CME Improving Outcomes and Preventing Chronic Kidney Disease Progression: Evaluating the Role of Novel Receptor Antagonists

Chair George L. Bakris, MD American Heart Association University of Chicago Medicine Chicago, Illinois

Faculty Rajiv Agarwal, MD, MS Indiana University School of Medicine Indianapolis, Indiana

What’s Inside 3 Current Guidance for Screening and Diagnosing Patients With or at Risk of Chronic Kidney Disease

5 Strategies for Managing Patients With Chronic Kidney Disease and the Interplay Among Common Comorbidities

9 Evaluating the Role of Mineralocorticoid Receptor Antagonists in Managing Chronic Kidney Disease: Current and Emerging Agents

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Media: Enduring Material Planning Committee Disclosures Accredited Activity Release Date: December 29, 2020 The planners from Medical Learning Institute, Inc., the accredited provider, and PVI, Accredited Activity Expiration Date: December 28, 2021 PeerView Institute for Medical Education, the joint provider, do not have any financial Time to Complete Activity: 30 minutes relationships with an ACCME-defined commercial interest related to the content of this accredited activity during the past 12 months unless listed below. Activity Description In this activity, two experts in nephrology discuss emerging evidence for improving Margery Tamas, MPH, has a financial interest/relationship or affiliation in the form of: outcomes and preventing chronic kidney disease (CKD) progression using Consultant for Fresenius Medical Care North America. nonsteroidal mineralocorticoid receptor antagonists. Content/Peer Reviewer Disclosures Target Audience The following Content/Peer Reviewer has nothing to disclose: This activity has been designed to meet the educational needs of nephrologists, endocrinologists, family practice/general practice physicians, and other clinicians Matthew A. Goodman, MD involved in the care of patients with CKD. Disclosure of Unlabeled Use Educational Objectives This educational activity may contain discussions of published and/or investigational Upon completion of this activity, participants should be better able to: uses of agents that are not indicated by the FDA. The planners of this activity • Apply current guidance consistent with the latest recommendations for screening, do not recommend the use of any agent outside of the labeled indications. The diagnosis, and treatment of patients with or at risk of developing CKD opinions expressed in the educational activity are those of the faculty and do • Describe the interrelationships among CKD and other common cardiometabolic not necessarily represent the views of the planners. Please refer to the official comorbidities prescribing information for each product for discussion of approved indications, • Evaluate the role and clinical potential of novel nonsteroidal mineralocorticoid contraindications, and warnings. receptor antagonists in providing renoprotection and preventing disease progression in patients diagnosed with CKD Disclaimer Participants have an implied responsibility to use the newly acquired information Providership, Credit, and Support to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for This CME activity is jointly provided by Medical Learning Institute, Inc. and PVI, patient management. Any procedures, medications, or other courses of diagnosis PeerView Institute for Medical Education. or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient's conditions and possible contraindications and/ This activity is supported by an educational grant from Bayer HealthCare or dangers in use, review of any applicable manufacturer's product information, and Pharmaceuticals Inc. comparison with recommendations of other authorities.

Physician Continuing Medical Education Method of Participation This activity has been planned and implemented in accordance with the There are no fees for participating in or receiving credit for this accredited activity. accreditation requirements and policies of the Accreditation Council for For information on applicability and acceptance of continuing education credit for Continuing Medical Education (ACCME) through the joint providership of this activity, please consult your professional licensing board. Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical Education. The Medical Learning Institute, Inc. is accredited by the ACCME to provide continuing A statement of credit will be issued only upon receipt of a completed activity medical education for physicians. evaluation form and will be emailed to you upon completion. You will receive your certificate from [email protected]. If you have questions regarding The Medical Learning Institute, Inc. designates this enduring material for a the receipt of your emailed certificate, please contact via email at info@PeerView. maximum of 0.5 AMA PRA Category 1 CreditTM. Physicians should claim only the credit com. commensurate with the extent of their participation in the activity. About This CME Activity Faculty Disclosures PVI, PeerView Institute for Medical Education, and Medical Learning Institute, Inc. are responsible for the selection of this activity’s topics, the preparation of editorial Chair content, and the distribution of this activity. Our activities may contain references George L. Bakris, MD to unapproved products or uses of these products in certain jurisdictions. The Professor of Medicine preparation of PeerView activities is supported by educational grants subject to Director, American Heart Association written agreements that clearly stipulate and enforce the editorial independence of Comprehensive Hypertension Center PVI and Medical Learning Institute, Inc. University of Chicago Medicine Chicago, Illinois The materials presented here are used with the permission of the authors and/or other sources. These materials do not necessarily reflect the views of PeerView or any George L. Bakris, MD, has a financial interest/relationship or affiliation in the form of: of its partners, providers, and/or supporters. Consultant and/or Advisor for Alnylam Pharmaceuticals, Inc.; AstraZeneca; Bayer Corporation; Ionis Pharmaceuticals, Inc.; Janssen Pharmaceuticals, Inc.; KBP Biosciences Co., Ltd; Merck & Co., Inc.; Novo Nordisk, Inc.; and Vascular Dynamics, Inc.

Faculty Rajiv Agarwal, MD, MS Professor of Medicine Indiana University School of Medicine Indianapolis, Indiana

Rajiv Agarwal, MD, MS, has a financial interest/relationship or affiliation in the form of: Consultant and/or Advisor for Akebia Therapeutics, Inc; Bayer Corporation; Boehringer Ingelheim GmbH; DiaMedica Therapeutics, Inc.; Eli Lilly and Company; Merck & Co., Inc.; Reata Pharmaceuticals, Inc.; Relypsa Inc.; and sanofi-aventis U.S. LLC. Data Safety Monitoring Board for AstraZeneca. Other Financial or Material Support for Bayer Corporation and Janssen Pharmaceuticals, Inc. as part of the adjudication committee. Steering committee for Akebia Therapeutics, Inc; Bayer Corporation; and Janssen Pharmaceuticals, Inc.

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Current Guidance for Screening If you actually look then at kidney disease, cardiovascular (CV) disease, and mellitus (T2DM) as interrelated and Diagnosing Patients With or disorders, it’s very clear that there’s a major overlap. Approximately 35% of patients—if you take a middle number—have diabetes at Risk of Chronic Kidney Disease and kidney disease, and then there is an even higher percentage of patients with heart failure (HF), diabetes, and kidney disease. So George L. Bakris, MD there’s no question about it, this is not just a kidney problem; this Rajiv Agarwal, MD, MS is a problem that relates to organs.

Dr. Bakris: Hello, I’m Dr. George Bakris from the University of Remember the heart and the kidney are married, they’re a married Chicago Medicine. Welcome to this educational activity on chronic couple, and if one isn’t doing well, the other one isn’t doing well. kidney disease (CKD). Joining me today is Dr. Rajiv Agarwal from Remember that concept. So what’s good for the kidney is good for Indiana University School of Medicine. Together, we plan to discuss the heart, and vice versa. some of the current guidelines pertaining to the screening and treatment of patients with CKD, including current and recent What Should Be Done to Detect and Monitor CKD Progression? advances with mineralocorticoid receptor antagonists. (Adapted From KDIGO Guidelines)1

• Check annually Prevalence of End-Stage Kidney Disease – BP 1 in 2000 and 2015 (People per Million) – Glucose/A1C – Lipid levels 2015 2000 – Albuminuria-spot urine (with blood test) • If kidney disease is present, eGFR is <60 mL/min/1.73 m2 – Check electrolytes and urine albumin every 6-8 months • If eGFR is <30 mL/min/1.73 m2 – Check electrolytes, kidney function, and albuminuria every 3-4 months

1. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. Kidney Int Suppl. 2013;3:1-150.

