Iperuricemia con deposito di urato: nuovi approcci terapeutici Enzo Manzato Uricemia ≤ 5,1 mg/dl Uricemia > 5,1 mg/dl HR = 1,30 (IC 95% 1,13-1,51) anni n = 2.910; follow-up 4,4 anni Diabetes Care 32, 153, 2009 sopravvivenza cumulata Uricemia ≤ 5,1 mg/dl Uricemia > 5,1 mg/dl HR = 1,30 (IC 95% 1,13-1,51) anni n = 2.910; follow-up 4,4 anni Diabetes Care 32, 153, 2009 sopravvivenza cumulata Uricemia ≤ 5,1 mg/dl Uricemia > 5,1 mg/dl HR = 1,30 (IC 95% 1,13-1,51) Sindrome Metabolica NO Sindrome Metabolica SÌ HR=1,25 (p<0,01) anni n = 2.910; follow-up 4,4 anni Diabetes Care 32, 153, 2009 Cardiovascular Conditions and Risk Factors Associated with Elevated Uric Acid - Hypertension and prehypertension - Renal disease (including reduced glomerular filtration rate and microalbuminuria) -Metabolic syndrome (including abdominal obesity, hypertriglyceridemia, low level of HDL cholesterol, insulin resistance, impaired glucose tolerance, elevated leptin level) - Obstructive sleep apnea - Vascular disease (carotid, peripheral, coronary artery) - Stroke and vascular dementia - Preeclampsia - Inflammation markers (CRP, PAI 1 inhibitor , s-ICAM 1) - Endothelial dysfunction - Oxidative stress - Sex and race (postmenopausal women, blacks) - Demographic (movement from rural to urban communities, Westernization, immigration to Western cultures) N Engl J Med 359, 1811, 2008 Q1 Q2 Q3 Q4 Q5 > 4,22 4,22 - 4,74 4,74 - 5,50 5,50 - 6,41 > 6,41 mg/dl n = 4.385; follow-up 8,4 anni Stroke 37, 1503, 2006 Health Professionals Follow-up Study MORTALITÁ TOTALE RISCHIO RELATIVO MULTIVARIATO 1.4 * 1.2 * 1 0.8 0.6 0.4 0.2 0 SENZA GOTTA CON GOTTA SENZA PRECEDENTE CHD SENZA GOTTA CON GOTTA CON PRECEDENTE CHD n = 51.297; follow-up 12 anni Circulation 116, 894, 2007 Health Professionals Follow-up Study RISCHIO RELATIVO MULTIVARIATO MORTALITÁ TOTALE CARDIOVASCOLARE 1.6 * 1.4 * 1.2 1 0.8 0.6 0.4 0.2 0 SENZA GOTTA CON GOTTA SENZA PRECEDENTE CHD SENZA GOTTA CON GOTTA CON PRECEDENTE CHD n = 51.297; follow-up 12 anni Circulation 116, 894, 2007 Health Professionals Follow-up Study Rischio di diabete aggiustato per età, sesso, IMC, circonferenza vita, pressione arteriosa e colesterolo HDL per quartili di acido urico Rischio relativo di diabete 1.8 1.6 1.4 1.2 1 0.8 0.6 0.4 0.2 0 ≤ 4,49 p for trend < 0.001 n = 4.536; follow-up 10,1 anni 4,50-5,21 5,22-6,22 ≥ 6,23 mg/dl ACIDO URICO Diabetes Care 31, 361, 2008 Framingham Heart Study original (n 4883) and offspring (n 4292) cohorts aged 29-62 years at time of recruitment in 1948, followed biennially, 26° examination [2000-2002] for the original cohort relative risk of incident diabetes 2.5 2 1.5 1 0.5 0 <5,0 5,0-5,9 6,0-6,9 URIC ACID 7,0-7,9 <8,0 mg/dL relative risk of incident diabetes adjusting for age, sex, physical activity, alcohol consumption, smoking, hypertension, body mass index, and blood levels of glucose, cholesterol, creatinine, and triglycerides. Am J Med 123, 957, 2010 Evidence Linking Uric Acid and Hypertension - An elevated uric acid level consistently