EMPA-Kidney in Context: Expanding Our Understanding of Sodium-Glucose Cotransporter 2 Inhibition in Chronic Kidney Disease Management

Activity Transcript

CHAPTER 1

Will Herrington, MD, FRCP: Hello, I'm Will Herrington, associate professor at the MRC Population Health Research Unit at the University of Oxford. Welcome to this series of presentations called "EMPA-KIDNEY in Context: Expanding our Understanding of SGLT2 Inhibition in Chronic Kidney Disease Management". In this series, experts from around the world will address implications for the practical management of patients with chronic kidney disease (CKD).

I'd like to begin this series of 5 presentations with a detailed summary and interpretation of the key findings from the EMPA-KIDNEY trial, which was presented at the American Society of Nephrology's Kidney Week.

The EMPA-KIDNEY trial was initiated by the Renal Studies Group at the University of Oxford, who led its design, analysis, and reporting with a steering committee of expert collaborators. EMPA-KIDNEY is a large double-blind placebo-controlled trial, and our aim was to assess the effects of sodium-glucose cotransporter 2 (SGLT2) inhibition on a broad range of patients with chronic kidney disease at risk of progression.

We had simple inclusion criteria. To be eligible, adults had to have a Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) estimated GFR of 20 to 45 on historical and screening results, or 45 to less than 90 with a level of albuminuria equivalent to greater than or equal to 200 milligrams per gram. We limited exclusion criteria to ensure widely generalizable results, but we did exclude patients with polycystic kidney disease or a kidney transplant.

Participants were required to be on investigator-judged clinically appropriate renin-angiotensin system (RAS)-inhibition, where indicated and tolerated. They were then randomized one to one to either empagliflozin 10 milligrams once daily versus a matching placebo, and we planned to follow participants until at least 1,070 had had a primary outcome event, which would provide 90% power at 2P equals 0.05 to detect at least an 18% relative risk reduction.

And the primary outcome was a composite of cardiovascular death or kidney disease progression, with kidney disease progression defined based on clinical outcomes of end-stage kidney disease, which included maintenance dialysis or kidney transplant or death from kidney failure. And it also included a kidney function component. estimated glomerular filtration rate (eGFR) change was required to be at least a 40% decline from the randomization value or to less than 10. And these changes were required to be sustained in that they had to be measured at consecutive visits or at the last.

Participants were on average 64 years of age, and one-third reported female sex. Just over one-half had no evidence of diabetes at baseline. Mean level of kidney function was 37 and about one-third had an eGFR less than 30. The median urine albumin-creatinine ratio was around 330 milligrams per gram, so just under one-half had A1 to A2 levels of albuminuria.

We included a broad range of primary kidney diagnoses with only 31% attributed to diabetic kidney disease, 25% were due to glomerular diseases, 22% due to hypertensive or renal vascular disease, 12% due to other causes, and 10% were unknown. About 85% were taking a RAS inhibitor at baseline. On March 7th, 2022, the Independent Data Monitoring Committee recommended the trial stop early for efficacy after performing the single pre-specified formal interim analysis, and all follow-ups complete on July the 5th with over 99% completeness. At this point, median follow up was 2 years, and adherence at the midpoint of the trial was about 90% in both groups. By the end of the trial, less than 1% of participants had started an open-label SGLT2 inhibitor.

Here is the main result of EMPA-KIDNEY. There were 558 primary outcomes in those allocated to placebo and 432 among those allocated empagliflozin. And this represents a highly statistically significant 28% relative risk reduction with a 95% confidence interval between 18% and 36%.

Of the 990 primary outcomes, 888 participants had kidney disease progression. Plotting this Kaplan-Meier curve is the clear effect on this outcome, a 29% relative risk reduction. In comparison, the rate of cardiovascular death in this population was low, and lower than we were expecting, limiting power to test effects on this component of the primary composite. But another secondary outcome was a composite of cardiovascular death or time-to-first dialysis or kidney transplant, and there was a clear 27% statistically significant reduction in these hard clinical outcomes.

Now, we pre-specified 3 key subgroup analyses of primary outcome. These were emphasized in our publication. The first was by diabetes status at randomization. And what you can see here is a forest plot with the overall effect of empagliflozin on the primary outcome plotted as a diamond. Above it are the effects in patients with and without diabetes plotted as boxes and whiskers. There were 466 first primary outcomes in patients without diabetes, providing important new information in this previously less well studied group. The P value for the statistical test of effect modification, a heterogeneity test, was nonsignificant at 0.06. And the interpretation of this plot is the best estimate of the treatment effect in patients with and without diabetes is the overall result of a 28% relative risk reduction.

