Characteristics of new users of recent antidiabetic drugs in Canada and the United Kingdom

Several new classes of drugs used to manage type 2 diabetes have entered the market over the last two decades, including dipeptidyl peptidase-4 inhibitors (DPP-4i), sodium-glucose co-transporter-2 inhibitors (SGLT-2i), and glucagon-like peptide-1 receptor agonists (GLP-1 RAs). American, United Kingdom (UK), and Canadian guidelines for the treatment of type 2 diabetes all recommend using these therapies as replacement or in addition to first-line treatment with metformin if target glycemic levels are not reached [1–4]. Because of additional beneficial effects, some of these drugs may be preferred over others in specific sub-populations. Randomized controlled trials (RCTs) suggest that GLP-1 RAs [5, 6] and SGLT-2i [7, 8] may also have cardioprotective and weight-loss effects, which may be particularly beneficial in some sub-population, such as patients at higher risk of cardiovascular outcomes [9, 10]. In addition, SGLT-2i have been shown to have beneficial effects on heart failure in patients with type 2 diabetes [11]. They also have benefits on renal outcomes [12] and are recommended for patients with type 2 diabetes and chronic kidney disease [2]. With the growing availability and diversity of antidiabetic treatments, it is essential to understand the characteristics of the patients using them, which remain unclear to date. The objective of this study was to describe the characteristics of new users of DPP-4i, SGLT-2i, and GLP-1 RA in Canada and in the UK between 2016 and 2018.

There were 2,175,815 users of antidiabetic drugs between 2016 and 2018. When data were pooled across jurisdictions, our study cohort included 194,070 new users of DPP-4i, 166,722 new users of SGLT-2i, and 27,719 new users of GLP-1 RA. Tables 2, 3 and 4 summarize the characteristics of new users of these treatments at each participating site. In general, the proportion of new users of DPP-4i and SGLT-2i was similar across study sites, with fewer patients initiating GLP-1 RA. Overall, new users of GLP-1 RA were younger than new users of DPP-4i or SGLT-2i. New users of GLP-1 RAs were also less likely to be male than new users of DPP-4i or SGLT-2i, except in Quebec and the UK. Mean duration of diabetes was similar for new users of DPP-4i and SGLT-2i across sites. However, differences in the duration of diabetes were observed among new users of GLP-1 RAs; approximately 20% of patients had <1 year of history of diabetes in all sites except in Quebec and in the UK, where <3% had a diabetes duration of <1 year.

In Canada, between 27.6% and 44.5% of new users of GLP-1 RAs used ≥3 antidiabetic medications in the year prior to initiation in all provinces except Quebec, where 81.0% used ≥3 antidiabetic medications in the prior year (Table 3). The majority of users in all three groups used metformin prior to initiating treatment with the study drugs (range: 61.7 – 89.4%) (Tables 2, 3, and 4). In addition, 16.2%, 25.9%, and 26.9% of new users in Canada had used insulin prior to initiating treatment with DPP-4i, SGLT-2i, and GLP-1 RA, respectively (Table S4). Concurrent antidiabetic drug use was generally similar across groups.

Comorbidities of new users of DPP-4i, SGLT-2i, and GLP-1 RAs in Canada are presented in Figure 1. Hypertension was the most prevalent comorbidity among new users of DPP-4i (58%), SGLT-2i (54%), and GLP-1 RA (41%). The prevalence of coronary artery disease and dyslipidemia were between 20% and 31%, while the prevalence of cancer and chronic obstructive pulmonary disease ranged from 9% to 14% in each of the three study groups. New users of DPP-4i were more likely to have a history of coronary artery disease (24%) than new users of SGLT-2i (23%) or GLP-1 RA (21%). The prevalence of ischemic stroke ranged from 0.1% to 0.7%. The prevalence of heart failure was 1.3% for new-users of DPP-4i, 0.5% for new-users of SGLT-2i, and 0.3% for new-users of GLP-1 RA.

The aim of this study was to describe the characteristics of new users of newer antidiabetic drugs in 7 Canadian provinces and in the UK between 2016 and 2018. Several characteristics differed amongst users of DPP-4i, SGLT-2i, and GLP-1 RA, namely age, sex, and the prevalence of certain comorbidities such as obesity and impaired renal function. Patients using DPP-4i had a higher prevalence of cardiovascular disease at baseline than those using SGLT-2i or GLP-1 RA.

