Antidiabeticele oraleAsist. Univ. dr. Ariel FlorentiuADO disponibileSulfonilureeMetforminMeglitinideTZDInhibitori -glucozidazAcarbozMiglitolRosiglitazonPioglitazonGlibenclamidGliclazidGlimepirideGlipizidGliquidonRepaglinidNateglinidInhibitori DPPVildagliptinSitagliptinSaxagliptinAlogliptinLinagliptinInhibitori SGLT2DapagliflozinCanagliflozinChoice of agents in current use

Sulphonylureas, -glucosidase inhibitors, thiazolidinediones and meglitinides, and of course metformin, are all available for use in type 2 diabetes. Metformin is located in the pivotal position given its role in reducing hyperglycaemia and excess risk of morbidity from life-threatening complications. The choice of single-agent therapy has never been so broad with at least a dozen candidate agents to select from. As a result there are a large number of potential combinations of oral antidiabetic agents.

Clase de ADO - Sediul de aciuneAdaptat dup Kobayashi M. Diabetes Obes Metab 1999; 1 (Suppl. 1):S32S40.

Glucoz (G)

esut adiposIntestinStomacFicatSulfoniluree i meglitinideBiguanideMuchi scheletic

PancreasInsulin Inhibitori a-glucozidazTiazolidindioneInhib DPPBiguanidele Substane hipoglicemiante cu structur biguanidic n extractele de plante cu aciune hipoglicemiant (Galega officinalis)

Efectul hipoglicemiant al nucleului guanidinic era cunoscut nc din 1918

Biguanidele au fost introduse n practica medical n 1957

Datorit acidozei lactice frecvente la pacienii tratai cu fenformin, biguanidele au fost interzise n SUA, Canada, Scandinavia i Germania

Metforminul i buforminul au fost utilizate n continuare n unele ri Europene (inclusiv n Romnia)

Metforminul reintrodus n SUA din 1995 (stimulat i de rezultatele extrem de favorabile n UKPDS)BiguanideleMetformin / Mecanism de aciune Scderea rezistentei la insulina la nivel hepatic (aciune puternic asupra hiperglicemiei bazale): Creterea sintezei de glicogen/ inhibitia glicocogenolizei Reducerea gluconeogenezei

Scaderea rezistentei la insulina la nivelul muchilor scheletici cu creterea captrii glucozei

Scaderea HbA1c cu 1-2%Tratamentul cu metformin / Avantaje Evitarea creterii ponderale

Nu determin hipoglicemii

Efect favorabil asupra riscului cardiovascular (tratamentul pe termen lung scade riscul de IM)

Efect favorabil asupra profilului lipidic

Asociat insulinoterapiei duce la reducerea dozelor cu 20-30%

Evitarea suprasolicitrii excesive a celulelor beta-pancreatice

Ar putea oferi protecie mpotriva unor forme de cancer

A fost aprobat recent n tratamentul DZ tip 2 la copii i adolesceni

Metformin / Mod de administrareIniierea: 500 mg de 1-2 ori/ziTitrare: cu 500 mg la 3-7 zileDoza optim: 2000-2500 mg/ziDoza maxim: 3000 mg/ziAdministrare dup mas (evitarea reaciilor adverse digestive) Metformin / Efecte secundare Tulburri digestive (dependente de doz, tranzitorii la initierea tratamentului) Anorexie Grea Balonare Diaree

Risc crescut de acidoz lactic (prin inhibitia gluconeogenezei din lactat)Salpeter et al. Cochrane Database Syst Rev 2010 limita superioar a incidenei reale a acidozei lactice pentru 100,000 pacieni-ani a fost de 4.3 cazuri pentru metformin i 5.4 cazuri pentru grupul cu alte ADO.

Nu exist nici o dovad din studiile prospective comparative sau din studiile observaionale de cohort c metformin ar fi asociat cu risc crescut de acidoz lactic, sau cu niveluri crescute de lactat comparativ cu alte tratamente anti-hiperglicemice.Acidoza lactica (?)Metformin / Contraindicatii clasice Intolerana digestiv la biguanide

Insuficiena renal moderata/severa

Afectarea hepatic sever

Toate situaiile susceptibile s asocieze creterea acidului lactic Insuficien cardiac decompensata Insuficien respiratorie Anemie severa Ischemie periferica acuta majora Pacienti critici (sepsis, colaps, oc hemoragic)Sulfoniluree / Mecanism de aciune Stimularea exocitozei granulelor secretorii insulinice prin legare de canalul KATP cu nchiderea acestuia