In this third plot, we see the forest plot by baseline level of albuminuria. There are 229 primary outcomes in those with A1 and A2 levels of albuminuria and only 84 in those with the lowest levels of albuminuria, the A1 category. Nevertheless, there was statistical evidence for a trend difference of effect by baseline albuminuria, a P value of 0.02, suggesting that the benefits of empagliflozin on the primary outcome were larger in patients with higher levels of baseline albuminuria. We'll come back to this subgroup analysis later.

A tertiary outcome was annual rate of change in eGFR. And plotted here is eGFR by time for the placebo group. You can see that on average they progressed at approximately 2.75 milliliters per minute per year. On starting empagliflozin, there was the expected acute negative dip followed by a slowing of the chronic slope. Thereafter, eGFR declined by 1.37 milliliters per minute per year, a between group difference of 1.37. This represents about a halving of the rate of chronic decline.

Now, because of the previous subgroup analysis by albuminuria, we elected to explore this subgroup in more detail using the chronic slope outcome. And plotted here is the overall result in the diamond, that 1.37 milliliters per minute per year difference. What you can see highlighted in the box is the rate of chronic progression by baseline level of albuminuria, with progression being slowest in those with A1 levels at 0.89 milliliters per minute per year, increasing to over 4 in those with A3 levels. And then here is plotted the effects in the empagliflozin group plus the difference. And what you can see is there is a slowing of the chronic rate of decline in all of the subgroups by baseline albuminuria. In those with A1 levels, the difference was .78 milliliters per minute per year. And those with A2 levels, it was 1.2. And this would predict over time a slowing of kidney disease progression

Now, although this was a CKD trial, we had key secondary outcomes which were based on non-kidney data. There were 3,500 hospitalizations during the trial. An allocation to empagliflozin reduced the risk of all-cause hospitalization by 14%. There was no significant effect on hospitalization for heart failure, cardiovascular death, or death from any cause. But the point estimates of effect are consistent with the overall evidence from the other trials, and we're going to hear more about this in the next talk.

For the safety outcomes, ketoacidosis occurred in 6 patients allocated empagliflozin and 1 with placebo. But overall event rates were low in this population. There were 28 versus 19 lower limb amputations. Three-quarters were in actual fact toe amputations. Serious adverse event rates for the urinary tract infection, hyperkalemia and serious acute kidney injury and liver injury events were generally similar between the 2 groups. These results are consistent with a known safety profile of SGLT2 inhibitors.

So, in conclusion, EMPA-KIDNEY randomized 6,609 patients with CKD with a broad range of causes. And its particular feature was the large numbers of patients with low levels of kidney function and also with the wide range of levels of albuminuria. We showed that empagliflozin safely reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death by 28%. And these relative benefits were consistent in the patients with and without diabetes and across the range of eGFR studied, down to at least 20 milliliters per minute. There was evidence that those with higher levels of albuminuria might benefit more from empagliflozin, but our chronic slope analyses showed that empagliflozin slowed the chronic eGFR decline in all patients irrespective of baseline albuminuria.

And thank you for your attention. Please now join EMPA-KIDNEY statistician Natalie Staplin and I as we present findings from a meta-analysis combining data from EMPA-KIDNEY with all the other large placebo-controlled SGLT2-inhibitor trials.

CHAPTER 2

Dr Herrington: Hello again. I'm Will Herrington and it's my pleasure to introduce you to my colleague Natalie Staplin, the EMPA-KIDNEY lead statistician. Together we will put the results of EMPA kidney in the context of the other large trials with a special focus on a recent meta-analysis. So, Natalie, tell us about the aims of your meta-analysis.

Natalie Staplin, PhD: The primary aim was to conduct a meta-analysis to compare effects on kidney outcomes in patients with and without diabetes. We used a common definition for kidney disease progression across all the trials, which required re-analysis of data from many of the trials, and this was provided by the Smart C collaboration. Our subsidiary aims were to assess effect modification by primary kidney diagnosis in the CKD trials and to compare the absolute benefits and harms in patients with and without diabetes.

