Gout and Hyperuricemia Prevention of Arthritis, Renal Disease

and Adverse CV Outcomes Kenneth G. Saag, MD MSc

Jane Knight Lowe Professor of Medicine Division of Clinical Immunology and Rheumatology

Director, UAB CERTs, Center for Outcomes, Effectiveness Research & Education and Center for Research Translation (CORT) in Gout

THE UNIVERSITY OF ALABAMA AT BIRMINGHAM

Overview

•  Gout associated comorbities •  Towards designing a prevention

study in hyperuricemia •  Example study design: Preventing

hypertension by lowering serum urate

Incidence of Gout Based on Urate Levels

1.  Campion EW, et al. Am J Med. 1987;82:421–426

§  In a study of men with hyperuricemia, 22% with serum urate levels >9 mg/dL developed gouty arthritis over 5 years1

0

10

20

30

0 1 2 3 4 5

Cum

ulat

ive

Inci

denc

e (%

)

Years

URATE n <7.0 5249 7.0 – 8.9 1642 ≥ 9.0 141

Comorbidities Associated with Hyperuricemia

•  Obesity1,2

•  Metabolic syndrome3, 4 •  Diabetes mellitus5

•  Heart failure6 •  Hyperlipidemia1

•  Hypertension7,8

1. Nakanish et al Int J Epi 1999;28:888 2. Denzer et al J Ped Endo Met 2003;16:1225 3. Ford ES et al JAMA. 2002;287:356 4. Choi HK et al Arth Rheum 2007;57:109 5. Boyko et al Diabetes Care 2000;23:1242

5. Anker SD et al Circulation 2003;107:1991 6. Gavin et al Am J Cardiovasc Dis 2003;3:309 7. Feig DI et al Hypertension. 2003;42:247

•  Gout associated with the Metabolic Syndrome •  Insulin resistance promotes increased renal urate reabsorption •  Metabolic Syndrome associated with other factors that increase

serum urate (hypertension, obesity)

Gout and The Metabolic Syndrome Cause or Effect?

Luk et al, Am J Manag Care 2005; 11: S435–42 Baker et al, Am J Med 2005; 118: 816–26

Metabolic Syndrome

Hyperuricemia and gout

§ 76% gout patients have Metabolic Syndrome in the US

§ Co-morbidities: •  central obesity; Ó BMI • Ó TG and Ô HDL • Ó BP •  hypertension

(≥130/88mmHg) •  insulin resistance •  glucose intolerance

A Model of Mild Hyperuricemia

Normal rat sUA (0.5 - 1.4 mg/dL)

Hyperuricemic rat sUA (1.7- 3.0 mg/dL)

Uricase inhibitor

Oxonic acid (OA)

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

Hyperuricemia and Hypertension A Potential Explanation of Association

•  Rats were divided into three groups

•  2% oxonic acid induced hyperuricemia •  At week 5, micropuncture procedures were

performed

Sanchez-Lozada Am J Physiol Renal Physiol. 2002;283:F1105.

Control Group OA/LS Group OA/LS/AP Group Low sodium diet (LS)

Low sodium diet (LS) Oxonic acid (OA)

Low sodium diet (LS) Oxonic acid (OA) Allopurinol (AP)

Hyperuricemia and Hypertension A Potential Explanation of Association

(cont’d) •  Effects on the afferent arteriole after 5 weeks

•  Proposed mechanism –  May occur due to a defect in renal uric acid clearance –  Association to glomerular hypertension may be caused by

afferent arteriole thickening ♦  Suggestive of hypertrophic vascular remodeling

Control group OA/LS Group OA/LS/AP Group

Uncontrolled hyperuricemia: Arteriole thicker, Lumen smaller

Controlled hyperuricemia: Arteriole thinner,

Lumen larger

Sanchez-Lozada Am J Physiol Renal Physiol. 2002;283:F1105.

Year 0 Year 5 Year 10 Year 15 Year 20 HTN (%) 0 5.1 11.7 20.7 28.5

n 2224 1992 1717 1509 1181

Gaffo A. Ann Rheum Dis. 2012

10 Uric Acid–Lowering Treatment Effects Blood Pressure

Randomized, Double-Blind, Placebo-Controlled, Crossover Trial

Outcome Measured Placebo Allopurinol P value Systolic BP load (%) 48.6 (34.0 to

50.2) 23.3 (15.8 to

30.9) 0.01

Diastolic BP load (%) 29.2 (25.6 to 37.1)

18.1 (12.3 to 23.8) 0.01

Hypertensive, No./total (%) 29/30 (97) 10/30 (33) 0.001

•  30 asymptomatic adolescents with high SUA levels (≥ 6.0 mg/dL) and newly diagnosed mild essential hypertension

•  Allopurinol 200 mg BID for 4 weeks, 2-week washout, and placebo BID for 4 weeks

Feig DI, et al. JAMA. 2008;300:924-932.

