Activity Transcript

Navdeep Tangri, MD, PhD: Hello, I'm Navdeep Tangri and I'm joined today by my colleague Leigh Perrault, to welcome you to this program on Chronic Kidney Disease -- Looking Beyond Diabetes, Expert Interpretation of Latest Evidence For SGLT2 Inhibitors. I'm a nephrologist in Canada who does clinical research and provides care for patients with CKD and Dr. Perrault is a leading endocrinologist at the University of Colorado and a physician scientist with expertise in diabetes and obesity. Hi, Leigh.

Leigh Perreault, MD: Hi, Nav.

Dr Tangri: I think I get to start off this conversation by talking about how sodium-glucose transport protein 2 (SGLT2) inhibitors really are not glucose lowering drugs, certainly not for the nephrologist. What they are for the nephrologist is drugs that lower the blood pressure inside the kidney and therefore protect the kidney from long-term damage.

Now, all of us from medical school and physiology are familiar with renin-angiotensin-aldosterone system (RAAS) blockade and the benefit from RAAS blockade by dilating the efferent arteriole or the exit pipe from the kidney. If you widen the exit, you lower the pressure inside the glomerulus, you decrease hyperfiltration, and you protect the kidney. What SGLT2 inhibitors do is they constrict the entry pipe, so the afferent arteriole gets constricted and again, that also results a decrease interglomerular pressure and decrease hyperfiltration. When you use both drugs together, you have this remarkable effect of almost normalizing the pressure inside the glomerulus, and that we have learned for the last 50, 60 years is that the lower the blood pressure inside the glomerulus, the greater the protection on the kidney long-term.

Now, this benefit or this mechanism of action really does seem, and it indeed is independent of the type of kidney disease you have. It turns out a lower pressure inside the kidney is beneficial whether you have diabetes or not. That is the physiology, but the clinical trials also back this up. When you look in DAPA-CKD, the benefit of SGLT2 inhibitors is unchanged whether you have diabetes at baseline or whether you do not, with a P-value of 0.24 for heterogeneity. The same thing is seen in EMPA-KIDNEY. Again, whether you have diabetes or you do not, the benefit is unchanged. These truly are cardiorenal drugs and drugs that protect the kidney rather than just lowering the glucose. Now, getting into that, to start off, Leigh, how early should we be screening patients with diabetes, now getting back to the origination of these drugs, who are at risk for CKD, and what do we need to do in our clinics to achieve this goal?

Dr Perrault: Yeah, it is a great question, and the answer is really from day one. The good news is that there are very established tests that we can use that are available in any clinic. This is supported by the American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) consensus guidelines that I am sure as you know now, were just updated in September 2022. As you can see, if you look on the left-hand side of this slide, we really need to be looking to see does our patients have either atherosclerotic cardiovascular disease, do they have congestive heart failure, or do they have chronic kidney disease (CKD) from day one and choosing medications that can favorably lower glycated hemoglobin (HbA1c) and risk of those diseases independent of the HbA1c. As an example, if a patient has CKD, they need to be on an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB) and also an SGLT2 inhibitor regardless of their HbA1c.

Shown here is the joint ADA/KDIGO consensus report of CKD screening and diagnosis. And if you just let your eyes gaze up to the purple box in the upper left-hand corner, when do we start screening in patients with type 1 diabetes (T1D), yearly starting about 5 years after diagnosis, in patients with type 2 diabetes (T2D), yearly starting at diagnosis. The screening tools are really easy and straightforward. They are established, they have been around a long time. We screen using a spot urine-to-albumin creatinine ratio, frequently abbreviated as UACR, and an estimated glomerular filtration rate, so the eGFR. If either of those tests come back abnormal, you want to repeat them, think about whether there is another reason somebody might have an abnormal result. Consider even using a cystatin C and creatinine to more precisely estimate the eGFR, because we must remember that CKD diagnosis is based on a persistent urine albumin-to-creatinine ratio (UACR) of greater than 30 mg/g and/or a persistent eGFR of less than 60 mL/min/1.73 m².

