Kidney protection and SGLT2i: What do we know? Prof. Mark Cooper, - PowerPoint PPT Presentation

Kidney protection and SGLT2i: What do we know? Prof. Mark Cooper, MD Melbourne, Australia June 7, 2020 - Virtual ERA-EDTA

KIDNEY PROTECTION AND SGLT2I: WHAT DO WE KNOW? Professor Mark Cooper, Melbourne Australia

CKD = increased risk of adverse outcomes Heart Sudden All Cause ADRs MACE ESKD Failure Death Mortality MACE Major acute coronary event; CKD, Chronic kidney disease; ESRD End-Stage kidney Disease, ADR adverse drug reactions Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. Kidney Int Suppl 2013;3:1

GLOBAL EPIDEMIOLOGY OF CKD Undiagnosed CKD 1 Leading causes of CKD 1 Estimated prevalence CKD rank of CKD globally: 10% 2 (causes of total number of global deaths) 1 #1 Diabetes 18 th 80 – 90% 27 th Early-stage #2 Hypertension 1990 2010 CKD, chronic kidney disease 1. JhaV, et al. Lancet 2013;382(9888):260 – 272; 2. World Kidney Day: Chronic Kidney Disease. 2015;Available at: http://www.worldkidneyday.org/faqs/chronic-kidney-disease/ (Accessed October 2019); 3. Bailey RA, et al. BMC Res Notes 2014;7:415

AND CKD WILL CONTINUE TO RISE 1 1 1 2 1. GBD 2017 Causes of Death Collaborators. Lancet 2018;392:1736 – 1788; 2. Foreman KJ, et al. Lancet 2018;392:2052 – 2090

DIABETES ACCOUNTS FOR ALMOST HALF OF ALL CKD CASES Age-Standardized Global Prevalence Rate of CKD by Cause per 100,000 Persons in 2016 1 • CKD impacts 1 in 10 people globally 2 Other 886,03 • In 2016, less than half of all CKD cases were 22% caused by diabetes (1690.73 per 100,000 persons) 1 Diabetes 1690,73 • This aligns with US prevalence data where almost 42% half of individuals with CKD also have diabetes. 3,4 Glomerulonep • ~44% of ESRD cases are due to diabetes 5 hritis 735,69 18% Hypertension 744,1 18% CKD = chronic kidney disease; ESRD = end-stage renal disease 1. XieY et al. Kidney Int. 2018;94:567-581; 2. Hill NR et al. PLoS One . 2016; 3. Kidney disease statistics for the United States. https://www.niddk.nih.gov/health-information/health- statistics/kidney-disease. Accessed April 10, 2019; 4. Webster AC et al. Lancet. 2017;389:1238-1252; 5. Burrows NR et al. MMWR Morb Mortal Wkly Rep . 2017;66:1165 – 1170

STANDARD OF CARE IN DKD Blood glucose control Treatment of hypertension MULTIFACTORIAL Blockade of the RAAS INTERVENTION Weight loss, diet, and lifestyle? Blood lipid lowering Thomas MC et al. Nat Rev Dis Primers. 2015 Jul 30;1:15018.

WHERE IS THE RENAL BENEFIT OF LOWERING GLUCOSE? standard Creatinine (umol/L) intensive intensive standard Perkovic et al. Kidney Int. 2013 Mar;83(3):517-23. Ismail-Beigi F et al. Lancet. 2010 Aug 7;376(9739):419-30.

Intensive glucose lowering and ESRD ADVANCE trial Standard management Cumulative ESRD (%) 0.4 Intensive glucose control HR= 0.35 0.3 (CI 0.15-0.83) p=0.012 0.2 0.1 0.0 36 42 48 54 60 66 0 6 12 18 24 30 Follow-up (months) Perkovic et al. Kidney International 2013

RENAAL - ESRD Placebo Risk Reduction: 28% 30 p=0.002 % with events 20 Losartan 10 0 0 12 24 36 48 Months Brenner, Cooper et. NEJM 2001

What is the renal benefit of Diet and Lifestyle ? Rate per 100 patient years, time to first occurrence 0·79 (0·66 – 0·96) 1,4 P=0·015 0·81 (0·66 – 1·01) 1,2 Standard Intensive * P=0·057 1 0·81 (0·61 – 1·07) 0,8 P=0·13 0,6 0·80 (0·49 – 1·30) 0,4 P=0·37 0,2 0 Overt DKD eGFR<45 RRT doubling of Cr The Look AHEAD Research Group. Lancet Diabetes Endocrinol. 2014; 2(10): 801 – 809

What is the benefit of Multifactorial intervention ? Long term legacy? if you live that long -2.5 Intensive STENO-2 Standard -3.3 Oellgaard J et all. Kidney Int. 2017 Apr;91(4):982-988.

What is the benefit of Multifactorial intervention ? Intensive Standard Temporary relief ONLY? STENO-2 Oellgaard J et all. Kidney Int. 2017

STANDARD OF CARE IN DKD Blood lipid lowering Blood glucose control GLP-1R agonists? Treatment of hypertension Blockade of the RAAS Weight loss, diet, and lifestyle?

RENAL ENDPOINTS INCLUDING  MACROALBUMINURIA 15 Giugliano et al. DOM (2019) Kristensen et al. Lancet Diabetes (2019)

REWIND : Dulaglutide on renal decline* 12 Placebo Dulaglutide 10,1 9,2 10 HR =0.70 Incidence (%) 8 P=0.0004 HR =0.56 * 6 4,8 HR=0.89 P=0.0002 3,4 P=0.066 4 * 2,2 1,2 2 0 >30% >40% >50% Decline in eGFR *sensitivity analysis – exploratory Gerstein et al. Lancet (2019)

STANDARD OF CARE IN DKD Blood lipid lowering Blood glucose control SGLT2 inhibition Treatment of hypertension Blockade of the RAAS Weight loss, diet, and lifestyle?

