Improving Cardiovascular Renal outcomes in Gouthyperuricemia What should

Improving Cardiovascular & Renal outcomes in Gout-hyperuricemia: What should we target? 中山醫學大學附設醫院 腎臟科 蔡博宇醫師

Gout-TW-2018013 Elevated Serum Uric Acid Gout Helix of the ear Olecranon bursa Common sites of tophus development 2 Ulnar of the forearm Wrist Finger pads Knee Achilles tendon Images one and three taken from Taylor and Grainger (2012); 3 image two taken from Girish, et al (2013). 4 1. Gutman AB. Arthritis Rheum 1973; 16: 431‒ 45; 2. Terkeltaub R, Edwards NL. Chapter 3. In: Terkeltaub R, Edwards NL (eds). Gout: Diagnosis and Management of Gouty Arthritis and Hyperuricemia (Third edition). Durant: Professional Communications, Inc, 2013; 3. Taylor W, Grainger R. Chapter 9. In: Terkeltaub R (ed). Gout and Other Crystal Arthropathies (First Edition). Philadelphia: Elsevier Saunders, 2012. ; 4. Girish G, et al. Arthritis 2013; 2013: 673401.

Gout-TW-2018013 Gout is very common § § § Prevalence ~3 % Higher in older people Men > women Western countries Increasing frequency Dalbeth. Lancet 2016

Gout-TW-2018013 Is there Cardio-Renal-Metabolic Risk Beyond Gout?

Gout-TW-2018013 Outline 1. Present a hypothesis 2. Discuss the evidence 3. Examine potential treatment strategies 4. Consider threshold targets

Gout-TW-2018013 Why should we consider Uric acid a therapeutic target ? • Biological evidence • Epidemiological evidence • Clinical trial evidence

Gout-TW-2018013 Theoretical Constructs (1) Vascular injury Kidney Injury Uric Acid CV Disease Chronic Kidney Disease (2) Uric Acid Hypertension Diabetes Metabolic Syndrome CV Disease Chronic Kidney Disease

Mechanistic Pathways for Atherosclerosis Jalal D et al. Uric Acid as a Target of Therapy in CKD. Am J Kidney Dis. 2013 January; 61(1): 134 -146.

Gout-TW-2018013 Biological Proof

Gout-TW-2018013 Does Hyperuricaemia cause Hypertension and Kidney Disease ? • Rats do not get gout! • Posess uricase enzyme in cells • Give them oxonic acid: develop elevated uric acid Experiment 1. Does hyperuricaemia elevate BP and cause kidney damage 2. Does control of hyperuricaemia lower BP and prevent kidney damage? 3. Is there a correlation between uric acid and BP? Mazzali M et al. Hypertension. 2001; 38: 1101 -1106

Gout-TW-2018013 Hyperuricaemia causes kidney injury Hyperuricaemia Rat Model • Elevates blood pressure • Induces mesangial expansion • Causes interstitial fibrosis Mazzali M et al. Hypertension. 2001; 38: 1101 -1106

Gout-TW-2018013 Hyperuricemia causes small-vessel disease (A) (B) (C) Hyperuricemia: increase in the afferent arteriolar wall thickness (A) Controls (B) Hyperuricaemia (C) Hyalinosis. Severity of arteriolar thickness correlated (H) systolic blood pressure (I) serum uric acid Marilda Mazzali et al. Am J Physiol Renal Physiol 2002; 282: F 991 -F 997

Gout-TW-2018013 Treatment with Allopurinol Lowers uric acid and Lowers BP Prevent or Correct Hyperuricaemia • Normalise BP • Prevent hypertension • Reduces interstitial fibrosis Mazzali M et al. Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism. Hypertension 2001; 38: 1101 -1106

Gout-TW-2018013 Febuxostat Lowers Uric acid and alleviates systemic hypertension Treatment with Febuxostat • Lowers uric acid • Normalises Blood pressure • Reduces interstitial fibrosis Plasma uric acid and systolic blood pressure in normal (N) and oxonic acid-dosed (OA) rats treated with placebo (P) or febuxostat (Fx). *P < 0. 001 versus Baseline; ° P < 0. 01 versus Week 4. Sanchez-Lozada et al Nephrol Dial Transplant. 2007; 23(4): 1179 -1185.

