Muthiah Vaduganathan, MD, MPH

Dr Busch, I’d love to hear a real-life example of 1 of your patients. We have a 78-year-old gentleman who has a long-standing history of diabetes, high blood pressure, and dyslipidemia. Could you walk us through how you approached this patient’s CKD [chronic kidney disease] and what you did for him?

 This gentleman was referred to us. He had diabetes, hypertension, and hyperlipidemia. He was on a statin. His LDL was at goal. His triglycerides were not high, and he was on a maximal-dose RAS blocker with quinapril. Often, patients who are referred in are on metformin and DPP4. He was on sitagliptin-metformin combination. His GFR [glomerular filtration rate] was in the 50s mL/min, and he had urine microalbumin in the 200s mg/dL.

He had stage IIIA chronic kidney disease. Previously he was on a RAS blocker. It was recommended, “Don’t take an NSAID or a COX2. If you go to a hospital, ask not to get x-ray dye if you could avoid x-ray dye, and don’t do any nephrotoxic drugs. Don’t take any over-the-counter drugs other than Tylenol. No Aleve, Motrin, or Advil.” We go through that every visit with the patient. There wasn’t much more you could do until recently, seeing the SGLT2 data that are out now. His A1C [glycated hemoglobin] was low 7%. We could say, “He’s 78-years-old, so low 7% isn’t so bad,” but we wanted to do better.

The goal when any of us walks in the exam room is, “What can I do better than the time before?” We added dapagliflozin 10 mg after seeing the results of Dapa-CKD. We also upgraded his DPP4 to a GLP1 for the weight and cardiovascular [CV] benefits. Dulaglutide has the primary prevention indication. This gentleman didn’t have previously known ASCVD [atherosclerotic cardiovascular disease], or he probably has some clinical disease. Instead of being on sitagliptin-metformin, he’s on GLP1 and metformin and dapagliflozin. The dapagliflozin specifically benefits the glucose as well, although the higher the GFR, the more glycosuria you would have. As we teach our students, if the kidney doesn’t see it, the kidney doesn’t pee it. You have to filter glucose.

 You’re giving the dapagliflozin. Even if the GFR were 30-something mL/min, you’re still giving the dapagliflozin to prevent worsening kidney disease, but there it wouldn’t benefit the sugar that much. We upgraded his DPP4 to GLP1, which has its glycemic benefit, and added the dapagliflozin for renal protection. Because we’re in the Northeast, instead of the Acela train to dialysis, hopefully we’re delaying that train to dialysis and we’re flattening the curve.

That’s a really good point on the eGFR [estimated GFR]. I remind our trainees the same thing. It’s not like a light switch that’s working at 45 mL/min but not at 44 mL/min. There’s a rate of diminishing return. You also need to recognize that it’s not always being looked at from the glycemic lens. We have a QI [quality improvement] project going on from renal in which everyone is getting dose maxed out on an ACE or an ARB. They’re looking at it from some of the other pleiotropic effects. We also know they’re not dose-dependent CV benefits or renal benefits. That’s a great real-life use case regarding the most recent data from Dapa-CKD.

As we close out this segment, I’d love it if both of you could share some closing remarks. We talked a little about diabetes as well as patients who don’t have diabetes and what you see happening in the next few years as more options become available. Do you have any parting comments regarding cardiovascular disease, CV risk, or some of the renal implications we talked about? We’ll start with you, Dr Vaduganathan.

 I have 2 comments. One is that I thought Dr Busch nicely framed that patients are acutely aware of their kidney function and especially their near-term risk of dialysis. That’s an event they ask about and want to avoid. Patient activation is a really important strategy to potentially overcome therapeutic inertia in these circumstances. Making patients aware that new strategies are available to delay the need for dialysis is an important message to the community.

The second is from a heart failure lens. SGLT2 inhibitors form 1 of 4 pillars of heart failure care. Uniquely, though, it’s 1 of the only, if not 1 of 2, therapies that actually slow kidney progression in heart failure. While earlier therapies like ACE inhibitors and ARBs in the context of patients with heart failure may have even accelerated kidney decline, in this case, SGLT2 inhibitors—for the first time—have been shown to definitively delay clinical events, including progression to dialysis. That’s another motivating feature and benefit seen even among high-risk patients with established heart failure.

I absolutely agree. Those were some relevant points. When you have a patient who’s motivated, the possibilities are endless. We’ve all had those patients who come in and want something or that intrinsic motivation is a big piece. Dr Busch?

