How does SGLT2 inhibition improve heart failure?

How does Sodium Glucose Cotransporter-2 (SGLT2) inhibition improve heart failure?

Different ways by which SGLT2 inhibition can improve heart failure are [1]:

1. Natriuresis
2. Osmotic diuresis

These in turn leads to reduction of plasma volume and preload. An associated decrease in blood pressure, after load and arterial stiffness follows. Reduction in afterload can improve subendocardial blood flow as well.
SGLT2 inhibitors are a new class of oral hypoglycemic agents. EMPA-REG OUTCOME trial with Empagliflozin (Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) [2] and CANVAS Program (Composite  of Canagliflozin Cardiovascular Assessment Study and CANVAS-R) [3] are the two important initial studies which demonstrated favorable cardiovascular effects with SGLT2 inhibitors. CANVAS-R was CANVAS Renal study. Total number of participants in CANVAS Program was 10,142, who had type 2 diabetes mellitus with high cardiovascular risk.

Four main potential reasons for protection against heart failure hospitalization by SGLT2 inhibitors [4]:

1. Contraction of plasma volume and reduction of blood pressure reducing preload and afterload.
2. Increased ketone production can be used for the production of ATP by the myocardium more efficiently.
3. Inhibition of sodium-hydrogen exchange in myocardial cells can lead to reduction of hypertrophy, systolic dysfunction, fibrosis and remodeling.
4. Reduced arrhythmic risk possibly due to suppression of sympathetic nervous system leading to lower sudden cardiac death.

Other proposed cardioprotective effects of SGLT2 inhibitors

Several other potential mechanisms for cardioprotection with SGLT2 inhibitors include [5]:

1. Increase in erythropoietin levels and erythropoiesis
2. Reduction in hyperuricemia mediated by glycosuria
3. Decreasing epicardial fat mass
4. Improving vascular function
5. Prevention of ischemia/reperfusion injury
6. Reduction of inflammation

Key advantages of SGLT2 inhibitors are their efficacy in treatment and prevention of heart failure, efficacy on top of excellent background therapy including ARNI (angiotensin receptor neprilysin inhibitor) blockade, rapid onset of benefit, efficacy independent of glycemic status and associated renal protection [5].

References

1. Lytvyn Y, Bjornstad P, Udell JA, Lovshin JA, Cherney DZI. Sodium Glucose Cotransporter-2 Inhibition in Heart Failure. Potential Mechanisms, Clinical Applications, and Summary of Clinical Trials. Circulation. 2017;136:1643-1658.
2. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015 Nov 26;373(22):2117-28. 
3. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR; CANVAS Program Collaborative Group. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017 Aug 17;377(7):644-657. 
4. Cherney DZ, Odutayo A, Aronson R, Ezekowitz J, Parker JD. Sodium Glucose Cotransporter-2 Inhibition and Cardiorenal Protection: JACC Review Topic of the Week. J Am Coll Cardiol. 2019 Nov 19;74(20):2511-2524.
5. Lopaschuk GD, Verma S. Mechanisms of Cardiovascular Benefits of Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitors: A State-of-the-Art Review. JACC Basic Transl Sci. 2020 Jun 22;5(6):632-644.