predicts the development of hypertension. - An elevated uric acid level is observed in 25–60% of patients with untreated essential hypertension and in nearly 90% of adolescents with essential hypertension of recent onset. - Raising the uric acid level in rodents results in hypertension with the clinical, hemodynamic, and histologic characteristics of hypertension. - Reducing the uric acid level with xanthine oxidase inhibitors lowers blood pressure in adolescents with hypertension of recent onset. N Engl J Med 359, 1811, 2008 Veterans Administration - Boston Multivariable-adjusted association of baseline serum uric acid level with incident hypertension p trend = 0,02 1.4 Relative risk 1.2 1 0.8 0.6 0.4 0.2 0 <4,99 4,99-5,41 5,50-5,90 6,00-6,41 6,51-6,89 >6,99 mg/dl uric acid n = 2.062; follow-up 21,5 anni Hypertension 48, 1031, 2006 n = 30 adolescents (aged 11-17 years) with newly diagnosed essential hypertension and uric acid >6 mg/dl, treated for 4 weeks with allopurinol 200 mg twice daily JAMA 300, 924, 2008 n = 30 adolescents (aged 11-17 years) with newly diagnosed essential hypertension and uric acid >6 mg/dl, treated for 4 weeks with allopurinol 200 mg twice daily JAMA 300, 924, 2008 Change in total exercise time from baseline n = 65 patients with angiographically documented coronary artery disease Lancet 375, 2161, 2010 J Clin Invest 120, 1791, 2010 CASO CLINICO Arch Gerontology Geriat 55, 497, 2012 CASO CLINICO Arch Gerontology Geriat 55, 497, 2012 Pharm Reviews 58, 87, 2006 % patients with uric acid <6 mg/dl at last visit 70 % patients 60 p < 0.001 50 40 30 20 10 0 Febuxostat 80 mg/day Febuxostat 120 mg/day Allopurinol 300 mg/day N Engl J Med 353, 2450, 2005 Subjects Requiring Treatment for Gout Flares N Engl J Med 353, 2450, 2005 Proportion of subjects (%) Proportion of subjects with serum urate levels <6.0 mg/dl at final visit 100 90 80 70 60 50 40 30 20 10 0 Placebo Febuxostat 80 mg/day Febuxostat 120 Febuxostat 240 Allopurinol 300 mg/day mg/day mg/day Arthritis & Rheumatism 59, 1540, 2008 J Rheumatol 36, 1273, 2009 Effect of baseline characteristics on treatment response subjects achieving sUA <6.0 mg/dL at final visit (%) 90 80 70 60 <9 mg/dl 50 9-10 mg/dl 40 >10 mg/dl 30 20 10 0 Febuxostat 40 mg/day n = 757 Febuxostat 80 mg/day n = 756 Allopurinol 200/300 mg/day n = 755 Arthritis Research & Therapy 12, R63, 2010 Proportion of patients who achieved sUA < 6.0 mg/dL Clinical Therapeutics 35, 180, 2013 Nota 91 Determinazione 2 novembre 2010 (GU 12 novembre 2010, n. 265): Modifiche, relative all’inserimento della Nota 91, alla determinazione 4 gennaio 2007 : “Note AIFA 2006-2007 per l’uso appropriato dei farmaci”. La prescrizione a carico del SSN è limitata alle seguenti condizioni: Trattamento dell'iperuricemia cronica con anamnesi o presenza di tofi e/o di artrite gottosa in soggetti che non siano adeguatamente controllati con allopurinolo o siano ad esso intolleranti. Xanthine oxidase inhibitors allopurinol febuxostat Lancet 377, 165, 2011