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Clinical Evidence Supporting Cardiovascular and Renal Indications in SGLT2 Inhibitors and GLP-1 Receptor Agonists


Om P. Ganda, MD, provides an overview of the clinical trials supporting the use of SGLT2 inhibitors and GLP-1 receptor agonists in cardiovascular and renal indications, and Jeffrey Turner, MD, comments on the kidney disease outcome measures of these trials.

Neil Minkoff, MD: Let’s dive into these SGLT2 inhibitors. Dr Ganda, could you tell us about each of the 3 entries and help us understand how they fit into your treatment paradigms?

Om P. Ganda, MD: We have the luxury of having benefited and learned from so many of these trials in the short span of 5 or 6 years. Starting with the SGLT2 inhibitors first, EMPA-REG OUTCOME was the first study that came out that showed a dramatic reduction in heart failure and in cardiovascular mortality. The curve started to diverge within weeks, and that was unheard of…except for maybe the occasional study like PROVE-IT. That was then replicated by DAPA-HF. There were 3 major cardiovascular trials: EMPA-REG, CANVAS, and VERTIS CV, as well as other trials that followed. Then there were dedicated trials for heart failure that included the EMPA heart failure and DAPA heart failure.

There are 2 kidney trials that have been done with SGLT2 trials. The first one was CREDENCE, which opened everybody’s eyes and showed a dramatic reduction in the progression of kidney disease and cardiovascular mortality in patients who already had proteinuria going from 300, 500 mg, all the way to nephrotic range. Of course, they had an eGFR [estimated glomerular filtration rate] down to 30, but most people were between the range of 45 and 60. That kind of dramatic effect was previously unheard of. We waited for a second trial to come out, and that was the DAPA-CKD trial. That showed a similar effect in people with or without diabetes, like in DAPA-HF—same type of effect, but the eGFR baseline was actually a little bit lower. They took people with a GFR of 25 or so. We have a new study that is still going on, the EMPA-KIDNEY trial, which has taken people with even more advanced kidney disease, with the GFR going down to 20. The question comes up of what level is safe to initiate these drugs because we have a large burden of kidney disease, but right now, there is an FDA-approved indication for both drugs, canagliflozin and dapagliflozin, for kidney disease protection, as well as cardiovascular disease protection. That’s a quick summary of the 3 areas in which SGLT2 trials have been carried out.

Now we’re looking at whether these drugs can even be effective for people with SGLT2 preserved ejection fraction and heart failure with preserved ejection fraction. I’m sure Dr Desai can talk more about that later if we have time. We know from the…study, a small subgroup, there was no heterogeneity between the 2 groups. The study that is looking at people with preserved ejection fraction is going to be presented in a few weeks in Europe with empagliflozin. We have results from similar trials yet to come, but we are looking at expanding the landscape, going not only from heart failure with reduced ejection fraction, but even those with preserved ejection fraction.

There are many trials with GLP-1 receptor agonists in the cardiovascular field as well, and we have found that the major primary end points were met, at least in 3 of these trials—LEADER trial, followed by the semaglutide trial, and the latest trial presented at the ADA [American Diabetes Association] and published in the New England Journal of Medicine just a few weeks ago. All of them confirm that these drugs have cardioprotective effects. What about heart failure? That’s where they differ, and it’s so far less of a consensus and not as much of an effect with these agents on heart failure protection.

Finally, renal disease. Unlike SGLT2, there is no dedicated trial yet in people with CKD [chronic kidney disease] with GLP-1 receptor agonists. They reduced proteinuria in almost all of these studies that have been positive for cardiovascular disease, including LEADER and the semaglutide trial. That’s not a hard end point. Dr Turner will agree. We need to look at the hard end point, currently defined as prevention of GFR reduction to more than 40% from baseline, or requiring renal replacement therapy, including dialysis and transplant, or renal death. That’s the standard end point that we need to look at. That end point has not been shown to be met by any GLP-1 receptor agonists yet. We have a new trial underway called FLOW, and that trial will take a few years to complete, but that’s the first dedicated trial for CKD with GLP-1 receptor agonists.

Neil Minkoff, MD: That was quite the tour de force. One of the things from my point of view that we struggle with, in terms of trying to understand these medications, is the effect on the kidney. There are results that might have not been reported yet about microalbuminuria. Jeff, can you shed light on this?

Jeffrey Turner, MD: With renal outcomes, what we’ve come to learn over the years from many failed trials is that surrogate outcomes can be misleading, and proteinuria is a surrogate outcome that has been abandoned for good measure. As Dr Ganda pointed out, the new bar that has been promoted to get a drug approved by the FDA for renal outcomes is showing a reduction in GFR less than 40% in kidney disease requiring dialysis or renal death. That composite outcome is the hard outcome that needs to be met to show that any drug is truly going to be beneficial to kidney function in the long- term. It’s good when proteinuria goes down along with it because we feel that’s a mechanism that probably contributes to how the kidney disease progresses, but it’s no longer accepted as a standard outcome.

Transcript edited for clarity.

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