Management of Diabetes and Renal Impairment - Episode 2

Risks and Complications for Chronic Kidney Disease

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An expert endocrinologist and cardiologist discuss the risks and complications of renal disease associated with diabetes and cardiovascular disease. Dr Robert Busch also provides an overview of some of the studies done in renal impairment.

Dhiren Patel, PharmD, CECES, BC-ADM: Dr Busch, can you talk to us about what we’ve had available to us as we manage CKD [chronic kidney disease] in patients with type 2 diabetes? We’re getting to a point where it’s not just patients with type 2 diabetes who can benefit from this. Could you talk to us a little about some of the options, risks, and complications that we’re trying to mitigate with this additional pharmacotherapy?

Robert Busch, MD: Until fairly recently, all we had were the ARB trials with RENAAL and the Irbesartan Diabetic Nephropathy Trial. If you recall, this came out the week after 9/11, so in 2001, it showed it lowered end-stage renal disease by 16%. What we don’t recall is there’s still huge persistent renal disease. It lowered it, but it’s still 40% in the treated groups, so we can still do a lot better. Many trials have been done with other drugs that were unsuccessful. When the SGLT2s were studied in the cardiovascular [CV] trials, interestingly, each of the trials showed a renal composite that was beneficial in terms of lowering dialysis or lowering GFR [glomerular filtration rate]. But they didn’t get the indication until dedicated renal trials were done.

The first renal trial was the CREDENCE trial with canagliflozin. They took patients whose urine microalbumin were over 300 mg/dL and GFR 30 to 75 mL/min. This trial showed that it lowered renal composite by 30%. Canagliflozin had the label that in a patient with type 2 diabetes with urine microalbumin over 300 mg/dL; they can be on canagliflozin 100 mg until they’re on dialysis. It lowered the high-speed train to dialysis. Instead of going down rapidly, it would level it off.

Dapagliflozin was studied in patients who did and didn’t have diabetic nephropathy. You had type 2 diabetes or patients with other types of nephropathy from hypertension or other illnesses. GFR there was 25 to 75 mL/min, urine microalbumin over 200 mg/dL, and the trial was stopped early. In 2.4 years, it ended up lowering end-stage renal disease 39%. This was on top of the RAS blocker. The patients were on a RAS, and this was on top of that. Then the EMPA-KIDNEY trial is still ongoing. In that study, they have GFR down to 20 mL/min with no requirement for proteinuria. We’ll see what goes on there.

Finally, a study has come out called the FIDELIO-DKD trial with the drug finerenone. It’s an aldosterone blocker but different from the other standard aldosterone blockers. In that trial, giving it on top of a RAS blocker in patients with diabetes lowered end-stage renal disease 18%. That drug isn’t on the market, but it’s soon to be. We’re going to have a whole array beyond ARBs that will benefit patients. So it’s no NSAIDs [nonsteroidal anti-inflammatory drugs], no COX2s, avoid dye studies, keep well hydrated, raise your ACE or ARB, raise your SGLT2, and maybe down the line raise your finerenone.

Dhiren Patel, PharmD, CECES, BC-ADM: Excellent. As we hear from the cardiology perspective, I have a question. I know I’m in this boat. I don’t think we really appreciated the CV risk that exists in patients with CKD and renal impairment. Now that we’re hearing more about the MRA [magnetic resonance angiography] and other options, and we’re starting to see the SGLT2 data, it’s been more front and center. If you can, talk about the CV risk there. We talk about it in diabetes, but we fail to talk about it. Maybe it’s because we never had anything that we can do for that. If you could shed some color there.

Muthiah Vaduganathan, MD, MPH: Absolutely. Unfortunately, cardiovascular disease is the leading cause of death among patients with chronic kidney disease, especially among those who progress to end-stage kidney disease. As we learn more, there’s no coincidence that the progress made in heart failure with reduced EF [ejection fraction] to identify 4 pillars of therapy have striking overlap with emerging pillars for chronic kidney disease, inclusive of renin angiotensin system inhibitor, MR [mineralocorticoid] antagonist, and an SGLT2 inhibitor. Three of the pillars are common to both disease states. That highlights the overlap in clinical practice of these conditions and the common disease mechanisms that facilitate ultimate disease progression and clinical events in practice.

We’re learning much more. I see so many parallels with what has happened in heart failure care where we have a long drought in therapeutics and then rapid progress. Very soon, we’ll be having identical conversations about how to implement multiple therapies. Short of definitive clinical outcomes, there are really promising data with the GLP1 receptor agonists in slowing albuminuria especially, as well as safely lowering and improving glycemic control, even in advanced CKD. There are also investigational therapies, such as an endothelin receptor antagonist called atrasentan, which also similarly improved renal risk in patients with chronic kidney disease. A multitude of therapies are coming to the forefront of care. Chief among them are those that modify cardiovascular disease pathways. It’s an exciting area ahead.

Transcript edited for clarity.