIABETES MELLITUS INDUCED BY STEROIDS 52 C10B000 STEROID INDUCED DIABETES MELLITUS WITHOUT COMPLICATION 53 C10y.00 DIABETES MELLITUS WITH OTHER SPECIFIED MANIFESTATION 54 C10y100 DIABETES MELLITUS, ADULT, + OTHER SPECIFIED MANIFESTATION 55 C10yy00 OTHER SPECIFIED DIABETES MELLITUS WITH OTHER SPEC COMPS 56 57 58 Page 7 of 33 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 32 of 82 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 3 C10yz00 DIABETES MELLITUS NOS WITH OTHER SPECIFIED MANIFESTATION 4 5 C10z.00 DIABETES MELLITUS WITH UNSPECIFIED COMPLICATION 6 C10z100 DIABETES MELLITUS, ADULT ONSET, + UNSPECIFIED COMPLICATION 7 C10zz00 DIABETES MELLITUS NOS WITH UNSPECIFIED COMPLICATION 8 C350011 BRONZED DIABETES 9 Cyu2.00 [X]DIABETES MELLITUS 10 Cyu2000 [X]OTHER SPECIFIED DIABETES MELLITUS 11 12 F171100 AUTONOMIC NEUROPATHY DUE TO DIABETES 13 F345000 DIABETIC MONONEURITIS MULTIPLEX 14 F35z000 DIABETIC MONONEURITIS NOS 15 F372.00 POLYNEUROPATHYFor peer IN DIABETES review only 16 F372.11 DIABETIC POLYNEUROPATHY 17 18 F372.12 DIABETIC NEUROPATHY 19 F372000 ACUTE PAINFUL DIABETIC NEUROPATHY 20 F372100 CHRONIC PAINFUL DIABETIC NEUROPATHY 21 F372200 ASYMPTOMATIC DIABETIC NEUROPATHY 22 F381300 MYASTHENIC SYNDROME DUE TO DIABETIC AMYOTROPHY 23 F381311 DIABETIC AMYOTROPHY 24 25 F3y0.00 DIABETIC MONONEUROPATHY 26 F420.00 DIABETIC RETINOPATHY 27 F420000 BACKGROUND DIABETIC RETINOPATHY 28 F420100 PROLIFERATIVE DIABETIC RETINOPATHY 29 F420200 PREPROLIFERATIVE DIABETIC RETINOPATHY 30 31 F420300 ADVANCED DIABETIC MACULOPATHY 32 F420400 DIABETIC MACULOPATHY 33 F420500 ADVANCED DIABETIC RETINAL DISEASE

34 F420z00 DIABETIC RETINOPATHY NOS http://bmjopen.bmj.com/ 35 F440700 DIABETIC IRITIS 36 F464000 DIABETIC CATARACT 37 38 G73y000 DIABETIC PERIPHERAL ANGIOPATHY 39 K01x100 NEPHROTIC SYNDROME IN DIABETES MELLITUS 40 M037200 CELLULITIS IN DIABETIC FOOT 41 M271000 ISCHAEMIC ULCER DIABETIC FOOT 42 M271100 NEUROPATHIC DIABETIC ULCER - FOOT on September 27, 2021 by guest. Protected copyright. 43 44 M271200 MIXED DIABETIC ULCER - FOOT 45 N030000 DIABETIC CHEIROARTHROPATHY 46 N030011 DIABETIC CHEIROPATHY 47 N030100 DIABETIC CHARCOT ARTHROPATHY 48 Q441.00 NEONATAL DIABETES MELLITUS 49 R054200 [D]GANGRENE OF TOE IN DIABETIC 50 51 R054300 [D]WIDESPREAD DIABETIC FOOT GANGRENE 52 ZC2C800 DIETARY ADVICE FOR DIABETES MELLITUS 53 ZC2CA00 DIETARY ADVICE FOR TYPE II DIABETES 54 ZL22500 UNDER CARE OF DIABETIC LIAISON NURSE 55 ZV65312 [V]DIETARY COUNSELLING IN DIABETES MELLITUS 56 57 58 Page 8 of 33 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 33 of 82 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 3 ZV6DA00 [V]ADMITTED FOR COMMENCEMENT OF INSULIN 4 5 ZV6DB00 [V]ADMITTED FOR CONVERSION TO INSULIN 6 13B1.00 Diabetic diet 7 U602300 [X]Insul/oral hypoglyc drugs caus adverse eff therapeut use 8 8A17.00 Self monitoring of blood glucose 9 8A18.00 Self monitoring of urine glucose+ 10 C11y000 Steroid induced diabetes 11 12 C100100 DIABETES MELLITUS, ADULT ONSET, NO MENTION OF COMPLICATION 13 C100111 MATURITY ONSET DIABETES 14 C100112 NON-INSULIN DEPENDENT DIABETES MELLITUS 15 C101100 DIABETESFor MELLITUS, peer ADULT review ONSET, WITH KETOACIDOSIS only 16 C102100 DIABETES MELLITUS, ADULT ONSET, WITH HYPEROSMOLAR COMA 17 18 C103100 DIABETES MELLITUS, ADULT ONSET, WITH KETOACIDOTIC COMA 19 C104100 DIABETES MELLITUS, ADULT ONSET, WITH RENAL MANIFESTATION 20 C105100 DIABETES MELLITUS, ADULT ONSET, + OPHTHALMIC MANIFESTATION 21 C106100 DIABETES MELLITUS, ADULT ONSET, + NEUROLOGICAL MANIFESTATION 22 C107100 DIABETES MELLITUS, ADULT, + PERIPHERAL CIRCULATORY DISORDER 23 C107200 DIABETES MELLITUS, ADULT WITH GANGRENE 24 25 C107400 NIDDM WITH PERIPHERAL CIRCULATORY DISORDER 26 C109.00 NON-INSULIN-DEPENDENT DIABETES MELLITUS 27 C109.11 NIDDM - NON-INSULIN DEPENDENT DIABETES MELLITUS 28 C109.12 TYPE 2 DIABETES MELLITUS 29 C109.13 TYPE II DIABETES MELLITUS 30 31 C109000 NON-INSULIN-DEPENDENT DIABETES MELLITUS WITH RENAL COMPS 32 C109011 TYPE II DIABETES MELLITUS WITH RENAL COMPLICATIONS 33 C109012 TYPE 2 DIABETES MELLITUS WITH RENAL COMPLICATIONS

34 C109100 NON-INSULIN-DEPENDENT DIABETES MELLITUS WITH OPHTHALM http://bmjopen.bmj.com/ 35 COMPS 36 C109111 TYPE II DIABETES MELLITUS WITH OPHTHALMIC COMPLICATIONS 37 38 C109112 TYPE 2 DIABETES MELLITUS WITH OPHTHALMIC COMPLICATIONS 39 C109200 NON-INSULIN-DEPENDENT DIABETES MELLITUS WITH NEURO COMPS 40 C109211 TYPE II DIABETES MELLITUS WITH NEUROLOGICAL COMPLICATIONS 41 C109212 TYPE 2 DIABETES MELLITUS WITH NEUROLOGICAL COMPLICATIONS 42 C109300 NON-INSULIN-DEPENDENT DIABETES MELLITUS WITH MULTIPLE COMPS on September 27, 2021 by guest. Protected copyright. 43 44 C109400 NON-INSULIN DEPENDENT DIABETES MELLITUS WITH ULCER 45 C109411 TYPE II DIABETES MELLITUS WITH ULCER 46 C109412 TYPE 2 DIABETES MELLITUS WITH ULCER 47 C109500 NON-INSULIN DEPENDENT DIABETES MELLITUS WITH GANGRENE 48 C109511 TYPE II DIABETES MELLITUS WITH GANGRENE 49 C109600 NON-INSULIN-DEPENDENT DIABETES MELLITUS WITH RETINOPATHY 50 51 C109611 TYPE II DIABETES MELLITUS WITH RETINOPATHY 52 C109612 TYPE 2 DIABETES MELLITUS WITH RETINOPATHY 53 C109700 NON-INSULIN DEPENDANT DIABETES MELLITUS - POOR CONTROL 54 C109711 TYPE II DIABETES MELLITUS - POOR CONTROL 55 C109712 TYPE 2 DIABETES MELLITUS - POOR CONTROL 56 57 58 Page 9 of 33 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 34 of 82 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 3 C109900 NON-INSULIN-DEPENDENT DIABETES MELLITUS WITHOUT 4 5 COMPLICATION 6 C109A00 NON-INSULIN DEPENDENT DIABETES MELLITUS WITH 7 MONONEUROPATHY 8 C109B00 NON-INSULIN DEPENDENT DIABETES MELLITUS WITH 9 POLYNEUROPATHY 10 C109B11 TYPE II DIABETES MELLITUS WITH POLYNEUROPATHY 11 12 C109C00 NON-INSULIN DEPENDENT DIABETES MELLITUS WITH NEPHROPATHY 13 C109C11 TYPE II DIABETES MELLITUS WITH NEPHROPATHY 14 C109C12 TYPE 2 DIABETES MELLITUS WITH NEPHROPATHY 15 C109D00 NON-INSULINFor peer DEPENDENT review DIABETES MELLITUS only WITH HYPOGLYCA 16 COMA 17 18 C109D11 TYPE II DIABETES MELLITUS WITH HYPOGLYCAEMIC COMA 19 C109D12 TYPE 2 DIABETES MELLITUS WITH HYPOGLYCAEMIC COMA 20 C109E00 NON-INSULIN DEPEND DIABETES MELLITUS WITH DIABETIC CATARACT 21 C109E11 TYPE II DIABETES MELLITUS WITH DIABETIC CATARACT 22 C109E12 TYPE 2 DIABETES MELLITUS WITH DIABETIC CATARACT 23 C109F00 NON-INSULIN-DEPENDENT D M WITH PERIPHERAL ANGIOPATH 24 25 C109F11 TYPE II DIABETES MELLITUS WITH PERIPHERAL ANGIOPATHY 26 C109F12 TYPE 2 DIABETES MELLITUS WITH PERIPHERAL ANGIOPATHY 27 C109G00 NON-INSULIN DEPENDENT DIABETES MELLITUS WITH ARTHROPATHY 28 C109G11 TYPE II DIABETES MELLITUS WITH ARTHROPATHY 29 C109H00 NON-INSULIN DEPENDENT D M WITH NEUROPATHIC ARTHROPATHY 30 31 C109H11 TYPE II DIABETES MELLITUS WITH NEUROPATHIC ARTHROPATHY 32 C109H12 TYPE 2 DIABETES MELLITUS WITH NEUROPATHIC ARTHROPATHY 33 C109J00 INSULIN TREATED TYPE 2 DIABETES MELLITUS

34 C109J11 INSULIN TREATED NON-INSULIN DEPENDENT DIABETES MELLITUS http://bmjopen.bmj.com/ 35 C109J12 INSULIN TREATED TYPE II DIABETES MELLITUS 36 C109K00 HYPEROSMOLAR NON-KETOTIC STATE IN TYPE 2 DIABETES MELLITUS 37 38 C10D.00 DIABETES MELLITUS AUTOSOMAL DOMINANT TYPE 2 39 C10D.11 MATURITY ONSET DIABETES IN YOUTH TYPE 2 40 C10F.00 TYPE 2 DIABETES MELLITUS 41 C10F.11 TYPE II DIABETES MELLITUS 42 C10F000 TYPE 2 DIABETES MELLITUS WITH RENAL COMPLICATIONS on September 27, 2021 by guest. Protected copyright. 43 44 C10F100 TYPE 2 DIABETES MELLITUS WITH OPHTHALMIC COMPLICATIONS 45 C10F200 TYPE 2 DIABETES MELLITUS WITH NEUROLOGICAL COMPLICATIONS 46 C10F300 TYPE 2 DIABETES MELLITUS WITH MULTIPLE COMPLICATIONS 47 C10F400 TYPE 2 DIABETES MELLITUS WITH ULCER 48 C10F500 TYPE 2 DIABETES MELLITUS WITH GANGRENE 49 C10F600 TYPE 2 DIABETES MELLITUS WITH RETINOPATHY 50 51 C10F700 TYPE 2 DIABETES MELLITUS - POOR CONTROL 52 C10F900 TYPE 2 DIABETES MELLITUS WITHOUT COMPLICATION 53 C10FA00 TYPE 2 DIABETES MELLITUS WITH MONONEUROPATHY 54 C10FB00 TYPE 2 DIABETES MELLITUS WITH POLYNEUROPATHY 55 C10FC00 TYPE 2 DIABETES MELLITUS WITH NEPHROPATHY 56 57 58 Page 10 of 33 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 35 of 82 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 3 C10FD00 TYPE 2 DIABETES MELLITUS WITH HYPOGLYCAEMIC COMA 4 5 C10FE00 TYPE 2 DIABETES MELLITUS WITH DIABETIC CATARACT 6 C10FF00 TYPE 2 DIABETES MELLITUS WITH PERIPHERAL ANGIOPATHY 7 C10FG00 TYPE 2 DIABETES MELLITUS WITH ARTHROPATHY 8 C10FH00 TYPE 2 DIABETES MELLITUS WITH NEUROPATHIC ARTHROPATHY 9 C10FJ00 INSULIN TREATED TYPE 2 DIABETES MELLITUS 10 C10FK00 HYPEROSMOLAR NON-KETOTIC STATE IN TYPE 2 DIABETES MELLITUS 11 12 C10FL00 TYPE 2 DIABETES MELLITUS WITH PERSISTENT PROTEINURIA 13 C10FL11 TYPE II DIABETES MELLITUS WITH PERSISTENT PROTEINURIA 14 C10FM00 TYPE 2 DIABETES MELLITUS WITH PERSISTENT MICROALBUMINURIA 15 C10FN00 TYPEFor 2 DIABETES peer MELLITUS review WITH KETOACIDOSIS only 16 C10FP00 TYPE 2 DIABETES MELLITUS WITH KETOACIDOTIC COMA 17 18 C10FQ00 TYPE 2 DIABETES MELLITUS WITH EXUDATIVE MACULOPATHY 19 C10y100 DIABETES MELLITUS, ADULT, + OTHER SPECIFIED MANIFESTATION 20 C10z100 DIABETES MELLITUS, ADULT ONSET, + UNSPECIFIED COMPLICATION 21 22 23 Acute Myocardial Infarction 24 25 26 323..00 ECG: MYOCARDIAL INFARCTION 27 3233.00 ECG: ANTERO-SEPTAL INFARCT 28 3234.00 ECG:POSTERIOR/INFERIOR INFARCT 29 3235.00 ECG: SUBENDOCARDIAL INFARCT 30 3236.00 ECG: LATERAL INFARCTION 31 32 323Z.00 ECG: MYOCARDIAL INFARCT NOS 33 889A.00 DIAB MELLIT INSULIN-GLUCOSE INFUS ACUTE MYOCARDIAL INFARCT

