14631326, 2021, 3, Downloaded from https://dom-pubs.onlinelibrary.wiley.com/doi/10.1111/dom.14264 by Readcube (Labtiva Inc.), Wiley Online Library on [11/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License Received: 1 July 2020 Revised: 4 November 2020 Accepted: 22 November 2020 DOI: 10.1111/dom.14264 BRIEF REPORT How many people with type 2 diabetes fulfil the eligibility criteria for randomized, controlled trials of insulin glargine 300 U/mL in a real-world setting? Dídac Mauricio MD1 | Jukka Westerbacka MD2 | Charlie Nicholls PhD3 | 4 5 6 Jasmanda Wu PhD | Rishab Gupta MTech | Björn Eliasson MD 1 Hospital de la Santa Creu i Sant Pau, CIBERDEM, Barcelona, Spain Abstract 2 Sanofi, Paris, France Randomized controlled trial (RCT) populations often do not reflect those typically 3 Sanofi, Reading, UK seen in clinical practice. This retrospective, observational cohort study analysed the 4 Sanofi, Bridgewater, New Jersey real-world data of people with type 2 diabetes (T2DM) prescribed basal insulin ana- 5 Accenture, Florham Park, New Jersey 6 logues from electronic medical records (EMRs) in the Explorys database, which Department of Medicine, University of Gothenburg, Sahlgrenska University Hospital, includes data from 39 integrated healthcare systems in the United States, to deter- Gothenburg, Sweden mine how representative selected RCTs investigating insulin glargine 300 U/mL (Gla- Correspondence 300) are of T2DM populations in a real-world setting. Applying eligibility criteria Dídac Mauricio, MD, Department of derived from the EDITION 1, 2 and 3 (Gla-300 vs. insulin glargine 100 U/mL [Gla- Endocrinology & Nutrition, Hospital de la Santa Creu i Sant Pau & Institut d'Investigació 100]) and BRIGHT (Gla-300 vs. insulin degludec) RCTs, we observed that only 17% Biomédica Sant Pau (IIB Sant Pau), 08041 (33 345/191 218) of people captured in the real-world database would have been Barcelona, Spain. Email: didacmauricio@gmail.com eligible for such trials. Those who were ineligible tended to be older, had more com- orbidities and a higher baseline hypoglycaemia rate than the eligible group. Using Funding information This study was funded by Sanofi. The authors another large US EMR database (Optum Humedica) as corroboration, we found that received editorial/writing support in the 15% (36 285/235 697) would have been eligible to participate in the EDITION/ preparation of this manuscript provided by Simon Rees, PhD, of Fishawack BRIGHT RCTs. Furthermore, only 7% (1734/24 547) would have been eligible for the Communications Ltd, funded by Sanofi. CONCLUDE (insulin degludec vs. Gla-300) RCT. Our findings remind us of the value of real-world data studies, complementing the results of RCTs, and providing addi- tional insights into groups who would typically be excluded from RCTs. KEYWORDS cohort study, database research, type 2 diabetes, basal insulin, randomized trial 1 | I N T RO DU CT I O N 100) (the EDITION 1, 2 and 3 trials2-4) and with insulin degludec (IDeg) (the BRIGHT and CONCLUDE trials5,6). However, to create a Randomized controlled trials (RCTs) are the gold standard setting in relatively homogeneous population and to avoid factors that may con- 1 which to evaluate the efficacy and safety of therapies. For example, found treatment comparisons, RCTs often have strict eligibility criteria in people with type 2 diabetes (T2DM), RCTs have been undertaken and consequently may not fully reflect all the populations treated in to compare the efficacy and safety of the basal insulin analogue insu- real-world clinical practice. RCTs can also be prone to investigator lin glargine 300 U/mL (Gla-300) with insulin glargine 100 U/mL (Gla- selection bias, and to the selection of more motivated populations This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. © 2020 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd. 838 wileyonlinelibrary.com/journal/dom Diabetes Obes Metab. 2021;23:838–843. 