Sodium-Glucose Cotransporter 2 Inhibition for the Prevention of Cardiovascular Events in Patients With Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis

Clare Arnott, Qiang Li, Amy Kang, Brendon L Neuen, Severine Bompoint, Carolyn S P Lam, Anthony Rodgers, Kenneth W Mahaffey, Christopher P Cannon, Vlado Perkovic, Meg J Jardine, Bruce Neal, Clare Arnott, Qiang Li, Amy Kang, Brendon L Neuen, Severine Bompoint, Carolyn S P Lam, Anthony Rodgers, Kenneth W Mahaffey, Christopher P Cannon, Vlado Perkovic, Meg J Jardine, Bruce Neal

Abstract

Background Several trials have demonstrated protective effects from inhibition of sodium-glucose cotransporter 2 among patients with type 2 diabetes mellitus. There is uncertainty about the consistency of the cardiovascular benefits achieved across patient subsets. Methods and Results We included 4 large-scale trials of sodium-glucose cotransporter 2 inhibition compared with placebo in patients with diabetes mellitus that reported effects on cardiovascular outcomes overall and for participant subgroups defined at baseline by cardiovascular disease, reduced kidney function, and heart failure. Fixed effects models with inverse variance weighting were used to estimate summary hazard ratios and 95% CIs. There were 38 723 patients from 4 trials, with a mean 2.9 years of follow-up. Of the patients, 22 870 (59%) had cardiovascular disease, 7754 (20%) had reduced kidney function, and 4543 (12%) had heart failure. There were 3828 major adverse cardiac events. There was overall benefit for major adverse cardiac events (0.88; 95% CI, 0.82-0.94; P<0.001) and no evidence that the effects of sodium-glucose cotransporter 2 inhibition varied across patient subgroups, defined by the presence of cardiovascular disease or heart failure at baseline (all P interaction >0.252; I2<25%). All patient subgroups benefited with respect to hospitalization for heart failure (all P interaction>0.302; I2<10%), cardiovascular death (all P interaction>0.167; I2<50%), and death from any cause (all P interaction>0.354; I2=0%). The only difference in effects across subgroups was for stroke, with protection observed among those with reduced kidney function but not those with preserved kidney function (P interaction=0.020; I2=81%). Conclusions Sodium-glucose cotransporter 2 inhibitors protect against cardiovascular disease and death in diverse subsets of patients with type 2 diabetes mellitus regardless of cardiovascular disease history.

Keywords: cardiovascular disease; meta‐analysis; sodium‐glucose cotransporter 2 inhibition; type 2 diabetes mellitus.

Figures

Figure 1
Figure 1
Effects of sodium‐glucose cotransporter 2 inhibition on death and cause‐specific cardiovascular (CV) events for patients with (secondary prevention) and without (primary prevention) CV disease at baseline. HF indicates heart failure; MACE, major adverse cardiac event.
Figure 2
Figure 2
Effects of sodium‐glucose cotransporter 2 inhibition on death and cause‐specific cardiovascular (CV) events for patients with (estimated glomerular filtration rate [eGFR] 2) and without (eGFR >60 mL/min per 1.73 m2) reduced kidney function at baseline. HF indicates heart failure; MACE, major adverse cardiac event. *Indicates subgroup event numbers not available for Empagliflozin Cardiovascular Outcome Event Trial in Type 2 diabetes Mellitus Patients (EMPA‐REG Outcome).
Figure 3
Figure 3
Effects of sodium‐glucose cotransporter 2 inhibition on death and cause‐specific cardiovascular (CV) events for patients with and without a history of heart failure (HF) at baseline. MACE indicates major adverse cardiac event. *Indicates subgroup event numbers not available for Empagliflozin Cardiovascular Outcome Event Trial in Type 2 diabetes Mellitus Patients (EMPA‐REG Outcome).
Figure 4
Figure 4
Effects of sodium‐glucose cotransporter 2 inhibition on serious adverse events. Relative risks are shown for Empagliflozin Cardiovascular Outcome Event Trial in Type 2 diabetes Mellitus Patient (EMPA‐REG Outcome) total serious adverse events and hypoglycemia, and hazard ratios are shown for other included studies and outcomes. CANVAS and CANVAS‐RENAl indicates Canagliflozin Cardiovascular Assessment Program; CREDENCE, The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation; DECLARE‐TIMI 58.

