Cardiovascular outcomes with GLP-1 receptor agonists vs. SGLT-2 inhibitors in patients with type 2 diabetes (original) (raw)

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Department of Cardiology and Clinical Research, Nordsjællands University Hospital

, Dyrehavevej 29, 3400 Hillerød,

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Heart Disease Prevention Program, Division of Cardiology, University of California, Irvine, Irvine

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Section of Biostatistics, Copenhagen University

, Copenhagen,

Denmark

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Section of Biostatistics, Copenhagen University

, Copenhagen,

Denmark

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Steno Diabetes Center North Jutland

, Aalborg,

Denmark

Department of Clinical Medicine and Endocrinology, Aalborg University Hospital

, Aalborg,

Denmark

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Department of Cardiology, Copenhagen University Hospital Herlev-Gentofte

, Hellerup,

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Department of Cardiology, Rigshospitalet, Copenhagen University Hospital

, Copenhagen,

Denmark

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Department of Cardiology, Rigshospitalet, Copenhagen University Hospital

, Copenhagen,

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Heart Disease Prevention Program, Division of Cardiology, University of California, Irvine, Irvine

, CA,

USA

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Department of Cardiology and Clinical Research, Nordsjællands University Hospital

, Dyrehavevej 29, 3400 Hillerød,

Denmark

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Department of Cardiology and Clinical Research, Nordsjællands University Hospital

, Dyrehavevej 29, 3400 Hillerød,

Denmark

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Revision received:

03 June 2021

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03 September 2022

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Caroline H Nørgaard, Liis Starkopf, Thomas A Gerds, Peter Vestergaard, Anders N Bonde, Emil Fosbøl, Lars Køber, Nathan D Wong, Christian Torp-Pedersen, Christina J-Y Lee, Cardiovascular outcomes with GLP-1 receptor agonists vs. SGLT-2 inhibitors in patients with type 2 diabetes, European Heart Journal - Cardiovascular Pharmacotherapy, Volume 8, Issue 6, October 2022, Pages 549–556, https://doi.org/10.1093/ehjcvp/pvab053
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Abstract

Aims

We examined cardiovascular outcomes associated with initiation of glucagon-like peptide-1 receptor agonist (GLP-1RA) vs. sodium–glucose co-transporter-2 inhibitor (SGLT-2i) treatment in a real-world setting among patients with type 2 diabetes.

Methods and results

This Danish nationwide registry-based cohort study included patients with type 2 diabetes with a first-ever prescription of either GLP-1RA or SGLT-2i from 2013 through 2015 with follow-up until end of 2018. All analyses were standardized with respect to age, sex, diabetes duration, comorbidity, and comedication. The main outcome was a composite of cardiovascular death, myocardial infarction, and stroke. Furthermore, the components of the composite outcome and hospitalization for heart failure were evaluated. Standardized average 3-year risks of outcomes and differences thereof were estimated using doubly robust estimation combining cause-specific Cox regression with propensity score regression. We identified 8913 new users of GLP-1RA and 5275 new users of SGLT-2i. The standardized 3-year risk associated with initiating GLP-1RA and SGLT-2i, respectively, was as follows: composite cardiovascular outcome, 5.6% [95% confidence interval (CI): 5.2–6.1] vs. 5.6% (95% CI: 4.8–6.3); cardiovascular mortality, 1.6% (95% CI: 1.3–1.9) vs. 1.5% (95% CI: 1.1–1.8); hospitalization for heart failure, 1.7% (95% CI: 1.5–2.0) vs. 1.8% (95% CI: 1.2–2.5); myocardial infarction, 2.1% (95% CI: 1.8–2.4) vs. 2.1% (95% CI: 1.5–2.6); and stroke, 2.5% (95% CI: 2.2–2.9) vs. 2.6% (95% CI: 2.2–3.1).

Conclusion

In this nationwide study of patients with type 2 diabetes, initiating GLP-1RA vs. SGLT-2i was not found to be associated with significant differences in cardiovascular risk.

