Understanding The Role of SGLT2 Inhibitors in Cardiovascular Risk Reduction for Type 2 Diabetes Patients-A Literature Review
Main Article Content
Abstract
Introduction: Type 2 diabetes mellitus (T2DM) is associated with an increased risk of cardiovascular events and heart failure. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have emerged as a novel class of antidiabetic agents with potential cardiovascular benefits. This systematic review aims to evaluate the impact of SGLT2 inhibitors on reducing cardiovascular events and heart failure hospitalizations in patients with T2DM.
Aims: The review aims to comprehensively evaluate the impact of SGLT2 inhibitors on reducing cardiovascular events, including MACE, and HF hospitalizations in patients with T2DM. Methods: A comprehensive literature search was conducted in major electronic databases like PubMed, Google Scholar and Science Direct to identify relevant studies. Studies investigating the cardiovascular outcomes of SGLT2 inhibitors in T2DM patients were included. Data extraction and quality assessment were performed independently by three reviewers using predefined criteria.
Results: A total of 17 studies met the inclusion criteria and were included in the review. The analysis of clinical trials, including EMPA-REG OUTCOME, CANVAS Program, and DECLARE-TIMI 58, demonstrated significant reductions in MACE and HF hospitalizations with SGLT2 inhibitors compared to placebo or standard care. Real-world evidence from studies such as the CVD-REAL and EASEL studies further supported these findings, showing consistent cardiovascular benefits of SGLT2 inhibitors in routine clinical practice. The findings suggest that SGLT2 inhibitors are associated with a reduction in cardiovascular events, including myocardial infarction, stroke, and cardiovascular mortality, as well as a decreased risk of heart failure hospitalizations in patients with T2DM.
Conclusion: This systematic review provides evidence supporting the cardiovascular benefits of SGLT2 inhibitors in T2DM management. The findings underscore the importance of considering these agents as part of comprehensive cardiovascular risk reduction strategies in T2DM patients. Further research is necessary to explicate the mechanisms underlying these benefits and optimize their clinical use.
Article Details
This work is licensed under a Creative Commons Attribution 4.0 International License.
References
I. GBD results [Internet]. Institute for Health Metrics and Evaluation. Available from: https://vizhub.healthdata.org/gbd-results/
II. McGuire DK, Shih WJ, Cosentino F, Charbonnel B, Cherney DZI, Dagogo‐Jack S, et al. Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes. JAMA Cardiology [Internet]. 2021 Feb 1;6(2):148. Available from: https://doi.org/10.1001/jamacardio.2020.4511
III. Nauck MA, Quast DR. Cardiovascular safety and benefits of semaglutide in patients with type 2 diabetes: Findings from SUSTAIN 6 and PIONEER 6. Frontiers in Endocrinology [Internet]. 2021 Mar 29;12. Available from: https://doi.org/10.3389/fendo.2021.645566
IV. Gyldenkerne C, Mortensen MB, Kahlert J, Thrane PG, Olesen KKW, Sørensen HT, et al. 10-Year cardiovascular risk in patients with newly diagnosed type 2 diabetes mellitus. Journal of the American College of Cardiology [Internet]. 2023 Oct 1;82(16):1583–94. Available from: https://doi.org/10.1016/j.jacc.2023.08.015
V. Sattar N, Rawshani A, Franzén S, Rawshani A, Svensson AM, Rosengren A, et al. Age at diagnosis of Type 2 diabetes mellitus and associations with cardiovascular and mortality risks. Circulation [Internet]. 2019 May 7;139(19):2228–37. Available from: https://doi.org/10.1161/circulationaha.118.037885
VI. Palmer SC, Tendal B, Mustafa RA, Vandvik PO, Li S, Qin H, et al. Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials. The BMJ [Internet]. 2021 Jan 13;m4573. Available from: https://doi.org/10.1136/bmj.m4573
