Nuove terapie del diabete: per chi?

Dialoghi di medicina e salute nel parco Maraini 19 aprile 2012 Nuove terapie del diabete: per chi? Dott Pietro Gerber FMH Endocrinologia Diabete e Medicina interna- Lugano

DIAGNOSI DIABETE TIPO 2 Normale Pre-prandiale: 3.9 5.4 mmol/l Post-prandiale: inferiore a 7.8 mmol/l Prediabete Pre-prandiale : 5.5 6.9 mmol/l Post-prandiale : 7.8 11.0 mmol/l Diabete Pre-prandiale : 7.0 mmol/l e superiore Post-prandiale : superiori a 11.0 mmol/l

DIAGNOSI DIABETE TIPO 2 In realtà una situazione che modifica il rischio cardiovascolare (cuore, circolazione, reni, occhi piedi). Questo aumento dipende da tanti altri fattori: PA, colesterolo, stile di vita. Dunque anche con valori non ottimi l aumento del rischio può restare più basso di quello di un non-diabetico

LIVELLI DI GLICEMIA RACCOMANDATI PRIMA E DOPO I PASTI Preprandiale 5.0 7.2 mmol/l Postprandiale inferiore a 10.0 mmol/l

Storia naturale del diabetico: Controllo glicemico nel tempo 9 Conventional (n=200) Glibenclamide (n=148) Metformin (n=181) Insulina (n=199) Chlorpropamide (n=129) Media HbA1c (%) 8 7 Raccomandazioni ADA (7.0%) 6 0 Limite superiore per una glicemia normale (6.2%) 0 2 4 6 8 10 Tempo dopo la Randomizazione (a) ADA=American Diabetes Association; HbA1c=hemoglobin A1c Adapted from UKPDS Group. Lancet. 1998; 352: 854 865.

Declino della funzione delle cellule β con tutti I tipi di terapia del diabete di tipo 2 100 Prima della diagnosi Sulfoniluree (n=511) Dieta (n=110) Metformina (n=159) Funzione delle cellule beta (%) 80 60 40 20 0 5 4 3 2 1 0 1 2 3 4 5 6 T2DM=type 2 diabetes mellitus β-cell function measured by homeostasis model assessment (HOMA) Adapted from UKPDS Group. Diabetes. 1995; 44: 1249 1258. Anni dalla diagnosi

Azione dei farmaci orali per il diabete Victosa, byetta (GLP-1 analoghi) (Stimolano il pancreas a produre insulina (β-cells), diminuiscono l appetito, dim la produzione di glucagone) Galvus, Januvia, Onglysa (DPP-4 inhibitori) Stimolano il pancreas a produre insulina (β-cells), diminuiscono l appetito, dim la produzione di glucagone) Actos (Thiazolidinedioni) Fanno entrare lo zucchero nel muscolo e nel tessuto adiposo Diamicron, amaryl, daonil Stimolano il pancreas a produre insulina (β-cells) Glucobay (α-glucosidase inhibitori) Rallentano lo zucchero nell, intestino) DDP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus Adapted from Cheng AY, Fantus IG. CMAJ. 2005; 172: 213 226.

Azione dei farmaci orali per il diabete sul peso Victosa, byetta (GLP-1 analoghi) Galvus, Januvia, Onglysa (DPP-4 inhibitori) Actos (Thiazolidinedioni) Diamicron, amaryl, daonil Insulina Insulina Glucobay (α-glucosidase inhibitori) ) DDP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus Adapted from Cheng AY, Fantus IG. CMAJ. 2005; 172: 213 226.

CONCETTO D INCRETINA GLP1

Proof of a Gastrointestinal Incretin Effect : Different Responses to Oral vs IV Glucose Oral Glucose Tolerance Test and Matched IV Infusion 200 400 Plasma Glucose (mg/dl) 150 100 50 50 g Glucose Plasma Insulin (pmol/l) 300 200 100 N=6 0 30 0 30 60 90 120 150 180 210 Time (Min) Oral 0 30 0 30 60 90 120 150 180 210 Time (Min) IV IV=intravenous Adapted from Nauck MA, et al. J Clin Endocrinol Metab. 1986; 63: 492 498.

