Insidie del binomio iperuricemia e rischio CV

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1 Insidie del binomio iperuricemia e rischio CV Claudio Borghi, FESC, FAHA Department of Medical and Surgical Sciences University of Bologna, Bologna, Italy

2 Claudio Borghi Potential conflicts of interest Sponsored Lectures: Menarini, Servier, Novartis, Sigma- Tau, Daichy-Sankyo, BMS-Pfizer Research grants: Menarini, Novartis. Advisor board memberships: Sanofi, Novartis, Menarini, Servier, Takeda, Roche, MSD, Berlin-Chemie, Alfasigma

3 Human urate homeostasis Oxidative stress Humans and higher primates Rest of mammals Uricase XO Hediger MA et al. Physiology (Bethesda) Apr;20:

6 Comparison of the prevalence of gout among US adults between NHANES-III ( ) and NHANES Zhu Y et al, Arthritis Rheum 2011

7 Quartiles of SUA and prevalence of CV risk factors and TOD in the cohort of the Brisighella Heart Study *p=0.005 Borghi C et al, J Hypertens 2013

8 Hyperuricemia and Blood Pressure in animals Mazzali M et al. Hypertension 2001;38:

9 Effects of fructose infusion and Allopurinol (AP) treatment on the development of MS in rats

10 Age and BP-adjusted HR for the associations between serum uric acid and cardiovascular disease: The Rotterdam Study Bos M J et al. Stroke. 2006;37:

11 Analysis on hospitalization for CV and renal disease and health care costs for high SUA in Italy SUA levels and Hx for kidney disease [Ref. 6 mg/dl] IRR (95% CIs) Total health care resource costs > 6 7 mg/dl 1.21 ( ) > 7 8 mg/dl > 8 mg/dl 1.24 ( ) 1.99 ( ) 2,752 2, SUA levels and Hx for CVD [Ref. 6 mg/dl] > 6 7 mg/dl > 7 8 mg/dl > 8 mg/dl IRR (95% CIs) 1.10 ( ) 1.24 ( ) 1.75 ( ) Hospitalizations costs 1.00 SUA levels and total mortality HR (95% CIs) [Ref. 6 mg/dl] 1,515 1,648 > 6 7 mg/dl > 7 8 mg/dl > 8 mg/dl 0.98 ( ) 1.20 ( ) 2.12 ( ) 1.00 Degli Esposti L, Borghi C et al, NMCD 2016

12 SUA and CV disease: Effects on target organ damage and overt CVD TOD LVH IMT PWV Microalbuminuria GFR Overt CVD Acute MI Chronic CAD CHF (HFrEF, HFpEF) Atrial Fibrillation CKD

13 Possible mechanisms of CV disease in patients with high SUA Concomitance with other RF s - Vascular urate deposition ± Genetic mechanism(s) ± Renal involvement/disease ± Associated oxidative stress ++

14 Sex and age-standardized cumulative incidence of HTN in relation to rs (a) and rs (b) XOR genotypes. Scheepers, L et el, J Hypertens 2016;

15 Possible mechanisms of CV disease in patients with high SUA Concomitance with other RF s - Vascular urate deposition ± Genetic mechanism(s) ± Renal involvement/disease ± Associated oxidative stress ++

16 Xanthine oxidase as a downstream mediator of oxidative stress, systemic and vascular activation of the RAS system and CV disease R.Magritte: La reproducion interdite Arterioscler Thromb Vasc Biol Apr;27(4):703-4

17 Serum Uric Acid and LDL-oxidation parameters LDL lag phase LDL diene LDL propagation phase Ox-LDL Cicero A et al, 2014

18 Impact of nldl, oxldl on AT 1 and LOX-1 protein expression *p<0.05 vs control p<0,05 vs nldl * * Catar RA et al, Horm Metab Res 2007

19 Urate uptake by VSMC

06 Baseline SUA < 6 mg/dl 0.125 0.250 0.727 0.001 0.

21 Number of patients with co-morbidities of gout and SUA at baseline and after 7.6 years of follow-up 0.06 Baseline SUA < 6 mg/dl Baseline SUA 6 mg/dl Joo K et al, JKMS 2014

22 Cumulative incidence of CV endpoints by gout status Krishnan E et al, Arthritis Res Ther 2012

23 Treating Asymptomatic hyperuricemia today: How to proceed? 30

24 How to approach asymptomatic hyperuricemia: A purpose Non-pharmacologic Education about the disease Individualized lifestyle advices (avoid fructose!!!) Screening for co-morbidities Nutraceuticals (?) Pharmacologic non-ult Consider (when indicated) Losartan, Fibrates, Statins (Atorvastatin) ULT treatment (EULAR-oriented) Initiation of ULT is recommended (close to the time of first diagnosis) in patients presenting at a: young age (<40 years) or with a very high SUA level (>8.0 mg/dl; 480 mmol/l) (>7 mg/dl?)