 You almost have to think to yourself, “Why shouldn’t I give an SGLT2? Where’s your ACE or ARB? Where’s your statin? Where’s your SGLT2? Look at all the benefits. Prove to me you don’t need the SGLT2 just like the statin and the RAS blocker. If we get to that, we’ll do more benefit than harm. You’re not going to give it to someone who has 6 yeast infections and is on an antibiotic. You’re not going to sneak it into a man with BPH [benign prostatic hyperplasia] who’s urinating every hour and say, “Now you can urinate every half-hour.” But you could sneak it in and give it every other day in the beginning. Try to get it on board and be comfortable with the safety profile for those who haven’t used it. It’s a terrific drug and has all those benefits we talked about.

Excellent. Thank you both for sharing this valuable information. We hope you found it very valuable in how you may think about implementing this in your practices. Thank you all for watching this 

Videos

A case study for a patient who required additional SGLT-2 inhibitors to help reduce progression of renal disease is presented, and Drs Robert Busch, Dhiren Patel, and Muthiah Vadugananthan share their final thoughts on renal protective agents.

Case Study: Reducing Renal Progression With SGLT-2 Inhibitors

You have a medication where you have an indication for type 2 diabetes, an indication for prevention of heart failure, an indication for treatment, and now an indication for CKD [chronic kidney disease], and a couple of those indications regardless of diabetes status. Whose responsibility is it now? Where do you start? I’d love both of your perspectives. You’re going to see a patient with heart failure who also has some of the others, and you’re going to see a patient with diabetes who also needs help with heart failure or CKD. How do we sort this?

 It’s everyone’s responsibility. Whose responsibility is for the statin? If I see the cardiologist’s patient and I want to be more aggressive with their lipid management, I’ll do it and put it in my note to them and vice versa. If the cardiologist is seeing my patient, I hope they would be aggressive and initiate the SGLT2 if it helps the patient. Whoever is lucky enough to see that patient should do it and not keep putting it off, otherwise the patient suffers.

 I completely agree. The overlap and these disease domains are so far-reaching that every clinician should become comfortable with initiating, continuing, and managing SGLT2 inhibitors. Specifically, similar to statin and ACE inhibitors and ARBs, the indications are so frequent, we need to identify patients who don’t meet indications for starting these therapies. Because of that and the cost implications of the system, we need to think broadly about first making sure our highest-risk patients are on therapy: those at risk for early progression or who have already established disease.

Unfortunately, there are large gaps there that still need to be filled, and earlier on in the disease. For instance, type 2 diabetes with multiple risk factors. For instance, with a naïve patient with type 2 diabetes who’s newly diagnosed, it’s difficult to understand where SGLT2 inhibitors should fit in. Once they become more affordable and accessible on a broader scale, we can think of them similar to statins and ACE inhibitors, so most of us feel comfortable starting them in patients most at risk for progression.

Speaking of ACE and ARBs, those are the traditional ones we’ve used. We have the SGLT2 class now, and Dr Busch, you mentioned we have other ones in the pipeline, such as finerenone. How do you start to incorporate these additional classes? I’ll be honest. When you put a patient on an ACE or an ARB, I’m documenting in my notes and it says patient is on maximum tolerated ACE or ARB, blood pressure is rate limiting, potassium is maybe a rate-limiting step, and that’s where we stop. In many cases, I don’t know if we even check the follow-up after that, because what’s the point? As you mentioned, we could probably count a handful of times you order 1 to begin with.

What do we do now? Do we start thinking of it like diabetes, where there are multiple medications and we’re trying to hit the different core defects of the ominous octet in different ways, the same way we have heart failure and these 4 pillars? What are your initial thoughts in any best practices that we can think of as we add more tools in the toolbox from a CKD standpoint? Dr Busch, I’d like to start with you.

 When I was recruiting for these studies from data mining, a lot of my associates didn’t order urine microalbumins once the patient was on a RAS blocker because they figured, “What more could I do?” I couldn’t recruit them in the study because I didn’t want to have screen fails. You’d screen fail if the urine microalbumin was too low. I mandated, and it’s in the guidelines to do a urine microalbumin at least yearly in someone with diabetes. What we did for the practice benefit—not for the benefit of recruiting patients—that everyone who had to have a urine microalbumin for a year, we mandated a urine microalbumin to be done in the lab.

By doing that, we found a lot of patients who had high urine microalbumin. We wouldn’t have known they had it because they were on the RAS and the clinician thought, “I’m protecting their kidneys. I’m not going to give an x-ray dye. No NSAIDs; they’re on a RAS. Goodbye, I’m done.” The other frustration is they weren’t on maximal dose of RAS. We have our PharmDs enforce this to maximize the RAS if it’s possible if the potassium isn’t going up and the blood pressure isn’t too low.