For the kidney disease progression outcome, we used a composite including a sustained of at least 50% decline in eGFR as this is slightly more specific for progression to kidney failure than a greater than or equal to 40% decline in eGFR in the context of acute dips. Acute kidney injury was defined using a specific Medical Dictionary for Regulatory Activities (MEDRA) preferred term.

The meta-analysis included 13 large trials with a total of 90,000 participants. The population studied were type 2 diabetes and high cardiovascular risk, heart failure and chronic kidney disease. And there has been a wide range of eGFRs studied across the trials from around 80 [mL/min/1.73 m²] in the type 2 diabetes and high cardiovascular risk to around 60 [mL/min/1.73 m²] in the heart failure trials and then lower in the chronic kidney disease trials, with EMPA-KIDNEY having the lowest eGFR of all, with a mean of 37 [mL/min/1.73 m²]. In the heart failure and chronic kidney disease trials, we now have 16,000 participants without diabetes.

Across all the trials, there were over 2000 kidney disease progression events. An allocation to an SGLT2 inhibitor reduced the risk of kidney disease progression by 37%. There are a total of just under 500 events in the subgroup without diabetes. And the relative risks associated with allocation to an SGLT2 inhibitor were similar for patients with and without diabetes, with no evidence of heterogeneity by diabetes.

Dr Herrington: Wow, these are very clear results, Natalie. But as a nephrologist, I'm really interested in studying patients with non-diabetic kidney disease now, and I know there are large numbers in the EMPA-KIDNEY study. Is there information from other CKD trials?

Dr Staplin: There are 3 other trials in patients with CKD. The CREDENCE and SCORED, it is assumed that all participants have a diagnosis of diabetic kidney disease. Like EMPA-KIDNEY, DAPA-CKD included some patients with ischemic and hypertensive kidney disease and glomerular disease. We have meta-analyzed the results and the relative risk reduction associated with allocation to an SGLT2 inhibitor in the CKD trials was 38% and there is no evidence that this beneficial effect carried across the different kidney disease diagnoses studied. The glomerular disease category can be further broken down into immunoglobulin A (IgA) nephropathy, focal segmental glomerulosclerosis (FSGS), and other glomerulonephritis (GN). With the caveat that there are limited numbers in the categories, there was no evidence that the effect of allocation to an SGLT2 inhibitor varied across these 3 subtypes of glomerular disease.

Dr Herrington: So that's very clear, consistent results. But in the last talk, we saw the acute negative dip in the eGFR, and one might postulate that that might result in an increased risk of acute kidney injury. Did you manage to collect information on acute kidney injury from all the trials?

Dr Staplin: We have collected information on clinical events of acute kidney injury from all 13 trials with around 2000 events. Even though this was originally considered as a safety outcome, overall, allocation to an SGLT2 inhibitor reduced the risk of acute kidney injury by 23%. Again, the relative risk reductions for acute kidney injury were similar for patients with and without diabetes, with no evidence of heterogeneity by diabetes data.

Although our meta-analysis was focused on renal outcomes, we also collected data on cardiovascular death or hospitalization for heart failure. Overall, there was a 23% relative risk reduction in this outcome among those allocated to an SGLT2 inhibitor with similar risk reductions among patients with and without diabetes.

We also collected data from all the trials on the safety outcomes of ketoacidosis and lower limb amputation by diabetes status. Among participants with diabetes, allocation to an SGLT2 inhibitor doubled the risk of ketoacidosis. Among the 16,000 participants without diabetes, there was only one recorded event of this type, so it's not possible to estimate the relative risk for this subgroup.

Using data from all the trials, allocation to an SGLT2 inhibitor increases the risk of lower limb amputation by 15%. However, this is primarily driven by the CANVAS trial where allocation to an SGLT2 inhibitor was associated with a doubling in risk. But in the other 12 trials, allocation to an SGLT2 inhibitor was not significantly associated with lower limb amputation.

Dr Herrington: Okay, so you've mentioned substantial beneficial effects, but there are also potential side effects. Have you looked at how these might balance out the studied populations?

Dr Staplin: Yes. We have estimated the predicted absolute effects of treatment with an SGLT2 inhibitor on each of the presented outcomes for patients with CKD. These bar plots give the number of events avoided or caused if we were to treat 1000 patients for a year with an SGLT2 inhibitor. On the left-hand side is the plot for patients with diabetes. And on the right-hand side, those without diabetes. Going from left to right on each plot, we show the 3 efficacy outcomes, so kidney disease progression, acute kidney injury, and cardiovascular death or hospitalization for heart failure, and then the 2 safety outcomes, ketoacidosis and lower limb amputation. For kidney disease progression, 11 events are avoided in those with diabetes versus 15 events in those without. The number of acute kidney injury events avoided is roughly the same in both groups, about 5 per 1000 patient years of treatment.

