John B. Buse, MD, PhD: One of the most interesting questions about the SGLT2 inhibitors is, how is it that cardiovascular risk is reduced by these agents? There are the straightforward, potential answers like, “It lowers glucose.” Because it’s associated with loss of glucose in the urine, losing calories, it is associated with weight loss. It’s also associated with a reduction in blood pressure. But the benefit seems to be greater than would be expected by those sorts of modest effects on classic cardiovascular risk factors.
It has been suggested that a number of mechanisms might be operative, one being that these drugs increase the amount of ketone bodies that circulate. These ketone bodies are important fuels, particularly for the heart, the brain, and the kidney. And there is a greater efficiency when tissues use ketone bodies as a fuel, as opposed to using glucose or fatty acids. That efficiency might really translate into particular benefits in the ischemic heart, the injured brain, or the failing kidney. So, that’s an idea that’s out there now. I’m not sure that’s the answer, because the increase in ketone bodies is really pretty modest, but it’s certainly one of the possibilities.
The other is that perhaps it’s more of an osmotic effect, a diuretic effect. I think there is some evidence that that’s not really the mechanism. Some suggest that it might be an anti-inflammatory effect. I think we really don’t know what the mechanism is. The benefit is really shockingly large, and it is of great interest to figure out how this large benefit occurs, because perhaps we can target those pathways more directly.