34 G30..00 ACUTE MYOCARDIAL INFARCTION http://bmjopen.bmj.com/ 35 G30..13 CARDIAC RUPTURE FOLLOWING MYOCARDIAL INFARCTION (MI) 36 G30..15 MI - ACUTE MYOCARDIAL INFARCTION 37 G30..17 SILENT MYOCARDIAL INFARCTION 38 39 G300.00 ACUTE ANTEROLATERAL INFARCTION 40 G301.00 OTHER SPECIFIED ANTERIOR MYOCARDIAL INFARCTION 41 G301000 ACUTE ANTEROAPICAL INFARCTION 42

G301100 ACUTE ANTEROSEPTAL INFARCTION on September 27, 2021 by guest. Protected copyright. 43 G301z00 ANTERIOR MYOCARDIAL INFARCTION NOS 44 45 G302.00 ACUTE INFEROLATERAL INFARCTION 46 G303.00 ACUTE INFEROPOSTERIOR INFARCTION 47 G304.00 POSTERIOR MYOCARDIAL INFARCTION NOS 48 G305.00 LATERAL MYOCARDIAL INFARCTION NOS 49 G306.00 TRUE POSTERIOR MYOCARDIAL INFARCTION 50 51 G307.00 ACUTE SUBENDOCARDIAL INFARCTION 52 G307000 ACUTE NON-Q WAVE INFARCTION 53 G308.00 INFERIOR MYOCARDIAL INFARCTION NOS 54 G309.00 ACUTE Q-WAVE INFARCT 55 G30X.00 ACUTE TRANSMURAL MYOCARDIAL INFARCTION OF UNSPECIF SITE 56 G30y.00 OTHER ACUTE MYOCARDIAL INFARCTION 57 58 Page 11 of 33 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 36 of 82 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 3 G30y000 ACUTE ATRIAL INFARCTION 4 5 G30y100 ACUTE PAPILLARY MUSCLE INFARCTION 6 G30y200 ACUTE SEPTAL INFARCTION 7 G30yz00 OTHER ACUTE MYOCARDIAL INFARCTION NOS 8 G30z.00 ACUTE MYOCARDIAL INFARCTION NOS 9 G35..00 SUBSEQUENT MYOCARDIAL INFARCTION 10 G31y100 MICROINFARCTION OF HEART 11 12 G350.00 SUBSEQUENT MYOCARDIAL INFARCTION OF ANTERIOR WALL 13 G351.00 SUBSEQUENT MYOCARDIAL INFARCTION OF INFERIOR WALL 14 G35X.00 SUBSEQUENT MYOCARDIAL INFARCTION OF UNSPECIFIED SITE 15 G30..11 AttackFor - heart peer review only 16 G30..12 Coronary thrombosis 17 18 G30..14 Heart attack 19 G30..16 Thrombosis - coronary 20 G30A.00 Mural thrombosis 21 G5yy600 Atrial thrombosis 22 G5yy700 Left ventricular thrombosis 23 G5yy800 Right ventricular thrombosis 24 25 G307100 Acute non-ST segment elevation myocardial infarction 26 G30B.00 Acute posterolateral myocardial infarction 27 G30X000 Acute ST segment elevation myocardial infarction 28 G38..00 POSTOPERATIVE MYOCARDIAL INFARCTION 29 G380.00 POSTOPERATIVE TRANSMURAL MYOCARDIAL INFARCTION ANTERIOR 30 31 WALL 32 G381.00 POSTOPERATIVE TRANSMURAL MYOCARDIAL INFARCTION INFERIOR 33 WALL

34 G384.00 POSTOPERATIVE SUBENDOCARDIAL MYOCARDIAL INFARCTION http://bmjopen.bmj.com/ 35 36 37 38 Any Cardiovascular Disease 39 40 G311.00 Preinfarction syndrome 41 G311.11 Crescendo angina 42 G311.13 Unstable angina on September 27, 2021 by guest. Protected copyright. 43 44 G311.14 Angina at rest 45 G311100 Unstable angina 46 G311200 Angina at rest 47 G311300 Refractory angina 48 G311400 Worsening angina 49 G311500 Acute coronary syndrome 50 51 G311z00 Preinfarction syndrome NOS 52 G33..00 Angina pectoris 53 G330.00 Angina decubitus 54 G330000 Nocturnal angina 55 G330z00 Angina decubitus NOS 56 57 58 Page 12 of 33 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 37 of 82 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 3 G331.00 Prinzmetal's angina 4 5 G331.11 Variant angina pectoris 6 G33z.00 Angina pectoris NOS 7 G33z000 Status anginosus 8 G33z100 Stenocardia 9 G33z200 Syncope anginosa 10 G33z300 Angina on effort 11 12 G33z400 Ischaemic chest pain 13 G33z600 New onset angina 14 G33z700 Stable angina 15 G33zz00 AnginaFor pectoris peer NOS review only 16 Gyu3000 [X] Other forms of angina pectoris 17 18 14A5.00 H/O: angina pectoris 19 14AJ.00 H/O: Angina in last year 20 662K.00 Angina control 21 662K000 Angina control - good 22 662K100 Angina control - poor 23 662K200 Angina control - improving 24 25 662K300 Angina control - worsening 26 662Kz00 Angina control NOS 27 8B27.00 Antianginal therapy 28 G33z500 Post infarct angina 29 323..00 ECG: myocardial infarction 30 31 3233.00 ECG: antero-septal infarct. 32 3234.00 ECG: posterior/inferior infarct 33 3235.00 ECG: subendocardial infarct

34 3236.00 ECG: lateral infarction http://bmjopen.bmj.com/ 35 323Z.00 ECG: myocardial infarct NOS 36 G30..00 Acute myocardial infarction 37 38 G300.00 Acute anterolateral infarction 39 G30..11 Attack - heart 40 G30..12 Coronary thrombosis 41 G30..14 Heart attack 42 G30..15 MI - acute myocardial infarction on September 27, 2021 by guest. Protected copyright. 43 44 G30..16 Thrombosis - coronary 45 G30..17 Silent myocardial infarction 46 G301.00 Other specified anterior myocardial infarction 47 G301000 Acute anteroapical infarction 48 G301100 Acute anteroseptal infarction 49 G301z00 Anterior myocardial infarction NOS 50 51 G302.00 Acute inferolateral infarction 52 G303.00 Acute inferoposterior infarction 53 G304.00 Posterior myocardial infarction NOS 54 G305.00 Lateral myocardial infarction NOS 55 G306.00 True posterior myocardial infarction 56 57 58 Page 13 of 33 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 38 of 82 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 3 G307.00 Acute subendocardial infarction 4 5 G307000 Acute non-Q wave infarction 6 G307100 Acute non-ST segment elevation myocardial infarction 7 G308.00 Inferior myocardial infarction NOS 8 G309.00 Acute Q-wave infarct 9 G30B.00 Acute posterolateral myocardial infarction 10 G30X.00 Acute transmural myocardial infarction of unspecif site 11 12 G30X000 Acute ST segment elevation myocardial infarction 13 G30y.00 Other acute myocardial infarction 14 G30y000 Acute atrial infarction 15 G30y100 AcuteFor papillary musclepeer infarction review only 16 G30y200 Acute septal infarction 17 18 G31y100 Microinfarction of heart 19 G30yz00 Other acute myocardial infarction NOS 20 G30z.00 Acute myocardial infarction NOS 21 G30A.00 Mural thrombosis 22 G5yy600 Atrial thrombosis 23 G5yy700 Left ventricular thrombosis 24 25 G5yy800 Right ventricular thrombosis 26 14A3.00 H/O: myocardial infarct <60 27 14A4.00 H/O: myocardial infarct >60 28 14AH.00 H/O: Myocardial infarction in last year 29 3232.00 ECG: old myocardial infarction 30 31 G32..00 Old myocardial infarction 32 G32..11 Healed myocardial infarction 33 G32..12 Personal history of myocardial infarction

34 G30..13 Cardiac rupture following myocardial infarction (MI) http://bmjopen.bmj.com/ 35 G310.00 Postmyocardial infarction syndrome 36 G310.11 Dressler's syndrome 37 38 G35..00 Subsequent myocardial infarction 39 G350.00 Subsequent myocardial infarction of anterior wall 40 G351.00 Subsequent myocardial infarction of inferior wall 41 G353.00 Subsequent myocardial infarction of other sites 42 G35X.00 Subsequent myocardial infarction of unspecified site on September 27, 2021 by guest. Protected copyright. 43 44 G36..00 Certain current complication follow acute myocardial infarct 45 G36..00 Certain current complication follow acute myocardial infarct 46 G360.00 Haemopericardium/current comp folow acut myocard infarct 47 G361.00 Atrial septal defect/curr comp folow acut myocardal infarct 48 G362.00 Ventric septal defect/curr comp fol acut myocardal infarctn 49 G363.00 Ruptur cardiac wall w'out haemopericard/cur comp fol ac MI 50 51 G364.00 Ruptur chordae tendinae/curr comp fol acute myocard infarct 52 G365.00 Rupture papillary muscle/curr comp fol acute myocard infarct 53 G366.00 Thrombosis atrium,auric append&vent/curr comp foll acute MI 54 Gyu3500 [X] Subsequent myocardial infarction of other sites 55 Gyu3600 [X] Subsequent myocardial infarction of unspecified site 56 57 58 Page 14 of 33 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 39 of 82 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 3 G38..00 Postoperative myocardial infarction 4 5 G380.00 Postoperative transmural myocardial infarction anterior wall 6 G381.00 Postoperative transmural myocardial infarction inferior wall 7 G382.00 Postoperative transmural myocardial infarction other sites 8 G383.00 Postoperative transmural myocardial infarction unspec site 9 G384.00 Postoperative subendocardial myocardial infarction 10 G38z.00 Postoperative myocardial infarction, unspecified 11 12 ZV71900 [V]Observation for suspected myocardial infarction 13 889A.00 Diab mellit insulin-glucose infus acute myocardial infarct 14 G312.00 Coronary thrombosis not resulting in myocardial infarction 15 G311000 MyocardialFor infarction peer aborted review only 16 G311011 MI - myocardial infarction aborted 17 18 792..00 Coronary artery operations 19 792..11 Coronary artery bypass graft operations 20 7920.00 Saphenous vein graft replacement of coronary artery 21 7920.11 Saphenous vein graft bypass of coronary artery 22 7920000 Saphenous vein graft replacement of one coronary artery 23 7920100 Saphenous vein graft replacement of two coronary arteries 24 25 7920200 Saphenous vein graft replacement of three coronary arteries 26 7920300 Saphenous vein graft replacement of four+ coronary arteries 27 7920y00 Saphenous vein graft replacement of coronary artery OS 28 7920z00 Saphenous vein graft replacement coronary artery NOS 29 7921.00 Other autograft replacement of coronary artery 30 31 7921.11 Other autograft bypass of coronary artery 32 7921000 Autograft replacement of one coronary artery NEC 33 7921100 Autograft replacement of two coronary arteries NEC

34 7921200 Autograft replacement of three coronary arteries NEC http://bmjopen.bmj.com/ 35 7921300 Autograft replacement of four of more coronary arteries NEC 36 7921y00 Other autograft replacement of coronary artery OS 37 38 7921z00 Other autograft replacement of coronary artery NOS 39 7922.00 Allograft replacement of coronary artery 40 7922.11 Allograft bypass of coronary artery 41 7922000 Allograft replacement of one coronary artery 42 7922100 Allograft replacement of two coronary arteries on September 27, 2021 by guest. Protected copyright. 43 44 7922200 Allograft replacement of three coronary arteries 45 7922300 Allograft replacement of four or more coronary arteries 46 7922y00 Other specified allograft replacement of coronary artery 47 7922z00 Allograft replacement of coronary artery NOS 48 7924.00 Revision of bypass for coronary artery 49 7924000 Revision of bypass for one coronary artery 50 51 7924100 Revision of bypass for two coronary arteries 52 7924200 Revision of bypass for three coronary arteries 53 7924300 Revision of bypass for four or more coronary arteries 54 7924400 Revision of connection of thoracic artery to coronary artery 55 7924500 Revision of implantation of thoracic artery into heart 56 57 58 Page 15 of 33 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 40 of 82 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 3 7924y00 Other specified revision of bypass for coronary artery 4 5 7924z00 Revision of bypass for coronary artery NOS 6 7925.00 Connection of mammary artery to coronary artery 7 7925.11 Creation of bypass from mammary artery to coronary artery 8 7925000 Double anastomosis of mammary arteries to coronary arteries 9 7925011 LIMA sequential anastomosis 10 7925012 RIMA sequential anastomosis 11 12 7925100 Double implant of mammary arteries into coronary arteries 13 7925200 Single anast mammary art to left ant descend coronary art 14 7925300 Single anastomosis of mammary artery to coronary artery NEC 15 7925311 LIMAFor single anastomosispeer review only 16 7925312 RIMA single anastomosis 17 18 7925400 Single implantation of mammary artery into coronary artery 19 7925y00 Connection of mammary artery to coronary artery OS 20 7925z00 Connection of mammary artery to coronary artery NOS 21 7926.00 Connection of other thoracic artery to coronary artery 22 7926000 Double anastom thoracic arteries to coronary arteries NEC 23 7926100 Double implant thoracic arteries into coronary arteries NEC 24 25 7926200 Single anastomosis of thoracic artery to coronary artery NEC 26 7926300 Single implantation thoracic artery into coronary artery NEC 27 7926y00 Connection of other thoracic artery to coronary artery OS 28 7926z00 Connection of other thoracic artery to coronary artery NOS 29 7927.00 Other open operations on coronary artery 30 31 7927000 Repair of arteriovenous fistula of coronary artery 32 7927100 Repair of aneurysm of coronary artery 33 7927200 Transection of muscle bridge of coronary artery