References

    1. Lahnwong S, Chattipakorn SC, Chattipakorn N. Potential mechanisms responsible for cardioprotective effects of sodium‐glucose co‐transporter 2 inhibitors. Cardiovasc Diabetol. 2018;17:101.
    1. Zheng Y, Ley SH, Hu FB. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol. 2018;14:88–98.
    1. Leon BM, Maddox TM. Diabetes and cardiovascular disease: epidemiology, biological mechanisms, treatment recommendations and future research. World J Diabetes. 2015;6:1246–1258.
    1. Vasilakou D, Karagiannis T, Athanasiadou E, Mainou M, Liakos A, Bekiari E, Sarigianni M, Matthews DR, Tsapas A. Sodium‐glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta‐analysis. Ann Intern Med. 2013;159:262–274.
    1. Abdul‐Ghani M, Del Prato S, Chilton R, DeFronzo RA. SGLT2 inhibitors and cardiovascular risk: lessons learned from the EMPA‐REG OUTCOME study. Diabetes Care. 2016;39:717–725.
    1. Mahaffey KW, Neal B, Perkovic V, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Fabbrini E, Sun T, Li Q, Desai M, Matthews DR; CANVAS Program Collaborative Group . Canagliflozin for primary and secondary prevention of cardiovascular events: results from the CANVAS Program (Canagliflozin Cardiovascular Assessment Study). Circulation. 2018;137:323–334.
    1. Radholm K, Figtree G, Perkovic V, Solomon SD, Mahaffey KW, de Zeeuw D, Fulcher G, Barrett TD, Shaw W, Desai M, Matthews DR, Neal B. Canagliflozin and heart failure in type 2 diabetes mellitus: results from the CANVAS Program (Canagliflozin Cardiovascular Assessment Study). Circulation. 2018;138:458–468.
    1. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA‐REG OUTCOME Investigators . Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–2128.
    1. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Silverman MG, Zelniker TA, Kuder JF, Murphy SA, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Ruff CT, Gause‐Nilsson IAM, Fredriksson M, Johansson PA, Langkilde AM, Sabatine MS; DECLARE‐TIMI 58 Investigators . Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380:347–357.
    1. Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, Edwards R, Agarwal R, Bakris G, Bull S, Cannon CP, Capuano G, Chu PL, de Zeeuw D, Greene T, Levin A, Pollock C, Wheeler DC, Yavin Y, Zhang H, Zinman B, Meininger G, Brenner BM, Mahaffey KW; CREDENCE Trial Investigators . Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380:2295–2306.
    1. Neal B, Perkovic V, Matthews DR. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:2099.
    1. Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Furtado RHM, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Sabatine MS. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta‐analysis of cardiovascular outcome trials. Lancet. 2019;393:31–39.
    1. Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Furtado RHM, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Sabatine MS. Comparison of the effects of glucagon‐like peptide receptor agonists and sodium‐glucose cotransporter 2 inhibitors for prevention of major adverse cardiovascular and renal outcomes in type 2 diabetes mellitus. Circulation. 2019;139:2022–2031.
    1. Pocock SJ, Collier TJ. Statistical appraisal of 6 recent clinical trials in cardiology: JACC State‐of‐the‐Art Review. J Am Coll Cardiol. 2019;73:2740–2755.
    1. Das SR, Everett BM, Birtcher KK, Brown JM, Cefalu WT, Januzzi JL Jr, Rastogi Kalyani R, Kosiborod M, Magwire ML, Morris PB, Sperling LS. 2018 ACC expert consensus decision pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes and atherosclerotic cardiovascular disease: a report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol. 2018;72:3200–3223.
    1. Davies MJ, D'Alessio DA, Fradkin J, Kernan WN, Mathieu C, Mingrone G, Rossing P, Tsapas A, Wexler DJ, Buse JB. Management of hyperglycemia in type 2 diabetes, 2018: a consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018;41:2669–2701.
    1. Standl E, Schnell O, McGuire DK. Heart failure considerations of antihyperglycemic medications for type 2 diabetes. Circ Res. 2016;118:1830–1843.
    1. Hutton B, Salanti G, Caldwell DM, Chaimani A, Schmid CH, Cameron C, Ioannidis JP, Straus S, Thorlund K, Jansen JP, Mulrow C, Catala‐Lopez F, Gotzsche PC, Dickersin K, Boutron I, Altman DG, Moher D. The PRISMA extension statement for reporting of systematic reviews incorporating network meta‐analyses of health care interventions: checklist and explanations. Ann Intern Med. 2015;162:777–784.
