Effect of SGLT2 Inhibitors on Stroke and Atrial Fibrillation in Diabetic Kidney Disease: Results From the CREDENCE Trial and Meta-Analysis
Zien Zhou, Meg J Jardine, Qiang Li, Brendon L Neuen, Christopher P Cannon, Dick de Zeeuw, Robert Edwards, Adeera Levin, Kenneth W Mahaffey, Vlado Perkovic, Bruce Neal, Richard I Lindley, CREDENCE Trial Investigators*
Abstract
Background and purpose: Chronic kidney disease with reduced estimated glomerular filtration rate or elevated albuminuria increases risk for ischemic and hemorrhagic stroke. This study assessed the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on stroke and atrial fibrillation/flutter (AF/AFL) from CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) and a meta-analysis of large cardiovascular outcome trials (CVOTs) of SGLT2i in type 2 diabetes mellitus.
Methods: CREDENCE randomized 4401 participants with type 2 diabetes mellitus and chronic kidney disease to canagliflozin or placebo. Post hoc, we estimated effects on fatal or nonfatal stroke, stroke subtypes, and intermediate markers of stroke risk including AF/AFL. Stroke and AF/AFL data from 3 other completed large CVOTs and CREDENCE were pooled using random-effects meta-analysis.
Results: In CREDENCE, 142 participants experienced a stroke during follow-up (10.9/1000 patient-years with canagliflozin, 14.2/1000 patient-years with placebo; hazard ratio [HR], 0.77 [95% CI, 0.55-1.08]). Effects by stroke subtypes were: ischemic (HR, 0.88 [95% CI, 0.61-1.28]; n=111), hemorrhagic (HR, 0.50 [95% CI, 0.19-1.32]; n=18), and undetermined (HR, 0.54 [95% CI, 0.20-1.46]; n=17). There was no clear effect on AF/AFL (HR, 0.76 [95% CI, 0.53-1.10]; n=115). The overall effects in the 4 CVOTs combined were: total stroke (HRpooled, 0.96 [95% CI, 0.82-1.12]), ischemic stroke (HRpooled, 1.01 [95% CI, 0.89-1.14]), hemorrhagic stroke (HRpooled, 0.50 [95% CI, 0.30-0.83]), undetermined stroke (HRpooled, 0.86 [95% CI, 0.49-1.51]), and AF/AFL (HRpooled, 0.81 [95% CI, 0.71-0.93]). There was evidence that SGLT2i effects on total stroke varied by baseline estimated glomerular filtration rate (P=0.01), with protection in the lowest estimated glomerular filtration rate (<45 mL/min/1.73 m2]) subgroup (HRpooled, 0.50 [95% CI, 0.31-0.79]).
Conclusions: Although we found no clear effect of SGLT2i on total stroke in CREDENCE or across trials combined, there was some evidence of benefit in preventing hemorrhagic stroke and AF/AFL, as well as total stroke for those with lowest estimated glomerular filtration rate. Future research should focus on confirming these data and exploring potential mechanisms. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02065791.
Keywords: atrial fibrillation; canagliflozin; glomerular filtration rate; hemorrhagic stroke; ischemic stroke.