>60% 50%-60% 40%-50% 30%-40% 20%-30% 10%-20% 0%-10% ND Now, what can you do to monitor CKD progression? This is very 1. Cheng HT et al. Diabetes Care. 2020;dc201913. simple, very simple. This has been reported over 30 years ago; nobody seems to pay attention or doesn’t want to believe it, it’s Dr. Bakris: I want to start off by actually giving you a little bit very simple. Get the blood pressure controlled to less than 130 of background in terms of end-stage kidney disease (ESKD) and mmHg. Get the glucose controlled, a hemoglobin A1C of less kidney disease around the world. It is clear that the prevalence of than 7%. And, importantly, control the lipids and get the LDL into ESKD has dramatically increased from 2000 to 2015, and even more double digits. This is especially true all the way down to an eGFR so today, as you’ll see in a second. But if you look at this map, it’s of 45 mL/min/1.73 m2. When you go below that, lipids are not as very clear that the darker the color, the greater the prevalence, and important, but glucose and blood pressure are, so it’s very, very definitely things are going in the wrong direction. important.

The other thing is that you properly have to stage kidney CKD, CVD, and T2DM Are Interrelated Disorders disease. You can’t just measure the eGFR; you have to measure albuminuria—you have to. An albuminuria-spot urine test is all you HF need. In the beginning, when kidney function is good, you only • 35%-45% of patients with HF have CKD1 have to do it once a year, but you need that to really properly stage • 20%-44% of patients with T2DM have CKD2,3 people. • 60% of patients with HF and T2DM have CKD4 CKD T2DM • 25%-45% of patients with HF have T2DM1,5

• 14% of the US population has diabetes3

• 32% of patients with CAD have T2DM2 ASCVD

1. Packer M. Diabetes Care. 2018;41:11-13. 2. Wanner C. Am J Cardiol. 2017;120:S59-S67. 3. https://www.cdc.gov/nchs/data/databriefs/db319.pdf. 4. https://www.cdc.gov/diabetes/data/statistics/statistics-report.html. 5. Kovell LC et al. PLoS One. 2015;10:e0132228.

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Monitoring Recommendations: Changes in Selected Risk Factors in Accuracy of Diagnostic Tests for CKD1 the Intensive- and Conventional-Therapy Groups During Follow-Up1

11 350 10 Conventional therapy 300 Conventional therapy Persistent Albuminuria Categories 9 250 Descriptions and Ranges 8 200 A1 A2 A3

7 mg/dL 150 Normal to mildly Moderately Severely 6 A1C = 7% Intensive therapy 100 Intensive therapy increased increased increased

5 Cholesterol, Total 50 Glycosylated Hb, %

2 <30 mg/g 30-300 mg/g >300 mg/g 0 0 0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8 Benefits and Limitations <3 mg/mmol 3-30 mg/mmol >30 mg/mmol G1 Normal or high ≥90 170 200 of UACR and eGFR 160 175 Conventional therapy G2 Mildly decreased 60-89 150 150 Conventional therapy 140 125 • Predictors of outcomes Mildly to moderately G3a 130 100 decreased 45-59 120 Systolic BP = 130 mmHg Intensive therapy 75 • Recommended LDL-C, mg/dL 110 50 Intensive therapy G3b Moderately to severely Systolic BP, mmHg Systolic BP, LDL-C = 70 mg/dL in KDIGO guidelines 0 0 decreased 30-44 0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8 • Values are G4 Severely decreased 15-29 approximations

95 350 Descriptions and Ranges 90 300 Conventional therapy G5 Kidney failure <15

85 Conventional therapy 250 eGFR Categories, mL/min/1.73 m 80 200 Low risk (if no other markers of kidney disease present, no CKD) 75 150 Moderately increased risk High risk Very high risk 70 100 Intensive therapy Intensive therapy 65 50 Diastolic BP, mmHg Diastolic BP, 0 mg/dL Triglycerides, 0 For help discussing CKD with patients, please see the accompanying downloadable Practice Aid 0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8 Follow-Up, y Follow-Up, y

1. Gaede P et al. N Engl J Med. 2003;348:383-393. 1. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. Kidney Int Suppl. 2013;3:1-150.

This is an example of data that I was telling you that’s relatively This is from the National Kidney Foundation and the KDIGO, the old but with a long-term follow up—it was actually a 21-year international guidelines of kidney disease—the so-called heat follow-up with this study now. You can see what it took for so- map. This is why, if you look at this carefully, eGFR is on the left called intensive therapy, even higher than some of the guideline and albuminuria is on the top—that’s why you have to measure recommendations today, and still a benefit was seen. both. Show the patient this as well, it’s very important. They’ll see if they’re in the red. You don’t have to say anything; they will know they’ve got a big problem. This is very, very important and very 1-7 Barriers to Diagnosis of CKD simple. It takes 2 seconds. Now, that’s the background, and with that background, I want to bring Dr. Rajiv Agarwal in to give us Comorbid Confusion Anxiety about conditions not around Lack of time informing patients some important strategies on managing patients. addressed in guidelines for screening of diagnosis guidelines

• Most patients (96%) with kidney damage or mildly reduced kidney function are not aware they have kidney disease6,a • Almost half of patients (48%) with severely reduced kidney function who are not on dialysis are not aware they have kidney disease6,a

a Defined as reduced kidney function (eGFR <60 mL/min/1.73 m2), severely reduced kidney function (eGFR <45 mL/min/1.73 m2), and/or evidence of kidney damage (usually indicated by albuminuria or proteinuria) for a period of >3 months. 1. Neale EP et al. BMC Nephrol. 2020;83. 2. Fraser SDS et al. Curr Opin Nephrol Hypertens. 2016;25:465-472. 3. Fraser SDS et al. BMC Nephrol. 2015;16:193. 4. Cowan E et al. Clin Med. 2020;20:28-30. 5. Du Vaure CG et al. BMJ Open. 2016;6. 6. https://www.cdc.gov/diabetes/pubs/pdf/kidney_ Factsheet.pdf. 7. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. Kidney Int Suppl. 2013;3:1-150.

Now, it’s critically important, I can’t overemphasize this enough, to tell patients they have kidney disease. Period. These data show that almost half of the patients with severely reduced kidney function—these are patients with eGFRs down in the 30s who were totally unaware that they had kidney disease. The patient’s adherence is critical. If patients know they have kidney disease and know that if they do the things you just told them, per what we discussed, then patients will follow it much more carefully if they know there’s a threat that they will lose their kidney function. This is very, very important.

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Strategies for Managing Patients said, that albuminuria is something that we are not measuring and With Chronic Kidney Disease and that’s something that is critical for our friends to start doing. the Interplay Among Common Dr. Bakris: I want to point out to the listenership that Alan Go is a cardiologist and not a nephrologist, so I think it’s important to Comorbidities understand that background. The other point is we should not allow, if we can and we can make a difference, kidney disease George L. Bakris, MD to progress that far before we jump in. We should be doing 2 Rajiv Agarwal, MD, MS something, even when the eGFRs are 60 and 70 mL/min/1.73 m , with the risk factor modulation that we’ve already talked about— blood pressure, glucose, lipids. Do you agree or disagree?

