Dott.ssa Paola Del Sindaco Città di Castello, 19 novembre 2011

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1 Dott.ssa Paola Del Sindaco Città di Castello, 19 novembre 2011
Il nuovo analogo del GLP-1 Liraglutide. Dalla fisiologia all’uso in terapia Dott.ssa Paola Del Sindaco Città di Castello, 19 novembre 2011 1

2 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 (%) 7 Target terapeutico raccomandato <7.0%† 6.5 6 6.2% – limite superiore di normalità 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 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 2

3 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 Con ipoglicemia diurna 40 Pazienti (%) con HbA1c <7% 30 20 Con ipoglicemia notturna 10 Glargine NPH Current treatment increase risk of hypoglycaemia Many drugs currently used for the treatment of type 2 diabetes cause hypoglycaemia Rosiglitazone 10% Metformin 12% Glibenclamide 39% References Riddle et al. Diabetes Care 2003;26:3080 Kahn et al (ADOPT). NEJM 2006;355:2427–43 *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 3

4 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 7 Insulina (n=409) 6 96 5 Glibenclamide (n=277) Cambio di peso (kg) 4 92 Peso (kg) 3 2 88 1 Metformina (n=342) 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 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 4

5 Aumento di pressione arteriosa e mortalità da patologia cardiaca
Mortalità per CHD a 10 anni aggiustata per l'età in base alla glicemia basale 12 WC AC IA 10 Maschi 8 20 Femmine 6 Δ pressione sistolica (mmHg) 4 2 % mortalità (CHD) 10 -2 -4 3 6 9 3 6 9 3 6 9 2437 2196 1962 Anni di diabete 257 239 220 246 238 221 Controlli (no diabete) Diabete Borderline Diabete Blood pressure and mortality from heart disease increase Systolic blood pressure Davis and colleagues have investigated the relationship among self-reported ethnicity, metabolic control, and blood pressure during treatment of type 2 diabetes. The study comprised 2,999 newly diagnosed type 2 diabetic patients recruited to the U.K. Prospective Diabetes Study who were randomized to conventional or intensive glucose control policies if their fasting plasma glucose levels remained >6 mmol/l after a dietary run-in. After adjustment for antihypertensive therapy, increase in systolic blood pressure at 9 years was greatest in AC patients (7 mmHg; P , 0.01 vs. WC patients). This study shows important ethnic differences in body weight, lipid profiles, and blood pressure, but not glycemic control, during 9 years after diagnosis of type 2 diabetes. AC patients maintained the most favorable lipid profiles, but hypertension developed in more AC patients than WC or IA patients. Ethnicity-specific glycemic control of type 2 diabetes seems unnecessary, but other risk factors need to be addressed independently. CHD Mortality rates from coronary heart disease and from all causes have been ascertained over ten years in three groups of people participating in the Bedford Survey--newly-diagnosed diabetics, borderline diabetics and control subjects with normal glucose tolerance. Age corrected mortality rates, from all causes and coronary heart disease, were highest in the diabetics and intermediate in the borderline diabetics and in both groups were similar in men and women. It was concluded that borderline diabetes (or impaired glucose tolerance) is associated with a relatively greater increase in mortality risk in women than men. References Davis et al. Diabetes Care 2001;24:1167–74 Jarrett et al. Diabetologia 1982;22(2):79–84 Numero di pazienti Media (barre) e 99% CIs (linee verticali) per le variazioni cross-sectional; WC, white Caucasian; AC, Afro-Caribbean; IA, Asian of Indian origin Davis et al. Diabetes Care 2001;24:1167–74; Jarrett et al. Diabetologia 1982;22(2):79–84. 5

6 NECESSITA’ DELLA DIABETOLOGIA MODERNA
Raggiungere la normoglicemia portando il paziente a target di HbA1c, FPG e PPG Ridurre problematiche quali l’aumento del peso corporeo e il rischio di ipoglicemia Effettuare una terapia multisistemica, personalizzata e il più tempestiva possibile Ridurre il rischio CV Terapia che intervenga su meccanismi fisiopatologici

7 X Ruolo delle incretine nell’omeostasi glicemica Ingestione di cibo
 Insulina da cellule beta (GLP-1 and GIP) Glucosio dipendente  Uptake di glucosio e immagazzina-mento nei muscoli e nel tessuto adiposo Tratto GI Rilascio di ormoni intestinali: incretine Pancreas Beta cellule Più stabile controllo della glicemia Alpha cellule GLP-1 e GIP attivi  Rilascio di glucosio nel sangue da parte del fegato X Enzima DPP-4  Glucagone da cellule alpha (GLP-1) Glucosio dipendente Metaboliti GLP-1 e GIP Brubaker PL et al Endocrinology 2004;145:2653–2659; Ahrén B Curr Diab Rep 2003;3:365–372; Drucker DJ Expert Opin Investig Drugs 2003;12:87–100; Zander M et al Lancet 2002; 359: 824–830; Holst JJ Diabetes Metab Res Rev 2002;18: 430–441; Holz GG et al Curr Med Chem 2003;10:2471–2483; Creutzfeldt WOC et al Diabetes Care 1996; 19:580–586; Drucker DJ Diabetes Care 2003; 26: 2929–2940

8 Effetto Incretinico Tempo (min)
IR-insulina (mU/L) 80 60 40 20 –10 –5 120 180 * Tempo (min) Effetto Incretinico Risposta Insulinica Glucosio per via orale (50 g/400 mL) Glucosio per via e.v glucosio plasmatico (mmol/L) 10 5 15 Glucosio Plasmatico 90 270 The incretin effect The effect of incretins on insulin secretion is clearly indicated in this study. Healthy volunteers (n=8) fasted overnight before they received an oral glucose load of 50 g/400 ml or an isoglycaemic intravenous glucose infusion for 180 minutes. As can be seen in the left figure, venous plasma glucose concentration was similar with both glucose interventions. However, insulin concentration was greater following oral glucose ingestion than following intravenous glucose infusion, demonstrating the contribution of incretins on insulin secretion. The incretin effect is the difference in insulin response between orally delivered and intravenously delivered glucose References Nauck et al. Diabetologia 1986;29:46–52 La risposta insulinica è maggiore in seguito a carico orale di glucosio rispetto ad una somministrazione di glucosio e.v, nonostante concentrazioni identiche di glucosio plasmatico Nauck et al. Diabetologia 1986;29:46–52. *p≤0.05. n=8 healthy volunteers

9 Storia del GLP-1 Analoghi long-acting (e.g., liraglutide) Scoperta del prodotto del gene proglucagone Conferma dell’azione insulinotropica delle incretine Normalizzazione di BG nel diabete tipo 2 Ulteriore definizione di incretine e asse enteroinsulare Definizione di incretine ‘Asse enteroinsulare’ Clonazione del recettore History of GLP-1 In 1930, Zunz and LaBarre described an intestinal extract that could produce hypoglycaemia. In a separate paper, LaBarre used the term ‘incretin’ to describe activity in the gut that might initiate pancreatic endocrine secretions. In 1963, McIntyre suggested that a humoral substance was released from the jejunum during glucose absorption, acting in concert with glucose to stimulate insulin release from pancreatic ß-cells. In 1969, Unger and Eisentraut referred to the gut—pancreas association as the enteroinsular axis. In 1979, this axis was subsequently described as involving nutrient, neural, and hormonal signals from the gut to the pancreatic islet cells that secrete insulin, glucagon, and somatostatin. Incretins acting on this pathway must be secreted in response to nutrient stimuli and must stimulate glucose-dependent insulin secretion (Creutzfeldt 1979). In the early 1980s, GLP-1, was discovered to be a product of the proglucagon gene. The GLP-1 receptor was initially cloned in 1992 by Bernard Thorens in the rat pancreatic islet cell (Thorens 1992). A year later, a human pancreatic GLP-1 receptor with 90% homology to the amino acid sequence of the rat receptor was cloned (Dillon et al. 1993, Graziano et al. 1993, Thorens et al. 1993). In 1993, Nauck et al. published the findings of a study investigating the blood glucose lowering potential of GLP-1 in ten type 2 diabetes patients with unsatisfactory metabolic control from diet or sulphonylurea treatment. Continuous intravenous (i.v.) infusion of GLP-1 during a fasting state significantly increased insulin and C-peptide secretion while reducing glucagon secretion. Plasma glucose returned to normal fasting glucose concentrations within 4 hours of GLP-1 administration: no such decrease was observed during placebo infusion. Once normal fasting plasma glucose levels were attained, insulin secretion and plasma glucose stabilised despite ongoing infusion of GLP-1, highlighting its glucose-dependent action. Despite its demonstrated blood glucose lowering capabilities, the short half-life of native GLP-1 is a major obstacle to its use in clinical practice. Thus, long-acting GLP-1 analogues with a prolonged action are in development. Liraglutide was patented in 1996. A pubmed search for ‘GLP-1 OR glucagon-like peptide-1’ revealed just 145 publications before 1992 (the earliest publication on pubmed was reported in 1982). However, the increased interest in and potential of GLP-1 as a treatment for diabetes is reflected by the rapid increase in publications relative to this topic in more recent years. Between the start of 1993 and the end of 2005, publications referring to GLP-1 were documented on pubmed. References Zunz, LaBarre. Arch Int Physiol Biochim 1929;31:20–44. LaBarre, Still. Am J Physiol 1930;91:649–653. McIntyre et al.: Lancet 1964; 2: Unger, Eisentraut. Arch Intern Med 1969;123:261–266. Creutzfeld. Diabetologia 1979;16:75–85. Thorens. Prac Natl Acad Sci USA 1992;89:8641–8645. Dillon et al. Endocrinology 1993;133:1907–1910. Graziano et al. Biochem Biophys Res Commun 1993;196:141–146. Thorens et al. Diabetes 1993;42:1678–1682. Nauck et al. Diabetologia 1993;36:741–744. Kieffer, Habener. Endocrine Reviews 1999;20:876–913 1930 1960 1970 1980 1990 2000 Pubblicazioni che citano GLP-1* Fino al 1992: 1993–2010: 3711 1993–2005: 1892 *Ricerca su Pubmed per ‘GLP-1 o glucagon-like-peptide-1’

