Does Real World Use of Liraglutide Match its Use in the LEADER Cardiovascular Outcome Trial? Study Protocol

Does Real World Use of Liraglutide Match its Use in the LEADER Cardiovascular Outcome Trial?... Diabetes Ther (2018) 9:1397–1402 https://doi.org/10.1007/s13300-018-0390-8 STUDY PROTOCOL Does Real World Use of Liraglutide Match its Use in the LEADER Cardiovascular Outcome Trial? Study Protocol . . . William Hinton Michael Feher Neil Munro Simon de Lusignan Received: January 31, 2018 / Published online: March 31, 2018 The Author(s) 2018 (RCGP) Research and Surveillance Center (RSC) ABSTRACT network database. People with T2DM will be identified from the dataset using a well-estab- Background: Liraglutide is an injectable ther- lished ontological process. Read and other clini- apy to treat type 2 diabetes (T2DM), belonging cal codes will be used to identify people to the glucagon-like peptide-1 receptor agonist prescribed liraglutide and those at high cardio- class of drugs. The Liraglutide Effect and Action vascular risk. We will use descriptive statistics to in Diabetes: Evaluation of Cardiovascular Out- report the characteristics of people with T2DM come Results (LEADER) trial established that prescribed liraglutide compared with those of the liraglutide demonstrated glucose-lowering ben- LEADER trial and the proportion of the wider efits and improved cardiovascular outcomes in T2DM cohort that matches the LEADER inclu- those individuals with T2DM at high cardio- sion criteria. In terms of ethical considerations, vascular risk. this study used pseudonymized data, and was Aims: The aim of this study is to report the classed as an ‘‘Audit of current practice’’. prevalence and characteristics of people treated Planned Outputs: The results of the study will with liraglutide compared with the LEADER be submitted for publication in a peer-reviewed trial. In addition, the remaining portion of the journal to report the applicability of the results T2DM population will be examined to deter- of the LEADER trial to real-world clinical mine the prevalence of those who meet the practice. inclusion criteria for the LEADER trial but who Funding: Novo Nordisk Limited. are not treated with this medication. Study Design and Methods: This is a cross- Keywords: Cardiovascular diseases; Cross- sectional analysis of routinely collected primary sectional studies; Diabetes mellitus, type 2; care data on all people with T2DM included in Liraglutide; Medical record systems, the Royal College of General Practitioners computerized Enhanced content To view enhanced content for this article go to https://doi.org/10.6084/m9.figshare.59092 INTRODUCTION Liraglutide is an established injectable therapy, W. Hinton  M. Feher  N. Munro S. de Lusignan (&) belonging to the glucagon-like peptide-1 (GLP- Department of Clinical and Experimental Medicine, 1) receptor agonist class of drugs, for the treat- University of Surrey, Guildford, UK ment of hyperglycemia in people with type 2 e-mail: s.lusignan@surrey.ac.uk 1398 Diabetes Ther (2018) 9:1397–1402 diabetes (T2DM). Like other medications within AIMS AND METHODS its class, liraglutide improves glycemic control by stimulating the GLP-1 receptor to produce We will perform a cross-sectional analysis of all more insulin, while simultaneously suppressing people with T2DM included in the Royal Col- the secretion of glucagon and prolonging gas- lege of General Practitioners (RCGP) Research tric emptying [1, 2]. Clinical trials have and Surveillance Center (RSC) database to demonstrated that liraglutide has various ben- identify people prescribed liraglutide and to efits, including reduced glycated hemoglobin describe their cardiovascular risk profile. In (HbA1c), decreased risk of hypoglycemia com- addition, the proportion of those with a car- pared with sulfonylurea, and weight loss [3, 4]. diovascular risk profile comparable to that of Liraglutide has also been shown to have reno- those included in the LEADER trial will be protective effects and to reduce systolic blood reported. pressure [5–7]. More recently, the effects of liraglutide have been explored in a cardiovas- Objectives cular outcome trial (CVOT). CVOTs are safety trials for the new classes of The aim of the study is to compare the clinical drugs used in the management of T2DM. The characteristics of patients prescribed liraglutide Liraglutide Effect and Action in Diabetes: Eval- with those people included in the LEADER trial. uation of Cardiovascular Outcome Results We also aim to identify the proportion of (LEADER) study was a double-blind randomized patients in the RCGP RSC database that meet controlled trial assessing the cardiovascular the inclusion criteria for liraglutide as used in effects of liraglutide compared