A LUCIANO RAFFAELE PASTORE Sapienza – Università di Roma Attualità nelle terapie del diabete tipo 2 MANAGEMENT MULTIDISCIPLINARE DELLE ULCERE CRONICHE  Il paziente anziano ed i fattori di rischio  Incontri di Vulnologia nell’ambito dei due Master: “TRATTAMENTO E PREVENZIONE DEL PIEDE DIABETICO” e “TRATTAMENTO E PREVENZIONE DELLE PIAGHE DA DECUBITO NELL’ANZIANO”   Policlinico Umberto I Aula “Pietro Valdoni” Policlinico Umberto I DAI di Chirurgia Generale “F. Durante” Presidente Prof. Piergiorgio Pastore In ricordo del Prof. Luciano Raffaele Pastore Roma 26 maggio 2011 Sebastiano Filetti sebastiano.filetti@uniroma1.it Dip. di Medicina Interna e Spec. Mediche http://www.medicinainterna.it/clinicamedica2/ DEDICATO A LUCIANO RAFFAELE PASTORE

DIABETE DI TIPO 2 DIABETE Insulino-resistenza Deficit β-cellulare Resnick et al. Diabetes Care 2003

STORIA NATURALE DEL DIABETE TIPO 2 Slide 1-25 CORE DISLIPIDEMIA IPERTENSIONE Obesita IGT* Diabete Iperglicemia Non controllata Glicemia post-prandiale Onset Glicemia plasmatica Glicemia a digiuno 120 (mg/dL) 104-105 Anni di diabete Funzionalità -cellulare relativa 100 (%) -20 -10 10 20 30 Insulino resistenza Livelli di insulina Natural History of Type 2 Diabetes This time slide shows changes in glucose uptake and beta-cell insulin secretion beginning in the prediabetic states of obesity and impaired glucose tolerance (IGT). Typically, type 2 diabetes begins with obesity and a period of impaired glucose tolerance before symptomatic diabetes is diagnosed. Ultimately, type 2 diabetes can reach the stage of uncontrolled hyperglycemia when beta-cells fail to produce insulin. The top chart shows the changes in fasting and postprandial plasma glucose and at the bottom are the changes in insulin function and insulin resistance. In the prediabetic state, insulin secretion rises to compensate for insulin resistance. During obesity, and even in the early phase of the IGT, hyperinsulinemia sufficiently controls plasma glucose levels to keep postmeal and fasting glucose at the normal level, below 125 mg/dL. (DeFronzo, 1992) *IGT =alterata tolleranza al glucosio.

The Finnish Diabetes Prevention Study (Dps) Studio sulla prevenzione del diabete in pazienti con ridotta tolleranza ai carboidrati Gruppo in trattamento intensivo con modificazione dello stile di vita Riduzione del peso > 5% Grasso totale <30 % Grassi saturi < 10 % Fibre > 15 g/1000 kcal Esercizio fisico > 30min/die Tuomilehto J, et al. N Engl J Med 2001;344:1343–1350

The Finnish Diabetes Prevention Study (Dps) Riduzione del rischio: 58% Tuomilehto J, et al. N Engl J Med 2001;344:1343–1350

Diabetes is NOT a mild disease

Mortalità cardiovascolare e intervento globale e intensivo su tutti i fattori di rischio Steno 2; NEJM 2003;348(5) 383-389 Target terapeutici più rigorosi nel controllo di tutti i singoli fattori di rischio per malattia cardiovascolare (A1c, PA, profilo lipidico) Terapia Convenzionale P= 0.007 -50% Mortalità cardiovascolare (%) Terapia Intensiva Mesi di follow-up

Strategie ipoglicemizzanti Captazione del glucosio Funzione pancreatica Produzione di glucosio Insulina Metformina Glitazoni Insulina Metformina Glitazoni Sulfoniluree Glinidi Analoghi GLP-1 Inibitori DPP-IV TZD, Metformina GR antag. GKAs Assorbimento del glucosio Escrezione del glucosio Inibitori glucosidasi Incretino-mimetici Amilina SGLT2 SGLT1 Inibitori SGLT-2

Ipoglicemizzanti orali 16 molecole 44 combinazioni 88 prodotti Farmaci ipoglicemizzanti nel Prontuario Farmaceutico Italiano, anno 2009 Ipoglicemizzanti orali 16 molecole 44 combinazioni 88 prodotti Insuline 8 molecole 8 combinazioni 38 prodotti