14631326, 2021, 3, Downloaded from https://dom-pubs.onlinelibrary.wiley.com/doi/10.1111/dom.14264 by Readcube (Labtiva Inc.), Wiley Online Library on [11/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License MAURICIO ET AL. 839 through the need for participants to provide informed consent and 2.2 | Outcomes and analysis adhere to structured follow-up. Such bias may affect population char- acteristics even if the effects on between-group comparisons are miti- The proportion of people with T2DM in the Explorys database who gated by randomization. would have been excluded from participating in RCTs based on eligi- Databases of electronic medical records (EMRs) often contain bility criteria adapted from the EDITION 1, 2 and 3 and BRIGHT large amounts of data from a broad spectrum of people. Analysing RCTs was estimated. The following characteristics for individuals eli- data from EMRs allows the clinical effectiveness of a therapy to be gible or ineligible for the RCTs based on these criteria (eligible and assessed in a real-world population, including those people who ineligible populations) were analysed: age, antihyperglycaemic medi- would have been excluded from most RCTs. The DELIVER series of cations, HbA1c, hypoglycaemic events, comorbidities and the studies, for example, has evaluated the effectiveness of Gla-100, insu- Elixhauser comorbidity index9 (an index that measures comorbidity lin detemir (IDet), Gla-300 and IDeg using real-world data drawn from based on ICD-9/-10 diagnosis codes and that includes prevalent a broad population with T2DM.7,8 comorbidities that are not encompassed by the well-known Charlson The aim of the present study was to determine the proportion index10). and characteristics of people with T2DM treated with basal insulin To ascertain whether similar results would be obtained with data analogues in the real world after applying eligibility criteria adapted from a different EMR database, a sensitivity analysis was undertaken. from the EDITION 1, 2 and 3, BRIGHT and CONCLUDE trials. The same eligibility criteria adapted from the EDITION 1, 2 and 3 and BRIGHT RCTs were applied to EMRs in the Optum Humedica data- base, which included data for 14 940 692 people with T2DM. As with 2 | METHODS the Explorys analysis, claims data were not included in the Optum Humedica analysis. A further analysis of data from the Optum 2.1 | Study design and participants Humedica database was conducted using eligibility criteria adapted from another RCT, CONCLUDE (comparing Gla-300 and IDeg in peo- In this retrospective, observational cohort study, EMRs were ple with T2DM switching their basal insulin6), results of which were obtained for adults in the United States from the Explorys (IBM not published at the time that the Explorys database analysis was con- Watson Health, Armonk, New York) database. This database con- ducted. CONCLUDE eligibility criteria were not pooled with those of tains longitudinal medical data from 39 major integrated delivery EDITION 1, 2 and 3 and BRIGHT, as CONCLUDE purposefully networks across the United States, and includes 3 997 077 people included only those people who had at least one risk factor for with T2DM. Claims-based data were not included in our analyses. hypoglycaemia.6 Adults eligible for inclusion in this analysis were those with T2DM As these analyses were exploratory and hypothesis-generating, all (presence of one or more International Classification of Diseases analyses were descriptive and no statistical comparisons were made. [ICD]- 9 or -10 diagnosis codes [ICD-9: 250.x0; 250.x2; ICD-10: E11] or one or more prescriptions for an antihyperglycaemic drug, plus exclusion of type 1 diabetes based on ICD-9/-10 codes) on 3 | RE SU LT S March 1, 2015 (the index date, corresponding to the launch date of Gla-300), who had received one or more prescriptions for a 3.1 | Study population basal insulin analogue (Gla-100, Gla-300, IDet or IDeg), had been enrolled in the database, and had data available, for at least Of the 3 997 077 people with T2DM in the Explorys database, EMRs 12 months prior to the index date, and had one or more glycated from 191 218 people who met the inclusion criteria for the present haemoglobin (HbA1c) value and one or more blood pressure mea- analysis (see Section 2.1) were evaluated (Figure 1). Based on the eli- surement available from the previous 12 months. The inclusion gibility criteria adapted from EDITION 1, 2 and 3 and BRIGHT, only criteria used in our analysis were selected to enable the specific 17% (33 345/191 218) of these people would have been eligible to RCT exclusion criteria to be applied. Exclusion criteria were participate in the RCTs; 83% (157 873) met at least one exclusion cri- adapted from those of the EDITION 1, 2 and 3 and BRIGHT terion (Figure 1). More people aged >65 years were