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References
- Toyoda K, Ninomiya T. Stroke and cerebrovascular diseases in patients with chronic kidney disease. Lancet Neurol. 2014;13:823–833. doi: 10.1016/S1474-4422(14)70026-2
- Mahmoodi BK, Yatsuya H, Matsushita K, Sang Y, Gottesman RF, Astor BC, Woodward M, Longstreth WT, Jr, Psaty BM, Shlipak MG, et al. . Association of kidney disease measures with ischemic versus hemorrhagic strokes: pooled analyses of 4 prospective community-based cohorts. Stroke. 2014;45:1925–1931. doi: 10.1161/STROKEAHA.114.004900
- Ghoshal S, Freedman BI. Mechanisms of stroke in patients with chronic kidney disease. Am J Nephrol. 2019;50:229–239. doi: 10.1159/000502446
- Chelluboina B, Vemuganti R. Chronic kidney disease in the pathogenesis of acute ischemic stroke. J Cereb Blood Flow Metab. 2019;39:1893–1905. doi: 10.1177/0271678X19866733
- Bilha SC, Burlacu A, Siriopol D, Voroneanu L, Covic A. Primary prevention of stroke in chronic kidney disease patients: a scientific update. Cerebrovasc Dis. 2018;45:33–41. doi: 10.1159/000486016
- Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, et al. ; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–2128. doi: 10.1056/NEJMoa1504720
- Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR; CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644–657. doi: 10.1056/NEJMoa1611925
- Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Silverman MG, Zelniker TA, Kuder JF, Murphy SA, et al. ; DECLARE–TIMI 58 Investigators. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380:347–357. doi: 10.1056/NEJMoa1812389
- Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, Edwards R, Agarwal R, Bakris G, Bull S, et al. ; CREDENCE Trial Investigators. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380:2295–2306. doi: 10.1056/NEJMoa1811744
- Arnott C, Li Q, Kang A, Neuen BL, Bompoint S, Lam CSP, Rodgers A, Mahaffey KW, Cannon CP, Perkovic V, et al. . Sodium-glucose cotransporter 2 inhibition for the prevention of cardiovascular events in patients with type 2 diabetes mellitus: a systematic review and meta-analysis. J Am Heart Assoc. 2020;9:e014908. doi: 10.1161/JAHA.119.014908
- Neuen BL, Young T, Heerspink HJL, Neal B, Perkovic V, Billot L, Mahaffey KW, Charytan DM, Wheeler DC, Arnott C, et al. . SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2019;7:845–854. doi: 10.1016/S2213-8587(19)30256-6
- Zhou Z, Lindley RI, Rådholm K, Jenkins B, Watson J, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Shaw W, et al. . Canagliflozin and stroke in type 2 diabetes mellitus. Stroke. 2019;50:396–404. doi: 10.1161/STROKEAHA.118.023009
- Neuen BL, Ohkuma T, Neal B, Matthews DR, de Zeeuw D, Mahaffey KW, Fulcher G, Desai M, Li Q, Deng H, et al. . Cardiovascular and renal outcomes with canagliflozin according to baseline kidney function. Circulation. 2018;138:1537–1550. doi: 10.1161/CIRCULATIONAHA.118.035901
- Zinman B, Inzucchi SE, Lachin JM, Wanner C, Fitchett D, Kohler S, Mattheus M, Woerle HJ, Broedl UC, Johansen OE, et al. ; EMPA-REG OUTCOME Investigators. Empagliflozin and cerebrovascular events in patients with type 2 diabetes mellitus at high cardiovascular risk. Stroke. 2017;48:1218–1225. doi: 10.1161/STROKEAHA.116.015756
- Wanner C, Lachin JM, Inzucchi SE, Fitchett D, Mattheus M, George J, Woerle HJ, Broedl UC, von Eynatten M, Zinman B; EMPA-REG OUTCOME Investigators. Empagliflozin and clinical outcomes in patients with type 2 diabetes mellitus, established cardiovascular disease, and chronic kidney disease. Circulation. 2018;137:119–129. doi: 10.1161/CIRCULATIONAHA.117.028268
- Jardine MJ, Mahaffey KW, Neal B, Agarwal R, Bakris GL, Brenner BM, Bull S, Cannon CP, Charytan DM, de Zeeuw D, et al. ; CREDENCE Study Investigators. The Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation (CREDENCE) study rationale, design, and baseline characteristics. Am J Nephrol. 2017;46:462–472. doi: 10.1159/000484633