Gout-TW-2018013 Uric acid induces Arteriolopathy and Hypertension Feig DI et al. Uric Acid and Cardiovascular Risk. N Engl J Med 2008; 359: 1811 -1821, 2008

Gout-TW-2018013 Epidemiological Evidence

Gout-TW-2018013 Rising Burden of CV Risk factors as Uric acid Increases Figure adapted from Zhu Y, et al. (2012) showing the calculated prevalence and population estimates from participants in the NHANES 2007– 2008 (n=5707) of comorbidities in those with and without gout. NHANES=National Health and Nutrition Examination Survey; CKD=chronic kidney disease. Zhu Y, et al. Am J Med 2012; 125: 679– 87.

Gout-TW-2018013 Uric Acid and risk of Hypertension N=18 prospective cohorts N= 55, 607 participants Outcome: BP ≥ 140/90 or ≥ 160/95, by self-report, or use of BP meds Hyperuricaemia > 6. 8 mg/dl RR=1. 41 (1. 23 -1. 58) For a I mg/dl rise RR=1. 13 (1. 06 -1. 20) Grayson PC et al: Hyperuricemia and incident hypertension: A systemic review and meta-analysis. Arthritis Care Res 2011, 63(1): 102– 110.

Gout-TW-2018013 Uric Acid and Risk of Type 2 Diabetes 8 Prospective cohorts N= 32, 016 Incident DM=2, 930 Highest vs Lowest quartile RR=1. 56, 95% CI (1. 39– 1. 76) Per 1 mg/dl RR= 1. 06, 95% CI (1. 04 -1. 07) Lv et al : PLo. S One. 2013; 8(2): e 56864. Feb 20, 2013.

Gout-TW-2018013 Uric Acid and Risk of Kidney Disease 11 Prospective cohorts Incident CKD =GFR< 60 ml/min Per 1 mg/dl uric acid RR= 1. 18, 95% CI (1. 15 -1. 22) Sedaghat S, et al. (2013) PLo. S ONE 8(11)

Gout-TW-2018013 Deaths per 1000 person years Uric Acid and CV Death Rates Uric acid in quartiles (µmol/L) N=15, 773 subjects representative of the US population Stack et al QJM (2013) 106 (7): 647 -658

Gout-TW-2018013 Uric Acid levels in the “normal range”predict CV Death Per 1 mg/dl increase HR Death HR=1. 15 (1. 08 -1. 21) Uric acid in quartiles (µmol/L) **P<0. 001 N=15, 773 subjects representative of the US population Adjusted for Framingham factors, comorbid conditions, BMI, and gout Stack et al QJM (2013) 106 (7): 647 -658

Gout-TW-2018013 Hyperuricemia and risk of Coronary Disease Mortality 26 studies N= 402, 997 adults Hyperuricaemia Men > 5. 6 mg/dl Women > 4. 7 mg/dl RR= 1. 16 (1. 01 -1. 30) Kim et al: Arthritis Care Res. Feb 2010; 62(2): 170– 180.

Gout-TW-2018013 Greated impact of Gout and Uric Acid on CV Mortality (than uric acid alone) Serum ur ic acid ¹Model adjusted for age, gender, hypertension, diabetes, systolic/diastolic BP, cholesterol, Family History MI, CRP, physical inactivity, tobacco use and e. GFR Stack et al QJM (2013) 106 (7): 647 -658

Gout-TW-2018013 Clinical Trial Does Lowering Uric Acid Reduce Risk?

Gout-TW-2018013 ……………more questions 1. Threshold effect ? 2. Dose-response effect?

Gout-TW-2018013 Clinical Trial Methods: • Randomised controlled cross-over trial Population • 30 adolescents (age 11 -17) • Newly diagnosed, never treated hypertension • Uric acid levels > 357 µmol/L Intervention • Allopurinol 200 mg BD for 4 weeks with cross over Outcomes: Changes in BP Feig DI, Effect of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension: JAMA. 2008; 300(8): 924 -932

Gout-TW-2018013 BP Response of Adolescents: Allopurinol v. Placebo Significant BP reduction SBP: - 6. 9 mm. Hg vs 2. 0 mm. Hg DBP: -5. 1 VS -2. 4 mm. Hg Two thirds achieved normal BP while taking allopurinol Feig DI, JAMA. 2008; 300(8): 924 -932.

