Korean Circ J.  2021 May;51(5):399-408. 10.4070/kcj.2021.0070.

Sodium-glucose Co-transporter 2 Inhibitors: a New Path for Heart Failure Treatment

• Oh J
• Lee SH
• Lee CJ
• Kang SM

• KMID: 2515763
• DOI: http://doi.org/10.4070/kcj.2021.0070

Abstract

Results from cardiovascular outcome trials (CVOT) with 5 different sodium-glucose cotransporter 2 inhibitors (SGLT2i; empagliflozin, canagliflozin, dapagliflozin, ertugliflozin, sotagliflozin), initially developed for their glucose-lowering effect by blocking tubular glucose reabsorption in kidney, have been shown to decrease the risk of heart failure hospitalization (HFH) across a range of patients with and without atherosclerotic cardiovascular disease in patients with type 2 diabetes mellitus (T2DM). Following these CVOT results, SGLT2i (dapagliflozin, empagliflozin, sotagliflozin) also were reported to reduce HFH and cardiovascular death in patients with heart failure with reduced ejection fraction (HFrEF), regardless of existence or absence of T2DM. Ongoing studies have been conducted to evaluate the clinical benefit of SGLT2i (empagliflozin, dapagliflozin) in patients with heart failure with preserved ejection fraction (HFpEF). Although SGLT2i brought us to the entrance of a new era for prevention of HF incidence and worsening of HF, the search for pivotal mechanism of SGLT2i to improve our pharmacological armamentarium should continue in order to protect every HF patient from fatal progression of HF disease. In this review, we summarized the updated clinical evidences on SGLT2i (rather than basic and translational evidence) for reduction of HF risk in T2DM patients and favorable clinical outcomes in both HFrEF and HFpEF patients.

Keyword

Sodium-glucose cotransporter; Heart failure; Type 2 diabetes

Reference

1. Wright EM, Loo DD, Hirayama BA. Biology of human sodium glucose transporters. Physiol Rev. 2011; 91:733–794. PMID: 21527736.

2. DeFronzo RA, Reeves WB, Awad AS. Pathophysiology of diabetic kidney disease: impact of SGLT2 inhibitors. Nat Rev Nephrol. 2021.

3. Zelniker TA, Braunwald E. Mechanisms of cardiorenal effects of sodium-glucose cotransporter 2 inhibitors: JACC state-of-the-art review. J Am Coll Cardiol. 2020; 75:422–434. PMID: 32000955.

4. Alicic RZ, Neumiller JJ, Johnson EJ, Dieter B, Tuttle KR. Sodium-glucose cotransporter 2 inhibition and diabetic kidney disease. Diabetes. 2019; 68:248–257. PMID: 30665953.

5. Gilbert RE, Krum H. Heart failure in diabetes: effects of anti-hyperglycaemic drug therapy. Lancet. 2015; 385:2107–2117. PMID: 26009231.

6. Zannad F, Ferreira JP, Pocock SJ, et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet. 2020; 396:819–829. PMID: 32877652.

7. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015; 373:2117–2128. PMID: 26378978.

8. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019; 380:347–357. PMID: 30415602.

9. McMurray JJ, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019; 381:1995–2008. PMID: 31535829.

10. Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020; 383:1413–1424. PMID: 32865377.

11. Pellicori P, Ofstad AP, Fitchett D, et al. Early benefits of empagliflozin in patients with or without heart failure: findings from EMPA-REG OUTCOME. ESC Heart Fail. 2020; 7:3401–3407.

12. Verma S, McMurray JJ. SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review. Diabetologia. 2018; 61:2108–2117. PMID: 30132036.

13. Neal B, Perkovic V, Matthews DR. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017; 377:2099. PMID: 29166232.

14. Cannon CP, Pratley R, Dagogo-Jack S, et al. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med. 2020; 383:1425–1435. PMID: 32966714.

15. Bhatt DL, Szarek M, Pitt B, et al. Sotagliflozin in patients with diabetes and chronic kidney disease. N Engl J Med. 2021; 384:129–139. PMID: 33200891.

16. Zannad F, Cowie MR. VERTIS-CV: more evidence that sodium glucose cotransporter 2 inhibition brings rapid and sustained heart failure benefit. Circulation. 2020; 142:2216–2218. PMID: 33284652.