Sfide chiave nel diabete di tipo 2 outcome 40-50% dei pazienti non raggiunge i target di glicemia . Ford et al (NHANES). Diabetes Care. 2008; 31: 102–4 10

FATTORI DI FALLIMENTO SECONDARIO

IMPORTANZA DEL TRATTAMENTO PRECOCE E INTENSIVO 25-40 %* 25-65%* * Riduzione media rischio Fonte: CORE/IMS basato su UKPDS con diagnosi a 52 aa

IL CONTROLLO GLICEMICO PEGGIORA NEL TEMPO Convenzionale* Rosiglitazone Glibenclamide Metformina UKPDS ADOPT Metformina Glibenclamide Insulina 9 8.0 6.0 7.5 7.0 6.5 Rosiglitazone vs Metformina –0.13 (–0.22 to –0.05), p=0.002 Rosiglitazone vs Glibenclamide –0.42 (–0.50 to –0.33), p<0.001 8.5 8 7.5 Mediana HbA1c (%) Over time, glycaemic control deteriorates UKPDS clearly showed the need for new diabetes treatments (Shorten UKPDS explanation; add ADOPT) In UKPDS, the yearly median HbA1c in patients receiving conventional treatment increased steadily throughout the trial. Indeed, within 2 years of diagnosis, this group had a median HbA1c above the recommended target level of < 7.0%. In contrast, median HbA1c fell during the first year in patients receiving intensive treatment (glibenclamide, metformin or insulin) but gradually increased subsequently and only remained within the recommended treatment target for the first 3–6 years of treatment (depending on assigned treatment). During the remaining years of follow-up, median HbA1c continued to rise steadily above treatment targets. This failure of existing treatments, even when used intensively in highly motivated patients highlights the need for new treatments in the management of type 2 diabetes. UKPDS methodology UKPDS recruited 5102 patients with newly diagnosed type 2 diabetes; 4209 were randomised. Conventional therapy aimed to maintain fasting plasma glucose (FPG) at < 15 mmol/l (270 mg/dl) using diet alone initially. However, sulphonylureas, insulin or metformin could be added if target FPG was not met. Patients assigned to intensive therapy had a target FPG < 6 mmol/l (108 mg/dl) and, in insulin-treated patients, a pre-meal FPG of 4–7 mmol/l (72–126 mg/dl). Non-overweight patients were randomised to insulin or sulphonylurea monotherapy initially. Overweight patients receiving intensive treatment could also be randomised to metformin. These agents could be combined if necessary to maintain target FPG during the trial. The data in this figure are from overweight patients (UKPDS 34). The HbA1c findings in non-overweight patients were similar; regardless of treatment, median HbA1c exceeded the recommended treatment targets within 8 years of therapy (UKPDS 33). References UKPDS 34. Lancet 1998;352:854–865 UKPDS 33. Lancet 1998;352:837–853 Disease progression in type 2 diabetes As UKPDS demonstrated, even with intensive therapy, target glycaemic levels are not maintained long-term. One of the main reasons for this is that type 2 diabetes is a progressive disease characterised by continued, worsening -cell failure. Indeed, at the time of diagnosis, -cell function is already markedly compromised (by approximately 50%), and, as the above slide shows, function continues to worsen. Furthermore, as the extrapolation on this slide demonstrates, -cell function may have been suboptimal for 10 years prior to diagnosis. The ideal long-term treatment for diabetes should therefore address continued -cell deterioration. Reference UKPDS 16. Diabetes 1995;44:1249–1258 7 Target terapeutico raccomandato <7.0%† 6.5 6 6.2% – limite superiore di normalità 1 2 3 4 5 2 4 6 8 10 Anni dalla randomizzazione Tempo (anni) * Inizialmente dieta quindi sulfoniluree, insulina e/o metformina se FPG>15 mmol/L †ADA raccomandazioni cliniche pratiche. UKPDS 34, n=1704 UKPDS 34. Lancet 1998:352:854–65; Kahn et al (ADOPT). NEJM 2006;355(23):2427–43 13

Il numero di farmaci assunti aumenta con la durata della malattia diagnosi di diabete fallimento monoterapia necessità di insulina 100 80 monoterapia doppia terapia terapia multipla ± insulina insulina 60 Beta-cell function (%) 40 IGT 20 10 15–25 Approximate time (years) IGT=impaired glucose tolerance. UKPDS 16. Diabetes. 1995;44:1249–1258. Turner RC et al. JAMA. 1999;281:2005–2012; Warren RE. Diabetes Res Clin Pract. 2004;65:S3–S8; Lebovitz HE. Med Clin N Am. 2004;88:847–863.