34 7927300 Transposition of coronary artery NEC http://bmjopen.bmj.com/ 35 7927400 Exploration of coronary artery 36 7927y00 Other specified other open operation on coronary artery 37 38 7927z00 Other open operation on coronary artery NOS 39 7927500 Open angioplasty of coronary artery 40 7928.00 Transluminal balloon angioplasty of coronary artery 41 7928.11 Percutaneous balloon coronary angioplasty 42 7928000 Percut transluminal balloon angioplasty one coronary artery on September 27, 2021 by guest. Protected copyright. 43 44 7928100 Percut translum balloon angioplasty mult coronary arteries 45 7928200 Percut translum balloon angioplasty bypass graft coronary a 46 7928300 Percut translum cutting balloon angioplasty coronary artery 47 7928y00 Transluminal balloon angioplasty of coronary artery OS 48 7928z00 Transluminal balloon angioplasty of coronary artery NOS 49 7929.00 Other therapeutic transluminal operations on coronary artery 50 51 7929000 Percutaneous transluminal laser coronary angioplasty 52 7929100 Percut transluminal coronary thrombolysis with streptokinase 53 7929111 Percut translum coronary thrombolytic therapy- streptokinase 54 7929200 Percut translum inject therap subst to coronary artery NEC 55 7929300 Rotary blade coronary angioplasty 56 57 58 Page 16 of 33 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 41 of 82 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 3 7929400 Insertion of coronary artery stent 4 5 7929500 Insertion of drug-eluting coronary artery stent 6 7929600 Percutaneous transluminal atherectomy of coronary artery 7 7929y00 Other therapeutic transluminal op on coronary artery OS 8 7929z00 Other therapeutic transluminal op on coronary artery NOS 9 793G.00 Perc translumin balloon angioplasty stenting coronary artery 10 793G000 Perc translum ball angio insert 1-2 drug elut stents cor art 11 12 793G100 Perc tran ball angio ins 3 or more drug elut stents cor art 13 793G200 Perc translum balloon angioplasty insert 1-2 stents cor art 14 793G300 Percutaneous cor balloon angiop 3 more stents cor art NEC 15 793Gz00 PercFor translum balloonpeer angioplasty review stenting coronary only art NOS 16 792B.00 Repair of coronary artery NEC 17 18 792B000 Endarterectomy of coronary artery NEC 19 792B100 Repair of rupture of coronary artery 20 792B200 Repair of arteriovenous malformation of coronary artery 21 792By00 Other specified repair of coronary artery 22 792Bz00 Repair of coronary artery NOS 23 792C.00 Other replacement of coronary artery 24 25 792C000 Replacement of coronary arteries using multiple methods 26 792Cy00 Other specified replacement of coronary artery 27 792Cz00 Replacement of coronary artery NOS 28 792D.00 Other bypass of coronary artery 29 792Dy00 Other specified other bypass of coronary artery 30 31 792Dz00 Other bypass of coronary artery NOS 32 792y.00 Other specified operations on coronary artery 33 792z.00 Coronary artery operations NOS

34 790H300 Revascularisation of wall of heart http://bmjopen.bmj.com/ 35 ZV45800 [V]Presence of coronary angioplasty implant and graft 36 ZV45L00 [V]Status following coronary angioplasty NOS 37 38 SP07600 Coronary artery bypass graft occlusion 39 ZV45K00 [V]Presence of coronary artery bypass graft 40 ZV45K11 [V]Presence of coronary artery bypass graft – CABG 41 G31..00 Other acute and subacute ischaemic heart disease 42 G31y.00 Other acute and subacute ischaemic heart disease on September 27, 2021 by guest. Protected copyright. 43 44 G31y.00 Other acute and subacute ischaemic heart disease 45 G31y000 Acute coronary insufficiency 46 G31y100 Microinfarction of heart 47 G31y200 Subendocardial ischaemia 48 G31y300 Transient myocardial ischaemia 49 G31yz00 Other acute and subacute ischaemic heart disease NOS 50 51 G34y.00 Other specified chronic ischaemic heart disease 52 G34y000 Chronic coronary insufficiency 53 G34y100 Chronic myocardial ischaemia 54 G34yz00 Other specified chronic ischaemic heart disease NOS 55 G34z.00 Other chronic ischaemic heart disease NOS 56 57 58 Page 17 of 33 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 42 of 82 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 3 G34z000 Asymptomatic coronary heart disease 4 5 G3...00 Ischaemic heart disease 6 G3...13 IHD – Ischaemic heart diease 7 G3y..00 Other specified ischaemic heart disease 8 G3z..00 Ischaemic heart disease NOS 9 G34..00 Other chronic ischaemic heart diease 10 G343.00 Ischaemic cardiomyopathy 11 12 G344.00 Silent myocardial ischaemia 13 G3...12 Atherosclerotic heart disease 14 G3...11 Arteriosclerotic heart disease 15 G342.00 AtheroscleroticFor peercardiovascular reviewdisease only 16 G5y2.00 Cardiovascular arteriosclerosis unspecified 17 18 G34..00 Other chronic ischaemic heart disease 19 G340.00 Coronary atherosclerosis 20 G340.11 Triple vessel disease of the heart 21 G340.12 Coronary artery disease 22 G340000 Single coronary vessel disease 23 G340100 Double coronary vessel disease 24 25 G670.00 Cerebral atherosclerosis 26 G670.11 Precerebral atherosclerosis 27 G70..00 Atherosclerosis 28 G70..11 Arteriosclerosis 29 G700.00 Aortic atherosclerosis 30 31 G700.11 Aorto-iliac disease 32 G701.00 Renal artery atherosclerosis 33 G702.00 Extremity artery atheroma

34 G702000 Monckeberg's medial sclerosis http://bmjopen.bmj.com/ 35 G702z00 Extremity artery atheroma NOS 36 G70y.00 Other specified artery atheroma 37 38 G70y000 Carotid artery atherosclerosis 39 G70y011 Carotid artery disease 40 G70z.00 Arteriosclerotic vascular disease NOS 41 Gyu7000 [X]Atherosclerosis of other arteries 42 G58..00 Heart failure on September 27, 2021 by guest. Protected copyright. 43 44 G58..11 Cardiac failure 45 G580.00 Congestive heart failure 46 G580.11 Congestive cardiac failure 47 G580.12 Right heart failure 48 G580.13 Right ventricular failure 49 G580.14 Biventricular failure 50 51 G580000 Acute congestive heart failure 52 G580100 Chronic congestive heart failure 53 G580200 Decompensated cardiac failure 54 G580300 Compensated cardiac failure 55 G581.00 Left ventricular failure 56 57 58 Page 18 of 33 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 43 of 82 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 3 G581.11 Asthma - cardiac 4 5 G581.12 Pulmonary oedema - acute 6 G581.13 Impaired left ventricular function 7 G581000 Acute left ventricular failure 8 G582.00 Acute heart failure 9 G58z.00 Heart failure NOS 10 G58z.11 Weak heart 11 12 G58z.12 Cardiac failure NOS 13 G5y3.00 Cardiomegaly 14 G5y3.11 Dilatation - cardiac 15 G5y3000 AtrialFor dilatation peer review only 16 G5y3100 Ventricular dilatation 17 18 G5y3200 Cardiac dilatation NOS 19 G5y3300 Atrial hypertrophy 20 G5y3400 Ventricular hypertrophy 21 G5y3411 Left ventricular hypertrophy 22 G5y3500 Cardiac hypertrophy NOS 23 G5y3z00 Cardiomegaly NOS 24 25 8B29.00 Cardiac failure therapy 26 R2y1000 [D]Cardiorespiratory failure 27 324..00 ECG:left ventricle hypertrophy 28 325..00 ECG:right ventricle hypertrop. 29 G232.00 Hypertensive heart&renal dis wth (congestive) heart failure 30 31 G234.00 Hyperten heart&renal dis+both(congestv) heart and renal fai 32 G21z011 Cardiomegaly - hypertensive 33 G31y000 Acute coronary insufficiency

34 G34y000 Chronic coronary insufficiency http://bmjopen.bmj.com/ 35 G1yz100 Rheumatic left ventricular failure 36 SP11111 Heart failure as a complication of care 37 38 SP11200 Cardiorespiratory failure as a complication of care 39 SP11100 Cardiac insufficiency as a complication of care 40 P6yy200 Congenital cardiomegaly 41 Q48y100 Congenital cardiac failure 42 Q490.00 Neonatal cardiac failure on September 27, 2021 by guest. Protected copyright. 43 44 14A6.00 H/O: heart failure 45 14AM.00 H/O: Heart failure in last year 46 47 Congestive Heart Failure 48 49 G58..00 Heart failure 50 51 G58..11 Cardiac failure 52 G580.00 Congestive heart failure 53 G580.11 Congestive cardiac failure 54 G580.12 Right heart failure 55 G580.13 Right ventricular failure 56 57 58 Page 19 of 33 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 44 of 82 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 3 G580.14 Biventricular failure 4 5 G580000 Acute congestive heart failure 6 G580100 Chronic congestive heart failure 7 G580200 Decompensated cardiac failure 8 G580300 Compensated cardiac failure 9 G581.00 Left ventricular failure 10 G581.11 Asthma - cardiac 11 12 G581.12 Pulmonary oedema - acute 13 G581.13 Impaired left ventricular function 14 G581000 Acute left ventricular failure 15 G582.00 AcuteFor heart failure peer review only 16 G58z.00 Heart failure NOS 17 18 G58z.11 Weak heart 19 G58z.12 Cardiac failure NOS 20 G5y3.00 Cardiomegaly 21 G5y3.11 Dilatation - cardiac 22 G5y3000 Atrial dilatation 23 G5y3100 Ventricular dilatation 24 25 G5y3200 Cardiac dilatation NOS 26 G5y3300 Atrial hypertrophy 27 G5y3400 Ventricular hypertrophy 28 G5y3411 Left ventricular hypertrophy 29 G5y3500 Cardiac hypertrophy NOS 30 31 G5y3z00 Cardiomegaly NOS 32 8B29.00 Cardiac failure therapy 33 R2y1000 [D]Cardiorespiratory failure

34 324..00 ECG:left ventricle hypertrophy http://bmjopen.bmj.com/ 35 325..00 ECG:right ventricle hypertrop. 36 G232.00 Hypertensive heart&renal dis wth (congestive) heart failure 37 38 G234.00 Hyperten heart&renal dis+both(congestv) heart and renal fai 39 G21z011 Cardiomegaly - hypertensive 40 G31y000 Acute coronary insufficiency 41 G34y000 Chronic coronary insufficiency 42 G1yz100 Rheumatic left ventricular failure on September 27, 2021 by guest. Protected copyright. 43 44 SP11111 Heart failure as a complication of care 45 SP11200 Cardiorespiratory failure as a complication of care 46 SP11100 Cardiac insufficiency as a complication of care 47 P6yy200 Congenital cardiomegaly 48 Q48y100 Congenital cardiac failure 49 Q490.00 Neonatal cardiac failure 50 51 14A6.00 H/O: heart failure 52 14AM.00 H/O: Heart failure in last year 53 54 55 Peripheral Vascular Disease 56 57 58 Page 20 of 33 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 45 of 82 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 3 4 5 RG73..00 Other peripheral vascular disease 6 RG73..11 Peripheral ischaemic vascular disease 7 RG73..12 Ischaemia of legs 8 RG73..13 Peripheral ischaemia 9 RG731.00 Thromboangiitis obliterans 10 RG731000 Buerger's disease 11 12 RG731100 Presenile gangrene 13 RG731z00 Thromboangiitis obliterans NOS 14 RG73y.00 Other specified peripheral vascular disease 15 RG73y000 DiabeticFor peripheral peer angiopathy review only 16 RG73y100 Peripheral angiopathic disease EC NOS 17 18 RG73y200 Acrocyanosis 19 RG73y400 Acroparaesthesia - Schultze's type 20 RG73y600 Acroparaesthesia - unspecified 21 RG73y700 Erythrocyanosis 22 RG73y800 Erythromelalgia 23 RG73y811 Erythralgia 24 25 RG73yz00 Other specified peripheral vascular disease NOS 26 RG73z.00 Peripheral vascular disease NOS 27 RG73z000 Intermittent claudication 28 RG73z011 Claudication 29 RG73z100 Spasm of peripheral artery 30 31 RG73zz00 Peripheral vascular disease NOS 32 33 Transient Ischemic Attack / Stroke

34 http://bmjopen.bmj.com/ 35 G63..00 Precerebral arterial occlusion 36 G63..11 Infarction - precerebral 37 38 G63..12 Stenosis of precerebral arteries 39 G630.00 Basilar artery occlusion 40 G631.00 Carotid artery occlusion 41 G631.11 Stenosis, carotid artery 42 G631.12 Thrombosis, carotid artery on September 27, 2021 by guest. Protected copyright. 43 44 G632.00 Vertebral artery occlusion 45 G634.00 Carotid artery stenosis 46 G63y.00 Other precerebral artery occlusion 47 G63y000 Cerebral infarct due to thrombosis of precerebral arteries 48 G63y100 Cerebral infarction due to embolism of precerebral arteries 49 G63z.00 Precerebral artery occlusion NOS 50 51 G64..00 Cerebral arterial occlusion 52 G64..11 CVA - cerebral artery occlusion 53 G64..12 Infarction - cerebral 54 G64..13 Stroke due to cerebral arterial occlusion 55 G640.00 Cerebral thrombosis 56 57 58 Page 21 of 33 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 46 of 82 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 3 G640000 Cerebral infarction due to thrombosis of cerebral arteries 4 5 G641.00 Cerebral embolism 6 G641.11 Cerebral embolus 7 G641000 Cerebral infarction due to embolism of cerebral arteries 8 G64z.00 Cerebral infarction NOS 9 G64z.11 Brainstem infarction NOS 10 G64z.12 Cerebellar infarction 11 12 G64z000 Brainstem infarction 13 G64z100 Wallenberg syndrome 14 G64z111 Lateral medullary syndrome 15 G64z200 LeftFor sided cerebral peer infarction review only 16 G64z300 Right sided cerebral infarction 17 18 G64z400 Infarction of basal ganglia 19 G65..00 Transient cerebral ischaemia 20 G65..11 Drop attack 21 G65..12 Transient ischaemic attack 22 G65..13 Vertebro-basilar insufficiency 23 G650.00 Basilar artery syndrome 24 25 G650.11 Insufficiency - basilar artery 26 G651.00 Vertebral artery syndrome 27 G651000 Vertebro-basilar artery syndrome 28 G652.00 Subclavian steal syndrome 29 G653.00 Carotid artery syndrome hemispheric 30 31 G654.00 Multiple and bilateral precerebral artery syndromes 32 G655.00 Transient global amnesia 33 G656.00 Vertebrobasilar insufficiency