Some use of DPP-4i, SGLT-2i, and GLP-1 RAs was not consistent with treatment guidelines in place during the study period. For example, between 16.2% and 26.9% of new users of all three classes of newer antidiabetic drugs had used insulin prior to treatment initiation with these drugs. However, American, Canadian, and UK guidelines generally recommend using insulin as a third line treatment, therefore only after failing treatment on second line therapies [1–3, 18] unless the patient has symptoms of hyperglycemia or evidence of metabolic decompensation at the time of type 2 diabetes diagnosis [2, 19]. Furthermore, a greater proportion of new users of DPP-4i had cardiovascular disease at baseline as compared to new users of SGLT-2i and GLP-1 RA, although SGLT-2i² and GLP-1 RA [20] have a greater cardioprotective effect and are indicated for use in patients with type 2 diabetes at elevated cardiovascular risk [2]. In addition, a smaller proportion of patients using SGLT-2i had renal insufficiency (eGFR <60 mL/min/1.73m²) compared to users of DPP-4i and GLP-1 RA, although SGLT-2i can provide renal benefits in patients with type 2 diabetes. These findings suggest that patients who are most likely to benefit from SGLT-2i and GLP-1 RA may not be receiving these drugs, which has important implications for their health. However, varying formulary restrictions between provinces and changes in clinical practice guidelines throughout the study period may explain these discrepancies. Further research is needed to understand the observed discrepancies between treatment guidelines and what is implemented in routine clinical practice.

In Canada, health is a provincial and territorial responsibility. Consequently, the provinces and territories have the responsibility to manage their own drug plans, which results in important differences in eligibility and participation in drug plans across the country. As described in Table 1, there were important differences in the provincial formulary listings for SGLT-2i and GLP-1 RA, whereas the coverage of DPP-4i was relatively similar across provinces [2]. Formulary restrictions are a potential source of confounding and channeling in etiologic studies that may vary across provinces [21]. These variations may explain differences observed in the characteristics of new users of GLP-1 RAs across provinces; they were, on average, younger and more likely to have a shorter duration of diabetes and no prior use of antidiabetic medications in all provinces except Quebec, compared to users of SGLT-2i and DPP-4i. This suggests that GLP-1 RA, in particular liraglutide, may have been used for indications other than type 2 diabetes among these patients. Liraglutide is commercialized under two labels in Canada: Victoza®, indicated for type 2 diabetes, and Saxenda®, indicated for weight loss. Although we did not include Saxenda® in our analyses, it is possible that Victoza® was dispensed for the indication of weight loss to ensure insurance coverage.

Observed inter-provincial differences may also be the result of differences in data capture across provinces. In Alberta, British Columbia, Manitoba, and Nova Scotia, prescription drug data capture all dispensations, regardless of payer. However, drug dispensing data in Ontario and Quebec are only available for drugs that are covered by the provincial drug plans, while dispensations covered by the federal government are also captured in Saskatchewan. Given this potential source of heterogeneity, we conducted an analysis in Manitoba where we stratified new users by prescription payer. The results of this analysis suggest that the characteristics of patients who are covered by the public drug plan were similar to those of individuals who were not covered by the public plan. These potential sources of heterogeneity must be considered in the design of multi-jurisdictional studies and interpretation of pharmacoepidemiologic studies.

This study has several strengths. The use of administrative health databases from 7 Canadian sites and from the UK allowed us to comprehensively assess the use of newer 2^nd to 3^rd line antidiabetic drugs and the characteristics of patients initiating their use. Furthermore, the lifestyle, clinical and laboratory data available with the CPRD allowed us to assess patient characteristics that are not typically available in other administrative databases.

Our study also has some limitations. First, the dispensing of certain drugs may not have been measured due to availability of drug samples, which would not have been recorded in our databases. However, this should only affect a small proportion of all patients in our study and such dispensing is likely to be of short duration and followed by a recorded prescription. Second, while some patients may have entered the base cohort due to a dispensing of an antidiabetic drug for an indication other than type 2 diabetes, the three drug classes under investigation were largely prescribed for type 2 diabetes during the study period. Consequently, we do not anticipate many patients without type 2 diabetes being included in our study population. Third, we are unable to determine if the observed inter-provincial differences are because of true differences in use or differences in data capture across the provincial databases. In addition, we were unable to compare the utilization of studied drugs by molecule due to differences in formulary listings between jurisdictions, and differences in data capture. Fourth, the utilization of the studied drugs may have changed in these jurisdictions since the end of our data availability in 2018. Despite these limitations, our results provide an insightful picture of the patients receiving these newer antidiabetic drugs, which may inform policy makers and other decision makers on approaches to provide the most beneficial care.

