SGLT2 inhibition in diabetes: extending from glycaemic control to renal and cardiovascular protection

Hiddo Lambers Heerspink

Department of Clinical Pharmacy and Pharmacology

University Medical Center Groningen

The Netherlands

Disclosures

• Research Support

• Abbvie, AstraZeneca, Boehringer Ingelheim, Janssen

• Consultancy

• Abbvie, Astellas, AstraZeneca, Boehringer Ingelheim, Fresenius, Gilead, Janssen, Merck, Mitsubishi Pharma.

Objectives

• Review results of recent outcome trials with SGLT2 inhibitors

• Summarize effects of SGLT2 inhibitors in Diabetic Kidney Disease

• Review mechanisms and effects of SGLT2 inhibitors on renal outcomes

• Discuss the potential role of SGLT2 inhibitors in non-diabetic kidney disease

• Summarize the position of SGLT2 inhibitors in context of other glucose lowering agents

The sodium glucose mechanism in the proximal tubule

Heerspink / Cherney Circulation 2016 134(10):752-72

~25 mmol/day

~60 g/day (240kCal)

Cardiovascular outcomes with SGLT-2 inhibitors

Patients with event/analysed

SGLT-2 Placebo HR (95% CI) p-value

EMPAREG 490/4687 282/23330.86

(0.74, 0.99)<0.001 (non-inferiority)

0.04 (superiority)

CANVAS 585/5795 426/43470.86

(0.75, 0.97)<0.001 (non-inferiority)

0.02 (superiority)

DECLARE 756/8582 803/85780.93

(0.84, 1.03)<0.001 (non-inferiority)

P=0.17 (superiority)

0.5 1 2

Hazard Ratio (95%CI)

Zinman B et.al. NEJM 2016; Neal B. et.al. NEJM 2017; Wiviott S et.al. NEJM 2018

Kidney outcomes in SGLT-2 inhibitor trials

Years since randomisation

Hazard ratio 0.60 (95% CI, 0.47-0.77)

2 3 4 5 610

Patients

with a

n e

vent

(%)

Placebo

Canagliflozin

0

1

2

3

4

5

6

7

8

0 6 12 18 24 30 36 42 48

HR 0.54 (95% CI 0.40, 0.75) Placebo

Empagliflozin

Months since randomization

Cum

ula

tive p

robabili

ty o

f event (%

)

20Hazard ratio 0.76 (95% CI, 0.67-0.87)

Placebo

Dapagliflozin

18

16

14

12

10

8

6

4

2

0

eGFR (ml/min/1.73m2): 74.0 76.5 86.1UACR (mg/g): 17.7 12.3 13.1

EMPA-REG CANVAS DECLARE

Wanner C et.al. NEJM 2016; Neal B. et.al. NEJM 2017; Wiviott S et.al. NEJM 2018

Summary of Product Characteristics

Dapagliflozin

Canagliflozin

Empagliflozin

Glycemic effects of dapagliflozin is blunted in patients with renal impairment

Excludes data after rescue. Adj., adjusted; BL, baseline; CI, confidence interval.

Placebo-adjusted change from baseline over time with dapagliflozin in HbA1c in the overall population

Petrykiv S, et al. Clin J American Soc Nephrol 2017;12:751–759

eGFR 45-60 ml/min/1.73m2

eGFR 60-90 ml/min/1.73m2

eGFR >90 ml/min/1.73m2

Albuminuria lowering effect of dapagliflozin persists in patients with renal impairment

30

20

10

0

–10

–20

–30

–40

–50

–60

UA

CR

, %

(9

5%

CI)

UACR ≥30 mg/g at baseline

12 16 20 24BL 4 8

Study week

≥45–<60

≥60–<90

≥90

eGFR

sub-group

No renal impairment or CKD stage 1–3A1a CKD stage 3B–42b

DAPA 5 mg

DAPA 10 mg

Placebo

0

–10

–20

–30

–40

–50

–60

–70

–80

BL 4 8 12 16 20 24 37 50 63

Study week

UA

CR

, m

g/g

(9

5%

CI)

aCKD stage 1–3A defined as eGFR ≥90–<60; bCKD stage 3B–4 defined as eGFR ≥15–<45CI, confidence interval; CKD, chronic kidney disease; DAPA, dapagliflozin; PBO, placebo; UACR, urine albumin:creatinine ratio1. Petrykiv S, et al. Clin J American Soc Nephrol 2017;12:751–759; 2. Dekkers CCJ, et al. Nephrol Dial Transplant 2018 [Epub ahead of print]

