Risks of stroke, its subtypes and atrial fibrillation associated with glucagon-like peptide 1 receptor agonists versus sodium-glucose cotransporter 2 inhibitors: a real-world population-based cohort study in Hong Kong

David Tak Wai Lui1, Eric Ho Man Tang2, Tingting Wu2, Ivan Chi Ho Au3, Chi Ho Lee1, Yu Cho Woo1, Kathryn Choon Beng Tan1, Carlos King Ho Wong4,3,2
1Division of Endocrinology and Metabolism, Department of Medicine, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
2Department of Family Medicine and Primary Care, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
3Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
4Laboratory of Data Discovery for Health Limited (D24H), Hong Kong Science Park, New Territories, Hong Kong SAR, China

Tóm tắt

There are limited data on head-to-head comparative risk of stroke between sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA). We compared risk of stroke with its subtypes and incident atrial fibrillation (AF) between them. A population-based, retrospective cohort of patients with type 2 diabetes between 2008 and 2020 were identified from the electronic health records of Hong Kong Hospital Authority. Patients who received SGLT2i or GLP-1RA were matched pairwise by propensity score. Risks of stroke and AF were evaluated by hazard ratios (HRs) from the Cox proportional hazard regression models. A total of 5840 patients (2920 SGLT2i users; 2920 GLP-1RA users) were included (mean age 55.5 years, 56.1% men, mean HbA1c 8.9% and duration of diabetes 13.7 years). Upon median follow-up of 17 months, there were 111 (1.9%) events of stroke (SGLT2i: 62, 2.1%; GLP-1RA: 49 1.7%). SGLT2i users had comparable risk of all stroke as GLP-1RA users (HR 1.46, 95% CI 0.99–2.17, p = 0.058). SGLT2i users had higher risk of ischemic stroke (HR 1.53, 95% CI 1.01–2.33, p = 0.044) but similar risk of hemorrhagic stroke compared to GLP-1RA users. Although SGLT2i was associated with lower risk of incident AF (HR 0.43, 95% CI 0.23–0.79, p = 0.006), risk of cardioembolic stroke was similar. Our real-world study demonstrated that GLP-1RA use was associated with lower risk of ischemic stroke, despite the association between SGLT2i use and lower risk of incident AF. There was no significant difference in hemorrhagic stroke risk. GLP-1RA may be the preferred agent for patients with type 2 diabetes at risk of ischemic stroke.