The beneficial effects on cardiovascular deaths or hospitalization for heart failure are markedly higher in those with diabetes than those without, 11 versus 2 events. This is due to the higher absolute risks of cardiovascular events in the diabetes subgroup.

For patients with diabetes, there were small increases in the numbers of ketoacidosis and lower limb amputations, about one additional event of each type. But these are clearly outweighed by the benefits on the kidney and cardiovascular outcomes. However, these harms were not observed in the patients without diabetes, as there were too few ketoacidosis events to estimate absolute effects. And the rates of lower limb amputation were also so low that no additional events of this type are caused in patients without diabetes.

So, in summary, SGLT2 inhibitors safely reduce risk of kidney disease progression and acute kidney injury irrespective of diabetes status and primary kidney diagnosis. And the absolute benefits clearly exceed harm in patients with CKD, again, regardless of diabetes status. I would like to thank all of the participants across all of the trials as well as my co-authors and collaborators.

Dr Herrington: Thank you on behalf my co-presenter Dr Staplin and I, and please do join Professor David Cherney for the next talk where he will be focusing on the similarities and differences between the study designs of EMPA-KIDNEY and the other major large trials.

CHAPTER 3

David Cherney, MD, PhD: Hello. I'm David Cherney, professor of medicine at the University of Toronto in Canada. And in this presentation, I will discuss similarities and differences between the study designs of EMPA-KIDNEY compared to other major cardiorenal outcome trials with SGLT2 inhibitors, and I'll really focus on the kidney outcome trials that have come before it.

By way of background, the CREDENCE trial was the first dedicated renal trial to examine the effect of an SGLT2 inhibitor on renal outcomes in people with established diabetic kidney disease. And as you can see, some of the important inclusion criteria included having type 2 diabetes, second, having an eGFR of 30 or higher, and also having urine albumin-creatinine ratio (UACR) levels in the 300 milligrams per gram and higher, up to 5000 milligrams per gram. And this is different compared to some of the trials that I'll discuss subsequently. Patients had to be on a maximum tolerated dose of an angiotensin-converting enzyme (ACE) or angiotensin-receptor blocker (ARB) for 4 weeks or more. Patients were then, of course, randomized to canagliflozin or placebo, and then were followed for the requisite number of events to lead to the end of the trial. And the CREDENCE trial was, of course, stopped early after a planned interim analysis because of an overwhelming benefit and showed a 30% reduction in the primary outcome in favor of canagliflozin versus placebo. So that's the CREDENCE trial. Importantly, people with type 2 diabetes and macroalbuminuria levels, quote unquote, so 300 mg/g or more.

The second trial in this area that was completed was the DAPA-CKD trial. And the objective of DAPA-CKD was slightly different. It was to determine the effect of dapagliflozin versus placebo in terms of the effect on renal and cardiovascular outcomes in patients now with and without type 2 diabetes who have chronic kidney disease. So, this is different than CREDENCE, which only included people with type 2 diabetes. The GFR at baseline, the mean GFR was lower in DAPA-CKD, 43 versus about 56 in CREDENCE. The level of albuminuria was roughly similar, about a gram per gram. And also, as in the credence trial, almost all patients were on a background of an ACE or ARB, so maximum background standard of care therapy. This is the trial design. So 4,300 patients roughly were randomized to dapagliflozin or placebo and then were followed for the requisite number of primary outcomes, as well as secondary outcomes, which were captured over time. DAPA-CKD was also stopped early due to overwhelming efficacy and showed a 39% reduction in the primary outcome in favor of dapagliflozin. And importantly, in the DAPA-CKD trial, approximately two-thirds of patients had type 2 diabetes and one third of patients had non-diabetic kidney disease.