MASSA -CELLULARE NEL DIABETE DI TIPO 2 -50% -63% Obese Lean Butler AE et al. Diabetes, 2003;52:102

PROGRESSIVA PERDITA DELLA SENSIBILITÀ AL GLUCOSIO DELLE CELLULE  NGT IGT DMT2

Molte terapie causano aumento di peso nel tempo UKPDS: fino a 8 kg in 12 anni ADOPT: fino a 4.8 kg in 5 anni 8 100 Differenze nel trattamento (95% CI) Rosiglitazone vs. metformina 6.9 (6.3 tp 7.4); p<0.001 Rosiglitazone vs. glibenclamide, 2.5 (2.0 to 3.1); p<0.001 7 Insulina (n=409) 6 96 5 Glibenclamide (n=277) Cambio di peso (kg) 4 Peso (kg) 92 3 Most therapies results in weight gain over time The influence of diabetes treatment on weight was evident in the UKPDS study (UKPDS 34): regardless of treatment, patients gained weight. Patients treated with insulin showed the largest weight increase, with an average gain of 4.0 kg more than conventional therapy at 10 years (UKPDS 33). The extent of weight gain observed in UKPDS in insulin-treated patients has been confirmed in subsequent studies. For example, in a 6-month study comparing bedtime insulin glargine with NPH insulin once daily (both agents added to existing oral therapy in a treat-to-target protocol), weight gain at the end of the trial period was 3.0 and 2.8 kg, respectively (Riddle et al, 2003). In the ADOPT study, rosiglitazone, metformin, and glibenclamide were evaluated as initial treatment for recently diagnosed type 2 diabetes in a double-blind, randomized, controlled clinical trial involving 4360 patients. The patients were treated for a median of 4.0 years. Rosiglitazone was associated with more weight gain and edema than either metformin or glibenclamide. Generally, weight gain is the consequence of an increase in calorie intake or a decrease in calorie utilisation. It can result from a number of specific factors: Poor glycaemic control increases metabolic rate and consequently, improving glycaemic control decreases metabolism. If calorie intake is not modified accordingly, then weight will increase. Improving metabolic control reduces glucosuria (excretion of glucose through the urine), thus fewer calories are lost in this manner. Normally, insulin suppresses food intake through its effect on CNS appetite control pathways. It has been suggested that this effect of insulin is lost in diabetes patients. Fear of hypoglycaemia may lead to increased snacking between meals, thus increasing calorie intake. Additionally, aside from modifications to calorie intake or utilisation, use of insulin can increase lean body mass through its anabolic nature. References UKPDS 34. Lancet 1998:352:854–65. Kahn et al (ADOPT). NEJM 2006;355(23):2427–43 2 88 1 Metformina (n=342) 3 6 9 12 1 2 3 4 5 Anni dalla randomizzazione Annualised slope (95% CI) Rosiglitazone, 0.7 (0.6 to 0.8) Metformin, -0.3 (-0.4 to -0.2)** Glibenclamide, -0.2 (-0.3 to 0.0)** Anni Terapia convenzionale (n=411); inizialmente solo dieta, successivamente sulfoniluree, insulina e/o metformina se FPG >15 mmol/L UKPDS 34. Lancet 1998:352:854–65. n=at baseline; Kahn et al (ADOPT). NEJM 2006;355(23):2427–43 17

LE ATTUALI TERAPIE AUMENTANO IL RISCHIO DI IPOGLICEMIA p<0.05 glibenclamide vs rosiglitazone Eventi ipoglicemici totali (%) 10 39 5 15 20 25 30 35 40 45 Rosiglitazone Metformina Glibenclamide 12 60 50 40 Pazienti (%) con HbA1c <7% 30 20 Con ipoglicemia notturna 10 Glargine NPH *Eventi ipoglicemici totali riportati dai pazienti alla visita di follow-up Riddle et al. Diabetes Care 2003;26:3080; Kahn et al (ADOPT). NEJM 2006;355:2427–43 18

Rischio di ipoglicemia con le diverse sulfaniluree Rischio relativo (%) Grave ipoglicemia n/1000 persone anno = Gliclazide 0,85 Glipizide 8,70 Glimepiride 0,86 Tolbutamide 3,50 Clorpropamide 16,00 Glibenclamide 16,00 *<50 mg/dl Tayek J. Diabetes Obes Metab 2008; 10:1128-1130