Introduction

Cardiovascular disease is the most common cause of morbidity and mortality in patients with type 2 diabetes.1 In recent years, numerous cardiovascular outcome trials (CVOTs) have demonstrated not only cardiovascular safety but also reductions in cardiovascular outcomes with two new classes of glucose-lowering drugs, namely glucagon-like peptide-1 receptor agonists (GLP-1RA)2–6 and sodium–glucose co-transporter-2 inhibitors (SGLT-2i),7–9 in patients with type 2 diabetes. Specifically, certain GLP-1RA have shown significant reductions in major adverse cardiovascular events (MACE),2–5 cardiovascular death,2,6 non-fatal stroke,3 and myocardial infarction.4 Differences in structure, potency, and the effect on cardiovascular risk reduction exist between the different GLP-1RA, but an overall favourable risk–benefit profile has been shown for the GLP-1RA class.10 For SGLT-2i, a lower risk of MACE,7,8 cardiovascular death,7 and hospitalization for heart failure (HHF)7–9 has been demonstrated. The trial design, including the number of patients with established cardiovascular disease and specification of outcomes, has differed for the respective SGLT-2i, making it difficult to definitively conclude on a class effect.

GLP-1RA mimic the natural incretin hormones that promote postprandial blood sugar control, and have been shown to lower haemoglobin A1c, body weight, and blood pressure.11 SGLT-2i work in the S1 segment of the proximal tubule to promote sodium and glucose excretion and have also been shown to lower haemoglobin A1c levels, body weight, and blood pressure.12 However, the mechanisms responsible for lowering cardiovascular outcomes for the two drug classes are not completely clear.13

No head-to-head comparisons of GLP-1RA and SGLT-2i exist, and it is unclear whether using one drug over the other yields differences in cardiovascular outcomes. Therefore, we aimed to examine the risk of cardiovascular outcomes in association with first-time initiation of GLP-1RA vs. SGLT-2i treatment in a nationwide cohort of patients with type 2 diabetes during a time period where results from CVOTs were not yet available to guide clinical decision making.

Methods

Data sources and ethics

Denmark has a comprehensive tax-funded nationwide health care system. All Danish residents are at birth or immigration provided a unique and permanent identification number through the civil registration system. The identification number is used for all administrative contacts, including the health care system.14 Information from several nationwide registries was linked using the identification number. Age, sex, vital status, and immigration and emigration status were obtained from the Civil Registration System. The National Prescription Registry (Danish Registry of Medicinal Product Statistics) holds information on all drug dispensations from pharmacies in Denmark listed by the Anatomical Therapeutic Chemical (ATC) Classification System and was used to identify patients who initiated GLP-1RA and SGLT-2i as well as other baseline pharmacotherapy use. The Danish National Patient Registry15 has information on all discharge diagnoses from Danish hospitals according to the World Health Organization's International Classification of Diseases (ICD) and was used to define comorbidities and outcomes. Physicians register one primary and optionally secondary discharge diagnoses according to ICD-10 in relation to all hospital contacts in Denmark. The quality of most diagnoses registered in the Danish National Patient Registry has been validated.14 Date of and causes of death were obtained from the Danish Registry of Causes of Death. ICD and ATC codes for all diagnoses and pharmacotherapies are listed in Supplementary material online, Table S1.

Ethical approval is not a requirement for retrospective registry-based studies in Denmark. This study has been approved by the Danish Data Protection Agency (ref. no. 2007-58-0015 and internal reference: GEH-2014-018 I-Suite no. 02736).

Study population

In Denmark, GLP-1RA have been available since 2009, while SGLT-2i have been available since December 2012. Patients with type 2 diabetes who were new users of GLP-1RA or SGLT-2i between 1 January 2013 and 31 December 2015, with no prior treatment with either drug class before 2013, were included, and baseline was date of first prescription (index). Patients were excluded if their age at baseline was below 40 or above 100 years or if they initially claimed a prescription for both GLP-1RA and SGLT-2i on the same day, indicating dual therapy, which was not a recommended treatment strategy during the inclusion period.

Outcomes

The main outcome of interest was a composite three-point (3P)-MACE, including cardiovascular mortality, non-fatal myocardial infarction, and non-fatal stroke (defined as cerebral infarction or transient ischaemic attack). Furthermore, the individual components of the 3P-MACE and HHF (defined as an inpatient hospital stay with a registered primary diagnosis of heart failure) were evaluated. The positive predictive values of myocardial infarction, stroke, and heart failure have previously been evaluated to be approximately 97%, 80%, and 80%, respectively.16

Comorbidity and concomitant pharmacotherapy

Comorbidities were defined based on hospital admissions prior to baseline. Hypertension was defined by claiming at least two antihypertensive drugs from two different classes within 180 days prior to baseline or a diagnosis of hypertension.17 Pharmacotherapy use included records of prescriptions claimed up to 180 days before baseline, indicating recent or concomitant treatment.