This brings us, of course, to the EMPA-KIDNEY trial. And the EMPA-KIDNEY trial was also different compared to the trials that came before it. This is a multinational, randomized, double-blind, placebo-controlled phase 3 trial in patients with chronic kidney disease, with and without type 2 diabetes. And you can see that patients were randomized to empagliflozin or placebo and then followed up for the requisite number of events, which accrued over time. This is the largest of the 3 trials, with more than 6,600 patients compared to roughly 4,300 patients in the other 2 trials that came before it. These are the inclusion criteria for EMPA-KIDNEY, which really does distinguish it compared to the trials that came before it. At least a third of patients had to have diabetic kidney disease and a third of patients at least had to have kidney disease without type 2 diabetes. And you can see the important GFR criteria, which include GFR 20 to 45. This is the lowest of the GFR criteria threshold. And in that range, patients could have any level of albuminuria, including normal albuminuria or albuminuria in the 30 to 300 milligram per gram range. However, in patients with GFRs of 45 and above, patients did have to have elevated levels of UACR, so 22.6 mg/mmol and higher. EMPA-KIDNEY excluded patients with polycystic kidney disease or a transplant, which was also similar to the trials that had come before it. So, this is some additional design information about the EMPA-KIDNEY trial. And you can see that patients did have to be on an appropriate level or dose of a renin angiotensin system blocker, where indicated and tolerated and patients then had empagliflozin or placebo added on top of that in this event-driven trial. The primary outcome was cardiovascular death or kidney disease progression. So, end-stage kidney disease was defined as dialysis or kidney transplant or renal death. And from a GFR perspective, 40% or more eGFR decline that was sustained or GFR to less than 10 mils per minute.

This provides a summary and some context for the EMPA-KIDNEY trial in light of the kidney outcome trials that had been completed and published before it. I want to thank you for your attention and please join Susanne Nicholas, who will be discussing the therapeutic implications of EMPA-KIDNEY for the practical management of patients with chronic kidney disease, with a focus on the need for early identification and treatment. Thank you again for your participation in this talk.

CHAPTER 4

Susanne Nicholas, MD, MPH, PhD: Hello, I'm Dr Susanne Nicholas, professor of medicine at the David Geffen School of Medicine at the University of California, Los Angeles in the United States. In this presentation, I'll discuss the therapeutic implications of EMPA-KIDNEY for the practical management of patients with chronic kidney disease, with a particular focus on the need for early identification and treatment, as well as improving physician patient communication. So, let's begin.

Diabetes is the most common cause of chronic kidney disease and kidney failure. Up to 537 million individuals in the United States have diabetes, and in 2021, 37 million individuals had chronic kidney disease. Approximately 20 to 40% of people with diabetes also have chronic kidney disease. And of all patients with chronic kidney disease, more than 40% of them have diabetic kidney disease.

It's important to understand that the cardiac, renal and metabolic systems are all linked, as shown in this diagram. There are 13% of US adults with type 2 diabetes, and 20% to 40% of patients with type 2 diabetes have chronic kidney disease. But in addition to that, 32.2% of patients with type 2 diabetes also have cardiovascular disease.

Type 2 diabetes and chronic kidney disease are also associated with a significantly high cardiovascular risk. By the year 2045, we expect that there will be 783 million individuals living with diabetes worldwide. Up to 95% of patients will have type 2 diabetes according to approximately 744 million individuals, and 5% will have type 1 diabetes according to about 39 million individuals. 40% of those with type 2 diabetes will develop diabetic kidney disease, and 30% of those with type 1 diabetes will develop diabetic kidney disease. Of all individuals with chronic kidney disease, up to 50% of these cases may be attributable to diabetes, and importantly, about 10% of these patients may progress to kidney failure and up to 90% of patients may develop heart failure, atherosclerotic cardiovascular disease, as well as death.

Here we see that early action is really critical to slowing progression and to prevent kidney failure, and we show you here the 5 stages of chronic kidney disease as are listed on the left hand side of this table with a description of each of these stages in the middle, according to their estimated glomerular filtration rate by the mL/min/1.73 m², and a depiction of what those stages of chronic kidney disease may look like.

Here we also look at the chronic kidney disease classification, and in the kidney disease improving global outcomes (KDIGO) heatmap, we see the stages of chronic kidney disease on the left hand side according to the albuminuria levels for stages, A1, A2, and A3. For individuals who fit in the green sections, they may have maybe a low risk of chronic kidney disease or no chronic kidney disease. For individuals in the yellow sections may have moderate risk. Individuals in the orange sections may have high risk, and those in the red sections will have very high risk for progression of their chronic kidney disease as well as cardiovascular mortality.