When you add an SGLT1, you might lower the blood pressure a little. First, if they’re on a thiazide, I usually get rid of the thiazide. The SGLT2 has blood pressure efficacy similar to a thiazide diuretic; not like a loop diuretic, which has more diuretic effect. If their blood pressure is lowish to start with, I might move the RAS blocker to bedtime to make room for the SGLT2 so it will have that much of an antihypertensive effect. The other thing is the creatinine can bump a little. You get the GFR [glomerular filtration rate] dips a little, and it stabilizes. Just as we lived through this with RAS blockers that you tolerate a 30% bump of creatinine, it’s a similar rule of thumb with an SGLT2. Don’t worry. People who know they have kidney disease get very worried if their GFR drops an iota. If the GFR goes even from 45 to 43 mL/min, they’re worried. “Oh my god, I’m heading to dialysis.” You have to reassure them that it drops and then stabilizes.

 That point needs to be reinforced over and over again. That correction of hyperfiltration is the core defect that’s corrected for each of these therapies: the renin-angiotensin system inhibitors, the SGLT2 inhibitors, and the selective nonsteroidal MR antagonist. The correction of hyperfiltration all leads to a predictable decline in eGFR [estimated GFR] early on therapy and then stabilization. That can almost be a pathway because initiation of each is going to result in almost identical eGFR dips. That should be an anticipated dip that shouldn’t lead to any clinical action.

In fact, in many cases, especially for the SGLT2 inhibitors, there may be little rationale to do follow-up testing of a basic metabolic panel early after initiation because they, unlike renin-angiotensin system inhibitors and finerenone, do not have a hyperkalemia risk. In fact, they help lower hyperkalemia. Because of that, the rationale for checking a laboratory result that you’re not going to act on is a little uncertain. In my practice, I waited with patients with chronic kidney disease especially, allowed the eGFR to stabilize and then, at their next clinical appointment as a part of routine care, I checked laboratory studies.

That makes a lot of sense. I started explaining it to the patients the same way when we use multiple diabetes medications to attack the problem, the same way you use hypertension medications. You might be on 2 or 3, and now we’re starting to do this. We didn’t have those options, but now that we do, it’s another great advancement in the CKD arena and also for our patients.

Robert Busch, MD, and Muthiah Vadugananthan, MD, MPH, share their thoughts on the multifunctional responsibility of managing a patient’s renal disease.

Managing Renal Impairment with Multiple Agents

Dr Busch, you’ve had a front-row seat. You’re an investigator in the Dapa-CKD trial. You saw what happened there. You saw the final label. One of the things that was intriguing in looking at that was the indication. Unlike prior ones, it wasn’t based on a certain cutoff. You have anyone that’s at risk of progression. To me, that’s pretty much anyone, right? All of us are at risk of progression, so to speak. Help me understand how you’re understanding that indication and how you’re talking to your peers about that. Depending on what continuum you sit, you might not be seeing those patients until they’re more severe. The way it’s written, this therapy can be very valuable even for patients who are on the mild to moderate side. What was your reaction to it, and how are you disseminating this information to your peers and colleagues?

 It’s a very generous label because with canagliflozin in CREDENCE, it was the study criteria, urine microalbumin over 300 mg/dL. Even though in this study, you had to have 200 mg/dL. The FDA was so impressed with the data and the 39% lowering of the composite end point for renal protection that they don’t have proteinuria in the label. As you mentioned, it’s who’s at risk for progression of kidney disease. It’s like beauty is in the eye of the beholder. If you think your patient is at risk, the GFR [glomerular filtration rate] could be higher than 60 or 70 mL/min, but they have proteinuria. Or they could have a GFR without proteinuria, but they’re at risk of getting worse. Those are the types of patients.

It’s a very generous label. You don’t just have to have diabetes. Even in a hypertensive patient who has some urine microalbumin present, whose GFR is in the 50s mL/min, that’s a patient who’s also at high risk to progress toward dialysis. That’s someone for whom you’d also want to slow down things, with not only a RAS blocker but going beyond that with dapagliflozin.

 I agree 100%. Both CREDENCE and Dapa-CKD had average UACRs [urine albumin-to-creatinine ratio] of about 1000 mg/g, based on the relative cutoffs. The FDA labeling, the documents, and the discussion during the advisory committee reflected on the parallel experiences between DECLARE-TIMI58 and Dapa-CKD, where you have a continuum of low-risk patients with type 2 diabetes who are at risk for progression, and then more advanced patients with established albuminuric kidney disease. There’s no heterogeneity in treatment effects across that spectrum based on UACR. That was the rationale behind not including it in the label.