to a placebo, the LEADER trial but who are not prescribed this when added to standard care in patients with medication. T2DM [8]. It was also designed to evaluate any The primary objectives are: inferiority or superiority in terms of cardiovas- 1. To identify the number of people prescribed cular benefit. liraglutide in UK primary care who meet the The study comprised 9340 individuals with inclusion criteria for the LEADER trial. T2DM and high cardiovascular disease risk. 2. To describe the characteristics of patients After a median follow-up of 3.8 years, time-to- taking liraglutide: event analysis confirmed the liraglutide was a. The number of people that meet each of associated with a lower rate of first occurrence the LEADER inclusion criteria. of death from cardiovascular causes, nonfatal b. The duration of their diabetes. myocardial infarction, or nonfatal stroke com- c. The number of people identified on pared with placebo. The results of the LEADER concurrent oral antihyperglycemic trial confirmed not only the non-inferiority of medications or on insulin. liraglutide with respect to cardiovascular safety 3. To describe the demographic (age, gender, but provided evidence of its superiority in terms ethnicity, socioeconomic status {SES, using of cardiovascular outcomes. the Index of Multiple Deprivation [9]}) and Whether these findings translate into real- clinical characteristics (HbA1c, blood pres- world clinical practice is unclear. Here we set sure, renal function, body mass index, etc.) out the method we will use to determine (1) the of people in each of the groups described current pattern of prescribing liraglutide within above. a nationally representative general practice The secondary objectives are: network and (2) the prevalence of people with 4. To identify the number of people in the T2DM possessing the same cardiovascular risk entire RCGP RSC cohort who meet the profile as those included in the LEADER trial. inclusion criteria for the LEADER trial. This will inform the extent to which the find- 5. To describe the characteristics of the people ings of the LEADER trial can be generalized to with T2DM eligible for the LEADER trial: routine clinical practice. Diabetes Ther (2018) 9:1397–1402 1399 a. The number of people who meet each of particularly in the population of people with the LEADER inclusion criteria. T2DM [10]. b. The duration of their diabetes. We will use all data collected from primary c. The number of those identified on care practices after 1 January 2016, which will concurrent oral antihyperglycemic comprise all patients with a T2DM diagnosis medications or on insulin. who are over the age of 18 years. Within this 6. To describe the demographic (age, gender, cohort, we will identify and report the propor- ethnicity, SES) and clinical characteristics tion of those with a prescription for liraglutide, (HbA1c, blood pressure, renal function, and all of those with similar cardiovascular body mass index, etc.) of people in each of risk/conditions to those of the LEADER trial. the groups described above. The demographic and clinical characteristics of these groups will be reported. Missing data for each variable of interest will also be stated. Data Source In the interests of information governance, the RCGP RSC data is pseudonymized by NHS The RCGP RSC is a primary care sentinel net- number. This study was classed as an ‘‘Audit of work that includes the records from over 200 current practice,’’ and therefore specific ethical primary care practices distributed across Eng- approval was not required. land covering a population of over 2,000,000 patients. This is a nationally representative Data Analysis sample [10], primarily used for the monitoring of respiratory disease and infections such as influenza for vaccine effectiveness [11–13]. People with T2DM will be identified using a UK general practice is suited to this type of two-step process that we have reported in detail study because it is a registration-based system; elsewhere [18]. This is an ontological-based each patient is registered with a single practice approach that integrates numerous data ele- and if they move their data move with them ments to enhance case definition [19]. Initially, [14]. Each patient also has a unique patient all people with diabetes are identified using a identifier, the National Health Service (NHS) combination of diagnostic codes, HbA1c and number, which not only facilitates specific blood glucose test results (two or more that patient–data linkage but also the potential for confirm diabetes), and medication use (except data linkage with other datasets, such as metformin). Codes specific to gestational dia- pathology results. Repeat prescription data have betes or other