CVD & Diabetes: A promise for epigenetics? August 25 th , 2018. - - PowerPoint PPT Presentation

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The real residual risk in patients with CVD & Diabetes: A promise for epigenetics? August 25 th , 2018. ESC, Munich, Germany Erik S Stroes Department of Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands Disclosures

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The real residual risk in patients with CVD & Diabetes:

A promise for epigenetics?

August 25th, 2018. ESC, Munich, Germany

Erik S Stroes Department of Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands

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Disclosures

 Speaker fees/ Ad-board fees have been paid to the institution for ES Stroes by:  Amgen, Sanofi, Regeneron, Novartis, Astra-Zeneca, Akcea, Athera.  Research grants / participation in clinical trials:  Amgen, Sanofi, Astra-Zeneca, Akcea, Athera, Resverlogix  Research funding:  European Union (FP7, Horizon-2020, ERA-CVD), Dutch Heart Foundation (CVON)

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Increased lifetime risk for CHD

in diabetic patients

Turin, Primary Care Diabetes 2017

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Large impact on survival

Large CV- morbidity / mortality increase

Seshasai, N Engl J Med 2011

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Residual risk after MI

Prospective REACH registry

Abtan, Clin Cardiol 2016

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Benefit of intensive glucose control?

Residual vascular risk minor reduction

Giugliano, Endocrine 2018

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LDL-c lowering potently reduces CV-risk

1 2 3 4 5 5 10 15 20

LDL cholesterol (mmol/L) Five year risk of a major vascular event, %

Control 22% relative risk reduction with 1.0 mmol/L reduction Statin 15% relative risk reduction with 0.5 mmol/L more reduction More statin 34% relative risk reduction with 1.5 mmol/L reduction Statin-ezetimibe 33% relative risk reduction With 1.6 mmol/L reduction* PCSK9 addition * Extrapolated > 1yr treatment

0.8

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Highest benefit in DM-patients

Meta-analysis of statin-ezetimibe

Kang, EnM 2018

Highest benefit in DM-patients

Meta-analysis of statin-ezetimibe

Kang, EnM 2018

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CHD, coronary heart disease; CHF, congestive heart failure; CV, cardiovascular; MI, myocardial infarction; UA, unstable angina. Shepherd et al. Diabetes Care 2006;29:1220–6 (TNT); Cannon et al, NEJM 2015;362:2387–97 and supplemental data (IMPROVE-IT).

High residual risk for DM-II patients

Using high-dose statin therapy Atorvastatin 80 mg Diabetes Yes No 39.8% 26.1% Eze 10 mg / Simva 40 mg Diabetes Yes No 40.0% 30.2%

*Cardiovascular death, non-fatal MI, rehospitalisation for UA, coronary revascularisation (occurring at least 30 days after randomisation) or stroke *Cerebrovascular event, CHF with hospitalisation, CHD death, MI, resuscitated cardiac arrest, coronary revascularisation and documented angina

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Residual Risk Factors predicting MACE in CVD Patients

with and without Diabetes Mellitus

Lin, Scientific Reports 2017

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High TG/low HDL-c ‘marking’ very high CV-risk in DM-II

Lipid changes in DM-II

Hermans, Curr Op Endo Diab Ob 2018

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Multifactorial intervention needed in DM-II

Ray, Lancet 2009

Multifactorial intervention needed in DM-II

Ray, Lancet 2009

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Is there more than lipids in CV-risk?

CRP & residual risk in statin-treated patients: MESA study

Wong, J Clin Lipidol 2017

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Role of inflammation in CVD-event

Lipids and Inflammation intertwined

Koenig W, Arterioscler Thromb Vasc Biol 2007;27:15–26.

Foam cell Fatty streak Intermediate lesions Atheroma Fibrous plaque Complicated lesion/rupture

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Increased arterial wall inflammation in DM-II

Bernelot-Moens, BMC Cardiovascular disorders 2016

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Mechanistic pathways for increased vascular inflammation in DM-II

Pechlivani, Frontiers Cardiov Med 2018

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Hyperglycaemia increases MMP activity

in smooth muscle cells

Hyperglycemia: (i) High expression of MMP-1/9 (ii) increase in MCP1 (iii) Mediated by PKCa/NFkB signalling → high vulnerability of atherosclerotic plaque In DM?