Stimularea insulinosecretiei independent de nivelul glicemieiSULFONILUREE SCDERE MEDIE HbA1c 1-2%Produs originalcp (mg)AdmDoza maxima (mg)Clorpropamid1001/zi100Tolbutamid5003/zi1500GlibenclamidManinil, Manirom, Gliburide, Euglucon1.75, 3.5, 55551-3/zi20GliclazidDiaprel, EsquelDiaprel MR80602/zi1/zi240120GlipizidMinidiabGlucotrol XL55, 103/zi1/zi20GliquidonaGlurenorm303/zi120GlimepiridAmaryl1, 2, 3, 4, 61/zi6 SulfonilureiceSulfoniluree / Efecte secundare Hipoglicemii Pruden la vrstnici si alte categorii de pacienti la risc

Creterea ponderal

Suprasolicitarea cronic a celulelor beta poate duce la epuizarea mai rapid a rezervei lor funcionale Deficit absolut de insulin (DZ tip 1)

Insuficiena renal moderata/severa (admisa gliquidona pn n stadiul IV, glipizid, gliclazid la doze mici)

Insuficiena hepatic (sever)

Hipersensibilitatea la sulfoniluree

Tranzitor n infecii severe, traumatisme, intervenii chirurgicale, intoleran digestiv, etc.Sulfoniluree / ContraindicatiiMeglitinide / Mecanism aciune - Farmacodinamic SUR1 are dou situsuri de legare: unul pentru gruparea sulfonilureic (de care se leaga sulfonilureele) i altul pentru gruparea benzamido (de care se leag meglitinidele)

Cresc prima faz a insulinosecreiei

Absorbie rapid i complet din tractul digestiv, cu atingerea unui maxim plasmatic dup o or

Insulinemia ncepe s creasc dup 10-15 minute

Maxim dup 30-60 minute

Durata de aciune: 4-6 oreMeglitinideGLINIDE Scdere HbA1c 0,8-2%cp (mg)AdmDoza maxim (mg)NateglinidaStarlix60, 1203/zi360RepaglinidaReneos, NovoNorm0.5, 1, 23/zi12Tiazolidindione / Mecanism de aciune Activarea receptorilor PPAR

Efect la nivelul tesutului adipos (diferentierea precursorilor adipocitari cu formarea de adipocite tinere)

Cresterea preluarii de AGL la nivelul tesutului adipos Scderea insulinorezistenei periferice, n special muscular i hepatic Scderea esutului adipos visceral Ameliorarea steatozei hepatice non-alcoolice

Ameliorarea profilului lipidic

Scderea produciei de citokine i adipokine

Efecte antiinflamatorii TZD folosite curent in clinicaTIAZOLIDINDIONE Scdere HbA1c 0,8-1%cp (mg)AdmDoza maxima (mg)TroglitazonaRetras datorit efectelor secundare hepatice

PioglitazonaActos15, 30, 451/zi45RosiglitazonaRetras datorit riscului crescut de evenimente CVTiazolidindione / Efecte secundare Cretere ponderal (2-5 kg n primul an de tratament)

Retenie hidrosalin (edeme la 2-3% din pacieni)

Crete riscul insuficienei cardiace

Creterea riscului de osteoporoz/fracturi

Cresterea riscului de carcinom urotelial (?)

Cresterea riscului de IM (rosiglitazona) (?)

Tiazolidindione / Contraindicaii Insuficiena cardiaca

Osteoporoz

Afectare hepatica severa, hepatita activaInhibitori de alfa-glicozidaz / Mecanism de aciune -glucozidaza este o enzim care particip la procesul de digestie a glucidelor

Mediaz scindarea polizaharidelor i a dizaharidelor pn la glucoz

Inhibarea -glucozidazei ntrzie digestia i absorbia glucidelorInhibitori de alfa-glicozidaz folosii curent n clinicInhibitori Glucozidaz Scdere HbA1c 0.5% cp (mg)AdmDoza maxim (mg)AcarbozaGlucobay50, 1003/zi600Inhibitori de alfa-glicozidaz / Efecte secundare Distensie abdominal

Flatulen

Diaree

Sindrom de malabsorbie n cazul dozelor foarte mariInhibitori de alfa-glicozidaz / Contraindicaii Intoleran

Boli gastrointestinale severe asociate (enterite, enterocolite, rectocolite, etc.)

Ciroza hepatica

Adaptat dup Flint A, et al. J Clin Invest. 1998;101:515-520.; Adaptat dup Larsson H, et al. Acta Physiol Scand. 1997;160:413-422.; Adaptat dup Nauck MA, et al. Diabetologia. 1996;39:1546-1553.; Adaptat dup Drucker DJ. Diabetes. 1998;47:159-169.Determin apariia senzaiei de saietate i reduce apetitulCelule beta:Amplific secreia de insulin dependent de glicemieFicat: Glucagonului reduce producia hepatic de glucozCelule alfa: secreia postprandial de glucagonStomac: reglarea evacurii coninutului gastricGLP-1 secretat dup ingestia alimentar Rspunsul celulelor Solicitarea funcional a celulelor Efectele GLP-1 la omDISCUSSIONBy decreasing -cell workload and improving -cell response, the incretin glucagon-like peptide 1 (GLP-1) is an important regulator of glucose homeostasisA thorough understanding of the five GLP-1 glucoregulatory effects is important to assess the value of GLP-1 in controlling glucose levels, particularly during the postprandial period Upon ingestion of food, GLP-1 is secreted in into the bloodstream and enhances glucose dependent insulin secretion from -cells GLP-1 suppresses inappropriately elevated glucagon secretion from alpha cells Lower levels of glucagon lead to a reduction of glucose output from the liver and indirectly reduce the -cell workloadBy slowing the gastric emptying rate, GLP-1 slows the release of nutrients into the gut allowing more time to control the postprandial increase in glucose levelsGLP-1 promotes satiety, potentially through centrally mediated mechanisms