Blood pressure (BP) load: (as measured by ambulatory BP) is the percentage of time during the study that BP exceeds the 95th percentile

11 Uric Acid–Lowering Treatment Effects Blood Pressure

Randomized, Double-Blind, Placebo-Controlled, Crossover Trial

•  30 asymptomatic adolescents with high SUA levels (≥ 6.0 mg/dL) and newly diagnosed mild essential hypertension

•  Allopurinol 200 mg BID for 4 weeks, 2-week washout, and placebo BID for 4 weeks

Feig DI, et al. JAMA. 2008;300:924-932.

Is it possible to prevent/postpone the onset of hypertension by reducing SUA levels?

Potential Associations with Hyperuricemia Cardiovascular Events and Mortality

Hyperuricemia ↑ development of cardiovascular disease, ischemic heart disease, and/or coronary heart disease Hyperuricemia ↑ risk of Cardiovascular events Hyperuricemia ↑ mortality from coronary heart disease, ischemic heart disease, and overall mortality

ü  Breckenridge et al. (Lancet, 1966) ü Santos et al (Am J Cardiol, 2007)

ü  SHEP (J Hypertens, 2000)

ü  Worksite Treatment Program (J Hypertens, 1998) ü  PIUMA (Hypertension, 2000) ü  LIFE 2003 (Kidney Int, 2000) ü  Darmawan et al. (J of Rheum, 2003) ü  Lehto et al. (Stroke, 1998)

ü  NHANES (JAMA, 2002) ü  Bickel et al. (Am J Cardiol, 2002) ü  Darmawan et al. (J of Rheum, 2003)

Finding Supportive Studies

13

Hyperuricemia: A Risk Factor for Stroke?

1Kim SY, et al. ACR Meeting 2008. Poster 1364. 2Gagliardi ACM, et al. Atherosclerosis. 2009;202:11-17. 3Dimitroula HV, et al. Neurologist. 2008;14:238-242.

Hyperuricemia appears to be an independent risk factor for stroke events1-3

Hyperuricemia and Stroke Mortality1

Study ID

Not adjusted Tofuku 1976 Takagi 1982 Kagan 1985 Baba 2007 Subtotal

Adjusted for other risk factors Lehto 1998 Chien 2005 Bos 2006 Hozawa 2006 Subtotal

Overall

Risk Ratio (95% CI)

Hyperuricemia and Stroke Incidence1

Normouricemia Hyperuricemia 0 1 3

•

• • • •

x

• Adjusted for other risk factors Sakata 2001 Mazza 2002 Jee 2004 Gerber 2006 Subtotal

Not adjusted Tofuku 1978 Tomita 2000 Bae 2007 Subtotal

Overall

Risk Ratio (95% CI) Study ID

Normouricemia Hyperuricemia 0 1 3

x

• • • •

Renal Disorders Linked to Hyperuricemia Renal Insufficiency

Manifestation Data Changes in renal function (eg, diminished GFR)

Occur in 30%-60% of gout patients1

Renal insufficiency sUA >8.0 mg/dL independently increased risk of developing renal insufficiency within 2 years (3-fold in men; 10-fold in women)2

Renal failure sUA >8.5 mg/dL associated with 8-fold increased risk of renal failure (P<.01)3

ESRD developed in 25% of gout patients prior to the availability of urate-lowering drugs4

1. Talbott et al. Medicine. 1960;39:405-467. 2.  Iseki et al. Hypertens Res. 2001;24:691-697. 3. Mazzali et al. Hypertension. 2001;38:1101-1106. 4. Kang et al. Semin Nephrol. 2005;25:43-49. 5. Kang et al. J Am Soc Nephrol. 2002;13:288-297.

~60% of patients with gout are found to have renal dysfunction5

Serum Urate Predicts ESRD After 7 Years

Urate independent of proteinuria, age,

creatinine, BMI, lipids, and blood

pressure

Iseki et al. Am J Kid Dis. 2004;44:642

10 9 8 7 6

5

4

3

2

1

0

10 9 8 7 6

5

4

3

2

1

0 <7.0 ≥7.0

15617 7332

19 34 19 31

21795 3433

<6.0 ≥6.0

Women Men

Cum

ulat

ive

inci

denc

e of

ESR

D

per 1

000

scre

enee

s

Serum urate mg/dL

Number of screenees

Number of ESRD

Renal Disorders Linked to Hyperuricemia Urate (or Gouty) Nephropathy Theory

• Sustained hyperuricemia causes interstitial urate crystal deposition1 – Inflammation, fibrosis, and

renal insufficiency follow

• At autopsy, 79%-99% of gout patients had urate nephropathy

2,3

Urate nephropathy caused tophaceous deposits in this medulla

1. Beck et al. Kidney Int. 1986;30:280-287. 2. Kang et al. Semin Nephrol. 2005;25:43-49. 3. Tarng et al. Am J Nephrol. 1995;15:31-37.