10 Che cos’è il glucagon-like peptide-1?
Lys His Ala Thr Ser Phe Glu Gly Asp Val Tyr Leu Gln Ile Trp Arg Due forme molecolari equipotenti circolanti: GLP-1 (7-37); GLP-1 (7-36) amide Viene scisso dal proglucagone nelle cellule L nel tratto GI (e nei neuroni dell’ipotalamo) Secreto in risposta all’ingestione di cibo (indiretta neuronale e stimolazione diretta luminale) Membro della famiglia delle incretine (peptidi naturali glucoregolatori) What is Glucagon-Like Peptide-1? Glucagon-like peptide-1 (GLP-1) is a 30 amino acid peptide. It is an incretin hormone that is secreted from L-cells in the gastrointestinal system in response to calorie intake, causing the glucose dependent secretion of insulin. Incretins are chemical excitants that promote pancreatic sections (glucose-dependent insulinotropic polypeptide [GIP] is another example). Holst JJ Physiol Rev 87: 1409–1439, 2007

11 Trigger Azioni del GLP-1 sulla beta-cellula che conducono
alla secrezione di insulina ATP [Ca2+] Metabolismo Mitocondriale Glucosio - K + Ca2+ Gs GLP-1 PKA cAMP deposito Potenziatore Trigger Insulin + Therapeutic intervention in the GLP-1 pathway in Type 2 diabetes J. C. Levy Diabetic Medicine, 23, 1–2 2006

12 GLP-1 stimola la rigenerazione e aumenta la massa delle b-cellule in modelli animali
Le frecce rosse indicano gli effetti di GLP-1 Proliferazione b-cellulare Apoptosi b-cellule b-cell GLP-1 stimulates -cell regeneration and mass in animal models Studies have demonstrated that GLP-1 plays an important role in maintaining -cells. In animal studies, GLP-1 increases -cell mass through the stimulation of -cell neogenesis, growth and proliferation. Proliferation results from differentiation and division of existing -cells, while neogenesis occurs through differentiation of insulin-secreting cells from precursor cells in the pancreatic ductal epithelium (Bulotta et al. 2002). Additionally, a recent study using freshly isolated human islets reported a reduction in the number of apoptotic -cells following 5 days of in vitro treatment with GLP-1 (Farilla et al. 2003). These observations of increased -cell mass and decreased apoptosis are of particular interest in the treatment of type 2 diabetes as progressive -cell dysfunction is one of the main pathophysiologies of the disease. References Bulotta et al. J Mol Endocrinol 2002;29:347–360 Farilla et al. Endocrinology 2003;144:5149–5158 Ipertrofia b-cellulare Neogenesi b-cellule Rigenerazione b-cellulare e aumento della massa reviewed in: Wajchenberg et al. Endocrine Reviews 28: , 2007

13 GLP-1: effetti pancreatici funzionali
-cell -cell -cell Secrezione di insulina glucosio dipendente Secrezione di glucagone Secrezione di somatostatina Cellule pancreatiche: Output epatico di glucosio Sintesi di insulina GLP-1: functional pancreatic effects GLP-1 has a direct functional effect on pancreatic cells, influencing secretions from alpha-, beta- and delta- cells. One of its most important effects is to increase insulin secretion. Importantly, however, its insulinotropic action is glucose dependent. Consequently, GLP-1 has the capacity to lower blood glucose while protecting against hypoglycaemia. GLP-1 also regulates glucagon secretion, partly via an increase in somatostatin secretion, and partly via a direct effect on the alpha-cell. This reduction in glucagon secretion serves to decrease hepatic glucose output. References Drucker et al. Proc Natl Acad Sci USA 1987;84:3434–3438 Ørskov et al. Endocrinology 1988;123: Ørskov et al. Endocrinology 1988;123:2009–13. Drucker et al. Proc Natl Acad Sci USA 1987;84:3434–8.

14 I pazienti con diabete mellito tipo 2 hanno un’alterata secrezione di GLP-1
5 10 15 20 60 120 180 240 * *p<0.05 diabete tipo 2 vs. sani Tempo (min) Sani Diabete di tipo 2 Alterata tolleranza glucidica Plasma GLP-1 (pM) Pasto Type 2 diabetes patients have impaired GLP-1 secretion GLP-1 has an important role in maintaining pancreatic secretions. Secretion of native GLP-1 has therefore been examined in patients with type 2 diabetes, because they show reduced insulin secretion. In this study of type 2 diabetes patients (n = 54), individuals with impaired glucose tolerance (n = 15) and healthy controls (n = 33), GLP-1 secretion was monitored for 240 minutes following a 2250 KJ mixed meal. The area under the curve (AUC) of GLP-1 secretion during this test period in patients with type 2 diabetes was significantly reduced relative to healthy controls and to those with impaired glucose tolerance (p < 0.05). GLP-1 secretion was also less pronounced in patients with impaired glucose tolerance relative to controls, although this did not reach significance in terms of AUC. Diminished secretion of GLP-1 in patients with type 2 diabetes may therefore contribute, at least in part, to the reduced insulin secretory response to food in these patients. The data presented are either mean ± SEM or mean ± 1 SD (it is not clear from the paper) References Toft-Nielsen et al. J Clin Endocrinol Metab 2001;86:3717–3723 Adapted from Toft-Nielsen et al. J Clin Endocrinol Metab 2001;86:3717–23

15 Infusione continua ev in corso di clamp iperglicemico (15 mmol/L)
Nel diabete tipo 2, l’infusione di GLP-1, ma non di GIP, ripristina la risposta insulinica GLP-1 (1 pmol) GIP (16 pmol) 500 1000 1500 2000 2500 –20 30 80 120 3000 Insulina (pmol/L) Infusione continua ev in corso di clamp iperglicemico (15 mmol/L) Tempo (min) In type 2 diabetes, GLP-1 infusion restores insulin response In type 2 diabetes, the early (first 20 minutes) and late phase insulin secretory response to glucose stimuli is impaired. In this study, the effect of incretin hormones on these insulin secretory responses was investigated in eight patients with type 2 diabetes. Patients’ plasma glucose concentration was maintained at 15 mmol/l for 240 mins using a continuous i.v. infusion of glucose (hyperglycaemic clamp). During this time, GLP-1 (1 pmol), or GIP (16 pmol) was also infused intravenously. Both GLP-1 and GIP increased early phase insulin secretion. However, this insulinotropic effect was only sustained during GLP-1 infusion. Thus, in patients with type 2 diabetes, GLP-1 infusion (but not GIP) markedly augments both the early and late phases of insulin secretion in response to glucose. References Vilsbøll et al. Diabetologia 2002;45:1111–1119 Adapted from Vilsbøll et al. Diabetologia 2002:45:1111–9. Data are means ± SEM.