34 G65y.00 Other transient cerebral ischaemia http://bmjopen.bmj.com/ 35 G65z.00 Transient cerebral ischaemia NOS 36 G65z000 Impending cerebral ischaemia 37 38 G65z100 Intermittent cerebral ischaemia 39 G65zz00 Transient cerebral ischaemia NOS 40 G66..00 Stroke and cerebrovascular accident unspecified 41 G66..11 CVA unspecified 42 G66..12 Stroke unspecified on September 27, 2021 by guest. Protected copyright. 43 44 G66..13 CVA - Cerebrovascular accident unspecified 45 G660.00 Middle cerebral artery syndrome 46 G661.00 Anterior cerebral artery syndrome 47 G662.00 Posterior cerebral artery syndrome 48 G663.00 Brain stem stroke syndrome 49 G664.00 Cerebellar stroke syndrome 50 51 G665.00 Pure motor lacunar syndrome 52 G666.00 Pure sensory lacunar syndrome 53 G667.00 Left sided CVA 54 G668.00 Right sided CVA 55 G669.00 Cerebral palsy, not congenital or infantile, acute 56 57 58 Page 22 of 33 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 47 of 82 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 3 G680.00 Sequelae of subarachnoid haemorrhage 4 5 G681.00 Sequelae of intracerebral haemorrhage 6 G682.00 Sequelae of other nontraumatic intracranial haemorrhage 7 G683.00 Sequelae of cerebral infarction 8 G68W.00 Sequelae/other + unspecified cerebrovascular diseases 9 G68X.00 Sequelae of stroke,not specfd as h'morrhage or infarction 10 G6W..00 Cereb infarct due unsp occlus/stenos precerebr arteries 11 12 G6X..00 Cerebrl infarctn due/unspcf occlusn or sten/cerebrl artrs 13 14 15 Chronic Liver DiseaseFor peer review only 16 17 18 A707.00 CHRONIC VIRAL HEPATITIS 19 A707000 CHRONIC VIRAL HEPATITIS B WITH DELTA-AGENT 20 A707100 CHRONIC VIRAL HEPATITIS B WITHOUT DELTA-AGENT 21 A707200 CHRONIC VIRAL HEPATITIS C 22 A707X00 CHRONIC VIRAL HEPATITIS, UNSPECIFIED 23 C310400 GLYCOGENOSIS WITH HEPATIC CIRRHOSIS 24 25 J61..00 CIRRHOSIS AND CHRONIC LIVER DISEASE 26 J610.00 ALCOHOLIC FATTY LIVER 27 J612.00 ALCOHOLIC CIRRHOSIS OF LIVER 28 J612.11 FLORID CIRRHOSIS 29 J612.12 LAENNEC'S CIRRHOSIS 30 31 J612000 ALCOHOLIC FIBROSIS AND SCLEROSIS OF LIVER 32 J613.00 ALCOHOLIC LIVER DAMAGE UNSPECIFIED 33 J613000 ALCOHOLIC HEPATIC FAILURE

34 J614.00 CHRONIC HEPATITIS http://bmjopen.bmj.com/ 35 J614000 CHRONIC PERSISTENT HEPATITIS 36 J614100 CHRONIC ACTIVE HEPATITIS 37 38 J614111 AUTOIMMUNE CHRONIC ACTIVE HEPATITIS 39 J614200 CHRONIC AGGRESSIVE HEPATITIS 40 J614300 RECURRENT HEPATITIS 41 J614400 CHRONIC LOBULAR HEPATITIS 42 J614y00 CHRONIC HEPATITIS UNSPECIFIED on September 27, 2021 by guest. Protected copyright. 43 44 J614z00 CHRONIC HEPATITIS NOS 45 J615.00 CIRRHOSIS - NON ALCOHOLIC 46 J615.11 PORTAL CIRRHOSIS 47 J615000 UNILOBULAR PORTAL CIRRHOSIS 48 J615100 MULTILOBULAR PORTAL CIRRHOSIS 49 J615111 POSTNECROTIC CIRRHOSIS OF LIVER 50 51 J615200 MIXED PORTAL CIRRHOSIS 52 J615300 DIFFUSE NODULAR CIRRHOSIS 53 J615400 FATTY PORTAL CIRRHOSIS 54 J615500 HYPERTROPHIC PORTAL CIRRHOSIS 55 J615600 CAPSULAR PORTAL CIRRHOSIS 56 57 58 Page 23 of 33 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 48 of 82 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 3 J615700 CARDIAC PORTAL CIRRHOSIS 4 5 J615711 CONGESTIVE CIRRHOSIS 6 J615800 JUVENILE PORTAL CIRRHOSIS 7 J615811 CHILDHOOD FUNCTION CIRRHOSIS 8 J615812 INDIAN CHILDHOOD CIRRHOSIS 9 J615900 PIGMENTARY PORTAL CIRRHOSIS 10 J615A00 PIPE-STEM PORTAL CIRRHOSIS 11 12 J615B00 TOXIC PORTAL CIRRHOSIS 13 J615C00 XANTHOMATOUS PORTAL CIRRHOSIS 14 J615D00 BACTERIAL PORTAL CIRRHOSIS 15 J615E00 CARDITUBERCULOUSFor peer CIRRHOSIS review only 16 J615F00 SYPHILITIC PORTAL CIRRHOSIS 17 18 J615G00 ZOOPARASITIC PORTAL CIRRHOSIS 19 J615H00 INFECTIOUS CIRRHOSIS NOS 20 J615y00 PORTAL CIRRHOSIS UNSPECIFIED 21 J615z00 NON-ALCOHOLIC CIRRHOSIS NOS 22 J615z11 MACRONODULAR CIRRHOSIS OF LIVER 23 J615z12 CRYPTOGENIC CIRRHOSIS OF LIVER 24 25 J615z13 CIRRHOSIS OF LIVER NOS 26 J615z14 LAENNEC'S CIRRHOSIS, NON-ALCOHOLIC 27 J615z15 HEPATIC FIBROSIS 28 J616.00 BILIARY CIRRHOSIS 29 J616000 PRIMARY BILIARY CIRRHOSIS 30 31 J616100 SECONDARY BILIARY CIRRHOSIS 32 J616200 BILIARY CIRRHOSIS OF CHILDREN 33 J616z00 BILIARY CIRRHOSIS NOS

34 J617000 CHRONIC ALCOHOLIC HEPATITIS http://bmjopen.bmj.com/ 35 J61y.00 OTHER NON-ALCOHOLIC CHRONIC LIVER DISEASE 36 J61y000 CHRONIC YELLOW LIVER ATROPHY 37 38 J61y100 NON-ALCOHOLIC FATTY LIVER 39 J61y700 STEATOSIS OF LIVER 40 J61yz00 OTHER NON-ALCOHOLIC CHRONIC LIVER DISEASE NOS 41 J61z.00 CHRONIC LIVER DISEASE NOS 42 J62..00 LIVER ABSCESS AND SEQUELAE OF CHRONIC LIVER DISEASE on September 27, 2021 by guest. Protected copyright. 43 44 J625.00 [X] HEPATIC FAILURE 45 J625.11 [X] LIVER FAILURE 46 J62y.00 OTHER SEQUELAE OF CHRONIC LIVER DISEASE 47 J62y.11 HEPATIC FAILURE NOS 48 J62y.12 LIVER FAILURE NOS 49 J62y.13 HEPATIC FAILURE 50 51 J62z.00 LIVER ABSCESS AND CHRONIC LIVER DISEASE CAUSING SEQUELAE NOS 52 J635300 TOXIC LIVER DISEASE WITH CHRONIC PERSISTENT HEPATITIS 53 J635400 TOXIC LIVER DISEASE WITH CHRONIC LOBULAR HEPATITIS 54 J635500 TOXIC LIVER DISEASE WITH CHRONIC ACTIVE HEPATITIS 55 J635600 TOXIC LIVER DISEASE WITH FIBROSIS AND CIRRHOSIS OF LIVER 56 57 58 Page 24 of 33 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 49 of 82 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 3 SP14200 HEPATIC FAILURE AS A COMPLICATION OF CARE 4 5 SP14211 LIVER FAILURE AS A COMPLICATION OF CARE 6 7 8 Venous Thromboembolism (both deep venous thrombosis and pulmonary embolism) 9 10 G801.11 Deep vein thrombosis 11 G801.12 Deep vein thrombosis, leg 12 13 G801.13 DVT - Deep vein thrombosis 14 G822.00 Embolism and thrombosis of the vena cava 15 G80y.11 PhlebitisFor and/or thrombophlebitis peer reviewof iliac vein only 16 G80y200 Phlebitis of the external iliac vein 17 G80y400 Thrombophlebitis of the common iliac vein 18 19 G80y600 Thrombophlebitis of the external iliac vein 20 G80y800 Phlebitis and thrombophlebitis of the iliac vein 21 G801.00 Deep vein phlebitis and thrombophlebitis of the leg 22 G801000 Phlebitis of the femoral vein 23 G801100 Phlebitis of the popliteal vein 24 G801200 Phlebitis of the anterior tibial vein 25 26 G801400 Phlebitis of the posterior tibial vein 27 G801500 Deep vein phlebitis of the leg unspecified 28 G801600 Thrombophlebitis of the femoral vein 29 G801700 Thrombophlebitis of the popliteal vein 30 G801A00 Thrombophlebitis of the posterior tibial vein 31 32 G801B00 Deep vein thrombophlebitis of the leg unspecified 33 G801z00 Deep vein phlebitis and thrombophlebitis of the leg NOS

34 G401.00 Pulmonary embolism http://bmjopen.bmj.com/ 35 G401.12 Pulmonary embolus 36 37 38 39 Oral Hypoglycemic Agents 40 41 ORAL ANTIDIABETICS_sulfonylureas 42

2108 Acetohexamide on September 27, 2021 by guest. Protected copyright. 43 2110 Tolazamide 44 45 2115 Tolbutamide 46 2116 Glibenclamide (aka Glyburide) 47 2133 Glibornuride 48 2139 Glipizide 49 2148 Gliclazide 50 51 2159 Glimepiride 52 2140 Gliquidone 53 2120 Chlorpropamide 54 55 ORAL ANTIDIABETICS_Acarbose 56 2157 Acarbose 57 58 Page 25 of 33 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 50 of 82 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 3 4 5 ORAL ANTIDIABETICS_Biguanides 6 2122 Metformin 7 8 ORAL ANTIDIABETICS_Glinides 9 2161 Repaglinide 10 2165 Nateglinide 11 12 13 Dipeptidyl peptidase 4 inhibitors 14 1079 SITAGLIPTIN 15 For peer review only 16 Oral Antidiabetics_PPAR agonists 17 18 2163 ROSIGLITAZONE 19 2167 ROSIGLITAZONE AND METFORMIN 20 2160 TROGLITAZONE 21 2162 PIOGLITAZONE 22 51050 ROSIGLITAZONE + GLIMEPIRIDE 23 51067 PIOGLITAZONE / METFORMIN 24 25 26 27 Insulin 28 29 2103 INSULIN 30 31 2109 (CZI CRYSTILLIN ZINC INSULIN 32 2111 INSULIN ZINC SUSPENSION 33 2112 INSULIN ZINC SUSPENSION EXTENDED

34 2125 DEPOT-INSULIN CS http://bmjopen.bmj.com/ 35 2128 GLOBIN ZINC INSULIN INJECTION 36 2129 KOMB-INSULIN 37 38 2136 INSULIN NOVO-RAPITARD 39 2138 INSULIN LEO 40 2141 LONG INSULIN 41 2144 INSULIN CS 42 2151 INSULIN HUM NPH W ISOPHANE on September 27, 2021 by guest. Protected copyright. 43 44 2154 INSULIN HUM NPH W NEUTRAL/SOLUBLE 45 46 2158 PRO-HUMAN INSULIN LISPRO 47 16221 INSULINS & ORAL ANTIDIABETIC AGENTS 48 51007 INSULIN PORC ZINK / LENTE SEMILENTE 49 51008 INSULIN BEEF 50 51 02170 HUMALOG 52 53 54 Statins 55 56 57 58 Page 26 of 33 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 51 of 82 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 3 1214 PRAVASTATIN 4 5 1217 FLUVASTATIN 6 1218 ATORVASTATIN 7 1219 CERIVASTATIN 8 1220 SIMVASTATIN 9 1221 ROSUVASTATIN CALCIUM 10 1222 EZETIMIBE + SIMVASTATIN 11 12 19103 SIMVASTATIN 13 1212 LOVASTATIN 14 15 For peer review only 16 Antihypertensive Agents 17 18 19 ACE-inhibitors_P 20 2202 IMIDAPRIL HCL 21 4555 CAPTOPRIL 22 4559 ENALAPRIL 23 4566 LISINOPRIL 24 25 4574 PERINDOPRIL 26 4575 RAMIPRIL 27 4578 CILAZAPRIL 28 4580 FOSINOPRIL 29 4592 MOEXIPRIL 30 31 4609 TRANDOLAPRIL 32 5776 QUINAPRIL 33 4584 Benazepril