in the ineligible RCTs, 2–5 but did not match them exactly as exclusion criteria var- population (47%) than in the eligible population (40%; Table 1). While ied slightly among the trials. These adapted exclusion criteria, non-basal insulins were more commonly prescribed in the ineligible chosen to approximate all four trials, were HbA1c <53/>86 mmol/ population, prescriptions for other classes of antihyperglycaemic med- mol (<7 %/>10 %), uncontrolled severe hypertension (systolic ications were similar in both populations (Table 1). blood pressure >180 mmHg and/or diastolic blood pressure >95 mmHg) and key comorbidities (myocardial infarction, heart failure, stroke, autonomic or diabetic neuropathy, diabetic foot 3.2 | Glycaemic control and hypoglycaemia ulcer, chronic or end-stage renal disease, pyelonephritis, diabetic retinopathy or severe mental illness; Table S1) in the previous In the ineligible population based on eligibility criteria adapted from 12 months. EDITION 1–3 and BRIGHT, 32% of people had good glycaemic 14631326, 2021, 3, Downloaded from https://dom-pubs.onlinelibrary.wiley.com/doi/10.1111/dom.14264 by Readcube (Labtiva Inc.), Wiley Online Library on [11/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 840 MAURICIO ET AL. (A) (B) F I G U R E 1 Schematic showing A, participant selection and percentage of people with type 2 diabetes (T2DM) in the Explorys database eligible to participate in randomized controlled trials (RCTs) using eligibility criteria adapted from the EDITION 1, 2 and 3 and BRIGHT trials, and B, the percentage of people with T2DM in the Optum Humedica database eligible to participate in RCTs using eligibility criteria adapted from the EDITION 1, 2 and 3 and BRIGHT trials and adapted from CONCLUDE. Main analysis: All exclusion criteria apply 12 months prior to the index date. Uncontrolled hypertension defined as systolic blood pressure >180 mmHg and/or diastolic blood pressure >95 mmHg at any point in the 12 months prior to the index date. Additional analysis: Eligibility criteria adapted from the CONCLUDE RCT are shown in Table S3. BI, basal insulin; DBP, diastolic blood pressure; Gla-300, insulin glargine 300 U/mL; HbA1c, glycated haemoglobin; SBP, systolic blood pressure control (HbA1c <53 mmol/mol [< 7 %]), while 19% had HbA1c levels using the same adapted EDITION 1, 2 and 3 and BRIGHT eligibility >86 mmol/mol (>10 %; Table 1). The proportion of people who had criteria. Of these, the percentage of people with T2DM eligible to par- one or more previous hypoglycaemic event and the annualized rate of ticipate in the RCTs based on these adapted criteria was 15% these events were higher in the ineligible population than in the eligi- (36 285/235 697; Figure 1; Table S2), corroborating the results from ble population (Table 1). the Explorys database. In a further analysis, using the Optum Humedica database and the eligibility criteria adapted from CON- CLUDE, an RCT that specifically recruited people with at least one risk 3.3 | Comorbidities factor for hypoglycaemia,6 the percentage of people with T2DM eligi- ble to participate in this RCT was 7% (1734/24 547; Figure 1: The mean (± SD) Elixhauser comorbidity index score was higher in the Table S3). This estimate is based on a smaller subset of the Optum ineligible population (4.19 ± 2.81) than in the eligible population Humedica database than the EDITION 1, 2 and 3 and BRIGHT esti- (2.16 ± 1.51), based on eligibility criteria adapted from EDITION 1, 2 mates, because the inclusion criteria required to enable the CON- and 3 and BRIGHT. A history of myocardial infarction was the most CLUDE exclusion criteria to be applied were more restrictive (for common comorbidity leading to exclusion (Table 1). Other non- example, an estimated glomerular filtration rate (eGFR) value was exclusionary comorbidities were generally more common in the ineli- required to enable the exclusion of those with eGFR 30–59 mL/min/ gible than the eligible populations (Table 1). 1.73 m2; Table S3). 