VII. Bailey CJ, Day C, Bellary S. Renal Protection with SGLT2 Inhibitors: Effects in Acute and Chronic Kidney Disease. Current Diabetes Reports [Internet]. 2022 Jan 1;22(1):39–52. Available from: https://doi.org/10.1007/s11892-021-01442-z
VIII. Jiang K, Xu Y, Wang D, Chen F, Tu Z, Qian J, et al. Cardioprotective mechanism of SGLT2 inhibitor against myocardial infarction is through reduction of autosis. Protein & Cell [Internet]. 2021 Jan 8;13(5):336–59. Available from: https://doi.org/10.1007/s13238-020-00809-4
IX. Andreadou I, Bell RM, Bøtker HE, Zuurbier CJ. SGLT2 inhibitors reduce infarct size in reperfused ischemic heart and improve cardiac function during ischemic episodes in preclinical models. Biochimica Et Biophysica Acta (BBA) - Molecular Basis of Disease [Internet]. 2020 Jul 1;1866(7):165770. Available from: https://doi.org/10.1016/j.bbadis.2020.165770
X. 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. Cardiovascular Diabetology [Internet]. 2022 Mar 16;21(1). Available from: https://doi.org/10.1186/s12933-022-01474-z
XI. Alfayez OM, Yami MSA, Alshibani M, Fallatah S, Khushaym NMA, Alsheikh R, et al. Network meta-analysis of nine large cardiovascular outcome trials of new antidiabetic drugs. Primary Care Diabetes [Internet]. 2019 Jun 1;13(3):204–11. Available from: https://doi.org/10.1016/j.pcd.2019.01.003
XII. Monteiro P, Bergenstal RM, Toural E, Inzucchi SE, Zinman B, Hantel S, et al. Efficacy and safety of empagliflozin in older patients in the EMPA-REG OUTCOME® trial. Age And Ageing [Internet]. 2019 Oct 3;48(6):859–66. Available from: https://doi.org/10.1093/ageing/afz096
XIII. Verma S, Mazer CD, Fitchett D, Inzucchi SE, Pfarr E, George JT, et al. Empagliflozin reduces cardiovascular events, mortality and renal events in participants with type 2 diabetes after coronary artery bypass graft surgery: subanalysis of the EMPA-REG OUTCOME® randomised trial. Diabetologia [Internet]. 2018 May 19;61(8):1712–23. Available from: https://doi.org/10.1007/s00125-018-4644-9
XIV. Arnott C, Huang Y, Neuen BL, Di Tanna GL, Cannon CP, Oh R, et al. The effect of canagliflozin on amputation risk in the CANVAS program and the CREDENCE trial. Diabetes, Obesity and Metabolism [Internet]. 2020 Jun 24;22(10):1753–66. Available from: https://doi.org/10.1111/dom.14091
XV. Mosenzon O, Wiviott SD, Cahn A, Rozenberg A, Yanuv I, Goodrich EL, et al. Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: an analysis from the DECLARE–TIMI 58 randomised trial. The Lancet Diabetes & Endocrinology [Internet]. 2019 Aug 1;7(8):606–17. Available from: https://doi.org/10.1016/s2213-8587(19)30180-9
XVI. Heerspink HJL, Karasik A, Thuresson M, Cohen CM, Chodick G, Khunti K, et al. Kidney outcomes associated with use of SGLT2 inhibitors in real-world clinical practice (CVD-REAL 3): a multinational observational cohort study. The Lancet Diabetes & Endocrinology [Internet]. 2020 Jan 1;8(1):27–35. Available from: https://doi.org/10.1016/s2213-8587(19)30384-5
XVII. Kyriakos G, Quiles-Sánchez LV, Garmpi A, Farmaki P, Kyre K, Savvanis S, et al. SGLT2 Inhibitors and Cardiovascular Outcomes: Do They Differ or There is a Class Effect? New Insights from the EMPA-REG OUTCOME trial and the CVD-REAL Study. Current Cardiology Reviews [Internet]. 2021 Jul 1;16(4):258–65. Available from: https://doi.org/10.2174/1573403x15666190730094215
XVIII. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. doi:10.1136/bmj.n71
XIX. Ouzzani M, Hammady HM, Fedorowicz Z, Elmagarmid AK. Rayyan—a web and mobile app for systematic reviews. Systematic Reviews [Internet]. 2016 Dec 1;5(1). Available from: https://doi.org/10.1186/s13643-016-0384-4
XX. Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.4
XXI. McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod M, Martínez F, et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. The New England Journal of Medicine [Internet]. 2019 Nov 21;381(21):1995–2008. Available from: https://doi.org/10.1056/nejmoa1911303
