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 ...
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 30
Cumulative Incidence (%)
URATE n 9 mg/dL developed gouty arthritis over 5 years1 1. Campion EW, et al. Am J Med. 1987;82:421–426
Comorbidities Associated with Hyperuricemia •
• Heart failure6
Obesity1,2
• Metabolic syndrome3, 4 • Diabetes mellitus5
• 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 and The Metabolic Syndrome Cause or Effect? § 76% gout patients have
Metabolic Syndrome
Metabolic Syndrome in the US § Co-morbidities: • central obesity; Ó BMI • Ó TG and Ô HDL • Ó BP • hypertension
Hyperuricemia and gout
(≥130/88mmHg) • insulin resistance • glucose intolerance
• 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) Luk et al, Am J Manag Care 2005; 11: S435–42 Baker et al, Am J Med 2005; 118: 816–26
A Model of Mild Hyperuricemia
Uricase inhibitor Oxonic acid (OA)
Normal rat
Hyperuricemic rat
sUA (0.5 - 1.4 mg/dL)
sUA (1.7- 3.0 mg/dL)
Mazzali et al. Hypertension. 2001;38:1101-1106.
Hyperuricemia and Hypertension A Potential Explanation of Association • Rats were divided into three groups Control Group Low sodium diet (LS)
OA/LS Group Low sodium diet (LS) Oxonic acid (OA)
OA/LS/AP Group Low sodium diet (LS) Oxonic acid (OA) Allopurinol (AP)
• 2% oxonic acid induced hyperuricemia • At week 5, micropuncture procedures were performed Sanchez-Lozada Am J Physiol Renal Physiol. 2002;283:F1105.
Hyperuricemia and Hypertension A Potential Explanation of Association (cont’d) • Effects on the afferent arteriole after 5 weeks
Control group
Uncontrolled hyperuricemia: Arteriole thicker, Lumen smaller
Controlled hyperuricemia: Arteriole thinner, Lumen larger
OA/LS Group
OA/LS/AP Group
• 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 Sanchez-Lozada Am J Physiol Renal Physiol. 2002;283:F1105.
Gaffo A. Ann Rheum Dis. 2012
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
Uric Acid–Lowering Treatment Effects Blood Pressure
10
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 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
29/30 (97)
10/30 (33)
0.001
Hypertensive, No./total (%)
Blood pressure (BP) load: (as measured by ambulatory BP) is the percentage of time during the study that BP exceeds the 95th percentile
Feig DI, et al. JAMA. 2008;300:924-932.
Uric Acid–Lowering Treatment Effects Blood Pressure
11
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
Is it possible to prevent/postpone the onset of hypertension by reducing SUA levels? Feig DI, et al. JAMA. 2008;300:924-932.
Potential Associations with Hyperuricemia Cardiovascular Events and Mortality Finding
Supportive Studies
Hyperuricemia ↑ development of cardiovascular disease, ischemic heart disease, and/or coronary heart disease
ü Breckenridge et al. (Lancet, 1966) ü Santos et al (Am J Cardiol, 2007)
Hyperuricemia ↑ risk of Cardiovascular events
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)
Hyperuricemia ↑ mortality from coronary heart disease, ischemic heart disease, and overall mortality
ü NHANES (JAMA, 2002) ü Bickel et al. (Am J Cardiol, 2002) ü Darmawan et al. (J of Rheum, 2003)
13
Hyperuricemia: A Risk Factor for Stroke? Hyperuricemia and Stroke Incidence1 Study ID
Hyperuricemia and Stroke Mortality1 Study ID
Risk Ratio (95% CI)
Not adjusted Tofuku 1976 Takagi 1982 Kagan 1985 Baba 2007 Subtotal
Not adjusted Tofuku 1978 Tomita 2000 Bae 2007 Subtotal
x
•
Adjusted for other risk factors Lehto 1998 Chien 2005 Bos 2006 Hozawa 2006 Subtotal
• ••
Risk Ratio (95% CI)
x
Adjusted for other risk factors Sakata 2001 Mazza 2002 Jee 2004 Gerber 2006 Subtotal
•
•
•
Overall
•• •
Overall
0 1 Normouricemia
3 Hyperuricemia
0 1 Normouricemia
3 Hyperuricemia
Hyperuricemia appears to be an independent risk factor for stroke events1-3 2Gagliardi
1Kim SY, et al. ACR Meeting 2008. Poster 1364. ACM, et al. Atherosclerosis. 2009;202:11-17. 3Dimitroula HV, et al. Neurologist. 2008;14:238-242.
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