GUIDA: I RISCHI DELL’IPOGLICEMIA IN UK 45 incidenti stradali gravi ogni mese Grossa percentuale riguarda pazienti affetti da DMT2 In un sondaggio su 106 operatori sanitari 40% ha risposto che non sapeva che i pazienti dovessero fare il test prima di guidare 13% pensava fosse sicuro guidare con valori di glucosio < 70 mg/dl In the UK, there are five fatal road traffic accidents each year and 45 serious road traffic events each month as a result of hypoglycaemia Although the data do not differentiate between hypoglycaemia due to type 1 or type 2 diabetes, it is likely that a proportion of these incidents will involve patients with type 2 diabetes A survey from Aberdeen Royal Infirmary of 106 primary and secondary health professionals (55% doctors) found that 40% of respondents said that they didn’t know patients should test before driving 13% thought it was safe to drive with blood glucose concentrations of less than 4 mmol/l Reference Hitchen L. BMJ 2006; 332: 812. Hitchen L. BMJ. 2006;332:812

HbA1c, FPG e PPG deteriorano Le necessità non soddisfatte nel diabete tipo 2 Con il progredire del diabete tipo 2: HbA1c, FPG e PPG deteriorano La funzione Beta-cellulare declina Aumento del rischio CVD Aumento del peso del paziente 21

…ma le terapie attualmente a disposizione… consentono di raggiungere obiettivi terapeutici? hanno come bersaglio i meccanismi responsabili della resistenza all'insulina e della disfunzione β cellulare ? Sono in grado di ridurre i fattori di rischio cardiovascolare, gli eventi cardiovascolari e la mortalità CV?

LE TERAPIE ATTUALI NON TRATTANO ADEGUATAMENTE LA DISFUNZIONE -CELLULARE Insulin Resistance (Impaired insulin action) Pancreatic Islet Dysfunction Inadequate glucagon suppression (-cell dysfunction) Insufficient Insulin secretion (β-cell dysfunction) Progressive decline of β-cell function Sulfonylureas Glinides TZDs Metformin ?? Current Oral Therapies Do Not Address Pancreatic Islet Cell Dysfunction The pathophysiologic hallmarks of type 2 diabetes mellitus (T2DM) are insulin resistance, pancreatic islet dysfunction (α- and β-cell dysfunction), and excessive hepatic glucose production.1 Current oral antidiabetics (OADs) address various aspects of these defects, focusing heavily on insulin resistance and glucose control.2 There remain unmet needs in the treatment armamentarium of T2DM, particularly with regard to pancreatic islet dysfunction. No currently available traditional OADs address α-cell dysfunction and the resulting inadequate suppression of glucagon, which leads to increased hepatic glucose production. While the insulin secretagogues are used to treat insufficient insulin secretion (β-cell dysfunction), no oral agents to date address the more progressive β-cell decline. References Moneva MH, Dagogo-Jack S. Multiple drug targets in the management of type 2 diabetes. Curr Drug Targets. 2002; 3: 203–221. DeFronzo RA. Impaired glucose tolerance: do pharmacological therapies correct the underlying metabolic disturbance? Br J Diabetes Vasc Dis. 2003; 3(suppl 1): S24–S40. TZD=thiazolidinedione; T2DM=type 2 diabetes mellitus Adapted from DeFronzo RA. Br J Diabetes Vasc Dis. 2003; 3(suppl 1): S24–S40.

Le incretine Le incretine Ormoni peptidici rilasciati dal tratto gastrointestinale e immessi nel torrente circolatorio in risposta all’assunzione di nutrienti (in particolare carboidrati) Funzione insulare Effetti acuti Migliore secrezione di insulina (β-cellule) Soppressione della secrezione di glucagone (α-cellule) Effetti cronici Rigenerazione beta-cellule  proliferazione -cellule  morte -cellule GLP-1: cell L, ileo e colon GLP-1 β Assunzione di cibo  Insula GIP β GIP: cell K, duodeno GLP-1: emivita (1-2 min), per inattivazione da parte dell’enzima dipeptidil peptidasi IV (DPP IV) GLP-1 = glucagon-like peptide–1; GIP = glucose-dependent insulinotropic polypeptide

Famiglia delle terapie basate su incretine

Data from BARDS Terapia combinata: Sitagliptin e Metformina Study 036 – Continuation Phase 2017/3/27 Terapia combinata: Sitagliptin e Metformina Adapted from Qi Daniel S., et al. 73-OR, EASD 2008. Data from BARDS 24-Week Phase Continuation Phase Extension Phase 9 8.5 8 HbA1c (LS mean change %) 7.5 7 6.5 6 0 6 12 18 24 30 38 46 54 62 70 78 91 104 Time (weeks) Sita 100 mg q.d. (n=50) Met 500 mg b.i.d. (n=64) Met 1000 mg b.i.d. (n=87) Sita 50 mg b.i.d. + Met 500 mg b.i.d. (n=96) Sita 50 mg b.i.d. + Met 1000 mg b.i.d. (n=105) 26

