Today Dec 01, 2021

A Treatment Option for Patients with Chronic Kidney Disease


Bruce Fisch, MD: Hi, everybody. My name is Bruce Fisch, and today I am going to give you a talk about dapagliflozin in the management of progressive CKD. Just a little bit about me briefly; I am a nephrologist. I was in clinical practice for about 30 years, in private practice. At this time, I’m a full-time employee of AstraZeneca as a medical director. So, here is a excerpt from the package insert for FARXIGA, also known as dapagliflozin.

Slide 3
And we are going to focus on the indications, the top one, and let me read that; that is to reduce the risk of sustained eGFR decline, end-stage kidney disease which means dialysis, cardiovascular death, and hospitalization for heart failure in adults with CKD at risk of progression. There are some other indications that we’ll touch upon and we will spend a fair amount of time looking at the limitations and the safety of this drug.

Slide 4
Today, I am going to be going over the progressive nature of CKD and how it leads mostly to cardiovascular morbidity and mortality that we can possibly influence. We’ll talk about the burden of CKD and then I will go over how SGLT2 inhibitors work and may be why they would work in type 2 diabetes and CKD, and then I will show you the DAPA-CKD trial which is a landmark trial demonstrating the value of FARXIGA in CKD patients. And what is not on here but is very important to me and I will review with you today, is the safety. Whenever I think as a nephrologist or a doctor, in general, I am using a new drug, I think I want to know safety and so by the time I am done with this, I think you will be comfortable with what to watch out for when you begin using dapagliflozin.

Slide 5
So, let’s talk about the burden of CKD. About 1 in 7 adults in the upper right there of which 35% progress to a worse stage within five years. So, this is a progressive disease and it is common. In the lower left, you see that by 2030 the prevalence of end-stage kidney disease which means dialysis will increase by 30%, so the prevalence is increasing despite our good [background noise 2:00] practices. And then in the lower right, the kind of social impact of the CKD expenditures represent 22% of the Medicare budget and when you look at just dialysis patients who represent 1% of the population, they account for 5% of spending, so this is a cost issue for our society.

Slide 6
This slide points out that if you are a primary care doctor or endocrinologist, your patients are much more likely to die of a cardiovascular event than they are to progress to ESRD or may be even to get referred to me. So, this is for a cohort of patients with a GFR of less than 60 and when you look over on the left most bar, this is the rate of occurrence per 100 patient years. 0.5 is the little yellow part, that’s development of end-stage kidney disease. The development of cardiovascular death or non-cardiovascular death exceeds that by many-fold. So, again patients are more likely to die or be referred than they are to actually end up with dialysis. So, I think one of our goals with these patients is to keep them alive and if we can keep them alive from a cardiovascular standpoint, we will have a positive impact overall.

Slide 7
GFR decline and UACR are both predictors of worse outcomes. So, UACR just to level set for everybody that means urinary albumin-to-creatinine ratio. That’s the albumin in urine that you test in the lab. It is not a dipstick. It is a lab test that when the patient goes in, you check their UACR. It is used as a screening test because you can have elevations in UACR before you ever get a dip in GFR, and as a primary care doctor if there’s one thing that you get from my talk today is that we need to be doing more UACRs to screen our patients for these risks. So, if you notice on the right, the hazard ratios of cardiovascular mortality go up dramatically even with tiny bits of urinary albumin-to-creatinine ratio increases. So even just 30 mg/g, 30 mg per day and you have more than a two-fold increase in the hazard ratio. That’s worse, then smoking, diabetes, hypertension, obesity your typical risk factors, so just albumin in the urine. The only thing that is worse than albumin in the urine is a low GFR and that’s demonstrated on the left. As GFR goes down, cardiovascular risk and cardiovascular mortality goes up.

Slide 8
Let’s talk about what I mean when I say CKD for the purposes of this talk. CKD means a GFR of less than 60. So even though stage 1 and stage 2 are above 60, we’re talking about a GFR of less than 60 or in the bottom panel albuminuria as determined by the UACR. Albuminuria of greater than 30 is considered moderately increased and albuminuria of greater than 300 is severely increased. Noted at the box in the bottom, you have to have these occurring over a three-month period of time to make the diagnosis of CKD and in this case progressive CKD.

