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Current Cardiology Reviews


ISSN (Print): 1573-403X
ISSN (Online): 1875-6557

Review Article

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

Author(s): Georgios Kyriakos, Lourdes V. Quiles-Sanchez, Anna Garmpi, Paraskevi Farmaki*, Konstantina Kyre, ">Spyridon Savvanis, Vasileios K. Antoniou and Eleni Memi

Volume 16 , Issue 4 , 2020

Page: [258 - 265] Pages: 8

DOI: 10.2174/1573403X15666190730094215

Price: $65


A new group of hypoglycemic drugs has been used to treat diabetes type 2. This group is active sodium glucose co-transporter (SGLT2) or SGLT2 inhibitors. It has been shown that besides the treatment of diabetes, this drug class is responsible for the mildness of the cardiovascular events shown in patients with diabetes type 2. However, there is an intriguing question regarding the range of SGLT2 inhibitors and if there is a difference between them or if there is a class effect among their results. EMPA-REG OUTCOME trial and the CVD-study are used to answer this question. Additional information from the DECLARE-TIMI 58 and Dapa-HF trials is studied.

Keywords: SGLT2 inhibitors, T2DM, diabetes type 2 mellitus, EMPA-REG OUTCOME trial, CVD-REAL study, class effect, cardiovascular events.