16 GLP-1 riduce la secrezione di glucagone
Nel diabete tipo 2, GLP-1 riduce la secrezione di glucagone 5 10 15 -20 50 120 190 Infusione continua ev in corso di clamp iperglicemico(15 mmol/L) GLP-1 (1 pmol) GIP (16 pmol) Glucagone (pmol/l) Tempo (min) Adapted from Vilsbøll et al. Diabetologia 45:1111–1119, 2002

17 GLP-1 migliora la funzione b-cellulare in pazienti con diabete tipo 2
1000 2000 3000 4000 5000 6000 7000 Minuti (clamp iperglicemico) GLP-1 10 30 50 70 90 Concentrazione C-peptide (pmol/l) Salina settimana 0 settimana 1 settimana 6 GLP-1 improves ß-cell function in patients with type 2 diabetes In this observational study, 20 patients with type 2 diabetes were assigned to continuous 6-week infusion of GLP-1 or saline (patients, but not physicians, were blinded to the treatment assignation). The infusion was administered using an insulin pump. Hyperglycaemic clamps (30 mmol/l) were used to assess ß-cell function before (week 0) and during (weeks 1 and 6) the study. C-peptide concentrations shown in this slide indicate that ß-cell function improved significantly in patients receiving GLP-1, but not in those receiving saline: incremental C-peptide concentrations (AUC0-90 min, pmol/l/min) in patients receiving GLP-1: Week 0: 41365, Week 1: (p< vs week 0), Week 6: (p< vs week 0). GLP-1 treatment in this study also significantly decreased fasting glucose, HbA1c and fructosamine (data not shown). References Zander et al. Lancet 2002;359:824–830. Adapted from: Zander et al. Lancet 2002;359:824–830

18 L’infusione di GLP-1 riduce la glicemia in pazienti con diabete tipo 2
18 16 Pazienti con diabete tipo 2, no GLP-1 14 Pazienti con diabete tipo 2, GLP-1 12 10 Glucosio (mmol/L) Controlli sani, salina 8 GLP-1 infusion lowers blood glucose in patients with type 2 diabetes This study examined the effect of continuous intravenous infusion of GLP-1 from to on glucose concentrations in eight patients with type 2 diabetes. For comparative purposes, six healthy volunteer received continuous intravenous infusion of saline. GLP-1 infusion markedly reduced glucose in patients with type 2 diabetes, to levels marginally (and not significantly) above control participants. References Rachman et al. Diabetologia 1997;40:205–211 6 4 Colazione Snack 2 Pranzo 22.00 02.00 06.00 10.00 14.00 18.00 Ora del giorno Rachman et al. Diabetologia 1997;40:205–11

19 apporto calorico, peso e senso di sazietà
Effetti del GLP-1: apporto calorico, peso e senso di sazietà Rene Glicemia Peso Pressione arteriosa GLP-1 Endotelio Miocardio Drucker DJ. Cell Metab. 2006; 3 (3): 19 19 19 19

20 Effetti del GLP-1 sull’apparato gastrointestinale
e sul sistema nervoso centrale GLP-1 Senso di sazietà Svuotamento gastrico Secrezione acida Introito calorico Kieffer, Habener. Endocr Rev 1999;20:876–913. Flint et al. J Clin Invest 1998;101:515–20 Wettergren et al. Dig Dis Sci 1993;38:665–73. During et al. Nat Med 2003;9:1173–9 20 20

21 GLP-1 riduce in modo significativo l’apporto calorico
Flint et al (n=19) Näslund et al (n=6) Näslund et al (n=8) Long et al (n=10) Gutzwiller et al. 1999a; 0.38 pmol/L Gutzwiller et al. 1999a; 0.75 pmol/L Gutzwiller et al. 1999a; 1.50 pmol/L Gutzwiller et al. 1999b (n=12) GLP-1 significantly decreases energy intake GLP-1 has also been shown to decrease calorie intake. In this meta-analysis, data from clinical studies were combined to investigate the effect of GLP-1 on energy intake in individuals with and without type 2 diabetes. All of the included studies were randomised and crossover in design, with i.v. infusion of GLP-1 (mean infusion rate: 0.89 pmol/kg/min) or saline 0–240 minutes before a test meal in which the individual was free to consume as much as was desired (ad libitum energy take). In all studies, individuals had consumed an earlier meal (of fixed size in some cases) 4–6 hours before the test meal. The results of the meta-analysis showed that energy intake during the test meal was reduced by 727 kJ (11.7%, p < 0.001) during GLP-1 infusion compared with saline infusion. The relative reduction in energy intake for overweight and lean patients was 9.3 and 13.2%, respectively (NS). The absolute and relative reductions in energy intake were greater in overweight patients with type 2 diabetes than in overweight patients without type 2 diabetes. The results also demonstrated that, in overweight patients, the gastric emptying rate was significantly lower during GLP-1 infusion than with saline. References Verdich et al. J Clin Endocrinol Metab 2001;86:4382–4389 Flint et al (n=17) Beglinger et al. (unpublished b) (n=12) Beglinger et al. (unpublished a) (n=15) Meta-analisi –4000 –2000 Differenze nell’apporto calorico* in rapporto al placebo (kJ) Adapted from: Verdich et al. J Clin Endocrinol Metab 2001;86:4382–9. *ad libitum. Data are mean and 95% CI. Gutzwiller et al 1999a, n=16

22 GLP-1 controlla la glicemia e il peso nel diabete di tipo 2
5 10 15 20 25 1 2 3 4 6 7 8 –3.0 –2.5 –2.0 –1.5 –1.0 –0.5 0.0 GLP-1 (n=10) 90 180 270 360 450 Glucosio plasmatico (mmol/l) Ore Settimana 0 Settimana 1 GLP-1 Settimana 6 GLP-1 Variazioni del peso (kg) p = valore assoluto p = 0.16 variazioni del peso Salina (n=9) Profilo glicemico 8-ore (GLP-1 pazienti, n=10) Peso Infusione sottocutanea continua di GLP-1 o di salina per 6 settimane Glucosio plasmatico(mg/dl) GLP-1 controls blood glucose and weight in type 2 diabetes The ability of GLP-1 to consistently reduce blood glucose over several weeks is shown in this trial. Type 2 diabetes patients (n = 20) were randomly assigned GLP-1 (4.8 pmol/kg/min) or saline as continuous subcutaneous infusion via a portable pump for 6 weeks. At weeks 0, 1 and 6 all patients underwent 8-hour blood glucose monitoring along with other assessments of glycaemic control and insulin activity. At week 6, in patients receiving GLP-1 infusion, fasting and 8-hour mean plasma glucose had significantly decreased relative to baseline by 4.3 and 5.5 mmol/l (77 and 99 mg/dl), respectively (p < for both comparisons). HbA1c decreased by 1.3% points (from 9.2 to 7.9, p = 0.003) and serum fructosamine fell from 349 to 282 μmol/l (p = ). Furthermore, gastric emptying was inhibited, appetite suppressed and body weight decreased by 1.9 kg (p = 0.013) during the 6-week period in patients receiving GLP-1. Insulin sensitivity increased by 77.3% (p = 0.002) and all indices of -cell function improved significantly during GLP-1 treatment. Saline infusion had no significant effect on glycaemic control (as measured by HbA1c and fasting plasma glucose), -cell sensitivity, gastric emptying or bodyweight. In this trial, GLP-1 therefore provided blood glucose control, while improving -cell function and reducing body weight. References Zander et al. Lancet 2002;359:824–830 Adapted from: Zander et al. Lancet 2002;359:824–830. Data are mean ± SE.

23 rene e apparato cardiovascolare
Effetti del GLP-1: rene e apparato cardiovascolare Rene Glicemia Peso Pressione arteriosa GLP-1 Endotelio Miocardio Drucker DJ. Cell Metab. 2006; 3 (3): 23 23 23 23

24 Effetti del GLP-1 sul sodio e sull’omeostasi idrica
GLP-1R è espresso sulle cellule tubulari prossimali Gli effetti del GLP-1 sono mediati dal GLP-1R nel rene: Aumento della diuresi Aumento dell’escrezione di sodio, cloro e calcio Riduzione della escrezione di H+ 24

25 GLP-1 e agonisti del recettore GLP-1: effetti sulla funzione cardiovascolare ed endoteliale
Effetti favorevoli sul miocardio Miglioramento della funzionalità endoteliale Miglioramento dei biomarkers di rischio cardiovascolare Riduzione della pressione arteriosa sistolica 1. Bose et al. Diabetes 2005;54:146– Nikolaidis et al. Circulation 2004;110:955– Kavianipour et al. Peptides 2003;24:569– Thrainsdottir et al. Diab Vasc Dis Res 2004;1:40–3. 5. Nikolaidis et al. Circulation 2004;109:962–5. 6. Nystrom et al. Am J Physiol Endocrinol Metab 2004;287:E1209– Nystrom et al. Regul Pept 2005;125:173–7. 8. Yu et al. J Hypertens 2003;21:1125– Gutzwiller et al. J Clin Endocrinol Metab 2004;89:3055–61. 25