Struttura degli agonisti del GLP-1R GLP-1 (forma amidata)‏ 7 10 15 20 25 30 35 36 Inattivazione proteolitica (DPP-4)‏ Exenatide Liraglutide Albumina C-16 ac. grasso libero Vildagliptin Sitagliptin Adapted from Drucker and Nauck, Lancet 2006;368:1696-705.

Variazione di HbA1c (%)‏ Effetto di exenatide in aggiunta a metformina, sulfonilurea o met+sulf su HbA1c dopo 30 settimane in soggetti con T2DM Placebo BID Exenatide 5 µg BID Exenatide 10 µg BID Met Sulf Met + Sulf -0.4 * -0.8 -1 -0.5 0.5 0.1 0.1 -0.5 * -0.9 0.2 -0.6 * -0.8 Variazione di HbA1c (%)‏ * * DeFronzo RA, et al. Diabetes Care. 2005;28:1092-1100.; Buse JB, et al. Diabetes Care. 2004;27:2628-2635.; Kendall DM, et al. Diabetes Care. 2005;28:1083-1091.

Effect on HbA1c when adding liraglutide LEAD-3 Monotherapy LEAD-2 Met combination LEAD-1 SU combination LEAD-4 Met + TZD combination LEAD-5 Met + SU combination Baseline HbA1c % 8.4 8.6 8.6 8.4 8.2 8.2 8.4 8.5 8.6 8.3 8.5 8.5 8.6 8.4 8.3 8.1 8.3 Change in HbA1c (%) * ** *** *** *** *** *** Liraglutide 1.8 mg Liraglutide 1.2 mg Glimepiride Rosiglitazone Insulin glargine Placebo #Patients reaching ADA target for overall population (LEAD-4,-5); add-on to diet and exercise failure (LEAD-3); or add-on to previous OAD monotherapy (LEAD-2,-1). *p<0.01, **p<0.001, ***p≤0.0001 vs. active comparator Garber et al. Lancet 2009;373(9662):473–81 (LEAD-3); Nauck et al. Diabetes Care 2009;32:84–90 (LEAD-2); Marre et al. Diabet Med 2009;26:268–78 (LEAD-1); Zinman et al. Diabetes Care 2009;32:1224–30 (LEAD-4); Russell-Jones et al. Diabetologia 2009;52:2046–55 (LEAD-5) 29

Liraglutide improves HbA1c by up to 2.5% in poorly controlled patients Baseline category of HbA1c Change in HbA1c (%) Nauck et al. IDF 20th World Diabetes Congress 2009;P-1400

Effetto della monoterapia con liraglutide sul controllo glicemico a lungo termine LEAD 3, precedente dieta ed esercizio (LOCF per le visite successive al baseline – ITT)‏ -0.2 62% 58% 31% -0.4 9.0 Glimepiride 8 mg -0.6 Liraglutide 1.2 mg monoterapia Variazione HbA1c (%)* -0.8 -1.0 Liraglutide 1.8 mg monoterapia -1.2 % del target ADA 8.5 -1.4 -1.6 8.0 HbA1c (%)‏ 7.5 Effect of liraglutide monotherapy on glycaemic durability The LEAD 3 study demonstrates that initiating liraglutide treatment as monotherapy is an attractive option for first-line treatment. Decreases in key efficacy endpoints such as FPG occur quickly after initiation of liraglutide treatment. At the higher dose of liraglutide, the decrease in HbA1c remained stable through the 52-week period for subjects previously treated with diet and exercise. 7.0 6.5 4 8 12 16 20 24 28 32 36 40 44 48 52 weeks *Variazie di HbA1c rispetto al basale nei pz in fallimento da dieta ed esercizio o di metà del dosaggio massimo di 1 OAD; media (SD)‏ A. Garber et al., Diabetes 2008;57(Suppl. 1):7LB. 31

Mantenimento di HbA1c <7% per due anni con liraglutide in monoterapia ( estensione LEAD3) EOT Table 14.2.5-2 Observed mean±2SE, no imputation for missing values. Completer analysis. Garber et al. Diabetes 2009;58(Suppl 1):162-OR