Slide 9
We are going to skip that slide and go on to the next slide which is what we call the heat map.

Slide 10
So let’s look at the heat map. It’s the albuminuria levels across the top and the GFR levels down vertically. When you combine these two, you can kind of get this combined risk. As you go from green to yellow to orange to red, your risk of progression increases, your risk of cardiovascular death increases, your need for referral increases, and your need for monitoring increases. So, if your patient has a normal or preserved GFR in the green area with no proteinuria but let’s say they have hypertension or diabetes or a risk factor, they probably need a urinary albumin-to-creatinine ratio once per year.

Slide 11
Other patients with established disease probably need to be checked more frequently. So that means UACR plus GFR and the impact of that is listed here. What this says on the left is that if we look at your patients, on average PCP’s patients in their EMR, of all the patients that qualify for the diagnosis of CKD, only about 12% have the diagnosis clicked on for an ICD code in their EMR. Now, I know you all are doing a wonderful job with this and the reason that we often do not put the diagnosis in there is because there’s nothing really to do. You have got all of your patients on ACE inhibitors and ARBs like you are supposed to, you monitor and monitor and monitor and then when you become uncomfortable you refer to nephrology. 

So, what’s the purpose of putting in the diagnosis? Well, we do think there is a purpose, and it probably heightens the recognition of the condition. Over on the right, we see that over a 15-month period, half the patients are not checked for UACR and as many as 15% don’t even have a GFR. Now, the GFR part should be pretty easy. The GFR comes to you automatically on a basic metabolic or a comprehensive metabolic panel. So again, getting back to the primary point that I made for diagnosis, we need to be doing UACR to identify these patients early and mitigate their cardiovascular and the renal risks.

Slide 12
Diabetes is the principal driver of CKD. So, more than 50% of CKD in the US is diabetes. We see hypertension, glomerulonephritis, etc, and the prevalence of diabetes and the prevalence of diabetic kidney disease on the right is gradually increasing. It says 9.4% of the population in 2008 has diabetes. Well, that’s going to be 14% of the population in 2030 and if a large percent of those patients progress to CKD, we’re talking about a very large public impact for diabetes and CKD.

Slide 13
Despite the fact that we do a pretty good job at recognizing diabetes and we do a pretty good job at GFR, and we manage this with ACE inhibitors and ARBs despite maximal therapy, there’s still a significant residual risk shown there on the left of developing diabetic nephropathy and needing more care such as dialysis. So when you apply maximal therapy to a patient, you have a relative risk reduction of 0.44 but yet there’s still a significant residual risk and let me tell you what that residual risk equates to in the real world. It means that all of the dialysis units in my neighborhood are completely full of patients despite your excellent care. 20% of my patients on dialysis die every year and they’re refilled with 20% new patients and so [cuts out 8:36] metformin, glucose control, blood pressure control and ACE inhibitors and ARBs there is still a progression to ESRD.

Slide 14
This is in the setting of a better job that we’ve done with stroke and myocardial infarction. When you look from 1990 through nearly the modern times, acute myocardial infarction has gone down by 60%, stroke has gone down yet end-stage kidney disease its gone down a little bit in incidence but not as great as those. So, it’s kind of a silent condition something we need to pay a little bit more attention to. Similar to hyperlipidemia and hyperglycemia, those are silent conditions and it’s in our control to mitigate the risks of death in those patients.

Slide 15
Okay, let’s go back to medical school or PA school or NP school for a second and talk about mechanisms of action and where FARXIGA works. So, here’s a glomerulus. Remember you have about a million glomeruli in each kidney. They are the first part of the nephron. The afferent arteriole there on the left delivers blood into and the efferent arteriole delivers blood out of the glomerulus. These two vessels regulate the pressure in the glomerulus and in diabetes specifically, the afferent arteriole is dilated. It’s a little bit beyond our discussion to say why, but its dilated, pounding that glomerulus with extra excess blood pressure and flow. On the left, when FARXIGA is administered, the mechanism of action involves return of that afferent arteriole to more normal tone and decreased pressure in the glomerulus.