26 Il GLP-1 nativo migliora la funzione ventricolare sinistra nei pazienti ad alto rischio cardiaco
Controlli GLP-1 Nativo LVEF (%) 10 20 30 40 50 Baseline Post i.v. p<0.01 60 Effetti dell’infusione di GLP-1 per 72 ore in pazienti con infarto miocardico acuto e ad alto rischio di insufficienza cardiaca post-infartuale, dopo efficace riperfusione (angioplastica) Dati espressi come media±SE; post i.v. GLP-1, post infusione endovenosa di GLP-1 per 72 ore Nikolaidis et al. Circulation 2004; 109:962–5; Moller et al. Am Heart J 2006; 151:419–25 26

27 Il GLP-1 nativo riduce l’area infartuata in un modello animale di infarto miocardico
Modello animale (ratto) di ischemia In vivo protezione verso l’infarto miocardico Protezione abolita dall’antagonista del recettore per il GLP-1 La protezione del GLP-1 nativo è mediata dall’induzione di diverse chinasi favorenti la sopravvivenza 70 *p<0.001 vs. Sol. salina e DPP-4 60 50 Dimensioni dell’infarto † (%) 40 30 * 20 10 Sol. salina Inhibitore DPP-4 GLP-1 + DPP-4 Nativo † infarto relativo all’area a rischio dopo occlusione venosa; dati medi + SE Bose et al. Diabetes 2005;54:146–51. 27 27

28 GLP-1: potenziali terapeutici
nel diabete di tipo 2 Diabete tipo Azioni del GLP-1 • Alterata funzione β-cellulare • Ridotta massa β-cellulare • Ipersecrezione di glucagone • Sovralimentazione, obesità • Complicanze macrovascolari • Resistenza insulinica •↑secrezione e biosintesi di insulina • Migliora la funzione β-cellulare (sensibilità al glucosio, rapporto proinsulina/insulina) • Sovraesprime geni essenziali per la funzione β-cellulare (eg. GLUT 2, glucochinasi) •↑proliferazione/differenziamento β-cellulare •↓apoptosi β-cellulare (studi animali + studi in vitro) •↓secrezione di glucagone •↓svuotamento gastrico, ↑ sazietà,↓appetito  ↓apporto di cibo & perdita di peso • Effetti benefici cardiovascolari Azioni possibilmente secondarie al miglioramento del controllo metabolico • Miglioramento della sensibilità insulinica

29 Il GLP-1 nativo ha valore clinico limitato a causa della sua breve emivita
Inattivazione proteolitica da parte di DPP-IV Bolo ev GLP-1 (15 nmol/L)‏ Sogg. sani (n=6)‏ 1000 Diabete tipo II (n=6)‏ His Ala Glu Gly Thr Phe Thr Ser Asp Val 7 9 GLP-1intatto (pmol/L)‏ 500 Ser Lys Ala Ala Gln Gly Glu Leu Tyr Ser Native GLP-1 has limited clinical value because of its short half-life The rapid degradation of GLP-1 into its inactive form by DPP-IV means that when administered as an i.v. bolus, it has a half-life of just 1.5–2.1 minutes. Combined with rapid clearance, this means that the action of GLP-1 has a very limited time span. References Vilsbøll et al. J Clin Endocrinol Metab 2003;88:220–224 1: J Clin Endocrinol Metab Jan;88(1):220-4. Similar elimination rates of glucagon-like peptide-1 in obese type 2 diabetic patients and healthy subjects. Vilsbøll T, Agersø H, Krarup T, Holst JJ. Department of Internal Medicine F, Gentofte Hospital, DK-290 Hellerup, Denmark. We have previously shown that type 2 diabetic patients have decreased plasma concentrations of glucagon-like peptide 1 (GLP-1) compared with healthy subjects after ingestion of a standard mixed meal. This decrease could be caused by differences in the metabolism of GLP-1. The objective of this study was to examine the pharmacokinetics of GLP-1 in healthy subjects and type 2 diabetic patients after iv bolus doses ranging from nmol/subject. Bolus injections iv of 2.5, 5, 15, and 25 nmol of GLP-1 and a meal test were performed in six type 2 diabetic patients [age, mean (range): 56 (48-67) yr; body mass index: 31.2 ( ) kg/m(2); fasting plasma glucose: 11.9 ( ) mmol/liter; hemoglobin A(1C): 9.6 ( )%]. For comparison, six matched healthy subjects were examined. Peak plasma GLP-1 concentrations increased linearly with increasing doses of GLP-1 and were similar for type 2 diabetic patients and healthy subjects. The peak concentrations of total GLP-1 (C-terminal) after 2.5, 5, 15, and 25 nmol of GLP-1 were 357 +/- 56, 647 +/- 141, /- 276, /- 331 pmol/liter in the type 2 diabetic patients and 315 +/- 37, 676 +/- 64, /- 146, /- 358 pmol/liter, respectively, in the healthy subjects (not statistically significant). Peak concentrations of the intact GLP-1 peptide (N-terminal) were: 69 +/- 17, 156 +/- 44, 703 +/- 77, and /- 117 pmol/liter in the type 2 diabetic patients and 75 +/- 14, 160 +/- 40, 664 +/- 79, 974 +/- 87 in the healthy subjects (not statistically significant). GLP-1 was eliminated rapidly with clearances of intact GLP-1 after 2.5, 5, 15, and 25 nmol of GLP-1 amounting to: 9.0 +/- 5.0, 8.1 +/- 6.0, 4.0 +/- 1.0, 4.0 +/- 1.0 liter/min in type 2 diabetic patients and 8.4 +/- 4.2, 7.6 +/- 4.5, 5.0 +/- 2.0, 5.0 +/- 1.0 liter/min in healthy subjects. The volume of distribution ranged from 9-26 liters per subject. No significant differences were found between healthy subjects and type 2 diabetic subjects. We conclude that elimination of GLP-1 is the same in obese type 2 diabetic patients and matched healthy subjects. The impaired incretin response seen after ingestion of a standard breakfast meal must therefore be caused by a decreased secretion of GLP-1 in type 2 diabetic patients. Glu Phe 37 Ile Ala Trp Leu Val Lys Gly Arg Gly –5 5 15 25 35 45 Tempo (min)‏ Clivaggio enzimatico Clearance elevata (4–9 L/min)‏ t½=1.5–2.1 min (bolo ev 2.5–25.0 nmol/L) Adapted from Vilsbøll et al. J Clin Endocrinol Metab 2003;88:220–4.

30 Il GLP-1 nativo deve essere somministrato
in maniera continua per mantenere il pieno potenziale terapeutico Glicemia (mmol/L)‏ Infusione di GLP-1 ev intermittente (8 ng/kg/min) (n=8)‏ 5 10 20 25 15 04 12 00 08 16 16h GLP-1 infusione Tempo (h)‏ Infusione di GLP-1 ev in continuo (8 ng/kg/min) (n=8)‏ 24h GLP-1 infusione Prima del trattamento con GLP-1 Profilo glicemico: Dopo 7 giorni di trattamento con GLP-1 Native GLP-1 must be administered continuously for full therapeutic potential Because of its short half-life, continuous administration of GLP-1 is required to obtain optimal, sustained glycaemic control. This was well-demonstrated in a randomised, double-blind, placebo-controlled study of 40 hospitalised type 2 diabetes patients who received infusion of GLP-1 (4 or 8 ng/kg/min) for 16 or 24 hours every day for 7 days. In patients receiving GLP-1 for 16 hours, phosphate-buffered saline solution was infused for the remaining 8 hours of the 24-hour period. The maximal blood glucose lowering effect was reported in patients receiving continuous 24-hour infusion of 8 ng/kg/min GLP-1; the average decrease from baseline to day 7 in 24-hour glucose area under the curve (AUC) was significantly greater in this group than in the other groups (p < 0.05). In patients receiving 16 hours of GLP-1 infusion, fasting and nocturnal plasma glucose (04.00 hours) at day 7 were significantly higher than in those receiving 24 hours of GLP-1 infusion (p < 0.05). This study therefore demonstrates that glucose control can only be maintained with GLP-1 during continuous infusion. Reference Larsen et al. Diabetes Care 2001;24:1416–21 ABSTRACT Diabetes Care Aug;24(8): Links Glucagon-like peptide-1 infusion must be maintained for 24 h/day to obtain acceptable glycemia in type 2 diabetic patients who are poorly controlled on sulphonylurea treatment. Larsen J, Hylleberg B, Ng K, Damsbo P. Clinical Development, Diabetes, and. Clinical Statistics, Novo Nordisk A/S, Bagsvaerd, Denmark. OBJECTIVE: To assess the efficacy and safety of glucagon-like peptide-1 (GLP-1) on the plasma glucose level when given as a continuous infusion for either 16 or 24 h per day to type 2 diabetic patients who were poorly controlled on sulfonylurea treatment. RESEARCH DESIGN AND METHODS: This single-center, randomized, parallel, double-blind, placebo-controlled trial was conducted in 40 hospitalized patients who were randomized to receive infusions of either placebo or GLP-1 4 or 8 ng. kg(-1). min(-1) for either 16 or 24 h per day for 7 days. At predetermined intervals, 24-h profiles of glucose, glucagon, and insulin were measured. Adverse events and clinical chemistry and hematology were recorded. RESULTS: For all active treatment groups, the change in average glucose (area under the curve [AUC] for day 7 minus AUC for day 0 divided by 24 h) was statistically significantly different from placebo (P < or = 0.001). The GLP-1 8 ng. kg(-1). min(-1) dose given for 24 h was more efficacious than any of the other doses (P < or = 0.05). Nocturnal and fasting plasma glucose levels at day 7 were greater in the 16-h groups compared with the 24-h groups (P < or = 0.05). Insulin AUC did not show any treatment effect for any of the treatment groups when change was assessed from day 0 to day 7. However, for the 16-h groups, the pattern of the insulin profiles changed; the insulin profiles were considerably higher during the initial 3-4 h after restart of the GLP-1 infusion on day 7, although there was a tendency for insulin levels to decrease during the afternoon and evening. Glucagon AUC decreased significantly for all active treatment groups compared with placebo. GLP-1 was generally well tolerated. CONCLUSIONS: This study demonstrated that GLP-1 should be given continuously to obtain the most optimal glycemic control. Because of the short plasma half-life of native GLP-1, long-acting derivatives should be developed to make GLP-1 treatment clinically relevant. Adapted from Larsen et al. Diabetes Care 2001; 24:1416–21 30