Although SGLT-2i, DPP-4i, and GLP-1 RAs are recommended as 2^nd or 3^rd line therapy for type 2 diabetes, important differences exist in the characteristics of users of these drugs. Our results also suggest that treatment for type 2 diabetes does not always follow recommended guidelines, where new users of DPP-4i had a higher prevalence of coronary artery disease than new users SGLT2i or GLP-1 RA. This study provides important insight into the complexity of treatment for type 2 diabetes. Further research is needed to better understand the consequences of differing drug plans across jurisdictions and differences in insurance systems across countries on medication utilization. In addition, future studies should examine the impact of changes in clinical evidence and guideline indications on prescribing trends.

This study was made possible through data sharing agreements between the CNODES member research centres and the respective provincial governments of Alberta, British Columbia, Manitoba (HIPC # 2018/2019-58), Nova Scotia, Ontario, Quebec, and Saskatchewan. This study was approved by the Independent Scientific Advisory Committee (ISAC; protocol # 19_007A2) of the CPRD; the approved protocol was made available to journal reviewers. The BC Ministry of Health approved access to and use of BC data for this study. Data sources were as follows (https://www2.gov.bc.ca/gov/content/health/conducting-health-research-evaluation/data-access-health-data-central↗): British Columbia Ministry of Health [creator] (2018): Medical Services Plan (MSP) Payment Information File. BC Ministry of Health [publisher]. MOH (2018); British Columbia Ministry of Health [creator] (2018): Consolidation File (MSP Registration & Premium Billing). BC Ministry of Health [publisher]. MOH (2018); British Columbia Ministry of Health [creator] (2018): PharmaNet. BC Ministry of Health [publisher]. Data Stewardship Committee (2018); and Canadian Institute for Health Information [creator] (2018): Discharge Abstract Database (Hospital Separations). BC Ministry of Health [publisher]. MOH (2018). BC Ministry of Health [publisher]. MOH (2018); BC Vital Statistics Agency [creator] (2018): Vital Statistics Deaths. V2. BC Ministry of Health [publisher]. This study was supported by ICES, which is funded by an annual grant from the Ontario Ministries of Health and Long-Term Care. Parts of this material are based on data and information compiled and provided by the Canadian Institute for Health information (CIHI). ICES thanks IQVIA Solutions Canada Inc for use of their Drug Information File. The opinions, results, and conclusions reported in this paper are those of the authors. No endorsement by the provinces, data stewards, ICES, CIHI, or the Institut national d'excellence en santé et en services sociaux is intended or should be inferred.

We thank Ms. Corine Mizrahi at the CNODES Coordinating Center for her important contributions to this work. We also acknowledge the programming and analytical support of the analysts at each site: Zhihai Ma MSc (Alberta), Greg Carney PhD and Jason Kim MPH, BHSc (British Columbia), Matthew Dahl BSc (Manitoba), Yan Wang MSc (Nova Scotia), C. Fangyun Wu MSc MA (Ontario), and Hui Yin MSc and Christopher Filliter MSc (CPRD). We also thank Antonios Douros MD, PhD, Michael Fralick MD, Hala Tamim PhD, and Eric Tremblay MSc for their contributions to this study.

Dr. Brunetti was supported by the Doctoral Training Scholarship from the Fonds de recherche du Quebec – santé (FRQS; Quebec Foundation for Research - Health), the Drug Safety and Effectiveness Training (DSECT) Program Award, funded by the Canadian Institutes of Health Research (CIHR) and the David G. Guthrie Fellowship from the Faculty of Medicine at McGill University. Dr. Yu holds a Chercheur-boursier clinicien Junior I salary support award from the FRQS. Dr. Filion holds a Chercher-boursier Senior salary support award from the FRQS and a William Dawson Scholar award from McGill University. Dr. Lix is supported by a Tier 1 Canada Research Chair.

CONSORTIUM NAME

The Canadian Network for Observational Drug Effect Studies (CNODES) Investigators are:

Samy Suissa^{1, 2}; Colin R. Dormuth³; Brenda R. Hemmelgarn¹²; Jacqueline Quail⁸; Dan Chateau⁹; J. Michael Paterson¹⁰; Jacques LeLorier^{15, 16}; Adrian R. Levy¹⁷; Pierre Ernst^{2, 14}; Kristian B. Filion^{1, 2, 14}; Lisa M. Lix¹³; Robert W. Platt¹; Ingrid S. Sketris¹⁷

¹ Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Canada

² Center for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Canada

³ Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada

⁴ Division of Endocrinology, Department of Medicine, Jewish General Hospital, Montreal, Quebec, Canada

⁵ College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada

⁶ School of Pharmacy, Memorial University of Newfoundland, St John's, Newfoundland and Labrador, Canada

⁷ Institut national d'excellence en santé et en services sociaux (INESSS), Quebec City, Quebec, Canada

⁸ The Health Quality Council, Saskatoon, Saskatchewan, Canada

⁹ Manitoba Centre for Health Policy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada

¹⁰ ICES, Toronto, Ontario, Canada

¹¹ Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada

¹² Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada

¹³ Department of Community Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada

¹⁴ Department of Medicine, McGill University, Montreal, Quebec, Canada

¹⁵ Faculté de Médecine, Université de Montréal, Montréal, Canada.

