HYPERURICEMIA AND ITS IMPLICATIONS

Benjamin Wang, M.D., FRCPC

Division of Rheumatology

Mayo Clinic

Jacksonville, FL

Disclosures

• None

Topics

• Hyperuricemia defined

• Consequences of hyperuricemia

• New data in gout

• Hypertension, cardiovascular disease, and renal failure

• Interventions and outcomes

Hyperuricemia • Uric acid concentrations in serum

• in people consuming traditional non-Western diets, is 2 to 4

mg/dL (120-240 μM).

• in industrialized populations, is 3-8 mg/dL (180-480 μM)

• diets richer in purines and fructose (both of which generate

urate)

• greater alcohol intake

• Higher prevalence of factors that reduce kidney urate

excretion (eg, insulin resistance, renal vasoconstriction

associated with hypertension, and decreased kidney function)

• interpopulation genetic differences

• in most non-primate mammals, serum urate concentrations are

low (1-3 mg/dL [60-180 μM]) due to the enzyme uricase

• humans lack uricase

Hyperuricemia

• Sustained hyperuricemia (≥7 mg/dL in men, ≥6 mg/dL in

women) is associated with tissue deposition of uric acid

and metabolic effects

• Hyperuricemia is most often familial, involving

polymorphisms is renal urate transport proteins

Complications of Hyperuricemia

• Confirmed

• Gout

• Nephrolithiasis

• Emerging Data

• Hypertension

• Cardiovascular disease

• Metabolic syndrome

• Still Controversial: Dementia

Case

• 70 year old Caucasian male – Consultation for sustained hyperuricemia

• First STEMI at age 54; three subsequent MIs; 3-vessel CABG at age 57

• Since then 15 coronary stenting procedures

• Currently asymptomatic, exercising

• Serum urate over last two years 8.2, 9.0, 8.8 mg/dL

• Recalls having 2 attacks of gout, last one15 years ago, classic podagra and instep of right foot; none since then

• BP 136/84; no tophi

• Labs: CBC and diff normal; Cr 1.3; Chol (total) 223, LDL 130, HDL 38, TG 230; hsCRP 22; HbA1c 6.3%; ESR 8 mm/h; RF, ANA negative

• Is there a reason to treat his elevated uric acid level?

Gout

• A disease of chronic urate accumulation; hence treatment

should result in gradual urate elimination

• Gout prevalence increasing worldwide

• Diagnostic modalities

• Treat-to-Target guidelines (American College of

Rheumatology) vs. don’t treat to target (ACP)

• Linisurad in combination with allopurinol

• Biologic therapy in gout

Dual-energy CT (DECT) for urate deposition

Gout is a disease of urate accumulation

• Uric acid will begin to precipitate

at a concentration of 6 mg/dL in

water at 37°C and pH 7.4

• Lowering concentration leads to

dissolution of crystals and

decreased tissue burden of

urate

• This is the basis of the treat-to-

target goal of serum urate

concentration [sUA] of 6.0

mg/dL, or ≤5.0 mg/dL in

tophaceous disease (Neogi 2015;

Richette 2016; Becker MA 2008)

Chronic urate-lowering treatment

• Allopurinol

• Begin at 100 mg/d in order to minimize chance of “initiation flare”

• Titrate upwards in 100 mg increments q6wk to reach target [sUA]

• Maximum daily dose 800 mg/d – frequently underdosed

• Hypersensitivity reactions very rare, but inform patient

• Higher risk of sensitivity reactions in CKD not confirmed

• Febuxostat (Uloric®)

• Start at 40 mg/d, increase to 80 mg/d

• Some increased CV risk? (White 2018)

• Probenecid – weak uricosuric; cannot use in GFR < 35

• Lesinurad (Zurampic®) – new uricosuric drug

Lesinurad inhibits URAT1 transporter

Reginato AM. Nat Rev Rheum 2012; 8(10):610-21.

Lesinurad in allopurinol nonresponders

Saag K et al. Arthritis Rheum 2017: 69(1):203–212.

n=603

Biologic therapy in gout

• Treating acute inflammation: IL-1 inhibitors (not FDA

approved)

• Anakinra

• Canakinumab

• Treating urate accumulation (severe tophaceous disease)

• pegloticase (Krystexxa®)

• rasburicase (Elitek®)

Hyperuricemia and hypertension: physiologic

mechanisms

Johnson RJ et al. Am J Kidney Dis. 2018:1-15. Published online.

Meta-analysis

demonstrates the

association of

hyperuricemia and

hypertension in

men and women

Random-effects analysis

of sex-specific adjusted

risk ratios of

hyperuricemia

associated with incident

hypertension.

95% CI =95%

confidence interval.

Grayson PC, Kim SY, LaValley M, Choi HK. Arthritis Care Res (Hoboken). 2011;63(1):102-110.

Epidemiologic data support an independent effect of

hyperuricemia on hypertension

Feig DI, et al. J Pediatr. 2013;162(5):896-902.

Effect of allopurinol treatment on BP in hypertensive

adolescents (crossover RCT)

Feig DI, Soletsky B, Johnson RJ.JAMA. 2008;300(8):924-932.

Allopurinol decreases SBP and carotid intimal

thickness in post-stroke prehypertensive patients

Higgins P et al. Heart 2014;100(14):1085-1092.

