La terapia del diabete nel paziente con insufficienza renale. Riccardo Candido S.S. Centro Diabetologico Distretto 3 A.S.S.

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1 La terapia del diabete nel paziente con insufficienza renale Riccardo Candido S.S. Centro Diabetologico Distretto 3 A.S.S. 1 Triestina

2 Ai sensi dell art. 3.3 del Regolamento applicativo dell Accordo Stato-Regioni , dichiaro che negli ultimi due anni ho avuto i seguenti rapporti anche di finanziamento con i seguenti soggetti portatori di interessi commerciali in campo sanitario: Novo Nordisk Farmaceutici Roche Diagnostics Johnson & Johnson Medical Eli Lilly Italy Merck Sharp & Dohme Chiesi Farmaceutici Novartis ForFarma Rottapharm In fede Riccardo Candido

3 STADIAZIONE DELLE MALATTIE RENALI CRONICHE Stadio K/DOQI Guidelines NKF, 2003 Definizione Nefropatia cronica con VFG normale o aumentato Nefropatia cronica con lieve riduzione di VFG Nefropatia cronica con moderata riduzione di VFG Nefropatia cronica con severa riduzione di VFG VFG (ml/min/1.73 m 2 ) > Uremia < 15 (o dialisi)

4 STADIAZIONE DELLE MALATTIE RENALI CRONICHE Stadio K/DOQI Guidelines NKF, 2003 Definizione Nefropatia cronica con VFG normale o aumentato Nefropatia cronica con lieve riduzione di VFG Nefropatia cronica con moderata riduzione di VFG Nefropatia cronica con severa riduzione di VFG VFG (ml/min/1.73 m 2 ) > Uremia < 15 (o dialisi) Si definisce come IRC una riduzione del VFG al di sotto di 60 ml/min/1.73 m 2 che persista per più di tre mesi

5 LA NEFROPATIA DIABETICA COME CAUSA DI ESRD ESRD: End Stage Renal Disease Dati U.S.A. Nefropatie causa di ingresso in dialisi illi illi lla lla

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7 Kidney disease is highly prevalent in type 2 diabetes, and moderate to severe renal functional impairment (egfr < 60 ml/min) occurs in approximately 20 30% of patients

8 Distribuzione della popolazione per classi di filtrato glomerulare (ml/min)

9 VFG ED ALBUMINURIA IN PAZIENTI CON DIABETE MELLITO DI TIPO pazienti; 109 con VFG<60 ml/min/1.73 m 2 MacIsaac RJ. Diabetes Care, 2004; 27,1:

10 VFG ED ALBUMINURIA IN PAZIENTI CON DIABETE MELLITO DI TIPO pazienti; 109 con VFG<60 ml/min/1.73 m 2 43/109 (39%) 38/109 (35%) 28/109 (26%) MacIsaac RJ. Diabetes Care, 2004; 27,1:

11 Clinical significance of nonalbuminuric renal impairment in type 2 diabetes. RIACE: studio multicentrico italiano pazienti DM2 I pz con GFR < a 60 ml/min (18,8% del tot) - 56,6% Normoalbuminurici - 30,8% Microalbuminurici - 12,6% Macroalbuminurici J Hypertens Sep;29(9):

12 M LASSILA, K. K. SEAH, T.J. ALLEN, V. THALLAS, M.C. THOMAS, R. CANDIDO, W.C. BURNS,J.M. FORBES, A.C. CALKIN, M.E. COOPER, K.A.M. JANDELEIT-DAHM

13 Modificazioni del GFR (ml/min per mese) decremento del GFR in uno studio Relazione tra controllo glicemico e prospettico in pazienti con DM tipo 1 decremento del GFR in pazienti con DM1 0,4-0, ,6-1,1-1,6 HbA1% Viberti GC et al., JAMA, 1993