types of secondary diabetes are been complete since the 1990s following the excluded. People are then categorized by dia- transition from paper-based to computerized betes type (T1DM, T2DM, undetermined dia- medical records (CMR) in UK primary care, betes type) using a seven-step algorithm that while the coding of chronic disease and labo- takes into account previous and current drug ratory links were standardized in 2004 [15]. We therapies used, diagnosis codes specific to dia- have recently demonstrated our ability to betes type, and other important clinical char- monitor adherence to different classes of ther- acteristics (age and body mass index at apies using this database [16]. diagnosis, and duration of oral anti-hyper- UK primary care CMR data are recorded glycemic medications). using the Read classification [17]. The coded We will use the high cardiovascular risk data includes patient demographics (age, sex, inclusion criteria for the LEADER trial to deter- ethnicity, and SES), diagnosis and processes of mine prevalence within the T2DM cohort care (referrals, annual reviews, care pathways, (Table 1). People will be identified with each etc.), prescriptions, and laboratory data. Inclu- cardiovascular risk factor using the most similar sion of data recording targets in the UK primary diagnostic codes, or other codes which deter- care pay-for-performance targets have led to a mine diagnosis of a risk factor. We will provide a high level of data completeness in these records, 1400 Diabetes Ther (2018) 9:1397–1402 Table 1 Inclusion criteria for the LEADER trial taken complete list of codes and a full description of from the supplementary material provided in the LEA- the process in the final manuscript. DER publication by Marso et al. [8] Statistical Methods LEADER trial inclusion criteria T2DM with HbA1c C 7% We will use descriptive statistics (percentages, Cardiovascular disease: C 50 years of age and C 1 of the means, standard deviations, etc.) to describe the characteristics of the cohorts. Crude rates of following: each variable of interest will be reported within Previous myocardial infarction each cohort, with 95% confidence intervals. Previous stroke or transient ischemic attack Previous coronary, carotid or peripheral arterial STRENGTHS AND LIMITATIONS revascularization A number of strengths of the dataset have been [50% stenosis of coronary, carotid, or lower described in the section ‘‘Data Source’’. The extremity arteries large denominator ([2 million patients) of this History of symptomatic coronary heart disease high-quality real-world evidence dataset is a documented by positive exercise stress test or any specific strength. We have also previously cardiac imaging or unstable angina with ECG demonstrated our ability to compare real-world and trial use of another class of medication in changes diabetes [20], and also to link complex data, in Asymptomatic cardiac ischemia documented by this example pancreatitis, to cases of diabetes positive nuclear imaging test, exercise test or [21]. However, given that the minority of peo- dobutamine stress echo ple with T2DM are prescribed liraglutide, there may not be enough statistical power to confirm Chronic heart failure New York Heart Association ‘‘true differences’’ between groups. class II–III Another potential limitation is missing data Chronic renal failure: in a patient’s primary care record, whereby a number of patients may have particular condi- eGFR\60 mL/min/1.73 m (Modification of tions that have not been recorded. Nonetheless, Diet in Renal Disease formula) the pay for performance scheme (P4P), i.e., the eGFR\60 mL/min (Cockcroft–Gault formula) Quality and Outcomes Framework (QOF), implemented in 2004 to incentivize primary No previous cardiovascular disease group: C 60 years care practices to achieve indicator thresholds and C 1 of the following: for the management of chronic diseases [22], Microalbuminuria (ACR) or proteinuria has improved data quality in primary care. Additional strengths and limitations found Hypertension and left ventricular hypertrophy by while undertaking the study will be reported in ECG or imaging the final version of the manuscript. Left ventricular systolic or diastolic dysfunction by imaging CONCLUSION Ankle-brachial index\0.9 This real-world evidence cross-sectional analysis T2DM Type 2 diabetes mellitus, HbA1c glycated hemo- will investigate the prevalence of people with globin, ECG electrocardiogram, eGFR estimated glomeru- T2DM in a nationally representative primary lar filtration rate, ACR albumin:creatinine ratio care population currently prescribed liraglutide and their cardiovascular risk profile; and those Diabetes Ther (2018) 9:1397–1402 1401 in the wider T2DM population that meet the