31 Terapie Incretiniche Analogo del GLP-1 umano, es. liraglutide
Agonista del GLP-1 umano, es. exenatide Agonisti del recettore del GLP-1 Inibitori di DPP-4, es. sitagliptin, vildagliptin saxagliptin Terapie incretiniche terapie orali terapie iniettive 31 31

32 Struttura degli agonisti del GLP-1R e degli inibitori del DPP-IV
GLP-1 (forma amidata) Inattivazione proteolitica (DPP-4) Exenatide (Byetta) Liraglutide (Victoza) Saxagliptin (Onglyza) Vildagliptin (Galvus) Sitagliptin (Januvia) DPP-4: Dipeptidyl peptidase-4. Adapted from Drucker DJ, et al. Lancet. 2006;368:1696–1705.

33 Cosa si conosce sugli agonisti del recettore
del GLP-1 e sugli inibitori del DPP-IV Inibitori del DPP-4 Aumento del GLP-1 e GIP Aumento dei livelli di GLP-1 nel range fisiologico Limitato dalla secrezione endogena Efficacia moderata Ben tollerato Nessuna variazione del peso Orale Agonisti del recettore del GLP-1 Azione selettiva GLP-1 Livelli farmacologici di GLP-1 Non è limitato dalla secrezione endogena Efficacia alta A volte nausea Calo ponderale Iniettivo GIP, gastric inhibitory peptide 33

34 Liraglutide, analogo once-daily del GLP-1 umano
GLP-1 umano nativo Liraglutide Catena di acido grasso C-16 (palmitico) 9 His Ala Thr Ser Phe Glu Gly Asp Val Tyr Leu Gln Lys Ile Trp Arg 7 36 97% di omologia con il GLP-1 nativo legame all’albumina plasmatica lento assorbimento dal sottocute resistenza al DPP-IV lunga emivita plasmatica Sito di degradazione del DPP-4 T½=13 ore Sito di degradazione del DPP-4 7 36 9 Lys His Ala Thr Ser Phe Glu Gly Asp Val Tyr Leu Gln Ile Trp Arg T½=1.5–2.1 min Il diabete tipo 2 è associato ad un incremento della pressione arteriosa1 e ad un aumentato rischio di malattia cardiovascolare. E’ stato dimostrato che una riduzione della pressione arteriosa sistolica di 5,6 mmHg è in grado di ridurre la mortalità per eventi cardiovascolari del 18% in pazienti con diabete tipo 2.2 Il poster in oggetto analizza l’effetto del trattamento con liraglutide sulla pressione arteriosa sistolica e diastolica in pazienti con diabete tipo 2. liraglutide, analogo once daily del GLP-1 umano con una omologia pari al 97% rispetto all’ormone nativo, e quindi un emivita di 13 h Agersø et al. Diabetologia 2002; 45:195–202 Knudsen et al. J Med Chem 2000; 43:1664–9 Degn et al. Diabetes 2004; 53:1187–94 Vilsbøll et al. J Clin Endocrinol Metab 2003;88(1):220–4

35 Liraglutide viene assorbita lentamente dal sottocute
Eptameri nella preparazione farmaceutica e nel sottocute Monomeri e complesso con l’albumina in circolo Peptide Acido grasso Steensgaard et al. Diabetes 2008;57(Suppl. 1):A164

36 Liraglutide e controllo glicemico
36

37 LEAD: “Liraglutide Effect and Action in Diabetes”
Dieta/esercizio Inizio antidiabetico orale (OHA) Aggiunta di un altro OHA Aggiunta di un terzo OHA o inizio insulina Liraglutide monoterapia vs. SU LEAD 3 Liraglutide+MET Vs. SU+MET LEAD 2 Liraglutide+SU vs. TZD+SU LEAD 1 Liraglutide+MET+TZD vs. MET+TZD LEAD 4 Liraglutide+MET+SU vs. glargine+MET+SU LEAD 5 Liraglutide +MET and/or SU vs. exenatide +MET and/or SU LEAD 6 Estensione LEAD 6 14 settimane Estensione LEAD 2 2 anni Estensione LEAD 3 2 anni LEAD: Liraglutide Effect and Action in Diabetes. All studies 26 weeks’ duration (LEAD-3=52 weeks); all RCT; 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;32:1224–30 (LEAD-4); Russell-Jones et al. Diabetologia 2009;52: (LEAD-5); Buse et al. Lancet 2009;374 (9683):39–47 (LEAD-6) 37

38 Variazione di HbA1c nelle 52 settimane
di trattamento(LEAD-3): pazienti precedentemente trattati con sola dieta Variazioni di HbA1c (%)* –1.4 –1.2 –1.0 –0.8 –0.6 –0.4 –0.2 –1.6 –0.9 6.5 9.0 8.5 8.0 7.5 7.0 Settimane HbA1c (%) Liraglutide 1.2 mg monoterapia Liraglutide 1.8 mg monoterapia 4 8 12 16 20 24 28 32 36 40 44 48 52 Glimepiride 8 mg 7.5% 7.1% 6.9% * ADA target ** Populazione ITT; dati medi ± SD ADA, American Diabetes Association; ITT, intention-to-treat * Liraglutide 1.2 mg vs. glimepiride, p=0.0376 ** Liraglutide 1.8 mg vs. glimepiride, p=0.0016 Garber et al. Lancet 2009;373:473–81 (LEAD-3) 38 38

39 Variazioni di HbA1c in 2 anni di trattamento (LEAD-3)
6.0 6.5 7.0 7.5 8.0 8.5 8 16 24 32 40 48 56 64 72 80 88 96 104 Time (weeks) Liraglutide 1.8 mg Liraglutide 1.2 mg Glimepiride 7.5% 7.1% 6.9% HbA1c (%) EOT Table Media osservata ± 2SE, analisi su set ITT Garber et al. Diabetes 2009;58 (Suppl. 1):162-OR 39 39

40 Effetti di liraglutide su HbA1c
LEAD-3 Monoterapia LEAD-2 Associato a Met LEAD-1 Associato a SU LEAD-4 Associato a Met + TZD LEAD-5 Associato a Met + SU 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 Variazioni di HbA1c (%) * ** *** *** *** *** *** Liraglutide 1.8 mg Liraglutide 1.2 mg Glimepiride Rosiglitazone Insulin glargine Placebo # Pazienti che hanno raggiunto i target ADA sulla popolazione totale (LEAD-4,-5); add-on dopo fallimento di dieta ed esercizio (LEAD-3); o add-on a precedente monoterapia con ipoglicemizzante orale (LEAD-2,-1). *p<0.01, **p<0.001, ***p≤ vs. comparatore attivo 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) 40 40

41 Efficacia di liraglutide su FPG e PPG (LEAD-2, 1, 4, 5)
Liraglutide riduce FPG (entro 2 settimane) Riduzione media di PPG su 3 pasti 10 LEAD 5 FPG (mmol/L) Settimane 18 2 8 12 26 9 7 Liraglutide 1.8 mg + met + SU Insulin glargine + met + SU Liraglutide 1.8 mg Liraglutide 1.2 mg 1 3 Riduzione della PPG (mmol/L) SU combi LEAD 1 Met combi LEAD 2 Met + TZD combi LEAD 4 Mono LEAD 3 Met + SU combi LEAD 5 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: /dc (LEAD-4); Russell-Jones et al. Diabetes 2008;57(Suppl. 1):A159 (LEAD-5). 41 41