Complications of Late Diagnosis and Treatment: Lower eGFR Is Associated With CV Events and Death1,a Dr. Agarwal: Totally. I think that, you know, what is good for the heart is good for the kidney in general. Death CV Events

15 40 14.14 36.60 14 13 35 12 1 11.36 30 Pathophysiology of CKD 11 10 25 9 21.80 8 20 7 Systemic hypertension 6 15 5 4.76 11.29 4 10 Age-Standardized Rate

of CV Events per 100 p-y Kidney injury 3 From Any Cause per 100 p-y From

Age-Standardized Rate of Death 2 5 3.65 1.08 1 0.76 2.11 0 0 Vasculature Glomerulus Tubule Interstitium ≥60 45-59 30-44 15-29 <15 ≥60 45-59 30-44 15-29 <15 • Endothelial • Glomerular • Tubular • Inflammation eGFR, mL/min/1.73 m2 eGFR, mL/min/1.73 m2 dysfunction hypertension damage • Oxidative No. of Events 25,803 11,569 8,024 4,081 842 No. of Events 73,108 34,690 18,580 8,809 3,824 • Endothelial • Glomerular • Tubular stress cell damage cell hypertrophy cell injury a A large integrated health system including 1,120,295 patients with sCr measured between 1996-2000 and median follow-up of 2.84 years. 1. Go AS et al. N Engl J Med. 2004;351:1296-1305. CKD progression

Arteriolar Tubular Interstitial Glomerulosclerosis Dr. Agarwal: Thank you, George. That was an excellent sclerosis atrophy fibrosis ESKD introduction, because, as you said, the kidney and the heart are a 1. Velasquez MT. In: Kimmel PL, Rosenberg ME, eds. Chronic Renal Disease. 1st ed. San Diego, CA: Academic Press; 2015:634-645. married couple and if one is sick, the other is not doing well. This is one of the landmark studies. It was published in The New England Journal of Medicine in 2004, and what it showed was that kidney So let’s talk about the pathophysiology of CKD. So we injure the disease was associated very strongly with all-cause mortality and kidney, and the kidney has four compartments: the vasculature, with CV events. What you see on this graph is that as the kidney the glomerulus, the tubule, and the interstitium. Any of those four disease progresses, people with an eGFR of less than 15 mL/ compartments, when injured, will lead to CKD progression. So min/1.73 m2, for example, have the highest risk for death and the there’s not really [a] CKD, [there are] CKDs. You know, there’s not highest risk for CV events. As Dr. Bakris pointed out, this starts one etiology; as you can see, it can be various etiologies. When you happening at an eGFR of about 45 mL/min/1.73 m2, so if you have injure the vasculature, it leads to arterial sclerosis; the glomerulus, that inflection point of 45 mL/min/1.73 m2, that’s where it starts it leads to glomerulosclerosis, the tubules, tubular atrophy, and happening. interstitium leads to interstitial fibrosis. So when this happens, then you’re marching towards ESKD. Dr. Bakris: So Rajiv, let me ask you something, and there’s a lot of discussion now in the CV community that advanced kidney 1 disease, an eGFR below 45 mL/min/1.73 m2, is actually a risk factor, Goals of CKD Management not a risk marker but a risk factor, for CV death. There’s a lot of data mechanistically that is evolving with that. What are your thoughts about that?

Prevent Minimize Promote Dr. Agarwal: So, you know, I think that we knew this all along, progression complications QOL that kidney disease is a risk factor for CV disease. We have known it from the times of Sir Richard Bright, you know, where he shows that sick kidneys are associated with sick hearts. Then it was the Framingham Heart Study that showed an association of dipstick 1. Vassolotti JA et al. Am J Med. 2016;129:13-162. proteinuria with left ventricular hypertrophy and CV events.

It wasn’t until we had the 2004 study published by Alan Go and The goal of CKD management is to prevent the progression of CKD colleagues that the community woke up and said, “Oh, this is to dialysis. That’s the most feared complication of kidney disease. happening.” But we have known it for a long time. I think, as you But also, more people will die of CV disease than end-stage kidney

Go online to complete the post-test and evaluation for CME credit PeerView.com/CWT900 5 Improving Outcomes and Preventing Chronic Kidney Disease Progression: Evaluating the Role of Novel Nonsteroidal Mineralocorticoid Receptor Antagonists failure, so we have to minimize complications, and we have to So let’s talk about a case now. George, would you like to walk us promote quality of life in these patients. through the case now?

Dr. Bakris: So Rajiv, we have a 68-year-old man with long-standing 1,2 Interventions to Reduce CKD Progression coronary disease and T2DM. He’s had hypertension for 22 years, hyperlipidemia for 15 years, kidney disease for 7 years, diabetes for 10 years, with 1+ pedal edema. He’s coming in with a blood pressure of 138/76 mmHg, and he’s got a creatinine of 1.6 mg/dL. He’s also got 494 mg of albumin. His medications are there, you Eat kidney-friendly Maintain foods healthy Control BP and can see them: lisinopril/ combo 10/12.5 mg/d (low sodium diet) body weight glucose levels and metoprolol 100 mg/d. He’s being treated for diabetes, and he’s being treated for lipids. What do you think of that blood pressure, Rajiv?

1. Blankenburg M et al. BMC Nephrol. 2019;20:171. 2. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. Kidney Inter Suppl. 2013;3:1-150. Dr. Agarwal: Well, George, clearly his blood pressure is high; 138/76 mmHg is above our guidelines of 130 mmHg. We need to So the interventions have to start early. There are kidney-friendly get the blood pressure down. Before we get the blood pressure foods, low-salt diets, fresh fruits, vegetables, less processed down, we have to be sure that the blood pressure that we are foods. They are good for the kidneys. What is good for the heart is measuring is the way in which it should be measured, which is good for the kidneys, so maintaining a healthy body weight and after seated rest for five minutes and triplicate measurement with controlling blood pressure and glucose levels. Again, this is the the appropriate technique. usual lifestyle modification advice that we give all patients with kidney disease. If we do all that, and we still find that the blood pressure is elevated, we need to get it down. There are several things we can

Since RENAAL and IDNT, New Therapeutic Strategies do. For example, in this patient, we can add a fourth drug. He is for Patients With T2DM and CKD Have Failed already on three drugs, so he clearly has resistant hypertension. The fourth drug that, in this case, I would probably pick is

Avosentan Sulodexide Lisinopril/losartan in this situation, because I’m worried about using Endothelin Various MOAs Dual antagonist2 suggested4 ACEi/ARB6 in this patient, as he has a potassium of 4.5 mEq/L 2 2010 2012 and eGFR of 45 mL/min/1.73 m , right at the threshold where the

