Generic placeholder image

Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Review Article

Cardio-protective Effects of Glucagon-like Peptide-1 Receptor Agonists: An Overview of Systematic Reviews and Publication Overlap

Author(s): Stefanos Zafeiropoulos, Areti Pagiantza, Ioannis Doundoulakis, Nikolaos Stalikas, Ioannis Farmakis, Athanasios Samaras, Christina Antza and George Giannakoulas*

Volume 27 , Issue 8 , 2021

Published on: 19 January, 2021

Page: [1068 - 1079] Pages: 12

DOI: 10.2174/1381612827666210119103153

Price: $65


Background: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as a new antihyperglycemic class with the demonstrated advantage of reducing major adverse cardiovascular events (MACE) among individuals with type 2 diabetes (T2DM), atherosclerotic cardiovascular disease, or high cardiovascular risk.

Objective: Τo summarize the evidence of systematic reviews (SRs) that assess MACE (cardiovascular mortality, nonfatal myocardial infarction, and stroke) and hospitalizations for heart failure in GLP-1RAs-treated patients and to evaluate possible overlap in pertinent SRs.

Methods: We performed a comprehensive search via MEDLINE, Cochrane Library, and PROSPERO databases up to February 23, 2020, for SRs examining cardiovascular outcomes of GLP-1RAs in T2DM patients. Three independent authors extracted data and assessed the methodological quality of the included SRs using the ROBIS tool.

Results: We found 37 SRs – published between 2009 and 2020 in English – of which 35 collected data only from randomized clinical trials while two from observational studies as well. The methodological quality of the 37 SRs ranged from low to high, while only 3 have evaluated the overall quality of evidence outcome using the Grading of Recommendations Assessments, Development and Evaluation (GRADE) approach. All the included SRs showed cardiovascular safety of GLP-1RAs while the latest ones demonstrated a reduction in composite MACE endpoint as well as its every individual component and heart failure hospitalizations.

Conclusion: In the first overview of SRs about cardiovascular outcomes of GLP-1RAs, they proved favorable effects on reducing cardiovascular events in T2DM patients. There are, however, many overlapping reviews based on relatively few cardiovascular outcomes trials.

Keywords: Glucagon-like peptide-1 receptor agonists, diabetes mellitus, cardiovascular outcomes, type 2 diabetes (T2DM), antihyperglycemic class, systematic reviews.