42 Il miglioramento di HbA1c con liraglutide non è influenzato
dalla riduzione del peso corporeo - 1.38* n=320 1.29* n=451 1.43* n=218 1.65* n=313 0.33 n=204 0.23 n=182 0.16 n=64 0.7 n=52 1.8 1.6 1.4 1.2 1 0.8 0.6 0.4 0.2 Weight gain – 3% weight loss 3 5% weight loss >5% weight loss Liraglutide 1.8 mg Placebo Categorie di riduzione percentuale di peso rispetto al baseline Variazioni di HbA1c (%) *p< vs placebo Schmidt et al. Diabetologia 2009;52 (Suppl 1):S289 (737-P)

43 Riduzione HbA1c in base al BMI
Variazioni di HbA1c (%) Schmidt WE et al EASD 09

44 Liraglutide migliora la funzionalità beta-cellulare - HOMA-B
p<0.05 Colore pieno = Baseline (%) Colore sfumato = Variazione (%) Marre et al. Diabetic Medicine 2009;26;268–78 (LEAD-1) 44 44

45 Liraglutide e funzione beta-cellulare:
HOMA-B e rapporto pro-insulina/insulina (LEAD-1) p=0.0313 p=0.0033 HOMA-B (%) Variazioni del rapporto proinsulina/insulin Liraglutide 1.8 mg Liraglutide 1.2 mg Rosi- glitazone Placebo Liraglutide 1.8 mg Liraglutide 1.2 mg Rosi- glitazone Placebo Dati espressi come media±2SE Marre et al. Diabetologia 2008;51(Suppl. 1):S359 (LEAD-1) 45 45

46 Confronto liraglutide vs exenatide:
steady-state dei livelli plasmatici nelle 24 h 18 140 16 Liraglutide 14 120 12 100 10 80 Concentrazione di liraglutide(nmol/L) Concentrazione di Exenatide (pmol/L) 8 60 6 Exenatide 40 4 20 2 2 4 6 8 10 12 14 16 18 20 22 24 Tempo dalla prima dose giornaliera (h) Exenatide è stato somministrato al mattino (timepoint 0 h) e alla sera (timepoint 10 h)(evidenziato dalle frecce). Rosenstock et al. Diabetes 2009; 58 (Suppl 1):558-P 46 46

47 Entrambi i trattamenti hanno significativamente
ridotto la HbA1c a 26 settimane (LEAD 6) Exenatide liraglutide Liraglutide  liraglutide Exenatide group switched to liraglutide (week 26) Exenatide Variazioni di HbA1c (%) dalla 26a alla 40a settimana Liraglutide Exenatideliraglutide Liraglutideliraglutide 7.21% p<0.0001 HbA1c target 6.95% Speaker note – important to highlight that the significance value at week 26 is: 1) for the LEAD 6 population (not the extension population) 2) that the statistical test was applied for the change in HbA1c, not the absolute values. Based on Table Updated with new LOCF data (provided by AJCO) 30/03/09 (EM) Mean (2 SE) Time (weeks) Media (2 SE) I dati per le settimane 0-26 sono solo per i soggetti che hanno partecipato alla fase di estensione dello studio Buse et al. Lancet 2009;374(9683):39–47 (LEAD-6); Buse et al. Diabetes Care March 23, 2010, doi: /dc (LEAD-6 Ext) 47 47

48 Liraglutide vs exenatide: efficacia su FPG
Exenatide group switched to liraglutide (week 26) Exenatide Liraglutide Variazioni di FPG (mmol/L) Dalla 26a alla 40a settimana NS p<0.0001 Exenatideliraglutide Liraglutideliraglutide 8.64 p<0.0001 7.73 Speaker note – important to highlight that the significance value at week 26 is: 1) for the LEAD 6 population (not the extension population) 2) that the statistical test was applied for the change in FPG, not the absolute values. Based on Table Updated with new LOCF data (provided by AJCO) 15/04/09 (EM) Settimane Media (2 SE) I dati per le settimane 0-26 sono solo per i soggetti che hanno partecipato alla fase di estensione dello studio Buse et al. Lancet 2009;374(9683):39–47 (LEAD-6); Buse et al. Diabetes Care March 23, 2010, doi: /dc (LEAD-6 Ext) 48 48

49 Liraglutide vs sitagliptin: efficacia su HbA1c
Variazioni medie LS dal baseline: –0.9 Entrambi p<0.0001 –1.2 –1.5 0.0 Media (1.96 SE) dati da full analysis set LOCF; LS: least squares Pratley RE, Lancet 2010; 375: 49 49

50 Liraglutide vs sitagliptin: efficacia su FPG
Variazioni medie LS dal baseline: – 0.8 Entrambi p<0.0001 –1.9 –2.1 Media (1.96 SE) dati da full analysis set LOCF; LS:least squares Pratley RE, Lancet 2010; 375: 50 50

51 Rischio di ipoglicemia molto basso
eventi minori Liraglutide 1.8 mg Placebo Glimepiride LEAD-2: add-on a met 0.0 1.0 2.0 3.0 Eventi/ soggetti-anno Liraglutide 1.2 mg 0.03 0.14 0.09 1.23 LEAD-3: mono Liraglutide 1.8 mg 1.2 mg 0.3 0.25 1.96 LEAD-4: add-on a met + TZD 0.4 0.6 0.2 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;32:1224–30 (LEAD-4) 51 51 51 51

52 Rischio di episodi di ipoglicemia minore
CE_Core Efficacy/Safety Rischio di episodi di ipoglicemia minore con liraglutide Liraglutide 0.6 mg Liraglutide 1.2 mg Liraglutide 1.8 mg 2.5 2.0 2 Eventi/soggetti-anno 1.5 1.3 1.2 1.2 1.0 1 Placebo Rosiglitazone 0.6 Placebo Placebo 0.5 0.5 0.5 Glimepiride Glimepiride 0.4 0.3 0.3 Placebo Placebo Glargine 0.2 0.2 0.1 0.1 0.1 0.2 0.1 Associata a MET LEAD-2 Associata a SU LEAD-1 Associata a MET + TZD LEAD-4 Associata a MET + SU LEAD-5 Monoterapia LEAD-3 52 52 52

53 Summary of overall treatment satisfaction (DTSQs)
Lighter bars = baseline values Darker bars = week 52 LOCF * *p= vs sitagliptin for change from baseline to week 52 Satisfaction score ranges from 0 (lowest satisfaction) to 36 (highest satisfaction Mean; data are from the PRO analysis set. Montanya, Diabetologia 2010 (EASD). DTSQ, Diabetes Treatment Satisfaction Questionnaire; LOCF, last observation carried forward

54 Liraglutide oltre la glicemia:
peso corporeo 54 54

55 Variazioni del peso dal baseline
a 52 settimane (LEAD-3) Variazioni del peso (Kg) Settimane p-values si riferiscono alle differenze stimate per trattamento rispetto al baseline***p<0.0001 Media (±2SE) Garber et al. Lancet 2009;373:473–81 (LEAD-3) 55 55

56 Variazioni del peso nel tempo:
risultati a 2 anni di trattamento (LEAD 3) +1.1 kg Variazioni del peso (kg) 8 16 24 32 40 48 56 64 72 80 88 96 104 -2.1 kg -2.7 kg Settimane Observed mean±2SE, no imputation for missing values. Diabetes. 2009; 58(Suppl 1), OP 162 56 56

57 Efficacia di liraglutide sul peso corporeo:
LEAD 1–6 Associato a MET Associato a SU Associato a MET+TZD Associato a MET + SU Associato a MET+SU Monoterapia Variazioni del peso (Kg) Significativo* vs. comparatore Media±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: /dc (LEAD-4); Russell-Jones et al. Diabetes 2008;57(Suppl. 1):A159 (LEAD-5); Buse et al. Lancet 2009; in press (LEAD-6) 57 57

58 Liraglutide vs sitagliptin: variazioni medie del peso corporeo in 26 settimane di trattamento
Variazioni medie LS dal baseline –1.0 Variazioni del peso (Kg) Entrambi p<0.0001 –2.9 –3.4 Media (1.96 SE) dati da full analysis set LOCF; LS: least squares Pratley RE, Lancet 2010; 375: 58 58