Compliance with Ethics Guidelines. This inclusion criteria for the LEADER trial. study is considered to be an ‘‘Audit of current practice’’ when tested against the Health Research Authority (HRA)/Medical Research Council (MRC) ‘‘Is my study research’’ tool and ACKNOWLEDGEMENTS therefore did not require specific ethical approval [23]. In addition, the processes and The authors would like to thank patients and systems are streamlined to operationalize these practices who are members of the RCGP RSC studies, as we consistently strive to follow best network, and the CMR system vendors: EMIS, In practices in surveillance and quality improve- Practice, and TPP. We would also like to thank ment [24, 25]. Approval for use of the data was Apollo Medical systems, the RCGP, and acquired from the RCGP RSC Study Approval University of Surrey colleagues: Filipa Ferreira Committee. (Programme Manager), Rachel Byford, and Julian Sherlock (SQL developers). Open Access. This article is distributed under the terms of the Creative Commons Funding. Sponsorship for this study and Attribution-NonCommercial 4.0 International article processing charges were funded by Novo License (http://creativecommons.org/licenses/ Nordisk Limited. All authors will have full by-nc/4.0/), which permits any non- access to all of the data in this study and will commercial use, distribution, and reproduction take complete responsibility for the integrity of in any medium, provided you give appropriate the data and accuracy of the data analysis. credit to the original author(s) and the source, provide a link to the Creative Commons license, Authorship. All named authors meet the and indicate if changes were made. International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole and have given final REFERENCES approval for the version to be published. 1. Baggio LL, Drucker DJ. Biology of incretins: GLP-1 Authorship Contributions. William Hinton and GIP. Gastroenterology. 2007;132(6):2131–57. led the drafting of the manuscript. Simon de 2. Nice Institute for Health Care Excellence. Liraglu- Lusignan, Michael Feher, and Neil Munro tide. Available at: https://bnf.nice.org.uk/drug/ reviewed the manuscript and study design and liraglutide.html. Accessed 10 Jan 2018. contributed to the final manuscript draft. 3. Kim SH, Abbasi F, Lamendola C, et al. Benefits of Disclosures. William Hinton receives liraglutide treatment in overweight and obese older individuals with prediabetes. Diabetes Care. research funding from Eli Lilly and Co. and 2013;36(10):3276–82. Novo Nordisk Ltd. Simon de Lusignan receives research funding from Eli Lilly Co., 4. Parks M, Rosebraugh C. Weighing risks and benefits GlaxoSmithKline, Takeda, AstraZeneca, and of liraglutide—the FDA’s review of a new antidia- betic therapy. N Engl J Med. 2010;362(9):774–7. Novo Nordisk Ltd. Neil Munro has received financial support for research, speaker meetings 5. Goud A, Zhong J, Peters M, Brook RD, Rajagopalan and consultancy from MSD, Merck, BMS, S. GLP-1 agonists and blood pressure: a review of AstraZeneca, Pfizer, Novo Nordisk Ltd, Eli Lilly the evidence. Curr Hypertens Rep. 2016;18(2):16. and Co., and Sanofi-Aventis. Michael Feher also 6. Sun F, Wu S, Guo S, et al. Impact of GLP-1 receptor receives financial support for research, speaker agonists on blood pressure, heart rate and hyper- meetings and consultancy from MSD, Merck, tension among patients with type 2 diabetes: a BMS, AstraZeneca, Pfizer, Novo Nordisk Ltd, Eli systematic review and network meta-analysis. Dia- betes Res Clin Pract. 2015;110(1):26–37. Lilly and Co., and Sanofi-Aventis. 1402 Diabetes Ther (2018) 9:1397–1402 7. von Scholten BJ, Persson F, Rosenlund S, et al. The 17. de Lusignan S. Codes, classifications, terminologies effect of liraglutide on renal function: a randomized and nomenclatures: definition, development and clinical trial. Diabetes Obes Metab. application in practice. Inform Prim Care. 2017;19(2):239–47. 2005;13(1):65–70. 8. Marso SP, Daniels GH, Brown-Frandsen K, et al. 18. McGovern A, Hinton W, Correa A, Munro N, Liraglutide and cardiovascular outcomes in type 2 Whyte M, de Lusignan S. Real-world evidence diabetes. N Engl J Med. 2016;375(4):311–22. studies into treatment adherence, thresholds for intervention and disparities in treatment in people 9. GOV.UK. English indices of deprivation 2015. with type 2 diabetes in the UK. BMJ Open. Available at: https://www.gov.uk/government/ 2016;6(11):e012801. statistics/english-indices-of-deprivation-2015. Accessed 17 Jan 2018. 19. Liaw ST, Taggart J, Yu H, de Lusignan S, Kuziemsky C, Hayen A. Integrating electronic health record 10. Correa A, Hinton W, McGovern A, et al. Royal information to support integrated care: practical College of General Practitioners Research and application of ontologies to improve the accuracy of diabetes disease registers. J Biomed Inform. Surveillance Centre (RCGP RSC) sentinel network: a cohort profile. BMJ Open. 2016;6(4):e011092. 