Whole Group Data 365/6678 Variable Beta 95% CI for Beta P value *Adjusted for: Age, smoking, ischaemic heart disease, peripheral vascular disease, cerebrovascular disease, baseline BP and days

26 Whole Group Data 365/6678 Variable Beta 95% CI for Beta P value *Adjusted for: Age, smoking, ischaemic heart disease, peripheral vascular disease, cerebrovascular disease, baseline BP and days between BP measurements, Lower limit Upper limit SBP change in no or continued unchanged antihypertensive patients Allopurinol use DBP change in no or continued unchanged antihypertensive patients Allopurinol use SBP change in new antihypertensive patients Allopurinol use DBP change in new antihypertensive patients Allopurinol use Hypertension Nov;64(5):1102-7

27 Risk of CV events Risk of stroke MacIsaac RL et al, Hypertension 2016

28 Effect of Febuxostat on plaque formation in ApoE -/- atherosclerotic mice Nomura J et al, Sci Rep, 2014

Xanthine Oxidase Inhibition with Febuxostat Attenuates Systolic Overload-induced Left Ventricular Hypertrophy and Dysfunction in Mice *p<0.

29 Xanthine Oxidase Inhibition with Febuxostat Attenuates Systolic Overload-induced Left Ventricular Hypertrophy and Dysfunction in Mice *p<0.05 as compared with sham group; #p<0.05 as compared with vehicle group TAC = Transverse aortic constriction. VH = vehicle. FBS = febuxostat Xu X et al. J Card Fail ; 14(9):

30 RCT with ULT: surrogate end-points Trial Drug 1 objective Reference BP control Coronary endothelial dysfunction BP control Exercise tolerance in chronic angina Vascular structure and function (FORWARD) New onset MS (FAST) Febuxostat vs. Allopurinol Febuxostat vs. Placebo Febuxostat vs. Placebo Febuxostat vs.placebo Febuxostat vs. Allopurinol Febuxostat vs. Placebo Clinic and ABPM Coronary flow ABPM Exercise test (ETT) Carotido- Femoral PWV INS-res and features MS NCT * ongoing NCT * completed NCT * completed NCT * terminated EUDRACT (enroll. closed) NCT * ongoing *ClinicalTrial.gov

RCT with ULT: Hard CV end-points Trial Drug 1 objective BP and CV complications (CARES) New onset MS (FAST) Treatment of CHD (ALL-HEART) Cerebrovascular protection (XILO-FIST) Major CV disease

31 RCT with ULT: Hard CV end-points Trial Drug 1 objective BP and CV complications (CARES) New onset MS (FAST) Treatment of CHD (ALL-HEART) Cerebrovascular protection (XILO-FIST) Major CV disease (FREED) Febuxostat vs. Allopurinol Febuxostat vs. Placebo Allopurinol vs. Standard care Allopurinol vs.placebo Febuxostat vs. Placebo Serious CV events INS-res and features MS Reference NCT * ongoing NCT * ongoing MACE EudraCT ongoing White matter protection MACE NCT * Starting recruitment NCT * ongoing *ClinicalTrial.gov

The treatment with XO-inhibitors (Allopurinol) improves overall survival What must be investigated: Serum Uric Acid and CVD: Evidence and Future targets of research The

32 What we know: Hyperuricemia (H-SUA) is largely prevalent in the population and contribute to CVD, metabolic and renal disease. H-SUA have a negative prognostic effect in patients at risk of CVD. The CV risk is to the levels of SUA and is confirmed after extensive statistical adjustment. The treatment with XO-inhibitors (Allopurinol) improves overall survival What must be investigated: Serum Uric Acid and CVD: Evidence and Future targets of research The role of SUA/XO levels ratio as a functional marker of CV risk The importance of intrinsic patients characteristics (e.g. hyper-producers vs. lowexcretors). The ultimate efficacy of ULT and the role of different compounds

Uricemia nei pazienti a. fattore o marker di rischio? Claudio Borghi, FESC, FAHA Dipartimento di Scienze Mediche e Chirurgiche Università di Bologna

Uricemia nei pazienti a. fattore o marker di rischio? Claudio Borghi, FESC, FAHA Dipartimento di Scienze Mediche e Chirurgiche Università di Bologna Uricemia nei pazienti a rischio CV: fattore o marker di rischio? Claudio Borghi, FESC, FAHA Dipartimento di Scienze Mediche e Chirurgiche Università di Bologna R.Magritte: La reproducion interdite Urate