17. Kramer CK, Ye C, Campbell S, Retnakaran R. Comparison of new glucose-lowering drugs on risk of heart failure in type 2 diabetes: a network meta-analysis. JACC Heart Fail. 2018; 6:823–830. PMID: 30196071.

18. 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; 37:1526–1534. PMID: 26819227.

19. Grant PJ, Cosentino F. The 2019 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: New features and the ‘Ten Commandments’ of the 2019 guidelines are discussed by Professor Peter J. Grant and Professor Francesco Cosentino, the Task Force chairmen. Eur Heart J. 2019; 40:3215–3217. PMID: 31608951.

20. Kato ET, Silverman MG, Mosenzon O, et al. Effect of dapagliflozin on heart failure and mortality in type 2 diabetes mellitus. Circulation. 2019; 139:2528–2536. PMID: 30882238.

21. Docherty KF, McMurray JJ. SOLOIST-WHF and updated meta-analysis: sodium-glucose co-transporter 2 inhibitors should be initiated in patients hospitalized with worsening heart failure. Eur J Heart Fail. 2021; 23:27–30. PMID: 33283384.

22. Bhatt DL, Szarek M, Steg PG, et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med. 2021; 384:117–128. PMID: 33200892.

23. Felker GM. Building the foundation for a new era of quadruple therapy in heart failure. Circulation. 2020; 141:112–114. PMID: 31736333.

24. Berliner D, Bauersachs J. Current drug therapy in chronic heart failure: the new guidelines of the European Society of Cardiology (ESC). Korean Circ J. 2017; 47:543–554. PMID: 28955380.

25. Vaduganathan M, Claggett BL, Jhund PS, et al. Estimating lifetime benefits of comprehensive disease-modifying pharmacological therapies in patients with heart failure with reduced ejection fraction: a comparative analysis of three randomised controlled trials. Lancet. 2020; 396:121–128. PMID: 32446323.

26. Shim CY. Heart failure with preserved ejection fraction: the major unmet need in cardiology. Korean Circ J. 2020; 50:1051–1061. PMID: 33150751.

27. Kim MS, Lee JH, Kim EJ, et al. Korean guidelines for diagnosis and management of chronic heart failure. Korean Circ J. 2017; 47:555–643. PMID: 28955381.

28. Solomon SD, McMurray JJ, Anand IS, et al. Angiotensin-neprilysin inhibition in heart failure with preserved ejection fraction. N Engl J Med. 2019; 381:1609–1620. PMID: 31475794.

29. Solomon SD, Vaduganathan M, L Claggett B, et al. Sacubitril/valsartan across the spectrum of ejection fraction in heart failure. Circulation. 2020; 141:352–361. PMID: 31736342.

30. Vaduganathan M, Jhund PS, Claggett BL, et al. A putative placebo analysis of the effects of sacubitril/valsartan in heart failure across the full range of ejection fraction. Eur Heart J. 2020; 41:2356–2362. PMID: 32221596.

31. Zelniker TA, Braunwald E. Clinical benefit of cardiorenal effects of sodium-glucose cotransporter 2 inhibitors: JACC state-of-the-art review. J Am Coll Cardiol. 2020; 75:435–447. PMID: 32000956.

32. Butler J, Packer M, Greene SJ, et al. Heart failure end points in cardiovascular outcome trials of sodium glucose cotransporter 2 inhibitors in patients with type 2 diabetes mellitus: a critical evaluation of clinical and regulatory issues. Circulation. 2019; 140:2108–2118. PMID: 31841369.

33. Patorno E, Pawar A, Franklin JM, et al. Empagliflozin and the risk of heart failure hospitalization in routine clinical care. Circulation. 2019; 139:2822–2830. PMID: 30955357.

34. Scheen AJ. Cardiovascular effects of new oral glucose-lowering agents: DPP-4 and SGLT-2 inhibitors. Circ Res. 2018; 122:1439–1459. PMID: 29748368.

35. Anker SD, Butler J, Filippatos G, et al. Baseline characteristics of patients with heart failure with preserved ejection fraction in the EMPEROR-Preserved trial. Eur J Heart Fail. 2020; 22:2383–2392. PMID: 33251670.

36. Packer M, Butler J, Filippatos G, et al. Design of a prospective patient-level pooled analysis of two parallel trials of empagliflozin in patients with established heart failure. Eur J Heart Fail. 2020; 22:2393–2398. PMID: 33251659.