Il controllo glicemico e il vantaggio della gestione multidisciplinare Dott. Carlo B. Giorda M.Metaboliche e Diabetologia ASL TO5 Regione Piemonte Centro Studi e Ricerche AMD

% DI DIABETICI NOTI IN REPARTI DI RICOVERO REGIONE PIEMONTE ANNO 2001

Prevalenza di diabete o alterazioni del metabolismo glucidico in pazienti con SCA The Euro Heart Survey on diabetes and the heart Diabete noto 31% Totale Diabete non noto 69% Bartnik M , European Heart Journal 2004; 25: 1880– 1890

DIAB ST ST NO DIAB McGuire DK GUSTO-IIb Eur Heart J 2000; 21:1750-8 Mi sembra un diapositiva molto importante di uno studio molto importante. Sia che si considerino i pazienti con ST sopraelevato sia che si considerino i pazienti senza ST sopraelevato, la presenza di diabete peggiora la prognosi Nota come le curve divergono presto e come tendono a divaricarsi sempre più col passare del tempo. McGuire DK GUSTO-IIb Eur Heart J 2000; 21:1750-8

ACS without ST elevation Cumulative event curves for different outcomes in patients with and without diabetes. RRs and CIs are given by univariate Cox regression analysis. Patients affected by ACS without ST elevation Studio molto importante, Malmberg è il primo autore Sono PZ con SCA senza sopralivellamento ST. Mi sembra importante documentare che i paziente con SCA e diabete hanno un rischio aumentato non solo di morte o reinfarto, ma anche un rischio di scompenso e di stroke OASIS Registry Malmberg K et al, Circulation 2000;102:1014

Mortalità dopo IMA in diabetici trattati con strategia invasiva precoce HR 2.11(95% CI: 1.33 to 3.36) HR 3.47 (95% CI: 1.57 -7.4) Impact of diabetes mellitus on long-term outcome after unstable angina and non-ST-segment elevation myocardial infarction treated with a very early invasive strategy C. Müller1, 2 · F. J. Neumann1 · M. Ferenc1 · A. P. Perruchoud2 · H. J. Büttner1 Abstract Aims/hypothesis. We sought to evaluate the impact of diabetes mellitus on long-term outcome in patients with unstable angina and non-ST-segment elevation myocardial infarction treated with a very early invasive strategy. Methods. We carried out a prospective cohort study in 270 diabetic and 1163 non-diabetic patients with unstable angina and non-ST-segment elevation myocardial infarction. All patients underwent coronary angiography and, if appropriate, subsequent revascularisation within 24 hours of admission. The primary endpoint was allcause mortality during follow-up for up to 60 months. Results. Diabetic patients had less favourable baseline characteristics including more advanced coronary artery disease and more severe unstable angina and non- ST-segment elevation myocardial infarction. Percutaneous coronary intervention was performed in 53% of diabetic patients and 56% of non-diabetic patients. Coronary artery bypass grafting was done in 21% of diabetic patients and 12% of non-diabetic patients. In-hospital mortality (4.1% vs 1.3%; hazard ratio 3.47; 95% CI: 1.57 to 7.64; p=0.002) and long-term mortality (9.7% vs 4.9%; hazard ratio 2.11; 95% CI: 1.33 to 3.36; p=0.002) were significantly higher in diabetic patients. After adjustment for differences in baseline characteristics, diabetes mellitus was no longer an independent predictor of long-term mortality (hazard ratio 1.43; 95% CI: 0.74 to 2.78; p=0.292). Conclusions/interpretation. Diabetic patients treated with a very early invasive strategy for unstable angina and non-ST-segment elevation myocardial infarction have a higher in-hospital and long-term mortality that is largely explained by their less favourable baseline ST-segment elevation myocardial infarction. Keywords Diabetes mellitus · Long-term mortality · Myocardial infarction · Revascularisation · Unstable Angina Adding very early percutaneous coronary intervention as a variable to the multivariate Cox regression analysis showed that very early percutaneous coronary intervention was independently associated with a favourable outcome (hazard ratio for long-term mortality 0.50; 95% CI: 0.30 to 0.85; p=0.011). This association would persist if the analysis was restricted to diabetic patients only (hazard ratio 0.47; 95% CI: 0.20 to 1.09; p=0.078). Müller C Diabetologia 2004; 47: 1188– 1195

Per quali ragioni il diabete comporta una prognosi particolarmente sfavorevole nell’ambito delle Sindromi Coronariche Acute ?

