Heart failure & diabetes: SGLT2 inhibition, a paradigm shift?
Until very recently, heart failure as a problem in diabetes was largely ignored, although it is one of the most common and most important complications in diabetes. But the EMPA-REG OUTCOME study6 put heart failure on the map; SGLT-2 inhibitors showed a remarkable reduction in heart failure hospitalisation and mortality.
How is heart failure prevented and mortality reduced by SGLT-2 inhibitors, and can these medications be used to treat established heart failure?
There are multiple possible explanations for the prevention of heart failure and reduction of mortality by these medications. These include the direct and indirect action on the myocardium, other myocardial effects such as through the extracellular matrix, antiarrhythmic effects, blood pressure-lowering and reducing sodium or extracellular fluid volume by the kidneys or other renal effects. Dr. McMurray further elaborated on these mechanisms.
A direct action of SGLT-2 inhibitors on the myocardium could be through a shift in myocardial energetics, resulting in a more fuel efficient heart. It is proposed that the heart metabolism is shifted away from fatty acids and glucose towards ketones. Indirect actions on the myocardium may also involve increased efficacy, thereby resulting in anti-ischaemic effects or reduced myocyte necrosis. But there is no evidence for this. Nevertheless, the EMPA-REG OUTCOME trial excluded a direct effect of SGLT-2 inhibitors on myocardial infarction as the number of these events were not reduced. Furthermore, SGLT-2 inhibitors may potentially cause an antiarrhythmic effect through a reduction in extracellular fluid volume, reducing atrial pressure and subsequently atrial arrhythmias. But so far, this remains only speculation.
More evidence exists on the effect of SGLT-2 inhibitors on blood pressure-lowering and heart failure. Many studies have shown the benefit of blood pressure-lowering on heart failure. Although the EMPA-REG OUTCOME study showed only a marginal reduction of 4-5 mmHg systolic blood pressure by SGLT-2 inhibitors, a meta-analysis showed that even a modest decrease in blood pressure reduction can result in a substantial decrease in the development of new-onset heart failure7. Moreover, blood pressure acts on the cardiac volume as well as on sodium concentrations. And on the other hand, sodium concentrations can also be altered by the diuretic effect of SGLT-2 inhibitors. The strong effect of diuretics on heart failure reduction has been evidenced by multiple studies. The diuretic and natriuretic effects of SGLT-2 inhibitors also reduce intravascular volume and thereby preload and perhaps also afterload. It is known that reducing the cardiac afterload and also preload improves the cardiac function. Taken together, the cardiac load, diuretic effect as well as the blood pressure-lowering may be critical in explaining the significant reduction in heart failure observed in the EMPA-REG OUTCOME trial. In addition, as it has been shown in several trials that blood pressure-lowering can have a very fast effect on heart failure incidence, this may explain the early benefit from SGLT-2 inhibitors observed in the EMPA-REG OUTCOME trial. Other large evidence regarding the heart failure benefit with SGLT-2 inhibitors comes from the renal function, as is known that the cardio-renal axis is critical in heart failure. Moreover, it was very recently shown that the incidence of worsening renal function in the EMPA-REG OUTCOME trial was remarkably decreased with SGLT-2 inhibitors.
Heart failure is related to mortality, which may explain the reduced number of mortality seen with SGLT-2 inhibitors. This relationship has been shown in the RECORD and SAVOR-TIMI-53 trials8,9; patients who develop heart failure have a 3- to 4-fold and 4-5-fold increased risk of mortality, respectively. Death as a result from heart failure is caused by either worsening heart failure or lethal ventricular arrhythmias. It is, however, not clear yet whether deaths are related to heart failure with a preserved or reduced left-ventricular ejection fraction.
Using SGLT-2 inhibitors to treat heart failure is an interesting thought and needs further investigation. Remarkably in the EMPA-REG OUTCOME study, patients with heart failure at baseline had a treatment benefit with SGLT-2 inhibitors similar to patients without heart failure, which seems promising.