Statistical analysis

The study period was 1 January 2013 to 31 December 2018 and patients were followed from index date until whichever came first: date of outcome of interest, emigration, death, or end of follow-up. Baseline characteristics are presented as frequencies with percentages or as medians with first and third interquartile ranges (IQR). We used a doubly robust estimator to estimate the average effect of treatment with GLP-1RA or SGLT-2i by combining a logistic regression model for the propensity of receiving GLP-1RA or SGLT-2i with cause-specific Cox regression models: one for the hazard rate of outcome and one for the hazard rate of death without outcome (competing risk).18 The outcome-specific Cox models were adjusted for age, sex, diabetes duration (time since first claim for a diabetes treatment), calendar year of inclusion, prior ischaemic heart disease, stroke, peripheral artery disease, heart failure, chronic kidney disease, hypertension, overweight and obesity, dyslipidaemia, and use of other baseline diabetes treatment (metformin, sulfonylureas, DPP-4 inhibitors, thiazolidinediones, and insulin). The logistic regression model for the propensity of treatment was adjusted for all variables listed in Table 1. The doubly robust estimator reduces the risk of bias of the model specification. Furthermore, the censoring distribution was modelled via a separate Cox regression model adjusted for the variables as the outcome-specific Cox model. Reported are the 3-year standardized absolute risks of the specified outcomes and differences thereof. The analyses were standardized to the patient characteristics of the full study population (GLP-1RA or SGLT-2i). The standardized difference in risk of the outcomes can, given the limitations of this study, be interpreted as what would have been observed had the patients been randomized to receive treatment with either GLP-1RA or SGLT-2i.

Table 1

Baseline characteristics

Values are n (%) or median (interquartile range).

Table 1

Baseline characteristics

Values are n (%) or median (interquartile range).

For descriptive purposes, adherence to the initiated drug class was investigated. All outcomes were examined in subgroups of patients with and without established cardiovascular disease and age above and below 70 years as well as in a subset of patients who initiated the most frequently prescribed GLP-1RA (liraglutide) and SGLT-2i (dapagliflozin) treatments during the inclusion period. As initiation of SGLT-2i has not been recommended in patients with a reduced estimated glomerular filtration rate, the analyses were repeated in a sensitivity analysis excluding patients with chronic kidney disease at baseline. Furthermore, HHF was investigated in a subset of patients with heart failure at baseline and the risk of incident heart failure was examined as a broad heart failure outcome (any hospital contact where heart failure was registered as a primary or secondary diagnosis) in patients without heart failure at baseline. Lastly, the 3-year standardized absolute risk of all-cause mortality was analysed for the two treatment groups. The level of significance was set at 5%. Statistical analyses were performed with SAS (version 9.4, SAS Institute, Cary, NC) and R version 3.6.1.19

Results

A total of 8913 new users of GLP-1RA and 5275 new users of SGLT-2i were identified between 1 January 2013 and 31 December 2015 (Figure 1). The median follow-up time was 4.3 years (IQR: 3.6–5.2). Completed 3 years of follow-up was available for all included patients, except 56 patients, who emigrated and were censored on the day of emigration. Baseline characteristics are shown in Table 1. The median age was 60.3 years in the GLP-1RA group and 62.7 years in the SGLT-2i group and there was a higher proportion of males in both groups. Patients initiating GLP-1RA were slightly younger and more patients in this group had a diagnosis of cardiovascular disease, chronic kidney disease, overweight/obesity, and hyperlipidaemia, and were treated with cardioprotective drugs and insulin compared with patients initiating SGLT-2i.

Figure 1

Selection of the study population. New users initiating GLP-1RA or SGLT-2i treatment in 2013–2015 identified from Danish registries. Exclusion criteria and number of patients excluded are listed. The percentage of drugs initiated within each class is summarized, with the majority initiating liraglutide in the GLP-1RA group and dapagliflozin in the SGLT-2i group.