Slide 16
FARXIGA is indicated across a spectrum of cardiovascular and renal diseases. Remember I mentioned that, there were actually four indications for FARXIGA. We have an indication for type 2 diabetes in addition to diet and exercise. There are indications to prevent hospitalization for heart failure, prevent CV death and then the combined indication there on the far right within CKD patients whether they have diabetes or not, this drug has been given to thousands of patients without diabetes in our clinical trials. So whether they have type 2 diabetes or not, its indicated to reduce those risks that you see here.

Slide 17
As I mentioned, I’ll pepper a little bit of safety throughout this, so let’s talk about SGLT2 inhibitors and ketoacidosis. This occurs more commonly in type 1 diabetics than type 2 and that’s why we have a limitation of use and we do not recommend the drug be used in type 1 diabetics, but ketoacidosis can also occur in type 2s and don’t be fooled. It’s a euglycemic ketoacidosis. So the blood sugar is only going to be 190 or 200 but the patient will be severely acidotic, that’s the time to stop the drug and think hard about whether you are ever going to re-initiate it. It’s potentiated by volume depletion and by lack of insulin or too low of an insulin dose and that leads me to the second point on this slide and that’s volume depletion. 

As you are beginning to use FARXIGA, think of its diuretic effect proportionate to a thiazide diuretic, so not a huge diuretic effect, you diurese 1 to 3 kg, systolic blood pressure goes down 3 to 6 points. If the patient’s already on a diuretic and they are already well-diuresed, you may want to stop that diuretic or reduce the Lasix. In our studies, some patients had to have their Lasix reduced. This is an important practice point. Before you begin the drug, think about the patient’s volume status, assess it just like you would with the diuretic. Also, it’s a sick day policy concept. Your nurses all know that when the patient calls up with vomiting and diarrhea and low blood pressure, the RN already knows to tell them to hold their Lasix that day, that would be also a good day to hold the FARXIGA.

Slide 18
Okay, so let’s talk about this landmark trial that I mentioned. It is called DAPA-CKD. It’s assessing for those four outcomes; preservation of GFR, preventing dialysis, preventing cardiac death, and heart failure hospitalization. Inclusion criteria in yellow box, it’s just adults with significant renal disease. You can see the GFR there. They have proteinuria, UACR up to 5000 mg and about 97% were already on ACE or ARB, so these are very well-treated patients. You can see the exclusion criteria. I will highlight type 1 diabetes and polycystic kidney disease. Please do not use FARXIGA in polycystic kidney disease patients. We don’t have data and we are not aware whether it will work good or cause more harm, so not for use. The study protocol was very simple, randomization is 1:1. Patients were given dapa 10 mg versus placebo, + plus they all get standard of care. They’re randomized for 2.4 years and then we follow the endpoints. You can see the primary endpoint which I’ve already set and there are secondary endpoints including all-cause mortality and cardiovascular mortality.

Slide 19
Here is a busy slide with randomization that you’re used to seeing, just showing that the randomization is clean, a third female. These patients are overweight, and their blood pressure could be a little bit better. There’s a lot of Asian patients in our study because this was a multinational trial. That is important mostly for nephrologist to be aware of. 

Slide 20
Here is the renal characteristics and I’ll direct your attention to the GFR 30 to 45 and less than 30, just to show you that we have plenty of patients with relatively severe CKD with a GFR of less than 45, so that’s stage 3B and 4 where you are probably thinking about referring the patient to nephrology and you can see the urinary albumin-to-creatinine ratio is average about 1000 significant proteinuria in these patients. Either way, I’ve harped on how you should be checking this. It’s something that you can monitor for effect also. So if your patient comes in with UACR of a 1000 and you do your magic with blood pressure control and FARXIGA and ACE inhibitors, you can see that UACR coming down 500 to 50, that’s feedback to you and the patient just like a cholesterol or an A1c to show that you’re probably having a good effect.

Slide 21
Here’s the spectrum of disease within these patients. In our study, only two-thirds were diabetic, plenty of nondiabetics, a third had cardiovascular disease and plenty with heart failure. You can see the medications used are your basic standard medications used in primary care and endocrinology for diabetes and hypertension.