BACKGROUNDGLP-1 is secreted from L cells of the small intestineGLP-1 decreases -cell workload, hence the demand for insulin secretion, by:Regulating the rate of gastric emptying such that meal nutrients are delivered to the small intestine and, in turn, absorbed into the circulation more smoothly, reducing peak nutrient absorption and insulin demand (-cell workload)Decreasing postprandial glucagon secretion from pancreatic alpha cells, which helps to maintain the counterregulatory balance between insulin and glucagon Reducing postprandial glucagon secretion, GLP-1 has an indirect benefit on -cell workload, since decreased glucagon secretion will produce decreased postprandial hepatic glucose outputHaving effects on the central nervous system, resulting in increased satiety (sensation of satisfaction with food intake) and a reduction of food intake

Effect on Beta cell: Drucker DJ. Diabetes. 1998;47:159-169.Effect on Alpha cell: Larsson H, et al. Acta Physiol Scand. 1997;160:413-422.Effects on Liver: Larsson H, et al. Acta Physiol Scand. 1997;160:413-422.Effects on Stomach: Nauck MA, et al. Diabetologia. 1996;39:1546-1553.Effects on CNS: Flint A, et al. J Clin Invest. 1998;101:515-520.Administrarea GLP-1 la om Administrarea GLP-1 la pacienii cu DZ tip 2 a dus la: Reducerea glicemiei a jeun Scderea excursiilor glicemice postprandiale Supresia eliberrii exagerate de glucagon postprandial Ameliorarea rspunsului celulelor beta la glucoz i creterea capacitii maximale de insulinosecreieAciunea dispare rapid dup ncetarea infuziei cu GLP-1, timpul de fiind de ~ 5 minuteGLP-1 nu poate fi administrat dect parenteralDISCUSSIONWhen given to patients with type 2 diabetes, glucagon-like peptide 1 (GLP-1) is associated with improved glycaemic control, suppression of inappropriately high glucagon secretion, improved beta-cell responsiveness, reduced food intake and weight loss

Inhibitori de Dipeptidil Peptidaza 4 Dipeptidil Peptidaza 4 (DPP4) degradeaz hormonul incretinic GLP-1

A fost dezvoltat o clasa de inhibitori specifici ai aciunii DPP4 cu scopul de a crete nivelul plasmatic de GLP-1

Inhibitorii DPP4 pot fi administrai oral

Efectul hipoglicemiant este moderat (scaderea HbA1c cu 0,6-0,8%)Inhibitori DPP4 pe piaInhibitori DPP4 Scdere HbA1c 0.6%-0.8%cp (mg)AdmDoza maxima (mg)SitagliptinJanuvia1001/zi100VildagliptinGalvus501x2/zi100SaxagliptinOnglyza51/zi5AlogliptinNesina251/zi25LinagliptinTradjenta51/zi5Analogi GLP-1/ Mecanism de actiuneAgenti administrati injectabil ce realizeaza nivele farmacologice de agonist GLP-1

Determina efectele GLP-1 pe tesuturile tintaStimularea secretiei de insulina si inhibarea secretiei de glucagon mediate de glucozaIntarzierea evacuarii gastriceEfect central de satietate precoceAnalogi GLP-1Scdere HbA1c 1-1.5%(g)(mg)AdmInj s.c.Doza maximExenatideByetta5,10 g2/zi20 g/ziExenatide LARBydureon2 mg1/sapt2 mg/sptLiraglutideVictoza0.6 mg1/zi1.8 mg/ziLixisenatideLyxumia10, 20 g1/zi20 g/ziInhibitori SGLT2 / Mecanism de aciune Blocarea transportorului de glucoz de la segmentului S1 al tubilor contori proximali

Scderea reabsorbiei tubulare a glucozei

Creterea eliminrii urinare de glucozInhibitori SGLT2 pe piaInhibitori SGLT2 Scdere HbA1c 0.5%cp (mg)AdmDoza maxima (mg)DapagliflozinForxiga101/zi10CanagliflozinInvokana1001-3/zi300Inhibitori SGLT2 / Efecte secundare Polakiurie

Deshidratare, hipotensiune arterial

Creterea riscului de ITU si candidoze genitale

Lombalgii