3.4 | Further analyses using the Optum Humedica 4 | DI SCU SSION database In the present analysis of data from the EMRs of people with T2DM Of the 14 940 692 people with T2DM in the Optum Humedica data- in the Explorys database, the majority of people (83%) would have base, 235 697 met the inclusion criteria for the sensitivity analysis been excluded from the EDITION 1, 2 and 3 and BRIGHT RCTs, based 14631326, 2021, 3, Downloaded from https://dom-pubs.onlinelibrary.wiley.com/doi/10.1111/dom.14264 by Readcube (Labtiva Inc.), Wiley Online Library on [11/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License MAURICIO ET AL. 841 T A B L E 1 Characteristics of people with type 2 diabetes from the on eligibility criteria adapted from the trials. Furthermore, of the 17% Explorys database either eligible or ineligible for randomized of people eligible to participate in these RCTs, it is likely that other, controlled trials based on the eligibility criteria adapted from the unmeasurable factors, specific to individual people (such as motivation EDITION 1, 2 and 3 and BRIGHT trials to participate in trials) would see the potential pool of participants fur- Ineligible Eligible ther reduced, so our figure may overestimate the representativeness Characteristic population population of RCTs. These results appear robust, as the percentage of people eli- (n = 157 873) (n = 33 345) gible to participate based on eligibility criteria adapted from the EDI- Age group, n (%) TION 1, 2 and 3 and BRIGHT trials was similar (15%) when these 18–34 years 5689 (4) 1714 (5) criteria were applied to EMR data from a different US database, the 35–44 years 10 387 (7) 2423 (7) Optum Humedica database. Our findings are not specific to the EDI- 45–54 years 25 008 (16) 5676 (17) TION 1, 2 and 3 and BRIGHT RCTs, as an even smaller proportion of 55–64 years 41 527 (26) 9730 (29) people in the Optum Humedica database were eligible for participa- ≥65 years 74 590 (47) 13 406 (40) tion based on criteria adapted from CONCLUDE (7%), which recruited Hypoglycaemia 12 months prior to the index date people with an increased risk of hypoglycaemia.6 Incidence, n (%) 33 333 (21) 3143 (9) This lack of representativeness of clinical trial participants for the Rate, events (per person-year) 86 698 (0.56) 5554 (0.17) general T2DM population is not specific to studies of basal insulin HbA1c level, n (%) analogues. Based on eligibility criteria adapted from five phase 3 stud- ies of the glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide, <53 mmol/mol (<7%) 50 645 (32) 0 (0) 27% of people with T2DM (2483/9251) in northern Denmark would 53–<64 mmol/mol (7–<8%) 36 205 (23) 14 555 (44) have been eligible for these RCTs,11 with people primarily excluded 64–<75 mmol/mol ( 8–<9%) 24 579 (16) 11 932 (36) owing to comorbidities or having HbA1c levels outside the criteria.11 Eli- 75–86 mmol/mol (9–10%) 16 674 (11) 6858 (21) gibility for GLP-1RA cardiovascular outcome trials has also been investi- >86 mmol/mol (>10%) 29 770 (19) 0 (0) gated, showing that only between 10% and 35% of people with T2DM Antihyperglycaemic medications, n (%) would have been eligible to participate based on the eligibility criteria of Basal insulin 95 710 (61) 20 530 (62) six such trials.12 One study reported that a higher proportion of people Other insulin 85 525 (54) 14 377 (43) with T2DM (45%; 3156/7034) would have been eligible for phase Oral medications 90 821 (58) 20 319 (61) 3 RCTs investigating glycaemic control with the sodium-glucose co- Sulphonylureas 43 536 (28) 10 019 (30) transporter-2 (SGLT2) inhibitor empagliflozin,13 with people being GLP-1RAs 10 833 (7) 3107 (9) excluded for reasons including use of glucose-lowering drugs that were Comorbidities in the 12 months prior to the index date, n (%) not permitted as per trial protocol or again having HbA1c levels outside Exclusion criteria the eligibility criteria.13 However, another study using eligibility criteria from an empagliflozin cardiovascular outcome RCT reported that only Autonomic neuropathy 2583 (2) 0 16% of people with T2DM in the United Kingdom had the same cardio- Chronic renal disease 28 737 (18) 0 vascular risk as those included in the RCT.14 In a combined analysis of Diabetic foot ulcer 3995 (3) 0 four cardiovascular outcome trials of SGLT2 inhibitors, the representa- Diabetic neuropathy 361 (0) 0 tiveness of the general T2DM population varied from 59% for Diabetic retinopathy 8237 (5) 0 DECLARE-TIMI 58 to 16% for VERTIS-CV, mainly reflecting the exclu- End-stage renal disease 6773 (4) 0 sion criteria of cardiovascular risk at baseline (eg, exclusion of people Heart failure 30 750 (19) 0 with cardiovascular risk factors but no established cardiovascular dis- Myocardial infarction 54 922 (35) 0 ease).15 A second