Dapagliflozin maintains modest Hba1c lowering efficacy in CKD stage 3

Treatment with dapagliflozin over 24 weeks significantly improved glycemic control, body weight, and systolic blood pressure in patients

with T2DM and CKD stage 3Aa, with no reduction in eGFR

aeGFR: 45–59 mL/min/1.73 m2

CKD, chronic kidney disease; CI, confidence interval; eGFR, estimated glomerular filtration rate; HbA1c, glycated hemoglobin; T2DM, Type 2 diabetes mellitus

Fioretto P, et al. Diabetes Obes Metab 2018 [Epub ahead of print]

HbA1c eGFR

Dapagliflozin 10 mg (n=159)

Placebo (n=161)

Follow-up

period

Ad

jus

ted

me

an

ch

an

ge f

rom

ba

se

lin

e

in e

GF

R,

mL

/min

/1.7

3 m

2(9

5%

CI)

Time (weeks)

0

–8

4

3

2

1

0

–1

–2

–3

–4

–5

–6

–7

4 12 24 27

Ad

jus

ted

me

an

ch

an

ge f

rom

ba

se

lin

e

in H

bA

1c,

% (

95

% C

I)

Time (weeks)

0

4

0.5

0.0

–0.5

–1.0

4 12 24

Dapagliflozin 10 mg (n=160)

Placebo (n=161)

Alterations in proximal sodium reabsorption modulate TGF

aRenal hyperfiltration: GFR ≥135 mL/min/1.73 m2

GFR, glomerular filtration rate; SGLT2, sodium–glucose co-transporter 2; TGF, tubuloglomerular feedback

Cherney D, et al. Circulation 2014;129:587–597

Restored TGF

Afferent

arteriole

constriction

Normalization

of GFR

Increased

Na+ delivery

to macula

densa

SGLT2

inhibition

in proximal

tubule

Glucosuria

SGLT2 inhibition reduces

hyperfiltration via TGF

Na+

1

2

3

4

5

Na+

Impaired TGF

Afferent

arteriole

vasodilation

Elevated

GFR Decreased

Na+ delivery to

macula densa

Increased

Na+/glucose

reabsorption

SGLT2

Hyperfiltrationa in early stages

of diabetic nephropathy

Normal TGF

Appropriate

afferent arteriole

toneNormal

GFR

Macula

densa

Na+/glucose

reabsorption

Normal physiology

SGLT2

SGLT2 inhibitors decrease RPF and GFR

172.0

139.0

0

20

40

60

80

100

120

140

160

180

200

T1D-H (Euglycemia)

Mea

n G

FR (

ml/

min

/1.7

3 m

2)1641

1156

0

200

400

600

800

1000

1200

1400

1600

1800

RBF

Mea

n R

BV

(m

l/m

in/1

.73

m2)

60

80

100

120

baseline week 12

Mea

n G

FR (

ml/

min

/1.7

3m

2)

Type 1 diabetes Type 2 diabetes

Cherney D et al. Circulation 2014:129;587-99

Heerspink et.al. Diab Obes Metab 2013: 15:853-62

1156

Baseline

SGLT2 inhibition

Mechanism of action of SGLT2 inhibitors and other antihypertensive agents

Rajasekeran et.al. Current Opinon Nephrology Hypertension 2017

Acetozolamide (proximal diuretic) decreases RBF and GFR in obese non-diabetic individuals

• Acetazolamide increases urinary sodium excretion and decreases GFR/ERPF

• Furosemide does not activate tubulo-glomerular feedback as it blocks sodium transport into the macula densa

Zingerman Plos One 2014

CANVAS: Canagliflozin attenuates eGFR decline

CANA, canagliflozin; eGFR, estimated glomerular filtration rate; PBO, placebo.