    1. Higgins JP, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, Savovic J, Schulz KF, Weeks L, Sterne JA; Cochrane Bias Methods Group and Cochrane Statistical Methods Group . The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.
    1. Carbone S, Dixon DL. The CANVAS Program: implications of canagliflozin on reducing cardiovascular risk in patients with type 2 diabetes mellitus. Cardiovasc Diabetol. 2019;18:64.
    1. Neuen BL, Ohkuma T, Neal B, Matthews DR, de Zeeuw D, Mahaffey KW, Fulcher G, Desai M, Li Q, Deng H, Rosenthal N, Jardine MJ, Bakris G, Perkovic V. Cardiovascular and renal outcomes with canagliflozin according to baseline kidney function. Circulation. 2018;138:1537–1550.
    1. Zhou Z, Lindley RI, Radholm K, Jenkins B, Watson J, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Shaw W, Oh R, Desai M, Matthews DR, Neal B. Canagliflozin and stroke in type 2 diabetes mellitus. Stroke. 2019;50:396–404.
    1. Kato ET, Silverman MG, Mosenzon O, Zelniker TA, Cahn A, Furtado RHM, Kuder J, Murphy SA, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Bonaca MP, Ruff CT, Desai AS, Goto S, Johansson PA, Gause‐Nilsson I, Johanson P, Langkilde AM, Raz I, Sabatine MS, Wiviott SD. Effect of dapagliflozin on heart failure and mortality in type 2 diabetes mellitus. Circulation. 2019;139:2528–2536.
    1. Furtado RHM, Bonaca MP, Raz I, Zelniker TA, Mosenzon O, Cahn A, Kuder J, Murphy SA, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Ruff CT, Nicolau JC, Gause‐Nilsson IAM, Fredriksson M, Langkilde AM, Sabatine MS, Wiviott SD. Dapagliflozin and cardiovascular outcomes in patients with type 2 diabetes and prior myocardial infarction: a sub‐analysis from DECLARE TIMI‐58 trial. Circulation. 2019;139:2516–2527.
    1. 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.
    1. Wanner C, Inzucchi SE, Zinman B. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375:1801–1802.
    1. Zinman B, Inzucchi SE, Lachin JM, Wanner C, Fitchett D, Kohler S, Mattheus M, Woerle HJ, Broedl UC, Johansen OE, Albers GW, Diener HC; EMPA‐REG OUTCOME Investigators (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) . Empagliflozin and cerebrovascular events in patients with type 2 diabetes mellitus at high cardiovascular risk. Stroke. 2017;48:1218–1225.
    1. Fitchett D, Zinman B, Wanner C, Lachin JM, Hantel S, Salsali A, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA‐REG OUTCOME® trial investigators . Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA‐REG OUTCOME(R) trial. Eur Heart J. 2016;37:1526–1534.
    1. Fitchett D, Inzucchi SE, Cannon CP, McGuire DK, Scirica BM, Johansen OE, Sambevski S, Kaspers S, Pfarr E, George JT, Zinman B. Empagliflozin reduced mortality and hospitalization for heart failure across the spectrum of cardiovascular risk in the EMPA‐REG OUTCOME trial. Circulation. 2019;139:1384–1395.
    1. McMurray JJV, Solomon SD, Inzucchi SE, Kober L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Belohlavek J, Bohm M, Chiang CE, Chopra VK, de Boer RA, Desai AS, Diez M, Drozdz J, Dukat A, Ge J, Howlett JG, Katova T, Kitakaze M, Ljungman CEA, Merkely B, Nicolau JC, O'Meara E, Petrie MC, Vinh PN, Schou M, Tereshchenko S, Verma S, Held C, DeMets DL, Docherty KF, Jhund PS, Bengtsson O, Sjostrand M, Langkilde AM; DAPA‐HF Trial Committees and Investigators . Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381:1995–2008.
    1. Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado V, Federici M, Filippatos G, Grobbee DE, Hansen TB, Huikuri HV, Johansson I, Juni P, Lettino M, Marx N, Mellbin LG, Ostgren CJ, Rocca B, Roffi M, Sattar N, Seferovic PM, Sousa‐Uva M, Valensi P, Wheeler DC; ESC Scientific Document Group . 2019 ESC guidelines on diabetes, pre‐diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J. 2019; pii: ehz486. DOI: 10.1093/eurheartj/ehz486. [Epub ahead of print].
    1. Lee M, Saver JL, Liao HW, Lin CH, Ovbiagele B. Pioglitazone for secondary stroke prevention: a systematic review and meta‐analysis. Stroke. 2017;48:388–393.
    1. Nassif ME, Windsor S, Tang F, Khariton Y, Husain M, Inzucchi SE, McGuire D, Pitt B, Scirica BM, Austin B, Drazner M, Fong M, Givertz MM, Gordon R, Jermyn R, Katz S, Lamba S, Lanfear D, LaRue S, Lindenfeld J, Malone M, Margulies KB, Mentz R, Mutharasan RK, Pursley M, Umpierrez G, Kosiborod M; DEFINE‐HF Investigators . Dapagliflozin effects on biomarkers, symptoms, and functional status in patients with heart failure with reduced ejection fraction: the DEFINE‐HF trial. Circulation. 2019;140:1463–1476.

Source: PubMed

스폰서 및 공동 작업자

건강 상태

약물 개입

3
구독하다