Impatto clinico delle ipoglicemie

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1 Impatto clinico delle ipoglicemie Ivano G Franzetti Endocrinologia - A.O. S. Antonio Abate Gallarate (VA) Roma. 8 novembre 2014

2 Outline: le ipoglicemie Impatto clinico Impatto sociale Impatto economico

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4 The physician s dilemma Severe hypoglycaemia (rate per 100 patient years) Severe hypoglycaemia The number of prior episodes of hypoglycemia was the strongest predictor of the risk of future episodes. The overall rates of severe hypoglycemia were 61.2 per 100 patient-years vs per 100 patient-years in the intensive and conventional treatment groups, respectively, with a relative risk (RR) of HbA 1c (%) 1. Adapted from: DCCT Research Group. NEJM 1993;329:977 86

5 I grandi trial nel diabete di tipo 2 L età e la durata del diabete sono espresse in anni. Ipoglicemie severe, Differenza di incidenza tra terapia intensificata e controllo, percentuale di pazienti annui; HbA 1c, Valori medi all endpoint nel gruppo intensificato vs gruppo di controllo; Eventi cardiovascolari (CV) e mortalità totale, Mantel-Henzel Odds Ratio calcolato per la terapia intensificata vs terapia convenzionale. 1. UK Prospective Diabetes Study Group. Lancet 1998; 352: Holman RR, et al. N Engl J Med 2008; 359: Dormandy JA, et al. Lancet 2005; 366: Gerstein HC, et al. N Engl J Med 2008; 358: Patel A, et al. N Engl J Med 2008; 358: Duckworth W, et al. N Engl J Med 2009; 360: Modificata da Mannucci E, et al. Nutr Metab Cardiovasc Dis 2009; 19:

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7 WHAT IS ALREADY KNOWN ON THIS TOPIC: The intensive glycaemia control intervention used in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial was associated with increased mortality. WHAT THIS STUDY ADDS: Patients with type 2 diabetes who experience symptomatic, severe hypoglycaemia are at increased risk of death, regardless of the intensity of glucose control. The increased risk of death seen in the ACCORD trial among participants in the intensive glycaemia control arm cannot be attributed to the increased rate of severe hypoglycaemia (only 5 of 57 excess deaths could be attributed to the excess hypoglycemia). BMJ 2010;340:b4909

8 A retrospective cohort of patients admitted to the general wards. Among 31,970 patients, 3349 (10.5%) had at least 1 episode of hypoglycemia. HR No. of deaths P Spontaneous hypoglycemia Drug-associated hypoglycemia < Adjusted In-Hospital Mortality of Patients with Spontaneous Hypoglycemia and Patients with Drug- Associated Hypoglycemia Compared with Normoglycemic Patient. CONCLUSION: Drug-associated hypoglycemia was not associated with increased in-hospital mortality risk in patients admitted to the general wards after adjustment for comorbidities, suggesting that hypoglycemia may be a marker of disease burden rather than a direct cause of death. Am J Med, 2011

9 Link between hypoglycaemia and acute CV events in T2DM Retrospective, observational study (N=860,845) assessing: association between hypoglycaemic events and acute cardiovascular events over a 1-year evaluation period 3.1% subjects experienced hypoglycaemia the findings should be considered an initial groundwork on which future research and understanding can be built Outpatients with hypoglycemic events had 79% higher odds for acute CV events (78% in patients aged > 65 y) Johnston et al. Diabetes Care 2011;34:

10 We designed a prospective study consisting of randomly selected hypoglycemic type 2 diabetic patients and matched type 2 diabetic patients without hypoglycemia. The study population, derived from the National Health Insurance Research Database released by the Taiwan National Health Research Institutes during , comprised 77,611 patients with newly diagnosed type 2 diabetes. HR 2,48 The results may not be easily generalized to other populations. Diabetes Care, 2013

11 What is already known on this topic: the association of hypoglycaemia and cardiovascular disease is controversial and some researchers have proposed that severe hypoglycaemia is merely a marker of comorbid severe illness. What this study adds: comorbid severe illness alone may not entirely explain the positive association between severe hypoglycaemia and risk of cardiovascular disease.