Insulina e glucagone nel diabete Funzione normale delle isole di Langherhans Disfunzionamento Insulina normale Glucagone normale Poca insulina Troppo glucagone

Sintesi del GLP-1 nell intestino dopo un pasto to Food Intake L-Cell (ileum) Proglucagon Victoza Byetta GLP-1 [7 37] GLP-1 [7 36 NH 2 ] P Galvus Januvia Onglyza GIP=glucose-dependent insulinotropic peptide; GLP-1=glucagon-like peptide-1 Adapted from Drucker DJ. Diabetes Care. 2003; 26: 2929 2940.

Declino della funzione delle cellule β con tutti I tipi di terapia del diabete di tipo 2 100 Prima della diagnosi Sulfoniluree (n=511) Dieta (n=110) Metformina (n=159) Funzione delle cellule beta (%) 80 60 40 20 0 5 4 3 2 1 0 1 2 3 4 5 6 T2DM=type 2 diabetes mellitus β-cell function measured by homeostasis model assessment (HOMA) Adapted from UKPDS Group. Diabetes. 1995; 44: 1249 1258. Anni dalla diagnosi

Le nuove terapie sono in grado di evitare questo?

Grazie

Die SGED empfiehlt GLP-1 Analoga als eine Option zur frühzeitigen Anwendung mit Metformin SGED = Schweizerische Gesellschaft für Endokrinologie und der Diabetologie Philippe et al. Schweiz Med Forum 2009;9(3):50-55

Traditional Current Oral Therapies Do Not Address Islet Cell Dysfunction Insulin Resistance (Impaired insulin action) Pancreatic Islet Dysfunction Inadequate glucagon suppression (α-cell dysfunction) Insufficient Insulin secretion (β-cell dysfunction) Progressive decline of β-cell function Metformin Metformin TZDs TZDs Sulfonylureas Glinides Liraglutide TZD=thiazolidinedione; T2DM=type 2 diabetes mellitus Adapted from DeFronzo RA. Br J Diabetes Vasc Dis. 2003; 3(suppl 1): S24 S40.

GLP-1 Restores Insulin and Glucagon Responses in a Glucose-Sensitive Manner in Patients with T2DM N=10 Glucose (mg/dl) C-Peptide (nmol/l) Glucagon (pmol/l) 300 GLP-1 infusion 3.0 GLP-1 infusion 30 GLP-1 infusion 250 2.5 25 200 150 100 50 2.0 1.5 1.0 0.5 20 15 10 5 0 30 0 30 60 90 120 150 180 210 240 Time (Min) GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus P <0.05 GLP-1(7 36 amide) infused at 1.2 pmol/kg/min for 240 minutes. Adapted from Nauck MA, et al. Diabetologia. 1993; 36: 741 744. 0.0 30 0 30 60 90 120 150 180 210 240 Time (Min) GLP-1 0 30 0 30 60 90 120 150 180 210 240 Time (Min) Placebo

Vildagliptin Enhances GLP-1 Levels in Patients with T2DM 16.0 Meal Vilda 100 mg (n=16) PBO (n=16) Active GLP-1 (pmol/l) 12.0 8.0 4.0 0.0 17:00 20:00 23:00 02:00 05:00 08:00 GLP-1=glucagon-like peptide-1; PBO=placebo; T2DM=type 2 diabetes mellitus; vilda=vildagliptin. P <0.05. Balas B, et al. J Clin Endocrinol Metab 2007; 92: 1249-1255. Time

Vildagliptin Suppresses Glucagon Secretion 20 Meal 10 PBO (n=16) Vilda 100 mg (n=16) 0 Delta glucagon (ng/l) 10 20 30 40 50 60 17:00 PBO=placebo; vilda=vildagliptin. P <0.05 vs PBO. Balas B, et al. J Clin Endocrinol Metab 2007; 92: 1249-1255. 20:00 23:00 02:00 05:00 08:00 Time

