13. Curs Studenti ADO_v3

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  • ANTIDIABETICELE ORALEAsist. Univ. Dr. Viviana ElianDiabet, Nutriie i Boli Metabolice

  • ADO disponibile

  • Clase de ADO - Sediul de aciune

  • 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)Biguanidele

  • Metformin / Mecanism de aciune Scderea debitului hepatic de glucoz (aciune mai puternic asupra hiperglicemiei bazale)

    Creterea aciunii periferice a insulinei la nivelul muchilor scheletici cu o cretere a captrii glucozei

    Creterea utilizrii glucozei de ctre celulele intestinale

    Scderea absorbiei intestinale a glucozei ?

    Inhibiia lipolizei i scderea nivelurilor de AGL

  • Metformin / Mecanism de actiuneCreterea sintezei de glicogen la nivel hepaticScderea glicogenolizeiReducerea gluconeogenezei hepatice

    Prezervarea funciei beta-celularePotentarea primei faze de secretie a insulinei

  • Metformin / Mod de administrareIniierea: 500mg de 1-2 ori/ziTitrare: 500mg la 3-7 zileDoza optim 2000-2500mg/zi

    Doza maxim 3000 mg/ziAdministrare dup mas (reacii adverse digestive)

  • Tratament cu Metformin / Avantaje Eficacitate similar cu cea a sulfonilureelor dar cu risc minim de hipoglicemie

    Evitarea creterii ponderale

    Efect favorabil asupra profilului lipidic

    Evitarea suprasolicitrii excesive a celulelor beta pancreatice

    Reducerea insulinemiei i proinsulinemiei cu rol aterogen

    Efect favorabil asupra riscului cardiovascular

  • Tratament cu Metformin / Avantaje Asociat insulinoterapiei duce la reducerea dozelor cu 20-30%

    Nu determin hipoglicemie n monoterapie

    Ar putea oferi protecie mpotriva unor forme de cancer

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

  • Cretere ponderal n UKPDSUKPDS 34. Lancet 352:854865, 1998 Cretere ponderal (kg)Ani de la randomizare

  • Metformin / Efecte secundare Tulburri digestive (dependente de doz, tranzitorii) Anorexie Grea Balonare Tulburri de tranzit, diaree

    Risc crescut de acidoz lactic

  • 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.Rezultate

  • Metformin / Contraindicatii clasice Intolerana digestiv la biguanide

    Insuficiena renal

    Afectarea hepatic (sever)

    Toate situaiile susceptibile s asocieze creterea acidului lactic Insuficien cardiac Insuficien respiratorie Efort fizic pe fond de arteriopatie obliterant Infecii severe, colaps, oc hemoragic Pacieni vrstnici

  • Metformin / Alte contraindicatii Deficit absolut de insulin (DZ tip 1) - Discutabil

    Sarcina - Discutabil

    n perioada investigaiilor radiologice folosind substane de contrast iodate - Discutabil

    Situaii speciale (IMA, AVC, stri critice, etc.)

    Pre i postoperator Discutabil

  • Metformin, previously contraindicated in heart failure, can now be used if the ventricular dysfunction is not severe, if patients cardiovascular status is stable ....

  • dovezile actuale indic clar un rol cheie al metformin n ameliorarea tulburrilor metabolice asociate cu NAFLD. De aceea, metformin, prin efectele sale benefice i profilul de siguran rmne o promisiune n tratamentul NAFLD, n special la pacienii cu diagnostic de sindrom metabolic

  • Sulfoniluree / Mecanism de aciune Stimularea exocitozei granulelor secretorii insulinice prin legare de canalul KATP cu nchiderea acestuia

    Aciuni extrapancreatice

    Creterea sensibilitii la insulin a celulelor periferice (efect secundar, probabil prin diminuarea glucotoxicitii)