12 Diabetes Care, 2010

13 Case report

14 Case report

15 Diabetes Care,2011 Euglycemia Hypoglycemia

16 Recurrent hypoglycaemia leads to hypoglycaemia unawareness Hypoglycaemia unawareness as an acquired complication of insulin therapy and unrecognised hypoglycaemia 1,2 Recurrent hypoglycaemia Disrupted counter regulatory response Increased frequency and severity of hypoglycaemic episodes Impaired hypoglycaemia awareness 1. Cryer PE. Diabetes 2009;58: Cryer PE. Diabetes 2008; 57(12):

17 Thresholds for hypoglycaemia symptoms vary with age 1,2 Men aged 23 ± 2 years (n=7) Men aged 65 ± 3 years (n=7) Blood glucose 1 (mg/dl) Hypoglycaemic awareness Greater reaction time for corrective action Onset of cognitive dysfunction Blood glucose 1 (mg/dl) Hypoglycaemic awareness Onset of cognitive dysfunction Less reaction time for corrective action Based on data in non-diabetic patients with no family history of diabetes 1. Zammitt NN, Frier BM. Diabetes Care 2005;28(12): Matyka K, et al. Diabetes Care 1997;20(2):

18 L ipoglicemia: dati italiani (studio osservazionale retrospettivo - Hypos-1) Ipoglicemie sintomatiche DMT2 OHA non secretagoghi DMT2 OHA secretagoghi DMT2 Basal/ oral DMT2 Altri schemi insulina DMT2 basal/ bolus Sintomatiche totali Sintomatiche diurne Sintomatiche notturne Numero di episodi/paziente/anno Incidenza generale di ipoglicemia severa 0.09 episodi/persona/anno (vs 9.3 episodi/persona/anno di ipoglicemia sintomatica). Nell anno il 4,7% ha sperimentato una ipoglicemia severa. Nel mese precedente il 28,1% una ipoglicemia sintomatica. J Diabetes Metab, 2014

19 J Diabetes Metab, 2014 L ipoglicemia: dati italiani (studio osservazionale retrospettivo - Hypos-1) Severe hypoglycaemia IRR Age 1.02 Female gender 2.23 Previous severe hypoglycaemia in the last year Symptomatic hypoglycaemic episodes in the last 4 weeks Insulin basal/bolus 2.04 Neoplasms 2.08

20 J Diabetes Metab, 2014 L ipoglicemia: dati italiani (studio osservazionale retrospettivo - Hypos-1) Symptomatic hypoglycaemia IRR Age 0.98 Female gender 1.44 Previous severe hypoglycaemia in the last year 1.72 Insulin (basal/bolus) 2.59 GFR < 60 ml/min 0.85!!!! Soggetti con maggior attenzione alle scelte terapeutiche.

21 Outline: le ipoglicemie Impatto clinico Impatto sociale Impatto economico

22 Hypo (n:5.582) No Hypo (n:27.910) HR (*p<0.05) Any accident 308 (5.5%) 777 (2.8%) 1.39* Accidant fall 161 (2.9%) 369 (1.3%) 1.36* Motor vehicle accident 32 (0.6%) 65 (0.6%) 1.82* Diabetes, Obesity and Metabolism 15: , 2013

23 Patients suffer the consequences of hypoglycaemia 1 Reduced well being Reduced productivity Increased treatment costs Increased anxiety Fear of repeated events compromising glycaemic control Lower quality of life & need for lifestyle changes (e.g. reduced driving) Average productivity loss is ~$2,300/person/year Following a nocturnal hypo: 23% arrive late/miss work 32% miss a meeting/do not finish a task on time BG testing goes up: 5.6 extra tests within 7 days of hypo (~$1/strip) Risk of suboptimal insulin dose (25% of pts reduce dose) 1. Brod M, et al. Value In Health 2011;14(5):

24 Patients rank fear of severe hypoglycaemia as high as fear of developing chronic complications Men Women Very worried Not worried Mild hypoglycaemia Severe hypoglycaemia Thoughts about diabetes Blindness Kidney complications *Based on patient (n=411, T1DM) attitudes on hypoglycaemia using a visual analog scale 1. Pramming S, et al. Diabetic Med 1991;8(3):