2014;52:364–72. 11. Fleming DM, Miles J. The representativeness of 20. McGovern A, Feher M, Munro N, de Lusignan S. sentinel practice networks. J Public Health (Oxf). Sodium-glucose co-transporter 2 (SGLT2) inhibitor: 2010;32(1):90–6. comparing trial data and real-world use. Diabetes Ther. 2017;8(2):365–76. 12. Fleming DM, Schellevis FG, Paget WJ. Health monitoring in sentinel practice networks: the con- 21. Woodmansey C, McGovern AP, McCullough KA, tribution of primary care. Eur J Public Health. et al. Incidence, demographics, and clinical char- 2003;13[3 Suppl]:80–4. acteristics of diabetes of the exocrine pancreas (type 3c): a retrospective cohort study. Diabetes Care. 13. Queenan JA, Williamson T, Khan S, et al. Repre- 2017;40(11):1486–93. sentativeness of patients and providers in the Canadian Primary Care Sentinel Surveillance Net- 22. Langdown C, Peckham S. The use of financial work: a cross-sectional study. CMAJ Open. incentives to help improve health outcomes: is the 2016;4(1):E28. quality and outcomes framework fit for purpose? A systematic review. J Public Health (Oxf). 14. de Lusignan S, van Weel C. The use of routinely 2014;36(2):251–8. collected computer data for research in primary care: opportunities and challenges. Fam Pract. 23. Health Research Authority. Is my study research? 2006;23(2):253–63. Available at:http://www.hra-decisiontools.org.uk/ research/. Accessed 17 Jan 2018. 15. de Lusignan S, Metsemakers JF, Houwink P, Gun- narsdottir V, van der Lei J. Routinely collected 24. Chan T, Di Iorio CT, De Lusignan S, Lo Russo D, general practice data: goldmines for research? A Kuziemsky C, Liaw ST. UK National Data Guardian report of the European Federation for Medical for Health and Care’s Review of Data Security: trust, Informatics Primary Care Informatics Working better security and opt-outs. J Innov Health Inform. Group (EFMI PCIWG) from MIE2006, Maastricht, 2016;23(3):627–32. The Netherlands. Inform Prim Care. 2006;14(3):203–9. 25. De Lusignan S, Liyanage H, Di Iorio CT, Chan T, Liaw ST. Using routinely collected health data for 16. McGovern A, Hinton W, Calderara S, Munro N, surveillance, quality improvement and research: Whyte M, de Lusignan S. A class comparison of framework and key questions to assess ethics, pri- medication persistence in people with type 2 dia- vacy and data access. J Innov Health Inform. betes: a retrospective observational study. Diabetes 2016;22(4):426–32. Ther. 2018;9(1):229–42. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Diabetes Therapy Springer Journals

Does Real World Use of Liraglutide Match its Use in the LEADER Cardiovascular Outcome Trial? Study Protocol

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Abstract

Diabetes Ther (2018) 9:1397–1402 https://doi.org/10.1007/s13300-018-0390-8 STUDY PROTOCOL Does Real World Use of Liraglutide Match its Use in the LEADER Cardiovascular Outcome Trial? Study Protocol . . . William Hinton Michael Feher Neil Munro Simon de Lusignan Received: January 31, 2018 / Published online: March 31, 2018 The Author(s) 2018 (RCGP) Research and Surveillance Center (RSC) ABSTRACT network database. People with T2DM will be identified from the dataset using a well-estab- Background: Liraglutide is an injectable ther- lished ontological process. Read and other clini- apy to treat type 2 diabetes (T2DM), belonging cal codes will be used to identify people to the glucagon-like peptide-1 receptor agonist prescribed liraglutide and those at high cardio- class of drugs. The Liraglutide Effect and Action vascular risk. We will use descriptive statistics to in Diabetes: Evaluation of Cardiovascular Out- report the characteristics of people with T2DM come Results (LEADER) trial established that prescribed liraglutide compared with those of the liraglutide demonstrated glucose-lowering ben- LEADER trial and the proportion of the wider efits and improved cardiovascular outcomes in T2DM cohort that matches the LEADER inclu- those individuals with T2DM at high cardio- sion criteria. In terms of ethical considerations, vascular risk. this study used pseudonymized data, and was Aims: The aim of this study is to report the classed as an ‘‘Audit of current practice’’. prevalence and characteristics of people treated Planned Outputs: The results of the study will with liraglutide compared with the LEADER be submitted for publication in a peer-reviewed trial. In addition, the remaining portion of the journal to report the applicability of the results T2DM population will be examined to deter- of the LEADER trial