How often we measure that eGFR and UACR depends on how significant the CKD. As you can see, moving from green to yellow to orange to red to darker red, those indicate the higher risk of people for the progression of CKD. Frequency of monitoring may be as much as 4 times or more a year in those with the lowest eGFR and highest UACR based on highest risk. This heatmap really shows that is because the degree of the CKD predicts the risk of end-stage kidney disease (ESKD) and cardiovascular disease by the decline in eGFR, which is shown on the left, as well as the increase in UACR that is shown on the top. Nav, I must admit, probably the most common question I hear from colleagues is when should we be referring to nephrology once CKD is found and can you comment on whether the trajectory of the declining eGFR or the rising UACR factor into when someone should be referred?

Dr Tangri: Thank you, Leigh. I think that the referral question is important no matter what country or setting you work in, but, actually, most CKD can and should be effectively managed in primary care. It's really a primary care condition. I think when people are talking about the trajectory of declining eGFR or rising UACR, what they are really referring to is high-risk patients. How do I identify high risk patients and refer those patients to a nephrologist while the low and intermediate risk patients can safely be managed in primary care? Let us look at what can be done in primary care. This is a simple illustration from the CREDENCE trial where we look at a hypothetical patient who is 63 years old and who is on placebo. If that patient is on placebo with diabetic kidney disease, they might be losing kidney function at 4.59 mL/year on placebo and they may be on dialysis in 10 years. Whereas if they get on an SGLT2 inhibitor and a RAS inhibitor, all of a sudden, they are now losing at 1.85 mL/min/1.73 m² a year and are 23 years away from dialysis and potentially a lifetime away. There is a massive lifetime benefit to early intervention. Now, this type of intervention at eGFR levels of 50, 60, 70, 80 [mL/min/1.73 m²] is only going to be happening in primary care. I think it is a primary care condition and a primary care treatment to identify patients with CKD with eGFR and albuminuria as you suggested and treat the high-risk patients early with SGLT2 inhibitors. What is high-risk? Well, one way to think about it is that most referrals typically happen when eGFR falls between 30 to 60 mL/min/1.73 m². At this time, depending on where you work, at some places 30, at other places it's 60 mL/min/1.73 m², you start to transition from primary care to nephrology care.

We would argue that this criteria for referral should not be based on eGFR, but rather on the risk of kidney failure calculated by the kidney failure risk equation. In different countries and healthcare settings, a threshold of 3% or 5% over 5 years has been used. What's the equation? Well, the equation is a very simple lab-based equation that uses age, sex, eGFR, and albuminuria to calculate the projected risk of kidney failure requiring dialysis. It has been validated in more than 30 countries and is part of the NICE CKD guideline and will be a main feature of the upcoming KDIGO CKD guidelines. On the website, which I helped develop, kidneyfailurerisk.com, not only can you calculate the risk for a patient, but you also can run through different treatment options and show the patient what would happen if they went on to treatment such as RAAS inhibitors (ACE inhibitors, ARBs), or SGLT2 inhibitors, or improve their blood pressure control.

One example of incorporating the risk in the referral pathway is done in the province of Ontario, Canada in this algorithm developed called the KidneyWise algorithm. In Ontario, just as you recommended, they endorse measurement of eGFR and ACR and a confirmation after 3 months. After that, they recommend referral to nephrology for patients who have a 5-year risk of greater than 5%. Interestingly, that same threshold is used in the United Kingdom as part of the NICE CKD guidance. It has really been used in many healthcare settings.

Dr Perrault: Wow, that was so helpful, thank you. Can you just briefly summarize the evidence to support the benefit of SGLT2 inhibitors and patients with chronic kidney disease?