2007 2011 2013 European Society of Cardiology (ESC) says that we should not be Ruboxistaurin Pirfenidone Aliskiren Bardoxolone methyl PKC-β TGF-β Renin Keap1-Nrf2 using spironolactone. So I would use that regimen to get the blood inhibitor1 production inhibitor3 inhibitor5 pathway activator7 pressure down, in addition to advising the patient to be on a low sodium diet. 1. Tuttle KR et al. Clin J Am Soc Nephrol. 2007;2:631-636. 2. Mann JFE et al. J Am Soc Nephrol. 2010;21:527-535. 3. Sharma K et al. J Am Soc Nephrol. 2011;22:1144-1151. 4. Packham DK et al. J Am Soc Nephrol. 2012;23:123-130. 5. Parving HH et al. N Engl J Med. 2012;367:2204-2213. 6. Fried LF et al. N Engl J Med. 2013;369:1892-1903. 7. de Zeeuw D et al. N Engl J Med. 2013;369:2492-2503. Dr. Bakris: So let me challenge you. This is a guy with 494 mg of albumin in his urine. He’s got an eGFR of 45 mL/min/1.73 m2, Now, we have many trials. We have had drugs that have been used, and he is not, per the guidelines on resistant hypertension, on starting from RENAAL and IDNT, but lots of these drugs failed. For maximally-tolerated lisinopril. He’s certainly on an inappropriate example, we had endothelin receptor antagonists—avosentan and . So you wouldn’t change that? atrasentan. We had sulodexide and a number of trials. We have been trying for the last 20 years, and we kept on failing and failing. Dr. Agarwal: Great question. And you know, I think that a snapshot may not reveal what was going on. In fact, the patient might have been on a higher dose of lisinopril and became 68-Year-Old Man With Long-Standing CAD, T2DM, and CKD hyperkalemic, and that’s why the physician chose to give the low-

Weight and Metabolism Current Therapy dose lisinopril/ hydrochlorothiazide combo to get the potassium • BMI: 33 kg/m2 High • Atorvastatin 80 mg/d • LDL-C: <70 mg/dL WNL • Metoprolol ER 100 mg/d down, perhaps. • African American man • Vitamin D: 38 ng/mL WNL • Lisinopril/HCTZ 10/12.5 mg/d • A1C: 7.1% WNL • Sitagliptin 100 mg/d • PMH – HTN: 22 years Cardiac Function – Hyperlipidemia: But you know, assuming that’s not the case, I absolutely agree 15 years • HR: 64 bpm, regular; no JVD WNL – CAD (two stents • BP: 138/76 mmHg High with you that, you know, 40 mg of lisinopril would be the • Lungs clear, COR-+S4; no S3 placed 14 years ago) – T2DM: 10 years guideline-recommended therapy for treating the albuminuria, – CKD: 7 years Renal Function • PE • eGFR: 45 mL/min/1.73 m2 Low and lisinopril in people with kidney disease who have an eGFR of – Abdomen benign • UACR: 494 mg/g High – 1+ pedal edema • sCr: 1.6 mg/dL High 2 • BUN: 37 mg/dL High 45 mL/min/1.73 m is a once-a-day drug, but if the eGFR is close to • Serum potassium: 4.5 mEq/L WNL normal, then it’s a twice-a-day drug.

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Dr. Bakris: Last point here. He’s got coronary disease, and the We then had the RALES trial that showed protection for lives data on metoprolol are very good. What would you think about in people who had HF with reduced ejection fraction, and that switching it out and giving him diltiazem at a higher dose? There progressed to numerous other trials leading to the discovery of the are some data with that but not as strong as metoprolol. nonsteroidal MRAs, which we will talk about next.

Dr. Agarwal: You’re right. I mean, yeah— High Residual Risk of CKD Progression With Current Therapies1-4 Dr. Bakris: That would give him additive antiproteinuric effects.

Hemodynamic1,2 Dr. Agarwal: Yes, I think that would be the added advantage • Elevated BP and/or intraglomerular pressure of using diltiazem. If we use diltiazem, we can have additional Inflammation and fibrosis1-3 antiproteinuric effects. You have shown that and some other studies have shown that. The downside of that is that it can Metabolic1,2 Not specifically targeted 1,4 interact with the atorvastatin. You know, diltiazem is a cytochrome • Poor glycemic control by existing treatments inhibitor and atorvastatin levels may go up, and that puts the patient at risk for rhabdomyolysis. This risk is particularly 1. Alicic RZ et al. Clin J Am Soc Neprhol. 2017;12:2032. 2. Mora-Fernández C et al. J Physiol. 2014;18:3997. 3. Bauersachs J et al. Hypertension. 2015;65:257. 4. Alicic RZ et al. Adv Chronic Kidney Dis. 2018;25:1941. magnified in people who have kidney failure, so I would worry a little bit about that. I’m happy with the metoprolol, because it’s providing cardiac protection and perhaps that’s more relevant So the three ways that we have protected the heart and the kidney than just giving an antiproteinuric drug. is to address blood pressure, both at the level of the circulation and in the glomerulus to control glycemia and have metabolic But because this patient’s BMI is high, some diabetologists may say effects through the control of diabetes. Now we are discovering that, you know, he needs to be on certain newer antidiabetics that that inflammation and fibrosis may be key factors. It’s not to are associated with weight loss and reduction in appetite. And, say that ACE inhibitors and ARBs, or SGLT2 inhibitors, may not you know, we can even think about the guideline-recommended have some effect on inflammation and fibrosis, but what we are therapy of an SGLT2 inhibitor in this case. discovering now is that the mineralocorticoid receptor activation is central to the role of inflammation and fibrosis, both in the heart Dr. Bakris: Absolutely, absolutely. All right, let’s move on and talk and in the kidneys. about MRAs in kind of a historical perspective. Thank you, Rajiv.

FIDELIO-DKD Rationale1-3 MRAs: Then and Now1 Mineralocorticoid receptor

FDA approval Hyperkalemia risk EMPHASIS-HF trial: of spironolactone is emerges after Eplerenone less efficacious than publication of the established as a Demonstration of CV protection of spironolactone RALES trial; risk life-saving drug Systematic review and DOCA as a spironolactone in in lowering BP may be due to in patients with HFrEF meta-analysis: MRAs sodium-retaining is an animals goes beyond in patients with higher doses of (NYHA class II) may provide benefit and kaliuretic endogenous MRA diuretic effects hypertension spironolactone and in patients with hormone in humans lower eGFR T2DM and CKD 1943 1957 1999 2003 2009 2014 2019

1938 1955 1960 2002 2004 2011 2016 Demonstration of Identification of RALES trial: EPHESUS trial: MRAs lower TOPCAT trial: Systematic review inflammation and progesterone-based Spironolactone Eplerenone proteinuria in Spironolactone and meta-analysis: fibrosis in kidney, spironolactone as established as a established as a CKD but risk of in HFpEF MRA used alone or on blood vessels, effective natriuretic life-saving drug in life-saving drug in hyperkalemia top of RAAS inhibition and heart agents in rats patients with HFrEF patients with LV increased threefold provides antiproteinuric with DOCA (NYHA class III/IV) dysfunction following effects in patients myocardial infarction with CKD First clinical is application of a ros synthetic MRA in Infl fib humans demonstrating ammation and MR blockade DNA in a patient with Addison’s disease and a patient TEXT = Milestones with CHF TEXT = Cardiac effects 1. Agarwal R et al. Eur Heart J. 2020. In press. 2. Bakris GL et al. JAMA. 2015;314:884. 3. Bakris GL et al. Am J Nephrol. 2019;50:333. TEXT = Risk of hyperkalemia

1. Agarwal R et al. European Heart J. 2020 Sep 1 [Epub ahead of print].

When we block that receptor using a nonsteroidal molecule, such Dr. Agarwal: Okay. So you know, we are going to talk about as finerenone, it can abrogate inflammation and fibrosis. So you MRAs, the mineralocorticoid receptor antagonists, and these have might think that while spironolactone and eplerenone might been studied since 1938. We had numerous people associated do it too—and they do—but when compared head-to-head in who are the who’s who of medicine, such as Grant Liddell and animals, we find that the nonsteroidal MRAs can actually abrogate George Thorn. These were the historical figures who studied inflammation and fibrosis much, much more than the other and subsequently found that if you block steroidal MRAs like spironolactone and eplerenone. mineralocorticoid receptors, you can derive benefits to the blood pressure.