34 http://bmjopen.bmj.com/ 35 ACE-inhibitor combinations 36 4618 PERINDOPRIL + INDAPAMIDE 37 38 39 ACE-inhibitors and diuretics 40 4569 CAPTOPRIL W HYDROCHLORTH 41 4577 LISINOPRIL W HYDROCHLORO 42 4581 ENALAPRIL W HYDROCHLOROT on September 27, 2021 by guest. Protected copyright. 43 44 4590 benazepril hydrochlorothiazide 45 46 ACE-inhibitors and calcium channel blockers 47 4598 FELODIPINE+RAMIPRIL 48 49 50 51 Angiotensin II antagonists 52 4589 LOSARTAN 53 4596 VALSARTAN 54 4615 TELMISARTAN 55 4617 EPROSARTAN 56 57 58 Page 27 of 33 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 52 of 82 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 3 6202 AMIAS (=Candesartan) 4 5 6203 APROVEL (= Irbesartan) 6 24518 OLMESARTAN MEDOXOMIL 7 8 Angiotensin II inhibitors and diuretics 9 4595 COZAAR-COMP 10 6207 IRBESARTAN+HYDROCHLOROTH 11 12 13 Beta-blockers incl. Combination with diuretics 14 1320 ACEBUTOLOL HCL 15 1321 TIMOLOLFor MALEATE peer review only 16 1326 ATENOLOL 17 18 4561 ATENOLOL W CHLORTHALIDON 19 4562 NADOLOL W BENDROFLUMETHI 20 4568 ATENOLOL W NIFEDIPINE 21 4583 CELIPROLOL 22 4611 NEBIVOLOL 23 5710 PROPRANOLOL 24 25 5723 OXPRENOLOL HCL 26 5732 PINDOLOL 27 5754 NADOLOL 28 5757 CLOPAMIDE W PINDOLOL 29 5769 BETAXOLOL 30 31 5770 TIMOLOL,AMILORIDE,HYDROC 32 5773 OXPRENOLOL W CYCLOPENTHI 33 5778 ESMOLOL

34 6140 METOPROLOL http://bmjopen.bmj.com/ 35 6178 PROPRANOLOL W BENDROFLUA 36 6180 METOPROLOL W HYDROCHLORO 37 38 6182 METOPROLOL W CHLORTHALID 39 6184 SOTALOL W HYDROCHLOROTHI 40 6185 TIMOLOL W BENDROFLUAZIDE 41 6188 BISOPROLOL FUMARATE 42 6191 CARTEOLOL HCL TABLETS on September 27, 2021 by guest. Protected copyright. 43 44 6196 BISOPROLOLFUMARATE W HYD 45 6798 AMILORIDE,ATENOLOL,HYDRO 46 16704 FUROSEMIDE W PENBUTOLOL 47 6164 LABETALOL HCL 48 6166 SOTALOL HCL 49 6198 CARVEDILOL 50 51 6797 HYDROCHLOROTHIAZIDE W AC 52 4594 TENBEN 53 4599 HYDROCHLOROTHIAZIDE+TIMO 54 5731 alprenolol 55 6160 bupranolol hcl 56 57 58 Page 28 of 33 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 53 of 82 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 3 1327 penbutolol 4 5 16704 furosemide w penbutolol 6 7 Calcium channel blockers 8 4579 FELODIPINE SR 9 4587 LACIDIPINE 10 4591 DILTIATEM + HYDROCHLOROT 11 12 4597 NISOLDIPINE 13 4598 FELODIPINE+RAMIPRIL 14 4607 ISRADIPINE 15 5733 VERAPAMILFor peer review only 16 5779 VERAPAMIL HCL 180MG/2MG 17 18 6136 AMLODIPINE 19 6145 NIFEDIPINE 20 6148 PERHEXILINE MALEATE 21 6156 LIDOFLAZINE 22 6175 DILTIAZEM 23 6189 NIMODIPINE 24 25 6187 NICARDIPINE 26 6204 ZANIDIP 27 6205 MIBEFRADIL 28 29 30 Diuretics 31 32 33 Thiazides 6716 Bendrofluazide

34 http://bmjopen.bmj.com/ 35 4527 Benzthiazide 36 6746 Chlorothiazide 37 6734 Hydrochlorothiazide 38 39 4524 Cyclopenthiazide 40 6737 Polythiazide 41 6742 Chlorthalidone (thiazide-like) 42 6574 Mefruside (thiazide-like) on September 27, 2021 by guest. Protected copyright. 43 6770 Xipamide (thiazide-like) 44 6758 Metolazone 45 46 6748 Hydroflumethiazide 47 6764 Clopamide 48 16703 Clopamide with potassium 49 4554 Indapamide 50 51 52 Loop diuretics 53 6718 Furosemide 54 6756 Bumetanide 55 16711 Torasemide 56 6720 Ethacrynic acid 57 58 Page 29 of 33 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 54 of 82 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 3 4 5 Kalium-sparing diuretics 6 6719 Triamterene 7 6753 Amiloride 8 6701 Spironolactone 9 6420 Metyrapone 10 11 12 Diuretics/combinations 13 6702 Acetazolamide 14 16710 Bumetanide + amiloride 15 6794 FurosemideFor + amiloride peer review only 16 6795 Furosemide + triamterene 17 18 6785 Chlorthalidone + triamterene 19 6721 Hydrochlorothiazide + triamterene 20 6796 Furosemide + spironolactone 21 6717 SPIRONOLACTONE W HYDROCHLOROTHIAZIDE 22 6763 Spironolactone + thiazides 23 6750 Amiloride + hydrochlorothiazide 24 25 4576 Amiloride + cyclopenthiazide 26 27 Thiazides with antihypertensives 28 4561 ATENOLOL W CHLORTHALIDONE 29 6798 AMILORIDE,ATENOLOL,HYDROCHLOROTHIAZIDE 30 31 32 4594 Atenolol 33 6797 Acebutolol

34 6196 Bisoprolol http://bmjopen.bmj.com/ 35 4562 Nadolol 36 5773 Oxprenolol 37 38 5757 Pindolol 39 5770 TIMOLOL,AMILORIDE,HYDROCHLORTHIAZIDE 40 6185 Timolol 41 4556 PROPRANOLOL W HYDROCHLORTHIAZIDE 42 6178 Propranolol on September 27, 2021 by guest. Protected copyright. 43 44 6180 METOPROLOL W HYDROCHLOROTHIAZIDE 45 6182 Metoprolol 46 6184 Sotalol 47 4569 Captopril 48 4581 Enalaparil 49 4608 Quinapril 50 51 4577 Lisinopril 52 4591 Diltiazem 53 4515 RESERPINE W HYDROCHLOROTHIAZIDE PLUS 54 4525 CYCLOPENTHIAZIDE W POTASSIUM CHLORIDE 55 4517 METHYLCLOTHIAZIDE W DESERPIDINE 56 57 58 Page 30 of 33 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 55 of 82 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 3 4530 CYCLOPENTHIAZIDE,RESERPINE,POTASSIUM CHLORIDE 4 5 4532 GUANETHIDINE,CYCLOPENTHIAZIDE,POTASSIUM CHLORIDE 6 4536 HYDROFLUMETHIAZIDE,KCL,RAUWOLFIA,SERPENTHE 7 4539 GUANETHIDINE W HYDROCHLOROTHIAZIDE 8 4544 BUTABARBITAL,HYDROCHLOROTHIAZIDE,RESERPINE 9 4552 CLONIDINE W CHLORTHIAZIDE 10 4557 HYDRALAZINE W HYDROCHLOROTHIAZIDE 11 12 4564 METHOSERPIDINE W BENZTHIAZIDE 13 4582 LISINOPRIL W HYDROCHLOROTHIAZIDE 14 4585 ALKAVERVIR W EPITHIAZIDE 15 4590 BENAZEPRIL,For HYDROCHLOROTHIAZIDE peer review only 16 4599 HYDROCHLOROTHIAZIDE+TIMOLOL+AMILORIDE 17 18 4601 METHYLDOPA W HYDROCHLOROTHIAZIDE 19 4602 (METHYLCLOTHIAZIDE W DESERPIDINE 20 4603 METHYLDOPA W CHLOROTHIAZIDE 21 6146 RESERPIN,DIHYDRALAZINE,HYDROCHLOROTHIAZIDE,KCL 22 6207 IRBESARTAN+HYDROCHLOROTHIAZIDE 23 6707 HYDROCHLOROTHIAZIDE W POTASSIUM CHLORIDE 24 25 6711 BENDROFLUMETHIAZIDE W POTASSIUM CHLORIDE 26 6723 METHYLCLOTHIAZIDE 27 6728 BENDROFLUMETHIAZIDE,RAUWOLFIA SERP,KCL 28 6735 TRICHLORMETHIAZIDE 29 6736 HYDROCHLOROTHIAZIDE W MEPROBAMATE 30 31 6738 TRICHLOMETHIAZIDE W RESERPINE 32 6739 CHLOROTHIAZIDE W RESERPINE 33 6741 (GUANETHIDINE W HYDROCHLOROTHIAZIDE

34 6744 CYCLOTHIAZIDE W POTASSIUM CHLORIDE http://bmjopen.bmj.com/ 35 6749 CYCLOTHIAZIDE 36 6750 HYDROCHLOROTHIAZIDE W AMILORIDE HCL 37 38 6762 POLYTHIAZIDE W RESERPINE 39 6771 BUTHIAZIDE 40 6783 (SPIRONOLACTONE W HYDROCHLOROTHIAZID 41 6789 TRIAMTERINE W BENZTHIAZIDE 42 6792 (AMILORIDE W HYDROCHLOROTHIAZIDE on September 27, 2021 by guest. Protected copyright. 43 44 9001 CRYPTENAMINE W METHYCLOTHIAZIDE 45 16701 CHLOROTHIAZIDE W SPIRONOLACTONE 46 16702 CHLOROTHIAZIDE W SPIRONOLACTONE,LACTOSE 47 16709 ETHIAZIDE 48 40007 HYDROCHLOROTHIAZIDE OR PLACEBO STUDY 49 6731 QUINETHAZONE 50 51 4545 DIHYDROERG,CLOPAMIDE,RESERPINE 52 5758 PINDOLOL W CLOPAMIDE 53 6742 CHLORTHALIDONE 54 6782 CHLORTHALIDONE/POT.CHLORIDE 55 6150 RESERPIN,MEFRUSID,INOSITONICOT 56 57 58 Page 31 of 33 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 56 of 82 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 3 4618 PERINDOPRIL + INDAPAMIDE 4 5 6752 CLOREXOLONE 6 6733 MERSALYL SODIUM 7 9198 PHENOBARBITAL W THEOBROMINE 8 4551 RESERPINE W FUROSEMIDE 9 6768 FUROSEMIDE W POTASSIUM 10 6793 (FUROSEMIDE W POTASSIUM 11 12 16704 FUROSEMIDE W PENBUTOLOL 13 6759 BUMETANIDE W POTASSIUM CHLORIDE 14 4605 PIRETANIDE 15 6790 TIENILICFor ACID peer review only 16 6784 ETHACRYNIC ACID W TRASICOR 17 18 6766 ETOZOLIN 19 6781 LASIX W SPIRONOLACTON 20 6783 (SPIRONOLACTONE W HYDROCHLOROTHIAZID 21 6786 SPIRONOLACTONE W COMBINATIONS 22 16701 CHLOROTHIAZIDE W SPIRONOLACTONE 23 16702 CHLOROTHIAZIDE W SPIRONOLACTONE,LACTOSE 24 25 16708 POTASSIUM CANRENOATE 26 16712 EPLERENONE 27 4599 HYDROCHLOROTHIAZIDE+TIMOLOL+AMILORIDE 28 4616 TRIAMTERINE+AMILORIDE 29 16710 BUMETANIDE W AMILORIDE 30 31 4616 TRIAMTERINE+AMILORIDE 32 6765 BEMETIZIDE W TRIAMTERENE 33 6789 TRIAMTERINE W BENZTHIAZIDE

34 http://bmjopen.bmj.com/ 35 Nitrates 36 37 38 B06106 NITROGLYCERINE EXT.RELEASE 39 B06127 NITROGLYCERIN 40 B06167 NITROGLYCERIN + ISOSORBIDEDNITRAT 41 B06171 NITROGLYCERIN W COMBINATIONS 42 B06174 NITROGLYCERINE DISC on September 27, 2021 by guest. Protected copyright. 43 44 B06176 ISOSORBIDE MONONITRATE 45 B06206 ISOSORBIDE MONONITRATE+ASPIRIN 46 B06128 ISOSORBIDE DINITRATE 47 B06141 SODIUM NITROPRUSSIDE 48 B06153 AMYL NITRITE 49 50 51 Antiplatelet Agents 52 53 1923 EPOPROSTENOL 54 1928 ABCIXIMAB 55 1930 CLOPIDOGREL 56 57 58 Page 32 of 33 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 57 of 82 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 3 5528 TICLOPIDIN 4 5 6105 DIPYRIDAMOLE 6 6201 DIPYRIDAMOLE 200MG/ASPIR 7 4979 Aloxiprin 8 1937 Tirofiban 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 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 Page 33 of 33 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 58 of 82 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

34 of controls per case http://bmjopen.bmj.com/ 35 Variables 7 Clearly define all outcomes, exposures, predictors, potential confounders, and x 36 37 effect modifiers. Give diagnostic criteria, if applicable 38 Data sources/ 8* For each variable of interest, give sources of data and details of methods of 39 measurement assessment (measurement). Describe comparability of assessment methods if 40 there is more than one group 41 Bias 9 Describe any efforts to address potential sources of bias x 42 43 Study size 10 Explain how the study size was arrived at x on September 27, 2021 by guest. Protected copyright. 44 Quantitative variables 11 Explain how quantitative variables were handled in the analyses. If applicable, x 45 describe which groupings were chosen and why 46 Statistical methods 12 (a) Describe all statistical methods, including those used to control for x 47 48 confounding 49 (b) Describe any methods used to examine subgroups and interactions x 50 (c) Explain how missing data were addressed N/A 51 (d) Cohort study—If applicable, explain how loss to follow-up was addressed N/A 52 53 Case-control study—If applicable, explain how matching of cases and controls 54 was addressed 55 Cross-sectional study—If applicable, describe analytical methods taking account 56 of sampling strategy 57 (e) Describe any sensitivity analyses N/A 58 59 Continued on next page 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml1 Page 59 of 82 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

34 http://bmjopen.bmj.com/ Interpretation 20 Give a cautious overall interpretation of results considering objectives, limitations, x 35 36 multiplicity of analyses, results from similar studies, and other relevant evidence 37 Generalisability 21 Discuss the generalisability (external validity) of the study results x 38 Other information 39 40 Funding 22 Give the source of funding and the role of the funders for the present study and, if x 41 applicable, for the original study on which the present article is based 42 on September 27, 2021 by guest. Protected copyright. 43 *Give information separately for cases and controls in case-control studies and, if applicable, for exposed and 44 unexposed groups in cohort and cross-sectional studies. 45 46 47 Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and 48 published examples of transparent reporting. The STROBE checklist is best used in conjunction with this article (freely 49 available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at 50 http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is 51 52 available at www.strobe-statement.org. 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml2 BMJ Open Page 60 of 82 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

