Comparative risk evaluation for cardiovascular events associated with dapagliflozin vs. empagliflozin in real-world type 2 diabetes patients: a multi-institutional cohort study

(2019) 18:120 Shao et al. Cardiovasc Diabetol https://doi.org/10.1186/s12933-019-0919-9 ORIGINAL INVESTIGATION Cardiovascular Diabetology Open Access Comparative risk evaluation for cardiovascular events associated with dapagliflozin vs. empagliflozin in real‑world type 2 diabetes patients: a multi‑institutional cohort study Shih‑Chieh Shao1,2, Kai‑Cheng Chang3, Ming‑Jui Hung4,5, Ning‑I Yang4,5, Yuk‑Ying Chan6, Hui‑Yu Chen3, Yea‑Huei Kao Yang2 and Edward Chia‑Cheng Lai2* Abstract Background: To compare the cardiovascular event risk in type 2 diabetes patients newly receiving dapagliflozin vs. empagliflozin. Methods: We conducted a retrospective cohort study by analyzing a multi-institutional electronic medical records database (Chang Gung Research Database) in Taiwan and included adult type 2 diabetes patients who were newly receiving sodium–glucose co-transporter 2 (SGLT2) inhibitors from 2016 to 2017. The primary outcome was a com‑ posite of cardiovascular death, myocardial infarction, ischemic stroke and heart failure. We followed up patients from initiation of SGLT2 inhibitors until the occurrence of cardiovascular events before December 31, 2018. We performed multivariable Cox proportional hazard modeling, adjusting for patients’ age, sex, laboratory data, co-morbidities, and concomitant medications. Results: We identified 12,681 new SGLT2 inhibitor users with a mean age of 58.9 (SD 11.8) years, of whom 43.9% were female and 45.8% were new dapagliflozin users. A total of 10,442 person-years of dapagliflozin use and 12,096 person-years of empagliflozin use were included. Compared to empagliflozin users, new users of dapagliflozin were found to have similar risks for primary composite outcome (adjusted HR: 0.91; 95% CI 0.73–1.14), cardiovascular death (adjusted HR: 0.54; 95% CI 0.14–2.12), myocardial infarction (adjusted HR: 0.77, 95% CI 0.49–1.19) and ischemic stroke (adjusted HR: 1.15; 95% CI 0.80–1.65), but a lower risk of heart failure (adjusted HR: 0.68; 95% CI 0.49–0.95). Conclusion: The risk of cardiovascular events was similar between dapagliflozin and empagliflozin new users, but dapagliflozin may have a better outcome in the reduction of heart failure in type 2 diabetes patients. Future prospec‑ tive studies are required to confirm the findings. Keywords: Sodium–glucose co-transporter 2 inhibitors, Cardiovascular disease, Heart failure, Real-world data *Correspondence: 2 School of Pharmacy, Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan 701, Taiwan Full list of author information is available at the end of the article © The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Shao et al. Cardiovasc Diabetol (2019) 18:120 Background Patients with type 2 diabetes suffer substantial morbidity and mortality from cardiovascular disease [1]. Current medication and lifestyle interventions may not be sufficient to reduce the risk of serious cardiovascular disease outcomes in the primary prevention cohorts of type 2 diabetes [2]. Although the largest absolute benefits of interventions for individual patients are achieved among those with established atherosclerotic cardiovascular disease, the large number of type 2 diabetes patients without a history of major cardiovascular disease makes knowledge about the effects of anti-diabetes medication on first events an additional priority [2]. Sodium–glucose co-transporter 2 (SGLT2) inhibitor which decreases glucose re-absorption in the kidney and increases excretion via the urine is the new drug class for type 2 diabetes management with favorable safety profiles [3, 4], and is recommended as an option for treatment intensification after the failure of metformin [5]. A meta-analysis of three large placebo-controlled cardiovascular outcome trials found that SGLT2 inhibitors reduced major adverse cardiovascular events by 11% (HR: 0.89, 95% CI 0.83–0.96). In addition, compared to incretin-based therapies, including glucagon-like-peptide 1 (GLP-1) agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors, SGLT2 inhibitors are associated with lower risks of all-cause and cardiovascular-specific mortality, and occurrence of heart failure and myocardial infarction [6]. Although the direct cardioprotective mechanisms are not fully understood, they may be related to hemodynamic and metabolic actions from SGLT2 inhibitors [7–9]. SGLT2 inhibitors, in addition to glycemic controls, also have a positive effect on the cardiometabolic markers, such as body weight, blood pressure and uric acid [10, 11], and as a result there has been increasing use of SGLT2 inhibitors for the management of type 2 diabetes in clinical practice [12]. However, not all SGLT2 inhibitors share the same pharmacokinetic properties; for example, dapagliflozin with its slower excretion by the kidney exerts its pharmacological effects longer, even after 18 h post-dose, whereas the effects of empagliflozin are markedly attenuated from 12 h post-dose [13]. Due to more stable and longer sodium excretion and osmotic diuresis effects when compared to empagliflozin, dapagliflozin has been reported to reduce the 24-h variability in systolic blood pressures and may be associated with a lower risk for cardiovascular diseases [14–17]. Current evidence has shown the beneficial effects of SGLT2 inhibitors on cardiovascular events, but the effects may differ between the individual SGLT2 inhibitors. Therefore, the purpose of this study was to determine the comparative cardiovascular event risk Page 2 of 15 associated with dapagliflozin vs. empagliflozin in realworld type 2 diabetes patients. Methods Data source This retrospective cohort study analyzed data from Chang Gung Research Database (CGRD), the largest multi-institutional electronic medical records database in Taiwan [18]. The CGRD was established for research purposes in 2016, and currently covers 1.3 million patients (6% of the population of Taiwan). The CGRD includes clinical data for all patients who had outpatient treatment or were hospitalized in one of the 7 Chang Gung Memorial Hospitals from northern to southern Taiwan. The CGRD identifies diseases based on the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) before 2016, and ICD-10-CM afterwards. Unlike administrative data, the CGRD contains laboratory data which can provide a valid esti (...truncated)