Vildagliptin: Improves β-cell Mass (Neonatal Rat Pancreatic Growth Model) Insulin Vehicle Vildagliptin 60 mg/kg 21 days Replication Apoptosis β-cell mass BrdU-Positive Cells (%) 120 100 80 60 40 20 0 Vehicle P <0.001 Vilda ApopTag-Positive Cells (%) 2.5 2.0 1.5 1.0 0.5 0.0 Vehicle P <0.05 Vilda β-cell Mass (mg) 0.14 0.12 0.10 0.08 0.06 0.04 0.02 0.00 Vehicle P <0.05 Vilda Day 7 Day 21 Vilda=vildagliptin Duttaroy A, et al. Diabetes. 2005; 54 (suppl 1): A141. Abstract 572-P and poster presented at ADA.

Victoza ist ein humanes GLP-1 Analogon, geeignet zur einmal täglichen Verabreichung Humanes GLP-1 7 Enzymatischer Abbau durch DPP-4 9 His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Lys Ala Ala Gln Gly Glu Leu Tyr Ser Glu Phe 36 Ile Ala Trp Leu Val Lys Gly Arg Gly C-16 Fettsäure (Palmitoyls.) Victoza (Liraglutide) 7 9 His Ala Glu Gly Thr Phe Thr SerAsp Val Glu Ser Lys Ala Ala Gln Gly Glu Leu Tyr Ser Glu Phe 36 Ile Ala Trp Leu Val Arg Gly Arg Gly Der therapeutische Nutzen von nativem GLP-1 ist limitiert, aufgrund des enzymatischen Abbaus durch DPP-4 (T ½ =~1.5 min) 1 Victoza ist das erste und einzige humane GLP-1 Analogon mit einer Sequenz-Homologie von 97% zum natürlichen GLP-1 2 Resistenz gegenüber DPP-4 bewirkt eine lange Plasmahalbwertszeit (T ½ =13h) und so eignet sich Victoza zur einmal täglichen Anwendung 2 1. Knudsen et al. J Med Chem 2000;43:1664 1669 2. Victoza Fachinformation, Arzneimittelkompendium der Schweiz

Victoza (Liraglutide) en association avec la Metformine réduit l HbA 1c de manière significative 1 Baseline 8.3% 8.4% 8.4% 8.4% Change de l'hba 1c (%) 0-0.2-0.4-0.6-0.8-1 -1.2-1.4-1.6-1.8 Liraglutide 1.2 mg + Met Liraglutide 1.8 mg + Met p<0.0001 Placebo + Met Glimepiride + Met Un groupe de patients avec une valeur initiale de l HbA 1c de >9.5% a montré une réduction de l HbA 1c de 2.74% sous Victoza 1.2 mg 2 Moyen±2SE LEAD-2, patients traités auparavant avec ADO en monothérapie 1. Nauck et al. Diabetes Care 2009;32;84 90 2. Nauck et al. Postgrad Med 2009;121(3):5-15

HbA 1c <7,0% continuel 52 semaines avec Victoza (Liraglutide) en monothérapie 9,0 8,5 Glimepiride 8 mg Liraglutide 1.2 mg monothérapie Liraglutide 1.8 mg monothérapie Change de l HbA 1c (%) -0,2-0,4-0,6-0,8-1,0-1,2-1,4-1,6-1.2-1.6-0.9 HbA 1c (%) 8,0 7,5 7,0 6,5 0 4 8 12 16 20 24 28 32 36 40 44 48 52 semaines LEAD 3, patients traités auparavant par régime et exercice Garber et al. Lancet 2009;373(9662):473 481 (LEAD 3). Valeurs moyennes (écart-type).

Azione dei farmaci orali per il diabete Victosa, byetta (GLP-1 analoghi) (Stimolano il pancreas a produre insulina (β-cells), diminuiscono l appetito, dim la produzione di glucagone) Galvus, Januvia, Onglysa (DPP-4 inhibitori) Stimolano il pancreas a produre insulina (β-cells), diminuiscono l appetito, dim la produzione di glucagone) Actos (Thiazolidinedioni) Fanno entrare lo zucchero nel muscolo e nel tessuto adiposo Diamicron, amaryl, daonil Stimolano il pancreas a produre insulina (β-cells) Glucobay (α-glucosidase inhibitori) Rallentano lo zucchero nell, intestino) DDP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus Adapted from Cheng AY, Fantus IG. CMAJ. 2005; 172: 213 226.

