Cardiovascular Benefits of SGLT-2 Inhibitors

Cardiovascular disease is the leading cause of mortality in type 2 diabetes mellitus. Most glucose-lowering drugs do not reliably improve cardiovascular outcomes, but SGLT-2 inhibitors, which reduce blood glucose by inhibiting its reabsorption in the kidneys, have been shown to also provide cardioprotective effects, making them a first-line therapy in heart failure.

Several landmark cardiovascular outcome trials have demonstrated consistent cardiovascular effects of SGLT-2 inhibitors in patients with type 2 diabetes, including empagliflozin (EMPA-REG), canagliflozin (CANVAS), and dapagliflozin (DECLARE-TIMI 58).

In EMPA-REG, empagliflozin reduced cardiovascular death (38%), hospitalization for heart failure (35%), and all-cause mortality (32%) in patients with type 2 diabetes, without significant effect on nonfatal myocardial infarction (MI), nonfatal stroke, or hospitalization for unstable angina.(1) Similarly, CANVAS found that canagliflozin decreased the occurrence of the primary outcome (cardiovascular death, nonfatal MI, or nonfatal stroke) by 14%, while DECLARE-TIMI 58 showed that dapagliflozin decreased cardiovascular death and hospitalization for heart failure, without a significant effect on MI or stroke.(2,3) Across these trials, SGLT-2 inhibitors consistently reduce hospitalization for heart failure and cardiovascular mortality.

SGLT-2 inhibitors consistently reduce heart failure hospitalization, with EMPEROR-Preserved and EMPEROR-Reduced showing benefits in heart failure regardless of ejection fraction and diabetes status.(4,5) Reviews confirm that SGLT-2 inhibitors improve cardiovascular outcomes in patients with or without history of heart failure, with consistent effects across both HFrEF and HFpEF populations.(6) Additionally, cardiovascular outcomes appear to improve in HFrEF patients regardless of whether their heart failure is of ischemic or non-ischemic origin.(7)

The most common adverse effect associated with SGLT-2 inhibitors across trials is genital mycotic infection, which is generally mild and manageable.(1,8) Increased risk of lower extremity amputation was observed only with canagliflozin.(2,8) Overall, these risks are rare and outweighed by cardiovascular benefits.(9)

Basic glucose-lowering action alone cannot explain the cardiovascular benefits of SGLT-2 inhibitors. Renal effects, including natriuresis and improved kidney function, likely contribute, along with reduced cardiac inflammation and improved cardiac energy metabolism.(10)

SGLT-2 inhibitors have shifted management of type 2 diabetes and heart failure, improving cardiovascular outcome regardless of diabetic or heart failure status. While mechanisms remain incompletely defined, renal and metabolic effects likely contribute. Ongoing research will clarify their role in cardiovascular care.

References:

1. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. New England Journal of Medicine [Internet]. 2015 Nov 26;373(22):2117–28. Available from: https://www.nejm.org/doi/full/10.1056/NEJMoa1504720
2. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. New England Journal of Medicine. 2017 Aug 17;377(7):644–57. Available from: https://www.nejm.org/doi/full/10.1056/NEJMoa1611925
3. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. The New England Journal of Medicine [Internet]. 2018 Nov 10;380(4):347–57. Available from: https://www.ncbi.nlm.nih.gov/pubmed/30415602/
4. Anker SD, Butler J, Filippatos G, Ferreira JP, Bocchi E, Böhm M, et al. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. New England Journal of Medicine [Internet]. 2021 Aug 27;385(16):1451–61. Available from: https://www.nejm.org/doi/full/10.1056/NEJMoa2107038
5. Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, et al. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. New England Journal of Medicine [Internet]. 2020 Aug 28;383(15). Available from: https://www.nejm.org/doi/full/10.1056/NEJMoa2022190
6. Razuk V, Chiarito M, Cao D, Nicolas J, Camaj A, Power D, et al. SGLT-2 inhibitors in patients with and without a history of heart failure: a meta-analysis. European Heart Journal. 2021 Oct 1;42(Supplement_1). Available from: https://academic.oup.com/eurheartj/article/42/Supplement_1/ehab724.0916/6392680?searchresult=1
7. D Patoulias, A Boulmpou, C Tsavousoglou, M Toumpourleka, F Siskos, Nikolaidis A, et al. Sodium-glucose co-transporter-2 inhibitors improve cardiovascular outcomes in heart failure with reduced ejection fraction regardless of ischemic etiology. European Heart Journal [Internet]. 2021 Oct 1 [cited 2025 Dec 18];42(Supplement_1). Available from: https://academic.oup.com/eurheartj/article/42/Supplement_1/ehab724.0889/6392211?searchresult=1#google_vignette
8. Rastogi A, Bhansali A. SGLT2 Inhibitors Through the Windows of EMPA-REG and CANVAS Trials: A Review. Diabetes Therapy [Internet]. 2017 Oct 26;8(6):1245–51. Available from: https://link.springer.com/article/10.1007/s13300-017-0320-1?utm
9. Marilly E, Cottin J, Cabrera N, Cornu C, Rémy Boussageon, 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. 2022 Aug 4;65(12):2000–10. Available from: https://pubmed.ncbi.nlm.nih.gov/35925319/
10. Lopaschuk GD, Verma S. Mechanisms of Cardiovascular Benefits of Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitors. JACC: Basic to Translational Science. 2020 Jun;5(6):632–44. Available from: https://pubmed.ncbi.nlm.nih.gov/32613148/