Updates in the Management of Chronic Kidney Disease and Type 2 Diabetes - Episode 16

Emerging Therapies for Chronic Kidney Disease

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An overview of therapies in the pipeline, including other nonsteroidal MRAs, that show potential in treating patients who have chronic kidney disease and type 2 diabetes.

Neil B. Minkoff, MD: Let me get you to continue on in this vein a little as we think about the pipeline and treatments potentially coming down the road for CKD [chronic kidney disease] and diabetes. There are other drugs in the pipeline. Maybe you could give us a primer.

George L. Bakris, MD: SGLT2 inhibitors have arrived. It’s in your face in the diabetes guidelines that they should probably be used simultaneously with metformin if you have kidney disease or heart failure. You want to start metformin for glucose control, that’s fine. If you’ve got kidney disease or heart failure, SGLT2s must be part of the initial therapeutic strategy. So they’re there.

There are 3 other agents in this new family of nonsteroidal mineralocorticoid receptor antagonists [MRAs] that are being developed, and 1 is approved. Esaxerenone is approved in Japan for blood pressure. It’s an antihypertensive. Finerenone isn’t. It doesn’t have significant blood pressure-lowering ability. But this one is. It also reduces albuminuria, which they’re now looking at in other studies.

There’s apararenone, which showed albuminuria reduction in a phase 2 trial just published, but that’s also an antihypertensive drug. Placebo-subtracted, it’s got a 6 mm Hg reduction in blood pressure. These are blood pressure-lowering drugs. And if that wasn’t enough, there’s another compound by KBP Biosciences called KBP-5074, which we just published a phase 2 trial on and are starting a phase 3 trial for resistant hypertension as a blood pressure-lowering agent, and that beats the pants off the other 2, with a 10 mm Hg placebo-subtracted blood pressure reduction.

Does it lower albuminuria? Yes, it does, but you’d expect that with that much blood pressure reduction. These agents are not the same as finerenone. And as Rajiv pointed out, this is a bit of a designer drug that you’re going to find on the Champs-Élysées vs the others that were somewhat offshoot molecules that are more in blood pressure lowering. And the KBP is going after resistant hypertension in kidney disease, but not going after prevention of kidney disease.

So there are differences coming, and there are going to be more data with the SGLT2s coming. And—hang on to your seat—there are going to be GLP-1 data with semaglutide on kidney disease published in 2023 from the FLOW trial. There’s a lot of stuff happening in kidney disease treatment.

Neil B. Minkoff, MD: Do you consider these new agents almost like a whole new class of medication for this disease state? Is this a new burgeoning field?

George L. Bakris, MD: There’s no question. The FDA has called them a new class, so they’re a new class of agents for diabetic kidney disease. They shouldn’t be compared with spironolactone or eplerenone because they’re not the same on many levels. They’re already proven to show benefit, and they’ll be in the 2022 ADA [American Diabetes Association] guidelines. We’re there, and the No. 1 question Rajiv and I are asked bar none—we haven’t talked about this but I bet a dollar Rajiv isn’t going to disagree with me—is what about the combination of SGLT2s and finerenone?

Neil B. Minkoff, MD: You read my mind.

George L. Bakris, MD: Yes, that’s a natural marriage. They have 2 distinct mechanisms and both independently protect the kidney. There’s an animal data paper. The human data are limited, and I’ll tell you about that in a second. But there’s a paper in animal studies just published in the American Journal of Nephrology showing additivity between low-dose SGLT2 and low-dose finerenone on albuminuria, changes in glomerular fibrosis, and inflammation within the kidney.

It does make sense to combine them, and we have data from the FIDELITY analysis where if you were on an SGLT2, you definitely [benefited]. It wasn’t something that’s statistically significant. We didn’t have large numbers. There are a lot of caveats with what I’m about to say, but there’s no question that if you were on an SGLT2 and finerenone, you did better than if you weren’t on an SGLT2. There are a number of reasons that the combination should be there. Can I defend it with outcome data? No, I can’t.

Eugene Wright Jr., MD: George, there’s also some literature coming out about the combination of SGLT2s with MRAs to reduce hyperkalemia.

George L. Bakris, MD: Yes, excellent point. I didn’t mention that. SGLT2s do mitigate against hyperkalemia, and there are some publications looking at SGLT2 impact on MRAs and reducing the risk for hyperkalemia. So that’s absolutely correct.

Transcript edited for clarity.