- Sacco RL, Kasner SE, Broderick JP, Caplan LR, Connors JJ, Culebras A, Elkind MS, George MG, Hamdan AD, Higashida RT, et al. ; American Heart Association Stroke Council, Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular and Stroke Nursing; Council on Epidemiology and Prevention; Council on Peripheral Vascular Disease; Council on Nutrition, Physical Activity and Metabolism. An updated definition of stroke for the 21st century: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;44:2064–2089. doi: 10.1161/STR.0b013e318296aeca
- Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Open Med. 2009;3:e123–e130. doi: 10.1371/journal.pmed.1000097
- DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–188. doi: 10.1016/0197-2456(86)90046-2
- McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Bělohlávek J, et al. ; DAPA-HF Trial Committees and Investigators. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381:1995–2008. doi: 10.1056/NEJMoa1911303
- Lee M, Saver JL, Chang KH, Liao HW, Chang SC, Ovbiagele B. Low glomerular filtration rate and risk of stroke: meta-analysis. BMJ. 2010;341:c4249. doi: 10.1136/bmj.c4249
- Kumar S, Lim E, Covic A, Verhamme P, Gale CP, Camm AJ, Goldsmith D. Anticoagulation in concomitant chronic kidney disease and atrial fibrillation: JACC review topic of the week. J Am Coll Cardiol. 2019;74:2204–2215. doi: 10.1016/j.jacc.2019.08.1031
- Ha JT, Neuen BL, Cheng LP, Jun M, Toyama T, Gallagher MP, Jardine MJ, Sood MM, Garg AX, Palmer SC, et al. . Benefits and harms of oral anticoagulant therapy in chronic kidney disease: a systematic review and meta-analysis. Ann Intern Med. 2019;171:181–189. doi: 10.7326/M19-0087
- Joubert M, Jagu B, Montaigne D, Marechal X, Tesse A, Ayer A, Dollet L, Le May C, Toumaniantz G, Manrique A, et al. . The sodium-glucose cotransporter 2 inhibitor dapagliflozin prevents cardiomyopathy in a diabetic lipodystrophic mouse model. Diabetes. 2017;66:1030–1040. doi: 10.2337/db16-0733
- Lee HC, Shiou YL, Jhuo SJ, Chang CY, Liu PL, Jhuang WJ, Dai ZK, Chen WY, Chen YF, Lee AS. The sodium-glucose co-transporter 2 inhibitor empagliflozin attenuates cardiac fibrosis and improves ventricular hemodynamics in hypertensive heart failure rats. Cardiovasc Diabetol. 2019;18:45. doi: 10.1186/s12933-019-0849-6
- Zelniker TA, Bonaca MP, Furtado RHM, Mosenzon O, Kuder JF, Murphy SA, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, et al. . Effect of dapagliflozin on atrial fibrillation in patients with type 2 diabetes mellitus: insights from the DECLARE-TIMI 58 trial. Circulation. 2020;141:1227–1234. doi: 10.1161/CIRCULATIONAHA.119.044183
- PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack. Lancet. 2001;358:1033–1041. doi: 10.1016/S0140-6736(01)06178-5
- Rist PM, Buring JE, Ridker PM, Kase CS, Kurth T, Rexrode KM. Lipid levels and the risk of hemorrhagic stroke among women. Neurology. 2019;92:e2286–e2294. doi: 10.1212/WNL.0000000000007454
- Jardine MJ, Zhou Z, Mahaffey KW, Oshima M, Agarwal R, Bakris G, Bajaj HS, Bull S, Cannon CP, Charytan DM, et al. ; CREDENCE Study Investigators. Renal, cardiovascular, and safety outcomes of canagliflozin by baseline kidney function: a secondary analysis of the CREDENCE randomized trial. J Am Soc Nephrol. 2020;31:1128–1139. doi: 10.1681/ASN.2019111168
- Imprialos KP, Boutari C, Stavropoulos K, Doumas M, Karagiannis AI. Stroke paradox with SGLT-2 inhibitors: a play of chance or a viscosity-mediated reality? J Neurol Neurosurg Psychiatry. 2017;88:249–253. doi: 10.1136/jnnp-2016-314704
- Konstantinidis I, Nadkarni GN, Yacoub R, Saha A, Simoes P, Parikh CR, Coca SG. Representation of patients with kidney disease in trials of cardiovascular interventions: an updated systematic review. JAMA Intern Med. 2016;176:121–124. doi: 10.1001/jamainternmed.2015.6102
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