28 5 29 Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, 30 31 GA, USA 32 33

56 57 Page 1 of 23 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 61 of 82 BMJ Open 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 secondline oral hypoglycaemic agent, which was sold in the 7 European Union starting in 2000; in after a series of regulatory decisions, its use was 8 first restricted and ultimately suspended in Europe, in September of 2010 9 • This article study examines utilization of rosiglitazone in Denmark and the United 10 Kingdom (UK), in 20002010 11 • On the patient level, this article study 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 metaanalysis 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 time of 32 initiation and discontinuation of medication intake 33

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33

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 populationbased data from the Aarhus University 12 13 Prescription Database (AUPD), in northern Denmark and from 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 haemoglobinA (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 at 15% in the GPRD, in May 2007, the month of publication of a 33 metaanalysis showing increased cardiovascular morbidity associated with rosiglitazone use. 34 http://bmjopen.bmj.com/ 35 36 Twelve months after discontinuation of rosiglitazonecontaining products, the mean change in 37 38 HbA1c was –0.16% (95% confidence interval [CI]: –3.4%, 3.1%) in northern Denmark and – 39 40 0.17% (95% CI: –0.21%, 0.13%) in the UK. Corresponding mean changes in FPG were 0.01 41 42 mmol/L (95% CI: –7.3 mmol/L, 7.3 mmol/L) and 0.03 mmol/L (95% CI: –0.22 mmol/L, 0.28 43 on September 27, 2021 by guest. Protected copyright. 44 mmol/L). 45 46 Conclusions Publication of evidence concerning potential cardiovascular risks of rosiglitazone 47 48 was associated with an irreversible decline in use of rosiglitazonecontaining products in 49 50 Denmark and the UK. Mean changes in HbA and FPG after drug discontinuation were slight. 51 1c 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 64 of 82 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 19 7 several riskbenefit assessments, especially concerning cardiovascular safety. In a May 2007 8 9 metaanalysis published in the New England Journal of Medicine, Nissen and Wolski reported

10 2 11 increased cardiovascular morbidity associated with rosiglitazone use . In 2008, the European 12 13 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 metaanalysis, 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 use12. 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 allcause 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 rosiglitazonecontaining

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 EMAcommissioned 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 rosiglitazonecontaining products over the entire period when rosiglitazone was available on 47 48 the European market. On the patient level, we assessed the impact of rosiglitazone 49 50 discontinuation on glycaemic control and reported oral hypoglycaemic agents prescribed after 51 52 postsuspension discontinuation of rosiglitazone. 53 54 55 METHODS 56 57 58 Setting and study population. 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 65 of 82 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 This study was based on routinely collected data in medical databases in Danish 3 4 Denmark and in the United Kingdom (UK) medical databases. In Denmark, the study 5 6 population included users of oral hypoglycaemic agents (OHAs) identified in the Aarhus 7 15 8 University Prescription Database (AUPD). . The database’s catchment area covers the North 9 10 and Central Regions of Denmark (hereafter referred to as ‘northern Denmark’), with a 11 12 combined population in mid2010 of 1.,8 million34,595 persons, which is about onethird of 13 14 the Danish population. The AUPD captures reimbursed prescriptions redeemed in the regions’ 15 For peer review only 16 outpatient pharmacies since 1998. In the UK, OHA users were identified from the General 17 18 Practice Research Database (GPRD), currently also known as the Clinical Practice Research 19 20 Datalink.16 21 22 We identified patients in each database with a prescription for any OHA between 1 23 24 January 2000 and 31 December 2010, encompassing the entire period of rosiglitazone 25 26 availability in Europe. We defined OHA users as persons who received at least one 27 28 prescription for any OHA during the study period. Prescriptions for OHAs were identified 29 30 using Anatomical Therapeutic Chemical (ATC) codes in the AUPD and Multilex codes in the 31 32 GPRD. People could have received prescriptions for multiple OHAs , including rosiglitazone, 33

34 http://bmjopen.bmj.com/ 35 during the study period, including rosiglitazone. Our use of the term ‘rosiglitazone’ includes 36 37 all preparations of the drug. 38 39 Start of rosiglitazone use was defined as the date of the firstrecorded prescription for a 40 41 rosiglitazonecontaining product. Patients were assumed to have discontinued rosiglitazone 42 43 therapy in the absence of a record of a new rosiglitazone prescription refill during a period on September 27, 2021 by guest. Protected copyright. 44 45 encompassing the estimated length of at least two prescriptions. Prescription length was 46 47 estimated at 45 days in AUPD and 130 days in the GPRD, based on observed intervals 48 49 between prescriptions and knowledge about typical clinical prescribing practice in Denmark, 50 51 as well as on the prescribing instructions in the British Monthly Index of Medications in the 52 53 UK. 54 55 To describe the study population, we obtained data on participants’ clinical and 56 57 demographic characteristics, including sex, age, body mass index (BMI), smoking, medical 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 66 of 82 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 diagnoses, and use of other medications (lipidlowering agents, antihypertensive agents, 3 4 diuretics, nitrates, and antiplatelet agents). These characteristics were measured as of 1 5 6 January 2000 for patients who started an OHA before 2000 and on the date of the first OHA 7 8 prescription for those who started thereafter. We used records from routine laboratory tests to 9 10 obtain data on measured glycated haemoglobinA1c (HbA1c) and fasting plasma glucose (FPG) 11 12 levels. 13 14 Data sources. 15 For peer review only 16 In northern Denmark, data on hospitalbased medical diagnoses, prescription 17 18 medications, and laboratory test results were obtained, respectively, from the Danish National 19 20 Registry of Patients (DNRP 17), from the AUPD, and from the Laboratory Information 21

22 18 23 Systems of the North and the Central Denmark Regions (the LABKA database ). The 24 25 LABKA database stores results of laboratory tests performed at hospitalbased laboratories. 26 27 Patients are referred to these laboratories by hospitals, general practitioners, and specialists. 28 29 Data on smoking and BMI were obtained from the Danish National Indicator Project diabetes 30 19 31 database. (http://www.nip.dk). All data were linked on the individual level using the 32 20 33 universal personal identifier. . In the UK all data were obtained from the GPRD. The GPRD

34 http://bmjopen.bmj.com/ 35 is a longitudinal database that has collected data from over 450 general practices in the UK 36 37 since 1987, covering a representative 6% sample of the UK population. The GPRD captures 38 39 prescriptions issued to patients by general practitioners, and it also includes information on 40 41 patient demographics, diagnoses, referrals, hospitalizations, and laboratory test results. 16 2123. 42 on September 27, 2021 by guest. Protected copyright. 43 Statistical analysis. 44 45 First, we examined changes in the proportion of rosiglitazone users among all users of 46 47 OHAs in the two countries between 2000 and 2010. Second, we compared distributions of 48 49 50 demographic and clinical characteristics between rosiglitazone users and users of other OHAs. 51 52 Third, we examined changes in HbA1c and FPG levels, comparing values before and after 53 54 discontinuation of rosiglitazone treatment. The prediscontinuation value of a laboratory 55 56 parameter was the value closest in time to the estimated discontinuation date within 24 months 57 58 before that date. We defined three nonoverlapping postdiscontinuation periods as follows: 3 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 67 of 82 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 months (90–179 days postdiscontinuation); 6 months (180–359 days postdiscontinuation); 3 4 and 12 months (360–479 days postdiscontinuation). We used the earliest available 5 6 measurement within each postdiscontinuation period. The postdiscontinuation values were 7 8 ascertained through 30 June 2011. Using the prediscontinuation and postdiscontinuation 9 10 values, we We calculated the mean (with standard deviation) level for HbA1c and FPG before 11 12 and after discontinuation and the mean change for each postdiscontinuation period. 13 14 Furthermore, we calculated the proportion of patients with new postdiscontinuation onset of 15 For peer review only 16 loss of glycaemic control, defined as of HbA1c >7.5%;, and the proportion of patients with new 17 18 postdiscontinuation onset of treatment failure, defined as FPG >10 mmol/L. To capture new 19 20 onset, these proportions first were computed among patients without evidence of treatment 21 22 failure/loss of glycaemic control before discontinuing rosiglitazone. We then calculated the 23

24 proportions of patients with clinically meaningful changes in HbA1c (change >0.6%) and FPG 25

26 (change >10%) after discontinuation of rosiglitazone. Finally, we examined changes in HbA1c 27 28 levels in patients who discontinued the drug on or after 23 September 2010, presumably in 29 30 response to the EMA’s suspension of the drug., We also and reported the distribution of the 31 32 first OHA prescribed to patients who discontinued rosiglitazone after rosiglitazone its 33

34 suspension. The algorithms used to define variables in this project are provided in the http://bmjopen.bmj.com/ 35 36 Appendix. We used SAS software version 9.2 (SAS Inc., Cary, NC, USA) to analyse the data. 37 38 39 Ethical approval 40 41 This study was approved by the Danish Data Protection Agency (record number 200941 42 43 3866) and by the Independent Scientific Advisory Committee of the GPRD. There was no on September 27, 2021 by guest. Protected copyright. 44 45 patient contact, and informed consent was therefore not required. 46 47 48 RESULTS 49 50 51 Utilisation of rosiglitazone and patient characteristics 52 53 During the study period, 67,525 OHA users were recorded in the AUPD and 191,276 in 54 55 the GPRD. Of these, 2,321 (3.4%) persons in the AUPD and 25,428 (13%) persons in the 56 57 GPRD received at least one prescription for a rosiglitazonecontaining product. Figure 1 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 68 of 82 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 shows changes in the proportion of rosiglitazone users among all OHA users within during the 3 4 study period. This proportion peaked at 4% in northern Denmark and at 15% in the UK in 5 6 May 2007, and rapidly decreased thereafter, with virtually no rosiglitazone users remaining 7 8 after 2010. 9 10 Table 1 compares demographic and clinical characteristics of users of rosiglitazone and 11 12 with users of other OHAs. Rosiglitazone users tended to be younger, but were more likely to 13 14 have had a prescription history of lipidlowering or antihypertensive agents. Rosiglitazone 15 For peer review only 16 users were more likely than the other OHA users to have used OHAs other than metformin 17 18 and sulfonylurea previouslybefore starting rosiglitazone. Based on data from the GPRD, users 19 20 of rosiglitazonecontaining products were slightly more likely than other OHA users to have a 21 22 BMI of ≥30 kg/m2. BMI data for patients in Denmark were sparse (Table 1). 23 24 25 Glycaemic control after discontinuation of rosiglitazone. 26 27 Among all rosiglitazone users in the LABKA AUPD, 1776 patients who discontinued the 28 29 drug had HbA1c measurements available. Among these patients, tThe mean median duration of 30 31 rosiglitazone use in these patients was 2419.1 months (standard deviation 21.1), median 32 33 18.8quartiles, 6–38 months). , and the median time from the last prediscontinuation HbA1c

34 http://bmjopen.bmj.com/ 35 measurement until discontinuation of rosiglitazone was 44 days (quartiles, 21–78 days). In the 36

37 GPRD, there were 21,145 rosiglitazone users with HbA1c measurements. Among these 38 39 patients, tThe mean median duration of rosiglitazone use was use in these patients was 30.3 40 41 (standard deviation 25.5), median, 24,0 months (quartiles, 8–47 months) and the median time 42 43 on September 27, 2021 by guest. Protected copyright. from the last prediscontinuation HbA1c measurement until discontinuation of rosiglitazone 44 45 was 70 days (quartiles, 25–153 days). Table 2 shows changes in HbA1c at three, six, and 12 46 47 months after discontinuation of rosiglitazone treatment at any time during the study period. At 48 49 12 months postdiscontinuation, a change of similar magnitude in the mean HbA1c was 50 51 observed in both the LABKA (Denmark) and Laboratory (UK) databases: –0.16% (95% 52 53 confidence interval [CI]: –3.4%, 3.1%) in northern Denmark, and –0.17% (95% CI: –0.21%, 54 55 0.13%) in the UK. Loss of glycaemic control, defined by new onset of HbA >7.5%, was 56 1c 57 registered for up to 29% of patients during the 12month followup period in Denmark and for 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 69 of 82 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 up to 37% of patients in the UK. Similar proportions of patients had HbA1c values consistent 3 4 with a clinically meaningful decrease (>0.6%) at 12 months postdiscontinuation. 5 6 Table 3 shows changes in HbA1c after among patients who discontinuation discontinuedof 7 8 rosiglitazonecontaining products on or after 23 September 2010. Thus, Table 3 represents 9

10 subset of patients described in Table 2. In the UK data, mean HbA1c decreased by 1.8% (95% 11 12 CI: –2.1%, –1.6%) at six months postdiscontinuation (95% CI: –2.1%, –1.6%), but the pre 13

14 discontinuation mean HbA1c in this group was 10%. A larger proportion of patients in the UK 15 For peer review only 16 than in Denmark had evidence of loss of glycaemic control and a substantially larger 17 18 proportion of patients in the UK experienced a clinically meaningful decrease in HbA1c after 19 20 discontinuation of rosiglitazone compared with Denmark (Table 3). 21 22 23 Table 4 shows changes in FPG at three, six, and 12 months after discontinuation of 24 25 rosiglitazone. At 12 months postdiscontinuation, there was virtually no change seen in either 26 27 of the databases: mean change of = 0.01 mmol/L (95% CI: –7.3 mmol/L; 7.3 mmol/L) in 28 29 northern Denmark, and mean change of = 0.03 mmol/L (95% CI: –0.22 mmol/L; 0.28 30 31 mmol/L) in the UK. Treatment failure, defined by new onset of FPG >10 mmol/L during one 32 33 of the followup periods, was observed in a maximum of 23% of patients in northern Denmark