Gout-TW-2018013 Quasi-experimental

Gout-TW-2018013 Allopurinol linked with lower mortality THIN Database UK Uric acid > 357 men > 416 women Time=2000 -2010 Propensity-Matched Cohort Hyperuricaemia: HR 0. 89 (0. 80 -0. 99) 5, 927 cases 5, 927 controls F/up: 2. 9 years Exposure: allopurinol use Gout: HR 0. 81 (0. 70 -0. 92) Dubreuil M et al. Ann Rheum Dis 2014

Gout-TW-2018013 Impact of Allopurinol dose on Cardiovascular Events Higher does of Allopurinol associated with lower Cohort study event rates MEMO database Scotland 95% CI HR 95% CI F/up: 2007 1 – 0. 94 0. 67– 1. 33 1. 01 0. 70– 1. 45 Uric acid measured 0. 66 0. 51– 0. 86** 0. 69 0. 50– 0. 94** between 2000 -2002 Compare allopurinol by dose 1 95% CI 0. 92 0. 70– 1. 21 0. 63 0. 52– 0. 77** 0. 75 0. 59– 0. 94* Univariate HR Cardiovascular outcome d l o h es 100 mg 200 mg ≥ 300 mg r Th All-cause mortality 100 mg 200 mg ≥ 300 mg t c e f f E Multivariate† Allopurinol daily dose N=7, 135 patients Wei et al: Br J Clin Pharmacol: 2011; 71(4): 600 -607.

Gout-TW-2018013 Cohort study • N=5, 090 CKD patients • 2003 to 2015 • Exposures Baseline serum uric acid Trajectory of uric acid (Serial measures of uric acid) • Outcomes: ESKD, death Tsai et al Nephrol Dial Transplant. 2017; 33(2): 231 -241

Gout-TW-2018013 Median Uric acid values for each Trajectory High: 9. 8 mg/dl Moderate-high 8. 4 mg/dl Moderate 7. 1 mg/dl Low 5. 6 mg/dl Tsai et al Nephrol Dial Transplant. 2017; 33(2): 231 -241

Gout-TW-2018013 Uric Acid and Risk of Dialysis and Death Trajectory Group Low Hazard Ratio ESKD 1. 00 Moderate 1. 89 (1. 37 -2. 60) Moderate-High 2. 49 (1. 75 -3. 55) High 2. 84 (1. 81 -4. 47) Tsai et al Nephrol Dial Transplant. 2017; 33(2): 231 -241

Gout-TW-2018013 Uric Acid Trajectory and Risk of Dialysis and Death Tsai et al Nephrol Dial Transplant. 2017; 33(2): 231 -241

Gout-TW-2018013 Urate Lowering Therapy Reduces Risk of Dialysis E ld o h s e r h T t c e f f Tsai et al Nephrol Dial Transplant. 2017; 33(2): 231 -241.

Gout-TW-2018013 Does Urate-Lowering Therapy protect Kidney Function? Methods: • Single center randomised clinical trial Population • N=113 adults • Chronic Kidney disease (stable mean GFR 40 ml/min) Intervention • Allopurinol 100 mg OD versus placebo • Follow-up 6, 12, 24 months Outcomes: Kidney disease progression (GFR) CV events & hospitalization Goicoechea et al: CJASN 2010

Gout-TW-2018013 Allopurinol prevents decline in Kidney Function Change in e. GFR Change in Uric acid § § Allopurinol Group Control Group Rise in GFR by + 1. 3 ml/min Fall in GFR by - 3. 3 ml/min RCT N=113 Average e. GFR 40 ml/min Follow-up 24 months Goicoechea et al: CJASN 2010

Gout-TW-2018013 Does Febuxostat protect Kidney Function? Methods: • Single center double blind randomised trial Population • N=93 adults (from 130 screened) • Age 18 -65 years with uric acid > 7 mg/dl • Stable e. GFR 15 -60 ml/min • Feb 2012 to July 2013 Intervention • Febuxostat 40 mg OD X 6 months versus placebo • Follow-up 6, 12, 24 months Outcomes: % Patients with > 10% decline in GFR from baseline Mean change in GFR Sircar et al: AJKD: 2015