59 Liraglutide riduce il tessuto adiposo sottostudio con TAC
LEAD-2 Tessuto adiposo viscerale Tessuto adiposo sottocutaneo 15 5 –5 –15 –25 –35 –45 * 15 5 –5 –15 –25 –35 –45 ** *** Variazioni medie dal basale (cm2) Variazioni medie dal basale (cm2) Liraglutide 1.2 mg/die + metformina (1.5–2 g) Liraglutide 1.8 mg/die + metformina (1.5–2 g) Placebo + metformina (1.5–2 g) Glimepiride 8 mg/die + metformina (1.5–2 g) Dati espressi come media ± SE; *p<0.05; **p<0.01; *** p<0.001 vs. glimepiride + metformina; n=160. Jendle et al. Diabet Obes Metabol 2009;11:1163–72 (LEAD-2 substudy). 59 59

60 Liraglutide oltre la glicemia:
effetti sui fattori di rischio cardiovascolare 60 60

61 Liraglutide riduce la pressione arteriosa sistolica nel diabete tipo 2
Mono- terapia LEAD-3 Associato a Met LEAD-2 Associato a SU LEAD-1 Associato a Met + TZD LEAD-4 Associato a Met + SU LEAD-5 Associato a Met + SU LEAD-6 1 –2.0 –0.7 0.4 0.5 –0.9 Glimepiride Rosiglitazone Glargine Exenatide –1.1 Placebo –1 –2 –2.1 –2.3 Variazioni della PAS (mmHg) –3 –2.6 –2.5 –2.8 * –2.8 * –4 –3.6 –4.0 * * –5 –6 –5.5 ** –7 –6.6 *** Liraglutide 1.2 mg Liraglutide 1.8 mg *p<0.05; **p<0.001; ***p< vs. baseline Colagiuri et al. Diabetes 2008;57(Suppl. 1):A16 (LEAD-1-5); Buse et al. Lancet 2009;374:39–47 (LEAD-6). 61 61 61

62 Liraglutide riduce la pressione arteriosa sistolica nei pazienti con diabete tipo 2 in 26 settimane
LEAD-1–6: meta-analisi Liraglutide 1.8 mg, n=1363 134 Liraglutide 1.2 mg, n=896 Placebo, n=524 133 132 131 LS means PAS (mmHg) 130 129 * ** 128 127 2 4 6 8 10 12 14 16 18 20 22 24 26 Settimane I dati della PAS sono espressi come least squares (LS) means ± 95% intervallo di confidenza (CI); *p=0.0030; **p=0.0001 Fonseca et al. Diabetes 2009; 58 (Suppl. 1):A146 62 62

63 Liraglutide migliora ulteriormente la pressione arteriosa sistolica nei pazienti con diabete tipo 2 con valori più alti al baseline LEAD-1–6: meta-analysis Baseline SBP: 80< SBP ≤120 120< SBP ≤130 130< SBP ≤140 140< SBP ≤190 Variazioni PAS dal basale Effetti statisticamente significativi sulla PAS in relazione ai quartili di PAS al baseline (p<0.0001) Maggiore riduzione osservata nel quartile con PAS più alta al basale Fonseca et al. Diabetes 2009;58(Suppl. 1):A146; Fonseca er al. Diabetologia 2009;52 (Suppl. 1): P-761 63 63

64 Liraglutide ha migliorato in maniera consistente
i biomarkers di rischio cardiovascolare nei pazienti con diabete tipo 2 LEAD-1–6: meta-analsi 1 1 2 Variazioni dal basale (%)* p<0.001 p<0.001 p<0.001 * Variazione dal basale a 26 settimane con liraglutide 1.8 mg una volta/die 1. plutzky et al. diabetologia 2009; 52(suppl. 1):s299. 2. plutzky et al. circulation 2009; 120:s397 [abstract 818]. 64 64

65 Liraglutide riduce il colesterolo totale
e le LDL nei pazienti con diabete tipo 2 LEAD 1–6: meta-analisi TC LDL-C 0.51 20 ** *** 0.38 15 Liraglutide 1.8 mg Rosiglitazone Glimepiride Insulin glargine Exenatide Placebo 0.26 10 ** * *** 0.13 5 Variazioni dal baseline (mmol/L) Variazioni dal basale (mg/dL) 0.00 –0.13 –5 –0.26 –10 –0.38 –15 *p<0.05; **p<0.01; ***p< vs. liraglutide. Dati espressi come valori medi ± 95% CI Plutzky et al. Diabetologia 2009; 52 (Suppl. 1):S299 65 65

66 Endpoint combinato 1: HbA1c<7.0%,
no aumento di peso, no ipoglicemia 45 39% 40 35 32%* 30 Pazienti a target (%) 25 24%* 20 15%** 15 10 8%**, ✝✝ 8%**, ✝✝ 6%**, ✝✝ 5 Liraglutide 1.8 mg (n=1363) Liraglutide 1.2 mg (n=896) SU (n=490) TZD (n=231) Glargine (n=232) Exenatide (n=231) Placebo (n=524) Liraglutide 1.8 mg è superiore (*p<0.01; ** p<0.0001) Liraglutide 1.2 mg è superiore (✝✝ p<0.0001) Zinman et al, Diabetologia 2009;52(Suppl 1):S292 (A743)

67 Endpoint combinato 2: HbA1C <7.0%,
SBP<130 mmHg, no aumento di peso 30 25% 25 21% 20 Pazienti a 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 Zinman et al. Diabetes 2009;58 (Suppl 1): 537-P

68 Liraglutide: tollerabilità
68 68

69 Frequenza della nausea
Percentuale di soggetti con nausea per settimana e trattamento – safety population Soggetti Settimane 26 Nausea transitoria e di intensità da lieve a moderata I ritiri dovuti alla nausea nel LEAD programme con 1.8 mg sono stati tra 1% all’8% Nauck et al. Diabetes Care 2009; 32:84–90 (LEAD-2) 69 69

70 La nausea è l’evento avverso più frequente
con gli agonisti del recettore del GLP-1 Percentuale di soggetti con nausea per settimana e trattamento 20 Exenatide 10 μg BID Liraglutide 1.8 mg OD 18 16 14 12 Percentuale di soggetti (%) 10 8 6 4 2 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Settimane La nausea è transitoria L’incidenza della nausea si riduce più rapidamente con liraglutide rispetto a exenatide nel LEAD-6 Buse et al. Lancet 2009;374(9683):39–47 (LEAD-6); 70 70

71 Liraglutide: elevata omologia con il GLP-1 nativo e ridotta formazione di anticorpi
Percentuale di pazienti con incremento di anticorpi GLP-1 umano nativo Liraglutide1 20 40 60 80 100 Exenatide + metformin2 43% 8.6% Liraglutide 97% omologia con il GLP-1 umano Exenatide 53% omologia con il GLP-1 umano Liraglutide: greater homology to native human GLP-1, less antibody formation Antibody data are from a meta-analysis of all LEAD studies (data on file). Non c’è correlazione tra formazione di anticorpi e riduzione dell’efficacia Study duration: Liraglutide 26 weeks; exenatide 30 weeks. 1LEAD1,2,3,4,5 meta-analysis of antibody formation; Data on file; 2DeFronzo et al. Diabetes Care 2005;28:1092 71 71

72 NECESSITA’ DELLA DIABETOLOGIA MODERNA
Raggiungere la normoglicemia portando il paziente a target di HbA1c, FPG e PPG Ridurre problematiche quali l’aumento del peso corporeo e il rischio di ipoglicemia Effettuare una terapia multisistemica, personalizzata e il più tempestiva possibile Ridurre il rischio CV Terapia che intervenga su meccanismi fisiopatologici

73 Liraglutide nel diabete tipo 2
Summary dei risultati HbA1c, glicemia a digiuno e post-prandiale Basso rischio di ipoglicemia Peso corporeo Pressione arteriosa sistolica The unmet need in type 2 diabetes Liraglutide addresses several of the previously outlined unmet needs in diabetes and may bring us closer to an ideal treatment for type 2 diabetes. Funzione beta-cellulare 73

74 …grazie dell’attenzione…

75 sicurezza e tollerabilità
Liraglutide: sicurezza e tollerabilità

76 Sicurezza e tollerabilità
76 Sicurezza e tollerabilità Pancreatite Cellule C della tiroide Insufficienza epatica e renale 76