    Potenarea aciunii insulinei

    Efecte la nivel: hepatic ( gluconeogeneza, glicoliza)muscular ( transportul de glucoz) adipocitar ( lipoliza)

  • Insulinosecreia fiziologic

  • 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). Sulfonilureicele din diferite generaii se leag de receptorul SUR1 pe regiuni aminoacidice diferite. nchiderea canalelor KATP prin sulfonilureice este reversibil. Situsuri de legare ale sulfonilureelor

  • Structura diferitelor sulfoniluree

  • Sulfoniluree folosite curent n clinic

    SULFONILUREE SCDERE MEDIE HbA1c 1-2%Produs originalcp (mg)AdmDoza maxima (cp)Clorpropamid1001/zi5Tolbutamid5003/zi6GlibenclamidManinil, Manirom, Gliburide, Euglucon1.75; 3.5; 55553/zi4GliclazidDiaprelDiaprel MR80602/zi1/zi32GlipizidMinidiabGlucotrol XL55,103/zi1/zi420 mgGliquidonaGlurenorm303/zi4GlimepiridAmaryl1, 2, 31/zi6 mg

  • Sulfoniluree / Efecte secundare Hipoglicemiile Pruden la vrsnici

    Creterea ponderal

    Efecte negative cardiace prin legarea de canalele de KATP de la nivel miocardic, cu afectarea potenialului de precondiionare ischemic

    Suprasolicitarea cronic a celulelor beta poate duce la epuizarea mai rapid a rezervei lor funcionale i la necesitatea introducerii mai precoce a insulinoterapiei

  • Deficit absolut de insulin (DZ tip 1, DKA, DZ tip 2 n bazal bolus)

    Sarcina

    Insuficiena renal (admis Glurenorm pn n stadiul IV)

    Insuficiena hepatic (sever)

    Intolerana sau hipersensibilitatea la sulfoniluree

    Tranzitor n infecii severe, traumatisme, intervenii chirurgicale, intoleran digestiv, etc.Sulfoniluree / Contraindicatii

  • Meglitinide / Mecanism aciune - Farmacodinamic 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 ore Se leag de situsuri specifice ale SUR1 (gruparea benzamido)

    prima faz a insulinosecreiei

    amplitudinea pulsaiilor insulinosecretorii

  • Meglitinide folosite curent n clinicNB - Din Ian 2010 Novonorm nu se mai regsete pe lista medicaie ADO gratuite

    GLINIDE Scdere HbA1c 1-2%cp (mg)AdmDoza maxim (cp)RepaglinidNovonorm0.5, 1, 21-3/zi12 mgRepaglinidReneos0.5, 1, 21-3/zi12 mg

  • Tiazolidindione / Mecanism de aciune Activarea receptorilor PPAR

    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 hormoni adipocitari

    Efecte antiinflamatorii ?

  • Structura TZD

  • TZD folosite curent in clinica

    TIAZOLIDINDIONE Scdere HbA1c ~1%cp (mg)AdmDoza maxima (cp)TroglitazonaRetras datorit efectelor secundare hepatice

    PioglitazonaActos15, 30, 451/zi45 mgRosiglitazonaRetras datorit riscului crescut de evenimente CV

  • Tiazolidindione / Efecte secundare Cretere ponderal (2-5 kg n primul an de tratament)

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

    Crete riscul insuficienei cardiace i anemiei

    Cretere a LDL plasmatic (Rosiglitazona)

    Creterea riscului de osteoporoz/fractur

  • Tiazolidindione / Contraindicaii Insuficiena cardiac

    Insuficiena renal

    Afectarea hepatic (niveluri ALT/AST peste 2-3 ori limita normalului)

    Anemia

    HTA necontrolat

    Intolerana la TZD

    BIC (Rosiglitazona)

    Osteoporoz

  • Rosiglitazone and pioglitazone increase fracture risk in women and men with type 2 diabetes.