La triade del glucosio per un trattamento ottimale … HbA1c Controllo glicemico a lungo termine Glicemia basale Picco glicemico Post-prandiale

PPG reduction (mmol/L) Effect of liraglutide on FPG and peak PPG (LEAD-2, 1, 4, 5) Liraglutide reduces FPG (before 2 weeks) Liraglutide 1.8 mg Liraglutide 1.2 mg 1 2 3 PPG reduction (mmol/L) SU combi LEAD 1 Met combi LEAD 2 Met + TZD combi LEAD 4 Met + SU combi LEAD 5 Mono LEAD 3 Mean PPG reduction over 3 meals 10 Liraglutide 1.8 mg + met + SU Insulin glargine + met + SU 9 FPG (mmol/L) 8 7 2 8 12 18 26 LEAD 5 Week LEAD: Liraglutide Effect and Action in Diabetes. Marre et al. Diabetic Medicine 2009;26;268–78 (LEAD-1); Nauck et al. Diabetes Care 2009;32;84–90 (LEAD-2); Garber et al. Lancet 2009;373:473–81 (LEAD-3); Zinman et al. Diabetes Care 2009; DOI:10.2337/dc08-2124 (LEAD-4); Russell-Jones et al. Diabetes 2008;57(Suppl. 1):A159 (LEAD-5). 34

Progressiva perdita della sensibilità al glucosio delle cellule b NGT IGT DMT2

A single dose of liraglutide restores beta-cell glucose sensitivity 14 Placebo Liraglutide 7.5 μg/kg Healthy 12 10 8 Insulin secretion rate (pmol/min/kg) 6 4 In this study, the effect of liraglutide on beta-cell sensitivity was assessed using a graded glucose infusion protocol, during which glucose is infused to create gradually rising plasma levels from 5–12 mmol/l (90–216 mg/dl) over 3 hours. Approximately 9 hours before the graded glucose infusion, patients with type 2 diabetes (n = 10) received a single subcutaneous dose of liraglutide (7.5 μg/kg) or a single dose of placebo in a double-blind, crossover design (3–6-week washout period). A group of healthy controls who did not receive any injections were also included. After an overnight fast and prior to glucose infusion, all groups received a small i.v. bolus of insulin (0.007–0.014 units/kg). This bolus reduced blood glucose to approximately 5 mmol/l (90 mg/dl) in healthy controls, and 6 mmol/l (108 mg/dl) in the liraglutide and placebo groups (this bolus probably explains the horizontal line between the first two measurements). Graded glucose infusion was then initiated and insulin secretion assessed. In all groups, insulin secretion increased concomitantly with increases in glucose concentration. However, after liraglutide dosing, the effect was more pronounced than following placebo, and the secretion rate was similar to that observed in the non-diabetic controls. Thus, a single dose of liraglutide is sufficient to reinstate the insulin response to glucose that is observed in healthy controls. Reference Study 2063. Chang et al. Diabetes 2003;52:1786–91. 2 4 6 8 10 12 mmol/l 80 100 120 140 160 180 200 220 mg/dl Glucose Adapted from: Chang et al. Diabetes 2003;52:1786–91. Data are mean ± SEM.

Subjects with type 2 diabetes have impaired first phase insulin secretion Control subjects Type 2 diabetes Plasma insulin (µU/ml) Plasma insulin (µU/ml) 120 120 100 80 60 40 20 –30 30 90 20 g glucose 20 g glucose 100 80 60 This slide shows the insulin response to 20 g of glucose delivered intravenously to individuals with or without type 2 diabetes. In control subjects, this glucose injection results in a striking increase in insulin; this response is severely diminished in patients with type 2 diabetes. Reference Ward WK et al. Diabetes Care 1984;7:491–502. 40 20 –30 30 60 90 100 Time (min) Time (min) Ward WK et al. Diabetes Care 1984;7:491–502.

