Cardiovascular outcome trials of GLP-1RAs and SGLT-2 inhibitors: a concise review from the clinicians’ perspective

Abstract

Prevention of cardiovascular disease (CVD) is one of the main objectives in the management of people with type 2 diabetes (T2DM). New glucose-lowering therapies such as glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 (SGLT-2) inhibitors have demonstrated not only cardiovascular safety but also cardiovascular benefits. In line with emerging evidence from the cardiovascular outcome trials (CVOTs), major international guidelines advocate GLP-1RAs and SGLT-2 inhibitors with proven cardiovascular benefits as a first add-on or monotherapy in individuals with T2DM and established CVD or CVD risk factors. Based on subsequent cardiorenal outcomes and heart failure trials, the licensed indications of some SGLT-2 inhibitors have been extended beyond glycaemic management. SGLT-2 inhibitors have now been approved for the management of chronic heart failure and chronic kidney disease, both irrespective of diabetes status. This review aims to summarise the CVOTs of GLP-1RAs and SGLT-2 inhibitors from the clinician’s perspective.

Keywords

CVOT / cardiovascular disease / type 2 diabetes / GLP-1RA / SGLT-2 inhibitor

References

[1] Einarson TR,Ludwig C.Prevalence of cardiovascular disease in type 2 diabetes: a systematic literature review of scientific evidence from across the world in 2007-2017.Cardiovasc Diabetol2018;17:83 PMCID:PMC5994068

[2] Gaede P,Larsen N,Parving HH.Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes.N Engl J Med2003;348:383-93

[3] Davies MJ,Collins BS.Management of hyperglycemia in type 2 diabetes, 2022. a consensus report by the american diabetes association (ADA) and the european association for the study of diabetes (EASD).Diabetes Care2022;45:2753-86 PMCID:PMC10008140

[4] FDA. Type 2 Diabetes Mellitus: Evaluating the Safety of New Drugs for Improving Glycemic Control Guidance for Industry. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/type-2-diabetes-mellitus-evaluating-safety-new-drugs-improving-glycemic-control-guidance-industry [Last accessed on 13 May 2023]

[5] Cosentino F,Aboyans V.ESC Scientific Document Group2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD.Eur Heart J2020;41:255-323

[6] Pfeffer MA,Diaz R.ELIXA InvestigatorsLixisenatide in patients with type 2 diabetes and acute coronary syndrome.N Engl J Med2015;373:2247-57

[7] Marso SP,Brown-Frandsen K.LEADER Steering CommitteeLEADER Trial InvestigatorsLiraglutide and cardiovascular outcomes in type 2 diabetes.N Engl J Med2016;375:311-22 PMCID:PMC4985288

[8] Marso SP,Consoli A.SUSTAIN-6 InvestigatorsSemaglutide and cardiovascular outcomes in patients with type 2 diabetes.N Engl J Med2016;375:1834-44

[9] Holman RR,Mentz RJ.EXSCEL Study GroupEffects of once-Weekly exenatide on cardiovascular outcomes in type 2 diabetes.N Engl J Med2017;377:1228-39 PMCID:PMC9792409

[10] Hernandez AF,Janmohamed S.Harmony Outcomes committees and investigatorsAlbiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial.Lancet2018;392:1519-29

[11] Gerstein HC,Dagenais GR.REWIND InvestigatorsDulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial.Lancet2019;394:121-30

[12] Husain M,Donsmark M.PIONEER 6 InvestigatorsOral semaglutide and cardiovascular outcomes in patients with type 2 diabetes.N Engl J Med2019;381:841-51

[13] Gerstein HC,Rosenstock J.AMPLITUDE-O Trial InvestigatorsCardiovascular and renal outcomes with efpeglenatide in type 2 diabetes.N Engl J Med2021;385:896-907

[14] Ruff CT,Im K,Fiedorek FT.Subcutaneous infusion of exenatide and cardiovascular outcomes in type 2 diabetes: a non-inferiority randomized controlled trial.Nat Med2022;28:89-95

[15] Yin WL,Min T.The effect of glucagon-like peptide-1 receptor agonists on renal outcomes in type 2 diabetes.Diabetes Ther2020;11:835-44 PMCID:PMC7136364

[16] Kristensen SL,Jhund PS.Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials.Lancet Diabetes Endocrinol2019;7:776-85

[17] Lam CSP,Branch KRH.Efpeglenatide and clinical outcomes with and without concomitant sodium-glucose cotransporter-2 inhibition use in type 2 diabetes: exploratory analysis of the AMPLITUDE-O trial..Circulation2022;145:565-74

[18] Neal B,Mahaffey KW.CANVAS Program Collaborative GroupCanagliflozin and cardiovascular and renal events in type 2 diabetes.N Engl J Med2017;377:644-57

[19] Wiviott SD,Bonaca MP.DECLARE–TIMI 58 InvestigatorsDapagliflozin and cardiovascular outcomes in type 2 diabetes.N Engl J Med2019;380:347-57

[20] Zinman B,Lachin JM.EMPA-REG OUTCOME InvestigatorsEmpagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.N Engl J Med2015;373:2117-28