At baseline, the majority of patients were treated with dapagliflozin in the SGLT-2i group (80.2% dapagliflozin, 16.1% empagliflozin, and 3.7% canagliflozin) and liraglutide in the GLP-1RA group (97.7% liraglutide, 1.4% exenatide, 0.7% lixisenatide, and 0.2% dulaglutide). The number of events and standardized absolute 3-year risks are shown in Table 2. When comparing the GLP-1RA (reference) group with the SGLT-2i group, no significant differences in the absolute standardized risk were found for the 3P-MACE composite outcome [−0.1; 95% confidence interval (CI): −1.0% to 0.8%]. Furthermore, no significant differences in secondary outcomes were detected, which included cardiovascular mortality (−0.1; 95% CI: −0.6% to 0.3%), HHF (0.1%; 95% CI: −0.6% to 0.8%), myocardial infarction (0.0%; 95% CI: −0.7% to 0.6%), and stroke (0.1%; 95% CI: −0.5% to 0.6%), as shown in Table 2. During the 3 years of follow-up, the standardized absolute risk of 3P-MACE (Figure 2) as well as secondary outcomes (Supplementary material online, Figure S1) did not differ for the two treatment groups. After 1.5 years, 74.4% in the GLP-1RA group and 63.3% in the SGLT-2i group still claimed a drug from these respective drug classes (Supplementary material online, Table S2). The unadjusted 3-year absolute risks of the secondary outcomes are shown in Supplementary material online, Figure S2.

Figure 2

Standardized absolute risk of 3P-MACE over 3 years of follow-up. Among patients with type 2 diabetes who were new users of GLP-1RA or SGLT-2i in 2013–2015, no significant differences in the standardized absolute risk of 3P-MACE were found over 3 years of follow-up.

Table 2

Standardized absolute 3-year risk of cardiovascular mortality, hospitalization for heart failure, myocardial infarction, and stroke

Table 2

Standardized absolute 3-year risk of cardiovascular mortality, hospitalization for heart failure, myocardial infarction, and stroke

Subgroup analyses

The risk of 3P-MACE was higher among patients with established cardiovascular disease (GLP-1RA: 11.1%; 95% CI: 9.9–12.2% vs. SGLT-2i: 10.0%; 95% CI: 8.3–11.6%; Supplementary material online, Table S3A) than in patients without cardiovascular disease (GLP-1RA: 3.2%; 95% CI: 2.7–3.7% vs. SGLT-2i: 3.6%; 95% CI: 2.8–4.3%; Supplementary material online, Table S3B), with no detected significant differences between the treatment groups. In patients ≥70 years (Supplementary material online, Table S4A), the risk of 3P-MACE was twice as high as in patients <70 years (Supplementary material online, Table S4B), with no significant differences found between groups for the evaluated outcomes. In the subset of patients initiating liraglutide (5.6%; 95% CI: 5.1–6.0%) vs. dapagliflozin (5.4%; 95% CI: 4.6–6.3%), the results were comparable to those of the full study population (Supplementary material online, Table S5).

Sensitivity analyses

Excluding patients with chronic kidney disease at baseline did not change the results of the outcome analyses (Supplementary material online, Table S6), although the risk estimates for the SGLT-2i group were lower than those in the primary analyses. In patients with established heart failure at baseline, the risk of HHF did not differ significantly for GLP-1RA (12.7%; 95% CI: 10.2–15.1%) vs. SGLT-2i (14.4%; 95% CI: 7.6–21.1%). Likewise, for incident heart failure (broad heart failure outcome) in patients without heart failure at baseline, the risk did not differ significantly for GLP-1RA (2.4%; 95% CI: 2.1–2.8%) vs. SGLT-2i (2.3%; 95% CI: 1.8–2.8%) (Supplementary material online, Table S7). In line with the investigated cardiovascular outcomes, no difference in all-cause mortality could be detected between the two treatment groups (Supplementary material online, Table S8).

Discussion

In this large Danish observational study, we examined the risk of cardiovascular outcomes in association with initiation of treatment with GLP-1RA vs. SGLT-2i in patients with type 2 diabetes. We found that the standardized 3-year absolute risk of 3P-MACE, cardiovascular mortality, HHF, myocardial infarction, and stroke did not differ significantly among patients who initiated treatment with GLP-1RA vs. SGLT-2i. Furthermore, no divergences in risk curves could be observed between the two groups. The results were consistent in subgroups of patients with and without cardiovascular disease, in different age groups, and across various sensitivity analyses.