Pourcentage des patients atteignant la valeur cible HbA 1c <7% sous traitement Victoza (Liraglutide) % atteignant la valeur cible de l ADA 70 60 50 40 30 20 10-0 Monothérapie LEAD 3 58% 62% Liraglutide 1.2 mg 51% 43% 31% Association Metformine LEAD 2 53% 66% Liraglutide 1.8 mg 56% Association SU LEAD 1 55% Association Met + TZD LEAD 4 p<0.0001 p<0.001 contre comparateur; patients atteignant les valeurs cibles de l HbA 1c de l ADA pour la totalité des patients (LEAD 4,5) administration après échec de régime et exercice ou dose demi maximale d un ADO (LEAD 3); ou en association avec une monothérapie ADO préalable (LEAD 2,1). 52% 36% 58% 54% 28% Association Met + SU LEAD 5 53% 46% Glimepiride Rosiglitazone Placebo Insuline Glargine Marre et al. Diabetic Medicine 2009;26:268 278 (LEAD 1); Nauck et al. Diabetes Care 2009;32;84 90 (LEAD 2); Garber et al. Lancet 2009;373(9662):473 481 (LEAD 3); Zinman et al. Diabetes Care 2009;23(7):1224-1230 (LEAD 4); Russell-Jones et al. Diabetologia 2009;52:2046-2055 (LEAD 5); études de 26 semaines (LEAD 3=52 semaines).

Victoza (Liraglutide) führt zu einer Gewichtsabnahme 1 Veränderung des Gewichts (kg) 1.0 0.0-1.0-2.0-3.0-4.0 p<0.0001 vs. Glim+Met -2.8 kg vom Ausgangsgewicht 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Glimepirid 4mg + Met nur Metformin Woche Liraglutide 1.2 mg + Met Liraglutide 1.8 mg + Met 2/3 des Gewichtsverlustes war Fett (hauptsächlich viszeral) 2 1. Nauck et al. Diabetes Care 2009;32;84 90 2. Jendle et al. Diabetes, Obesity and Metabolism 2009;11(12):1163-1172

UKPDS: Intensive Therapy With Metformin in Overweight Patients Glucose Control Study showed that intensive glucose control with a sulfonylurea or insulin is effective in reducing the risk of complications in both overweight and nonoverweight patients Metformin Study was designed to determine whether same results achievable with metformin in overweight patients In addition to diet, sulfonylurea, or insulin, overweight (>120% IBW), asymptomatic patients with FPG 108-270 mg/dl eligible for randomization to intensive glucose control policy with metformin

UKPDS: Randomization of Overweight Patients in Metformin Study Main randomization of UKPDS 4209 patients in 23 centers Metformin Study 1704 overweight patients in 15 centers Conventional policy 411 Intensive policy 1293 Sulfonylurea or insulin 542 409 Metformin 342

UKPDS: Any Diabetes-Related Endpoint in Metformin Study Proportion of patients with event 60% 40% 20% Conventional (n=411) Intensive (n=951) Metformin (n=342) M vs C P=0.0023 M vs I P=0.0034 0% 0 3 6 9 12 15 Years from randomization UKPDS Group. Lancet. 1998;352:854-865.

UKPDS: Diabetes-Related Deaths in Metformin Study Proportion of patients with events 35% 30% 20% 10% 0% Conventional (n=411) Intensive (n=951) Metformin (n=342) M vs C P=0.017 M vs I P=0.11 0 3 6 9 12 15 Years from randomization UKPDS Group. Lancet. 1998;352:854-865.

UKPDS: Myocardial Infarction in Metformin Study Proportion of patients with events 35% 30% 20% 10% 0% Conventional (n=411) Intensive (n=951) Metformin (n=342) M vs C P=0.01 M vs I P=0.12 0 3 6 9 12 15 Years from randomization UKPDS Group. Lancet. 1998;352:854-865.