It's really important to understand the risks for kidney disease in individuals with type 2 diabetes and to know that we have to initiate therapy early. Here we see several risk factors for chronic kidney disease in patients with type 2 diabetes, and these include poorly controlled diabetes, elevated albuminuria, poorly controlled blood pressure, and a number of other risk factors such as related to race and ethnicity as well as family history. In addition, there may be fast declining glomerular filtration rate and other comorbidities such as cardiovascular disease, congestive heart failure, metabolic dysfunction, associated fatty liver disease, and retinopathy. Once we identify risk factors such as these in patients with chronic kidney disease and type 2 diabetes, we need to make the diagnosis. We can make that diagnosis with a urine albumin to creatinine ratio from a urine sample and an estimated glomerular filtration rate from a blood sample measuring serum creatinine. We can then consider initiating treatment early if an individual has chronic kidney disease where their eGFR is less than 60 mL/min/1.73 m².

The KDIGO has provided guidelines related to a comprehensive care strategy for patients with chronic kidney disease and diabetes as shown in this pyramid. And the foundation of care is in the prevention of complications related to diabetes, particularly related to lifestyle modification, including at least 150 minutes per week of moderate aerobic activity with the intention to avoid a sedentary lifestyle and inclusion of protein at 0.8 grams per kilogram per day, as well as low sodium intake, less than 2 grams per day, and following the ABCs of diabetes, targeting A1c, blood pressure and cholesterol. In addition, many patients may require therapies to prevent progression of complications such as chronic kidney disease and as shown in the pyramid.

So, there are a number of benefits to early screening, identification and treatment, and these include detecting CKD within the early stages prior to symptomatic stages, which are in stages CKD-4, particularly the late-stage CKD-4 and CKD-5, to facilitate early initiation of appropriate therapies to slow down CKD progression and to facilitate multidisciplinary team management and prevent cardiovascular and other comorbidities. In addition, it may facilitate early referral to nephrology in order to enable timely initiation of dialysis.

With that, I'd like to thank you for your attention, and please join doctors Christoph Wanner and David Cherney, who will now discuss how to define patients with CKD who would benefit from treatment with an SGLT2 inhibitor. Thank you.

CHAPTER 5

Christoph Wanner, MD: Hello. I'm Christoph Wanner, professor of medicine at the University of Wurzburg, in Christoph, Germany. In this presentation together with Professor David Cherney, from the University of Toronto, in Canada, we will discuss how to identify and define patients with CKD, chronic kidney disease, who would benefit from treatment with an SGLT2 inhibitor.

So, David, let's do a case. And I had a patient, he was referred to me a couple of years ago already. And let's call him Martin. The question was, can this patient receive an SGLT2 inhibitor? So, you see, it's a male. And I found in his chart, IgA nephropathy. He had a biopsy a couple of years ago, but he also had type 2 diabetes diagnosed 4 years ago. So, you can look at his kidney function, glomerular filtration rate, his albuminuria, UACR, is quite high. Blood pressure, body mass index, low-density lipoprotein (LDL) cholesterol, hemoglobin A1c, and hemoglobin. So, he was on standard of care treatment. And maybe you want to know what he will receive or what he's getting but tell me what you think about these values.

David Cherney, MD, PhD: Sure. Sure, so this is a very interesting case for a couple of reasons. And there are multiple factors that are not quite at target, and where we still have a lot of room to improve. These include the fact that he has impaired kidney function and albuminuria, so we can certainly target the albuminuria. And that's now part of our guidelines to not only use these newer therapies including SGLT2 inhibitors and others, in patients with kidney disease, but specifically to try to suppress the albuminuria. The blood pressure is not a target, so that can certainly be ameliorated as well. The LDL cholesterol is not a target either, for someone with type 2 diabetes. And the glycemic control is also not a target. So we have multiple clinical parameters that still need to be improved. And that could be achieved through probably changes in several medications, that would impact on several mechanisms. But there's certainly still long ways to go here, in terms of reaching targets for someone with his background and risk factors.

Dr Wanner: Okay. So I give you the medication, and you can tell me how long you need, how many years you need, to optimize the profile.

Dr Cherney: Perfect.

Dr Wanner: So, look at this standard of care treatment according to the general practitioner. And Martin told me that he is struggling with lifestyle. All the past years he was trying, but he also experienced dyspnea when climbing stairs just recently. So he gave me a sign of a warning, "I already take 7 pills per day." So what do you think about this medication?