to real-world clinical mine the prevalence of those who meet the practice. inclusion criteria for the LEADER trial but who Funding: Novo Nordisk Limited. are not treated with this medication. Study Design and Methods: This is a cross- Keywords: Cardiovascular diseases; Cross- sectional analysis of routinely collected primary sectional studies; Diabetes mellitus, type 2; care data on all people with T2DM included in Liraglutide; Medical record systems, the Royal College of General Practitioners computerized Enhanced content To view enhanced content for this article go to https://doi.org/10.6084/m9.figshare.59092 INTRODUCTION Liraglutide is an established injectable therapy, W. Hinton  M. Feher  N. Munro S. de Lusignan (&) belonging to the glucagon-like peptide-1 (GLP- Department of Clinical and Experimental Medicine, 1) receptor agonist class of drugs, for the treat- University of Surrey, Guildford, UK ment of hyperglycemia in people with type 2 e-mail: s.lusignan@surrey.ac.uk 1398 Diabetes Ther (2018) 9:1397–1402 diabetes (T2DM). Like other medications within AIMS AND METHODS its class, liraglutide improves glycemic control by stimulating the GLP-1 receptor to produce We will perform a cross-sectional analysis of all more insulin, while simultaneously suppressing people with T2DM included in the Royal Col- the secretion of glucagon and prolonging gas- lege of General Practitioners (RCGP) Research tric emptying [1, 2]. Clinical trials have and Surveillance Center (RSC) database to demonstrated that liraglutide has various ben- identify people prescribed liraglutide and to efits, including reduced glycated hemoglobin describe their cardiovascular risk profile. In (HbA1c), decreased risk of hypoglycemia com- addition, the proportion of those with a car- pared with sulfonylurea, and weight loss [3, 4]. diovascular risk profile comparable to that of Liraglutide has also been shown to have reno- those included in the LEADER trial will be protective effects and to reduce systolic blood reported. pressure [5–7]. More recently, the effects of liraglutide have been explored in a cardiovas- Objectives cular outcome trial (CVOT). CVOTs are safety trials for the new classes of The aim of the study is to compare the clinical drugs used in the management of T2DM. The characteristics of patients prescribed liraglutide Liraglutide Effect and Action in Diabetes: Eval- with those people included in the LEADER trial. uation of Cardiovascular Outcome Results We also aim to identify the proportion of (LEADER) study was a double-blind randomized patients in the RCGP RSC database that meet controlled trial assessing the cardiovascular the inclusion criteria for liraglutide as used in effects of liraglutide compared to a placebo, the LEADER trial but who are not prescribed this when added to standard care in patients with medication. T2DM [8]. It was also designed to evaluate any The primary objectives are: inferiority or superiority in terms of cardiovas- 1. To identify the number of people prescribed cular benefit. liraglutide in UK primary care who meet the The study comprised 9340 individuals with inclusion criteria for the LEADER trial. T2DM and high cardiovascular disease risk. 2. To describe the characteristics of patients After a median follow-up of 3.8 years, time-to- taking liraglutide: event analysis confirmed the liraglutide was a. The number of people that meet each of associated with a lower rate of first occurrence the LEADER inclusion criteria. of death from cardiovascular causes, nonfatal b. The duration of their diabetes. myocardial infarction, or nonfatal stroke com- c. The number of people identified on pared with placebo. The results of the LEADER concurrent oral antihyperglycemic trial confirmed not only the non-inferiority of medications or on insulin. liraglutide with respect to cardiovascular safety 3. To describe the demographic (age, gender, but provided evidence of its superiority in terms ethnicity, socioeconomic status {SES, using of cardiovascular outcomes. the Index of Multiple Deprivation [9]}) and Whether these findings translate into real- clinical characteristics (HbA1c, blood pres- world clinical practice is unclear. Here we set sure, renal function, body mass index, etc.) out the method we will use to determine (1) the of people in each of the groups described current pattern of prescribing liraglutide within above. a nationally representative general practice The secondary objectives are: network and (2) the prevalence of people with 4. To identify the number of people in the T2DM possessing the same cardiovascular risk entire RCGP RSC cohort who meet the profile as those included in the LEADER trial. inclusion criteria for the LEADER trial. This will inform the extent to which