Diabetes and Kidney Disease: Inflammation as target to reduce - - PowerPoint PPT Presentation

Cardiovascular disease in Diabetes and Kidney Disease:

Inflammation as target to reduce residual risk? May 25th, 2018. ERA-EDTA

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

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)

Cardiovascular disease caused by atherogenesis

LDLc accumulation in lipid-rich core

Boren J. Curr Opin Lipidol 2016

Fatty streak Intermediate lesions Atheroma Fibrous plaque Complicated lesion/rupture

Koenig W, ATvB 2007

Cardiovascular disease ‘cured’ by LDL-c eradication?

The lower The better

Giugliano RP, Lancet 2017

LDL-C (mM) Adj HR (95% CI) <0.5 0.69 (0.56-0.85) 0.5-1.3 0.75 (0.64-0.86) 1.3-1.8 0.87 (0.73-1.04) 1.8-2.6 0.90 (0.78-1.04) > 2.6 referent

P = 0.0001

Is there an ‘end’ to LDL-c lowering mediated risk reduction?

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

Residual inflammatory risk ? Irreversible risk

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

Higher inflammatory status in FH compared to controls

• Patients not treated statins

▲patients treated with statins

Hyperlipidemia induces arterial wall inflammation

Elevated PET/CT signal in familial hypercholesterolemia

FH patients Healthy controls 2.0 2.5 3.0 3.5 4.0 p = 0.003

TBRmax Ascending aorta

Van Wijk, Stroes, JACC 2014

Hyperlipidemia induces Bone Marrow activation

Increased 18FDG-PET signal in Bone Marrow

Bone marrow Control Hyperlipidemia

Yellow = FDG uptake

Bernelot-Moens, Stroes, Kroon, ATvB 2017

Control Hyperlipidemia

Myocardial Infarction induces prolonged systemic inflammation

Increased 18F-DPA-714 uptake in Bone Marrow and Spleen

C o n tro s A c u te p h a s e 3 m o n th s 1 2 3 4 5

B M S U V m e a n A * * *

C

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t r

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s a c u t e p h a s e a f t e r 3 m

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t h s 2 4 6 8

B M S U V m a x B * * *

c o n tro ls A c u te p h a s e 3 m o n th s 2 4 6 8

S p le e n S U V m a x * C ns

SUV Mean BM SUVmax BM SUVmax Spleen

Verweij, Stroes, Eur J Nuc Med Mol Imaging 2018

Persistent increased hematopoietic activity

in CVD patients

Van der Valk, Stroes, Eur Heart J 2016

Hematopoietic activity predicts CV-risk

in patients following myocardial infarction

Spleen and BM activity increased in ACS patients Spleen and BM-activity correlates with arterial activity Spleen and BM activity Correlate with CVD risk

Emami, JACC CV imaging 2015

Involvement of ‘myeloid’ cells in human CVD

Interaction between lipids and immune cells in plasma

Swirski & Nahrendorf, Science 2013;339:161-6

?

Intracellular lipid accumulation drives cellular activation/migration

Bernelot, Stroes, Eur Heart J 2017

Relevance in Chronic Kidney Disease?

 CKD and CVD:  30% decline in GFR: 20-30% increase CVD-risk  Impact of LDLc reduction:  Non-CKD: 22% CVD reduction for every mmol/L LDLc reduction  CKD (eGFR < 15 ml/min): 15% CVD reduction for every mmol LDLc reduction  Impact of ‘inflammation’:  3-fold increase in CRP: 28% higher MACE  Not ‘attenuated’ during statin therapy

CTT, Lancet Diab endocrin 2016; Ridker, N Engl J Med 2008; Tonelli, JASN 2013

Clinical characteristics of CKD patients

Bernelot-Moens, JASN 2017

Increased arterial wall inflammation in CKD ‘prior’ to overt CVD

Bernelot-Moens, JASN 2017

Activated plasma monocytes in CKD with increased migratory capacity

Relevance in Diabetes Mellitus type II?

Large CV- morbidity / mortality increase

Seshasai, N Engl J Med 2011

Multifactorial intervention needed in DM-II

Ray, Lancet 2009

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 patients with diabetes in secondary prevention

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

Increased arterial wall inflammation in DM-II

Bernelot-Moens, BMC Cardiovascular disorders 2016

Inflammation as therapeutic target?

 Inflammation is a hallmark in CVD  Will ‘reducing’ inflammation decrease CVD-events?

Preliminary observations support CVD-benefit

Colchicine and methotrexate

Renata Micha, Am J Cardiol 2011 Nidorf, JACC 2015

Colchicine, LoDoCo study Methotrexate, CIRT study

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

• 100
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25 50

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25 50

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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

Placebo SC q 3 months Canakinumab 150/300 mg SC q 3 months

HR 0.85 95%CI 0.76-0.96 P = 0.007

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

Cumulative Incidence (%) Follow-up Years

Primary Cardiovascular Endpoints

HR 0.83 95%CI 0.74-0.92 P = 0.0006

MACE MACE - Plus

Follow-up Years

1 2 3 4 5

Cumulative Incidence (%)

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

Clinical Outcome Placebo (N = 3182) Canakinumab On-treatment hsCRP > 2mg/L (N = 2868) Canakinumab On-treatment hsCRP < 2 mg/L (N = 3484) MACE HR (adjusted) 95% CI P 1.0 Referent Referent 0.90 0.79-1.02 0.11 0.75 0.66-0.85 <0.0001 MACE - Plus HR (adjusted) 95% CI P 1.0 Referent Referent 0.91 0.81-1.03 0.14 0.74 0.66-0.83 <0.0001 CV Death HR (adjusted) 95% CI P 1.0 Referent Referent 0.99 0.82-1.21 0.95 0.69 0.56-0.85 0.0004 All-Cause Mortality HR (adjusted) 95% CI P 1.0 Referent Referent 1.05 0.90-1.22 0.56 0.69 0.58-0.81 <0.0001

Hazard Ratios for CV Outcomes According to CRP Levels >/< 2 mg/L After Drug Initiation

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

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  BET-inhibition 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;

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

CKD and ‘cardiorenal’ disease:

Epigenetic links?

 Epigenetic modifications in CKD particularly at level of histone-modifying enzymes  uremia affects DNA methylation  Increased homocysteine affects DNA methylation.  DNA methylation & histone modification affect transcriptional activity of Endothelin-1  Epigenetic control of nitric oxide synthase in CKD  epigenetics and their influence on inflammation and ‘cardiorenal syndrome’ link warrants consideration

Kingma, J Cardiov Dev Disease 2017

Summary

 A systemic, multilevel inflammatory reaction contributes to the cardiovascular risk  Maximal LDLc reduction does not remove residual inflammatory risk  Diabetes & CKD are both characterized by an enhanced pro-inflammatory ‘systemic & local’ state  Reducing inflammation reduces CV-events  Best way to ‘safely’ reduce inflammation remains to be established