Dennis Scanlon, PhD: Bob, what have we learned about the mechanism of action of SGLT2 (sodium-glucose co-transporter 2) inhibitors that explains the cardiovascular effects?
Robert Gabbay, MD, PhD: It’s a great question. To be honest, I think the results were surprising and I don’t think many people expected there to be the dramatic effect that there was. And so, trying to figure out why that was is really a little bit of thinking backwards, and trying to understand the way the drugs work and, therefore, what it could do. What we do know about SGLT2 inhibitors is they result in a little bit of dieresis and volume contraction, and that, certainly, could be one of the factors (particularly in terms of congestive heart failure incidence and hospitalizations for congestive heart failure), which they saw benefit for. There’s also a small amount of weight loss which could also be a factor.
There was a regression model that took the data from the EMPA-REG OUTCOME trial and tried to look at this, and (to whatever degree you could believe that you could go back afterwards and do this kind of analysis), about half of the effects seemed to be volume related. They uncovered another strong correlation which, hard to know clinically, this makes sense, but it is at least hypothesis generating—there seemed to be a correlation with uric acid levels. Whether that’s an explanation or an epiphenomenon is difficult to know for sure. So, I think we have some theories as to why this has been effective, but it was a surprising result and we’re left to try to figure it out.
Dennis Scanlon, PhD: What do we need to do to go beyond those theories and try to get that causal mechanism?
Robert Gabbay, MD, PhD: I think we need to study designs, as Dr Inzucchi mentioned, that would tease that out. So, either you’re comparing it to another drug or you’re controlling things more effectively to be able to look at contributions. And I guess the other big piece of all of this (and I know we’ll be talking about this) is class effect or not. And if it is not a class effect (where you don’t see the results corroborate), does that tell you something that is a hint into what the mechanism is?
Zachary Bloomgarden, MD: There’s another finding of the empagliflozin trial, EMPA-REG, which is fascinating and may shed light on this— the effect on renal disease. Another very important publication looked at renal outcomes, and it appears that these drugs are not just diuretics but they act on sodium secretion, very proximally, in the kidney in such a fashion as to, in a certain sense, work in a lovely way with angiotensin blocking agents. So, at the level of the macula densa, delivering more sodium to that part of the kidney seems to then potentiate the benefit of not having so much angiotensin action on board. Well, this fits very nicely into a lot of our clinical knowledge of what’s good for heart failure and our theoretical ideas of what’s good for the heart and what’s good for the kidneys.
Silvio Inzucchi, MD: I think we really need mechanistic studies, at this point, to understand, in retrospect, what we found in this large clinical trial. It’s really exciting, not only from a cardiovascular standpoint but also from the renal standpoint, which is another scourge of diabetes—the end-stage renal disease. And, as Dr Bloomgarden pointed out, there was about a 40% reduction in the development of the composite renal outcome in EMPA-REG OUTCOME, which was the combination of a doubling of serum creatinine, persistent microalbuminuria, the need for dialytic therapy, end-stage renal disease, and renal death. And that was not driven solely by the microalbuminuria, which some nephrologists feel is a softer endpoint than something quite hard like the need for dialysis or doubling of serum creatinine. So, it’s really causing us to go back and try to understand the physiology of the renal tubule. And, as Dr Bloomgarden pointed out, this may be a special, unique type of diuretic class because of the proximal effect on sodium excretion. Perhaps bathing the macula densa with sodium can lead to an attenuation of the normal neurohormonal activation (renin-angiotensin antidiuretic hormone) that could have counterproductive effects in, particularly, patients with left ventricle dysfunction.
Robert Gabbay, MD, PhD: And, of course, we know that nephropathy is a major risk factor for cardiovascular disease. And so, one could imagine a mechanism through which nephropathy is improved and because of that, can lower your risk for cardiovascular disease.