the find- 5. To describe the characteristics of the people ings of the LEADER trial can be generalized to with T2DM eligible for the LEADER trial: routine clinical practice. Diabetes Ther (2018) 9:1397–1402 1399 a. The number of people who meet each of particularly in the population of people with the LEADER inclusion criteria. T2DM [10]. b. The duration of their diabetes. We will use all data collected from primary c. The number of those identified on care practices after 1 January 2016, which will concurrent oral antihyperglycemic comprise all patients with a T2DM diagnosis medications or on insulin. who are over the age of 18 years. Within this 6. To describe the demographic (age, gender, cohort, we will identify and report the propor- ethnicity, SES) and clinical characteristics tion of those with a prescription for liraglutide, (HbA1c, blood pressure, renal function, and all of those with similar cardiovascular body mass index, etc.) of people in each of risk/conditions to those of the LEADER trial. the groups described above. The demographic and clinical characteristics of these groups will be reported. Missing data for each variable of interest will also be stated. Data Source In the interests of information governance, the RCGP RSC data is pseudonymized by NHS The RCGP RSC is a primary care sentinel net- number. This study was classed as an ‘‘Audit of work that includes the records from over 200 current practice,’’ and therefore specific ethical primary care practices distributed across Eng- approval was not required. land covering a population of over 2,000,000 patients. This is a nationally representative Data Analysis sample [10], primarily used for the monitoring of respiratory disease and infections such as influenza for vaccine effectiveness [11–13]. People with T2DM will be identified using a UK general practice is suited to this type of two-step process that we have reported in detail study because it is a registration-based system; elsewhere [18]. This is an ontological-based each patient is registered with a single practice approach that integrates numerous data ele- and if they move their data move with them ments to enhance case definition [19]. Initially, [14]. Each patient also has a unique patient all people with diabetes are identified using a identifier, the National Health Service (NHS) combination of diagnostic codes, HbA1c and number, which not only facilitates specific blood glucose test results (two or more that patient–data linkage but also the potential for confirm diabetes), and medication use (except data linkage with other datasets, such as metformin). Codes specific to gestational dia- pathology results. Repeat prescription data have betes or other types of secondary diabetes are been complete since the 1990s following the excluded. People are then categorized by dia- transition from paper-based to computerized betes type (T1DM, T2DM, undetermined dia- medical records (CMR) in UK primary care, betes type) using a seven-step algorithm that while the coding of chronic disease and labo- takes into account previous and current drug ratory links were standardized in 2004 [15]. We therapies used, diagnosis codes specific to dia- have recently demonstrated our ability to betes type, and other important clinical char- monitor adherence to different classes of ther- acteristics (age and body mass index at apies using this database [16]. diagnosis, and duration of oral anti-hyper- UK primary care CMR data are recorded glycemic medications). using the Read classification [17]. The coded We will use the high cardiovascular risk data includes patient demographics (age, sex, inclusion criteria for the LEADER trial to deter- ethnicity, and SES), diagnosis and processes of mine prevalence within the T2DM cohort care (referrals, annual reviews, care pathways, (Table 1). People will be identified with each etc.), prescriptions, and laboratory data. Inclu- cardiovascular risk factor using the most similar sion of data recording targets in the UK primary diagnostic codes, or other codes which deter- care pay-for-performance targets have led to a mine diagnosis of a risk factor. We will provide a high level of data completeness in these records, 1400 Diabetes Ther (2018) 9:1397–1402 Table 1 Inclusion criteria for the LEADER trial taken complete list of codes and a full description of from the supplementary material provided in the LEA- the process in the final manuscript. DER publication by Marso et al. [8] Statistical Methods LEADER trial inclusion criteria T2DM with HbA1c C 7% We will use descriptive statistics (percentages, Cardiovascular disease: C 50 years of age and C 1 of the means, standard deviations, etc.) to describe the characteristics of the cohorts. Crude rates