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Chronic kidney disease in patients with type 2 diabetes: What is the place for mineralocorticoid receptor antagonists? Disclaimer ∙ Unapproved products or unapproved uses of approved products may be discussed by the faculty; these situations may reflect the approval status in one or more jurisdictions. ∙ The presenting faculty have been advised by touchIME to ensure that they disclose any such references made to unlabelled or unapproved use. ∙ No endorsement by touchIME of any unapproved products or unapproved uses is either made or implied by mention of these products or uses in touchIME activities. ∙ touchIME accepts no responsibility for errors or omissions. How is our understanding of the pathophysiology of CKD in T2D influencing treatment approaches?

Dr Luiza Caramori

Associate Professor and Director of the Inpatient Diabetes Service University of Minnesota Minneapolis, MN, USA Rising prevalence of diabetes and CKD

• The global prevalence of diabetes was 9.3% (463 million people) in 2019 and is projected to increase to 10.2% (578 million) by 20301

• Globally, CKD in people with diabetes is the leading cause of end-stage renal disease2 • In 2017, CKD resulted in 35.8 million DALYs globally, with diabetic nephropathy accounting for almost a third of these3

CKD, chronic kidney disease; DALYs, disability-adjusted life years. 1. Saeedi P, et al. Diabetes Res Clin Pract. 2019;157:107843; 2. Fu H, et al. Mol Metab. 2019;30:250–63; 3. GBD Chronic Kidney Disease Collaboration. Lancet. 2020;395:709–33. Early detection of CKD

• Symptoms of CKD, such as peripheral oedema, usually appear at a relatively late stage1

Specific prognostic and diagnostic biomarkers for CKD are needed5

eGFR and UACR should be assessed at least once a year as recommended by ESC-EASD, ADA and KDIGO2–4

ADA, American Diabetes Association; CKD, chronic kidney disease; EASD, European Association for the Study of Diabetes; eGFR, estimated glomerular filtration rate; ESC, European Society of Cardiology; KDIGO, Kidney Disease: Improving Global Outcomes; UACR, urine albumin-to-creatinine ratio. 1. Persson F, Rossing P. Kidney Int Suppl. 2018;8:2–7; 2. Cosentino F, et al. Eur Heart J. 2020;41:255–323; 3. American Diabetes Association. Diabetes Care 2020;43(Suppl. 1):S135–51; 4. Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group. Kidney Int. 2020;98:S1–115; 5. Toth-Manikowski S, Atta MG. J Diabetes Res. 2015;2015:697010. CKD symptoms progress over time1,2

Worsening glomerular Cardiovascular sclerosis and inflammation Early signs disease (variable time of Hypertension Kidney onset in T2D) complications* Hyperglycaemia Cellular injury Declining eGFR and symptom progression ESRD ± Microalbuminuria Cardiovascular disease ↑ Morbidity Macroalbuminuria ↑ Mortality

*Anaemia, bone and mineral metabolism, retinopathy and neuropathy. CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; T2D, type 2 diabetes. 1. Alicic R, et al. Clin J Am Soc Nephrol. 2017;12:2032–45; 2. Pugliese G, et al. J Nephrol. 2020;33:9–35. Key pathways for CKD development in T2D

Physiological Pathophysiological effects factors Glomerular hypertrophy Haemodynamic Intracellular Mesangial expansion Metabolic signaling and Diabetes transcription Tubulointerstitial CKD factors inflammation and fibrosis Inflammatory

Glomerulosclerosis Fibrotic

Kidney fibrosis

CKD, chronic kidney disease; RAAS, renin-angiotensin-aldosterone system; T2D, type 2 diabetes. Alicic R, et al. Clin J Am Soc Nephrol. 2017;12:2032–45. Target pathways for current treatments Possible renal mechanisms of action of RAAS blockers, MR antagonists, SGLT2 inhibitors and GLP-1 agonists

Albuminuria Altered haemodynamics Inflammation RAAS blockers RAAS blockers RAAS blockers MR antagonists MR antagonists MR antagonists SGLT2 inhibitors SGLT2 inhibitors SGLT2 inhibitors

Podocyte injury Bioenergetic changes GLP-1 agonists SGLT2 inhibitors

Endothelial injury CKD in T2D Fibrosis RAAS blockers RAAS blockers MR antagonists MR antagonists

Oxidative stress Hyperglycaemia – obesity RAAS blockers SGLT2 inhibitors MR antagonists GLP-1 agonists

CKD, chronic kidney disease; GLP-1, glucagon-like peptide-1; MR, mineralocorticoid receptor; RAAS, renin-angiotensin-aldosterone system; SGLT2, sodium-glucose cotransporter 2; T2D, type 2 diabetes. Barrera-Chimal J, Jaisser F. Diabetes Obes Metab. 2020;22:16–31. What is the rationale for targeting the mineralocorticoid receptor in the treatment of CKD in T2D?