    Aubert RE, Herrera V, Chen W, Haffner SM, Pendergrass M. Diabetes Obesity & Metabolism Apr 2010, 12:716-721

  • Thiazolidinediones and associated risk of Bladder Cancer: a Systematic Review and Meta-analysis.

    Turner RM, Kwok CS, Chen-Turner C, Maduakor CA, Singh S, Loke YK.Br J Clin Pharmacol. 2013 Dec 10. doi: 10.1111/bcp.12306. Subgroup analysis of observational studies by cumulative dose showed the risk of bladder cancer to be greatest with >28.0 grams of pioglitazone (OR 1.64, 95%CI 1.28-2.12) >2.5 ani la 30 mg/zi

  • Inhibitori 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 mtrzie digestia i absorbia glucidelor

    Eficacitate mai mare la pacienii cu aport glucidic de peste 50-55%, n special format din glucide complexe

  • Inhibitori de alfa-glicozidaz folosii curent n clinic

    Inhibitori Glucozidaz Scdere HbA1c 0.5-1% cp (mg)AdmDoza maxim (mg)AcarbozaGlucobay50, 1001-3/zi300 mg

  • Inhibitori de alfa-glicozidaz / Efecte secundare Distensie abdominal

    Flatulen

    Diaree

    Sindrom de malabsorbie n cazul dozelor foarte mari

    Atenie la tratarea hipoglicemiilor la cei cu asociere SU/INS

  • Inhibitori de alfa-glicozidaz / Contraindicaii Intoleran

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

  • Efectul incretinic

  • 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.Efectele GLP-1 la om

  • Administrarea GLP1 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 insulinosecreie Aciunea dispare rapid dup ncetarea infuziei cu GLP-1, timpul de fiind de ~ 5 minuteGLP-1 nu poate fi administrat dect parenteral

  • 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 ( HbA1c cu ~ 0.8%) mai puternic n cazul asocierii cu metformin

    Nu au reactii adverse

  • Inhibitori DPP4 + Structur Chimic

  • Inhibitori DPP4 pe pia

    Inhibitori DPP4 Scdere HbA1c 0.5%-0.7%cp (mg)AdmDoza maxima (cp)SitagliptinJanuvia1001/zi100 mgVildagliptinGalvus501x2/zi100 mgSaxagliptinOnglyza51/zi5 mgAlogliptinNesina251/zi25 mgLinagliptinTradjenta51/zi5 mg

  • Analogi GLP-1

    Scdere HbA1c 1-1.5%(g)(mg)AdmInj s.c.Doza maximExenatideByetta5,10 g2/zi20 g/ziExenatide LARBydureon2 mg1/sapt1/sptLiraglutideVictoza0.6 mg1/zi1.8 mgLixisenatideLyxumia10, 20 g1/zi20 g/zi

  • GLP-1-reactii adeverseFlatulentaDispepsieScadere ponderalaNoduli la locul injectarii (Bydureon)

  • Holst et al Trends Mol Med 2008NIVEL FIZIOLOGICNIVEL FARMACOLOGICDiferene Agonisti GLP-1 vs Inhibitori DPP-4

  • Inhibitori 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 glucoz

    Pot fi asociai cu orice alt clas medicamentoas de ADO i/sau insulin

  • Structura SGLT2i

  • SGLT2 aciune fiziologic

  • Inhibitori SGLT2 pe pia

    Inhibitori SGLT2 Scdere HbA1c 0.5%-1%cp (mg)AdmDoza maxima (cp)DapagliflozinForxiga101/zi10 mgCanagliflozinInvokana1001-3/zi300 mg

  • Inhibitori SGLT2 / Efecte secundare Deshidratare

    Hipotensiune arterial

    Creterea risc infestare micotic ci urinare

    Cretere risc infecii urinare ?