Perkovic V. et.al. Lancet D&E 2018

CANVAS CANVAS-R

80

79

78

77

76

75

74

73

72

71

70

69

68Baseline 18/26 52 78 104 130 156 182 208 234 260 286 312 338

Ad

just

ed m

ean

eG

FR(m

L/m

in/1

.73

m2)

CANA

PBO

Weeks since randomizationPatients, n

PBO

CANA

4276

5711

4038

5355

3967

5212

3538

4867

3212

4570

1740

2964

1030

2230

881

1961

899

2039

785

1795

809

1895

726

1695

694

1653

243

548

Ad

just

ed m

ean

eG

FR(m

L/m

in/1

.73

m2)

CANA

PBO

80

79

78

77

76

75

74

73

72

71

70

69

68Baseline 26 52 78 104 30 days

off-treatmentWeeks since randomizationPatients, n

PBO

CANA

2859

2868

2728

2752

2649

2675

2440

2512

2124

2206

2485

2518

CREDENCE stopped early for overwhelming efficacy

Intraglomerular Hypertension is a common feature and driver of disease progression in chronic kidney disease

CKD, chronic kidney disease; FF, filtration fraction; GFR, glomerular filtration rate; RAAS, renin–angiotensin–aldosterone system; RBF, renal blood flow

Obesity-induced CKD

• Renal plasma flow ↑

• GFR ↑ with resulting FF ↑

• Caloric restriction has been shown to

reverse glomerular hyperfiltration

Glomerular

hyperfiltration

Focal segmental

glomerulosclerosis

• Single-nephron level;

plasma flow per nephron ↑

• Intrarenal vasodilation and

glomerular hypertension

Hypertensive nephrosclerosis

• Arterial stiffening ↑

• Renal plasma flow ↑

• Intraglomerular hypertension ↑

Diabetic nephropathy

• Whole kidney RBF ↑

• FF ↑

• Vasodilation of afferent arteriole

• Proximal tubular sodium

reabsorption and glomerular

hypertension ↑

• RAAS ↑

Canagliflozin lowers body weight and CV risk factors in obese non-diabetic individuals (N=376)

-3.0

-2.0

-1.0

0.0

Bo

dy w

eig

ht ch

an

ge

(%

)

-3.0

-2.0

-1.0

0.0

Systo

lic B

P c

ha

ng

e (

mm

Hg)

-80.0

-60.0

-40.0

-20.0

0.0

Uri

c A

cid

ch

an

ge

(u

mo

l/L

)

-2.0

-1.0

0.0

1.0

eG

FR

ch

an

ge

f(m

l/m

in/1

.73

m2)

50 100 300 Placebo

Body Weight

50 100 300 Placebo

Systolic BP

50 100 300 Placebo

Uric Acid

50 100 300 Placebo

eGFR

Bays et.al. Obesity 2014;14:1042-1049

Not reported

DAPA-CKD and EMPA-KIDNEY: SGLT2 inhibition in patients with diabetic and non-diabetic CKD

ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CKD, chronic kidney disease; CV, cardiovascular; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; hHF, hospitalized heart failure; SoC, standard of care; T2DM, Type 2 diabetes mellitus; UACR, urine albumin:creatinine ratio

Placebo

+ SoCPopulation:

• Patients with CKD stage 2–4

(eGFR 25–75 mL/min/1.73m2)

• UACR ≥200 mg/g

• Stable ACE inhibitor / ARBDapagliflozin 10 mg

+ SoC

Primary endpoint:

Time to composite of 50%

sustained decline in eGFR, onset

of ESRD, CV, or renal death

Anticipated targets

• 4000 patients

• Event-driven

• Duration 45 months

Ra

nd

om

iza

tio

n

1:1

Placebo

+ SoCPopulation:

• Patients with CKD stage 2–4 (eGFR

20–90 mL/min/1.73m2)

• UACR ≥300 mg/g if eGR>45 ml/min

• Stable ACE inhibitor / ARB Empagliflozin

+ SoC

Primary endpoint:

Time to composite of 40% eGFR

decline, onset of ESRD, CV, or

renal death

Anticipated targets

• 5000 patients

• Event-driven

• Duration 54 months

Ra

nd

om

iza

tio

n

1:1

EMPA-KIDNEY

DAPA-CKD

EASD Guideline

RAAS and SGLT2 inhibitors reduce intraglomerular pressure through different mechanisms