Whiting DR, Guariguata L, Weil C, Shaw J. IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract 2011; 94(3): 311-21.
[] [PMID: 22079683]
Lotfy M, Adeghate J, Kalasz H, Singh J, Adeghate E. Chronic complications of diabetes mellitus: a mini review. Curr Diabetes Rev 2017; 13(1): 3-10.
[] [PMID: 26472574]
Lehrke M, Marx N. Diabetes mellitus and heart failure. Am J Cardiol 2017; 120(1S): S37-47.
[] [PMID: 28606342]
Cosentino F, Grant PJ, Aboyans V, et al. ESC Scientific Document Group. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J 2020; 41(2): 255-323.
[] [PMID: 31497854]
Yusuf S, Pitt B, Davis CE, Hood WB, Cohn JN. SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991; 325(5): 293-302.
[] [PMID: 2057034]
Fitchett DH, Udell JA, Inzucchi SE. Heart failure outcomes in clinical trials of glucose-lowering agents in patients with diabetes. Eur J Heart Fail 2017; 19(1): 43-53.
[] [PMID: 27653447]
Monami M, Dicembrini I, Mannucci E. Dipeptidyl peptidase-4 inhibitors and heart failure: a meta-analysis of randomized clinical trials. Nutr Metab Cardiovasc Dis 2014; 24(7): 689-97.
[] [PMID: 24793580]
Zinman B, Wanner C, Lachin JM, et al. EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015; 373(22): 2117-28.
[] [PMID: 26378978]
Neal B, Perkovic V, Mahaffey KW, et al. CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017; 377(7): 644-57.
[] [PMID: 28605608]
Wiviott SD, Raz I, Bonaca MP, et al. DECLARE–TIMI 58 Investigators. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019; 380(4): 347-57.
[] [PMID: 30415602]
Fitchett D, Zinman B, Wanner C, et al. 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® trial. Eur Heart J 2016; 37(19): 1526-34.
[] [PMID: 26819227]
Inzucchi SE, Zinman B, Fitchett D, et al. How does empagliflozin reduce cardiovascular mortality? insights from a mediation analysis of the EMPA-REG OUTCOME trial. Diabetes Care 2018; 41(2): 356-63.
[] [PMID: 29203583]
Verma L, Leiter A, Sharma Z, et al. How Early after Treatment Initiation Are the CV Benefits of Empagliflozin Apparent? A Post Hoc Analysis of EMPA-REG OUTCOME. Diabetes 2020; 69: 28.
Swoboda PP, McDiarmid AK, Erhayiem B, et al. Diabetes mellitus, microalbuminuria, and subclinical cardiac disease: identification and monitoring of individuals at risk of heart failure. J Am Heart Assoc 2017; 6(7): e005539.
[] [PMID: 28716801]
Maack C, Lehrke M, Backs J, et al. Heart failure and diabetes: metabolic alterations and therapeutic interventions: a state-of-the-art review from the Translational Research Committee of the Heart Failure Association-European Society of Cardiology. Eur Heart J 2018; 39(48): 4243-54.
[] [PMID: 30295797]
Mahaffey KW, Neal B, Perkovic V, et al. 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(4): 323-34.
[] [PMID: 29133604]
Fitchett D, Butler J, van de Borne P, et al. EMPA-REG OUTCOME® trial investigators. Effects of empagliflozin on risk for cardiovascular death and heart failure hospitalization across the spectrum of heart failure risk in the EMPA-REG OUTCOME® trial. Eur Heart J 2018; 39(5): 363-70.
[] [PMID: 29020355]
Rådholm K, Figtree G, Perkovic V, et al. Canagliflozin and Heart Failure in Type 2 Diabetes Mellitus: Results From the CANVAS Program. Circulation 2018; 138(5): 458-68.
[] [PMID: 29526832]
McMurray JJV, Solomon SD, Inzucchi SE, et al. DAPA-HF Trial Committees and Investigators. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019; 381(21): 1995-2008.
[] [PMID: 31535829]
Nassif ME, Windsor SL, Tang F, et al. 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(18): 1463-76.
[] [PMID: 31524498]
Fitchett D, Inzucchi SE, Cannon CP, et al. Empagliflozin reduced mortality and hospitalization for heart failure across the spectrum of cardiovascular risk in the EMPA-REG OUTCOME trial. Circulation 2019; 139(11): 1384-95.
[] [PMID: 30586757]
Damman K, Beusekamp JC, Boorsma EM, et al. Randomized, double-blind, placebo-controlled, multicentre pilot study on the effects of empagliflozin on clinical outcomes in patients with acute decompensated heart failure (EMPA-RESPONSE-AHF). Eur J Heart Fail 2020; 22(4): 713-22.
[] [PMID: 31912605]
A Study to Test the Effect of Empagliflozin in Patients Who Are in Hospital for Acute Heart Failure. EMPULSE trial ClinicalTrialsgov Identifier NCT04157751, 2020.