In practice, that removes a substantial barrier to use because albumin-creatinine ratios are often not measured. Sometimes there aren’t even structures in place to measure them. For instance, in a cardiology clinic, I could probably count the number of times we’ve measured UACR. It’s an extension beyond the trial, for sure, but it borrows on adjacent disease states and trials that have studied the exact same compound.

Dr Robert Busch and Dr Muthiah Vadugananthan provide insights on educating their peers on the importance of decreasing renal progression.

Importance of Education on Reducing Renal Progression

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?

 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.

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.

 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.

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.

Risks and Complications for Chronic Kidney Disease

 program titled “Management of Diabetes and Renal Impairment.” I’m Dhiren Patel, an adjunct associate professor of pharmacy practice at the Massachusetts College of Pharmacy [and Health Sciences] in Boston, and an endocrine clinical pharmacy specialist. Joining me in this discussion are Dr Robert Busch, the director of clinical research and a practicing endocrinologist at the Albany Medical College Faculty Practice in Albany, New York; and Dr Muthiah Vaduganathan, a cardiologist at Brigham and Women’s Hospital and faculty at Harvard Medical School in Boston, Massachusetts. Thank you both for taking the time to be here today.

One thing we’re increasingly finding out in patients with diabetes is that it’s no longer just about diabetes. There’s a long list of comorbidities we need to take into consideration. I always say that I don’t know the last time I saw a patient who had only diabetes and I didn’t have to go through their past medical history and factor in 3 or 4 different things as I decide how to counsel that patient and what pharmacotherapy to consider. Dr Busch, can you talk a little about the prevalence of renal impairment? This is something we’ve always talked about from the beginning days where we’ve had to keep an eye on the patient’s eGFR [estimated glomerular filtration rate] as we think about drug therapy. What are you seeing in terms of the prevalence of CKD [chronic kidney disease] and diabetes?

 It’s extremely common, but patients don’t know they have it. If the caregiver doesn’t inform the patient, the patient feels fine even though they could have stage IIIB chronic kidney disease with a GFR [glomerular filtration rate] of 35 mL/min and urine microalbumin that’s high, and they have no idea that they have kidney disease. When patients need a statin, they may choose not to take it, but they know they have a lipid problem. If someone has diabetes, they may choose not to treat it, but they know they have diabetes. But in terms of chronic kidney disease, they don’t know it unless they have a nephrologist or are heading toward dialysis. That’s pretty sad, because we have terrific drugs that could help, besides lifestyle, not taking an NSAID [nonsteroidal anti-inflammatory drug], keeping good blood pressure management, and giving the RAS blocker. We have a lot of drugs beyond RAS blocker that may benefit their kidneys, and unfortunately the patients don’t know it. It’s up to the caregiver to inform them about it. It’s very common.

Dr Vaduganathan, when you talk about this and what you see, I would love to get the cardio-renal. There’s a huge implication in access. How should we be looking at this, and what’s the interplay as we talk about CKD, CV [cardiovascular] disease, and diabetes?

 It’s a similar intersection that’s large and under-recognized. If routinely screened with not just eGFR but also UACR [urine albumin-to-creatinine ratio] measurements, urine albumin and creatinine measurements, the overlap is likely to be even more substantial between heart failure, chronic kidney disease, and diabetes. In fact, recent series of hospitalized patients with heart failure suggest that over 60% have some degree of chronic kidney disease. Unfortunately, the heart and kidney have been considered enemies for a long time in terms of therapeutics. In many cases, patients who are at that intersection face the highest risks for near-term mortality and clinical events, yet are treated with the least amount of medical therapy. There’s this unfortunate risk-treatment paradox where high-risk patients are undertreated. That needs to be corrected. It’s fortunate that we now have therapies that target the intersection that may simultaneously benefit the heart and kidneys and don’t necessarily work against one another.

Absolutely. This is another space in which we haven’t had innovation in a really long time.

Dhiren Patel, PharmD, CECES, BC-ADM, Robert Busch, MD, and Muthiah Vadugananthan, MD, MPH, provide an overview of the prevalence of renal impairment in patients with diabetes.

Muthiah Vaduganathan, MD, MPH

Articles

Case Study: Reducing Renal Progression With SGLT-2 Inhibitors

Managing Renal Impairment with Multiple Agents

Importance of Education on Reducing Renal Progression

Risks and Complications for Chronic Kidney Disease

Overview of Diabetes and Renal Impairment