14 Relazione tra controllo glicemico e decremento del GFR EDIC/DCCT Study 0.7% of the previously intensive-treatment group and 2.8% of the previously conventional-treatment group developed serum creatinine concentrations of 2.0 mg/dl or greater (P 0.004), and 1% versus 4%, respectively, developed measured creatinine clearance values less than 70 ml/min/ 1.73 m2 (P 0.001). UKPDS Study intensive treatment in the UKPDS was associated with a 67% risk reduction for a doubling of plasma creatinine levels at 9 years (0.71% of the intensive group and 1.76% of the conventional group; P 0.027) The Epidemiology of Diabetes Interventions and Complications (EDIC) Study. JAMA 290: , UK Prospective Diabetes Study (UKPDS) Group: (UKPDS 33). Lancet 352: , 1998

15 Ridotto rischio di sviluppare macroalbuminuria: 2.9%, vs.4.1% (P<0.001) Tendenza a riduzione del rischio di ESRD: 0.4% vs. 0.6% (P = 0.09) Nessun effetto sul rischio del raddoppio della creatininemia: 1.2% vs. 1.1% (P = 0.42)

16 Arch Intern Med May 28;172(10): Role of intensive glucose control in development of renal end points in type 2 diabetes mellitus: systematic review and metaanalysis intensive glucose control in type 2 diabetes. Coca SG, Ismail-Beigi F, Haq N, Krumholz HM, Parikh CR. BACKGROUND: Aggressive glycemic control has been hypothesized to prevent renal disease in patients with type 2 diabetes mellitus. A systematic review was conducted to summarize the benefits of intensive vs conventional glucose control on kidney-related outcomes for adults with type 2 diabetes. METHODS: Three databases were systematically searched (January 1, 1950, to December 31, 2010) with no language restrictions to identify randomized trials that compared surrogate renal end points (microalbuminuria and macroalbuminuria) and clinical renal end points (doubling of the serum creatinine level, end-stage renal disease [ESRD], and death from renal disease) in patients with type 2 diabetes receiving intensive glucose control vs those receiving conventional glucose control. RESULTS: We evaluated 7 trials involving adults who were monitored for 2 to 15 years. Compared with conventional control, intensive glucose control reduced the risk for microalbuminuria (risk ratio, 0.86 [95% CI, ]) and macroalbuminuria (0.74 [ ]), but not doubling of the serum creatinine level (1.06 [ ]), ESRD (0.69 [ ]), or death from renal disease (0.99 [ ]). Meta-regression revealed that larger differences in hemoglobin A1c between intensive and conventional therapy at the study level were associated with greater benefit for both microalbuminuria and macroalbuminuria. The pooled cumulative incidence of doubling of the serum creatinine level, ESRD, and death from renal disease was low (<4%, <1.5%, and <0.5%, respectively) compared with the surrogate renal end points of microalbuminuria (23%) and macroalbuminuria (5%). CONCLUSIONS: Intensive glucose control reduces the risk for microalbuminuria and macroalbuminuria, but evidence is lacking that intensive glycemic control reduces the risk for significant clinical renal outcomes, such as doubling of the serum creatinine level, ESRD, or death from renal disease during the years of follow-up of the trials.

17 The target hemoglobin A1c level associated with the best clinical outcome in diabetic dialysis patients has not yet been established. Hemoglobin A1c level is not an ideal index for assessing glycemic control in diabetic dialysis patients and advanced CKD.

18 Special Considerations in CKD Stages 3 to 5 Patients with decreased kidney function (CKD stages 3 to 5) have increased risks for hypoglycemia: (1)decreased clearance of insulin and some of the oral agents used to treat diabetes. (2) impaired kidney gluconeogenesis.

19 I problemi Dati insufficienti o discordanti in letteratura sull uso dei farmaci in IRC Classificazione disomogenea dell IRC nelle schede tecniche dei farmaci Differenti indicazioni in schede tecniche nazionali ed internazionali Aggiornamento delle schede tecniche alla letteratura più recente talora carente Opinioni e indicazioni discordanti in linee guida e consensus

20 Metformina Secondo la scheda tecnica italiana il farmaco non deve essere utilizzato in presenza di insufficienza renale con livelli di creatinina sierica > 1,53 mg/dl negli uomini > 1,25 mg/dl nelle donne Le attuali linee-guida del National Institute for Health and Clinical Excellence (NICE) raccomandano : rivedere il dosaggio della metformina qualora il tasso stimato di filtrazione glomerulare (egfr) sia <45 ml/min/1,73 m 2, di interromperla nei pazienti in cui l'egfr risulti <30 ml/min/1,73 m 2.