Dr Cherney: Yeah. So, there are certainly good medications that he's being treated with right now. So a couple of things that could potentially be changed include combination pills, to combine some of these therapies together. Sort of so-called polypills, that's an option.

Second is the addition of an SGLT2 inhibitor. There's certainly an indication here from the perspective of his albuminuria. Potentially there may be some issues with volume. He's at risk of heart failure, including heart failure with preserved ejection fraction (HFpEF), given that he's struggling when climbing stairs. That would be another reason to think about a therapy like an SGLT2 inhibitor. And one of the other reasons of course to add an SGLT2 inhibitor would be to not only target the heart and the kidney risk, but also to improve his level of hyperglycemic burden and also his weight. There could be an effect on weight loss. So, there are several metabolic factors that may be targeted there as well. And then there are certainly a good rationale for intensifying his lipid lowering therapy. And those are a couple of places to at least start.

Dr Wanner: So, I thought to double the dose of the ACE inhibitor, of the calcium channel blocker. Switched to atorvastatin, 40 milligrams.

Dr Cherney: Yeah.

Dr Wanner: And why the DPP-4 inhibitor? But this takes maybe another year to optimize this profile.

Dr Cherney: Yeah.

Dr Wanner: And the general practitioner was also already doing it before.

Dr Cherney: Yeah.

Dr Wanner: So, I decided actually to give him an SGLT2 inhibitor, and ask him, "Come back in 3 months."

Dr Cherney: Sure. Yeah.

Dr Wanner: So what did he do? He didn't come back at 3 months; he came back 6 months later. And look at this parameters now. I was really surprised. What was going on? This is quite optimal.

Dr Cherney: Yeah.

Dr Wanner: Actually it was one of my stars in my outpatient clinic.

Dr Cherney: Yeah.

Dr Wanner: But can you give me an interpretation about this?

Dr Cherney: Sure. So, in terms of the blood pressure lowering effect, if all that was added was an SGLT2 inhibitor, that would be a pretty big blood pressure lowering effect for just an SGLT2 inhibitor. They do tend to lower blood pressure, but by more like 5 millimeters systolic over 1 to 2 diastolic. So that would be a big effect for just an SGLT2, unless the other medications were modified.

The eGFR dip. So, there's an unhappy face next to the eGFR reduction, compared to where it was previously. But it's important to recognize that after, especially a brief period of time, there is this phenomenon called the eGFR dip. Whereby there is a hemodynamic effect of the SGLT2 inhibitors. Which we understand now very well from the cardiovascular safety studies, from the renal trials, including of the kidney and others, where there is an eGFR dip that occurs that's usually around 2 to 4 mLs per minute of GFR. And that acute effect on GFR, which is hemodynamic, is also reversible. So even when the GFR is observed or rechecked after a washout period, if an SGLT2 inhibitor is stopped, the GFR will rebound back to where it was. Even after several years, because of a reversibility of that hemodynamic effect.

Dr Wanner: The red face came from the general practitioner.

Dr Cherney: Yes.

Dr Wanner: He had a concern.

Dr Cherney: Yes.

Dr Wanner: Is this a concern for you?

Dr Cherney: So, it's not a concern. That dip in eGFR, which is hemodynamic, is actually linked long term benefits. So, we know that people who dip in response to an SGLT2 inhibitor actually do the best over the long term. And again, it's reversible, and it's not excessive in almost all patients who are started on these therapies. So, this shows exactly the phenomenon around the GFR dip. So you can see in the pink line, there's a little dip in GFR initially, and then you can see that over time, that little dip sort of evens out and the GFR is then very stable over time. And that dip is the hemodynamic reversible effect. And in contrast, with the blue line, which is placebo, the GFR is declining more quickly compared to the empagliflozin-treated patients. So initially at 3 months, there is that little dip that occurs, but over the long term it's like an investment that pays off. You have this long-term benefit of preserving kidney function in a much more stable way with an SGLT2 inhibitor versus a placebo, which is in blue. So that's a so-called slope effect, whereby the slope or decline in eGFR is less steep with an SGLT2 inhibitor versus a non-SGLT2, or placebo. So, it's not a red face, it should be a green face. It's expected, and we think it's actually linked with benefit.

Dr Wanner: So, the general practitioner was happy to hear this.

Dr Cherney: Yes.

Dr Wanner: I explained this to him.