34 http://bmjopen.bmj.com/ 35 and 20% in the UK. The number of persons with available measurements for northern 36 37 Denmark, however, was small (Table 4). Table 5 shows the distribution of OHA prescribed to 38 39 patients after who terminatingdiscontinued rosiglitazone on 23 September 2010 or later. The 40 41 majority of the patients switched to another OHA (82% in northern Denmark; 97% in the UK) 42 43 after the last recorded pioglitazone rosiglitazone prescription. The majority of patients – on September 27, 2021 by guest. Protected copyright. 44 45 56.8% in Denmark and 41.7% in the UK – received a prescription for metformin. In the UK, 46 47 23.6% of patients had a prescription for pioglitazone, and 14.5% for pioglitazone and + 48 49 metformin. Pioglitazone was prescribed only to 4.4% of the patients in northern Denmark. 50 51 52 DISCUSSION 53 54 55 We examined use of rosiglitazonecontaining products over the entire period of 56 57 availability of this drug in Europe (2000–2010) using routinely collected data in medical 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 70 of 82 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 databases in Denmark and in the United Kingdom. Overall, the drug was more widely used in 3 4 the UK than in Denmark, with the proportion of rosiglitazone users among all users of OHA 5 6 peaking at 15% and 4% in the two countries, respectively. The timing of both peaks, which 7 8 marked the beginning of a steep decline in use, coincided with the May 2007 publication of 9 10 the metaanalysis by Nissen and Wolski 2 and subsequent regulatory warnings from the EMA. 11 12 This decline occurred three years before the regulatory decision to suspend rosiglitazone in 13 14 Europe. Similarly, a sharp decline in prescribing occurred in the United States after the FDA 15 For peer review only 16 added a boxed warning to the rosiglitazone label in May 2007. 24. On the patient level, 17 18 discontinuation of rosiglitazone was associated with a slight overall decrease in the mean level 19 20 of glycated haemoglobin. However, close to onethird of patients had evidence consistent with 21 22 loss of glycaemic control during the 12 months of followup, including patients who 23 24 discontinued rosiglitazone after the EMA decision to suspend the drug. The majority ofMost 25 26 patients who discontinued rosiglitazone after the EMAmandated suspension started receiving 27 28 metformin. 29 30 Meaning of the findings 31 32 33 While on the market, rosiglitazone represented a larger proportion of all OHA use in the

34 http://bmjopen.bmj.com/ 35 UK than in Denmark. This may reflect conservative recommendations issued in Denmark, 36 25 37 suggesting that treatment first be attempted with metformin, sulfonurea, and insulin. . 38 39 Guidelines from the National Institute for Health and Clinical Excellence (NICE) in the UK 40 41 stated that rosiglitazone should only be prescribed if other classes of OHA were not effective 42 43 in lowering plasma glucose concentrations. Therefore rosiglitazone was recommended only as on September 27, 2021 by guest. Protected copyright. 44 26 45 second or third line therapy. . The high prediscontinuation level of HbA1c in UK patients 46 47 who discontinued rosiglitazone following the drug suspension is also consistent with this 48 49 guideline. Among patients terminating rosiglitazone after the drug was suspended, a larger 50 51 proportion of UK patients compared with their Danish counterparts experienced a clinically 52 53 meaningful decrease in glycated haemoglobin. The prediscontinuation values among the UK 54 55 patients were substantially higher, probably reflecting heightened medical attention drawn to. 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 71 of 82 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 We thus attribute this to the result of patients with poor glycaemic control coming to medical 3 4 attention. 5 6 Strengths and weaknesses 7 8 The data presented here were obtained from medical databases containing that provide 9 10 data on routine and independent registration of healthrelated events in two European 11 12 countries. Such data are therefore likely to reflect typical clinical practice. The data from the 13 14 two data systems are also complementary. The AUPD records filled purchased prescriptions, 15 For peer review only 16 while the GPRD records prescriptions issued by general practitioners. Furthermore, the 17 18 databases draw on different health sectors for information on patient characteristics: . iIn 19 20 Denmark data on diagnoses originate from hospital discharge summaries, while in the GPRD, 21 22 23 data on diagnoses originate from generalpractitioner records. Despite these differences and 24 25 potential differences in the underlying patient populations, the results obtained from the two 26 27 data systemscountries were generally consistent. 28 29 Because OHA are distributed by prescription only and need to be taken longterm, the 30 31 information we present on rosiglitazone utilization over calendar time is likely to be accurate. 32 33 The pattern of use for the two Danish regions included here mirrors the nationwide pattern

34 http://bmjopen.bmj.com/ 35 reported by the Danish Medicines Agency. 27. However, because automated prescription 36 37 records provide no information on the exact timing of drug intake, we had to make 38 39 assumptions about timing of rosiglitazone discontinuation and prescription length. We 40 41 speculate that shortterm changes in laboratory parameters following discontinuation of 42 on September 27, 2021 by guest. Protected copyright. 43 rosiglitazone are subject to more misclassification due to errors in assigning the 44 45 discontinuation status than are longterm changes in these parameters. Therefore, our 12 46 47 month estimates of postdiscontinuation change in laboratory parameters may be more robust 48 49 than the 3month estimates. The information on glycated haemoglobin A1c and on fasting 50 51 plasma glucose originated from routinely collected laboratory data, although patients with 52 53 laboratory measurements may differ from the entire population of rosiglitazonetreated 54 55 patients. For example, physicians may be less likely to routinely collect laboratory data for 56 57 patients with less severe diabetes. 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 72 of 82 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 Conclusion 3 4 In summary, a decline in use of rosiglitazone occurred immediately following the May 5 6 2007 publication of a metaanalysis describing adverse cardiac side effects of this drug. 2. 7 8 Changes in glycaemic control after discontinuation of rosiglitazone were, on average, small on 9 10 average during the 12 months after discontinuation of rosiglitazonefollowup period, although 11 12 about onethird of patients had evidence of loss of glycaemic control upon discontinuation. 13 14 Most patients who discontinued rosiglitazone after EMAmandated suspension were switched 15 For peer review only 16 to a metformincontaining regimen. 17 18 19 20 ACKNOWLEDGMENTS 21 22 We thank the Pharmacovigilance Working Party (PhVWP) at the European Medicines 23 24 Agency for helpful comments. We are grateful to Hanne Kjeldahl Schlosser, Helle Vester, and 25 26 Kathleen Jick for outstanding administrative support. 27 28 29 FUNDING 30 31 32 This study was commissioned and funded by the European Medicines Agency (Procurement 33

34 Procedure No. EMA/2010/38/CN). The funding agency had no direct role in preparation of http://bmjopen.bmj.com/ 35 36 this manuscript. 37 38 39 DISCLAIMER 40 41 42 This document expresses the opinions of the authors of the paper, and may not be understood 43 on September 27, 2021 by guest. Protected copyright. 44 or quoted as being made on behalf or of reflecting the position of the European Medicines 45 46 Agency or one of its committees or working parties. 47 48 49 CONTRIBUTION STATEMENT 50 51 52 V. Ehrenstein participated in conception and design of the study, led the writing, and 53 54 contributed to data analysis. R. K. Hernandez contributed to study design and data analysis in 55

56 the GPRD. S. P. Ulrichsen conducted the data analyses in Denmark, J. Rungby contributed to 57 58 study design and analysis, and provided clinical expertise, T.L. Lash participated in 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 73 of 82 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 conception and design of the study, A.H. Riis contributed to data analysis of the AUPD data, 3 4 L. Li contributed to data analysis of the GPRD data, H.T. Sørensen oversaw the study and 5 6 provided clinical expertise, and S. S. Jick participated in conception and design of the study. 7 8 All authors participated in revisions of the manuscript draft for intellectual content. 9 10 11 12 This study has received the ENCePP Study Seal (Reference number ENCEPP/SDPP/1777). 13 14 15 For peer review only 16 Exclusive license statement 17 18 The Corresponding Author has the right to grant on behalf of all authors and does grant 19 20 on behalf of all authors, an exclusive licence (or nonexclusive for government employees) on a 21 22 worldwide basis to the BMJ Publishing Group Ltd and its Licensees to permit this article (if 23 24 accepted) to be published in BMJ editions and any other BMJPGL products and sublicenses to 25 26 exploit all subsidiary rights, as set out in our licence. 27 28 29 30 Competing interest statement 31 32 All authors have completed the ICMJE uniform disclosure form at and declare: being 33

34 funded by the EMA (through institutional contracts and subcontracts) for this work; no http://bmjopen.bmj.com/ 35 36 financial relationships with any organisations that might have an interest in the submitted 37 38 work in the previous three years, no other relationships or activities that could appear to have 39 40 influenced the submitted work. 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 BMJ Open Page 74 of 82 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 REFERENCES 3 4 5 1. Home PD, Pocock SJ, BeckNielsen H, Gomis R, et al. Rosiglitazone evaluated 6 for cardiovascular outcomesan interim analysis. N Engl J Med 2007;357:2838. 7 2. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial 8 infarction and death from cardiovascular causes. N Engl J Med 2007;356:245771. 9 3. Psaty BM, Furberg CD. Rosiglitazone and Cardiovascular Risk. New England 10 Journal of Medicine 2007;356:252224. 11 4. Margolis DJ, Hoffstad O, Strom BL. Association between serious ischemic 12 cardiac outcomes and medications used to treat diabetes. Pharmacoepidemiol Drug Saf 13 2008;17:7539. 14 15 5. For EMEA statementpeer on recent review publication on cardiac safetyonly of rosiglitazone 16 (Avandia, Avandamet, Avaglim). 2009. 17 http://www.emea.europa.eu/docs/en_GB/document_library/Press_release/2009/11/WC500013 18 467.pdf (accessed August 2013). 19 6. Home PD, Pocock SJ, BeckNielsen H, Curtis PS, et al. Rosiglitazone 20 evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes 21 (RECORD): a multicentre, randomised, openlabel trial. Lancet 2009;373:212535. 22 7. Graham DJ, OuelletHellstrom R, MaCurdy TE, Ali F, et al. Risk of acute 23 myocardial infarction, stroke, heart failure, and death in elderly Medicare patients treated with 24 rosiglitazone or pioglitazone. JAMA 2010;304:4118. 25 26 8. Nissen SE. The rise and fall of rosiglitazone. Eur Heart J 2010;31:7736. 27 9. Blind E, Dunder K, de Graeff PA, Abadie E. Rosiglitazone: a European 28 regulatory perspective. Diabetologia 2011;54:2138. 29 10. EMEA recommends new warnings and contraindications for rosiglitazone 30 2009. 31 http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2009/11/WC5000154 32 20.pdf (accessed August 2013). 33 11. European Medicines Agency confirms positive benefitrisk balance for

34 http://bmjopen.bmj.com/ rosiglitazone and pioglitazone. 2009 35 36 http://www.emea.europa.eu/docs/en_GB/document_library/Press_release/2009/11/WC500011 37 009.pdf (accessed August 2013). 38 12. Nissen SE, Wolski K. Rosiglitazone Revisited: An Updated Metaanalysis of 39 Risk for Myocardial Infarction and Cardiovascular Mortality. Arch Intern Med 2010. 40 13. European Medicines Agency recommends suspension of Avandia, Avandamet 41 and Avaglim. 2010 42

http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2010/09/WC5000969 on September 27, 2021 by guest. Protected copyright. 43 96.pdf (accessed August 2013). 44 14. The European Commission. Commission Decision of 3.12.2010 suspending, 45 under Article 20 of Regulation (EC) No 726/2004 of the European Parliament and of the 46 Council, the marketing authorisation, granted by Decision C(2000)1799, for "Avandia 47 Rosiglitazone" a medicinal product for human use. 48 49 15. Ehrenstein V, Antonsen S, Pedersen L. Existing data sources for clinical 50 epidemiology: Aarhus University Prescription Database. Clin Epidemiol 2010;2:2739. 51 16. Clinical Practice Research Datalink. http://www.cprd.com (accessed August 52 2013). 53 17. Lynge E, Sandegaard JL, Rebolj M. The Danish National Patient Register. 54 Scand J Public Health 2011;39:303. 55 56 18. Grann AF, Erichsen R, Nielsen AG, Froslev T, et al. Existing data sources for 57 clinical epidemiology: The clinical laboratory information system (LABKA) research database 58 at Aarhus University, Denmark. Clinical epidemiology 2011;3:1338. 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 75 of 82 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1 2 19. Danish National Indicator Project. http://www.nip.dk (accessed August 2013). 3 20. Pedersen CB, Gotzsche H, Moller JO, Mortensen PB. The Danish Civil 4 Registration System. A cohort of eight million persons. Dan Med Bull 2006;53:4419. 5 21. Jick H, Jick SS, Derby LE. Validation of information recorded on general 6 practitioner based computerised data resource in the United Kingdom. BMJ 1991;302:7668. 7 22. Garcia Rodriguez LA, Perez Gutthann S. Use of the UK General Practice 8 9 Research Database for pharmacoepidemiology. Br J Clin Pharmacol 1998;45:41925. 10 23. Jick SS, Kaye JA, VasilakisScaramozza C, Garcia Rodriguez LA, et al. 11 Validity of the general practice research database. Pharmacotherapy 2003;23:6869. 12 24. Shah ND, Montori VM, Krumholz HM, Tu K, et al. Responding to an FDA 13 warninggeographic variation in the use of rosiglitazone. N Engl J Med 2010;363:20814. 14 25. 15 Forhttp://hjertedoktor.dk/content/pdf/dsams%20vejledning%20for%20type2%20di peer review only 16 abetes.pdf (accessed August 2013). 17 18 26. National Collaborating Centre for Chronic Conditions. Type 2 diabetes: 19 national clinical guideline for management in primary and secondary care (update). 2009 20 London: Royal College of Physicians. 21 27. The Danish Medicines Agency. Polypharmacy in diabetes care. 22 http://www.dkma.dk/1024/visUKLSArtikel.asp?artikelID=1665 (accessed May 2013). 23 24 25 26 27 28 29 30 31 32 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 BMJ Open Page 76 of 82 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from FIGURE LEGEND 1 Figure 1. Proportion of users of rosiglitazone among all users of oral hypoglycaemic agents 2 (OHA), 20002010 in northern Denmark and in the United Kingdom. The maximum points of 3 both graphs correspond to May 2007, the month of publication of the initial metaanalysis by 4 Nissen and Wolski.2 5 6 7 8 9 10 11 12 13 14 15 For peer review only 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33

(8.6)

