Iperuricemia con deposito di urato: nuovi approcci terapeutici

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1 Iperuricemia con deposito di urato: nuovi approcci terapeutici
Enzo Manzato

2 n = 2.910; follow-up 4,4 anni anni 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

3 sopravvivenza cumulata
Uricemia ≤ 5,1 mg/dl sopravvivenza cumulata 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

4 sopravvivenza cumulata
Uricemia ≤ 5,1 mg/dl Sindrome Metabolica NO sopravvivenza cumulata Uricemia > 5,1 mg/dl Sindrome Metabolica SÌ HR = 1,30 (IC 95% 1,13-1,51) HR=1,25 (p<0,01) anni n = 2.910; follow-up 4,4 anni Diabetes Care 32, 153, 2009

5 - Hypertension and prehypertension
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

6 Q1 > 4,22 Q2 4,22 - 4,74 Q3 4,74 - 5,50 Q4 5,50 - 6,41 Q5 > 6,41 mg/dl n = 4.385; follow-up 8,4 anni Stroke 37, 1503, 2006

7 Health Professionals Follow-up Study RISCHIO RELATIVO MULTIVARIATO
SENZA PRECEDENTE CHD CON PRECEDENTE CHD SENZA GOTTA CON GOTTA * RISCHIO RELATIVO MULTIVARIATO n = ; follow-up 12 anni Circulation 116, 894, 2007

8 Health Professionals Follow-up Study RISCHIO RELATIVO MULTIVARIATO
SENZA PRECEDENTE CHD CON PRECEDENTE CHD SENZA GOTTA CON GOTTA * RISCHIO RELATIVO MULTIVARIATO n = ; follow-up 12 anni Circulation 116, 894, 2007

9 n = 294 patients with congestive heart failure
≤6,72 mg/dl; n = 100 SURVIVAL - % 6,74-10,09 mg/dl; n = 143 10,10-13,45 mg/dl; n = 39 >13,45 mg/dl; n = 12 n = 294 patients with congestive heart failure Circulation 107, 1991, 2003

10 Rischio relativo di diabete
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 ≤ 4,49 4,50-5,21 5,22-6,22 ≥ 6,23 mg/dl p for trend < 0.001 ACIDO URICO n = 4.536; follow-up 10,1 anni Diabetes Care 31, 361, 2008

11 Framingham Heart Study original (n 4883) and offspring (n 4292) cohorts
aged years at time of recruitment in 1948, followed biennially, 26° examination [ ] for the original cohort relative risk of incident diabetes mg/dL URIC ACID 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

12 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

13 N Engl J Med 359, 1811, 2008

14 Veterans Administration - Boston
Multivariable-adjusted association of baseline serum uric acid level with incident hypertension p trend = 0,02 Relative risk mg/dl uric acid n = 2.062; follow-up 21,5 anni Hypertension 48, 1031, 2006

15 n = 30 adolescents (aged 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

16 n = 30 adolescents (aged 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

17 Change in total exercise time from baseline
n = 65 patients with angiographically documented coronary artery disease Lancet 375, 2161, 2010

18 J Clin Invest 120, 1791, 2010

19 ANAMNESI PATOLOGICA REMOTA
CASO CLINICO ANAMNESI FAMILIARE Padre affetto da gotta ANAMNESI PATOLOGICA REMOTA Ipertensione arteriosa da molto tempo Arch Gerontology Geriat 55, 497, 2012

20 CASO CLINICO In buona salute fino a 52 anni, quando iniziano i primi attacchi di gotta acuta: prima il ginocchio sinistro e poi le articolazioni metatarso-falangee. In questo periodo si cura solamente con rimedi omeopatici, senza beneficio. A due anni dal primo attacco acuto per la persistenza della sintomatologia e per un cospicuo aumento dell’acido urico sierico inizia trattamento con allopurinolo, sospeso dopo 3 mesi. Arch Gerontology Geriat 55, 497, 2012

21 CASO CLINICO A 61 anni, mentre si trova in Cina, si ulcera un tofo dell’alluce destro, con ospedalizzazione e trattamento chirurgico della lesione Continua negli anni seguenti ad assumere medicamenti a base vegetale, come da medicina tradizionale cinese Chalk stone Arch Gerontology Geriat 55, 497, 2012

22 CASO CLINICO Arch Gerontology Geriat 55, 497, 2012

23 CASO CLINICO Arch Gerontology Geriat 55, 497, 2012

24 Lancet 375, 318, 2010

25 Lancet 375, 318, 2010

26 Pharm Reviews 58, 87, 2006

27 % patients with uric acid <6 mg/dl at last visit
N Engl J Med 353, 2450, 2005

28 Subjects Requiring Treatment for Gout Flares
N Engl J Med 353, 2450, 2005

29 Proportion of subjects (%)
Proportion of subjects with serum urate levels <6.0 mg/dl at final visit Proportion of subjects (%) Arthritis & Rheumatism 59, 1540, 2008

30 J Rheumatol 36, 1273, 2009

31 Effect of baseline characteristics on treatment response
subjects achieving sUA <6.0 mg/dL at final visit (%) Febuxostat 40 mg/day Febuxostat 80 mg/day Allopurinol 200/300 mg/day Arthritis Research & Therapy 12, R63, 2010

32 Effect of baseline characteristics on treatment response
subjects achieving sUA <6.0 mg/dL at final visit (%) 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

33 Proportion of patients who achieved sUA < 6.0 mg/dL
Clinical Therapeutics 35, 180, 2013

34 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 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.

35 Xanthine oxidase inhibitors allopurinol febuxostat
Lancet 377, 165, 2011

36