  • Management of Hyperglycemia in Type 2Diabetes: A Patient-Centered Approach

    Position Statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)Diabetes Care 2012;35:13641379Diabetologia 2012;55:15771596

  • ClassMechanismAdvantagesDisadvantagesCostBiguanides(Metformin) Activates AMP-kinase Hepatic glucose production Extensive experience No hypoglycemia Weight neutral ? CVD events Gastrointestinal Lactic acidosis B-12 deficiency ContraindicationsLowSUs / Meglitinides Closes KATP channels Insulin secretion Extensive experience Microvascular risk Hypoglycemia Weight gain Low durability ? Ischemic preconditioningLow

    TZDs Activates PPAR-g Insulin sensitivity No hypoglycemia Durability TGs, HDL-C ? CVD events (pio) Weight gain Edema / heart failure Bone fractures ? MI (rosi) ? Bladder ca (pio)Higha-GIs Inhibits a-glucosidase Slows carbohydrate absorption No hypoglycemia Nonsystemic Post-prandial glucose ? CVD events Gastrointestinal Dosing frequency Modest A1cMod.

  • ClassMechanismAdvantagesDisadvantagesCostDPP-4inhibitors Inhibits DPP-4 Increases GLP-1, GIP No hypoglycemia Well tolerated Modest A1c ? Pancreatitis UrticariaHighGLP-1 receptor agonists Activates GLP-1 receptor Insulin, glucagon gastric emptying satiety Weight loss No hypoglycemia ? Beta cell mass ? CV protection GI ? Pancreatitis Medullary carcino InjectableHighAmylin mimetics Activates amylin receptor glucagon gastric emptying satiety Weight loss Post-prandial glucose GI Modest A1c Injectable Hypo w/ insulin Dosing frequencyHighBile acid sequestrants Binds bile acids Hepatic glucose production No hypoglycemia Nonsystemic LDL-C GI Modest A1c TGs Dosing frequencyHighDopamine-2agonists Activates DA receptor Modulates hypothalamic control of metabolism Insulin sensitivity No hypoglycemia ? CVD events Modest A1c Dizziness/syncope Nausea FatigueHigh

  • Table 1. Properties of anti-hyperglycemic agentsDiabetes Care 2012;35:13641379Diabetologia 2012;55:15771596

    ClassMechanismAdvantagesDisadvantagesCostInsulin Activates insulin receptor Glucose disposal Hepatic glucose production Universally effective Unlimited efficacy Microvascular risk Hypoglycemia Weight gain ? Mitogenicity Injectable Training requirements StigmaVariable

  • Choice 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.

    Increasing weight may occur with all oral antidiabetic agents as well as with insulin, but as the UKPDS demonstrated, the most weight was gained by patients receiving insulin therapy, aimed at achieving FPG of < 6.0 mmol/l. In this study, conventional therapy was dietary advice every 3-months, aiming to attain normal body weight and FPG. This group was only randomised to drug treatment if FPG rose to > 15 mmol/l.UKPDS 34. Lancet 1998;352:85465. DISCUSSIONThe incretin effect is essentially the difference in beta-cell response between administration of oral glucose and intravenous (IV) glucose There is a sharp difference between the insulin response to oral glucose (as measured by C-peptide, a surrogate marker for insulin) compared with the insulin response to IV glucose. That difference, or effect, is the incretin effect, which is shown on the right graph by the shaded area.There is little difference between the venous plasma glucose profiles over time in response to oral glucose compared with the response to IV glucose

    BACKGROUNDThis was a crossover study involving healthy subjects Six young healthy subjects were given a 25, 50, or 100g oral glucose load or isoglycaemic intravenous glucose infusions. The 50g data are shown above.C-peptide may be a better measure of insulin secretion than plasma insulin, because C-peptide levels are not affected by hepatic insulin extraction This difference in C-peptide levels in response to oral versus intravenous glucose suggests that other factors (incretins), and not merely the direct actions of plasma glucose, affect the insulin secretory responseDISCUSSIONBy 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.DISCUSSIONWhen 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

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