Maximal beta-cell secretory capacity First-phase insulin response Effetto di GLP-1 analogo sulla funzione beta-cellulare Mean clamp profiles for insulin Maximal beta-cell secretory capacity 2716 Mean First Phase Insulin (Clamp) Profiles Figure 8.1 2477 256 241 2238 226 211 1999 195 GLP1 analogo 180 Concentration (pmol/L)‏ 165 Placebo 1761 150 135 1522 119 Concentration (pmol/L)‏ 104 1283 89 2 4 6 8 10 12 14 16 18 20 1044 First-phase insulin response 805 Effect of liraglutide on beta-cell function This study assessed the effect of liraglutide on pancreatic B-cell function. Patients with Type 2 diabetes (n=39) were randomized to treatment with 0.65, 1.25 or 1.9 mg/day liraglutide or placebo for 14 weeks. First- and second-phase insulin release were measured by means of the insulin-modified frequently sampled intravenous glucose tolerance test. Arginine-stimulated insulin secretion was measured during a hyperglycaemic clamp (20 mmol/l). Glucose effectiveness and insulin sensitivity were estimated by means of the insulin-modified frequently sampled intravenous glucose tolerance test. Fourteen weeks of treatment with liraglutide showed improvements in first- and second-phase insulin secretion, together with improvements in arginine- stimulated insulin secretion during hyperglycaemia. The two highest doses of liraglutide (1.25 and 1.9 mg/day) significantly increased first-phase insulin secretion by 118 and 103%, respectively (P<0.05). Second-phase insulin secretion was significantly increased only in the 1.25 mg/day group vs. placebo. Arginine-stimulated insulin secretion increased significantly at the two highest dose levels vs. placebo by 114 and 94%, respectively (P<0.05). Reference Vilsboll et al. Diabet Med 2008; 25: 152–6 567 328 89 15 30 45 60 75 90 105 Arginine bolus 135 150 Time (min)‏ Misura della prima fase di risposta insulinica e della capacità secretoria beta-cellulare massimale. Profilo insulinico medio durante un bolo di glucosio (dettaglio), clamp iperglicemico e test di stimolazione con argininina Vilsboll et al. Diabet Med 2008; 25: 152–6 38

Liraglutide improves beta-cell function as measured by HOMA-B Solid colour = Baseline (%) Graded colour = Change (%) Marre et al. Diabetic Medicine 2009;26;268–78 (LEAD-1) 39

LEAD 1–6: weight change Significant * vs. comparator Mean±2SE Marre et al. Diabetic Medicine 2009;26;268–78 (LEAD-1); Nauck et al. Diabetes Care 2009;32;84–90 (LEAD-2); Garber et al. Lancet 2009;373:473–81 (LEAD-3); Zinman et al. Diabetes Care 2009; DOI:10.2337/dc08-2124 (LEAD-4); Russell-Jones et al. Diabetes 2008;57(Suppl. 1):A159 (LEAD-5); Buse et al. Lancet 2009; in press (LEAD-6)

Body weight change by BMI baseline subgroup (LEAD-3) Statistical analysis not performed Mean±2SE Garber et al. Lancet 2009;373:473–81 (LEAD-3)

Mantenimento della riduzione di peso per due anni liraglutide in monoterapia (esten del LEAD 3) Garber et al. Diabetes 2009;58(Suppl 1):162-OR

Most weight loss with liraglutide comes from fat tissue LEAD-2 LEAD-3 4 4 Fat tissue Lean tissue Fat tissue Lean tissue ** *** 2 2 Change in tissue mass (kg) Change in tissue mass (kg) NS NS –2 –2 ** ** –4 –4 –6 –6 Liraglutide 1.2 mg/day + metformin Liraglutide 1.8 mg/day + metformin Placebo + metformin Glimepiride 8 mg/day + metformin Liraglutide 1.2 mg/day Liraglutide 1.8 mg/day Glimepiride 4 mg/day DEXA, dual-energy X-ray absorptiometry;Data are mean ± SE; **p<0.01; *** p<0.001 vs. glimepiride + metformin in LEAD-2 and vs. glimepiride in LEAD-3 Jendle et al. Diabet Obes Metabol 2009;11:1163–72 (LEAD-2 and LEAD-3 substudies). 43

Waist circumference (LEAD-2) *p<0.0001 for treatment difference in changes versus glimepiride Mean±2SE Nauck et al. Diabetes Care 2009;32:84–90 (LEAD-2)

Variazioni di peso con le terapie per il diabete di tipo 2 12 – 10 – 8 – 6 – 4 – 2 – 0 – -2 – -4 – -6 – Weight (lbs) SFU MET TZD INS Studio retrospettivo 1996-2002. N=9546 hanno iniziato e mantenuto una terapia stabile per almeno 12 mesi Predittori di aumento di peso: giovane età, sesso maschile, elevata HbA1c, uso di SSRI. Nichols GA, et al: Presented at 65th Annual Session of ADA, San Diego, June 2005.