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FIDELIO-DKD Rationale1-3 (Cont’d) Benefits and Limitations of MRAs in CKD1,2

Finerenone Mineralocorticoid receptor • Finerenone is potentially Tissue Distributiona Steroidal Nonsteroidal Potency Selectivity Metabolites a first-in-class nonsteroidal, (Kidney/Heart) selective MRA and currently being investigated to assess Higher  its effects on kidney and Spironolactone – High Low Multiple, active in kidney CV outcomes • A New Drug Application was No active Higher  recently submitted to the Eplerenone – Low Medium metabolites in kidney FDA, as well as a Marketing Authorization Application to of is the European Medicines Agency Inhibition ros No active Balanced in heart inf fib –  High High DNA lammation and Finerenone metabolites and kidney

a Based on standard whole body quantitative analysis in healthy rats. 1. Agarwal R et al. Eur Heart J. 2020. In press. 2. Bakris GL et al. JAMA. 2015;314:884. 3. Bakris GL et al. Am J Nephrol. 2019;50:333. 1. Kolkhof P et al. Handb Exp Pharmacol. 2017;243:271-305. 2. Agarwal R et al. Eur Heart J. 2020 Sep 1 [Epub ahead of print].

So a New Drug Application has recently been submitted to the Let us discuss the benefits and limitations of the conventional FDA, as well as a Marketing Authorization Application to the EMA MRAs in CKD. There are two steroidal MRAs, eplerenone and for getting approval for finerenone for protecting the heart and spironolactone. These are called steroidal, because they have the the kidneys in people T2DM and CKD. steroidal structure, which is cyclopentanoperhydrophenanthrene ring, the cholesterol nucleus that constitutes the molecule.

FIDELIO-DKD Rationale (Cont’d) Finerenone is nonsteroidal, because it’s got a dihydropyridine structure; it doesn’t resemble these drugs. The result of this Finerenone Mineralocorticoid receptor • Finerenone inhibits inflammation and fibrosis and chemistry is that the finerenone is highly selective for the protects against progressive kidney disease and CV mineralocorticoid receptor. Spironolactone has low selectivity, dysfunction in preclinical models1 and when the selectivity is low, it is more prone to causing • ARTS-DN showed improved albuminuria independent and sexual adverse reactions. Eplerenone has of measured changes in BP in patients with CKD medium selectivity. f is 2 Inhibition o os and T2DM inf fibr DNA lammation and

Hypothesis: Mineralocorticoid receptor antagonism with finerenone slows CKD progression Potency is another factor. For example, we know that 3 and reduces CV morbidity and mortality in patients with advanced CKD and T2DM spironolactone can bind with high affinity to the receptor; 1. Agarwal R et al. Eur Heart J. 2020. In press. 2. Bakris GL et al. JAMA. 2015;314:884. 3. Bakris GL et al. Am J Nephrol. 2019;50:333. therefore, it can have potent antimineralocorticoid receptor effects. Finerenone shares that property. However, the effect of This was based on the trial that we’ll discuss shortly. But before finerenone on blood pressure reduction is minimal compared we designed the phase 3 trial, we did a phase 2 trial; it was called with spironolactone, and this is in part because spironolactone the ARTS-DN. ARTS-DN was about 800 patients, and they had has metabolites that are active. For example, and escalating doses of finerenone all the way from placebo to 0 mg, 7α-thiomethylspironolactone (7α-TMS), which are very long- 2.5, 5, all the way to 20 mg once a day. The primary endpoint was acting. 7α-TMS has a half-life of almost a week, and when they to look at the reduction in albuminuria from baseline to 12 weeks, accumulate, they can have profound [effects on lowering] blood and we did find improvement in albuminuria, about 30% to 40%. pressure. There are no active metabolites known for eplerenone or finerenone; therefore, they don’t have as much blood pressure What we found was also there was not much of a signal for reduction as seen with spironolactone. hyperkalemia, and this led us to hypothesize that MR antagonism with finerenone, which is a nonsteroidal MRA, can slow kidney Tissue distribution is important. The spironolactone in the kidney disease progression and reduce CV morbidity and mortality in is concentrated six times as much as the heart. Eplerenone, three patients with advanced CKD and T2DM. times as much as the heart, and finerenone, the heart and kidney are equal in concentration. Why this is important is because the kidney distribution, again, affects the hyperkalemic potential. In fact, we look at randomized trials that have compared head-to- head spironolactone with finerenone, which is the ARTS program, we found that spironolactone was much more likely to cause hyperkalemia compared with finerenone.

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Evaluating the Role of This is the primary endpoint, which was wildly significant, favoring an 18% risk reduction with finerenone versus placebo. Remember, Mineralocorticoid Receptor placebo was a maximally-tolerated ACE inhibitor or ARB in >99% Antagonists in Managing Chronic of the patients in the trial, so this is truly maximal therapy, plus statins, plus everything else. So you can still do better adding Kidney Disease: Current and finerenone versus placebo. And you can see the P value of .0014. Emerging Agents FIDELIO-DKD: Secondary Endpoint1 CV Death, Nonfatal MI, Nonfatal Stroke, or HHF George L. Bakris, MD 25 HR = 0.86 (95% CI, 0.75-0.99) P = .0339 Placebo (420/2,841) Rajiv Agarwal, MD, MS 20 Finerenone (367/2,833)

15

10

1,2 5 FIDELIO-DKD Study Design Cumulative incidence, % 0 13,911 patients enrolled 5,734 patients randomized 2.6 years median follow-up 0 6 12 18 24 30 36 42 48 Time to First Event, mo No. at risk Post-treatment Finerenone 10 or 20 mg once dailya Placebo 2,841 2,653 1,969 951 115 follow-up Run-in Finerenone 2,833 2,688 2,017 984 111 Screening (4-16 weeks) R Post-treatment Placebo follow-up 1. Bakris G et al. N Engl J Med. 2020 Oct 23 [Epub ahead of print].