Macarie, J Cell Mol Med 2018

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Will anti-inflammatory strategies benefit CV-patients with/without diabetes?

Colchicine and methotrexate

Renata Micha, Am J Cardiol 2011 Nidorf, JACC 2015

Colchicine, LoDoCo study Methotrexate, CIRT study

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Stable CAD (post MI) On Statin, ACE/ARB, BB, ASA Persistent Elevation

f hsCRP (> 2 mg/L)

Randomized Canakinumab 150 mg SC q 3 months Randomized Placebo SC q 3 months Primary CV Endpoint: Nonfatal MI, Nonfatal Stroke, Cardiovascular Death (MACE) Randomized Canakinumab 300 mg SC q 3 months* Key Secondary CV Endpoint: MACE + Unstable Angina Requiring Unplanned Revascularization (MACE+) Randomized Canakinumab 50 mg SC q 3 months

Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS)

N = 10,061 39 Countries April 2011 - June 2017 1490 Primary Events

Ridker PM, et al. N Engl J Med. 2017

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25 50

Percent Change in hsCRP Percent Change in IL-6 Percent Change in LDL-C Placebo Canakinumab 50 mg Canakinumab 150 mg Canakinumab 300 mg

Ridker PM et al. N Engl J Med. 2017;377:1119-31

Drug Response to IL1-b ab (Canakinumab)

n CRP, IL-6, and LDL-C

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1 2 3 4 5 0.00 0.05 0.10 0.15 0.20 0.25 Cumulative Incidence

Placebo On Treatment hsCRP: Top Tertile On Treatment hsCRP: Middle Tertile On Treatment hsCRP: Lowest Tertile

Confirmed MACE by Tertiles of 3 Month hsCRP

HR (95% CI) P ___________________________________________________________ 1.0 (ref) (ref) 0.99 (0.86,1.14) 0.93 0.83 (0.72,0.96) 0.014 0.71 (0.61,0.82) <0.0001

Follow-up (years)

No. at risk:

Placebo 3182 3014 2853 2525 1215 200 Canakinumab: Top Tertile 2090 1983 1866 1632 789 139 Middle Tertile 2044 1947 1866 1660 821 146 Lowest Tertile 2218 2147 2056 1856 888 153

CRP Tertiles Measured After the Initial Canakinumab dose

Placebo Tertile 1 (hsCRP>2.6mg/L) Tertile 2 (hsCRP >1.2-<2.6) Tertile 3 (hsCRP <1.2mg/L)

MACE 29% reduction for those achieving lowest hsCRP tertile 17 % reduction for those achieving middle hsCRP tertile 1 % reduction for those achieving highest hsCRP tertile

Ridker PM et al. N Engl J Med. 2017;377:1119-31

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Ridker, N Engl J Med 2017

Benefit, with ‘risks’…

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Working towards ‘safer’ anti- inflammatory interventions

 Targeting immune-metabolism  Inhibiting inducible glycolysis  Targeted delivery of inhibitors of signalling cascades  nanotherapy (rHDL, liposomes)  CD40-TRAF signalling  Targeting ‘epigenetic’ inflammatory amplification loops  Epigenetic modulation and CAD-risk  Trained immunity

Li, Carmeliet, Science 2018 Lameijer, Duivenvoorden, Nature Biotechnology 2018 Nicchols, Am J Cardiov Drugs 2018; Leentjes, Riksen, Circ Res 2018;

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Type 2 Diabetes Mellitus and CVD:

Epigenetic Links ?

 Epigenetic mechanisms linking DM-II to CVD:  Histone lysine modification / DNA methylation:

High glucose: Hyper-insulinemia Reactive oxygen species Advanced glycation end-products

De Rosa, Frontiers in Endocrinology 2018 R Sallerman, 2012

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Summary

 High residual CV-risk in DM-II, despite LDL-C lowering  DM-II characterized by pro-inflammatory state:  Hyperinsulinemia, hyperglycemia  Insulin resistance, ----  Anti-inflammatory interventions effective in CV-therapy  New challenge: Identify effective and safe ‘anti-inflammatory’ intervention able to reduce residual CV-burden in DM-II