Agonistas del Receptor de GLP-1 en el tratamiento de la diabetes mellitus tipo 2

Transcripción

1 Agonistas del Receptor de GLP-1 en el tratamiento de la diabetes mellitus tipo 2 Manel Puig Domingo Servei d Endocrinologia Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona

2 Conflictos de interés Comités de asesoramiento internacional: Lilly, Novartis Comités de asesoramiento nacional: Lilly, Novartis, Novo-Nordisk, Sanofi-Aventis Conferencias: Lilly, Novo-Nordisk

3 Opciones Terapéuticas en la Diabetes Tipo 2 hasta el 212 Insulina animal? Lispro Metformina Insulina Humana Sulfonilureas Inhibidores de DPP-4 Agonistas del R de GLP-1 Detemir Glargina Glinidas Glitazonas Aspart s

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5 La DM2 es una enfermedad progresiva: UKPDS 6-Year Data (y tampoco la terapia insulínica) HbA 1C (Median %) 1c (Median %) Los tratamientos clásicos no modifican la historia natural de la DM2 Los tratamientos clásicos producen hipoglicemias, 6.2% HbA 1c upper limit of normal ganancia ponderal, y actualmente se discute su seguridad, 1 2 y 3 esto 4 también 5 6 es Time from Randomisation randomization (Years) válido para la insulina Conventional Chlorpropamide Glibenclamide Insulin Metformin UKPDS. Lancet. 1998;352:

6 La función de la célula β disminuye a lo largo del tiempo en pacientes con Diabetes Tipo 2 1 Función de la Célula β (%) Tiempo desde el Diagnóstico (años) Es posible que la función de la célula β ya haya disminuido en un 5% en el momento del diagnóstico La función de la célula β disminuye progresivamente con el tiempo aproximadamente un 6% por año Holman RR. Diabetes Res Clin Pract. 1998;4(suppl 1):S21-S25.; UKPDS. Diabetes. 1995;44:

7 La función de la célula β disminuye a lo largo del tiempo en pacientes con Diabetes Tipo 2 1 Función de la Célula β (%) Tiempo desde el Diagnóstico (años) Es posible que la función de la célula β ya haya disminuido en un 5% en el momento del diagnóstico La función de la célula β disminuye progresivamente con el tiempo aproximadamente un 6% por año Holman RR. Diabetes Res Clin Pract. 1998;4(suppl 1):S21-S25.; UKPDS. Diabetes. 1995;44:

8 βcell mass in T2 DM 3,5 3, β-cell volume (%) 2,5 2, 1,5 1, -5% -63% -41%,5, ND IFG T2DM ND T2DM Obese Lean ND=non-diabetic; IFG=impaired fasting glucose; T2DM=Type 2 diabetes mellitus Butler AE et al. Diabetes. 23;52:12-11.

9 The ideal antidiabetic drug Longer durability of glucose control/efficacy Agents that delay/prevent loss of β-cell function Agents that increase β-cell mass and function Therapies that provide superior control of postprandial glucose Agents that do not cause increased weight gain, and/or increase cardiovascular risk in any manner Agents that improve metabolic syndrome risk factors Agents that directly affect the progression of diabetic complications

10 Acciones clásicas y nuevas de la molécula de supervivencia GLP-1 Cerebro Corazón Cardioprotección Función Cardiaca Neuroprotección Apetito Estómago Intestino Vaciamiento Gástrico GLP-1 Hígado Páncreas Producción de Glucosa Tejido Adiposo Músculo Sensibilidad a la Insulina { Secreción de Insulina Secreción de Glucagón Biosíntesis de Insulina Absorción de glucosa y almacenamiento Proliferación de la célula Beta Apoptosis de la célula Beta Baggio LL, Drucker DJ. Gastroenterology. 27;132:

11 Structure of native GLP-1 and two GLP-1 R agonists 11

12 Agonistas del Receptor GLP-1 de acción prolongada

13 PLG indicates poly(d,l-lactide-co-glycolide). 1. Malone J et al. Expert Opin Investig Drugs. 29;18: Tracy MA et al. Biomaterials. 1999;2: Langer R, Folkman J. Nature. 1976;263: Bawa R. et al. J. Controlled Release. 1985:1: Exenatide LAR: Microsphere Delivery System for Continuous Therapeutic Levels Exenatide is incorporated into PLG microspheres 1 PLG is a medical biodegradable polymer (degraded to CO 2 and water) 2 Via hydration, exenatide at or near the surface dissolves and diffuses away (initial release) 3 PLG degrades, creating pores for exenatide diffusion and release from microspheres (sustained release) 4 Allows gradual drug delivery at a controlled rate 2