Hierarchical endpoints

1. Kidney composite 2. CV composite Death 3. from any cause

Time to kidney failure, sustained Time to CV death, nonfatal MI, Hospitalization ≥40% decrease in eGFR from nonfatal stroke, or HHF 4. for any cause If you look at the CV prespecified effect, you can see here it’s also baseline, or renal death 5. Change in UACR wildly positive, with a 14% risk reduction for CV events. And again,

Second kidney 6. composite a P value of .0339, so definitely positive.

a 10 mg if screening eGFR <60 mL/min/1.73 m2; 20 mg if ≥60 mL/min/1.73 m2, uptitration encouraged from month 1 if serum potassium ≤4.8 mEq/L and eGFR stable. 1. Bakris G et al. Am J Nephrol. 2019;50:336. 2. Bakris G et al. N Engl J Med. 2020 Oct 23 [Epub ahead of print]. FIDELIO-DKD: Hierarchical Endpoint Analysis1

Dr. Bakris: So I’m going to pick up now and move into the Finerenone Placebo Hazard Ratio P Endpoint (n = 2,833) (n = 2,841) (95% CI) FIDELIO-DKD trial and show you its design and results. This is the n, % n, % Primary kidney 0.82 1 504 (17.8) 600 (21.1) .0014 largest renal outcome trial ever done to date; 5,734 patients were composite endpoint (0.73-0.93) Key secondary CV 2 367 (13.0) 420 (14.8) 0.86 .0339 composite endpoint (0.75-0.99) randomized, depending on their eGFR above or below 45 mL/ Death from any 0.90 3 219 (7.7) 244 (8.6) .2348 2 cause (0.75-1.07) Hospitalization from 0.95 min/1.73 m , to either 10 or 20 mg of finerenone or placebo. The 4 1,263 (44.6) 1,321 (46.5) – any cause (0.88-1.02) median follow-up was 2.6 years, and the primary endpoint was 5 Change in UACRa – – 0.69 – (0.66-0.71)a Secondary composite 0.76 6 252 (8.9) 326 (11.5) – kidney failure, dialysis, renal death, or a greater than 40% decrease kidney endpoint (0.65-0.90) in eGFR compared with the placebo group. 0.50 1.00 2.00 Favors Favors finerenone placebo a Ratio of LSMs. 1. Bakris G et al. N Engl J Med. 2020 Oct 23 [Epub ahead of print]. There was also a prespecified secondary endpoint, and the prespecified secondary endpoint was CV death, nonfatal MI, nonfatal stroke, or hospitalization for HF (HHF). And then, there If you look at the hierarchical analysis, meaning we go down was a hierarchical analysis that then looked at all-cause mortality, primary kidney endpoint, significant, secondary CV endpoint hospitalization, change in UACR, and other factors—we’ll get into prespecified, significant. And then all-cause mortality, trend is that. positive, but there were not enough events so didn’t make it significant, so unfortunately everything after that, even if it looks

FIDELIO-DKD: Primary Endpoint1 significant, we can’t really discuss it statistically. But you can see Kidney Failure,a Sustained ≥40% Decrease in eGFR From Baseline, or Renal Death the data for yourself and certainly from kidney standpoints, it is

40 very positive. HR = 0.82 (95% CI, 0.73-0.93) P = .0014 Placebo (600/2,841) 30 Finerenone (504/2,833)

20

10 Cumulative incidence, %

0 0 6 12 18 24 30 36 42 48 Time to First Event, mo No. at risk Placebo 2,841 2,586 1,758 792 82 Finerenone 2,833 2,607 1,808 787 83

a ESKD or an eGFR <15 mL/min/1.73 m2. 1. Bakris G et al. N Engl J Med. 2020 Oct 23 [Epub ahead of print].

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What you see there in 23% was the hyperkalemia rate in the group FIDELIO-DKD: Adverse Events1,a that got placebo instead of the binder. So you can see that adding

Adverse Events Affecting ≥5% of Patients in Either Group Finerenone, n (%) Placebo, n (%) spironolactone to an ACE inhibitor or an ARB wildly increases Hyperkalemia 446 (15.8) 221 (7.8) Investigator-reported hyperkalemia 516 (18.3) 255 (9.0) it, tenfold higher than what you saw with finerenone, so in a Serious hyperkalemia 44 (1.6) 12 (0.4) Hospitalization because of hyperkalemia 40 (1.4) 8 (0.3) Nasopharyngitis 241 (8.5) 250 (8.8) similar population. So I think it’s important to keep in mind that Hypertension 212 (7.5) 273 (9.6) Anemia 209 (7.4) 191 (6.7) finerenone is not your mother’s spironolactone. Peripheral edema 186 (6.6) 304 (10.7) Diarrhea 184 (6.5) 189 (6.7) Upper respiratory tract infection 181 (6.4) 189 (6.7) Glomerular filtration rate decreased 179 (6.3) 133 (4.7) Urinary tract infection 179 (6.3) 192 (6.8) Back pain 175 (6.2) 175 (6.2) 1 Hypoglycemia 151 (5.3) 194 (6.9) FIDELIO-DKD: Key Takeaways Dizziness 146 (5.2) 153 (5.4) Arthralgia 142 (5.0) 149 (5.3) Bronchitis 134 (4.7) 151 (5.3) Constipation 131 (4.6) 163 (5.8) • Finerenone reduced the risk of kidney failure or sustained decrease in eGFR Pneumonia 128 (4.5) 181 (6.4) (primary endpoint,17.8% vs 21.1%; HR = 0.82 [95% CI, 0.73-0.93]; P = .0001) a These events were classified according to the MedDRA preferred term. – 3.4% absolute difference after 3 years (95% CI, 0.6-6.2) 1. Bakris G et al. N Engl J Med. 2020 Oct 23 [Epub ahead of print]. – NNT = 29 (95% CI, 16-166) • Finerenone reduced the risk of CV death, nonfatal MI, stroke, or HHF (secondary endpoint, 13.0% vs 14.8%; HR = 0.86 [95% CI, 0.75-0.99]; P = .03) Now, adverse events. Well as you would expect, the major adverse – 2.4% absolute difference after 3 years (95% CI, 0.3-4.5) event is related to potassium. But I think it’s important for us to – NNT = 42 (95% CI, 22-397) discuss this, because this is the only trial where maximizing RAAS • Early reduction in albuminuria and separation of KM curves for CV outcomes • No unexpected AEs; hyperkalemia was approximately twice as frequent with finerenone blockade, especially with an MRA, did not lead to early stopping of vs placebo (11.8%-18.3% vs 4.8%-9.0%), but discontinuation because of hyperkalemia the trial or a large number of people permanently discontinuing. In was infrequent in patients who received finerenone (2.3% vs 0.9%) compared with placebo 1. Bakris G et al. N Engl J Med. 2020 Oct 23 [Epub ahead of print]. fact, only 2.3% of the finerenone group permanently discontinued, and 0.9% of the placebo group. So what are the takeaway messages? Well, the takeaway messages

Benefit–Risk in Studies Investigating RAAS Inhibition from this trial are (1) finerenone reduced the risk of kidney in Similar Patient Populations failure or sustained decrease in eGFR. There was a 3.4% absolute difference after 3 years between the placebo and the finerenone ALTITUDE1 VA NEPHRON-D2,a AMBER4 FIDELIO-DKD3 (CKD + T2DM) (CKD + T2DM) (CKD) group, and you had to treat 29 patients to prevent dialysis or Efficacy not studied Lack of efficacy Lack of efficacy Kidney and CV efficacy (Phase 2) reduction in eGFR. 25 25 25 40 Aliskiren + ACEi/ARB ACEi + ARB Finerenone + ACEi/ARB Placebo + spiro + (n = 4,272) (n = 724) (n = 2,827) ACEi/ARB (n = 148) 20 Placebo + ACEi/ARB 20 Placebo + ARB 20 Placebo + ACEi/ARB Patiromer + spiro + (n = 4,285) (n = 724) (n = 2,831) 30 ACEi/ARB (n = 147) 15 15 15 23.0% As far as CV events go—and we went through those—CV death, 9.9% 20 10 10 10

