Cardiovascular disease: The new risk management challenge ... · Cardiovascular disease: The new...
Transcript of Cardiovascular disease: The new risk management challenge ... · Cardiovascular disease: The new...
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
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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