Prof. Peter Rossing

Head of Complications Research and Chief Physician Steno Diabetes Center Copenhagen Copenhagen, Denmark Renal effects of MRAs in patients with CKD and T2D

Tissue effects Clinical effects

Mineralocorticoid Reduces: receptor blockade Tubular injury Prevents/reduces: Glomerulosclerosis CKD progression Vasoconstriction Hypertension Podocyte injury Inflammation Proteinuria Vascular injury CV outcomes Fibrosis Mesangium expansion

CKD, chronic kidney disease; CV, cardiovascular; MRA, mineralocorticoid receptor antagonist; T2D, type 2 diabetes. Barrera-Chimal J, et al. Kidney Int. 2019;96:302–19. PRIORITY study: Efficacy of spironolactone in high-risk patients

Multicentre, prospective observational study

Median follow-up: 2.5 years Progression to Development of microalbuminuria stage 3 CKD* Spironolactone 25% 36% 25 mg/day (n=102) High vs vs CKD risk 1,775 patients with T2D Placebo (n=107) 33% 17% and normal UACR HR 0.81; p=0.41 HR 2.62; p=0.0021 • eGFR >45 mL/min/1.73 m2 • ACEi or ARB allowed, Low Observation • Spironolactone did not prevent but not dual blockade CKD risk (n=1,559) microalbuminuria in high-risk patients • No prior MRA • No differences seen in eGFR changes over time

*In patients with baseline eGFR >60 mL/min/1.73 m2. ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; HR, hazard ratio; MRA, mineralocorticoid receptor antagonist; T2D, type 2 diabetes; UACR, urinary albumin-to-creatinine ratio. Tofte N, et al. Lancet Diabetes Endocrinol. 2020.8:301–12. PRIORITY study: Increased hyperkalaemia risk with spironolactone

Spironolactone vs placebo in patients with T2D at high risk of CKD

Spironolactone 25 mg/day Placebo AE (n=102) (n=107) AE leading to discontinuation 25% 9% Hyperkalaemia (reported as an AE) 9% 1% Plasma potassium >5.5 mol/L 13% 4% Gynaecomastia 3% 0% Hypotension 3% 1% CKD stage 3 32% 14% (eGFR <60 mL/min/1.73 m²) 30% decrease in eGFR from baseline 24% 17%

AE, adverse event; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; T2D, type 2 diabetes. Tofte N, et al. Lancet Diabetes Endocrinol. 2020.8:301–12. Characteristics of novel MRAs Finerenone and esaxerenone are non-steroidal MRAs1

Esaxerenone: Finerenone: Highly selective No effect on androgen or No affinity for androgen or 1 vs steroidal MRAs progesterone receptors2 progesterone receptors3

High potency vs steroidal MRAs1

Balanced tissue distribution between heart and kidney1,4

MRA, mineralocorticoid receptor antagonist. 1. Kolkhof P, Bärfacker L. J Endocrinol. 2017;234:T125–40; 2. Arai K, et al. Eur J Pharmacol. 2015;761:226–34; 3. Bramlage P, et al. Eur J Heart Fail. 2016;18:28–37; 4. Arai K, et al. Eur J Pharmacol. 2015;769:266–73. What are the trial data for novel mineralocorticoid receptor antagonists for CKD in patients with T2D?