Graphical Abstract
Soares I, Carneiro AV. Drug class effects: Definitions and practical applications. Rev Port Cardiol 2002; 21(9): 1031-42.
[PMID: 12416274]
Chao EC, Henry RR. SGLT2 inhibition--a novel strategy for diabetes treatment. Nat Rev Drug Discov 2010; 9(7): 551-9.
[] [PMID: 20508640]
Tancredi M, Rosengren A, Svensson AM, et al. Excess mortality among persons with type 2 diabetes. N Engl J Med 2015; 373(18): 1720-32.
[] [PMID: 26510021]
Valentine V. The role of the kidney and sodium-glucose cotransporter-2 inhibition in diabetes management. Clin Diabetes 2012; 30(4): 151-5.
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(5): 717-25.
[] [PMID: 27208375]
Foote C, Perkovic V, Neal B. Effects of SGLT2 inhibitors on cardiovascular outcomes. Diab Vasc Dis Res 2012; 9(2): 117-23.
[] [PMID: 22381403]
Birkeland KI, Jørgensen ME, Carstensen B, et al. Cardiovascular mortality and morbidity in patients with type 2 diabetes following initiation of sodium-glucose co-transporter-2 inhibitors versus other glucose-lowering drugs (CVD-REAL Nordic): A multinational observational analysis. Lancet Diabetes Endocrinol 2017; 5(9): 709-17.
[] [PMID: 28781064]
Neal B, Perkovic V, de Zeeuw D, et al. Efficacy and safety of canagliflozin, an inhibitor of sodium-glucose cotransporter 2, when used in conjunction with insulin therapy in patients with type 2 diabetes. Diabetes Care 2015; 38(3): 403-11.
[] [PMID: 25468945]
Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019; 380: 4.
McMurray JJV, DeMets DL, Inzucchi SE, 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). Eur J Heart Fail 2019; 21(5): 665-75.
[] [PMID: 30895697]
Rosenstock J, Aggarwal N, Polidori D, et al. Dose-ranging effects of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to metformin in subjects with type 2 diabetes. Diabetes Care 2012; 35(6): 1232-8.
[] [PMID: 22492586]
Safety and effectiveness of SGLT-2 inhibitors in patients with heart failure and diabetes. Available from:.
Inzucchi SE, Zinman B, Wanner C, et al. SGLT-2 inhibitors and cardiovascular risk: Proposed pathways and review of ongoing outcome trials. Diab Vasc Dis Res 2015; 12(2): 90-100.
[] [PMID: 25589482]
Swedberg K, Rydén L. Treatment of diabetes and heart failure. Joint Forces 2016; 37(19): 1535-7.
Sattar N, McLaren J, Kristensen SL, Preiss D, McMurray JJ. SGLT2 Inhibition and cardiovascular events: Why did EMPA-REG Outcomes surprise and what were the likely mechanisms? Diabetologia 2016; 59(7): 1333-9.
[] [PMID: 27112340]
Inzucchi S, 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]
Saad M. Sodium-glucose cotransporter-2 inhibitors and cardiovascular outcomes: Insights from the CVD-REAL study. Ann Transl Med 2018; 6(3): 55.
[] [PMID: 29610747]
Basile JN. The potential of sodium glucose cotransporter 2 (SGLT2) inhibitors to reduce cardiovascular risk in patients with type 2 diabetes (T2DM). J Diabetes Complications 2013; 27(3): 280-6.
[] [PMID: 23375850]
Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016; 375(4): 323-34.
[] [PMID: 27299675]
Fitchett D, Zinman B, Wanner C, et al. 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]
Zinman B, Inzucchi SE, Lachin JM, et al. Rationale, design, and baseline characteristics of a randomized, placebo-controlled cardiovascular outcome trial of empagliflozin (EMPA-REG OUTCOME™). Cardiovasc Diabetol 2014; 13(1): 102.
[] [PMID: 24943000]
Verma S, Mazer C, Al-Omran M, et al. Cardiovascular outcomes and safety of empagliflozin in patients with type 2 diabetes mellitus and peripheral artery disease: A subanalysis of EMPA-REG OUTCOME Circulation 2018; 137(4): 405-7..
[ ] [PMID: 29133602]
Fitchett D, Butler J, van de Borne P, et al. 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]
Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015; 373(22): 2117-28.
[] [PMID: 26378978]
Neal B, Perkovic V, de Zeeuw D, et al. Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS)--a randomized placebo-controlled trial. Am Heart J 2013; 166(2): 217-223.e11.
[] [PMID: 23895803]
Wu JH, Foote C, Blomster J, et al. Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: A systematic review and meta-analysis. Lancet Diabetes Endocrinol 2016; 4(5): 411-9.
[] [PMID: 27009625]
Kosiborod M, Cavender MA, Fu AZ, et al. Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs: The CVD-REAL study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors). Circulation 2017; 136(3): 249-59.
[] [PMID: 28522450]
Kosiborod M. Lower risk of cardiovascular events and death associated with initiation of SGLT-2 inhibitors versus other glucose lowering drugs - real world data across three major world regions with more than 400,000 patients: The CVD-REAL 2 study. American College of Cardiology 67th Annual Scientific Session..
Terra SG, Focht K, Davies M, et al. Phase III, efficacy and safety study of ertugliflozin monotherapy in people with type 2 diabetes mellitus inadequately controlled with diet and exercise alone. Diabetes Obes Metab 2017; 19(5): 721-8.
[] [PMID: 28116776]
Raedler LA. Glyxambi (Empagliflozin/Linagliptin): A dual-acting oral medication approved for the treatment of patients with type 2 diabetes. Am Health Drug Benefits 2015; 8(Spec Feature): 171-5..
[PMID: 26629285]
DeFronzo RA, Lewin A, Patel S, et al. Combination of empagliflozin and linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin. Diabetes Care 2015; 38(3): 384-93.
[] [PMID: 25583754]
] Safety alerts for human medical products – canagliflozin (invokana, invokamet) and dapagliflozin (Farxiga, Xigduo XR): drug safety communication - strengthened kidney warnings. Available online: .
Multicenter Trial to Evaluate the effect of dapagliflozin on the incidence of cardiovascular events. Available online:.
Saad M, Mahmoud AN, Elgendy IY, et al. Cardiovascular outcomes with sodium-glucose cotransporter-2 inhibitors in patients with type II diabetes mellitus: A meta-analysis of placebo-controlled randomized trials. Int J Cardiol 2017; 228(228): 352-8.
[] [PMID: 27866027]

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