study examining cardiovascular outcome studies iden- Pyelonephritis 2839 (2) 0 tified a similar trend for the generalizability of DECLARE-TIMI (49.5%) Severe mental illness 32 480 (21) 0 and VERTIS-CV (19.0%).16 Together, these analyses of antihyper- Stroke 18 684 (12) 0 glycaemic therapies show that the proportion of people with T2DM eli- Depression 38 423 (24) 2021 (6) gible to participate in RCTs is generally low, but that the range is broad Hyperlipidaemia 119 814 (76) 23 233 (70) depending on which RCT criteria were applied. This is reflected in a study of the total population of people with T2DM in Scotland in 2008, Hypertension 25 351 (16) 889 (3) which identified that between 4% and 51% of these people would be eli- Obesity 35 201 (22) 5154 (15) gible for seven large RCTs that investigated various drug interventions.17 Abbreviations: GLP-1RA, glucagon-like peptide 1 receptor agonist; HbA1c, From the present study, in general terms, the population ineligible glycated haemoglobin. based on criteria adapted from the EDITION 1, 2 and 3 and BRIGHT 14631326, 2021, 3, Downloaded from https://dom-pubs.onlinelibrary.wiley.com/doi/10.1111/dom.14264 by Readcube (Labtiva Inc.), Wiley Online Library on [11/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License 842 MAURICIO ET AL. RCTs appears to be older, to have more comorbidities and to be at represented as they fail to meet the eligibility criteria for inclusion. higher risk of hypoglycaemia based on higher rates and incidence of RCTs that focus on specific subgroups of people with T2DM may bet- hypoglycaemia at baseline, than those eligible to participate. There- ter reflect other groups of people shown to be excluded in this EMR fore, it is noteworthy that this ineligible population represents people study (eg, older people in the EDITION SENIOR study18); however, who may benefit most from reducing their risk of hypoglycaemia. such focused RCTs are few in number and are still restrictive in their The strengths of the present study include the use of large, compre- inclusion. Our finding reinforces the value of real-world studies that hensive, real-world EMR databases, and particularly the consistency of assess the clinical effectiveness of basal insulin analogues, which can results from analyses of the Explorys and Optum Humedica databases. complement the results of RCTs. These results also highlight that such However, this study was only designed to assess the proportion of peo- real-world evidence may provide additional insights into diabetes man- ple with T2DM who would be eligible for RCTs of Gla-300 based on agement for those people who would typically be excluded from RCTs. adapted criteria, and so is limited in that detailed analyses of the over- looked populations were not conducted. Related to this, it is worth not- ACKNOWLEDG MENTS ing that although the observed characteristics of people in the ineligible This study was funded by Sanofi. The authors received editorial/writ- and eligible populations provide useful information (Table 1), the study ing support in the preparation of this manuscript provided by Simon design means that certain values may differ from expectations. For Rees, PhD, of Fishawack Communications Ltd, funded by Sanofi. The example, the prevalence of hypertension and obesity seems lower than authors would like to thank Arjun Menon (previously of Accenture) that typically found in populations of people with T2DM, but as this for assistance with data analysis. These data were previously pres- information is from ICD codes it is possible that they are underesti- ented at the 79th American Diabetes Association Scientific Sessions, mates. Furthermore, the large difference between ineligible and eligible June 7–11, 2019, San Francisco, California, and the 55th Annual populations in the prevalence of depression (24% vs. 6%, respectively) Meeting of the European Association for the Study of Diabetes, may primarily reflect the inclusion of severe mental illness (ICD codes September 16–20, 2019, Barcelona, Spain. which include depressive disorders) as an exclusion criterion. This study is also limited specifically by the focus on trials of Gla-300, and so can- CONFLIC T OF INT ER E ST not be fully generalized to all RCTs of basal insulin analogues. Another D.M. has served on Advisory boards for AstraZeneca, Ferrer, Merck, factor to consider is the pooling of