77 Frequenza della pancreatite e fattori di rischio
Date of Preperation September 2009 UK/LR/0809/0318 77 Frequenza della pancreatite e fattori di rischio Incidenza di pancreatite nei soggetti con diabete mellito tipo 2 I pazienti con diabete tipo 2 hanno un rischio aumentato di 2,8 volte rispetto alla popolazione generale2 Equivale a circa 4,2 casi per soggetti/anno2 Incidenza di pancreatite nella popolazione generale EU: 0.04–0.5 casi per soggetti sani/anno1 US: 0.5–0.8 casi di ospedalizzazione per soggetti/anno US: Circa 1.5 casi per soggetti sani/anno2 Altri fattori di rischio per pancreatite Obesità, alcool, ipertrigliceridemia e calcolosi della colecisti sono fattori di rischio per pancreatite3,4 1. Yadav et al. Trends in the epidemiology of the first attack of acute pancreatitis: a systematic review. Pancreas 2006;33(4):323–30. 2. Noel et al. Increased risk of acute pancreatitis observed in patients with type 2 diabetes. Diabetes Care 2009;32(5):834–8. 3. Linares et al. Acute pancreatitis in a cohort of 129 patients referred for severe hypertriglyceridemia. Pancreas 2008;37(1):13–2. 4. Martinez et al. Is obesity a risk factor in acute pancreatitis? A meta-analysis. Pancreatology 2004;4:42–8. 77 77

78 Casi di pancreatite negli studi LEAD
Date of Preperation September 2009 UK/LR/0809/0318 Casi di pancreatite negli studi LEAD Pancreatiti n=7 Pancreatiti n=7 Acute n=5 Acute n=5 Croniche (n=2) Croniche (n=2) Liraglutide n=4 Liraglutide n=4 Comparatore n=1 Comparatore n=1 Numero atteso di casi di pancreatite nella stessa popolazione background (diabetici tipo 2): Liraglutide: Comparatore: 4 NN2211: FDA 120 day safety update 78

79 Date of Preperation September 2009 UK/LR/0809/0318
79 L’incidenza tra i soggetti in terapia con liraglutide e i farmaci di confronto è in accordo con quanto atteso nella popolazione di diabetici tipo 2 Ci sono troppi pochi casi (0.2%) per poter stabilire se esiste una rapporto causa-effetto tra la pancreatite acuta e la terapia con liraglutide. In base a questi dati l’EMEA non ha ritenuto opportune restrizioni all’uso in scheda tecnica 79

80 Sicurezza e tollerabilità
80 Sicurezza e tollerabilità Pancreatite Cellule C della tiroide Insufficienza epatica e renale 80

81 81 La calcitonina è un ormone prodotto dalle cellule C della tiroide e il carcinoma di queste cellule è una rara forma di tumore tiroideo Con liraglutide sono stati osservati casi di carcinoma a cellule C nei ratti e nei topi I roditori hanno un elevato numero di cellule C tiroidee che sono molto sensibili al GLP-1. L’uomo ha un numero molto minore di cellule C e tali cellule non sono risultate sensibili agli effetti del GLP-1. Knudsen et al. Endocrinology 2010; DOI: /en

82 82 Come conseguenza delle osservazioni nei roditori e per assicurare la sicurezza nell’uomo, i livelli di calcitonina sono stati monitorati in tutti i pazienti del programma clinico di liraglutide Degli oltre pazienti trattati con liraglutide, nessuno ha sviluppato il carcinoma a cellule C e tutti gli studi LEAD (inclusi i dati a 2 anni) non evidenziano alcun aumento dei valori di calcitonina rispetto ai farmaci di confronto. Knudsen et al. Endocrinology 2010; DOI: /en

83 Livelli di calcitonina negli studi LEAD
83 Livelli di calcitonina negli studi LEAD Confrontate con le variazioni durante lo studio (curva del placebo), le differenze tra comparatori sono molto piccole e abbondantemente nei range di normalità Upper Normal Range Males Calcitonina (pg/mL) Upper Normal Range Females Comparatore attivo Geometric means; Studies 1572 and 1573 Settimane Knudsen et al. Endocrinology 2010; DOI: /en 83

84 Gli effetti sulle cellule C sono limitati ai roditori
Non ci sono evidenze per un aumentato rischio di carcinoma midollare nell’uomo

85 Sicurezza e tollerabilità
85 Sicurezza e tollerabilità Pancreatite Cellule C della tiroide Insufficienza epatica e renale 85

86 Insufficienza epatica e insufficienza renale: indicazioni
86 Insufficienza epatica e insufficienza renale: indicazioni “Insufficienza renale: non è richiesta correzione della dose per i pazienti con lieve insufficienza renale (clearance della creatinina ≤ ml/min). Vi è una esperienza terapeutica molto limitata in pazienti con una moderata insufficienza renale (clearance della creatinina di ml/min) e non vi è esperienza terapeutica in pazienti con grave insufficienza renale (clearance della creatinina inferiore a 30 ml/min). Liraglutide attualmente non può essere raccomandato per l’uso in pazienti con moderata o grave insufficienza renale, compresi i pazienti con malattia renale all’ultimo stadio”. “Insufficienza epatica: l’esperienza terapeutica in pazienti con insufficienza epatica di qualsiasi grado è ad oggi troppo limitata per raccomandare l’uso in pazienti con insufficienza epatica lieve, moderata o grave”. Scheda tecnica Victoza® 86

87 Dimensioni dell’infarto Noyan-Ashraf et al. Diabetes 2009;58:975–83.
Con liraglutide le dimensioni dell’infarto si riducono dopo 28 giorni dall'evento Infarto Infarto Dimensioni dell’infarto (21% vs. 29%; p=0.02) 30 * 20 Dimensioni infarto (% o area a rischio) 10 Placebo Liraglutide *p<0.05 vs. placebo Noyan-Ashraf et al. Diabetes 2009;58:975–83. 87 87

88 Degradazione ed escrezione di liraglutide
88 Degradazione ed escrezione di liraglutide La lunga emivita osservata in vivo e in vitro conferma che la struttura di liraglutide (high self-association e la capacità di legarsi all’albumina) contribuisce a una più lenta degradazione rispetto al GLP-1 e a exenatide Liraglutide viene degradato in vitro dal DPP-IV e dal NEP in modo simile al GLP-1 nativo – sebbene in tempi più lunghi Bjørnsdottir et al., Diabetologia 2008; 51 (Suppl 1):PS 891 88

89 Degradazione ed escrezione di liraglutide
89 Degradazione ed escrezione di liraglutide I bassi livelli di metaboliti nel plasma, nelle urine e nelle feci e la mancata escrezione di liraglutide intatto dimostrano che liraglutide è completamente degradato nell’organismo a differenza di exenatide che viene escreto per via renale Liraglutide viene dunque metabolizzato in modo simile al GLP-1, e più in generale alle proteine di grandi dimensioni. Non vi è pertanto un organo specifico come principale via di eliminazione. Bjørnsdottir et al., Diabetologia 2008; 51 (Suppl 1):PS 891; 89

90 La riduzione della PAS nel diabete tipo 2 con liraglutide è indipendente dalla terapia antipertensiva LEAD-1–6: meta-analysis Bracci Liraglutide 1.8 mg Placebo Differenze nella riduzione della PAS tra Liraglutide e Placebo Totale -2.55* (n=1363) -0.19 (n=524) -2.37 (p=0.0005) Trattamento antiipertensivo (26 sett) SI NO -2.03** (n=797) -3.07*** (n=566) 0.76 (n=287) -1.13 (n=237) -2.79 (p=0.0015) -1.95 (p=0.0485) Variazioni della Pressione Arteriosa Sistolica dal baseline alla settimana 26 (mmHg) Oltre la glicemia, dopo slide 31 *p< 0.01, **p< 0.05, *p< 0.001 Fonseca et al. Diabetes 2010; 296 PO

91 Liraglutide ha molteplici effetti favorevoli sulla beta cellula
 Funzione secretoria  Rapporto proinsulina:insulina  Prima fase della secrezione insulinica  Funzione delle beta-cellule (HOMA)  Massa delle beta-cellule Pazienti con diabete tipo 2 Animali In vitro  Apoptosi delle beta-cellule  Sensibilità delle beta-cellule al glucosio (ISR) Beta-cellule Madsbad et al. Diabetologia 2006; 49(Suppl. 1):A004; Sturis et al. Br J Pharmacol 2003;140:123–32. Rolin et al. Am J Physiol Endocrinol Metab 2002;283:E745–52; Bregenholt et al. Diabetologia 2001;44(Suppl. 1):A19; Bregenholt et al. Diabetes 2001:50(Suppl. 2):A31; Degn et al. Diabetes 2004;53:1187–94; Chang et al. Diabetes 2003;52:1786–91 91

92 Glucagon-Like Peptide 1 induce natriuresi
in soggetti sani e obesi in risposta all’infusione di soluzione salina ipertonica GLP-1 1.5 pmol/kg x min P=0.0013 P=0.015 Escrezione di sodio (mmol/180 min) Controllo Soggetti sani Soggetti obesi insulino-resistenti Gutzwiller et al. J Clin Endocrinol Metab 89: , 2004