IL “CONTENITORE” DIABETE DI TIPO 2 dislipidemia obesità ipertensione trombofilia iperglicemia insulino- resistenza

IPERGLICEMIA N.B. :L’Iperglicemia all’esordio della Sindrome Coronarica Acuta può presentarsi anche in soggetti non noti per essere diabetici

Dal diabete al ruolo dell’iperglicemia “da stress”: due problematiche diverse

Iperglicemia da stress e rischio relativo di mortalità intraospedaliera nei pazienti ricoverati per SCA Non diabetici Diabetici La parte superiore della diapositiva si riferisce al rischio non aggiustato per soggetti non diabetici con iperglicemia verso soggetti non diabetici senza (RR 3.9) La parte inferiore a diabetici iperglicemici al momento del ricovero verso diabetici non iperglicemici (RR 1.7) Come si vede le soglie glicemiche utilizzate sono molto variabili I dati pooled danno comunque un RR significativo in entrambi i casi, logicamente più elevato nei non diabetici con iperglicemia da stress, perché i diabetici iperglicemici sono comunque confrontati con diabetici Adjusted relative risks of mortality after myocardial infarction in patients with stress hyperglycaemia compared with those without stress hyperglycaemia were reported in two of the ten studies. In one study,24 patients without diabetes who had hyperglycaemia on admission had a 2·8-fold (0·9–8·30) higher risk of mortality than those without hyperglycaemia on admission, after adjustment for age. In the second study,26 the relative risk of mortality after myocardial infarction associated with stress hyperglycaemia in patients without diabetes was 2·48 (1·52–4·97) after adjustment for age and Killip class. Congestive heart failure or cardiogenic shock, were reported in four studies. Stress hyperglycaemia was associated with an increased risk of congestive heart failure or cardiogenic shock in patients without diabetes; this association was not seen in patients with diabetes (table 3). Results of these four studies could not be pooled because of statistical heterogeneity. Adjusted relative risk of mortality was reported in one study, in which patients without diabetes who had stress hyperglycaemia had a 3·1-fold (1·2–7·4) higher risk of congestive heart failure or cardiogenic shock than those without stress hyperglycaemia after adjustment for age.24 Capes SE, Lancet 2000; 355: 773– 78

Metanalisi: iperglicemia e rischio relativo di mortalità entro 30 giorni dall’ictus R.R. Iperglicemia definita da >110 a >144 mg/dl Iperglicemia definita da >110 a >126 mg/dl Iperglicemia definita da >120 a >126 mg/dl La iperglicemia da tress è associata a prognosi peggiore a breve termine nei non diabetici in ogni ictus e nell’ictus ischemico In pochi studi è stata fatta analisi multivariata che correla la glicemia con mortalità e ridotto recupero funzionale nel’ictus ( nell’ischemico, non in tutti nell’emorragico) Capes SE, Stroke 2001; 32:2426-2432

Relation of Chronic and Acute Glycemic Control on Mortality in Acute Myocardial Infarction with Diabetes Mellitus. Cao JJ et a,, Am J Cardiol 96:183-186, 2005 Multivariate Predictors of Diabetic Patients in-Hospital Mortality after Acute Myocardial Infarction Predictor OR p Age 1.06 <0.0001 SPB 0.98 <0.0001 HR/5 beats 1.13 <0.001 Current smoker 0.29 0.02 Previous Aspirin Use 0.35 0.002 Peak troponin/10 U 1.02 0.02 Admission Glucose <161 mg/dl 1.0 162-217 mg/dl 1.14 ns 218-300 mg/dl 2.84 0.04 >301 mg/dl 5.03 0.001