Increased intraglomerular pressure and hyperfiltration are key steps in the progression of diabetic kidney disease

ACEi and ARB ↓ efferent arteriole tone and ↓

intraglomerular pressure

SGLT2i ↑ tubuloglomerular feedback, ↑ afferent arteriole tone and

↓intraglomerular pressure

Initial ↓ in eGFR followed by stabilization

↓ albuminuria

Renal Protection

Initial ↓ in eGFR followed by stabilization

↓ albuminuria

Renal Protection (to be determined)

Perkovic et.al. Cur Med Res Opin 2015:31;2219-31

EMPAREG: Empagliflozin reduces risk of AKI

Acute renal failure

Acute kidney injuryCu

mu

lati

ve

pro

ba

bil

ity

of

eve

nt

(%)

Months

0

1

0

5

1

5

2

0

0 6 1

2

1

8

2

4

3

0

3

6

4

2

4

8

Empagliflozin

Placebo

No. of patients

Acute renal failure

Empagliflozin

Placebo

Acute kidney injury

Empagliflozin

Placebo

4687

2333

4687

2333

4359

2167

4415

2194

4159

2031

4238

2078

3937

1889

4037

1944

3398

1588

3505

1653

2463

1133

2545

1178

1897

866

1965

902

975

403

1014

427

108

279

111

268

Empagliflozin had a protective effect against acute renal failure and acute kidney failure vs placebo

CI, confidence interval; HR, hazard ratio;

Wanner C, et al. N Engl J Med. 2016 Jul 28;375(4):323-34

AKI is less frequently observed during SGLT2 inhibition in two large contemporary cohorts of two major US health systems

Mount Sinai (unadjusted)

Mount Sinai (adjusted)

Geisinger(unadjusted)

Geisinger(adjusted)

0.2 0.4 0.6 0.8 1 1.2 1.4 1.6

Hazard ratio (95% confidence interval)

Mount Sinai Geisinger

P1 and P2 are P values for primary and secondary analyses, respectively.

Mount Sinai cohort Geisinger cohort

Need for acutedialysis

1 (0.3) 1 (0.3) 1.00 0 (0.0) 1 (0.1) 0.317

Change in serumcreatinine during AKIKDIGO events

0.5 (0.4–0.7) 0.9 (0.8–1.3) 0.004 0.6 (0.5–1.0) 0.6 (0.4–1.2) 0.80

Peak creatinine in AKIKDIGO events

1.6 (1.4–1.8) 1.9 (1.6–2.4) 0.02 1.7 (1.4–2.6) 1.6 (1.3–2.4) 0.91

AKIICD 22 (5.9) 40 (10.8) 0.02 15 (1.2) 36 (3.0) 0.003

AKIKDIGO-inpatient 14 (3.8) 36 (9.7) 0.002 26 (2.2) 55 (4.6) 0.001

User(n=372)

Nonuser(n=372) P1

User(n=1,207)

Nonuser(n=1,207) P2

AKI, acute kidney injury; SGLT2, sodium–glucose co-transporter 2; US, United States.

Nadkarni et al. Diabetes Care 2017 40:1479–1485

Summary

• Recent outcome trials with SGLT2 inhibitors confirmed the CV safety and efficacy of these agents (particular

protection for Heart Failure and Kidney Failure protection)

• Hba1c lowering effects attenuated in Diabetic Kidney Disease but other effects persists

• CREDENCE trial in Diabetic Kidney Disease prematurely stopped for overwhelming efficacy

• Benefits of SGLT-2 inhibitors mediated by:

• Diuresis / Natriuresis

• Activation Tubulo-Glomerular Feedback

• Reducing intra-renal hypoxia?

• Given that effects of SGLT2 inhibitors are unlikely mediated by glycemic improvements and SGLT-2 inhibitors can

be safely used without inducing hypoglycmemica current trials examine the efficacy in non-diabetic kidney

diseases

• Guidelines recommend SGLT-2 inhibitors as second line treatment (adjunct to metformin) in indivduals with

diabetes and CKD