21 AIFA Luglio 2011 Raccomandazioni sull utilizzo dei medicinali a base di Metformina nella gestione del diabete mellito tipo 2 - Evitare l uso di Metformina in caso di grave insufficienza renale o disfunzione renale cronica (filtrato stimato < 60 ml/min/1,73 m 2 ; assolutamente controindicato per filtrato stimato < 30 ml/min - Si raccomanda pertanto di stimare il filtrato glomerulare a partire dai livelli di creatinina sierica mediante la formula MDRD o CKD-EPI - La stima del filtrato deve essere eseguita ad intervalli regolari (ogni anno nei soggetti con funzione nella norma e ogni 6 mesi nei pz anziani o con funzione renale ridotta - Evitare l uso di Metformina in patologie acute che possano causare ipossia tissutale (insufficienza respiratoria, scompenso cardiaco acuto, infarto miocardico recente, shock), di digiuno o malnutrizione, di insufficienza epatica, di intossicazione acuta da alcool e alcolismo, condizioni nelle quali vi è un aumentato rischio di acidosi lattica

22 Repaglinide Secondo la scheda tecnica italiana. l'8% di una dose di repaglinide e' escreta attraverso i reni e la clearance plasmatica del prodotto e' ridotta nei pazienti con insufficienza renale e' opportuno porre attenzione nell'aggiustare la dose in questi pazienti. Le attuali linee-guida Nefrologiche raccomandano:

23 Metformina Metformin is not a nephrotoxic drug Classification of lactic acidosis in metformin therapy into three main types: unrelated to metformin; metformin-associated, which refers to metformin and concurrent pathologies as co-precipitating factors; metformin-induced, precipitated only by metformin without apparent associated pathology. The literature is sparse and consists of case reports and case series.

24 Diabetes Obes Metab Jun;3(3): Lactic acidosis in metformin therapy: searching for a link with metformin in reports of 'metformin-associated lactic acidosis'. Lalau JD, Race JM. Abstract OBJECTIVE: The link between metformin and lactic acidosis therapy may be causal, associated or coincidental. Our objective was to investigate this link While by studying the and term analysing 'metformin-associated published reports of so-called 'metformin-associated lactic acidosis' lactic acidosis'. is RESEARCH DESIGN AND METHODS: commonly systematically used searched to depict in the BIOSIS, all situations DERWENT, EMBASE, of lactic MEDLINE, acidosis and PASCAL databases of the English language and non-english language literature for all reports of so-called 'metformin-associated lactic acidosis' published from May 1995 through in January metformin We did not therapy, include reports true related metformin-associated to overdose contrast media-induced lactic renal failure. Metformin accumulation and concurrent pathologies were critically reviewed as precipitating factors metforminassociated lactic acidosis. Metformin acidosis, accumulation i.e. was assessed one in terms which of the recorded refers measurement to metformin of concentration and in plasma or, if not available, by the presence of primary renal failure, i.e. renal failure that was not secondary to a shock syndrome. concurrent pathologies as co-precipitating factors, was RESULTS: We found 21 reports describing a total of 26 patients. Criteria of lactic acidosis (lactate > 5 mmol/l, ph <or= 7.35) were not met in four patients. In the remaining never 22 observed patients, plasma in metformin the concentration studied was reports. determined As in only there four, of was whom one no had a normal value. In the 18 patients with lactic acidosis where plasma concentration data was not available, the presence of primary renal failure was absent mortality unlikely in six patients, due to uncertain metformin two, and likely alone, or proven it in 14. is With important regard to these that 14 patients, the precipitating factor was metformin in 12 patients (in the context of renal failure either chronic or acute) and intercurrent pathologies in two others. Overall, physicians lactic acidosis was are either absent familiar (n = 4), precipitated with the by concurrent range pathology of (n other = 8), precipitated risk by metformin without apparent associated factors pathology that (n = contribute 12) or of uncertain to origin lactic (n = 2). Death acidosis occurred 10 times in but patients only once in the 12 patients with metformin-induced lactic acidosis and this was not related to metformin. CONCLUSIONS: While the term treated 'metformin-associated with metformin. lactic acidosis' is commonly used to depict all situations of lactic acidosis in metformin therapy, true metformin-associated lactic acidosis, i.e. one which refers to metformin and concurrent pathologies as coprecipitating factors, was never observed in the studied reports. As there was no mortality due to metformin alone, it is important that physicians are familiar with the range of other risk factors that contribute to lactic acidosis in patients treated with metformin.