XXII. Voors AA, Angermann CE, Teerlink JR, Collins SP, Kosiborod M, Biegus J, et al. The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trial. Nature Medicine [Internet]. 2022 Feb 28;28(3):568–74. Available from: https://doi.org/10.1038/s41591-021-01659-1
XXIII. Packer M, Anker SD, Butler J, Filippatos G, Pocock S, Carson PE, et al. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. The New England Journal of Medicine [Internet]. 2020 Oct 8;383(15):1413–24. Available from: https://doi.org/10.1056/nejmoa2022190
XXIV. Wheeler DC, Stefánsson BV, Jongs N, Chertow GM, Greene T, Hou FF, et al. Effects of dapagliflozin on major adverse kidney and cardiovascular events in patients with diabetic and non-diabetic chronic kidney disease: a prespecified analysis from the DAPA-CKD trial. The Lancet Diabetes & Endocrinology [Internet]. 2021 Jan 1;9(1):22–31. Available from: https://doi.org/10.1016/s2213-8587(20)30369-7
XXV. Bhatt DL, Szarek M, Steg PG, Cannon CP, Leiter LA, McGuire DK, et al. Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure. The New England Journal of Medicine [Internet]. 2021 Jan 14;384(2):117–28. Available from: https://doi.org/10.1056/nejmoa2030183
XXVI. Filippatos G, Butler J, Farmakis D, Zannad F, Ofstad AP, Ferreira JP, et al. Empagliflozin for heart failure with preserved left ventricular ejection fraction with and without diabetes. Circulation [Internet]. 2022 Aug 30;146(9):676–86. Available from: https://doi.org/10.1161/circulationaha.122.059785
XXVII. Cannon CP, Pratley RE, Dagogo‐Jack S, Mancuso JP, Huyck S, Masiukiewicz U, et al. Cardiovascular Outcomes with Ertugliflozin in Type 2 Diabetes. The New England Journal of Medicine [Internet]. 2020 Oct 8;383(15):1425–35. Available from: https://doi.org/10.1056/nejmoa2004967
XXVIII. Petrie MC, Verma S, Docherty KF, Inzucchi SE, Anand I, Bělohlávek J, et al. Effect of dapagliflozin on worsening heart failure and cardiovascular death in patients with heart failure with and without diabetes. JAMA [Internet]. 2020 Apr 14;323(14):1353. Available from: https://doi.org/10.1001/jama.2020.1906
XXIX. Furtado RHM, Bonaca MP, Raz I, Zelniker TA, Mosenzon O, Kuder J, et al. Dapagliflozin and cardiovascular outcomes in patients with type 2 diabetes mellitus and previous myocardial infarction. Circulation [Internet]. 2019 May 28;139(22):2516–27. Available from: https://doi.org/10.1161/circulationaha.119.039996
XXX. McMurray JJV, DeMets DL, Inzucchi SE, Køber L, Kosiborod M, Langkilde AM, et al. A trial to evaluate the effect of the sodium–glucose co‐transporter 2 inhibitor dapagliflozin on morbidity and mortality in patients with heart failure and reduced left ventricular ejection fraction (DAPA‐HF). European Journal of Heart Failure [Internet]. 2019 Mar 21;21(5):665–75. Available from: https://doi.org/10.1002/ejhf.1432
XXXI. Bhatt DL, Szarek M, Pitt B, Cannon CP, Leiter LA, McGuire DK, et al. Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease. The New England Journal of Medicine [Internet]. 2021 Jan 14;384(2):129–39. Available from: https://doi.org/10.1056/nejmoa2030186
XXXII. Vaduganathan M, Sattar N, Xu J, Butler J, Mahaffey KW, Neal B, et al. Stress cardiac biomarkers, cardiovascular and renal outcomes, and response to canagliflozin. Journal of the American College of Cardiology [Internet]. 2022 Feb 1;79(5):432–44. Available from: https://doi.org/10.1016/j.jacc.2021.11.027
XXXIII. Fitchett D, Inzucchi SE, Cannon CP, McGuire DK, Scirica BM, Johansen OE, et al. Empagliflozin reduced mortality and hospitalization for heart failure across the spectrum of cardiovascular risk in the EMPA-REG OUTCOME trial. Circulation [Internet]. 2019 Mar 12;139(11):1384–95. Available from: https://doi.org/10.1161/circulationaha.118.037778
XXXIV. Waijer SW, Vart P, Cherney DZI, Chertow GM, Jongs N, Langkilde AM, et al. Effect of dapagliflozin on kidney and cardiovascular outcomes by baseline KDIGO risk categories: a post hoc analysis of the DAPA-CKD trial. Diabetologia [Internet]. 2022 Apr 21;65(7):1085–97. Available from: https://doi.org/10.1007/s00125-022-05694-6