¹⁶ Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.

¹⁷ Department of Community Health and Epidemiology, Dalhousie University, Halifax, NS, Canada.

VCB drafted the manuscript. All authors contributed to the study design and implementation, interpreted results, and critically reviewed the manuscript for important intellectual content. Site-specific analysts conducted analyses at each site, and VCB pooled data across the sites. All authors approved the final version of the manuscript. KBF is the guarantor.

CNODES, a collaborating centre of the Drug Safety and Effectiveness Network (DSEN), is funded by the Canadian Institutes of Health Research (Grant Number DSE-146021).

This study was conducted by CNODES using administrative health data obtained through data-sharing agreements between its member research centres and their respective provincial data stewards. Data availability thus differs by site. Alberta: The authors cannot make the dataset used in this study available to other researchers due to their contractual arrangements with the provincial health ministry (Alberta Health), who is the data custodian. Researchers may make requests to obtain a similar dataset at https://absporu.ca/research-services/service-application/↗. British Columbia: The authors do not have permission to share data from this study. The data that support the findings of this study are available from Population Data BC (https://www.popdata.bc.ca/↗), but restrictions apply to the availability of these data, which were used under licence for the current study and so are not publicly available. CPRD: This study is based in part on data from the Clinical Practice Research Datalink obtained under license from the UK Medicines and Healthcare products Regulatory Agency. The data are provided by patients and collected by the UK National Health Service as part of their care and support. The interpretation and conclusions contained in this study are those of the author/s alone. Because electronic health records are classified as “sensitive data” by the UK Data Protection Act, information governance restrictions (to protect patient confidentiality) prevent data sharing via public deposition. Data are available with approval through the individual constituent entities controlling access to the data. Specifically, the primary care data can be requested via application to the Clinical Practice Research Datalink (https://www.cprd.com↗). Manitoba: Data used in this article was derived from administrative health and social data as a secondary source. The data was provided under specific data sharing agreements only for approved use at Manitoba Centre for Health Policy (MCHP). The original source data is not owned by the researchers or MCHP and as such cannot be provided to a public repository. The original data source and approval for use has been noted in the acknowledgments of the article. Where necessary, source data specific to this article or project may be reviewed at MCHP with the consent of the original data providers, along with the required privacy and ethical review bodies. Nova Scotia: Data in this study were obtained from Health Data Nova Scotia of Dalhousie University. These data can be acquired by researchers with an academic affiliation who submit a research protocol that is obtained by a Data Access Committee and Research Ethics Board. Ontario: The dataset from this study is held securely in coded form at ICES. While legal data sharing agreements between ICES and data providers (e.g., health organizations and government) prohibit ICES from making the dataset publicly available, access may be granted to those who meet pre-specified criteria for confidential access, available at www.ices.on.ca/DAS↗ (email: das@ices.on.ca). Quebec: The data that support the findings of this study come from an analysis conducted by the Institut national d’excellence en santé et en services sociaux (INESSS). The results of this analysis are publicly available on INESSS’s Website. The original data used to produce this analysis are subject to confidentiality restrictions, and so are not publicly available under Quebec legislation. Authors may provide information concerning the original data upon reasonable request and with permission of INESSS. Saskatchewan: This study is based in-part on de-identified data provided by the Saskatchewan Ministry of Health. Restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data may be available from the authors upon reasonable request and with permission of the Saskatchewan Ministry of Health.

Kristian B. Filion, Email: kristian.filion@mcgill.ca

for the Canadian Network for Observational Drug Effect Studies (CNODES) Investigators:

Samy Suissa↗, Colin R. Dormuth↗, Brenda R. Hemmelgarn↗, Jacqueline Quail↗, Dan Chateau↗, J. Michael Paterson↗, Jacques LeLorier↗, Adrian R. Levy↗, Pierre Ernst↗, Kristian B. Filion↗, Robert W. Platt↗, and Ingrid S. Sketris↗