Incretinele : mai mult decit hipoglicemiante

Ofelia Spinu

disfunctia celulelor α

in diabet efectul de amplificare ↓↓ sau absent

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

GLP-1

GIP

GLP-1

GLP-1-stimularea secretiei de insulina indusa de glucoza

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

Efecte digestive

scaderea ponderala

GIP

Efect hipolipemiant

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