HbA1c measured within 2 years before admission did not predict Relation of Chronic and Acute Glycemic Control on Mortality in Acute Myocardial Infarction with Diabetes Mellitus. Cao JJ et a,, Am J Cardiol 96:183-186, 2005 HbA1c measured within 2 years before admission did not predict In-hospital mortality after AMI in Diabetic Patients HbA1c measured within 2 years OR (95% CI) before admission (>2) First quartile 1.0 Second quartile 0.64 (0.17-2.33) Third quartile 1.01 (0.31-3.27) Fourth quartile 1.08 (0.31-3.23) CONCLUSION: ACUTE HYPERGLYCEMIA, AND NOT LONG-TERM GLYCEMIC CONTROL, AFFECTS IN-HOSPITAL AMI MORTALITY IN DIABETIC PATIENTS

Antonio Ceriello European Heart Journal 26: 328-331, 2005 ACUTE HYPERGLYCAEMIA: A “NEW” RISK FACTOR DURING MYOCARDIAL INFARCTION. Antonio Ceriello European Heart Journal 26: 328-331, 2005 HYPERGLYCEMIA FREE RADICAL FORMATION Coagulation activation Amplified Inflammatory Immune reactions Endothelial dysfunction

Hyperglycemia during AMI ACUTE HYPERGLYCAEMIA: A “NEW” RISK FACTOR DURING MYOCARDIAL INFARCTION. Antonio Ceriello European Heart Journal 26: 328-331, 2005 Hyperglycemia during AMI Arrhythmias and QT elongation Impaired LV function Increased infarct size Impairment of ischemic pre-conditioning Increased incidence of no-reflow phenomenon

Iperglicemia in corso di sindromi coronariche acute Iperglicemia in paziente diabetico noto Iperglicemia in paziente diabetico non diagnosticato Iperglicemia in paziente NON diabetico: “da stress” A qualunque gruppo appartenga, l’iperglicemia è sempre un fattore prognostico sfavorevole e deve essere comunque trattata L’HbA1c durante il ricovero potrebbe aiutare la diagnosi differenziale Entro tre mesi dall’evento, OGTT !

A QUALE LIVELLO DI GLICEMIA INIZIA IL RISCHIO ? Cooperative Cardiovascular Project 2005

Chi trattare? Tutte le iperglicemie indipendentemente dalla diagnosi di diabete Gli accertamenti diagnostici vanno eseguiti dopo

Significato prognostico delle ipoglicemie nelle prime ore post-infartuali

AIM: To investigate the associations between glycometabolic state at ASSOCIATION BETWEEN HYPER- AND HYPOGLYCAEMIA AND 2 YEAR ALL-CAUSE MORTALITY RISK IN DIABETIC PATIENTS WITH ACUTE CORONARY EVENTS Svensson Ann-Marie et al, Eur Heart Journal 26:1255-61,2005 AIM: To investigate the associations between glycometabolic state at admission and during hospitalization and 2 yrs all-cause mortality risk among a cohort of patients with diabetes admitted with ACS -Unstable Angina -Non Q wave MI using data from a single-centre consecutive patient registry collected during 1988-98 (Goteborg, Sweden) 713 consecutive patients : 105 on diet alone 204 on insulin alone 254 on SU alone 8 on MET alone 115 on combination therapies

Adjusted all cause mortality according to the quartile of ASSOCIATION BETWEEN HYPER- AND HYPOGLYCAEMIA AND 2 YEAR ALL-CAUSE MORTALITY RISK IN DIABETIC PATIENTS WITH ACUTE CORONARY EVENTS Svensson Ann-Marie et al, Eur Heart Journal 26:1255-61,2005 Adjusted all cause mortality according to the quartile of BG at admission Quartiles 1 2 3 4 mg/dl <153 154-208 209-274 >275 (n=177) (n=168) (n=169) (n=172) Adjusted HR quartile 4 vs 1 (95% CI) Deaths in-hospital 2.46 (1.12-5.42) p<0.0001 Deaths within 30 days 2.41 (1.22-4.77) p<0.0001 Death within 2 years 1.69 (1.14-2.51) p<0.0001