Both GLP-1RA and SGLT-2i have been shown to reduce the risk of cardiovascular outcomes in CVOTs, but no trial has directly compared drugs from the two classes. Of note, in this study approximately 30% of patients had established cardiovascular disease at diagnosis, whereas the majority of CVOTs has studied patients with established or at high risk of cardiovascular events.2–5,8,9,20–22 Overall, the event rate for the investigated cardiovascular outcomes was low for both treatment groups, but was in the subgroup of patients with established CVD comparable to previous CVOTs including patients with established cardiovascular disease.2,7

The results for cardiovascular mortality, myocardial infarction, and stroke are consistent with network meta-analyses comparing GLP-1RA with SGLT-2i, which have shown no significant differences in risk associated with using one class over another.23,24

We did not find a significant difference in the standardized absolute 3-year risk of HHF with GLP-1RA vs. SGLT-2i. To that end, sensitivity analyses examining patients with and without prior heart failure at baseline did not yield differences for GLP-1RA vs. SGLT-2i. CVOTs have shown reductions in HHF with SGLT-2i vs. placebo7–9 and network meta-analyses have found that SGLT-2i were associated with a lower risk of HHF in comparison to GLP-1RA.23–25 Cohort differences may explain why we do not detect differences between GLP-1RA and SGLT-2i with regards to HHF, such as increased cardiovascular comorbidity and longer diabetes duration; i.e. patients included in the CVOTs were overall frailer than those in the current cohort. The LEADER trial did show non-significant benefits for HHF for liraglutide vs. placebo,2 although the clinical impact of this is uncertain. Furthermore, lack of power and residual confounding may have influenced the results. Our results on HHF are, however, consistent with a recent observational study comparing initiation of GLP-1RA with SGLT-2i in Italy, which neither found significant differences comparing patients who initiated GLP-1RA vs. SGLT-2i.26 In contrast with the present study, they found that initiation of SGLT-2i may be associated with a better 3P-MACE compared with GLP-1RA.26 Their results may be influenced by confounding by indication, as the inclusion period (2014–18) coincides with the majority of CVOTs results being known. Other differences were a shorter median follow-up time (13 months), fewer patients having cardiovascular disease, and the majority of patients initiating empagliflozin. Another observational study found a significantly lower risk of HHF associated with use of canagliflozin vs. GLP-1RA during a mean follow-up of 0.6 years using a US commercial healthcare database.27 In contrast to the current study, which only included 3.7% patients initiating canagliflozin, this study included a larger patient population (20 539 in each treatment group) and found a divergence in the Kaplan–Meier curves starting within 6 months of treatment initiation. This is consistent with CVOTs with SGLT-2i, which found almost immediate implications for reducing the risk of HHF,7–9 indicating that benefits of SGLT-2i can be attributed to abrupt effects, mediated by osmotic diuresis as well as other proposed mechanisms.28 Other observational studies have shown that SGLT-2i compared with ‘other glucose-lowering drugs’ were associated with a decreased risk of HHF, including the multinational CVD-REAL29 and CVD-REAL 2 studies.30 However, in the CVD-REAL study, the adjusted analysis for risk of HHF, including a sensitivity analysis excluding patients without GLP-1RA at baseline, did not show a significantly lower risk of HHF associated with SGLT-2i vs. other glucose-lowering drugs in the Danish cohort, which is consistent with the current study.

Results from CVOTs have led to updated guidelines for use of newer diabetes therapies, with US and European guidelines both stating that a GLP-1RA or SGLT-2i with proven cardiovascular benefits is recommended for all patients with established atherosclerotic cardiovascular disease,31–33 but with SGLT-2i being preferred in patients with existing heart failure or chronic kidney disease if estimated glomerular filtration rate is adequate.

Specific inclusion and exclusion criteria, thorough safety monitoring, as well as the placebo-controlled comparisons limit the generalizability of randomized controlled trial results to the general population. Therefore, comparisons of specific drugs, including findings from the current study, where almost all patients initiated liraglutide in the GLP-1RA group and the majority initiated dapagliflozin in the SGLT-2i group, yield additional insights regarding treatment of patients with type 2 diabetes. However, the results presented here can only be interpreted as hypothesis generating and do not substantially impact clinical practice or compromise trial results.