Gout-TW-2018013 Febuxostat protects kidney function after 6 months e. GFR Febuxostat Placebo Diff (95% CI) Between. Group P Baseline 31. 5 ± 13. 6 32. 6 ± 11. 6 − 1. 1 (− 6. 4 to 4. 1) 0. 7 Month 3 33. 7 ± 16. 6 30. 0 ± 9. 4 3. 7 (− 1. 9 to 9. 2) 0. 2 Month 6 34. 7 ± 18. 1 28. 2 ± 11. 5 6. 5 (0. 08 to 12. 8) 0. 05 P-value 0. 3 0. 003 38% 54% Decline GFR > 10% of baseline P=0. 004 [Changes in Kidney Function at Baseline, 3 Months, and 6 Months] Sircar et al: AJKD: 2015

Gout-TW-2018013 Urate Lowering Therapy reduces risk of major Kidney Events § 16 Trials in total § 10 RCT trials were identified which reported Kidney failure events § n=706 patients with CKD, § Outcome: Major Kidney events ULT reduced major Kidney events RR= 0. 45, 95% CI (0. 31 -0. 64) Su X, Xu B, Yan B, Qiao X, Wang L (2017) PLOS ONE 12(11)

Gout-TW-2018013 ULT reduced GFR decline by 4. 1 ml/min/1. 73 m² per year § 8 RCT trials were identified which measured changes in e. GFR § n=669 patients § Outcome: Change in e. GFR per year ULT reduced annual e. GFR decline by 4. 10 ml/min/1. 73 m² (95% CI- 1. 86 -6. 35) Su X, Xu B, Yan B, Qiao X, Wang L (2017) PLOS ONE 12(11)

Gout-TW-2018013 Reduction in Uric acid corelates with better e. GFR • • Systematic review and metaanalysis: 8 Clinical Trials 319 intervention, 323 controls Outcome: Change in e. GFR ml/min/1. 73 m² Benefit of 3 ml/min/1. 73 m 2 for ULT compared with controls Erlandsson et al, ASN 2017, New Orleans, USA

Gout-TW-2018013 Allopurinol use and New-onset Kidney Failure Methods: • Retrospective cohort 2006 -2012 • 5% Medicare claims files Population • Age > 65 • N=30, 022 allopurinol treatment episodes from 3, 2 million patients • Excluded patients with kidney failure • Intervention • Dose and duration of allopurinol with risk of kidney failure • Follow-up December 2012 Outcomes: Kidney Failure (from medical codes) Singh et al: Ann Rheum Dis 2017

Gout-TW-2018013 Allopurinol use: lower risk of Kidney Failure Risk of Kidney Failure 1. 20 1. 00 Referent 1. 00 0. 81 ** 0. 80 0. 60 0. 40 0. 71 ** Dose Effect! 1 -199 200 -299 >300 Allopurinol dose (mg) Singh et al: Ann Rheum Dis 2017

Gout-TW-2018013

Gout-TW-2018013 Febuxostat and Benzbromarone reduced progression of CKD in patients who reached target (7 mg/dl) E ld o h es r Th t c e f f Chou et al: Nephrol Dial Transplant 1 -8 2017

Gout-TW-2018013 ULT and Prevention of Kidney Disease Progression Study population and Design Kaiser Permanente, Cohort enrolment period: January 1, 2002 December 31, 2010 Patients ≥ 18 years with serum Uric Acid (s. UA) ≥ 7 mg/dl enrolled Study follow up period: Index Date + 3 months to 36 months End of study: December 31, 2011 N=16, 196 Levy GD, J Rheumatol. 2014 May; 41(5): 955 -62.

Gout-TW-2018013 Uric acid < 360 µmol/L: lower rates of Progression Treatment Strategy UA at Goal vs Not at Goal HR (95% CI) P-value 0. 63 0. 5 -0. 78 <0. 0001 t c e f f E d l o h s e r Th Target Uric Acid of 360 µmol/L 37% reduction in progression of renal disease. Levy GD, J Rheumatol. 2014 May; 41(5): 955 -62.

Gout-TW-2018013 Does Gout Control Reduce Risk of Kidney Failure?

Gout-TW-2018013 Patients with Gout have many CKD risk factors (2) Gout (2) Medical Conditions • Hypertension • Diabetes Mellitus • Myocardial infarction • Heart failure • Stroke Lifestyle Factors • Obesity • Smoking • Alcohol Medications • NSAIDS • ACE • ARB Chronic Kidney Disease Stack et al (2015) Current Medical Research and Opinion, 31: sup 2, 21 -26