SGLT2 INHIBITOR CVOT POPULATIONS: RENAL RISK AT BASELINE Albuminuria categories (mg/g) A2: 30 – 300 A1: <30 A2: >300 120 Low ≥90 eGFR categories (mL/min/1.73 m 2 ) Moderately increased 90 DECLARE-TIMI 58 1 High 60 – 90 CANVAS 2 EMPA-REG-OUTCOME 3 Very high 60 45 – 59 CREDENCE 4 30 – 44 30 <30 0 1 30 900 CVOT, cardiovascular outcomes trial; eGFR, estimated glomerular filtration rate; SGLT2, sodium – glucose co-transporter 2 1. Wiviott SD, et al. N Engl J Med 2019;380:347 – 357; 2. Neal B, et al. N Engl J Med 2017;377:644 – 657; 3. Zinman B, et al. N Engl J Med 2015;373:2117 – 2128; 4. PerkovicV, et al. N Engl J Med 2019;380:2295 – 2306

(n=4142) (n=1995) (n=764) Cherney D et al. Lancet Diabetes Endocrinol 2017;5:610

ESKD, DOUBLING OF SERUM CREATININE, OR RENAL DEATH Participants with an event (%) 25 Placebo Canagliflozin 20 224 participants Hazard ratio, 0.66 15 (95% CI, 0.53 – 0.81) P <0.001 153 participants 10 5 0 0 26 52 78 104 130 156 182 6 12 18 24 30 36 42 Months since randomization No. at risk Placebo 2199 2178 2131 2046 1724 1129 621 170 Canagliflozin 2202 2181 2144 2080 1786 1211 646 196 Composite of ESKD [RRT or sustained eGFR <15 ml/min/1.73 m 2 ], Perkovic V et al. N Engl J Med 2019; 380:2295-2306

KIDNEY OUTCOMES IN RCTS WITH SGLT2 INHIBITORS 21 SGLT2i Placebo n event/N Rate/ n event/N Rate/ Trial analysed (%) 1000 PY analysed (%) 1000 PY HR (95% CI) p- value Dedicated cardiovascular outcomes trials: Exploratory analysis EMPA-REG OUTCOME 1 (T2DM) 0.54 (0.40, <0.001 † Doubling of serum creatinine,* RRT or 81/4645 6.3 71/2323 11.5 0.75) death from kidney causes DECLARE-TIMI 58 2 (T2DM) ≥40% decrease in eGFR to 0.53 (0.43, 127/8582 3.7 238/8578 7.0 NR <60 ml/min/1.73 m 2 , new ESRD or 0.66) death from kidney causes CANVAS Program 3 (T2DM) 0.53 (0.33, Doubling of serum creatinine, ESKD or NR 1.5 NR 2.8 NR 0.84) death from kidney causes Dedicated kidney outcomes trial: Primary analysis CREDENCE 4 (T2DM) 0.66 (0.53, Doubling of serum creatinine, ESKD or 153/2202 27.0 224/2199 40.4 <0.001 0.81) death from kidney causes Dedicated HF outcome trial: Exploratory analysis DAPA-HF 5 (non-T2DM and T2DM) 0.71 (0.44, Sustained ≥50% ‡ reduction in eGFR, 28/2373 NR 39/2371 NR 0.17 1.16) 0,25 0,5 1 2 ESKD, or death from kidney causes Favours SGLT2i Favours placebo Comparisons of trials should be interpreted with caution due to differences in study design, populations and methodology *Accompanied by eGFR ≤45 ml/min/1.73 m 2 ; † Nominal p- value; ‡ Sustained for ≥28 days. eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; ESRD, end-stage renal disease; NR, not reported; PY, patient-years; RRT, renal replacement therapy; SGLT2i, sodium-glucose co-transporter-2 inhibitor; T2DM, type 2 diabetes mellitus. 1. Wanner C et al. N Engl J Med 2016;375:323; 2. Wiviott SD et al. N Engl J Med 2019;380:347; 3. Perkovic V et al. Lancet Diabetes Endocrinol 2018;6:691; 4. Perkovic V et al. N Engl J Med 2019;380:2295; 5. McMurray J. ESC Congress 2019; oral presentation

META-ANALYSIS OF SGLT2I CVOTS: SUBSTANTIAL LOSS OF KIDNEY FUNCTION, ESRD OR DEATH DUE TO KIDNEY DISEASE Substantial loss of kidney function, ESRD or death due to kidney disease Events Patients RR (95% CI) CREDENCE 377 4401 0.66 (0.53, 0.81) DECLARE-TIMI 58 365 17,160 0.53 (0.43, 0.66) CANVAS programme 73 10,142 0.53 (0.33, 0.84) EMPA-REG OUTCOME 152 6968 0.54 (0.40, 0.75) RE model ( P< 0.0001) 0.58 (0.51, 0.66) I ²=0.0%; Ρ heterogeneity =0.49 0 0,5 1 1,5 2 Favours treatment Favours placebo CI, confidence interval; CVOT, cardiovascular outcomes trial; ESRD, end-stage renal disease; RE, random-effects; RR, relative risk; SGLT2i, sodium – glucose co-transporter 2 inhibitor Neuen B, et al. Lancet Diabetes Endocrinol 2019;7:845 – 854