Slide 22
Here is the primary outcome with that composite of GFR preservation, dialysis, cardiac death, and heart failure. The curves are event curves with dapagliflozin in purple and the placebo in gray. The curves begin to separate at 12 months and by the end of the trial, there’s a 39% relative risk reduction for these major outcomes saving lives and saving kidneys essentially. The study was terminated early for ethical reasons and by the way this is the second SGLT2 study looked at for kidney outcomes which was terminated early, so we now have two studies which qualify for termination early because they helped the kidneys that much. The number needed to treat in this chronic disease is 19. I encourage you to compare that to what your typical number needed to treat is for things like cholesterol medications.

Slide 23
Whether the patient is diabetic or not, the primary composite outcome holds up and in fact numerically the outcome is better for patients without diabetes. So this drug clearly works in non-glycemic ways with other mechanisms of action and helps patients with kidney disease and prevents cardiac and heart failure disease regardless of the patient’s diabetic status.

Slide 24
Let’s talk about a couple of safety and practice pearls. So what this shows is the GFR drop overtime, placebo versus dapa, dapa in purple. You can see that right away there’s an immediate decline in GFR of about less than 5% in the dapagliflozin patients. We call this eGFR dip. It occurs in about 30% of patients and you should know it and be aware of it, not be afraid of it. The curves cross at 1 year and that is where we begin to lessen the slope of decline of GFR. This is where we start saving patients. Noticed also that this dip is completely reversible whether you check for it in two weeks or not, is up to you. I think if the patient is exquisitely fragile, I would check sooner than later like I do with an ACE inhibitor, but not necessarily if the GFR is well preserved. 

Slide 25
Here’s couple other endpoints on the left showing the cardiovascular endpoints of death and hospitalizations for heart failure with relative risk reduction you can see there, and we even reduce all-cause mortality with dapagliflozin by 31% relative risk reduction in this study.

Slide 26
Let’s talk now more in detail about safety and this is safety in the DAPA-CKD trial. You can see just broadly speaking that adverse reactions were balanced between treatment patients and placebo patients in terms of hypoglycemia, volume depletion. There’s this severe condition called Fournier's gangrene, we can talk about later. That’s a deadly form of fasciitis that has been reported with SGLT2 inhibitors, in small number, but you should at least be aware of it.

Slide 27
By diabetic status, we look at the outcomes and this is to assuage your fears that if you’re giving this drug to a nondiabetic, does it cause hypoglycemia? It doesn’t. We have 0 cases here of major hypoglycemia in nondiabetic patients and you can kind of compare the adverse events. You can see the diabetics generally have more adverse events, but again they are balanced.

Slide 28
A couple of callout adverse events that you need to be aware of. We are putting sugar into the urine, so there is a potential risk of urosepsis and polynephritis, it was reported in earlier studies. In the DAPA-CKD trial, there wasn’t much difference but if your patient has recurrent UTIs, think twice again about implementing an SGLT2 inhibitor and whether you’re going to monitor. Hypoglycemia occurs because it is a hypoglycemic agent. It usually only occurs in a patient on insulin and a secretagogue. Necrotizing fasciitis, I mention, rare, but you need to know what it means and what it is. It is a severe pain in the perineum and that’s the patient you need to evaluate sooner and then I am going to speak at length about genital mycotic infections. Well, maybe I’ll talk about it here. So, the rate of general mycotic infections in dapa-treated patients is about 6.9% versus 1.5 in placebo, so clearly there’s a risk of mycotic infection so much so that if I gave this to a woman for the first time, I would inform her, tell her to call me if she gets the yeast infection and I will treat it with something like Diflucan or lotrimine.

Slide 29
Let’s talk about briefly the DECLARE subgroup.

Slide 30
DECLARE was a very large trial looking at preventing heart failure in patients at risk of heart failure with diabetes and risk factors. 17,000 patients again placebo versus dapagliflozin with the endpoints being MACE, which is death, MI, stroke, and another composite of CV death and hospitalization for heart failure.