4.8% 4.4% 10 6.8% nonfatal MI, stroke, or HHF, there was a 2.4% absolute difference 5 5 5 2.6% 2.3% 0.9% Permanent Discontinuation Because of Hyperkalemia, % 0 0 0 0 after 3 years. You had to treat 42 people to get the benefit on Median 2.7 years Median 2.2 years Median 2.6 years 12 weeks CV events. There was an early reduction in albuminuria that was

a Hyperkalemia in VA NEPHRON-D was reported as defined as potassium level >6.0 mEq/L, ED visit, or admission for hyperkalemia. 1. Parving HH et al. N Engl J Med. 2012;367:2204. 2. Fried LF et al. N Engl J Med. 2013;369:1892. sustained. That is critical, because it’s totally independent of blood 3. Bakris G et al. N Engl J Med. 2020 Oct 23 [Epub ahead of print]. 4. Agarwal R et al. Lancet. 2019;394:1540. pressure; this was not a hemodynamic effect. And so, it gets back to what Dr. Agarwal was saying earlier about inflammation and Now how does this compare with other trials? I think this other mechanisms. Glucose was certainly not affected. is important. There are two other trials with very similar populations—T2DM, advanced kidney disease—that looked at Lastly, there were no unexpected adverse events, and the maximizing RAAS inhibition, VA NEPHRON-D and ALTITUDE. In hyperkalemia that was noticed with finerenone is nowhere near both of these trials, they were stopped early for lack of efficacy that of what you see with these traditional steroidal agents. And and safety issues. And you can see in purple, the hyperkalemia rate again, it was not a reason to stop the trial. in these trials, and you can see that the FIDELIO-DKD trial pales by comparison in terms of hyperkalemia rates. It was not stopped early for any issue.

Now, you see the AMBER trial. What is the AMBER trial? The AMBER trial was conducted by Dr. Agarwal and colleagues. It was an interesting trial. This was not a kidney disease trial per se; it had people with advanced kidney disease, similar to the other three studies, but this was a study to control resistant hypertension, so everybody, per guidelines, got spironolactone. The question was, “Can we maintain the spironolactone if we give a potassium binder?” In this trial, patiromer was the potassium binder randomized.

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finerenone in this patient, 10 mg once a day, he has an 18% relative 68-Year-Old Man With Long-Standing CAD, T2DM, and CKD risk reduction in kidney endpoint and a 14% relative risk reduction in cardiac endpoint—that’s an amazing risk reduction. No question Weight and Metabolism Current Therapy • BMI: 33 kg/m2 High • Atorvastatin 80 mg/d about using finerenone in this patient once it’s available. • LDL-C: <70 mg/dL WNL • Metoprolol ER 100 mg/d • African American man • Vitamin D: 38 ng/mL WNL • Olmesartan 40 mg/d • A1C: 7.1% WNL • Sitagliptin 100 mg/d • PMH – HTN: 22 years Cardiac Function Dr. Bakris: So there are many clinicians that when you mention – Hyperlipidemia: 15 years • HR: 64 bpm, regular; no JVD WNL – CAD (two stents • BP: 138/76 mmHg High mineralocorticoids the next thing out of their mouth is • Lungs clear, COR-+S4; no S3 placed 14 years ago) – T2DM: 10 years “Hyperkalemia, not doing it.” What’s different about finerenone? – CKD: 7 years Renal Function • PE • eGFR: 45 mL/min/1.73 m2 Low And how would you monitor it, because, as I said, it’s not your – Abdomen benign • UACR: 494 mg/g High – 1+ pedal edema • sCr: 1.6 mg/dL High • BUN: 37 mg/dL High mother’s spironolactone? • Serum potassium: 4.5 mEq/L WNL Dr. Agarwal: Yes, so this patient has a potassium level that is quite reasonable. You know, in the FIDELIO-DKD trial, we did not expose So given the case we already discussed, there was no SGLT2 people who had a potassium of 4.9 mEq/L or greater to finerenone inhibitor used. It’s certainly in the guidelines. Would you give this at the start. This patient has less, so this patient certainly would guy, even with the changes that we made, an SGLT2 inhibitor? qualify to participate in the FIDELIO-DKD trial.

Dr. Agarwal: George, as you pointed out, the guidelines are We called patients back after 1 month, and if you look at the pretty clear on it. The patient has an eGFR of 45 mL/min/1.73 m2, trajectory of change of hyperkalemia, for instance, it’s not albuminuria in the macroalbuminuria range, and all the guidelines happening, it’s not concentrated right at the beginning; it’s sort will tell us that this patient will have a benefit for his kidneys and of evenly distributed throughout the 3 years of the trial. So I think heart if we use an SGLT2 inhibitor, so there is no question in my that patient requires potassium monitoring. Call them back in 1 mind that I would place this patient on an SGLT2 inhibitor. I think month, and then 4 months subsequently, and then just treat the it’s a good thing. potassium and the patient just like you would manage an ACE inhibitor or an ARB. The only place where you won’t perhaps do it is if the patient had a history of diabetic ketoacidosis and some patients tell me, after I I don’t think that there’s any magic about it, but we have to be tell them that there’s a small risk of genital fungal infections, they cognizant that we have to monitor potassium. This is not a fire- just refuse to take the drug. So sometimes people refuse also, and-forget drug, it’s not like a statin, you use the drug and okay, but, you know, if you tell them the risks and they’re happy to take come back in a year. This will require some monitoring. And if it, I would take it. If I were the patient or if I was treating a family you’re careful, I think we can save lives and we can save kidneys. member, I’d certainly use an SGLT2 inhibitor. Dr. Bakris: So Dr. Agarwal, it’s easy for you to say as a

68-Year-Old Man With Long-Standing CAD, T2DM, nephrologist, and easy for me to accept as a nephrologist, but for and CKD: Return Office Visit our primary care audience, you really want to wait a month? Don’t

Weight and Metabolism Current Therapy you want to check it in a week, because I’m a little nervous? • BMI: 33 kg/m2 High • Atorvastatin 80 mg/d • LDL-C: <70 mg/dL WNL • Metoprolol ER 100 mg/d • African American man • Vitamin D: 38 ng/mL WNL • Olmesartan 40 mg/d • A1C: 7.1% WNL • SGLT2 inhibitor • PMH Dr. Agarwal: Well, you know, according to what we did in this – HTN: 22 years Cardiac Function – Hyperlipidemia: trial, we called them in a month. The question is how many people 15 years • HR: 64 bpm, regular; no JVD WNL – CAD (two stents • BP: 130/72 mmHg WNL were discovered hyperkalemic at 1 month, when they were not • Lungs clear, COR-+S4; no S3 placed 14 years ago) – T2DM: 10 years hyperkalemic, and you would have to screen 100 people before – CKD: 7 years Renal Function • PE • eGFR: 45 mL/min/1.73 m2 Low you will find one patient who gets hyperkalemia. – Abdomen benign • UACR: 312 mg/g High – 1+ pedal edema • sCr: 1.6 mg/dL High • BUN: 37 mg/dL High • Serum potassium: 4.5 mEq/L WNL This is not a drug that will raise potassium dramatically. The main change in potassium that we saw was 0.23 mmol/L [mEq/L] at 4 months. This is not a hugely hyperkalemic drug. Yes, you can Dr. Bakris: There is no question I agree with you. Okay, so we put call them in a week, but you’ll be calling a lot of patients with no him on an SGLT2 inhibitor, we got his blood pressure controlled, results. This is not something like spironolactone. we made the changes. He’s coming back now, his pressure is less than 130/72 mmHg, so he’s at goal. His glucose is better. But you Dr. Bakris: I thank you again, want to make the point this is not repeat the albumin, and he’s come down from about 500 g/dL, but your mother’s spironolactone. he’s still at 300 g/dL. Now what would you do?