Cardiovascular Outcomes Following Ertugliflozin Treatment in Type 2 Diabetes Mellitus Participants With Vascular Disease, The VERTIS CV Study (MK-8835- 004). Available at:
Verma S, McMurray JJV, Cherney DZI. The metabolodiuretic promise of sodium-dependent glucose cotransporter 2 inhibition: the search for the sweet spot in heart failure. JAMA Cardiol 2017; 2(9): 939-40.
[] [PMID: 28636701]
Verma S, McMurray JJV. SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review. Diabetologia 2018; 61(10): 2108-17.
[] [PMID: 30132036]
Hallow KM, Helmlinger G, Greasley PJ, McMurray JJV, Boulton DW. Why do SGLT2 inhibitors reduce heart failure hospitalization? A differential volume regulation hypothesis. Diabetes Obes Metab 2018; 20(3): 479-87.
[] [PMID: 29024278]
Sano M, Goto S. Possible mechanism of hematocrit elevation by sodium glucose cotransporter 2 inhibitors and associated beneficial renal and cardiovascular effects. Circulation 2019; 139(17): 1985-7.
[] [PMID: 31009585]
Mazer CD, Hare GMT, Connelly PW, et al. Effect of Empagliflozin on Erythropoietin Levels, Iron Stores, and Red Blood Cell Morphology in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease. Circulation 2020; 141(8): 704-7.
[] [PMID: 31707794]
Verma S, Mazer CD, Yan AT, et al. Effect of Empagliflozin on Left Ventricular Mass in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease: The EMPA-HEART CardioLink-6 Randomized Clinical Trial. Circulation 2019; 140(21): 1693-702.
[] [PMID: 31434508]
Ferrannini E, Mark M, Mayoux E. CV Protection in the EMPA-REG OUTCOME Trial: A “Thrifty Substrate” Hypothesis. Diabetes Care 2016; 39(7): 1108-14.
[] [PMID: 27289126]
Santos-Gallego CG, Requena-Ibanez JA, San Antonio R, et al. Empagliflozin Ameliorates Adverse Left Ventricular Remodeling in Nondiabetic Heart Failure by Enhancing Myocardial Energetics. J Am Coll Cardiol 2019; 73(15): 1931-44.
[] [PMID: 30999996]
Yurista SR, Silljé HHW, Oberdorf-Maass SU, et al. Sodium-glucose co-transporter 2 inhibition with empagliflozin improves cardiac function in non-diabetic rats with left ventricular dysfunction after myocardial infarction. Eur J Heart Fail 2019; 21(7): 862-73.
[] [PMID: 31033127]
Gormsen LC, Svart M, Thomsen HH, et al. Ketone Body Infusion With 3-Hydroxybutyrate Reduces Myocardial Glucose Uptake and Increases Blood Flow in Humans: A Positron Emission Tomography Study. J Am Heart Assoc 2017; 6(3): e005066.
[] [PMID: 28242634]
Nielsen R, Møller N, Gormsen LC, et al. Cardiovascular Effects of Treatment With the Ketone Body 3-Hydroxybutyrate in Chronic Heart Failure Patients. Circulation 2019; 139(18): 2129-41.
[] [PMID: 30884964]
Kidokoro K, Cherney DZI. Evaluation of Glomerular Hemodynamic Function by Empagliflozin in Diabetic Mice Using In Vivo Imaging. Circulation 2019; 140(4): 303-15.
Griffin M, Rao VS, Ivey-Miranda J, et al. Empagliflozin in Heart Failure: Diuretic and Cardiorenal Effects. Circulation 2020; 142(11): 1028-39.
[] [PMID: 32410463]
Ye Y, Jia X, Bajaj M, Birnbaum Y. Dapagliflozin Attenuates Na+/H+ Exchanger-1 in Cardiofibroblasts via AMPK Activation. Cardiovasc Drugs Ther 2018; 32(6): 553-8.
[] [PMID: 30367338]
Miyachi Y, Tsuchiya K, Shiba K, et al. A reduced M1-like/M2-like ratio of macrophages in healthy adipose tissue expansion during SGLT2 inhibition. Sci Rep 2018; 8(1): 16113.
[] [PMID: 30382157]
Baartscheer A, Schumacher CA, Wüst RC, et al. Empagliflozin decreases myocardial cytoplasmic Na+ through inhibition of the cardiac Na+/H+ exchanger in rats and rabbits. Diabetologia 2017; 60(3): 568-73.
[] [PMID: 27752710]
Liu T, Takimoto E, Dimaano VL, et al. Inhibiting mitochondrial Na+/Ca2+ exchange prevents sudden death in a Guinea pig model of heart failure. Circ Res 2014; 115(1): 44-54.
[] [PMID: 24780171]
Uthman L, Baartscheer A, Bleijlevens B, et al. Class effects of SGLT2 inhibitors in mouse cardiomyocytes and hearts: inhibition of Na+/H+ exchanger, lowering of cytosolic Na+ and vasodilation. Diabetologia 2018; 61(3): 722-6.
[] [PMID: 29197997]
Verma S. Are the Cardiorenal Benefits of SGLT2 Inhibitors Due to Inhibition of the Sympathetic Nervous System? JACC Basic Transl Sci 2020; 5(2): 180-2.
[] [PMID: 32142070]
