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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

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Kidney protection and SGLT2i: What do we know?

  • Prof. Mark Cooper, MD

Melbourne, Australia

June 7, 2020 - Virtual ERA-EDTA

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KIDNEY PROTECTION AND SGLT2I:

WHAT DO WE KNOW?

Professor Mark Cooper, Melbourne Australia

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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

All Cause Mortality MACE ESKD Heart Failure ADRs

CKD = increased risk of adverse outcomes

Sudden Death

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GLOBAL EPIDEMIOLOGY OF CKD

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

Early-stage

80–90%

CKD rank (causes of total number

  • f global deaths)1

Estimated prevalence

  • f CKD globally: 10%2

Undiagnosed CKD1 Leading causes of CKD1

2010 18th 1990 27th

#2 Hypertension #1 Diabetes

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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
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DIABETES ACCOUNTS FOR ALMOST HALF OF ALL CKD CASES

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 Diabetes 1690,73 42% Hypertension 744,1 18% Glomerulonep hritis 735,69 18% Other 886,03 22%

Age-Standardized Global Prevalence Rate of CKD by Cause per 100,000 Persons in 20161

  • CKD impacts 1 in 10 people globally2
  • In 2016, less than half of all CKD cases were

caused by diabetes (1690.73 per 100,000 persons)1

  • This aligns with US prevalence data where almost

half of individuals with CKD also have diabetes.3,4

  • ~44% of ESRD cases are due to diabetes5
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STANDARD OF CARE IN DKD

Blood glucose control Treatment of hypertension Blockade of the RAAS Weight loss, diet, and lifestyle?

Blood lipid lowering

Thomas MC et al. Nat Rev Dis Primers. 2015 Jul 30;1:15018.

MULTIFACTORIAL INTERVENTION

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WHERE IS THE RENAL BENEFIT OF LOWERING GLUCOSE?

intensive standard intensive standard

Creatinine (umol/L)

Perkovic et al. Kidney Int. 2013 Mar;83(3):517-23. Ismail-Beigi F et al. Lancet. 2010 Aug 7;376(9739):419-30.

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Cumulative ESRD (%) 0.0 0.1 0.2 0.3 0.4 Follow-up (months) 6 12 18 24 30 36 42 48 54 60 66

Standard management Intensive glucose control

Intensive glucose lowering and ESRD ADVANCE trial

HR= 0.35 (CI 0.15-0.83) p=0.012 Perkovic et al. Kidney International 2013

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Months % with events 12 24 36 48 10 20 30 p=0.002 Risk Reduction: 28%

Placebo

Losartan

RENAAL - ESRD

Brenner, Cooper et. NEJM 2001

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0,2 0,4 0,6 0,8 1 1,2 1,4

Overt DKD eGFR<45 RRT doubling of Cr

Standard Intensive

0·81 (0·61–1·07) P=0·13 0·81 (0·66–1·01) P=0·057 0·79 (0·66–0·96) P=0·015 0·80 (0·49–1·30) P=0·37

*

Rate per 100 patient years, time to first occurrence The Look AHEAD Research Group. Lancet Diabetes Endocrinol. 2014; 2(10): 801–809

What is the renal benefit of Diet and Lifestyle?

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Intensive Standard

Long term legacy? if you live that long

STENO-2

Oellgaard J et all. Kidney Int. 2017 Apr;91(4):982-988.

  • 2.5
  • 3.3

What is the benefit of Multifactorial intervention?

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Intensive Standard Temporary relief ONLY?

STENO-2 What is the benefit of Multifactorial intervention?

Oellgaard J et all. Kidney Int. 2017

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STANDARD OF CARE IN DKD

Blood lipid lowering Blood glucose control Treatment of hypertension Blockade of the RAAS Weight loss, diet, and lifestyle?

GLP-1R agonists?

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RENAL ENDPOINTS INCLUDING MACROALBUMINURIA

15

Kristensen et al. Lancet Diabetes (2019)

Giugliano et al. DOM (2019)

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10,1 4,8 2,2 9,2 3,4 1,2

2 4 6 8 10 12

>30% >40% >50% Incidence (%) Decline in eGFR Placebo Dulaglutide

REWIND: Dulaglutide on renal decline*

HR=0.89 P=0.066 HR =0.70 P=0.0004 HR =0.56 P=0.0002

*sensitivity analysis – exploratory Gerstein et al. Lancet (2019) * *

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STANDARD OF CARE IN DKD

Blood lipid lowering Blood glucose control Treatment of hypertension Blockade of the RAAS Weight loss, diet, and lifestyle?