25 Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus Salpeter S, Greyber E, Pasternak G, Salpeter E. Aprile 2010 There is no evidence from prospective comparative trials or from observational cohort studies that metformin is associated with an increased risk of lactic acidosis, or with increased levels of lactate, compared to other antihyperglycemic treatments.

26 HR per malattie cv acidosi/ infezioni gravi, mortalità per ogni causa in pazienti con diversi gradi di IRC Conclusions: Patients with renal impairment showed no increased risk of CVD, all-cause mortality or acidosis/serious infection. Ekström N, BMJ Open 2012;2:e001076

27 Metformina e insufficienza renale VFG > 60 ml/min ml/min ml/min Non contraindicazioni renali per metformina Monitorare funzionalità renale annualmente Continuare il suo uso Controllo della funzionalità renale ogni 3-6 mesi Prescrivere metformina con cautela Usare una dose più bassa (metà della dose massima ) Controllare molto frequentemente la funzione renale (ogni 3mesi ) < 30 m/min Interrompere metformina Lipska KJ, Bailey CJ, Inzucchi SE. Diabetes Care 2011;34:

28 Indicazioni recenti Pharmacokinetic studies of metformin suggest that metformin doses should be reduced by one third in patients with egfrs of <45 ml/min/1.73 m2. Metformin is likely to be tolerated at egfrs of <30 ml/min/1.73 m2, particularly in patients with stable chronic kidney disease with no other significant liver or respiratory failure. However, more detailed pharmacokinetic investigation of metformin elimination in renal patients is required before current dosing guidelines can be modified. Furthermore, plasma concentrations are not available in routine clinical practice Rocha A, J Nephrol. 2012: 0. doi: /jn [Epub ahead of print]

29 Utilizzare particolare cautela per filtrato glomerulare <60 ml/ min/1,73m2 e sospendere per filtrato glomerulare <30 ml/ min/1,73m2 o in pazienti a rischio di insufficienza renale acuta.

30 Glyburide (known as glibenclamide in Europe), which has a prolonged duration of action and active metabolites, should be specifically avoided in this group. Inzucchi SE et al. Diabetes Care 2011; 34:

31 Second-generation sulfonylureas (eg, glipizide, gliclazide, glyburide, and glimepiride), glipizide and gliclazide are preferred agents because they do not have active metabolites and do not increase the risk of hypoglycemia in patients with CKD.

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33 SULFONILUREE e GLINIDI GFR > 60 ml/min ml/min < 30 ml/min Dialisi GLIBENCLAMIDE GLIPIZIDE GLICLAZIDE GLIMEPIRIDE 1 mg Dose ridotta Dose ridotta Dose ridotta Dose ridotta GLIQUIDONE REPAGLINIDE Inizia con 0,5 mg MODIFICATO da Schernthaner, G. et al. Nephrol. Dial. Transplant :

34 Percentuale di pazienti trattati con sulfaniluree in relazione alla classe di età e ai livelli di filtrato glomerulare.

35 Utilizzo delle diverse sulfaniluree (da sole o in associazione) sulla popolazione divisa per classi di età

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38 Conclusion Addition of PIO to insulin in patients with type 2 diabetes requiring hemodialysis resulted in a decrease of the daily insulin dose and an improved glycemic control. Furthermore, PIO administration was well tolerated without any indications of volume overload and negative influence on hypoglycemia risk.