Slide 31
I’m not going to go over those results. I’m going to go over the renal results from that 17,000-patient trial and what this shows is that very early on in patients with a GFR of greater than 60 with minimal proteinuria just qualifying for albuminuria, we have a 57% relative risk reduction in this 3-point composite with eGFR decline and UACR advancement. So, this trial not even designed to necessarily look at renal outcomes in post hoc analysis. So, there’s caution of light because it is post hoc, shows a reduction in renal endpoints in patients very early on in their course of disease, in terms of renal disease. So, these are again, patient should try to keep out of the hospital and keep them from ever getting to a nephrologist.

Slide 32
A couple more bits of safety information, not to use this drug in pregnancy or lactation. Any medication that alters renal tubular function, which SGLT2 inhibitors do can cause fetal malformations and by the tubular function I mean that the SGLT2 that means sodium, glucose, cotransporter that’s in the proximal tubule and it causes re-absorption of sodium and glucose. We block that and that’s why a patient given FARXIGA gets glycosuria and natriuresis and that’s why they diurese and that is why lose sugar. That’s the mechanism of reduction in blood sugar in these patients.

Slide 33
Okay, here’s that slide I mentioned about the female genital mycotic infections. This is pooled data from 12 studies. You can see 6.9% yeast infection in woman versus 1.5% in placebo. Even males get yeast infections driven mostly by uncircumcised males 2.7% versus 0.3%. So, very important for you to know that one, know about increased urination, know about volume depletion as I’ve mentioned.

Slide 34
So to summarize and I have got a couple more slides after this, FARXIGA’s the only SGLT2 FDA approved for preservation of GFR and these other indications in diabetics and nondiabetics. Dapagliflozin specifically reduces the risk of progression of kidney disease and CV mortality. The effect is consistent regardless of type 2 diabetes. We showed the effect in DECLARE trial with less advanced disease and I’ve outlined in detail the safety findings. Don’t give FARXIGA to patients on dialysis.

Slide 35
So some quick clinical considerations.

Slide 36
We need to be screening a little bit better and that screening is with UACR and GFR combined in patients with these risk factors. You get the diagnosis of CKD [cough 22:43] if you show abnormalities three months apart.

Slide 37
Guidelines have begun to catch up with this. In type 2 diabetics with CKD, SGLT2 inhibitors are indicated first line as they are in the diabetic guidelines, first line regardless of diabetic control, regardless of whether the patient is on ACE inhibitor or ARB, regardless of metformin status. We should be using these drugs first line 1A recommendation in most of these guidelines. Even the cardiovascular Heart Association Guidelines say consider this in your patients with CKD. So, this is now pervasively recommended for diabetics with CKD. The recommendation for nondiabetics with CKD is hopefully pending we don’t know yet because the data is too new.

Slide 38
So some clinical considerations; very simple dosing 10 mg once per day, no dose titration, don’t worry about the dose titration when you’re giving FARXIGA for kidney or heart failure indications. Don’t give it again to dialysis patients and have a sick day policy.

Slide 39
So, the clinical implications and I believe this is my final slide and then we’ll open it up for some questions. Diabetes is one of the leading causes of CKD. It is the leading cause more than 50% of cases. Due to the burden of CKD, we need to be looking at UACR a little more frequently than we are now to make this diagnosis get ahead of it. Your patients don’t come in complaining of cholesterol if you treat it. Your patients don’t complain of urinary albumin, yet it needs to be treated. Patients with type 2 diabetes should be screened with both of these tests and then SGLT2 inhibitors are recommended by guidelines for initial therapy in type 2 diabetics with CKD plus there is that indication of FARXIGA as the first therapy approved for patients with or without diabetes who have CKD. I think with that I’ll catch my breath and we’ll open this up for any questions.

CCO: Thank you, Dr. Fisch. If you have any questions regarding this presentation, please feel free to drop them into the Q&A box. Currently, I don’t see any questions for you Dr. Fisch, so we can give it a couple seconds.

Dr. Fisch: Alright.

CCO: And still seeing none. I think this concludes this presentation. Thank you.

Dr. Fisch: Thank you, everybody, for your attention.


Bruce Fisch, MDField Physician

AstraZeneca US Medical Affairs
Littleton, CO

*Describe the progressive nature of CKD and its link to significant mortality and morbidity.
*Highlight the importance of screening and diagnosis for CKD.
*Discuss new treatment options for patients with CKD and T2D and supporting data from the DAPA-CKD trial. 

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