Dr Clyde Yancy: We Must Continue to Explore Why SGLT2 Inhibitors Are Effective in HF

We do not yet know the exact mechanism of action of sodium glucose co-transporter-2 (SGLT2) inhibitors in heart failure (HF), but there are many exciting pssibilities, stated Clyde W. Yancy, MD, MSc, of Northwestern University’s Feinberg School of Medicine.

We do not yet know the exact mechanism of action of sodium glucose co-transporter 2 (SGLT2) inhibitors in heart failure (HF), so we must explore the possibility that a novel mechanism is at work, stated Clyde W. Yancy, MD, MSc, professor of medicine, chief of cardiology, and vice dean for diversity and inclusion at Northwestern University’s Feinberg School of Medicine.


Are we learning more about why SGLT2 inhibitors are so effective at reducing heart failure related hospitalizations?

We’d love to say that we've sorted out the mechanism of action of the [SGLT2] inhibitors. We can think only about what we know is not happening. For example, every other heart failure therapy that's been shown to be beneficial has been associated with reverse remodeling, restoring the original geometry and function of the heart muscle—except with the SGLT2 inhibitors. We have seen insufficient data to say that that's the mechanism. Other therapies that are beneficial in heart failure retard or reduce neurohormonal activation. We don't see a real strong signal of that either.

What that means, then, is that we must consider that there is a novel mechanism not previously explored. Some of us think that might be in mitochondrial respiration. Some of us think that might be with mitochondrial energetics. But here is something that we do know: Small numbers, they’re very compelling. When we administer a loop diuretic to decongest the patient with symptomatic heart failure, there is a concomitant exaggeration of a neurohormonal activation cascade, almost attenuating any potential benefit we might get from volume contraction. With the SGLT2 inhibitors, there is an increase in the fractional excretion of sodium, so it does function as a diuretic, when in addition, there is not an elaboration of these same neural hormones.

Does that mean that the SGLT2 inhibitors are a better diuretic and the diuretic is more in line with homeostasis of the cardiovascular profile, particularly the neuronal activation cascade? It's just theoretical. But the point that I make here is that in the context of everything else that we're exploring, what happens to hemoglobin, for example, when we give the SGLT2 inhibitor? What happens to collagen turnover?

There's so many exciting considerations. None yet have come forward as the mechanism, and it may be multiple mechanisms. But it's very clear that we're in new territory, and we're eager to find these new questions and then solve these new answers, because I don't think that what we've known previously is going to apply to this drug.

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