of following: each variable of interest will be reported within Previous myocardial infarction each cohort, with 95% confidence intervals. Previous stroke or transient ischemic attack Previous coronary, carotid or peripheral arterial STRENGTHS AND LIMITATIONS revascularization A number of strengths of the dataset have been [50% stenosis of coronary, carotid, or lower described in the section ‘‘Data Source’’. The extremity arteries large denominator ([2 million patients) of this History of symptomatic coronary heart disease high-quality real-world evidence dataset is a documented by positive exercise stress test or any specific strength. We have also previously cardiac imaging or unstable angina with ECG demonstrated our ability to compare real-world and trial use of another class of medication in changes diabetes [20], and also to link complex data, in Asymptomatic cardiac ischemia documented by this example pancreatitis, to cases of diabetes positive nuclear imaging test, exercise test or [21]. However, given that the minority of peo- dobutamine stress echo ple with T2DM are prescribed liraglutide, there may not be enough statistical power to confirm Chronic heart failure New York Heart Association ‘‘true differences’’ between groups. class II–III Another potential limitation is missing data Chronic renal failure: in a patient’s primary care record, whereby a number of patients may have particular condi- eGFR\60 mL/min/1.73 m (Modification of tions that have not been recorded. Nonetheless, Diet in Renal Disease formula) the pay for performance scheme (P4P), i.e., the eGFR\60 mL/min (Cockcroft–Gault formula) Quality and Outcomes Framework (QOF), implemented in 2004 to incentivize primary No previous cardiovascular disease group: C 60 years care practices to achieve indicator thresholds and C 1 of the following: for the management of chronic diseases [22], Microalbuminuria (ACR) or proteinuria has improved data quality in primary care. Additional strengths and limitations found Hypertension and left ventricular hypertrophy by while undertaking the study will be reported in ECG or imaging the final version of the manuscript. Left ventricular systolic or diastolic dysfunction by imaging CONCLUSION Ankle-brachial index\0.9 This real-world evidence cross-sectional analysis T2DM Type 2 diabetes mellitus, HbA1c glycated hemo- will investigate the prevalence of people with globin, ECG electrocardiogram, eGFR estimated glomeru- T2DM in a nationally representative primary lar filtration rate, ACR albumin:creatinine ratio care population currently prescribed liraglutide and their cardiovascular risk profile; and those Diabetes Ther (2018) 9:1397–1402 1401 in the wider T2DM population that meet the Compliance with Ethics Guidelines. This inclusion criteria for the LEADER trial. study is considered to be an ‘‘Audit of current practice’’ when tested against the Health Research Authority (HRA)/Medical Research Council (MRC) ‘‘Is my study research’’ tool and ACKNOWLEDGEMENTS therefore did not require specific ethical approval [23]. In addition, the processes and The authors would like to thank patients and systems are streamlined to operationalize these practices who are members of the RCGP RSC studies, as we consistently strive to follow best network, and the CMR system vendors: EMIS, In practices in surveillance and quality improve- Practice, and TPP. We would also like to thank ment [24, 25]. Approval for use of the data was Apollo Medical systems, the RCGP, and acquired from the RCGP RSC Study Approval University of Surrey colleagues: Filipa Ferreira Committee. (Programme Manager), Rachel Byford, and Julian Sherlock (SQL developers). Open Access. This article is distributed under the terms of the Creative Commons Funding. Sponsorship for this study and Attribution-NonCommercial 4.0 International article processing charges were funded by Novo License (http://creativecommons.org/licenses/ Nordisk Limited. All authors will have full by-nc/4.0/), which permits any non- access to all of the data in this study and will commercial use, distribution, and reproduction take complete responsibility for the integrity of in any medium, provided you give appropriate the data and accuracy of the data analysis. credit to the original author(s) and the source, provide a link to the Creative Commons license, Authorship. All named authors meet the and indicate if changes were made. International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole and have given final REFERENCES approval for the version to be published. 1. Baggio LL, Drucker DJ. 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Journal

Diabetes TherapySpringer Journals

Published: Mar 31, 2018

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