N N (%) 725 725 (3.5) 882 882 (3.6) agents 147 147 (5.5) 358 358 (5.6) , , , , 5 5 90,682 (55)90,682 95,607 (58)95,607 57,984 (35)57,984 9 9 14,194 12,257 (7.4)12,257 78,772 (48)78,772 87,076 (53)87,076 28,430 (17)28,430 42,030 (25)42,030 38,668 (23)38,668 25,023 (15) 25,023 144,881 144,881 (87) 114,378 114,378 (69) 13,192 (8.0)13,192 (n=165,848)

hypoglycaemic hypoglycaemic Users of Users of oralother

(n=191,276)

United Kingdom (1.3) 582(10) 297(37) 925(31) N (%) 242 242 (8.8) 434 434 (25) 661 661 (30) 513 513 (22) , , , 426 426 (9.5) 469 469 (9.7) , , , , 857 (3.4)857 , , 336 336 589 589 (2.3) 2 9 7 2 6 7 5 19,489 (77)19,489 23,836 (94)23,836 16,646 (65)16,646 22,223 (87) 22,223 2 2 (n=25,428) 11,259 (44)11,259 14,169 (56)14,169 Users of rosiglitazone Users of BMJ Open

http://bmjopen.bmj.com/ other oral other 423 (16)423 724 (24)724 219 (16) 219 (26)751 , N N (%) 530(8.5) 149(6.4) 551(7.0) 121(4.8) 967(7.6) 999(6.1) ,, ,, , ,, , , , , , , 196 196 (0.30) 4 4 3 5 3 4

(n=65,204) 30,845 (47)30,845 40,327 (62) 40,327 39,931 (61)39,931 51,022 (78)51,022 19,470 (30) 19,470 41,183 (63)41,183 34,359 (53)34,359 10 16 10 15 Users Users of hypoglycaemic agentshypoglycaemic on September 27, 2021 by guest. Protected copyright. (n=67,525)

Northern Northern Denmark

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml N N (%) 939(84) 730(74) 279(98) 694(73) 345(58) 66 (2.8)66 83 (3.6)83 , 81 (3.5) 81 , , , 9 9 (0.39) , 976 (42) 976 517 (22) 517 561 (24) 561 595 (26) 595 757 (33) 757 497 (21) 497 286 (12) 286 (n=2,321) 2 1 1 1 For peer review1 only Users of rosiglitazone Users of

54 2

Lipid lowering agentsLipid lowering Other oral Other glucose oral lowering drugs** Pioglitazone DPP Inhibitor 4 Metformin 1 3+ 0 Male ≥85 Female 45 5564 3544 <35 <35 Sulfonylurea 7584 (6.3) 147 6574 (19) 444 TABLES TABLES 1. Table Denmark and the United Kingdom. Kingdom. United the and Denmark History History of medication other use Sex Age Age group, years Characteristic Charlson Charlson comorbidity index History History OHA of use before baseline* Page 77 of 82 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from Page 78 of 82 Page 19 of2319 Page

322 (0.19)322 623 (0.38) 623 73,225 (44)73,225 66,725 (40)66,725 75,119 (45)75,119 27,403 (17)27,403 49,463 (30)49,463 21,634 (13)21,634 18,624 (11)18,624 43,985 (27)43,985 28,120 (17)28,120 15,223 (9.2) 15,223 126,897 126,897 (77)

035(16) 458(29) 675(11) 128(12) 102(24) 878(11) 499(18) , , , , , , , 35 (0.14) 35 52 (0.20) 52 4 7 2 3 6 2 4 13,516 (53)13,516 21,846 (86)21,846 11,225 (44)11,225 11,699 (46)11,699

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456 456 (14) 454(8.4) 257(5.0) 257(1.9) 534(5.4) 451(3.8) 121(4.8) , , , , , , , 32 (0.05) 32 9 3 1 3 3 2 55,204 (85) 55,204 56,098 (86) 56,098 33,060 (51) 33,060 34,650 (53)34,650 48,016 (74)48,016 on September 27, 2021 by guest. Protected copyright.

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 629(70) 673(72) 409(61) 404(60) 991(86) 51 (2.2)51 , , 2 (0.09) , , , 351 (15) 351 258 (11) 258 215 (9.3)215 177 (7.6)177 175 (7.5) 175 1 1 1 1 1

For peer review only

anuary 1, anuary date 2000 first OHA or prescription,of whichever came la

gents gents Antihypertensive a Missing Missing < 18.5 <25 – 18.5 Antiplatelet agents Antiplatelet Current Former Diuretics ≥ 30 (20) 462 5 25 <3025 – Nitrates Never

Baseline date was J * **Other excludingglucoselowering insulinsdrugs acarbose,arerepaglinide, exenatide, liraglutide.and Body Body mass index category, kg/m Smoking 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

0.13) 0.21; 0.21; 8.2 (1.8) 8.2 8.4 (1.9) 8.4 (n=8635) 12 12 months 0.17 ( 0.17 Page 20 of 23 of 23 20 Page

0.53) 448) , 0.62; 0.62; 8.7 (2.2)8.7 8.1 (1.7)8.1 3 months 3 (n=9 31 (30; 33)31 23 (22; 24)23 40 (39; 41)40 1,026/3,286 0.57 ( 0.57

162) , 3.4; 3.4; 3.1) 7.9 (1.7)7.9 7.7 (1.5)7.7 (n=1 12 12 months 0.16 ( 0.16 mong patients with available preand postdiscontinuation measurements, in in measurements, postdiscontinuation preand available with patients mong BMJ Open

http://bmjopen.bmj.com/ 496) , 3.1; 3.1; 3.0) 7.8 (1.6)7.8 7.7 (1.5)7.7 6 months 6 (n=1 0.05 ( 0.05 orthern Denmarkorthern N

on September 27, 2021 by guest. Protected copyright. 242) , 3.0; 3.0; 2.8) 160/670 160/670 228/827 179/610 7.8 (1.7)7.8 7.7 (1.5)7.7 3 months3 (n=1 24 (21; 27) 24 (25; 31) 28 (26; 33) 29 26 (24; 29) 26 (26; 30) 28 (26; 31) 28 28 (25; 30) 28 (25; 29) 27 (27; 32) 30 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 0.10 ( 0.10 For peer review only

before and after discontinuation of rosiglitazone a rosiglitazone of discontinuation after and %) before

,glycated ,glycated A; SD, haemoglobin standard deviation >7.5%, 1c 1c 7.5% after 7.5% baseline/N ≤7.5% ≤7.5% 1c

b level>

Glycated haemoglobin ( haemoglobin Glycated 1c

northern Denmark and in the United Kingdom, 20002011. 20002011. Kingdom, United in the and Denmark northern

Table 2. Table CI, confidenceCI, HbAinterval; *Clinically *Clinically meaningful change defined using to European the Agency’sMedicines as definition change of thanmore 0.6% the (% is unit)test Characteristic Change from Change from baseline, (95% mean CI) Proportion with clinically a meaningful Followup mean (SD) increase, percent (95% CI) with baseline HbA Proportion Proportion with clinically a meaningful* decrease, percent (95% CI) Baseline Baseline (SD)mean glycaemic glycaemic control with HbA N with HbANwith New postdiscontinuation loss of onset of percent (95%percent CI) Page 79 of 82 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from

1.6)

Page 80 of 82 2.1; 2.1; 18/55 10 (2.5) 10 (n=338) 8.3 (2.1)8.3 6 months 6 69 (64; 74)69 15 (12; 19)15 33 (22; 46) 33 1.8 ( 1.8 Page 21 of 23 of 23 21 Page

United Kingdom 1.8)

2.2; 87/196 10 (2.5)10 8.0 (2.0) 8.0 3 3 months (n=1081) 44 (38;51) 44 14 (12; 14 16) 72 (69; 72 75) 2.0 ( 2.0

1.8;2.5) 94/350 (n=455) (n=455) 7.4 (1.4)7.4 7.1 (1.2)7.1 6 months6 33 (29;38)33 27 (22; 32) 27 12 (9.3; 12 15) 0.34 ( 0.34

orthern Denmarkorthern

N 1.9; 1.9; 2.7) 76/285 (n=376) 7.5 (1.5)7.5 7.1 (1.2)7.1 3 months 3 34 (29;38)34 27 (22; 32) 27 13 (9.5; 13 16) 0.40 ( 0.40 BMJ Open http://bmjopen.bmj.com/ >7.5%, percent

HbA

≤7.5%

with 1c on September 27, 2021 by guest. Protected copyright. For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml For peer review only increase, percent(95% CI) decrease, (95%percent CI) * *

, glycated haemoglobinglycated , SD, A; standard deviation 1c onset of loss of glycaemic control level>7.5% after baseline/N with baseline HbA

post

Page 22 of 23 of 23 22 Page 0.22; 0.22; 0.28) (n=800) 12 12 months 0.03 (

256) , 0.12; 0.12; 0.27) ( 6 6 months (n=1 United KingdomUnited 0.08 0.08

98/610 182/911 99/583 (n=820) (n=820) 8.6 (3.2)8.6 (3.2) 8.7 (3.4) 8.7 8.8 (3.2)8.8 (3.1) 8.8 (3.1) 8.7 3 months3 0.27 (0.04;0.27 0.49)

7.3; 7.3; 7.3) 8/54 (n=77) 9.1 (3.5)9.1 9.1 (3.5)9.1 12 12 months 40 (30; 51)40 (27; 33) 30 (31; 33 36) (31; 38) 34 32 (23; 43)32 (36; 43) 39 (38; 40 43) (37; 44) 40 15 (7.3; 15 26) (13, 16 19) (18; 20 23) (14; 20) 17 0.01 ( 0.01 BMJ Open

http://bmjopen.bmj.com/ 8.2;7.6) 18/79 (n=109) 9.3 (3.4)9.3 9.0 (3.4)9.0 6 months6 35 (26; 44)35 35 (26; 44)35 23 (15; 33)23 orthern Denmark orthern 0.27 ( 0.27 N

on September 27, 2021 by guest. Protected copyright. 9.0; 9.0; 8.2) 14/65 14/65 (n=95) 9.5 (3.6) 9.5 9.2 (3.7) 9.2 3 3 months For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 39 (30; 39 49) 40 (31; 40 50) 22 (13; 22 33) 0.38 ( 0.38 For peer review only

, glycated haemoglobinglycated , SD, A; standard deviation 1c Fasting plasma glucose (mmol/L) before and after discontinuation of rosiglitazone among patients with available preand postdiscontinuation laboratory laboratory postdiscontinuation preand withavailable patients among rosiglitazone of discontinuation after and before (mmol/L) glucose plasma Fasting

measurements, in northern Denmark and in the United Kingdom, 20002011. 20002011. Kingdom, in United the and Denmark in northern measurements, Table 4. Table Characteristic Proportion Proportion with a clinically meaningful* percentdecrease,(95% CI) Change from Changebaseline, (95%CI) mean Proportion with a clinically meaningful Followup Followup mean (SD) percent increase, (95% CI) with baseline FPG ≤10 mmol/L Baseline mean (SD) Baseline mean treatment treatment failure, mmol/L, FPG>10 *Clinically *Clinically meaningful changeEuropean defined using to the definition Agency’sMedicines as change more of than 10 mmol/L. confidenceCI, interval;HbA N with N with afterFPG >10 mmol/L baseline/N New postdiscontinuationNew onset of (95%percent CI) Page 81 of 82 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2013-003424 on 24 September 2013. Downloaded from Page 82 of Page 23 of 23 of 23 23 Page

3.8 (3.1; 3.8 4.6) 0.3 (0.2; 0.3 0.6) 0.2 (0.1; 0.2 0.4) 0.6 (0.4; 0.6 1.0) (0.0; 0.1 0.3) (0.2; 0.3 0.6) 2.1 (1.6; 2.1 2.7) 14.5 (13.2;14.5 15.9) 23.6 (22.0;23.6 25.2) 12.9 (11.7;12.9 14.2) 41.7 (39.9;41.7 43.6) Percent (95% Percent (95% CI) ) + (n=2810

9 4 2 9 16 57 136 394 394 103 103 641 641 351 1 Practice Research Database, United Kingdom Number General BMJ Open

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5.3) northern

0.6 (0.1; 0.6 1.3) 4.4 (2.6; 4.4 6.3) 1.7 (0.5; 1.7 2.8) 0.8 (0.1; 0.8 1.7) 0.4 (0.1; 0.4 1.0) 7.4 (5.0; 7.4 9.7) (3.4; 5.5 7.5) (1.9; 3.6 (0.5; 1.7 2.8) (0.1; 0.8 1.7) (0.1; 0.6 1.3) (0.1; 0.2 0.6) 9.5 (6.9; 9.5 12.1) 10.3 (7.6; 13.1) 56.8 (52.3; (52.3; 56.8 61.2) (14.3; 17.7 21.2) Percent (95% Percent (95% CI) on September 27, 2021 by guest. Protected copyright. Denmark (n=474*)Denmark For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

3 8 4 2 8 4 3 1 49 49 45 45 21 21 35 26 17 84 269

Number For peer review only Aarhus University AarhusPrescription Database,

Table 5. Table 88 record 88 patients had another no of OHA afterlastthe rosiglitazone prescription Glipizide Metformin+vildagliptin Liraglutide Gliclazide Glibenclamide Vildagliptin Repaglinide Tolbutamide *83 patients recordhad no another OHA afterlastof rosiglitazonethe prescription. Acarbose Metformin Glimepiride Metformin+sitagliptin Pioglitazone Saxagliptin Exenatide + Sitagliptin

Pioglitazone + metformin 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Miscellaneous Correction

Ehrenstein V, Hernandez RK, Ulrichsen SP, et al. Rosiglitazone use and post-discontinuation glycaemic control in two European countries, 2000–2010. BMJ Open 2013;3:e003424. In the section ‘Ethics approval’ the record number with the Danish Data Protection Agency is incor- rect. The sentence should read: ‘Ethics approval This study was approved by the Danish Data Protection Agency (record number 2004-41-4693) and by the Independent Scientiﬁc Advisory Committee of the GPRD.’

BMJ Open 2014;4:e003424corr1. doi:10.1136/bmjopen-2013-003424corr1

BMJ Open 2014;4:e003424corr1. doi:10.1136/bmjopen-2013-003424corr1 1