39 PIOGLITAZONE PIOGLITAZONE ISUF. RENALE LIEVE GFR INSUF. RENALE MODERATA 60>GFR>30 INSUF. RENALE SEVERA 30>GFR>15 OK OK OK DIALISI o GFR<15 NO No aggiustamento della dose Ritenzione idrica, edemi, scompenso cardiaco, osteoporosi, aumento di peso, anemia aumentato rischio infarto miocardio, non raccomandato pazienti >75 anni ritenzione idrica, edemi, scompenso cardiaco, osteoporosi, aumento di peso, anemia, cautela > 75 aa ritenzione idrica, edemi, scompenso cardiaco, osteoporosi, aumento di peso, anemia, cautela > 75 aa

40 ACARBOSIO Because long-term clinical trials in diabetic patients with significant renal dysfunction (GFR < 30 ml/min) have not been conducted, treatment of these patients with acarbose is not recommended.

41 Studi sulla farmacocinetica delle gliptine in diversi gradi di insufficienza renale Graefe-Mody U. et al. Diabetes Obesity and Metabolism 2011; 13:

42 Tollerabilità ed efficacia del sitagliptin nell IRC Efficacia Eventi avversi Chan JCN Diabetes, Obesity and Metabolism 2008; 10:

43 Variazione media di HbA1c (%) dalla baseline Variazioni medie corrette di HbA1c (%) dalla baseline Vildagliptin: riduzioni clinicamente rilevanti di HbA1c nei pazienti con DMT2 e insufficienza renale moderata o severa -0,0 Variazione media dalla baseline N=157 N=128 BL=7.86 BL=7.79 IR Moderata Differenza tra i trattamenti vs placebo -0,0 Variazione media dalla baseline N=122 N=95 BL=7.69 IR Severa BL=7.65 Differenza tra i trattamenti vs placebo -0, , * p< vs placebo; BL = baseline Vildagliptin 50 q.d Placebo Differenza tra i trattamenti vs placebo Incidenza di ipoglicemia simile al placebo e nessuna progressione della malattia renale Lukashevich et al. Diabetes Obes Metab Oct;13(10):

44 HbA 1c media (%) PPG Vildagliptin efficace e sicuro anche nei pazienti con DMT2 sottoposti ad emodialisi 7,1 Vildagliptin Controllo 190 Vildagliptin Controllo 6, ,4 6,1 5,8 * * * * * Settimane *P<0,005 vs controllo * * * ** Settimane ** ** ** *P<0,05,* * P<0,01 vs controllo Nessun paziente in trattamento con Vildagliptin ha presentato eventi avversi come ipoglicemia sintomatica o problemi epatici Non vi è stato alcun caso di interruzione del trattamento Endocrine Journal, Vol. 58, No. 11. (2011), pp

45 Tollerabilità ed efficacia del saxagliptin nell insufficienza renale cronica Efficacia Eventi avversi Nowicki M, Int J Clin Pract, 2011; 65:

46 Tollerabilità ed efficacia del linagliptin nell insufficienza renale cronica severa McGill JB Diabetes Care Publish Ahead of Print, published online October 1, 2012

47 INIBITORI DPP-4 Aggiustamenti del dosaggio in CKD Farmaco IR lieve (VFG ml/min) IR moderata (VFG ml/min) IR grave (VFG ml/min) Dialisi o VFG < 15 ml/min Sitagliptin Dose normale 50 mg uid 25 mg uid 25 mg uid Vildagliptin Dose normale 50 mg uid 50 mg uid 50 mg uid* Saxagliptin Dose normale 2,5 mg uid 2,5 mg uid 2,5 mg uid* Linagliptin** Dose normale Dose normale Dose normale Dose normale aumentato rischio infarto miocardio, non raccomandato pazienti >75 anni *Limitazioni in scheda tecnica (vildagliptin usato con cautela in questi pazienti; saxagliptin con esperienza molto limitata ritenzione idrica, edemi, scompenso cardiaco, osteoporosi, aumento di peso, anemia, cautela > 75 aa ** Al momento non disponibile in Italia

48 Comparisons of the change in (a) A1c, (b) body weight and (c) SBP from baseline following 6 months of liraglutide 1.2 mg treatment in T2D patients with normal renal function and mild or moderate RI. Thong, Poster number 1113 Diabetes 2012 (ADA 2012)