Study limitations

Major strengths of the current study are the nationwide scope allowing better generalizability to routine care, complete follow-up with every patient having at least 3 years of full follow-up, the accuracy of Danish registries to identify the study population (all drug prescriptions in Denmark are partially reimbursed and registered), and well-validated outcomes.14 The estimates of this study rely on the assumptions of causal inference methodology, including positivity (that any patient has a positive probability of receiving either treatment), consistency (a patient's potential outcome given the exposure history is the outcome that will actually be observed for that patient), and conditional exchangeability (no unmeasured confounders and no informative censoring based on the available patient characteristics), and our results can be interpreted within the limitations thereof.

In regard to the positivity assumption, clinical considerations for choosing one treatment over another cannot be elucidated as we only had access to information about claimed prescriptions from the registry. However, the inclusion period reflects a time period where GLP-1RA and SGLT-2i could be considered equal choices of second-line drugs for patient with type 2 diabetes, reducing the potential for confounding by indication. Our sensitivity analysis, which showed consistent results when patients with established chronic kidney disease were excluded, is supportive of this. We cannot rule out residual confounding from unmeasured clinical variables, e.g. creatinine, haemoglobin A1c, body mass index, and smoking status; however, we were able to utilize important information on comorbidities and medication use.

The doubly robust estimation offers protection against potential mismodeling, ensuring that as long as the propensity score model or the regression model has been specified correctly, the estimate is correct.

As this study largely was a comparison of liraglutide vs. dapagliflozin, the results may be different for other specific drugs from the GLP-1RA and SGLT-2i classes. Several baseline characteristics differed for the two treatment groups; however, the doubly robust estimation modelling attempted to account for these differences. This was an active comparator, new user design that seeks to reduce biases by imitating the design of a head-to-head randomized controlled trial.34 Although some patients as expected suspend treatment along the course of the follow-up period, the absolute risk curves showing cumulative risk for the two treatment groups did not deviate over time.

Studies elucidating the mechanism by which GLP-1RA and SGLT-2i lower cardiovascular risk would help to further elucidate subgroups of patients likely to benefit from these drugs. Furthermore, since combinations of GLP-1RA and SGLT-2i have proved safe,35,36 studies assessing cardiovascular benefits with the combination of these drug classes are warranted.

Conclusions

Within the limitations of our study, we were not able to identify a significant difference in the 3-year risk of 3P-MACE, cardiovascular mortality, HHF, myocardial infarction, and stroke in association with first-time initiation of treatment with GLP-1RA vs. SGTL-2i in a nationwide cohort of patients with type 2 diabetes.

Funding

Danish Heart Foundation (18-R125-A8381-22082).

Conflict of interest: All authors have completed the Unified Competing Interest form at http://www.icmje.org/disclosure-of-interest/ (available on request from the corresponding author). C.H.N., L.S., T.A.G., A.N.B., P.V., E.F., and C.J.-Y.L. declare no conflict of interest. L.K. reports personal fees from speaker honorarium from Novo Nordisk, Novartis, AstraZeneca, and Boehringer, outside the submitted work. N.D.W. reports grants from Novo Nordisk, Amgen, Novartis, and Boehringer Ingelheim, outside the submitted work. C.T.-P. reports grants from Bayer and Novo Nordisk, outside the submitted work.

Data availability

The information presented in this paper combines several Danish administrative registries. The data use is subject to the European Union's General Data Protection Regulation (GDPR) per Danish regulations (May 2018). The data are stored on computers at Statistics Denmark and may not be transferred to computers outside Statistics Denmark due to security considerations. Researchers interested in obtaining access to the registry data employed in this paper must submit a written application to gain approval from Statistics Denmark. The application must include a detailed description of the proposed project, its purpose, and social contribution, along with a description of the required datasets, variables, and target population. Applications can be submitted by researchers affiliated with Danish institutions accepted by Statistics Denmark and by researchers outside of Denmark who collaborate with researchers affiliated with these institutions.

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© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Topic:

• myocardial infarction
• cerebrovascular accident
• ischemic stroke
• heart failure
• diabetes mellitus, type 2
• cardiovascular system
• comorbidity
• cardiovascular death
• sodium-glucose transport proteins
• glucagon-like peptide-1 agonists

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