CV Risk in T2D: Role of SGLT2 Inhibition

Keith C. Ferdinand, MD, FACC, FAHA, FASH, FNLA: I’m going to go back to kidney disease because I know, Peter, that’s something you’re really interested in. But let’s stick with the cardiovascular events. You agree the SGLT2 [sodium-glucose cotransporter 2] inhibitors have a place for cardiovascular events?

Seth J. Baum, MD, FACC, FACPM, FAHA, FNLA, FASPC: Oh my god, yes. I think that really revolutionized cardiovascular medicine because now when we see our patients with diabetes, we can no longer say, oh yeah, talk to your endocrinologist or your diabetologist. We have to say are you on that medicine, if they have established cardiovascular disease, and if they’re not, you have to ask yourself why they’re not.

Keith C. Ferdinand, MD, FACC, FAHA, FASH, FNLA: Even if their A1C [glycated hemoglobin] is controlled, you still think there may be a benefit there?

Seth J. Baum, MD, FACC, FACPM, FAHA, FNLA, FASPC: Yes. In fact, you mentioned several trials, in those trials there was no difference. When doing subgroup analyses, there was no difference in outcomes when baseline hemoglobin A1Cs varied quite significantly or even when drop in hemoglobin A1C varied significantly. Everybody responded the same.

Keith C. Ferdinand, MD, FACC, FAHA, FASH, FNLA: OK. I don’t want to get too deep. Keep it kind of simple for me, why these drugs work, Peter. What do they do?

Peter McCullough, MD, MPH, FACC, FACP, FAHA, FCCP, FNKF: They have an effect where they block any abnormal reclamation of glucose from the urine. So paradoxically, in diabetes, there’s actually greater amounts of glucose in nascent urine. All glucose, by the way, is filtered. It ends up in the urine and then the body calls it back.But in diabetes, more of the glucose is brought back. So the drugs block those channels, but they also are blocking sodium transport at the same time. So glucose and sodium go downstream. There probably is a whole myriad of effects of feedback between the tubules and the glomerulus. The glomerulus initially drops its filtration a little bit. So GFR [glomerular filtration rate] actually drops on these drugs a little bit, but then it’s much more sustained over time.

And as Chris pointed out, there’s actually less progression of proteinuria, there’s less doubling of serum creatinine, and there’s less cases of end-stage renal disease. So there looks like there’s a bona fide renal protective benefit. There’s a great search to explain deeper mechanisms. For instance, there is homology of the SGLT2 channel with what’s called the sodium-hydrogen antiporter channel. And this is a channel that’s been a drug target in prior clinical trials of other attempts to try to protect the myocardium. So there’s great homology. There’s now been binding that’s been demonstrated. So this may evolve into a story of a pleiotropic effect. This class of drugs does more than just lower hemoglobin A1C.

Keith C. Ferdinand, MD, FACC, FAHA, FASH, FNLA: So it’s not just about urine and having more urine put out. There are some other things metabolically that may be going on.

Peter McCullough, MD, MPH, FACC, FACP, FAHA, FCCP, FNKF: Yes. And this change, while these channels are located in the kidneys and some of the channels are also in the gut, that the body, once it gets into a mode of losing glucose, there’s a variety of changes. There’s a shift toward a ketone metabolism. As an example, there’s changes in, as Chris pointed out, body weight. So it’s interesting. Patients lose calories, but they don’t seem to reconsume those calories and maintain body weight. In all the studies, body weight comes down, blood pressure comes down. It really is a very interesting development.

Keith C. Ferdinand, MD, FACC, FAHA, FASH, FNLA: Chris?

Christopher P. Cannon, MD: Another point in the kidney protection is that this is on top of the benefit from ACE [angiotensin-converting enzyme] or ARB [angiotensin receptor blocker], and it’s different mechanisms. It’s either side of the glomerulus I think that’s helping. And so we’re looking like we are making an additive step, and we’ll have 2 ways to help protect the kidneys that are under siege in diabetes.

Keith C. Ferdinand, MD, FACC, FAHA, FASH, FNLA: Intraglomerular pressure must be part of it because you see that same little drop in the GFR with ACE and ARBs, correct?

Peter McCullough, MD, MPH, FACC, FACP, FAHA, FCCP, FNKF: Well as Chris pointed out, with ACE or ARBs, the reason why that drops is this efferent arteriole, this vasoconstriction with ACE or ARB is relieved, and so there’s efferent vasodilation. With the SGLT2s, one of the theories is their tubular glomerular feedback, that in fact the efferent arteriole, the input is reduced. So, while the input is reduced with the SGLT2, the output is opened up with the RAS [renin-angiotensin system] inhibition, and so therefore, the glomerulus is very much depressurized.

Keith C. Ferdinand, MD, FACC, FAHA, FASH, FNLA: So we’re not taking away the benefit of the ACE or ARB. This is an additional benefit.

Peter McCullough, MD, MPH, FACC, FACP, FAHA, FCCP, FNKF: They appear mechanistically and clinically very complementary.

Transcript edited for clarity.