Association between the lowest recorded BG during ASSOCIATION BETWEEN HYPER- AND HYPOGLYCAEMIA AND 2 YEAR ALL-CAUSE MORTALITY RISK IN DIABETIC PATIENTS WITH ACUTE CORONARY EVENTS Svensson Ann-Marie et al, Eur Heart Journal 26:1255-61,2005 Association between the lowest recorded BG during Hospitalization and incidence of death within 2 years. Adjusted HR (95% CI) < 55 mg/dl (n=44) 1.93 (1.18-3.17) 56-119 mg/dl (n=364) 1.0 > 120 mg/dl (n=276) 1.48 (1.09-1.99)

Counterregulatory catecholamine increase ASSOCIATION BETWEEN HYPER- AND HYPOGLYCAEMIA AND 2 YEAR ALL-CAUSE MORTALITY RISK IN DIABETIC PATIENTS WITH ACUTE CORONARY EVENTS Svensson Ann-Marie et al, Eur Heart Journal 26:1255-61,2005 Hypoglycemia Counterregulatory catecholamine increase Precipitation or acceleration of ischemia Increased Myocardial damage The association of both hyper- and hypoglycemia with post-ACS Mortality risk underscores the importance of continuous investigation To define the optimal glycemic control strategies during and after ACS

Le prove di efficacia dei trattamenti

Studio DIGAMI: mortalità nei gruppi a rischio diverso n.s. n.s. n.s. n.s. -52%; p= .046 n.s. -52%; p= .020 n.s. La mortalità è ridotta nei casi meno gravi. Che significato ha? L’insulina che gli altri facevano è protettiva? Malmberg K JACC 1995; 26: 57- 65

Studio Van den Berghe 2001: mortalità intraospedaliera La mortalità è interrotta indipendentemente dalla pregressa diagnosi di diabete Van den Bergh G, NEJM 2001, 345: 1359- 1367

Controllo glicemico nei 3 gruppi Malmberg K. et al. EHJ 2005 DIGAMI 2

DIGAMI 2: mortalità Mortality-intention to treat Overall, there were 277 deaths in the study (21.3%). Mortality did not differ significantly among the three groups as presented in Figure 2. After 2 years of follow-up, the Kaplan–Meier estimated mortality was 23.4% among patients in group 1 when compared with 21.2% in group 2 (HR=1.03; 95% CI=0.79–1.34; P=0.832). The corresponding proportion in group 3 was 17.9% (group 1 vs. 3: HR=1.26, CI=0.92–1.72; P=0.157). The adjusted HR for the slight imbalance in previous diseases between groups 1 and 3 was 1.19 (CI=0.86–1.64; P=0.29). Comparing groups 2 and 3, the HR=1.23 (CI=0.89–1.69; P=0.203). The following variables were selected for the adjusted endpoint analysis owing to their univariate relation with a P-value<0.20: myocardial infarction, chronic congestive heart failure, early ventricular fibrillation, and cardiogenic shock. Gender did not influence mortality. Specific causes of death are outlined in Table 5. Cardiovascular causes were most common without any significant differences among the groups, whereas a lower incidence of non-cardiovascular deaths in group 3 explained the trend towards a somewhat lower overall mortality in this group compared with groups 2 and 3. There was a slight difference in mortality from malignancies, with a higher incidence in group 1 (n=16) compared with group 2 (n=5) and group 3 (n=2; group 1 vs. 2, P=0.016; group 1 vs. 3, P=0.011). Eleven out of the 16 deaths due to malignancies in group 1 occurred during the first year of follow-up but none in groups 2 and 3, in which the first death due to malignant disease occurred after 1.2 and 1.9 years, respectively. Malmberg K European Heart J 2005; 26: 650- 661

DIGAMI 2: analisi epidemiologica Predittori di mortalità Mortality–epidemiological analysis Disregarding group allocation, entering patients characteristics, which in a univariate relation had a P-value<0.20 [updated mean HbA1c or updated mean blood glucose (depending on the analysis) together with age, gender, diabetes duration, previous heart failure, previous myocardial infarction, smoking, renal function expressed as s-creatinine at the time of randomization] into a multivariable analysis of mortality predictors (Figure 3). Updated blood glucose (HR=1.20 for 3 mmol/L; P<0.001) was a significant and independent predictor together with increasing age (HR=2.14 for 10 years; P<0.001), previous heart failure (HR=1.71; P<0.001), and elevated serum creatinin (HR=1.13 for 40 µmol/L; P<0.001). Applying this model introducing a 2% increase of updated HbA1c as a measure of glucose control revealed an HR of 1.19 (P=0.027). Un aumento della glicemia di 54 mg/ dl o della Hb A1c del 2% è associato ad un aumento della mortalità del 20% Malmberg K European Heart J 2005; 26: 650- 661

Riflessione E’ possibile eseguire RCT sull’iperglicemia un acuto nella situazione attuale?