Hyperuricemia and Cardiovascular Outcomes – Select

Observations

• Coronary heart disease is more severe in hyperuricemic patients with

asymptomatic urate crystal deposition than normouricemic or hyperuricemic

patients without crystal deposits, which suggests a vascular deleterious effect of

monosodium urate crystals (Andres M et al. Arthritis Rheumatol 2016;68:1531-9)

• High-dose allopurinol (600 mg/day) led to regression of left ventricular mass in 66

patients with ischaemic heart disease (Rekhraj Set al. J Am Coll Cardiol 2013;61:926) and

enhanced exercise capacity in patients with chronic stable angina (Norman A. Lancet

2010;375:2161).

• Reduced risk of myocardial infarction in those receiving allopurinol (Larsen KS. Am J

Med 2016;129:299; de Abajo FJ. Heart 2015;101:679)

• Large epidemiological studies found that allopurinol decreased morbidity and

mortality rates in patients with congestive heart failure and a history of gout (Higgins

P. Cardiovasc Ther 2012;30:217)

• In one RCT, patients (n = 253) with symptomatic HF and hyperuricaemia [serum

uric acid (sUA) level 59.5 mg/dl] were randomized to receive allopurinol (600

mg/day) or a placebo (Givertz MM et al. Circulation 2015;131:1763).

• The primary composite endpoint at 24 weeks was based on survival, worsening

HF and patient global assessment. At 24 weeks, clinical status did not differ

between the allopurinol- and placebo-treated patients

Elevated serum urate contributes to conventional cardiac risk

factors to develop moderate coronary calcification

J.E. Jun, et al. Atherosclerosis (2018), https://doi.org/10.1016/j.atherosclerosis.2018.02.014

• CARES (Cardiovascular Safety of Febuxostat or

Allopurinol in Patients with Gout and Cardiovascular

Disease)

• Prospective, double-blind, 320-center North American

clinical trial

• 6,190 patients were randomized to febuxostat (Uloric) at

40-80 mg once daily or 200-600 mg of allopurinol once

daily.

• Primary endpoint : composite of cardiovascular death, MI,

stroke, and unstable angina resulting in urgent

revascularization

Febuxostat and increased cardiovascular mortality: the

CARES Study

White W et al. N Engl J Med. 2018 Mar 12. doi: 10.1056/NEJMoa1710895

Febuxostat and increased cardiovascular mortality: the

CARES Study

White W et al. N Engl J Med. 2018 Mar 12. doi: 10.1056/NEJMoa1710895

Febuxostat and increased cardiovascular mortality: the

CARES Study

White W et al. N Engl J Med. 2018 Mar 12. doi: 10.1056/NEJMoa1710895

• Because of the high lost-to-follow-up rate, a private

investigator was hired to look for missed deaths among

study subjects. An extra 199 deaths were found. When

those were added to the total, all-cause mortality in the

febuxostat group was no longer significantly higher than

allopurinol.

• Nonfatal MI, nonfatal stroke, and urgent revascularization

due to unstable angina – were neutral or were less

common with febuxostat.

Febuxostat and increased cardiovascular mortality: the

CARES Study

White W et al. N Engl J Med. 2018 Mar 12. doi: 10.1056/NEJMoa1710895

Lowering Uric Acid With Allopurinol Improves Insulin Resistance and

Systemic Inflammation in Asymptomatic Hyperuricemia

• Allopurinol 300 mg/d for three

months (n=43) vs. placebo (n=33)

• Allopurinol-treated subjects showed

• reduction in serum uric acid

• Improved fasting glucose

• Improved fasting insulin

• Improved HOMA-IR index

• Reduction in high-sensitivity

C-reactive protein

• The number of subjects with

impaired fasting glucose

significantly decreased in the

allopurinol group at 3 months

compared with baseline (n=8 [20%]

vs n=30 [75%], 3 months vs

baseline, P < 0.001).

Takir M, Kostek O, Ozkok A, et al. J Investig Med.

2015;63(8):924-929.

Allopurinol stabilzes metabolic syndrome: a 3-year

controlled trial in patients with T2DM (n=176)

• Intervention: allopurinol adjusted

to maintain [sUA] below 6.0

mg/dL vs. placebo

• Usual antihypertensives (except

losartan) and oral hypoglycemics

maintained

• The allopurinol-treated

group

• Lower SBP and DBP

• Less worsening of

HOMA-IR and serum

triglyceride concentration

• Lower albuminuria

• Higher eGFR

• Less new-onset diabetic

nephropathy (defined as urine

albumin excretion >

200μg/min (4.9% vs 10%)

Liu P et al. Clinical Endo 2015; 83:475-482

Summary

• Hyperuricemia has wide ranging inflammatory and

metabolic effects, with implications in arthritic,

cardiovascular, and metabolic disease

• Available evidence suggests that intervention with urate-

lowering drugs has positive benefits in the above domains

• Larger clinical trials and observational studies will be

needed to confirm these benefits

• Febuxostat may have an independent, increased risk of

cardiovascular disease compared to allopurinol

Conclusion of the case

• What would you do?

• My considerations

• High risk for adverse cardiovascular outcomes

• He’s had gout in the remote past, indicating some urate deposition

• I’m pretty comfortable managing urate-lowering drugs

• If he has a gout attack, he gets urate lowering drugs immediately

• My leanings

• I would probably treat his elevated uric acid level

• I would probably stay away from febuxostat

wang.benjamin@mayo.edu

Thank you