Importance of protection

and prevention in cardiorenal

disease

John Deanfield, MD

London, United Kingdom

June 15, 2019 - Budapest, Hungary

Protection and Prevention in Diabetic Cardio-renal Disease

Professor John Deanfield - University College London, UKBudapest ERA EDTA - 15 June 2019

Deanfield UCL

CVD Challenge in Diabetes is Clear

Source: Seshasai et al, N Engl J Med 2011; 364:829-41

On average, a 50-year old with diabetes but no history of vascular disease is

~6 years younger at time of death than a counterpart without diabetes

Men Women

0

7

6

5

4

3

2

1

0

40 50 60 70 80 90

Age (years)

Years

of

life

lo

st

7

6

5

4

3

2

1

040 50 60 70 80 900

Age (years)

Vascular deaths Non-vascular deaths

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Need for Joint Approach…CVD and CKD Go Together!

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“It is observable, that the hypertrophy

of the heart seems, in some degree, to

have kept pace with the advance of

disease in the kidneys; for in by far the

majority of cases, when the heart was

increased, the hardness and

contraction of the kidney bespoke the

probability of long continuance of the

disease.”

- R Bright, 1836

Diabetes

CKD CVD

Cardio-renal Disease in Diabetes

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Novel treatments can improve cardio-renal outcomes in

patients with diabetes

Prevention is important as long term exposure to risk

factors drives cardio-renal disease

Never Too Late…Never Too Early…!!

Leveraged gain from early intervention on common

pathways to disease

Emerging early role for new drugs?

• Statins

• BP Lowering

• Metformin

• ACEi / ARB

SGLT2-iGLP1-RA

Evidence Based Cardiorenal Risk Reduction

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Empagliflozin, CV Outcomes and Mortality in T2DM

Source: Zinman N Engl J Med 2015;373:2117-28

Primary Outcome Death from Cardiovascular Causes

Death from Any Cause Hospitalization for Heart Failure

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Source: Marso SP et al. N Engl J Med 2016;375:311–322 Source: Marso SP et al. N Engl J Med 2016;375:1834–1844

LEADER

Time to first occurrence of CV death, non-fatal MI or non-fatal stroke

0 6 1 2 1 8 2 4 3 0 3 6 4 2 4 8 5 4

0

5

1 0

1 5

2 0

Pati

en

ts w

ith

even

t (%

)

Placebo

Liraglutide

HR: 0.87(95% CI: 0.78 ; 0.97)p<0.001 for non-inferiorityp=0.01 for superiority

Time from randomisation (months)

SUSTAIN 6

Semaglutide

Placebo

Pati

en

ts w

ith

even

t (%

)

HR: 0.74(95% CI: 0.58 ; 0.95)p<0.001 for non-inferiorityp=0.02 for superiority

Time from randomisation (months)

GLP-1RA CV Outcome Trials

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Source: Newman JD, et al, J Am Coll Cardiol 2018; 72(15):1856-69

Diabetes Treatment for CVD ReductionSGLT-2 Inhibitors GLP-1R Agonists

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Source: Newman JD, et al, J Am Coll Cardiol 2018; 72(15):1856-69

Renal Benefit from GLP-1RA and SGLT-2i

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9,900

individuals

with T2DM

and eGFR of

≥ 15mL/min;

Dulaglutide

v Placebo; >

two thirds

primary CV

prevention

Source: Hertzel C Gerstein, Lancet x.doi.org/10.1016/S0140-6736(19)31150-XDeanfield UCL

REWIND

Cu

mu

lati

ve

(%

)

Time Since Randomisation (yrs)

Exciting New Era for CVD Management in DM

Diabetologists Cardiologists

Primary Care Nephrology

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A Thought…

“Why just strive to treat a

disease like Diabetes better

when you could prevent

it?”

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Source: IDF Diabetes Atlas. 7th edn. 2015

2015 2040

Source Bjerregaard et al, N Engl J Med 2018;378:1302-12

Diabetes Epidemic : Risk Factors start Early!

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The Ticking Clock: CV Risk Before Glucose(Nurses’ Health Study)

Source: Hu et al, Diabetes Care 2002; 25: 1129-1134

20 yr F/U of 117,629 women: n=1,508 diabetes at B/L;

n=5,894 developed diabetes; n=110,227 free from diabetes

0.0Re

lati

ve

ris

k o

f M

I o

r s

tro

ke

Nondiabetic

throughout

the study

Risk of event

prior to

DM diagnosis

Risk of event

after DM

diagnosis

Diabetic

at B/L

6.0

5.0

4.0

3.0

2.0

1.0

5.02

3.71

2.82

1.0

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Source: Lean, M et al, Lancet 2018; 391: 541–51

Primary Care-led Weight Management For Remission of T2DM (DiRECT)

> 10kg Weight Loss 64%Remission

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Impact of GLP1-RA on Obesity

Source: O’Neil et al, Lancet 2018; 392: 637–49

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Four Weeks Of Liraglutide Inhibits Progression Of Atherosclerotic Lesions In ApoE-/- mice

Gaspari T et al. Diab Vasc Dis Res 2013;10:353‒60.

IMR

0.4

0.3

0.2

0.1

0.0

Vehicle Lira Lira + Ex-9

*

IMR analysis performed in the aortic arch

Intima‒media ratio (IMR)

N=6‒10

Lesio

n a

rea (

%)

15

10

5

0

Vehicle Lira Lira + Ex-9

Oil red O staining performed in the aorta

Lipid deposition

N=13‒16

Vehicle Lira Lira + Ex-9

MM

I

M

I

Lesion development

Haemotoxylin and eosin staining in the aortic arch

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Semaglutide s.c. 2.4 mg once-weekly

Placebo s.c. once-weekly

Event driven1225 first MACEs Randomisation (1:1)

N=17,500 patientsMale or female

≥45 years of ageBMI ≥27

PriorMI

Prior stroke

PAD

SELECT: GLP1-RA in high CVD risk Non Diabetics

Primary endpoint:Time from randomisation to first occurrence of a composite endpoint consisting of either: • CV death• Non-fatal myocardial infarction• Non-fatal stroke

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CV RFs Drive Multiple Diseases Through Common Pathways

Obesity

Stress

BP

Smoking

Systemic Inflammation

Ageing

DiabetesCKD CVD

Cancer

Cholesterol

Oxidative Stress

DementiaStroke

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Impact of Periodontitis Treatment on Glucose Control, Vascular and Renal Function in T2DM

Source: D’Aiuto Lancet Diabetes 2018

In UK population

▪Severe in 5-10%

▪Mild/mod. in 40%

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How Early Should

Prevention Start?

“Poor Start in Life”

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Obesity at 2 yrs Predicts Status at 35 yrs...

Source: Ward et al, N Engl J Med 2017;377:2145-53

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Source: Twig G et al, NEJM 2016;374:2430-40

BMI During Adolescence and CV Mortality

Diabetes and Hypertension

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Cardio-renal Disease in Diabetes: Protection & Prevention

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New era for treatment of cardio-renal

disease

Earlier management is needed to target

disease in the population

Emerging role for new drugs and lifestyle in

pre-clinical disease

Final Thought…

“It should be the function of

medicine to have people die

young as late as possible”

- Ernest L. Wynder M.D

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