14 Plasma Exenatide LAR reaches Steady-State State Concentrations Within Weeks Plasma Exenatide (pg/ml) hours Treatment Period Follow-up Period 2. mg exenatide QW.8 mg exenatide QW 1 µg exenatide BID (single dose) Time (weeks) Data are mean ± SD Fineman M et al. Clin Pharmacokinet. 21;5(1):65-74.

15 HbA 1c Changes Over 52 Weeks of Exenatide LAR treatment. Controlled Extension (All Exe LAR) LS Mean Change (SE) in HbA 1c (%) * * * Exe LAR, n = 12; BL = 8.3% Exenatide BID EQW, n = 121; BL = 8.2% -2.% * * -2.% * * * Time (Weeks) *p<.5 Buse et al. Diabetes Care 21;33(6):

16 Exenatide LAR: Subjects Achieving HbA 1c Target Goals After 2 Years % Achieving Target % 55% EQW, 2-Year Completers (N = 216) EQW, Intent-to-Treat (N = 295) 39% 36% 17% 16% <7.% 6.5% 6.% Target HbA1c EQW: exenatide once a week (Exenatide LAR) Taylor, et al. BMC Endocr Disord. 211;11(1):9 [Epub].

17 Changes in HbA 1c vs. Comparators DURATION-1 1 DURATION-5 2 DURATION-2 3 DURATION-3 4 Baseline (%) N = LS Mean Change (SE) In HbA 1c (%) * * * * -1.3 Exe LAR Exenatide BID Sitagliptin Pioglitazone Insulin Glargine *p<.5 vs. comparator, intent-to-treat population 1. Drucker et al. Lancet 28;372(9645): Blevins et al. J Clin Endocrinol Metab 211;96(5): Bergenstal et al. Lancet 21;376(9739): Diamant et al. Lancet 21;375(9733):

18 Proportion of Subjects Achieving HbA 1c Target of 7% (or <7%) vs. Comparators Proportion (%) DURATION-1 1 p< DURATION-5 2 p< DURATION-2 3,4 p<.5 p< DURATION-3 5 p = Exe LAR Exenatide BID Sitagliptin Pioglitazone Insulin Glargine 2 1 N = DURATION-1: evaluable population; DURATION-5, -2, and -3: intent-to-treat population; DURATION-5 and -3: target of <7% 1. Drucker et al. Lancet 28;372(9645): Blevins et al. J Clin Endocrinol Metab 211;96(5): Bergenstal et al. Lancet 21;376(9739): Data on file, Amylin Pharmaceuticals, Inc. 5. Diamant et al. Lancet 21;375(9733):

19 Postprandial Glucose Changes: Exenatide LAR vs Exenatide twice a day Exenatide LAR 2 mg, n = 27 Exenatide 1 mg BID, n = 24 Mean Glucose (mmol/l) Mean Glucose (mmol/l) Time (Hours) Baseline (Dotted line, circle) Week 14 (Solid line, square) p =.124, Exenatide LAR vs. exenatide twice a day Time (Hours) Drucker et al. Lancet 28;372(9645):124-5.

20 Changes in Fasting Glucose vs. Comparators DURATION-1 1 DURATION-5 2,3 DURATION-2 3, 4 DURATION-3 5 Baseline (mmol/l) N = LS Mean Change (SE) in FG (mmol/l) * * EQW Exenatide BID Sitagliptin Pioglitazone Insulin Glargine *p<.1 vs. exenatide BID, p=.4 vs. sitagliptin, p=.1 vs. insulin glargine Intent-to-treat population 1. Drucker et al. Lancet 28;372(9645): Blevins et al. J Clin Endocrinol Metab 211;96(5): Data on file, Amylin Pharmaceuticals, Inc. 4. Bergenstal et al. Lancet 21;376(9739): Diamant et al. Lancet 21;375(9733):

