Learning More About SGLT2 Inhibitors for Heart Failure

Transcript: Deepak L. Bhatt, MD, MPH: I’ve got to give a chance here for George to opine, Scott, because you were talking about the kidney and he might be offended. He doesn’t like when cardiologists speak too much or too authoritatively about the kidney. George, is everything Scott said accurate? Do we need to keep him honest?

George Bakris, MD: No, what he said was on point. But I think it’s important to understand, and I’ve already put this in print, that this class of drugs, the SGLT2s [sodium glucose cotransporter 2s], are cardiorenal risk-reducing agents that happen to have glucose lowering as a beneficial adverse event. What I mean by that is all of these original studies that Scott talked about had people with GFRs [glomerular filtration rates] in the 60s, 70s, and 80s. So people walked away thinking, “Well, this is a mild diuretic,” and off they went. This couldn’t be further from the truth. The CREDENCE trial, which was a pure renal trial with pure renal end points and a mean GFR in the 40s that also looked at cardiovascular medications, looked at 4400 patients. The trial was stopped early for overwhelming efficacy. The primary end point was dialysis or a greater than 50% reduction in GFR, along with cardiovascular death. The bottom line was there was a 30% risk reduction, and that’s on top of ACEs [angiotensin-converting enzymes] or ARBs [angiotensin receptor blockers]. So clearly, there was a message there.

What has not yet published but has been submitted and presented as a late-breaker at the American Society of Nephrology is a subgroup of people with GFRs below 30. There were 174 patients in that trial with GFRs at baseline below 30, and they received the same benefit that the whole group did. So this is not a diuretic effect. Glucose lowering was 0 there. But there are some very interesting mechanistic things coming out. A very recent paper and good study showed that dapagliflozin, compared with chemical denervation, gave you the exact same effect. In other words, these drugs are reducing sympathetic tone by affecting innervation at the proximal tubule. This was a beautiful study, and it makes sense. That’s why you get the same reduction in blood pressure in a GFR of 30 that you do with a GFR of 70. And if you’re a believer—that denervation helps heart failure—it could be a contributing mechanism. This hasn’t been studied, but it’s there.

I think if you put that together with the beautiful data that led the FDA to indicate it down to a GFR of 30… The DAPA-CKD study was just stopped for overwhelming efficacy. While the baseline data are not published, I can tell you that they set up recruitment to have a minimum of 30% of that trial not have diabetes—so I think that’s an important point—and only a maximum of 10% GFR above 60. So this is a pretty sick group of patients. I think it’s 4200-plus patients. We’re going to find out what the results are soon. But, no question about it, I think what we saw in DAPA-HF, we’re going to see in DAPA-CKD. By the way, we did an analysis in CREDENCE with a GFR in the 40s and basically showed the benefit for heart failure was still seen there. So, it was not restricted to people with good kidney function.

This cuts across everything. There are multiple mechanisms, and you can’t just pick 1. But I think to walk away thinking this is tubuloglomerular feedback and diuresis couldn’t be further from the truth.

Deepak L. Bhatt, MD, MPH: Yeah, I think that’s really terrific. CREDENCE was clearly a homerun. And DAPA-CKD, at least from a press release, is looking good. We need to see the details, obviously, but the press release made things sound promising. As you mentioned, the study of people without diabetes in there would be particularly informative.

Along those lines, Scott, what about DAPA-HF? That taught us a lot about SGLT2 inhibitors in those with heart failure with reduced ejection fraction, with, but importantly, without diabetes as well.

Scott David Solomon, MD: Yeah, it certainly did. In DAPA-HF, we saw a similar benefit in those with and without diabetes. We also saw a similar benefit in those on mineralocorticoid receptor antagonists, or not; in patients on ARNIs [angiotensin receptor neprilysin inhibitors], or not; and in virtually every subgroup that we looked at—the patients with lower ejection fraction, higher ejection fraction, lower GFR, higher GFR, across the board. We saw a similar pattern to the GFR, to the reduction in renal events, but we didn’t have the power in DAPA-HF to show what CREDENCE showed or probably what DAPA-CKD is going to show. But, we do see a flattening of the GFR slope over time. It’s really fascinating.

Transcript Edited for Clarity