25 L ipoglicemia: dati italiani (studio Hypos-1) Impatto delle ipoglicemie severe e sintomatiche su diverse dimensioni della qualità di vita nelle persone con DMT2 EQ-5D VAS: benessere fisico; WHO-5: benessere psicologico; PAID-5: distress legato al diabete; FHQ: paura delle ipoglicemie. J Diabetes Metab, 2014

26 L effetto iperglicemizzante dell ipoglicemia Timori, ansia, paura La metà dei soggetti Riduzione con DMT1 dell intensità e un quarto di quelli con DMT2 riduce la dose della successiva cura, adattamento di farmaco a ed uno su dieci per entrambi i glicemie tipi di diabete più elevate non assume la dose successiva Curanti Paziente, familiari Peggioramento del controllo glicemico

27 Outline: le ipoglicemie Impatto clinico Impatto sociale Impatto economico

28 SIMEU Study Analisi dell impatto economico delle ipoglicemie (data base delle ASL Regione Puglia Istituto Mario Negri Sud). Ricoveri con codice ICD9 CM e dal 1 gennaio 2003 al 31 dicembre Coorte di diabetici di cui 9021 (2,34%) hanno avuto un ricovero per ipoglicemia (incidenza di 5.3/mille/anno). Un singolo ricovero per ipoglicemia costa Il costo complessivo dei ricoveri è stato di al SSN quanto un anno di cura per un (costo medio per ricovero è di = nell ultimo anno ). diabetico di tipo 2 Informazione Farmaci, 2014

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30 Grazie per l attenzione

31 Patient fear of hypoglycaemia increases with severity of hypoglycaemia 1 % patients reporting fear of future hypoglycaemia Type 1 Type 2 *46.5% (type 1) and 58% (type 2) of severe episodes are reported during sleep 1 Fear of hypoglycaemia can be an impediment to effective management 2, treatment satisfaction 3 and can lead some patients who have experienced severe hypoglycaemia to deliberately maintain a state of hyperglycaemia 4 1. Leiter, Yale, et al. Can J Diabetes 2005;29(3): Nakar S, et al. J Diabetes Complications 2007;21(4): Guisasola A, et al. Diabetes Obes Metab 2008;10(Suppl 1): Frier BM. Diabetes Metab Res Rev 2008;24(2):87-92

32 Ipo inavvertite circolo vizioso (Cryer ) rapporti patogenetici con CVD? Morbilità (cadute, demenza, ). Le ipo peggiorano il compenso (BMJ, Miller da Accord 2010) Impatto sociale! fig. 1(Nicolucci AMD) Impatto economico idem

33 SIMEU Study

34 SIMEU Study L ipoglicemia è spesso riportata come diagnosi secondaria ad altre patologie, tuttavia una quota rilevante delle patologie segnalate in diagnosi prinicpale sono direttamente correlate all evento ipoglicemico (fratture, contusioni, sincope o collasso, ipoacusia etc) anche se non si può escludere che l ipo sia successiva agli eventi segnalati.

35 Conclusioni Le ipoglicemie sono certamente associate ad outcome clinici negativi (per pazienti critici si sono rivisti in alto gli obiettivi glicemici; riscontri molto suggestivi anche in pazienti non critici). Il ruolo causale dell ipoglicemia nel determinare questi effetti non è ancora stato accertato ma è molto probabile/plausibile. Vi è ormai l indicazione assoluta ad ottenere il compenso glicemico personalizzato per il singolo paziente evitando nel contempo il più possibile l ipoglicemia.

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37 Numero di episodi/paziente/anno Incidenza generale di ipoglicemia severa 0.09 episodi/persona/anno (vs 9.3 episodi/persona/anno di ipoglicemia sintomatica). Nell anno il 4,7% ha sperimentato una ipoglicemia severa. Nel mese precedente il 28,1% una ipoglicemia sintomatica. J Diabetes Metab, 2014 L ipoglicemia: dati italiani (studio osservazionale retrospettivo - Hypos-1) Ipoglicemie sintomatiche DMT2 OHA non secretagoghi DMT2 OHA secretagoghi DMT2 Basal/ oral DMT2 Altri schemi insulina DMT2 basal/ bolus DMT1 Sintomatiche totali Sintomatiche diurne Sintomatiche notturne

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39 Case report