Cardiovascular disease in Diabetes and Kidney Disease: Inflammation as target to reduce residual risk? May 25 th , 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 Fibrous Complicated Fatty Intermediate Atheroma plaque lesion/rupture streak lesions Boren J. Curr Opin Lipido l 2016 Koenig W, ATvB 2007
Cardiovascular disease ‘cured’ by LDL -c eradication? The lower The better 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) P = 0.0001 1.3-1.8 0.87 (0.73-1.04) 1.8-2.6 0.90 (0.78-1.04) > 2.6 referent Giugliano RP, Lancet 2017
Is there an ‘end’ to LDL -c lowering mediated risk reduction? Control 20 Five year risk of a major 22% relative risk reduction Statin with 1.0 mmol/L reduction vascular event, % 15 More statin 15% relative risk reduction with 0.5 mmol/L more reduction Statin-ezetimibe 34% relative risk reduction with 1.5 mmol/L reduction PCSK9 addition 10 33% relative risk reduction With 1.6 mmol/L reduction* Residual inflammatory risk ? 5 Irreversible risk 0 0.8 0 1 2 3 4 5 LDL cholesterol (mmol/L) * Extrapolated > 1yr treatment
Role of inflammation in CVD-event Lipids and Inflammation intertwined Foam Fatty Intermediate Atheroma Fibrous Complicated cell streak lesions plaque lesion/rupture Koenig W, Arterioscler Thromb Vasc Biol 2007;27:15 – 26.
Hyperlipidemia induces arterial wall inflammation Elevated PET/CT signal in familial hypercholesterolemia Higher inflammatory status in FH compared to controls p = 0.003 4.0 Ascending aorta 3.5 TBRmax 3.0 2.5 2.0 FH patients Healthy controls ● Patients not treated statins ▲ patients treated with statins Van Wijk, Stroes, JACC 2014
Hyperlipidemia induces Bone Marrow activation Increased 18 FDG-PET signal in Bone Marrow Control Hyperlipidemia Bone marrow Control Hyperlipidemia Yellow = FDG uptake Bernelot-Moens, Stroes, Kroon , ATvB 2017
Myocardial Infarction induces prolonged systemic inflammation Increased 18 F-DPA-714 uptake in Bone Marrow and Spleen SUV Mean BM SUVmax BM SUVmax Spleen A B * * * * * * C 8 5 8 ns * 4 6 B M S U V m e a n B M S U V m a x S p le e n S U V m a x 6 3 4 4 2 2 1 2 0 0 0 s e s A c u te p h a s e C o n tro s 3 m o n th s s h l o a t n c o n tro ls A c u te p h a s e 3 m o n th s r h t o p n m o e C t 3 u c r e a t f a 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 Correlate with CVD risk Spleen and BM-activity correlates with arterial activity 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
High residual risk for patients with diabetes in secondary prevention Atorvastatin 80 mg Eze 10 mg / Simva 40 mg Diabetes Diabetes Yes No Yes No 39.8% 26.1% 40.0% 30.2% *Cerebrovascular event, CHF with hospitalisation, CHD death, *Cardiovascular death, non-fatal MI, rehospitalisation for UA, MI, resuscitated cardiac arrest, coronary revascularisation and coronary revascularisation (occurring at least 30 days after documented angina randomisation) or stroke Shepherd et al. Diabetes Care 2006;29:1220 – 6 (TNT); CHD, coronary heart disease; CHF, congestive heart failure; Cannon et al, NEJM 2015;362:2387 – 97 and supplemental data (IMPROVE-IT). CV, cardiovascular; MI, myocardial infarction; UA, unstable 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 Methotrexate, CIRT study Colchicine, LoDoCo study Nidorf, JACC 2015 Renata Micha, Am J Cardiol 2011
Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) Stable CAD (post MI) N = 10,061 On Statin, ACE/ARB, BB, ASA 39 Countries Persistent Elevation April 2011 - June 2017 of hsCRP (> 2 mg/L) 1490 Primary Events Randomized Randomized Randomized Randomized Canakinumab 150 mg Canakinumab 300 mg Canakinumab 50 mg Placebo SC q 3 months SC q 3 months* SC q 3 months SC q 3 months Primary CV Endpoint: Nonfatal MI, Nonfatal Stroke, Cardiovascular Death (MACE) Key Secondary CV Endpoint: MACE + Unstable Angina Requiring Unplanned Revascularization (MACE+) Ridker PM, et al. N Engl J Med . 2017
Drug Response to IL1-b ab (Canakinumab) on CRP, IL-6, and LDL-C Percent Change in hsCRP -100 -75 -50 -25 0 25 50 Percent Change in IL-6 -100 -75 -50 -25 0 25 50 Percent Change in LDL-C -100 -75 -50 -25 0 25 50 Canakinumab Canakinumab Canakinumab Placebo 50 mg 150 mg 300 mg Ridker PM et al. N Engl J Med . 2017;377:1119-31
Primary Cardiovascular Endpoints Placebo SC q 3 months Canakinumab 150/300 mg SC q 3 months MACE MACE - Plus HR 0.85 HR 0.83 Cumulative Incidence (%) Cumulative Incidence (%) 95%CI 0.76-0.96 95%CI 0.74-0.92 P = 0.007 P = 0.0006 0 1 2 3 4 5 Follow-up Years Follow-up Years Ridker PM et al. N Engl J Med . 2017;377:1119-31
CRP Tertiles Measured After the Initial Canakinumab dose Confirmed MACE by Tertiles of 3 Month hsCRP HR (95% CI) P ___________________________________________________________ 0.25 Placebo 1.0 (ref) (ref) On Treatment hsCRP: Top Tertile 0.99 (0.86,1.14) 0.93 On Treatment hsCRP: Middle Tertile 0.83 (0.72,0.96) 0.014 On Treatment hsCRP: Lowest Tertile 0.71 (0.61,0.82) <0.0001 0.20 Placebo Tertile 1 (hsCRP>2.6mg/L) Cumulative Incidence Tertile 2 (hsCRP >1.2-<2.6) 0.15 Tertile 3 (hsCRP <1.2mg/L) 0.10 0.05 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 0.00 0 1 2 3 4 5 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 Ridker PM et al. N Engl J Med . 2017;377:1119-31
Hazard Ratios for CV Outcomes According to CRP Levels >/< 2 mg/L After Drug Initiation Clinical Outcome Placebo Canakinumab Canakinumab (N = 3182) On-treatment On-treatment hsCRP > 2mg/L hsCRP < 2 mg/L (N = 2868) (N = 3484) MACE HR (adjusted) 1.0 0.90 0.75 95% CI Referent 0.79-1.02 0.66-0.85 P Referent 0.11 <0.0001 MACE - Plus HR (adjusted) 1.0 0.91 0.74 95% CI Referent 0.81-1.03 0.66-0.83 P Referent 0.14 <0.0001 CV Death HR (adjusted) 1.0 0.99 0.69 95% CI Referent 0.82-1.21 0.56-0.85 P Referent 0.95 0.0004 All-Cause HR (adjusted) 1.0 1.05 0.69 Mortality 95% CI Referent 0.90-1.22 0.58-0.81 P Referent 0.56 <0.0001 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;
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