21 Changes in Body Weight vs. Comparators DURATION-1 1 DURATION-5 2 DURATION-2 3 DURATION-3 4 Baseline (kg) N = LS Mean Change (SE) in Body Weight (kg) * Exe LAR Exenatide BID Sitagliptin Pioglitazone Insulin Glargine *p<.1 vs. sitagliptin and p<.1 vs. pioglitazone p<.5 vs. insulin glargine, intent-to-treat population 1. Drucker et al. Lancet 28;372(9645): Blevins et al. J Clin Endocrinol Metab 211;96(5): Bergenstal et al. Lancet 21;376(9739): Diamant et al. Lancet 21;375(9733):

22 Changes in HbA1c and Body Weight: Exenatide LAR vs insulin glargine Weight Change from Baseline (kg) % 62.7% 79.4% 31.4%.% 4.5% Exenatide LAR (N = 233) Insulin Glargine (N = 223) 4.4% 1.4% HbA 1c (%) Change from Baseline Intent-to-treat population Diamant et al. Lancet 21;375(9733):

23 Changes in Systolic Blood Pressure vs. Comparators LS mean change (SE) in SBP (mmhg) DURATION-1 1 DURATION-5 2 DURATION-2 3,5 DURATION-3 4 Baseline (mmhg) N = * ITT Patients EQW Exenatide BID Sitagliptin Pioglitazone Insulin Glargine *p =.1 vs. sitagliptin, intent-to-treat (ITT) population 1. Drucker et al. Lancet 28;372(9645): Blevins et al. J Clin Endocrinol Metab 211;96(5): Bergenstal et al. Lancet 21;376(9739): Diamant et al. Lancet 21;375(9733): Data on file, Amylin Pharmaceuticals, Inc.

24 Changes in Diastolic Blood Pressure vs. Comparators Baseline (mmhg) N = 2 LS mean change (SE) in DBP (mmhg) DURATION-1 1 DURATION-5 2 DURATION-2 3,5 DURATION No statistically significant between-group differences in diastolic blood pressure reduction were observed. Intent-to-treat (ITT) population EQW: exenatide once a week (LAR), BID: twice a day 1. Drucker et al. Lancet 28;372(9645): Blevins et al. J Clin Endocrinol Metab 211;96(5): Bergenstal et al. Lancet 21;376(9739): Diamant et al. Lancet 21;375(9733): Data on file, Amylin Pharmaceuticals, Inc. ITT Patients EQW Exenatide BID Sitagliptin Pioglitazone Insulin Glargine

25 Changes in LDL-C: Exenatide LAR vs Comparators Baseline (mmol/l) LS Mean Change (SE) in LDL-C (mmol/l) DURATION-1 1,5 DURATION-5 2 DURATION-2 3,5 DURATION N = * Exe LAR Exenatide BID Sitagliptin Pioglitazone Insulin Glargine *p=.2 vs. exenatide BID, p<.1 vs. exenatide BID, intent-to-treat population 1. Drucker et al. Lancet 28;372(9645): Blevins et al. J Clin Endocrinol Metab 211;96(5): Bergenstal et al. Lancet 21;376(9739): Diamant et al. Lancet 21;375(9733): Data on file, Amylin Pharmaceuticals, Inc.

26 Changes in HDL-C: Exenatide LAR vs Comparators Baseline (mmol/l) N = LS Mean Change (SE) in HDL-C (mmol/l) DURATION-1 1,5 DURATION-5 2 DURATION-2 3,5 DURATION * *p<.1 EQW vs. pioglitazone, intent-to-treat population Exenatide LAR Exenatide BID Sitagliptin Pioglitazone Insulin Glargine 1. Drucker et al. Lancet 28;372(9645): Blevins et al. J Clin Endocrinol Metab 211;96(5): Bergenstal et al. Lancet 21;376(9739): Diamant et al. Lancet 21;375(9733): Data on file, Amylin Pharmaceuticals, Inc.