49 Br J Clin Pharmacol Sep;64(3): Epub 2007 Apr 10. Effect of renal impairment on the pharmacokinetics of exenatide. Linnebjerg H, Kothare PA, Park S, Mace K, Reddy S, Mitchell M, Lins R. AIMS: To evaluate the pharmacokinetics (PK), safety and tolerability of a single exenatide dose in patients with renal impairment (RI). METHODS: Exenatide (5 or 10 microg) was injected subcutaneously in 31 subjects (one with Type 2 diabetes) stratified by renal function [Cockcroft-Gault creatinine clearance (CrCL), number of subjects]: normal (>80 ml min(-1), n = 8), mild RI (51-80 ml min(-1), n = 8), moderate RI (31-50 ml min(-1), n = 7) or end-stage renal disease (ESRD) requiring haemodialysis (n = 8). PK data were combined with four previous single-dose studies in patients with Type 2 diabetes to explore the relationship of exenatide clearance (CLp/F) and CrCL. RESULTS: Mean half-life for healthy, mild RI, moderate RI and ESRD groups were 1.5, 2.1, 3.2 and 6.0 h, respectively. After combining data from multiple studies, least squares geometric means for CLp/F in subjects with normal renal function, mild RI, moderate RI and ESRD were 8.14, 5.19, 7.11 and 1.3 l h(-1), respectively. Exenatide was generally well tolerated in the mild and moderate RI groups, but not in subjects with ESRD due to nausea and vomiting. Simulations of exenatide plasma concentrations also suggest patients with ESRD should have a propensity for poor tolerability at the lowest available therapeutic dosage (5 microg q.d.). CONCLUSIONS: Since tolerability and PK changes were considered clinically acceptable in patients with mild to moderate RI, it would be appropriate to administer exenatide to these patients without dosage adjustment. However, poor tolerability and significant changes in PK make the currently available therapeutic doses (5 and 10 microg) unsuitable in severe RI or ESRD.

50 GLP-1 agonisti nell insufficienza renale cronica EXENATIDE GFR > 60 ml/min ml/min < 30 ml/min Dialisi Cautela 5 mcg x 2 LIRAGLUTIDE MODIFICATO da Schernthaner, G. et al. Nephrol. Dial. Transplant :

51 Impaired kidney function

52 ALGORITMO TERAPEUTICO NELL INSUFFICIENZA RENALE CRONICA

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57 Schemi di terapia insulinica La scelta di quale agente antidiabetico e di quale schema di terapia insulinica utilizzare, va fatta in considerazione del profilo glicemico del singolo paziente, ossia se prevale l iperglicemia a digiuno o quella post-prandiale. SBMG Approccio abituale Approccio alternativo 1 Approccio alternativo 2 Iperglicemia prevalentemente a digiuno Iperglicemia prevalentemente post-prandiale Iperglicemia a digiuno e post-prandiale Basale Analogo rapido* Premiscelata Basale + bolus Basal plus* Premiscelata * Prima dei pasti dopo i quali la glicemia è al di sopra dell obiettivo.

58 Tabella sinottica per l uso della terapia antidiabetica nell insufficienza renale Farmaco IR lieve (VFG ml/ min) IR moderata (VFG ml/min) IR grave (VFG ml/min) Dialisi o VFG < 15 ml/ min Metformina Dose normale Dose ridotta, monitoraggio no no Glibenclamide Dose ridotta, monitoraggio Dose ridotta,monitoraggio no no Gliclazide Dose normale Dose ridotta, monitoraggio no no Repaglinide Dose normale Attenzione alla titolazione no no Pioglitazone* Dose normale Dose normale Dose normale no Acarbose Dose normale Dose normale no no Sitagliptin Dose normale 50 mg uid 25 mg uid 25 mg uid Vildagliptin Dose normale 50 mg uid 50 mg uid no Saxagliptin Dose normale 2.5 mg uid 2.5 mg uid no Linagliptin** Dose normale Dose normale Dose normale Dose normale Exenatide Dose normale 5 g (10 g con cautela) no no Liraglutide Dose normale No (scarsa esperienza) No (nessuna esperienza) no Insulina Dose normale Possibile riduzione Possibile riduzione Possibile riduzione fabbisogno fabbisogno fabbisogno * Può causare ritenzione idrica che può esacerbare o precipitare una insufficienza cardiaca. ** Al momento non disponibile in Italia.