Fallito per arruolamento insufficiente

Come trattare? Schemi terapeutici

Esempio di protocollo di terapia insulinica e.v. Obiettivo glicemico: 80-180 mg/dL Infusione: 10- 100 Unità/ 100 ml 0.9% Na Cl con pompa Inizio terapia: I pazienti trattati con ipoglicemizzante orale entro 24 ore iniziano quando glicemia >120 mg/dL. Tutti gli altri quando è >70 mg/ dl Fine terapia: quando il paziente si alimenta ed ha ricevuto la prima dose di insulina s.c. Fluidi endovenosi: 5-10 g di glucosio per ora (soluzioni glucosate, TPN, nutrizione enterale…) The use of a "priming bolus" to initiate intravenous insulin infusion is controversial (265). The half-life of an intravenous insulin bolus is about 4–5 min (309), and, although tissue effects are somewhat delayed, by 45 min insulin blood levels return virtually to baseline. Because repeated intravenous bolus insulin therapy does not maintain adequate blood insulin levels or target tissue action of insulin, the initial priming bolus of intravenous insulin, if used, must be followed by maintenance insulin infusion therapy (310,311). Markovitz L. Endocr Pract 2002, 8: 10– 18

Glicemia Algoritmo (U/h di insulina) 1 2 3 4 <70 no 70-109 0.2 0.5 1.5 110-119 120-149 5 150-179 7 180-208 9 210-239 6 12 240-269 8 16 270-299 10 20 300-329 24 > 330 14 28 (D.L. Trence et al., J. Clin. Endocrinol. Metab. 88: 2430-2437, 2003)

Nuove frontiere Esiste un “door to needle” del trattamento insulinico dell’iperglicemia?

Diabete iperglicemia e outcomes

Le raccomandazioni operative più recenti sull’ iperglicemia nella SCA (1) La glicemia deve sempre essere presente negli esami di lab all’ingresso (evidenza A) Prevedere il successivo monitoraggio glicemico (B) Considerare trattamento intensivo per valori > 180. indipendentemente dalla diagnosi di diabete (B) In assenza di evidenze conclusive, l’obiettivo da porsi è di mantenere tra 90 e 140 senza ipo AHA Statement 2008

Le raccomandazioni operative più recenti sull’ iperglicemia nella SCA (2) L’infusione endovenosa di insulina è attualmente il trattamento più efficace (evidenza B) Iniziare il trattamento il più presto possibile (C) Se l’ospedalizzazione avviene in non ICU prevedere almeno terapia con insulina s.c. (B) Nei soggetti senza diagnosi precedente di diabete definire la diagnosi prima della dimissione (OGGT, Hba1c) (B) AHA Statement 2008

La gestione multicollaborazione cardiologo diabetologo

LG ESC EASD 2007

Durata del ricovero Esistono molti lavori che evidenziano come la durata del ricovero dei diabetici sia aumentata sino al 60%, con aumento dei re-ricoveri (anche dati italiani). Esistono più lavori (anche un trial) che evidenziano come la presenza di un team multidisciplinare intraospedaliero riduca la durata della degenza e la frequenza di re-ricovero Non esistono dati di tale tipo specificamente su ricoveri cardiologici o SCA (auspicabili)

Necessità di nuovi modelli di assistenza Auspicare superamento della consulenza, a favore della creazione di team medici e infermieristici per il problema delle SCA nel paziente iperglicemico Arrivare a protocolli condivisi intraospedalieri. Raccolta dati per audit. Riunioni periodiche per la revisione Formazione comune di tutti le figure coinvolte (anche infermieri) Coinvolgimento del MMG già alla dimissione?