27 Changes in Triglycerides: Exenatide LAR vs. Comparators Baseline (mmol/l) 1.5 DURATION-1 1,5 DURATION-5 2,5 DURATION-2 3,5 DURATION-3 4, N = Geometric LS Mean (SE) Ratio Endpoint to Baseline * Exenatide LAR Exenatide BID Sitagliptin Pioglitazone Insulin Glargine *p=.6 EQW vs. pioglitazone, intent-to-treat population 1. Drucker et al. Lancet 28;372(9645): Blevins et al. J Clin Endocrinol Metab 211;96(5): Bergenstal et al. Lancet 21;376(9739): Diamant et al. Lancet 21;375 (9733): Data on file, Amylin Pharmaceuticals, Inc.

28 Fasting Lipid Profile Changes After 2 Years of Exenatide LAR treatment Total Cholesterol LDL-C HDL-C Triglycerides Baseline (mmol/l) Change from Baseline (mmol/l) * -.12*.1-15%* Exenatide LAR(N = 148) Change from Baseline (%) *p<.5 vs. baseline, completer sample Kim et al. 69 th ADA 29.

29 Changes in Cardiovascular Risk Biomarkers under exenatide LAR BNP ACR hs-crp LS Mean Change (SE) from Baseline (%) p<.1 p = * 33* * * -14* -33* Exenatide LAR (N = 16) Sitagliptin (N = 166) Pioglitazone (N = 165) *p<.5 vs. baseline, intent-to-treat population BNP: B-type natriuretic peptide, ACR: albumin-to-creatine ratio, hs-crp: high-sensitivity C-reactive protein Bergenstal et al. Lancet 21;376(9739):431-9.

30 Exenatide LAR: Adverse Events 5% ExeLAR 1-5 N=67 n (%) ExeBID 1,2,5 N=268 n (%) SITA 3,5 N=166 n (%) PIO 3,5 N=165 n (%) Insulin Glargine 4,5 N=223 n (%) Nausea 126 (18.8) 93 (34.7) 16 (9.6) 8 (4.8) 4 (1.8) Diarrhea 83 (12.4) 24 (9.) 16 (9.6) 12 (7.3) 8 (3.6) Headache 55 (8.2) 17 (6.3) 15 (9.) 7 (4.2) 2 (9.) Nasopharyngitis 51 (7.6) 9 (3.4) 4 (2.4) 5 (3.) 4 (17.9) Vomiting 51 (7.6) 38 (14.2) 4 (2.4) 5 (3.) 3 (1.3) Injection site pruritus 43 (6.4) 3 (1.1) (.4) Intent-to-treat population, SITA: sitagliptin, PIO: pioglitazone 1. Drucker et al. Lancet 28;372(9645): Blevins et al. J Clin Endocrinol Metab 211;96(5): Bergenstal et al. Lancet 21;376(9739): Diamant et al. Lancet 21;375(9733): Data on file, Amylin Pharmaceuticals, Inc.

31 Incidence of Hypoglycemia by SU use Incidence (%) of Minor Hypoglycemia DURATION 1 1 DURATION 5 2,3 No SU Concomitant SU 1 Exenatide LAR 1 8 Exenatide BID Sitagliptin 8 Pioglitazone 6 Insulin Glargine * * n = DURATION 2 4 DURATION 3 5 DURATION 1 1 DURATION DURATION 3 5 *p<.5 Exenatide LAR vs. insulin glargine, intent-to-treat population 1. Drucker et al. Lancet 28;372(9645): Blevins et al. J Clin Endocrinol Metab 211;96(5): Data on file, Amylin Pharmaceuticals, Inc. 4. Bergenstal et al. Lancet 21;376(9739): Diamant et al. Lancet 21;375(9733):

32 Exenatide LAR:Changes in Heart Rate 1 Mean Change in Heart Rate from Baseline (bpm) * * * 4. 3 * *p<.5 vs. baseline bpm: beats per minute DURATION-1 1 DURATION-5 2 DURATION-2 1 DURATION Data on file, Amylin Pharmaceuticals, Inc. 2. Blevins et al. J Clin Endocrin Metab 211;96(5): Diamant et al. Lancet 21;375(9733):

33 Are GLP-1 R agonists the ideal antidiabetic drugs? Longer durability of glucose control/efficacy Agents that delay/prevent loss of β-cell function? Agents that increase β-cell mass and function? Therapies that provide superior control of postprandial glucose Agents that do not cause increased weight gain, and/or increase cardiovascular risk in any manner Agents that improve metabolic syndrome risk factors Agents that directly affect the progression of diabetic complications

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