Herat LY, Magno AL, Rudnicka C, et al. SGLT2 inhibitor–induced sympathoinhibition: a novel mechanism for cardiorenal protection. JACC Basic Transl Sci 2020; 5(2): 169-79.
[] [PMID: 32140623]
Liu J, Li L, Li S, et al. Effects of SGLT2 inhibitors on UTIs and genital infections in type 2 diabetes mellitus: a systematic review and meta-analysis. Sci Rep 2017; 7(1): 2824.
[] [PMID: 28588220]
Patakfalvi L, Brazeau AS, Dasgupta K. Physician experiences with sodium-glucose cotransporter (SGLT2) inhibitors, a new class of medications in type 2 diabetes, and adverse effects. Prim Health Care Res Dev 2018; 23: 1-6.
[PMID: 30032729]
Kim YG, Jeon JY, Han SJ, Kim DJ, Lee KW, Kim HJ. Sodium-glucose co-transporter-2 inhibitors and the risk of ketoacidosis in patients with type 2 diabetes mellitus: A nationwide population-based cohort study. Diabetes Obes Metab 2018; 20(8): 1852-8.
[] [PMID: 29569427]
Koufakis T, Mustafa OG, Ajjan RA, et al. The use of sodium-glucose co-transporter 2 inhibitors in the inpatient setting: Is the risk worth taking? J Clin Pharm Ther 2020; 45(5): 883-91.
[] [PMID: 31905245]
Merovci A, Solis-Herrera C, Daniele G, et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest 2014; 124(2): 509-14.
[] [PMID: 24463448]
Goldenberg RM, Berard LD, Cheng AYY, et al. SGLT2 inhibitor-associated diabetic ketoacidosis: clinical review and recommendations for prevention and diagnosis. Clin Ther 2016; 38 (2654 ): 2664.
Garcia-Ropero A, Badimon JJ, Santos-Gallego CG. The pharmacokinetics and pharmacodynamics of SGLT2 inhibitors for type 2 diabetes mellitus: the latest developments. Expert Opin Drug Metab Toxicol 2018; 14(12): 1287-302.
[] [PMID: 30463454]
Cherney DZI, Udell JA. Use of sodium glucose cotransporter 2 inhibitors in the hands of cardiologists: with great power comes great responsibility. Circulation 2016; 134(24): 1915-7.
[] [PMID: 27956401]
Scheen AJ. Reappraisal of the diuretic effect of empagliflozin in the EMPA-REG OUTCOME trial: Comparison with classic diuretics. Diabetes Metab 2016; 42(4): 224-33.
[] [PMID: 27291329]
Opingari E, Partridge ACR, Verma S, Bajaj HS. SGLT2 inhibitors: practical considerations and recommendations for cardiologists. Curr Opin Cardiol 2018; 33(6): 676-82.
[] [PMID: 30148719]
Wanner C, Inzucchi SE, Lachin JM, et al. EMPA-REG OUTCOME Investigators. Empagliflozin and progression of kidney disease in type 2 diabetes. Further analysis of the renal outcomes and benefits seen with empagliflozin from the EMPA-REG OUTCOME trial. N Engl J Med 2016; 375(4): 323-34.
[] [PMID: 27299675]
Perkovic V, Jardine MJ, Neal B, et al. CREDENCE Trial Investigators. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019; 380(24): 2295-306.
[] [PMID: 30990260]
Heerspink HJL, Kosiborod M, Inzucchi SE, Cherney DZI. Renoprotective effects of sodium-glucose cotransporter-2 inhibitors. Kidney Int 2018; 94(1): 26-39.
[] [PMID: 29735306]
Ruanpeng D, Ungprasert P, Sangtian J, Harindhanavudhi T. Sodium-glucose cotransporter 2 (SGLT2) inhibitors and fracture risk in patients with type 2 diabetes mellitus: A meta-analysis. Diabetes Metab Res Rev 2017; 33(6): e2903.
[] [PMID: 28440590]
Diabetes Atlas IDF. IDF Diabetes Atlas, 9th ed Brussels, 2019. Available at:
Davies MJ, D’Alessio DA, Fradkin J, et al. 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(12): 2669-701.
[] [PMID: 30291106]
Verma S, Sharma A, Zinman B, et al. Empagliflozin reduces the risk of mortality and hospitalization for heart failure across Thrombolysis In Myocardial Infarction Risk Score for Heart Failure in Diabetes categories: Post hoc analysis of the EMPA-REG OUTCOME trial. Diabetes Obes Metab 2020; 22(7): 1141-50.
[] [PMID: 32227432]
NIH US National Library of Medicine. A Study to Test the Effect of Empagliflozin in Patients Who Are in Hospital for Acute Heart Failure. Available at:
NIH US National Library of Medicine. Effects of Empagliflozin on Diuresis and Renal Function in Patients With Acute Decompensated Heart Failure (EMPAG-HF). Available at:
Kubota Y, Yamamoto T, Tara S, et al. Effect of empagliflozin versus placebo on cardiac sympathetic activity in acute myocardial infarction patients with type 2 diabetes mellitus: rationale. Diabetes Ther 2018; 9(5): 2107-16.
[] [PMID: 30097993]

Rights & Permissions Print Export Cite as
© 2022 Bentham Science Publishers | Privacy Policy