Dr George Bakris

Director of the American Heart Association Comprehensive Hypertension Center University of Chicago Medicine Chicago, IL, USA Esaxerenone

Novel non-steroidal MRA1,2

Approved in Japan for the treatment of hypertension2

Assessed in studies looking at microalbuminuria and albuminuria1,3

PRIMARY ENDPOINT • ESAX-DN: Multicentre, randomized phase III trial of esaxerenone vs placebo1 UACR remission rate was significantly higher • 455 Japanese patients with T2D, with esaxerenone vs placebo hypertension and microalbuminuria1 (22.1% vs 4.0%; p<0.0001)1 • Receiving ACEi or ARB1

ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blockers; MRA, mineralocorticoid receptor antagonist; T2D, type 2 diabetes; UACR, urinary albumin-to-creatinine ratio. 1. Kashihara N, et al. J Am Soc Nephrol. 2019;30(Suppl.):B8; 2. Duggan S. Drugs. 2019;79:477–81; 3. Ito S, et al. Clin J Am Soc Nephrol. 2019;14:1161–72. FIDELIO-DKD: CKD progression and CV outcomes in T2D

Multicentre, randomized phase III study

5,674 patients Finerenone (n=2,833) 10 mg/day (eGFR <60 mL/min/1.73m2)* • T2D and CKD 20 mg/day (eGFR ≥60 mL/min/1.73m2) • Maximized ACEi or ARB therapy Placebo (n=2,841) Primary endpoint: • Persistent, moderately elevated UACR, Composite of kidney failure, sustained ≥40% decrease eGFR 25–<60 mL/min/1.73 m2 and a in eGFR from baseline or death from renal causes history of diabetic retinopathy, or • Persistent, severely elevated UACR, Key secondary endpoint: eGFR 25–<75 mL/min/1.73 m2 Composite of CV death, nonfatal MI, nonfatal stroke or hospitalization for heart failure

*Increase to 20 mg/day encouraged after 1 month if stable eGFR and serum potassium ≤4.8 mmol/L. ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CKD, chronic kidney disease; CV, cardiovascular; eGFR, estimated glomerular filtration rate; MI, myocardial infarction; T2D, type 2 diabetes; UACR, urinary albumin-to-creatinine ratio. Bakris GL, et al. New Engl J Med. 2020;doi:10.1056/NEJMoa2025845. FIDELIO-DKD: Significantly improved renal and CV outcomes with finerenone vs placebo

Primary outcome Secondary outcome

17.8% finerenone 13.0% finerenone vs 21.1% placebo vs 14.8% placebo HR 0.82 HR 0.86 95% CI 0.73–0.93 95% CI 0.75–0.99 p=0.001 p=0.03

Significant reduction in kidney failure, Significant reduction in CV death, sustained ≥40% decrease in eGFR from nonfatal MI, nonfatal stroke or baseline or death from renal causes hospitalization for heart failure

CI, confidence interval; CV, cardiovascular; eGFR, estimated glomerular filtration rate; HR, hazard ratio; MI, myocardial infarction. Bakris GL, et al. New Engl J Med. 2020;doi:10.1056/NEJMoa2025845. FIGARO-DKD: Cardiorenal morbidity and mortality in patients with T2D and CKD Multicentre, randomized phase III study 7,354 patients Finerenone 10 mg/day (eGFR <60 mL/min/1.73m2) T2D with CKD 20 mg/day (eGFR ≥60 mL/min/1.73m2)

Placebo • UACR ≥30–<300 mg/g and eGFR ≥25–≤90 mL/min/1.73 m2 2 • Persistent UACR ≥300 mg/g and eGFR ≥60 mL/min/1.73 m Dose titration according to eGFR and potassium • Prior ACEi and ARB; potassium ≤4.8 mEq/L Patients with high CV risk: • 96% with hypertension Primary endpoint: • 31% with diabetic retinopathy Composite of time to first occurrence of CV death, • 44% with CVD nonfatal MI/stroke, or heart failure hospitalization

ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CKD, chronic kidney disease; CV, cardiovascular; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; MI, myocardial infarction; T2D, type 2 diabetes; UACR, urinary albumin-to-creatinine ratio. Ruilope LM, et al. Am J Nephrol. 2019;50:345–56. Considerations for the future clinical use of novel MRAs in CKD and T2D

Novel MRAs have a different side-effect profile to other agents for the treatment of CKD in T2D, e.g. SGLT2 inhibitors1,2

Finerenone has a smaller effect on serum potassium levels K+ than spironolactone2

In FIDELIO-DKD, finerenone had only modest effects on blood pressure2

CKD, chronic kidney disease; MRA, mineralocorticoid receptor antagonists; SGLT2, sodium-glucose cotransporter 2; T2D, type 2 diabetes. 1. Lupsa BC, Inzucchi SE. Diabetologia. 2018;61:2118–25; 2. Bakris GL, et al. New Engl J Med. 2020;doi:10.1056/NEJMoa2025845.