LEAD 2 e 4- minor rischio di eventi ipoglicemici Liraglutide 0.6 mg 1.8 mg Placebo Glimepiride LEAD-2 Met 0.0 1.0 2.0 3.0 Events/ subject-year 1.2 mg LEAD-4 Met+Ros Events/ subject-year 0.0 1.0 2.0 3.0 Rosiglitazone Liraglutide 1.8 mg Placebo 1.2 mg Nauck M et al. Diabetes Care 2009;32:84 (LEAD-2); Zinman B et al. Diabetes Care 2009; i32:1224 (LEAD-4) 46 46 46

Patients reaching target (%) End-point composito: HbA1c < 7% , nessun aumento di peso e nessuna ipoglicemia 45 39% 40 32%* Liraglutide 1.2 mg (n=896) 35 30 24%* Exenatide (n=231) 25 Patients reaching target (%) 20 15%** Glargine (n=232) 15 8%**,  SU (n=490) 8%**,  Placebo (n=524) 6%**,  TZD (n=231) 10 5 Liraglutide 1.8 mg (n=1363) Liraglutide 1.8 mg is superior (*p<0.01; ** p<0.0001) Liraglutide 1.2 mg is superior ( p<0.0001) Percentages are from logistic regression model adjusted for trial, previous treatment and with baseline HbA1c and weight as covariates Zinman et al, Diabetologia 2009;52(Suppl 1):S292 (A743)

Liraglutide e fattori di rischio cardiovascolari Sistolic blood pressure (mmHg) -2.51 Diastolic blood pressure (mmHg) -1.05 Total cholesterol (mmol/l) -0.20 LDL-cholesterol (mmol/l) -0.44 Triglycerides (mmol/l) -0.41 De Block CE, Van Gaal L Lancet 2009;374:4

Composite endpoint 2 HbA1C <7.0%,SBP<130 mmHg, no weight gain 30 25% 25 21% 20 Patients reaching target (%) 15 14%* 10 7%* 5%* 5%* 5 3%* Liraglutide 1.8 mg Liraglutide 1.2 mg SU TZD Glargine Exenatide Placebo (n=1363) (n=896) (n=490) (n=231) (n=232) (n=231) (n=524) *p<0.01 vs liraglutide 1.8 mg

Introduzione incretine come terapia di base Pro Contro Riduzione della glicemia Prevenzione aumento di peso Ridotto rischio di ipoglicemia Potenziali benefici CV Potenziale preservazione della β cellula Effetti su obiettivi difficili da raggiungere? Efficacia a lungo termine? Costi del trattamento Raccomandazioni di linee guida Adapted from Nauck M. and Smitu U. Clin Endocrinol Metab 2009;23:513

Risk of acute pancreatites in a retrospective observational study in a cohort of 337,067 individual with T2DM and 337,067 non diabetic control [4,31 – 6,42] [2,61 – 3,06] 5,26 2,83 Noel RA, Diabetes Care 2009, 32:834

Relative Risk of Pancreatites in T2DM patients treated with Exenatide, Sitagliptin or Metformin/Glyburide

GLP-1 receptor agonists vs DPP-4 Inhibitors: GLP-1 Receptor Agonists Il Confronto Action GLP-1 Receptor Agonists DPP-4 Inhibitors Reduction HbA1c ++ + Reduction PPG Reduction Body Weight +++ = Safety Patient Compliance Tolerability HL Ref DeFronzo_Curr_Med_Res_Opin_2008_p12,13,14_ms.doc DISCUSSION1,2 GLP-1 agonists and DPP-4 inhibitors have some overlapping actions that are beneficial in the treatment of type 2 diabetes Both suppress glucagon secretion, leading to a reduction in glucose output Both enhance glucose-dependent insulin secretion GLP-1 agonists have additional therapeutic actions for which DPP-4 inhibitors exhibit marginal or no obvious effects GLP-1 agonists suppress appetite/induce satiety GLP-1 agonists decelerate gastric emptying REFERENCES 1. Drucker DJ and Nauck MA. Lancet. 2006;368:1696-1705 2. DeFronzo RA, et al. Curr Med Res Opin. In press 53

Il presente: AMD-SID 2010 Metformina + basal-bolus DIAGNOSI Intervento su stile di vita metformina MET + insulina basale MET + glitazone MET + analogo GLP-1 MET + gliptina MET + SU o glinide MET + SU o glinide + TZD MET + SU o glinide + analogo GLP-1 MET + SU + gliptina MET + MET + SU o glinide + insulina basale Metformina + basal-bolus

A LUCIANO RAFFAELE PASTORE Grazie per l’attenzione ANNA CARNOVALE MARCO ROSSETTI GIOVANNA TARQUINI IRENE TURINESE SUSANNA MORANO DEDICATO A LUCIANO RAFFAELE PASTORE