Claudio Borghi, FESC, FAHA Department of Medical and Surgical Sciences

University of Bologna, Bologna, Italy

Insidie del binomio iperuricemia e rischio CV

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

Human urate homeostasis

Uricase

Oxidative stress

Humans and higher primates

Rest of mammals

Hediger MA et al. Physiology (Bethesda). 2005 Apr;20:125-33.

XO

Comparison of the prevalence of gout among US adults

between NHANES-III (1988-1994) and NHANES 2007-2008

Zhu Y et al, Arthritis Rheum 2011

Quartiles of SUA and prevalence of CV risk factors and TOD

in the cohort of the Brisighella Heart Study

Borghi C et al, J Hypertens 2013

*p=0.005

Hyperuricemia and Blood

Pressure in animals

Mazzali M et al. Hypertension 2001;38:1101-1106

Effects of fructose infusion and Allopurinol (AP) treatment

on the development of MS in rats

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;37:1503-1507

1.00

1.99 (1.77-2.24)

1.24 (1.08-1.41)

1.21 (1.09-1.35)

IRR (95% CIs)[Ref. ≤ 6 mg/dl]

> 6 ≤ 7 mg/dl

> 7 ≤ 8 mg/dl

> 8 mg/dl

Analysis on hospitalization for CV and renal disease and

health care costs for high SUA in Italy

1.00

1.99 (1.77-2.24)

1.24 (1.08-1.41)

1.21 (1.09-1.35)

IRR (95% CIs)[Ref. ≤ 6 mg/dl]

> 6 ≤ 7 mg/dl

> 7 ≤ 8 mg/dl

> 8 mg/dl

1.75 (1.65-1.85)

1.24 (1.18-1.32)

1.10 (1.05-1.15)

IRR (95% CIs)[Ref. ≤ 6 mg/dl]

> 6 ≤ 7 mg/dl

> 7 ≤ 8 mg/dl

> 8 mg/dl

1.00

[Ref. ≤ 6 mg/dl]

> 6 ≤ 7 mg/dl

> 7 ≤ 8 mg/dl

> 8 mg/dl

1.00

2.12 (1.98-2.27)

1.20 (1.11-1.29)

0.98 (0.92-1.04)

HR (95% CIs)

SUA levels and Hx for kidney disease

SUA levels and Hx for CVD

SUA levels and total mortality

€ 2,752 € 2,957

€ 1,648 €

1,515

Total health care resource costs

Hospitalizations costs

Degli Esposti L, Borghi C et al, NMCD 2016

SUA and CV disease: Effects on target organ damage and overt CVD

LVH

IMT

PWV

Microalbuminuria

GFR

Acute MI

Chronic CAD

CHF (HFrEF, HFpEF)

Atrial Fibrillation

CKD

TOD Overt CVD

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 ++

Scheepers, L et el, J Hypertens 2016;

Sex and age-standardized cumulative incidence of

HTN in relation to rs148756340 (a) and

rs11904439 (b) XOR genotypes.

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 ++

Xanthine oxidase as a downstream mediator of oxidative stress, systemic

and vascular activation of the RAS system and CV disease

Arterioscler Thromb Vasc Biol. 2007 Apr;27(4):703-4

R.Magritte:

La reproducion interdite

Serum Uric Acid and LDL-oxidation parameters

Cicero A et al, 2014

LDL lag phase

LDL diene

LDL propagation phase Ox-LDL

Impact of nLDL, oxLDL on AT1 and LOX-1 protein expression

§

* *p<0.05 vs control

§ p<0,05 vs nLDL

Catar RA et al, Horm Metab Res 2007

*

Urate uptake by VSMC

Number of patients with co-morbidities of gout and SUA at

baseline and after 7.6 years of follow-up

Baseline SUA < 6 mg/dL

Baseline SUA ≥ 6 mg/dL

0.001

0.001

0.004

0.10

0.06

0.125

0.250 0.727

Joo K et al, JKMS 2014

Cumulative incidence of CV endpoints by gout status

Krishnan E et al, Arthritis Res Ther 2012

30

Treating Asymptomatic

hyperuricemia today:

How to proceed?

• 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?)

How to approach asymptomatic hyperuricemia:

A purpose

*Adjusted for: Age, smoking, ischaemic heart disease, peripheral vascular disease, cerebrovascular disease,

baseline BP and days between BP measurements,

Whole Group Data 365/6678

Variable Beta 95% CI for Beta P value

Lower limit Upper limit

SBP change in ‘no or continued unchanged’ antihypertensive patients

Allopurinol use -7.424 -10.104 -4.744 0.000

DBP change in ‘no or continued unchanged’ antihypertensive patients

Allopurinol use -5.385 -6.719 -4.050 0.000

SBP change in new antihypertensive patients

Allopurinol use -9.231 -14.880 -3.582 0.001

DBP change in new antihypertensive patients

Allopurinol use -6.708 -9.423 -3.994 0.000

Hypertension. 2014 Nov;64(5):1102-7

MacIsaac RL et al, Hypertension 2016

Risk of CV events Risk of stroke

Effect of Febuxostat on plaque formation in

ApoE-/- atherosclerotic mice

Nomura J et al, Sci Rep, 2014

Xu X et al. J Card Fail. 2008 ; 14(9): 746–753

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

Trial Drug 1° objective Reference

BP control Febuxostat vs.

Allopurinol

Clinic and

ABPM

NCT01701622*

ongoing

Coronary endothelial dysfunction Febuxostat vs.

Placebo

Coronary flow NCT01763996*

completed

BP control Febuxostat vs.

Placebo

ABPM NCT01496469*

completed

Exercise tolerance in chronic angina Febuxostat

vs.Placebo

Exercise test

(ETT)

NCT01549977*

terminated

Vascular structure and function

(FORWARD)

Febuxostat vs.

Allopurinol

Carotido-

Femoral PWV

EUDRACT2014-

5567-33 (enroll.

closed)

New onset MS (FAST) Febuxostat vs.

Placebo

INS-res and

features MS

NCT01654276*

ongoing

*ClinicalTrial.gov

RCT with ULT:

surrogate end-points

RCT with ULT:

Hard CV end-points

Trial Drug 1°

objective

Reference

BP and CV complications (CARES) Febuxostat vs.

Allopurinol

Serious CV

events

NCT01101035*

ongoing

New onset MS (FAST) Febuxostat vs.

Placebo

INS-res and

features MS

NCT01654276*

ongoing

Treatment of CHD (ALL-HEART) Allopurinol vs.

Standard care

MACE EudraCT 2013-

003559-39

ongoing

Cerebrovascular protection (XILO-FIST) Allopurinol

vs.Placebo

White matter

protection

NCT02122718*

Starting

recruitment

Major CV disease (FREED) Febuxostat vs.

Placebo

MACE NCT01984749*

ongoing *ClinicalTrial.gov

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: •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. low-

excretors). •The ultimate efficacy of ULT and the role of different compounds

Serum Uric Acid and CVD:

Evidence and Future targets of research