The Promise of SGLT-2 Inhibition in Heart Failure

The Promise of SGLT-2 Inhibition in Heart Failure
Elizabeth So, Pharm.D, MBA, Cub Pharmacy 

Recent studies have demonstrated that antidiabetic agents can significantly reduce cardiovascular risk, but only sodium-glucose cotransporter 2 (SGLT2) inhibitors can reduce the risk of the development or progression of heart failure. Two large studies examining empagliflozin (EMPA-REG Outcomes) and canagliflozin (CANVAS) support this finding. In the EMPA-REG trial, statistically significant decreases in hospitalization for heart failure, incidence of heart failure, and use of newly-prescribed loop diuretics were observed. The CANVAS trial found a decrease in the hospitalization for heart failure, however this was not considered statistically significant. While these studies and other existing data support the ability of SGLT-2 inhibitors to prevent heart failure, there is no data on their ability to treat patients with established heart failure. 

SGLT-2 inhibitors do not appear to exhibit their cardioprotective effects through glucose reabsorption. The most common proposed mechanism is diuresis. Certain diuretics reduce the incidence of heart failure in patients at increased cardiovascular risk through their short-term increase in urine volume, followed by a sustained decrease in systolic blood pressure.  In addition to these effects, SGLT-2 inhibitors have sustained reduction of body weight and plasma volume, without electrolyte disturbances. These important differences imply that SGLT-2 inhibitors do not simply act as conventional diuretics. 

The cardioprotective effects of SGLT-2 inhibitors are better explained through natriuresis caused by inhibition of sodium-hydrogen exchangers (NHE3) in the kidneys and heart. The activity of NHE3 is increased in heart failure and believed to be responsible for resistance to diuretics and endogenous natriuretic peptides. In the kidneys, SGLT-2 inhibitors primarily act on the proximal tubule to reduce cardiac wall stress through natriuresis, hemoconcentration, and decreased body weight and blood pressure. SGLT-2 is not expressed in the human heart, but inhibition of SGLT-2 has been found to slow the development and progression of cardiac hypertrophy and cardiomyopathy in animal models. 

While studies support the benefit of SGLT-2 inhibition in preventing heart failure, further studies are needed to determine if they have a role as adjunctive treatment in patients with established heart failure.

References:
1.       Packer M, Anker SD, Butler J, et al. Effects of sodium-glucose cotransporter 2 inhibitors for the treatment of patients with heart failure: proposal of a novel mechanism of action. JAMA Cardiol. 2017;2(9):1025-1029.

2.       Neal B, Perkovic V, Mahaffey KW et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017; 377(7): 644-657.