[21] Cannon CP,Dagogo-Jack S.VERTIS CV InvestigatorsCardiovascular outcomes with ertugliflozin in type 2 diabetes.N Engl J Med2020;383:1425-35

[22] Cosentino F,Cherney DZI.Efficacy of ertugliflozin on heart failure–related events in patients with type 2 diabetes mellitus and established atherosclerotic cardiovascular disease.Circulation2020;142:2205-15

[23] Suzuki Y,Okada A.Comparison of cardiovascular outcomes between SGLT2 inhibitors in diabetes mellitus.Cardiovasc Diabetol2022;21:67 PMCID:PMC9115977

[24] McMurray JJV,Inzucchi SE.DAPA-HF Trial Committees and InvestigatorsDapagliflozin in patients with heart failure and reduced ejection fraction.N Engl J Med2019;381:1995-2008

[25] Solomon SD,Claggett B.DELIVER Trial Committees and InvestigatorsDapagliflozin in heart failure with mildly reduced or preserved ejection fraction.N Engl J Med2022;387:1089-98

[26] Packer M,Butler J.EMPEROR-Reduced Trial InvestigatorsCardiovascular and renal outcomes with empagliflozin in heart failure.N Engl J Med2020;383:1413-24

[27] Anker SD,Filippatos G.EMPEROR-Preserved Trial InvestigatorsEmpagliflozin in heart failure with a preserved ejection fraction.N Engl J Med2021;385:1451-61

[28] FDA. FDA approves treatment for wider range of patients with heart failure. Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-treatment-wider-range-patients-heart-failure [Last accessed on 11 May 2023]

[29] Perkovic V,Neal B.CREDENCE Trial InvestigatorsCanagliflozin and renal outcomes in type 2 diabetes and nephropathy.N Engl J Med2019;380:2295-306

[30] Heerspink HJL,Chertow GM.DAPA-CKD Trial Committees and InvestigatorsEffect of dapagliflozin on the rate of decline in kidney function in patients with chronic kidney disease with and without type 2 diabetes: a prespecified analysis from the DAPA-CKD trial.Lancet Diabetes Endocrinol2021;9:743-54

[31] Jongs N,Chertow GM.DAPA-CKD Trial Committees and InvestigatorsEffect of dapagliflozin on urinary albumin excretion in patients with chronic kidney disease with and without type 2 diabetes: a prespecified analysis from the DAPA-CKD trial.Lancet Diabetes Endocrinol2021;9:755-66

[32] Das SR,Birtcher KK.2020 expert consensus decision pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes: a report of the American college of cardiology solution set oversight committee.J Am Coll Cardiol2020;76:1117-45 PMCID:PMC7545583

[33] Kidney Disease: improving global outcomes (KDIGO) diabetes work groupKDIGO 2022 clinical practice guideline for diabetes management in chronic kidney disease.Kidney Int2022;102:S1-S127

[34] Mascolo A,Balzano N.Safety profile of sodium glucose co-transporter 2 (SGLT2) inhibitors: a brief summary.Front Cardiovasc Med2022;9:1010693 PMCID:PMC9532622

[35] Toyama T,Jun M.Effect of SGLT2 inhibitors on cardiovascular, renal and safety outcomes in patients with type 2 diabetes mellitus and chronic kidney disease: A systematic review and meta-analysis.Diabetes Obes Metab2019;21:1237-50

[36] Barraclough JY,Figtree GA.Cardiovascular and renal outcomes with canagliflozin in patients with peripheral arterial disease: Data from the CANVAS Program and CREDENCE trial.Diabetes Obes Metab2022;24:1072-83

[37] Htike ZZ,Papamargaritis D,Khunti K.Efficacy and safety of glucagon-like peptide-1 receptor agonists in type 2 diabetes: a systematic review and mixed-treatment comparison analysis.Diabetes Obes Metab2017;19:524-36

[38] Vilsbøll T,Leiter LA.Semaglutide, reduction in glycated haemoglobin and the risk of diabetic retinopathy.Diabetes Obes Metab2018;20:889-97 PMCID:PMC5888154

[39] Marx N,Lehrke M,Sattar N.GLP-1 receptor agonists for the reduction of atherosclerotic cardiovascular risk in patients with type 2 diabetes.Circulation2022;146:1882-94

[40] Majewski C.Blood pressure reduction: an added benefit of sodium-glucose cotransporter 2 inhibitors in patients with type 2 diabetes.Diabetes Care2015;38:429-30 PMCID:PMC4876696

[41] Sun F,Wang J.Effect of glucagon-like peptide-1 receptor agonists on lipid profiles among type 2 diabetes: a systematic review and network meta-analysis.Clin Ther2015;37:225-241.e8

[42] Lazarte J,Hegele RA.Lipid effects of sodium-glucose cotransporter 2 inhibitors.Curr Opin Lipidol2021;32:183-90

[43] Schernthaner G,Ametov AS.Worldwide inertia to the use of cardiorenal protective glucose-lowering drugs (SGLT2i and GLP-1 RA) in high-risk patients with type 2 diabetes.Cardiovasc Diabetol2020;19:185 PMCID:PMC7585305