XXXV. Kato E, Silverman MG, Mosenzon O, Zelniker TA, Cahn A, Furtado RHM, et al. Effect of dapagliflozin on heart failure and mortality in Type 2 diabetes mellitus. Circulation [Internet]. 2019 May 28;139(22):2528–36. Available from: https://doi.org/10.1161/circulationaha.119.040130
XXXVI. Furtado RHM, Bonaca MP, Raz I, Zelniker TA, Mosenzon O, Kuder J, et al. Dapagliflozin and cardiovascular outcomes in patients with type 2 diabetes mellitus and previous myocardial infarction. Circulation [Internet]. 2019 May 28;139(22):2516–27. Available from: https://doi.org/10.1161/circulationaha.119.039996
XXXVII. Szarek M, Bhatt DL, Steg PhG, Cannon CP, Leiter LA, McGuire DK, et al. Effect of sotagliflozin on total hospitalizations in patients with type 2 diabetes and worsening heart failure. Annals of Internal Medicine [Internet]. 2021 Aug 1;174(8):1065–72. Available from: https://doi.org/10.7326/m21-0651
XXXVIII. Kelsey MD, Nelson A, Green JB, Granger CB, Peterson ED, McGuire DK, et al. Guidelines for cardiovascular risk reduction in patients with Type 2 diabetes. Journal of the American College of Cardiology [Internet]. 2022 May 1;79(18):1849–57. Available from: https://doi.org/10.1016/j.jacc.2022.02.046
XXXIX. Nathan DM, Lachin JM, Bebu I, Burch HB, Buse JB, Cherrington A, et al. Glycemia reduction in Type 2 diabetes — microvascular and cardiovascular outcomes. The New England Journal of Medicine [Internet]. 2022 Sep 22;387(12):1075–88. Available from: https://doi.org/10.1056/nejmoa2200436
XL. Marilly E, Cottin J, Cabrera N, Cornu C, Boussageon R, Moulin P, et al. SGLT2 inhibitors in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials balancing their risks and benefits. Diabetologia [Internet]. 2022 Aug 4;65(12):2000–10. Available from: https://doi.org/10.1007/s00125-022-05773-8
XLI. Monteiro P, Bergenstal RM, Toural E, Inzucchi SE, Zinman B, Hantel S, et al. Efficacy and safety of empagliflozin in older patients in the EMPA-REG OUTCOME® trial. Age And Ageing [Internet]. 2019 Oct 3;48(6):859–66. Available from: https://doi.org/10.1093/ageing/afz096
XLII. Yi TW, Wong M, Neuen BL, Arnott C, Poirier P, Seufert J, et al. Effects of canagliflozin on cardiovascular and kidney events in patients with chronic kidney disease with and without peripheral arterial disease: Integrated analysis from the CANVAS Program and CREDENCE trial. Diabetes, Obesity and Metabolism [Internet]. 2023 Apr 24;25(7):2043–7. Available from: https://doi.org/10.1111/dom.15065
XLIII. Deerochanawong C, Chan SP, Matawaran BJ, Sheu WHH, Chan JCN, Man NH, et al. Use of sodium‐glucose co‐transporter‐2 inhibitors in patients with type 2 diabetes mellitus and multiple cardiovascular risk factors: An Asian perspective and expert recommendations. Diabetes, Obesity and Metabolism [Internet]. 2019 Jul 17;21(11):2354–67. Available from: https://doi.org/10.1111/dom.13819
XLIV. D’Andrea E, Wexler DJ, Kim SY, Paik JM, Alt EM, Patorno E. Comparing Effectiveness and Safety of SGLT2 Inhibitors vs DPP-4 Inhibitors in Patients With Type 2 Diabetes and Varying Baseline HbA1cLevels. JAMA Internal Medicine [Internet]. 2023 Mar 1;183(3):242. Available from: https://doi.org/10.1001/jamainternmed.2022.6664
XLV. Zannad F, Ferreira JP, Pocock S, Anker SD, Butler J, Filippatos G, et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. The Lancet [Internet]. 2020 Sep 1;396(10254):819–29. Available from: https://doi.org/10.1016/s0140-6736(20)31824-9
XLVI. Fitchett D, Inzucchi SE, Cannon CP, McGuire DK, Scirica BM, Johansen OE, et al. Empagliflozin reduced mortality and hospitalization for heart failure across the spectrum of cardiovascular risk in the EMPA-REG OUTCOME trial. Circulation [Internet]. 2019 Mar 12;139(11):1384–95. Available from: https://doi.org/10.1161/circulationaha.118.037778
XLVII. Zhou Z, Lindley RI, Rådholm K, Jenkins B, Watson JDG, Perkovic V, et al. Canagliflozin and stroke in type 2 diabetes mellitus. Stroke [Internet]. 2019 Feb 1;50(2):396–404. Available from: https://doi.org/10.1161/strokeaha.118.023009