Dr Tangri: Yeah, absolutely. The equation that I just showed you works for people with or without diabetes and in fact, so do these drugs. The drugs work just as well for people with or without diabetes. As you can see in the meta-analysis shown on the one side of the slide with kidney disease progression and then even if you drill down by the underlying diagnosis, just diabetic kidney disease, glomerular disease, hypertensive disease, or other diseases, there just does not appear to be a difference in the benefit from these drugs. They really work irrespective of disease status. I think I have really enjoyed presenting the evidence to support SGLT2 inhibitors for cardiorenal protection in patients with or without diabetes. That is really something I am very excited about is using these drugs in patients irrespective of cause. There are also new drugs on the block. Leigh, would you guide us through the latest updates to the guidelines to see what can we do, and how can we do everything possible for patients with diabetes and CKD?

Dr Perrault: Gosh, I would be happy to. There was recently a pooled analysis of two different trials, one from the FIDELIO-DKD and the FIGARO-DKD trials put into a single pooled analysis looking at the effects of finerenone, so a nonsteroidal mineral receptor antagonist (MRA) on both kidney and cardiovascular outcomes. If you let your eyes focus on the left-hand panel, you will see that the composite kidney outcomes are on the left, cardiovascular outcomes are on the right, and you can see that that composite kidney outcome was highly favorable with the use of finerenone in people who had diabetes and chronic kidney disease. The composite kidney outcome was a combination of kidney failure, end-stage kidney disease, eGFR dropping below 15 mL/min/1.73 m², as well as a decline in eGFR of at least 57% or renal deaths. You can see that all those little diamonds are all on the left side of the line of unity, showing that there is collectively a benefit in each of these different endpoints. On the right is shown the cardiovascular benefits. Overall, the composite cardiovascular benefit again was positive by itself. This was largely driven by the benefit in the reduction in hospitalization for heart failure (HHF). The endpoints of CV death, non-fatal myocardial infarction (MI), and non-fatal stroke were not by themselves statistically significantly different. But you can see again they are all trending towards benefit. It is really important to put those data from the pooled analysis into context.

As an example, we routinely use ACE inhibitors and ARBs in patients to lower blood pressure and avoid ESKD, but they do not improve mortality, as is shown in the darker compared to the lighter blue bars on the left-hand part. In contrast, if you look at the SGLT2 inhibitors, as shown in orange compared to dark blue, which is the placebo, the SGLT2 inhibitors have shown a decrease in mortality. Nav, as you and I were chatting earlier before this program, there was a sub-analysis from that pooled analysis in finerenone showing that patients that take both an SGLT2 inhibitor and finerenone had an additional benefit in a subgroup analysis. Really telling us that doing everything is what we should be doing if we want to avoid poor renal outcomes.

Putting everything together to prevent CKD onset or progression, it looks like this. Unless contraindicated or formally not tolerated, we must use an ACE inhibitor or an ARB for anyone with diabetes and hypertension and/or albuminuria, and then start an SGLT2 inhibitor for anyone with diabetes with CKD, even if their HbA1c is that goal. That is such an important point. Even if their HbA1c is at goal, because like you said earlier, this is a kidney protective drug, not just a glucose-lowering drug. Then we would consider adding a nonsteroidal MRA if CKD is progressing in the face of a controlled HbA1c, controlled blood pressure, and somebody who is taking maximally tolerated RAS inhibition and an SGLT2 inhibitor.

Dr Tangri: Thank you, Leigh. I think that is really well summarized. It is amazing that we have all these interventions available to us now. What does this mean, do you think, for nephrologists, endocrinologists, and our primary care colleagues? You go first.

Dr Perrault: It means that we need to be measuring eGFR and UACR in all our patients with diabetes at least once per year. We need these tests to prevent CKD when we can, to halt its progression we must, and avoid ESKD at all costs. We have never had better medications and better data to support what we do.

Dr Tangri: Yeah, I could not agree more. I think nephrologists have an important role in the management of CKD, but their role is more late stage. It is really in the hands of primary care physicians (PCPs) and I think PCPs now have the tools to manage and slow the decline of kidney function so that for most people, dialysis is never a reality. Thank you for this terrific discussion, Leigh.

Dr Perrault: Thanks to our audience for participating in this activity. Continue and answer the questions that follow, and please complete the evaluation. Thank you so much.

This transcript has not been copyedited.