incretinele mai mult decit hipoglicemiante
TRANSCRIPT
incretine/efectul de potentare
definitie – diferenta dintre rata de secretie a insulinei ca raspuns la ingestia orala vs administrarea sistemica a glucozeidefinitie – diferenta dintre rata de secretie a insulinei ca raspuns la ingestia orala vs administrarea sistemica a glucozei
GLP-1
GRPP GLUCAGON GLP-1 GLP-2
GRPP GLUCAGON GLP-1 GLP-2
GRPP GLUCAGON GLP-1 GLP-2
proglucagon
Celule α pancreatice
Celule L intestinale
THE GLUCAGONOSTATIC AND INSULINOTROPIC EFFECTS OF GLUCAGON-LIKEPEPTIDE-1 CONTRIBUTE EQUALLY TO ITS GLUCOSE-LOWERING ACTION, Kristine J. Hare, Diabetes, feb 2010
↓ secretia de glucagon
Diabetologia 1993,M. A. Nauk Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in Type 2 (non-insulin-dependent) diabetic patientsAdministrarea continua de GLP-1 amide iv 4h la pacienti in tratament cu SU, HbA1c 11.7%+/- 1.7%→↑ insulina serica si peptidul C ,↓ glucagonului seric, normalizarea glicemiei.
Lancet, martie 2002 , M. Zander , Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and β-cell function in type 2 diabetes: a parallel-group studyAdministrarea de GLP-1 nativ 6 saptamini → ↓ HbA1c 1.3%, glicemia fasting ↓ 4.3 mmol/L, ↓ 30% conc AG , ↓ G 1.9 kg
GLP-1 nativ la pacientii cu diabet zaharat tip 2
eficienta terapeutica
Clinical Therapeutics Volume 34, Number 6, 2012 Vanita R. Aroda, Efficacy of GLP-1 Receptor Agonists and DPP-4 Inhibitors: Meta-Analysis and Systematic Review
80 studii eligibile/362 publicate dupa 2005, durata 24-30 sapt (65%), faza III, HbA1c medie initiala 8-8.6%
↓HbA1c max 1.54% exenatide actiune prelungita, 1.08% exenatid bd, 1.22% liraglutideDPP-4 I 0.6% linagliptina, 0.98% vildagliptina
↓ glicemia fasting – scadere semnificativa ambele clase, maxim exenatide actiune prelungita si vildagliptina
Efficacy of GLP-1 Receptor Agonists and DPP-4 Inhibitors: Meta-Analysis and Systematic ReviewVanita R. Aroda, MD, Robert R. Henry, MD, Jenny Han, MS, Wenying Huang, PhDClinical Therapeutics Volume 34, Issue 6 2012 1247 - 1258.e22
efecte cardiovasculare
↑ FE post IM, CMD
Sokos GG, Nikolaidis LA, Mankad S, Elahi D, Shannon RP. Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure. J Card Fail. 2006
miocard ischemic post revascularizatie percutana
Nikolaidis LA Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circulation. 2004
scad TA, sistolica si diastolica; vasodilatatie, ↑natriureza
A, Hoogwerf et al. Effect of exenatide on heart rate and blood pressure in subjects with type 2 diabetes mellitus: A double-blind, placebo-controlled, randomized pilot study. Cardiovasc Diabetol. 2010 Tanaka T The role of incretins in salt-sensitive hypertension: The potential use of dipeptidyl peptidase-IV inhibitors. Curr Opin Nephrol Hypertens. 2011
disfunctia endoteliala si placa de aterom
M, Mita T, et al. Inhibition of monocyte adhesion to endothelial cells and attenuation of atherosclerotic lesion by a glucagon-like peptide-1 receptor agonist, exendin-4. Diabetes. 2010 Nyström T, et al. Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease. Am J Physiol Endocrinol Metab. 2004
efecte cardiovasculare
hipolipemiante : ↓ TG, ↓ apo B48, ↑HDL, ↓ lipemia postprandiala
Bunck M et al. One-year treatment with exenatide vs.insulin glargine: Effects on postprandial glycemia, lipid profiles, and oxidative stress. Atherosclerosis. 2010 Horton ES Weight loss, glycemic control, and changes in cardiovascular biomarkers in patients with type 2 diabetes receiving incretin therapies or insulin in a large cohort database. Diabetes Care. 2010
↓ riscul cardiovascular mediat prin ↓ ponderala
Williamson Intentional weight loss and mortality among overweight individuals with diabetes. Diabetes Care. 2000 DeFronzo RA Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care. 2005
scaderea ponderala
↓ Ponderala – semnificativa la analogii de GLP-1, maxim exenatide cu actiune prelungita -2.4 kg, gliptine 0.2- 0.6 kg
Vanita R. Aroda Efficacy of GLP-1 Receptor Agonists and DPP-4 Inhibitors: Meta-Analysis and Systematic Review Clinical Therapeutics Volume 34, Issue 6 2012
Clasa Compusi Mecanisme celulare Actiune fiziologica Avantaje Dezavantaje cost
DPP-4i SitagliptinVildagliptinaSaxagliptinLinagliptinAlogliptin
Inhiba activitatea DPP-4, creste concentratiile plasmatice ale incretinelor active (GLP-1, GIP)
↑Secretia de insulina dependenta de glucoza↓ Secretia de glucagon dependenta de glucoza
Toleranta bunaNu dau hipoglicemie
Eficacitate modesta (HbA1c)Urticarie/edem? Pancreatita
mare
Agonisti rec. GLP-1
Exenatide ExenatideextendedreleaseLiraglutide
Activeaza receptorii GLP-1
↑Secretia de insulina dependenta de glucoza↓Secretia de glucagon dependenta de glucoza↓ evacuarea gastrica↑ satietatea
Nu produc hipoglicemieScadere ponderala? Posibil efect trofic celule β? Posibil efect ↑functional? Posibil efecte protectoare cardiovasculare
Efecte digestive ( greata, varsaturi)? Pancreatita acutaMod de administrare injectabilNecesita instruirea pacientilor
mare
Management of Hyperglycemia in Type2 Diabetes: A Patient-Centered Approach Position Statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)
DIABETES CARE, VOLUME 35, JUNE 2012
Management of Hyperglycemia in Type2 Diabetes: A Patient-Centered Approach Position Statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) DIABETES CARE, VOLUME 35, JUNE 2012
amplificarea axei incretinelor – nou concept terapeutic
interfera un mecanism patogenic important in patogenia diabetului zaharat tip 2
scadere ponderala
beneficii cardiovasculare
efecte trofice celule celule β↑ sintezei de insulina
efecte anti inflamatorii→insulinorezistenta
studii suplimentare pentru precizarea impactului clinic
concluzii