Từ khóa


Tài liệu tham khảo

Brown E, Heerspink HJL, Cuthbertson DJ, Wilding JPH. SGLT2 inhibitors and GLP-1 receptor agonists: established and emerging indications. Lancet. 2021;398(10296):262–76. American Diabetes Association Professional Practice Committee, Draznin B, Aroda VR, Bakris G, Benson G, Brown FM, et al. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes—2022. Diabetes Care. 2022;45(1):S125–43. Giugliano D, Longo M, Signoriello S, Maiorino MI, Solerte B, Chiodini P, et al. The effect of DPP-4 inhibitors, GLP-1 receptor agonists and SGLT-2 inhibitors on cardiorenal outcomes: a network meta-analysis of 23 CVOTs. Cardiovasc Diabetol. 2022;21(1):42. Zhou Z, Jardine MJ, Li Q, Neuen BL, Cannon CP, de Zeeuw D, et al. Effect of SGLT2 inhibitors on stroke and atrial fibrillation in diabetic kidney disease: results from the CREDENCE trial and meta-analysis. Stroke. 2021;52(5):1545–56. Tsai WH, Chuang SM, Liu SC, Lee CC, Chien MN, Leung CH, et al. Effects of SGLT2 inhibitors on stroke and its subtypes in patients with type 2 diabetes: a systematic review and meta-analysis. Sci Rep. 2021;11(1):15364. Gerstein HC, Hart R, Colhoun HM, Diaz R, Lakshmanan M, Botros FT, et al. The effect of dulaglutide on stroke: an exploratory analysis of the REWIND trial. Lancet Diabetes Endocrinol. 2020;8(2):106–14. Zheng RJ, Wang Y, Tang JN, Duan JY, Yuan MY, Zhang JY. Association of SGLT2 inhibitors with risk of atrial fibrillation and stroke in patients with and without type 2 diabetes: a systemic review and meta-analysis of randomized controlled trials. J Cardiovasc Pharmacol. 2022;79(2):e145–52. Scheen AJ. Antidiabetic agents and risk of atrial fibrillation/flutter: a comparative critical analysis with a focus on differences between SGLT2 inhibitors and GLP-1 receptor agonists. Diabetes Metab. 2022;48(6): 101390. Lui DTW, Lee CH, Chow WS, Fong CHY, Woo YC, Lam KSL, et al. A territory-wide study on the impact of COVID-19 on diabetes-related acute care. J Diabetes Investig. 2020;11(5):1303–6. Lui DTW, Au ICH, Tang EHM, Cheung CL, Lee CH, Woo YC, et al. Kidney outcomes associated with sodium-glucose cotransporter 2 inhibitors versus glucagon-like peptide 1 receptor agonists: a real-world population-based analysis. EClinicalMedicine. 2022;50: 101510. Wong CKH, Lau KTK, Tang EHM, Lee CH, Lee CYY, Woo YC, et al. Cardiovascular benefits of SGLT2 inhibitors in type 2 diabetes, interaction with metformin and role of erythrocytosis: a self-controlled case series study. Cardiovasc Diabetol. 2022;21(1):92. https://doi.org/10.1186/s12933-022-01520-w. Tang EHM, Mak IL, Tse ETY, Wan EYF, Yu EYT, Chen JY, et al. Ten-year effectiveness of the multidisciplinary risk assessment and management programme-diabetes mellitus (RAMP-DM) on macrovascular and microvascular complications and all-cause mortality: a population-based cohort study. Diabetes Care. 2022;45(12):2871–82. Guan W, Ko D, Khurshid S, Trisini Lipsanopoulos AT, Ashburner JM, Harrington LX, et al. Automated electronic phenotyping of cardioembolic stroke. Stroke. 2021;52(1):181–9. Raghunathan TW, Lepkowksi JM, Van Hoewyk J, Solenbeger P. A multivariate technique for multiply imputing missing values using a sequence of regression models. Surv Methodol. 2001;27:85–95. van Buuren S. Multiple imputation of discrete and continuous data by fully conditional specification. Stat Methods Med Res. 2007;16(3):219–42. Rubin DB. Multiple imputation for nonresponse in surveys. New York: Wiley; 2004. Austin PC. Balance diagnostics for comparing the distribution of baseline covariates between treatment groups in propensity-score matched samples. Stat Med. 2009;28(25):3083–107. Caruso I, Cignarelli A, Sorice GP, Natalicchio A, Perrini S, Laviola L, et al. Cardiovascular and renal effectiveness of GLP-1 receptor agonists vs other glucose-lowering drugs in type 2 diabetes: a systematic review and meta-analysis of real-world studies. Metabolites. 2022;12(2):183. https://doi.org/10.3390/metabo12020183. Patorno E, Htoo PT, Glynn RJ, Schneeweiss S, Wexler DJ, Pawar A, et al. Sodium–glucose cotransporter-2 inhibitors versus glucagon-like peptide-1 receptor agonists and the risk for cardiovascular outcomes in routine care patients with diabetes across categories of cardiovascular disease. Ann Intern Med. 2021;174(11):1528–41. Patorno E, Pawar A, Bessette LG, Kim DH, Dave C, Glynn RJ, et al. Comparative effectiveness and safety of sodium-glucose cotransporter 2 inhibitors versus glucagon-like peptide 1 receptor agonists in older adults. Diabetes Care. 2021;44(3):826–35. Pineda ED, Liao IC, Godley PJ, Michel JB, Rascati KL. Cardiovascular outcomes among patients with type 2 diabetes newly initiated on sodium–glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists, and other antidiabetic medications. J Manag Care Spec Pharm. 2020;26(5):610–8. DeRemer CE, Vouri SM, Guo J, Donahoo WT, Winterstein AG, Shao H. Comparing cardiovascular benefits between GLP-1 receptor agonists and SGLT2 inhibitors as an add-on to metformin among patients with type 2 diabetes: a retrospective cohort study. J Diabetes Complicat. 2021;35(9): 107972. Norgaard CH, Starkopf L, Gerds TA, Vestergaard P, Bonde AN, Fosbol E, et al. Cardiovascular outcomes with GLP-1 receptor agonists vs. SGLT-2 inhibitors in patients with type 2 diabetes. Eur Heart J Cardiovasc Pharmacother. 2022;8(6):549–56. Longato E, Di Camillo B, Sparacino G, Gubian L, Avogaro A, Fadini GP. Cardiovascular outcomes of type 2 diabetic patients treated with SGLT-2 inhibitors versus GLP-1 receptor agonists in real-life. BMJ Open Diabetes Res Care. 2020;8:e001451. https://doi.org/10.1136/bmjdrc-2020-001451. Lugner M, Sattar N, Miftaraj M, Ekelund J, Franzen S, Svensson AM, et al. Cardiorenal and other diabetes related outcomes with SGLT-2 inhibitors compared to GLP-1 receptor agonists in type 2 diabetes: nationwide observational study. Cardiovasc Diabetol. 2021;20(1):67. Fu EL, Clase CM, Janse RJ, Lindholm B, Dekker FW, Jardine MJ, et al. Comparative effectiveness of SGLT2i versus GLP1-RA on cardiovascular outcomes in routine clinical practice. Int J Cardiol. 2022;352:172–9. Ueda P, Wintzell V, Dahlqwist E, Eliasson B, Svensson AM, Franzen S, et al. The comparative cardiovascular and renal effectiveness of sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide-1 receptor agonists: a Scandinavian cohort study. Diabetes Obes Metab. 2022;24(3):473–85. Xie X, Atkins E, Lv J, Bennett A, Neal B, Ninomiya T, et al. Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: updated systematic review and meta-analysis. Lancet. 2016;387(10017):435–43. Zhang L, Zhang W, Tian X. The pleiotropic of GLP-1/GLP-1R axis in central nervous system diseases. Int J Neurosci. 2021. https://doi.org/10.1080/00207454.2021.1924707. Strain WD, Frenkel O, James MA, Leiter LA, Rasmussen S, Rothwell PM, et al. Effects of semaglutide on stroke subtypes in type 2 diabetes: post hoc analysis of the randomized SUSTAIN 6 and PIONEER 6. Stroke. 2022;53(9):2749–57. Zhuo M, D’Andrea E, Paik JM, Wexler DJ, Everett BM, Glynn RJ, et al. Association of sodium–glucose cotransporter-2 inhibitors with incident atrial fibrillation in older adults with type 2 diabetes. JAMA Netw Open. 2022;5(10): e2235995. Pistoia F, Sacco S, Tiseo C, Degan D, Ornello R, Carolei A. The epidemiology of atrial fibrillation and stroke. Cardiol Clin. 2016;34(2):255–68. Li HL, Lip GYH, Feng Q, Fei Y, Tse YK, Wu MZ, et al. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and cardiac arrhythmias: a systematic review and meta-analysis. Cardiovasc Diabetol. 2021;20(1):100.