LA POSIZIONE DELLA CARDIOLOGIA USA Compelling evidence for tight glucose control in patients in the intensive care unit (…) supports the importance of intensive insulin therapy to achieve a normal blood glucose level in critically ill patients ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction—Executive Summary. Circulation. 2004; 110: 588- 636

Grazie per l’attenzione

Effetti del GLP- 1 sulla disfunzione del VS in corso di infarto del miocardio Effects of Glucagon-Like Peptide-1 in Patients With Acute Myocardial Infarction and Left Ventricular Dysfunction After Successful Reperfusion Lazaros A. Nikolaidis, MD; Sunil Mankad, MD; George G. Sokos, DO; Glen Miske, DO; Ankur Shah, MD; Dariush Elahi, PhD; Richard P. Shannon, MD Background—Glucose-insulin-potassium infusions are beneficial in uncomplicated patients with acute myocardial infarction (AMI) but are of unproven efficacy in AMI with left ventricular (LV) dysfunction because of volume requirements associated with glucose infusion. Glucagon-like peptide-1 (GLP-1) is a naturally occurring incretin with both insulinotropic and insulinomimetic properties that stimulate glucose uptake without the requirements for concomitant glucose infusion. Methods and Results—We investigated the safety and efficacy of a 72-hour infusion of GLP-1 (1.5 pmol/kg per minute) added to background therapy in 10 patients with AMI and LV ejection fraction (EF)
40% after successful primary angioplasty compared with 11 control patients. Echocardiograms were obtained after reperfusion and after the completion of the GLP-1 infusion. Baseline demographics and background therapy were similar, and both groups had severe LV dysfunction at baseline (LVEF292%). GLP-1 significantly improved LVEF (from 292% to 392%, P
0.01), global wall motion score indexes (1.940.1131.630.09, P
0.01), and regional wall motion score indexes (2.530.0832.020.11, P
0.01) compared with control subjects. The benefits of GLP-1 were independent of AMI location or history of diabetes. GLP-1 was well tolerated, with only transient gastrointestinal effects. Conclusions—When added to standard therapy, GLP-1 infusion improved regional and global LV function in patients with AMI and severe systolic dysfunction after successful primary angioplasty. (Circulation. 2004;109:962-965.) Lazaros A Circulation 2004; 109: 962- 965

Protezione del miocardio ischemico con Glucagon Like Peptide- 1 In vivo In vitro Controlli Controlli GLP- 1 GLP- 1 Glucagon-like Peptide 1 Can Directly Protect the Heart Against Ischemia/Reperfusion Injury Amal K. Bose,1 Mihaela M. Mocanu,1 Richard D. Carr,2 Christian L. Brand,2 and Derek M. Yellon1 Glucagon-like peptide 1 (GLP-1), a gut incretin hormone that stimulates insulin secretion, also activates antiapoptotic signaling pathways such as phosphoinositide 3-kinase and mitogen-activated protein kinase in pancreatic and insulinoma cells. Since these kinases have been shown to protect against myocardial injury, we hypothesized that GLP-1 could directly protect the heart against such injury via these prosurvival signaling pathways. Both isolated perfused rat heart and whole animal models of ischemia/reperfusion were used, with infarct size measured as the end point of injury. In both studies, GLP-1 added before ischemia demonstrated a significant reduction in infarction compared with the valine pyrrolidide (an inhibitor of its breakdown) or saline groups. This protection was abolished in the in vitro hearts by the GLP-1 receptor antagonist exendin (9-39), the cAMP inhibitor Rp-cAMP, the PI3kinase inhibitor LY294002, and the p42/44 mitogen-activated protein kinase inhibitor UO126. Western blot analysis demonstrated the phosphorylation of the proapoptotic peptide BAD in the GLP-1–treated groups. We show for the first time that GLP-1 protects against myocardial infarction in the isolated and intact rat heart. This protection appears to involve activating multiple prosurvival kinases. This finding may represent a new therapeutic potential for this class of drug currently undergoing clinical trials in the treatment of type 2 diabetes. Diabetes 54:146–151, 2005 Dimensione dell’infarto espressa come percentuale della zona a rischio Bose AK Diabetes 2005; 54: 146– 151