What Are the Questions? What are the Interventions?

•  Can reduction in SUA lead to primary or secondary prevention of: –  Hypertension –  Atherosclerotic vascular disesae –  Renal disease

•  Potential interventions –  Xanthine oxidase inhibitors –  Uricosurics –  Diet and dietary supplements –  Weight loss –  Other CVD risk factor modification

What are the Populations of Interest?

•  Persons with: – Gouty arthritis – Hypertension – CVD or other CVD risk factors – CKD or other CKD risk factors – Varying combinations

•  General population with hyperuricemia

Effects of Urate Lowering Therapy on Inflammation,

Endothelial Function, and Blood Pressure

UAB Center of Research Translation (CORT) in Gout and Hyperuricemia

Grant # P50AR060772

Urate Lowering Effects on Hypertension Study Team

UAB Investigators Role Kenneth G. Saag, MD, MSc Principal Investigator

David Calhoun, MD Co-Principal Investigator Angelo Gaffo, MD, MSPH Lead Investigator Tanja Dudenbostel, MD Investigator Suzanne Oparil, MD Investigator David Redden, PhD Investigator, Statistician

Paul Muntner, PhD Investigator

Dan Feig, MD Investigator Jose Leon de la Rocha, MD Research Associate Sebastian Sattui, MD Research Associate Kerry Renfroe, RN Study Coordinator

Randall Parks, RN Program Director

Jeff Foster, MPH Program Manager

Urate Lowering Effects on Hypertension Specific Aims

To determine in young adults with pre or stage 1 hypertension whether urate lowering therapy (ULT) with allopurinol will: •  Lower blood pressure (BP)

–  Four weeks of ULT therapy will induce a greater reduction in ambulatory blood pressure levels when compared to four weeks on placebo

–  ULT will induce a greater reduction in ambulatory blood pressure levels in African Americans when compared with other races/ethnicities

Urate Lowering Effects on Hypertension Specific Aims (cont’d)

•  Reduce serum levels of high sensitivity C-reactive protein (hsCRP) –  Four weeks of ULT will induce a greater reduction in serum

levels of high sensitivity C-reactive protein (hsCRP) than placebo

–  ULT will induce a greater reduction in hsCRP in African Americans when compared with other races/ethnicities

•  Improve endothelial function –  ULT will induce a greater reduction in hsCRP in African

Americans when compared with other races/ethnicities

–  ULT will induce a greater increase in FMD in African Americans when compared with other races/ethnicities

Urate Lowering Effects on Hypertension Intervention and Outcomes

•  Intervention: allopurinol (300mg/d) or placebo in four-week study with crossover

•  Outcomes of interest –  Serum urate –  CRP/hsCRP –  Endothelial function as measured by flow mediated dilation (FMD) –  24 hr Ambulatory BP

Screening    

(wks  0)  

First  phase  of  crossover    (wks  3-­‐6)  

Washout  period    

(wks  7-­‐10)  

Second  phase  of  cross-­‐over    (wks  11-­‐14)  

No  intervenAon  

Allopurinol  

Placebo   Allopurinol  

Placebo  

Placebo  Run-­‐In  

(wks  1-­‐2)      No  

intervenAon  No  

intervenAonCrossover    

Urate Lowering Effects on Hypertension Safety Monitoring

• Risk for allopurinol hypersensitivity (.69 per

1000 person years)

• Rate of AHS in younger ambulatory patients with normal kidney function not established

•  Screening for HLAB5801 gene in individuals of Han Chinese/Thai descent

1. Kim SC, et al. Severe Cutaneous Reactions Requiring Hospitalization in Allopurinol Initiators: A Population Based Cohort Study. Arthritis Care & Research Vol. 65, No.4, April 2013, pp 578–584

Acknowledgements U Nebraska •  Ted Mikuls MD MSPH UAB •  Jeroan Allison, MD MS •  Jeffrey Curtis, MD MPH •  Mary Elkins •  Angelo Gaffo, MD, MSPH •  Pauline Jolly, PhD, MPH •  Beth Lewis MD, MSPH •  Ryan Outman, MS •  Jeffrey Rosman, PhD •  Jasvinder Singh, MD, MPH •  Gim Gee Teng, MD U Penn CERTs •  Warren Bilker, PhD •  John Farrar, MD MSPH •  Shawn Fernandez •  Brian Strom, MD, MPH HMO Research Network CERTs •  Leslie Harrold, MD MPH •  Arnold Chan, PhD •  Richard Platt, MD MPH •  Robert Yood, MD

Grant U18 HS 10389

United States Pharmacopeia •  Rodney Hicks, PhD, ARNP U Minn •  David Jacobs, PhD