Dr. Agarwal: I think, George, at this point finerenone is a great option. This patient has still a residual albuminuria. If I use

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So I mean, from my standpoint, what we could do here is actually 68-Year-Old Man With Long-Standing CAD, T2DM, and CKD: Alternate Scenario increase the diltiazem to 360 mg, and he needs a fourth drug now. Is he on an SGLT2 inhibitor? Doesn’t look like it. Let’s assume for Optimized Antihypertensive Therapy • Tapered metoprolol ER 100 mg/d the sake of argument that he is taking the drugs. We can add an • Stopped lisinopril/HCTZ 10/12.5 mg/d • African American man • Started diltiazem CD 300 mg/d, olmesartan 40 mg/d, • PMH and chlorthalidone 25 mg/d SGLT2 inhibitor that’ll help his blood pressure a little bit, but he’s – BMI: 31.4 – HTN: 22 years Cardiac Function (2 Weeks Later) going to need more. So what would you add here? Would you – Hyperlipidemia: 15 years • HR: 64 bpm, regular; no JVD WNL • BP: 168/70 mmHg High give him spironolactone? Let’s say his potassium is 4.3 mEq/L, I – CAD (two stents • Lungs clear; COR-+S4; no S3 placed 14 years ago) – T2DM: 10 years mean, that would be the recommendation. He’s got 600 mg of (A1C: 7.1%) Renal Function (2 Weeks Later) – CKD: 7 years • eGFR: 30 mL/min/1.73 m2 Low albuminuria. Would you give him spironolactone here? • PE • UACR: 600 mg/g High – Abdomen benign • sCr: 1.9 mg/dL High – 1+ pedal edema • BUN: 37 mg/dL High • Serum potassium: 4.3 mEq/L WNL Dr. Agarwal: So, you know, according to the ESC, they say that if you have an eGFR of less than 45 mL/min/1.73 m2, and a potassium level of more than 4.5 mEq/L, you shouldn’t be using it. Because he Okay, Rajiv, I’m going to give you a different scenario—similar case has an eGFR of 30 mL/min/1.73 m2, he technically wouldn’t qualify. but different scenario than what we just discussed. The patient The package insert for eplerenone says that microalbuminuria is a is an African American man; his past medical history includes 22 contraindication to using the drug, and clearly an eGFR of 30 mL/ years of hypertension and hyperlipidemia for 15 years. He’s got min/1.73 m2 would be a contraindication for eplerenone as well. coronary disease, and two stents were replaced 14 years ago. He’s had T2DM for 10 years and CKD for 7 years. The patient also has 1+ So yes, those drugs would be contraindicated. I think finerenone pedal edema. would be a good choice. I think that in this patient, because you increase diltiazem and he comes in with muscle pain the next Now, he’s on a medication regimen that is similar to what we had time, I would check a CK, because, you know, diltiazem can inhibit and you optimized his therapy by starting him on diltiazem and the metabolism of atorvastatin and sometimes you can get olmesartan and chlorthalidone, tapered the metoprolol, and rhabdomyolysis if you have super-high levels of these drugs. So stopped lisinopril and hydrochlorothiazide. He comes in, and 2 those are the two caveats I would have on this. weeks later he’s got a blood pressure of 168/70 mmHg and still has the S4, but he’s got no JVD and his heart rate is 64 bpm. What Dr. Bakris: Okay. Now, we already said if you give finerenone, that would you do then? would definitely help the proteinuria, but it’s not going to help the blood pressure. So we need something for the blood pressure, Dr. Agarwal: That’s a great question, George, because this so what would you do? Would you add hydralazine? If you can’t patient—you have optimized his therapy; you went to olmesartan use the mineralocorticoids, what would you do to get the blood and the newer drugs, and his blood pressure is high. The first pressure down? thing I will ask is, “Did he fill his drugs?” A lot of these patients will go out, they will read on the internet the stuff on the Dr. Agarwal: Hydralazine is absolutely a lousy drug, in my opinion. medications, they’ll never take it, or they might have a problem You know, a drug that has to be taken three times a day to control with the insurance not filling it, or they might simply not take the blood pressure is a nonstarter. I hardly ever use it for blood medication. So first thing is adherence. pressure control in these individuals. He’s on chlorthalidone 25 mg a day. There’s room there; you can go to 50 mg. That might The second is the patient has a high BMI. Perhaps people who are help the potassium as well, because finerenone might get you a diabetologists might need to use some other antidiabetic drugs slight increase in potassium and increasing chlorthalidone might that will cause weight loss also, and that might actually improve actually allow the use of finerenone better and get the blood his BMI and glycemic control. 168 is terrible blood pressure, and if pressure down. it’s happening despite increasing the therapy, I think the first thing I would focus on is adherence. Dr. Bakris: So thank you for saying that about hydralazine; I fully agree with you. It turns out, full disclosure, this patient was not As you know, if we do random drug testing on these people, that taking his medications. And so, when he went on his medications, means our test for not drugs of abuse but drugs that they are we didn’t need to make all those adjustments, because he actually supposed to be taking, oftentimes we will find none. So I think that did far better. I think that’s an important point, and I just want to would be a very important part of the therapy. reinforce that. You say, “Are you taking your drugs?” and they’ll say “Yes.” But it turns out, they’re only taking one, but they’re taking Dr. Bakris: That’s a very important point. Just for the listener, why their drugs. So I think it’s important to keep that perspective when was diltiazem chosen and not amlodipine, because diltiazem has you’re talking to patients. been shown in multiple studies to have additive antiproteinuric effects. And at higher doses, good blood pressure-lowering effects, albeit 300 mg is a medium dose.

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Conclusions

T2DM, CKD, and HF are interrelated conditions with growing prevalence, and strategies for managing these conditions are limited

MRAs can interrupt the binding of to its receptor, thus preventing the inflammation and fibrosis in CKD

Finerenone offers high efficacy and low rates of AEs versus other MRAs for DKD; monitoring for hyperkalemia is recommended

So I’m going to conclude by basically saying that T2DM, CKD, and HF are interrelated conditions with growing prevalence. Strategies for these conditions are limited. MRAs can definitely interrupt the binding of aldosterone to its receptor, thus preventing inflammation and fibrosis in patients with CKD, and finerenone, the nonsteroidal, nonspironolactone-type MRA, offers high efficiency, high efficacy, and low rates of adverse events compared with the steroidal MRAs in diabetic kidney disease. And yes, in the beginning, you do have to monitor for hyperkalemia. This ends our discussion for today. Rajiv and I hope that you found today’s presentation useful.

Narrator: This activity has been jointly provided by Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical Education.

Go online to complete the post-test and evaluation for CME credit PeerView.com/CWT900 13 CME Improving Outcomes and Preventing Chronic Kidney Disease Progression: Evaluating the Role of Novel Nonsteroidal Mineralocorticoid Receptor Antagonists

This CME activity is jointly provided by Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical Education.

This activity is supported by an educational grant from Bayer HealthCare Pharmaceuticals Inc.

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