Cardiovascular disease: The new risk

management challenge in diabetes

Diabetes & Cardiovascular Disease: What are the challenges?

Asian Cardio Diabetes ForumMarch 30-31, 2019 - Hanoi, Vietnam

Prof. John E Deanfield,

MDLondon, United Kingdom

Healthy Ageing?

CV Disease is the Major

Cause of Morbidity and

Mortality

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

Deanfield UCL

Diabetes UK: The Impact of Diabetes Today

Source: Diabetes UK

DM and 1-yr Composite Outcome and All-cause Mortality for ASIAN-HF Men and Women

Source: Chandramouli C et al, EJHF, (2019) 21, 297–307

Deanfield UCL

4 X Hospitalization for

Heart Failure in Diabetes

Major Diabetes Complications in USA

PACE Dubai 2018

CVD AdmissionsHyperglycaemic Deaths

Deanfield UCL

Deanfield UCL

Treatment Goals in T2DM

Management should be targeted at

reducing / delaying CV complications in

patients with T2DM with and without

clinical CVD

Not just icing on the cake!!!

Insulin Resistance: An Inflammatory

Atherothrombotic Syndrome

INSULIN RESISTANCE

Hyperglycaemia

Hyperinsulinaemia

Hypertension

Smoking Fibrinogen

Factor VII

Factor XII

PAI-1

tPA

Triglyceride

Cholesterol

CRP

Monocytes

Cytokines

Adhesion Molecules

Insulin Resistance

Deanfield UCL

Risk Factors for CVD in patients with T2DM

Source: Rawshani et al, N Engl J Med 2018;379:633-44

Stroke Heart Failure

Death From Any Cause Acute Myocardial

Infarction

271,174 pts with T2DM matched to 1,355,870 controls

Median F/U = 5.7 years with 175,345 deaths

Deanfield UCL

Benefit of different interventions per 200 patients

with diabetes treated for 5 years

Using traditional glucose lowering treatments

Source: Ray, Lancet 2009 Meta-analysis of intensive glucose-lowering trials.

Per 0.9% lower HbA1c

Per 4mm Hg lower SBP

Per 1mmol/L lower LDL-C

CV

Events

5

0

-5

-12.5-15

-20

-10 -8.2

-2.9

Deanfield UCL

Diabetes Medications and Increased CV Risk

Source: Nissen SE, Wolski K. N Engl J Med 2007; 356: 2457-2471

Deanfield UCL

▪ Sulphonyl Ureas

▪ Thiazolidinediones

▪ DPP-4 Inhibitors

▪ Insulin

ESC Munich 2018

Diabetes Medications and Possible Increased CV Risk

FDA / EMA requirements:

▪ New diabetes drugs should demonstrate

CV safety with meta-analysis and CV

outcome trial

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

Deanfield UCL

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

Deanfield UCL

CVD-REAL 2: Lower CV Risk Associated With SGLT-2 i6 Countries Asia Pacific, Middle East, North America -27% established CVD

Source: Kosiborod, M. et al. J Am Coll Cardiol. 2018;71(23):2628–39.

Deanfield UCL

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

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

Deanfield UCL

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

Meta-analysis of SGLT2i trials on the composite of renal worsening, end-stage renal disease, or renal death stratified by the presence of

established atherosclerotic CVD

Deanfield UCL

Source: Zelniker, T et al., Lancet 2019; 393: 31–39

Meta-analysis of SGLT2i trials on hospitalisation for HF and CV death stratified by the presence of established atherosclerotic CVD

Deanfield UCL

Source: Zelniker, T et al., Lancet 2019; 393: 31–39

Meta-analysis of SGLT2i trials on hospitalisation for HF and CV death stratified by history of heart failure

Source: Zelniker, T et al., Lancet 2019; 393: 31–39

Deanfield UCL

Medical History HF-REF (%) HF-PEF (%) p value

IHD 48.4 37.9 <0.001

Atrial fibrillation 49.1 40 0.857

MI 30.7 18.1 <0.001

Valve disease 23.9 31.4<0.001

Hypertension 52.1 59.9<0.001

Diabetes 33.3 33.5 0.577

Asthma 8.4 9.4<0.001

COPD 16.7 18.9<0.001

Diabetes is very common in Heart Failure

NHE-dependent Pathways That May Underlie the Interplay of Pathogenesis of HF and DM

Source: Packer, M, Circulation. 2017;136:1548–1559

Deanfield UCL

Novel ‘Diabetes’ Drugs: Unanswered Questions

Which patients benefit

most from each drug?

e.g. patients with HF or

kidney disease

Mechanisms by

which drugs mediate

CV benefit?

‘Bedside to Bench!’

? ?Are these drugs equally

effective in patients without

CVD or without DM

(primary prevention)?

?

Future CVOTs

Heart failure

Nephropathy

Obesity

?

Deanfield UCL

PACE Dubai 2018

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

SGLT2i In Different Patient Populations

Source: Verma,S, et al, Lancet, Vol 393 January 5, 2019, 3-5

Deanfield UCL

CVOT Impact on Clinical Guidelines

Source: American Diabetes Association. Diabetes Care 2018;41 (Suppl 1):S73–S85

ADA 2018 recommendation

In patients with type 2 diabetes and

established atherosclerotic cardiovascular

disease, antihyperglycemic therapy

should begin with lifestyle management

and metformin and subsequently

incorporate an agent proven to reduce

major adverse cardiovascular events and

cardiovascular mortality (currently,

empagliflozin and liraglutide), after

considering drug-specific and patient

factors (Table 8.1).

Deanfield UCL

Deanfield UCL

Exciting New Era for CVD Management in DM

Diabetologists Cardiologists

Primary Care Nephrology

▪ Opportunity to improve outcomes in

millions of patients with diabetes

▪ Likely to be benefits beyond current

evidence from trials

▪ Transform clinical care including the

preclinical phase of cardiometabolic

risk