SGLT2 inhibition

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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

SGLT2 INHIBITOR CVOT POPULATIONS: RENAL RISK AT BASELINE

30 60 90 120 1 30 900

A1: <30 A2: 30–300 A2: >300

Albuminuria categories (mg/g)

≥90 60–90 45–59 30–44 <30

eGFR categories (mL/min/1.73 m2) DECLARE-TIMI 581 CANVAS2 EMPA-REG-OUTCOME3 CREDENCE4

Low Moderately increased High Very high

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

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ESKD, DOUBLING OF SERUM CREATININE, OR RENAL DEATH

5 10 15 20 25 26 52 78 104 130 156 182

Months since randomization

  • No. at risk

Placebo 2199 2178 2131 2046 1724 1129 621 170 Canagliflozin 2202 2181 2144 2080 1786 1211 646 196

Hazard ratio, 0.66 (95% CI, 0.53–0.81) P <0.001 224 participants 153 participants

6 12 18 24 30 36 42

Participants with an event (%) Placebo Canagliflozin

Composite of ESKD [RRT or sustained eGFR <15 ml/min/1.73 m2],

Perkovic V et al. N Engl J Med 2019; 380:2295-2306

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21

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 m2; †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

KIDNEY OUTCOMES IN RCTS WITH SGLT2 INHIBITORS

Trial SGLT2i Placebo HR (95% CI) p-value n event/N analysed (%) Rate/ 1000 PY n event/N analysed (%) Rate/ 1000 PY

Dedicated cardiovascular outcomes trials: Exploratory analysis

EMPA-REG OUTCOME1 (T2DM) Doubling of serum creatinine,* RRT or death from kidney causes 81/4645 6.3 71/2323 11.5 0.54 (0.40, 0.75) <0.001† DECLARE-TIMI 582 (T2DM) ≥40% decrease in eGFR to <60 ml/min/1.73 m2, new ESRD or death from kidney causes 127/8582 3.7 238/8578 7.0 0.53 (0.43, 0.66) NR CANVAS Program3 (T2DM) Doubling of serum creatinine, ESKD or death from kidney causes NR 1.5 NR 2.8 0.53 (0.33, 0.84) NR

Dedicated kidney outcomes trial: Primary analysis

CREDENCE4 (T2DM) Doubling of serum creatinine, ESKD or death from kidney causes 153/2202 27.0 224/2199 40.4 0.66 (0.53, 0.81) <0.001

Dedicated HF outcome trial: Exploratory analysis

DAPA-HF5 (non-T2DM and T2DM) Sustained ≥50%‡ reduction in eGFR, ESKD, or death from kidney causes 28/2373 NR 39/2371 NR 0.71 (0.44, 1.16) 0.17

0,25 0,5 1 2

Favours SGLT2i Favours placebo

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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) I²=0.0%; Ρheterogeneity=0.49 0.58 (0.51, 0.66)

0,5 1 1,5 2

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

META-ANALYSIS OF SGLT2I CVOTS: SUBSTANTIAL LOSS OF KIDNEY FUNCTION, ESRD OR DEATH DUE TO KIDNEY DISEASE

Favours treatment Favours placebo

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SGLT2 INHIBITOR TRIALS PRIMARILY FOCUSED ON CKD/DKD

*The IDMC of the trial has recommended to stop the trial early based on the achievement of pre-specified efficacy criteria at the time of a planned interim analysis3
  • 1. Jardine MJ et al. Am J Nephrol 2017;46:462; 2. ClinicalTrials.gov. NCT02065791; 3. Janssen Pharmaceuticals, Inc. Press release. 2018. www.jnj.com/phase-3-credence-renal-outcomes-trial-of-invokana-
canagliflozin-is-being-stopped-early-for-positive-efficacy-findings; 4. ClinicalTrials.gov. NCT03036150; 5. ClinicalTrials.gov. NCT03594110 (all accessed September 2018)

Dapa-CKD4 EMPA-KIDNEY5 Study drug Dapagliflozin vs placebo Empagliflozin vs placebo Population CKD including ✓ T2D ✓ Non-DM x T1D CKD including ✓ T2D ✓ Non-DM ✓ x T1D Sample size 4000 ~5000 Key inclusion criteria eGFR ≥25 to ≤75 ml/min/1.73 m2 and UACR ≥200–≤5000 mg/g eGFR ≥20 to <45 ml/min/1.73 m2

  • r eGFR ≥45 to <90 ml/min/1.73 m2

and UACR ≥200 mg/g Primary endpoints Composite of ≥50% sustained decline in eGFR or reaching ESKD,

  • r renal or CV death

Composite of a sustained decline in eGFR to ≥10 ml/min/1.73 m2, ≥40% sustained decline in eGFR or reaching ESKD, or renal death Secondary endpoints

  • Composite of CV death or HHF
  • All-cause mortality
  • Composite of CV death or HHF
  • All-cause hospitalisation
  • All-cause mortality

Start date Expected completion date February 2017 November 2020 (early cessation 30 March 2020) November 2018 June 2022

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ASCVD, atherosclerotic cardiovascular disease; GLP-1 RA, glucagon-like peptide-1 receptor agonist

  • 1. Davies MJ et al. Diabetes Care 2018;41:2669; 2. American Diabetes Association. Diabetes Care 2019;42:S1

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2018 ADA-EASD Consensus Report and ADA 2019 Standards of Medical Care in Diabetes1,2

DIABETES SOCIETIES RECOMMEND THAT THE CHOICE OF SECOND-LINE THERAPY SHOULD BE BASED ON ASSESSMENT OF ESTABLISHED ASCVD, HF OR CKD

First-line therapy is metformin and comprehensive lifestyle change; if HbA1c is above target, proceed as below Established ASCVD, HF or CKD If ASCVD predominates Treat with a GLP-1 RA or SGLT2 inhibitor with proven CV benefit If HF or CKD predominates Treat with an SGLT2 inhibitor with evidence of reducing HF and/or CKD progression