Dr Cherney: Good. The reduction in albuminuria is tremendous, remembering that he started with 1.2 grams per gram. So, that's much more than what we'd typically be seeing with an SGLT2 inhibitor alone. Usually, it's a 30 or 40% reduction. This is a great effect.

And having the weight loss of 8 kilograms. Again, that's a great magnitude of an effect. Usually, it's more like 2 kilograms of weight loss with an SGLT2 inhibitor alone. The LDL cholesterol is improved. SGLT2 inhibitors do not impact on LDL, so that's probably from other changes that have occurred in the clinical background.

Dr Wanner: The albuminuria came down, and so LDL will drop also.

Dr Cherney: Sure. Yeah. So, it can come down too, but usually the SGLT2 inhibitor alone, by itself, doesn't have much of an effect on LDL.

Dr Wanner: Yes. Yeah.

Dr Cherney: Usually it's-

Dr Wanner: Yeah.

Dr Cherney: At least the balance between LDL and HDL are usually pretty balanced. And then the HbA1c coming down to 6.5% is a very nice effect as well. Again, maybe on the high end of what you'd expect to see with just an SGLT2 inhibitor alone. And the rise in hemoglobin, also not a surprise, because there's some hemoconcentration that occurs with SGLT2 inhibitors. And typically, the hemoglobin/hematocrit does increase by a little bit, by several percentage points. And interestingly, in various analyses called mediation analyses, which sort of account for how much of a clinical factor accounts for a benefit on an outcome, it's thought that the rise in a hemoglobin and hematocrit is most closely statistically linked with long-term cardiovascular benefits. So it's actually interesting to see this happen here, and it's not a surprise because it's typically seen.

Dr Wanner: The general practitioner was working with a diabetologist together.

Dr Cherney: Yeah.

Dr Wanner: So now finally, the medication. What was changed overall? You mentioned already the polypill. Which is available in some countries, not all countries, across-

Dr Cherney: Yeah.

Dr Wanner: ... the world. But give me some ideas what's going on here?

Dr Cherney: Yeah. So, the effect of a diuretic may be helping to see the benefit on blood pressure that we saw. There was something like a more than 10 millimeter reduction in blood pressure, or so. That's very nice. And that can be seen with adding a diuretic, like indapamide. The SGLT2 inhibitor is in place now too. And we've talked about the effects of SGLT2 inhibitors, and what we'd anticipate seeing with just an SGLT2 inhibitor alone. The fact that the patients also on glucagon-like peptide 1 (GLP-1) receptor agonist, I think really explains a lot of this sort of clinical magnitude of effect that we see with regard to the 8 kilograms of weight loss and the improvements in some other parameters, including albuminuria. Because we know that SGLT2 inhibitors reduce albuminuria generally by 30, 40%. And interestingly, GLP-1 receptor agonists also lower albuminuria by probably about a similar amount in people who have albuminuria at baseline. So that likely accounts for a lot of this kind of really tremendous clinical benefit, in terms of the magnitude of effect that we're seeing. It's because there is an SGLT2 inhibitor added, plus a GLP-1 receptor agonist. And there is probably a combinatory or additive effect on some of those parameters that I mentioned, based on having both of those agents in place.

Dr Wanner: So now, I think good insights of a clinician who is dealing every day with patients. Martin did not report side effects, and he has stopped aspirin to reduce pill burden. The diabetologist switch to GLP-1 RA. And now we can think about the next stage. Maybe we add now finerenone.

Dr Cherney: Yeah. So, in patients who have underlying residual risk, and we know that RAS inhibitors reduce the risk of CKD progression and primary endpoints. SGL2 inhibitors do the same in patients who are already in the background of an ACE or an ARB. And so now we have newer therapies such as finerenone, that have been used in trials like FIDELIO and FIGARO to further reduce residual risk in patients who are on standard of care. And so that would certainly be an option in patients who have residual albuminuria to try to reduce that risk of CKD progression and the risk of cardiovascular disease progression, because we know that there's also benefit from a cardiovascular perspective too.

Dr Wanner: Thank you, David, for your valuable insights. And I would like to thank you also for participating in this activity. And I hope you have enjoyed the individual presentations and gained new insights into the implication of updated data also from EMPA-KIDNEY, in addition to improving our understanding of SGLT2 inhibition in CKD management. So please continue to answer the questions and complete the evaluation. Thank you.

This transcript has not been copyedited.

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