Kidney protection and SGLT2i: What do we know?

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

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

MortalityMACEESKDHeart

FailureADRs

CKD = increased risk of adverse outcomes

Sudden

Death

GLOBAL EPIDEMIOLOGY OF CKD

CKD, chronic kidney disease1. 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

of global deaths)1

Estimated prevalence

of CKD globally: 10%2

Undiagnosed CKD1 Leading causes of CKD1

2010

18th

1990

27th

#2 Hypertension

#1 Diabetes

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

CKD = chronic kidney disease; ESRD = end-stage renal disease1. 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

Diabetes1690,73

42%

Hypertension744,118%

Glomerulonephritis

735,6918%

Other886,0322%

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

https://www.niddk.nih.gov/health-information/health-statistics/kidney-disease

STANDARD OF CARE IN DKD

Blood glucose control

Treatment of hypertension

Blockade of the RAAS

Weight loss, diet, and lifestyle?

Blood lipid loweringThomas MC et al. Nat Rev Dis Primers. 2015 Jul 30;1:15018.

MULTIFACTORIAL

INTERVENTION

WHERE IS THE RENAL BENEFIT OF LOWERING GLUCOSE?

intensive

standardintensive

standard

Cre

atin

ine (

um

ol/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.

Cu

mu

lati

ve

ES

RD

(%)

0.0

0.1

0.2

0.3

0.4

Follow-up (months)

0 6 12 18 24 30 36 42 48 54 60 66

Standard managementIntensive 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

Months

% w

ith

even

ts

0 12 24 36 480

10

20

30 p=0.002

Risk Reduction:

28%

Placebo

Losartan

RENAAL - ESRD

Brenner, Cooper et. NEJM 2001

0

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?

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?

Intensive

Standard

Temporary relief ONLY?

STENO-2

What is the benefit of Multifactorial intervention?

Oellgaard J et all. Kidney Int. 2017


Blood lipid lowering





GLP-1R agonists?

RENAL ENDPOINTS INCLUDING MACROALBUMINURIA

15

Kristensen et al. Lancet Diabetes (2019) Giugliano et al. DOM (2019)

10,1

4,8

2,2

9,2

3,4

1,2

0

2

4

6

8

10

12

>30% >40% >50%

Inci

dence

(%

)

Decline in eGFR

Placebo Dulaglutide

REWIND: Dulaglutide on renal decline*

HR=0.89P=0.066

HR =0.70P=0.0004

HR =0.56P=0.0002

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

*

*


Blood lipid lowering





SGLT2 inhibition

CVOT, cardiovascular outcomes trial; eGFR, estimated glomerular filtration rate; SGLT2, sodium–glucose co-transporter 21. 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

0

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

eG

FR

cate

go

ries (

mL

/min

/1.7

3 m

2)

DECLARE-TIMI 581

CANVAS2EMPA-REG-OUTCOME3

CREDENCE4

Low

Moderately

increased

High

Very high

(n=4142)

(n=1995)

(n=764)

Cherney D et al. Lancet Diabetes Endocrinol 2017;5:610

ESKD, DOUBLING OF SERUM CREATININE, OR RENAL DEATH

0

5

10

15

20

25

0 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 42Parti

cip

an

ts w

ith

an

even

t (%

)

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

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 PYn 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 11.50.54 (0.40,

0.75)<0.001†

DECLARE-TIMI 582 (T2DM)

≥40% decrease in eGFR to

<60 ml/min/1.73 m2, new ESRD or


127/8582 3.7 238/8578 7.00.53 (0.43,

0.66)NR

CANVAS Program3 (T2DM)

Doubling of serum creatinine, ESKD or


NR 1.5 NR 2.80.53 (0.33,

0.84)NR

Dedicated kidney outcomes trial: Primary analysis

CREDENCE4 (T2DM)

Doubling of serum creatinine, ESKD or


153/2202 27.0 224/2199 40.40.66 (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 NR0.71 (0.44,

1.16)0.17

0,25 0,5 1 2

Favours SGLT2i Favours placebo

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=0.490.58 (0.51, 0.66)

0 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

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 criteriaeGFR ≥25 to ≤75 ml/min/1.73 m2

and UACR ≥200–≤5000 mg/g

eGFR ≥20 to <45 ml/min/1.73 m2

or 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,

or 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

http://www.jnj.com/phase-3-credence-renal-outcomes-trial-of-invokana-canagliflozin-is-being-stopped-early-for-positive-efficacy-findings

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

24

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

Documents

Kidney protection and SGLT2i: What do we know?