eligibility criteria from the EDITION Novo Nordisk, Praxis Pharmaceutical and Sanofi, and on the Speakers' 1, 2 and 3 and BRIGHT trials, because although these trials were simi- bureau for Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Menarini, larly designed there were some differences and the adapted criteria Merck, Novartis, Novo Nordisk and Sanofi. J. Westerbacka and used in our analyses do not fully reflect each individual trial. For exam- C.N. are employees of Sanofi. J. Wu was a Sanofi employee when the ple, our adapted criteria used an upper HbA1c value of 10% (86 mmol/ work was conducted but has since left the company. R.G. has pro- mol), whereas the EDITION 3 RCT included those with HbA1c between vided consultancy work for Sanofi. B.E. has served on Advisory boards 7% (53 mmol/mol) and 11%, so this may have lowered our final esti- and received consultancy fees from Amgen, AstraZeneca, Boehringer mates of eligibility. However, this can be balanced against the fact that Ingelheim, Eli Lilly, MSD, Mundipharma, Navamedic, Novo Nordisk our pooled adapted criteria did not include every eligibility criterion from and RLS Global, and has received research support from Sanofi. each trial (for example, BRIGHT excluded participants with a body mass index of <25 kg/m2 or >40 kg/m2), which may increase our final esti- AUTHOR CONTRIBU TIONS mates of eligibility. The requirement for laboratory data as a require- J. Westerbacka, C.N. and J. Wu were involved in the concept and design ment for inclusion in this study reduced the total evaluable population of this analysis. R.G performed the descriptive analyses. All authors were and may have lowered our estimates of trial eligibility as shown in a pre- involved in the interpretation of the data, writing and reviewing drafts 15 vious study of cardiovascular outcome trials. Of 592 890 people with of the manuscript and approved the final version for submission. T2DM in the Explorys database who received a basal insulin following the launch of Gla-300, only 191 218 also had data for at least PE ER RE VIEW 12 months, and one or more HbA1c and one or more blood pressure The peer review history for this article is available at https://publons. measurement/s in the 12 months prior to the index date. In addition to com/publon/10.1111/dom.14264. reducing the population for our analyses, potentially excluding people who may have been eligible for the RCTs based on the adapted criteria DATA AVAILABILITY STAT EMEN T used, the loss of the group of people with T2DM without laboratory Requests concerning data access should be addressed to the measures may provide a selection bias in terms of selecting for a popula- corresponding author tion who are more actively managed. In conclusion, this analysis of data from EMRs demonstrates that OR CID because RCTs are designed to test the efficacy and safety of treat- Dídac Mauricio https://orcid.org/0000-0002-2868-0250 ments in a very controlled setting, a large proportion of people with Charlie Nicholls https://orcid.org/0000-0003-4856-4369 T2DM who may receive treatment with basal insulin analogues are not Jasmanda Wu https://orcid.org/0000-0001-9346-7715 14631326, 2021, 3, Downloaded from https://dom-pubs.onlinelibrary.wiley.com/doi/10.1111/dom.14264 by Readcube (Labtiva Inc.), Wiley Online Library on [11/01/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License MAURICIO ET AL. 843 RE FE R ENC E S initiators of the glucagon-like peptide 1 receptor agonist liraglutide. 1. Schulz KF, Altman DG, Moher D, Group C. 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Diabetes Obes Metab. 2018;20:2148-2158. How to cite this article: Mauricio D, Westerbacka J, 9. Elixhauser A, Steiner C, Harris DR, Coffey RM. Comorbidity measures for use with administrative data. Med Care. 1998;36:8-27. Nicholls C, Wu J, Gupta R, Eliasson B. How many people with 10. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of type 2 diabetes fulfil the eligibility criteria for randomized, classifying prognostic comorbidity in longitudinal studies: develop- controlled trials of insulin glargine 300 U/mL in a real-world ment and validation. J Chronic Dis. 1987;40:373-383. setting? Diabetes Obes Metab. 2021;23:838–843. https://doi. 11. Knudsen JS, Thomsen RW, Pottegard A, Knop FK, Sorensen HT. Dif- ferences between randomized clinical trial patients and real-world org/10.1111/dom.14264