MUNI MED ANTIDIABETICS Alena Machalová 1 Define footer - presentation title / Department of Pharmacology Diabetes Mellitus Chronic, metabolic, etiopathogenetically heterogeneous disease, the underlying feature is hyperglycemia: • < 5.6 mmol/L • IFG 5.6 (6,1)-6.9 mmol/L • IGT 2hPG >7.8 <11.1 mmol/L after oGTT Due to the insufficient effect of insulin or its absolute or relative deficiency The genetic predisposition of both forms of DM Statistics • In 20 years there is a 10% increase in number of patients with diabetes • 31.12.2006 there is about 750 000 of diabetics • From this number 91,5 % is II. type, 6,7 % l.type, other forms are rare • Absolute number of 2. type diabetics is constantly increasing • Therapy of 2.type diabetes represents 5-10 % expenses in healthcare Adipose tissue impaired utilisaton of Glc lipolysi: faty acids production tketogenesis i lack of insulin , ▼ "N*. Muscles i glucose uptake by ;g|UCOSe oxidation insulin - senzitive cells ^ proteosyntheis tproteins turnover... J t AA • HYPERGLYCEMIA I OSMOTIC DIURESIS 1 ■t AA in liver i acidosis -»CNS insult, coma, exitus t - dehydration - hypovolemia - impaired renal functions protein catabolism Acute diabetic syndrome hyperglycemia glycosuria, osmotic dehydration intracelular lack of Glu -» catabolism, lipolysis metabolic acidosis deep breathing ketoacidotic coma Chronic diabetic syndrome protein glycation, autooxidation, peroxidation of lipids, lipoproteins micro / macro - angiopaties late complications of DM • Nefropathy • Diabetic foot • Infections • Retinopathy DM l.type • absolute lack of insulin peak between 13 and 15 years, high mortality if not treated A - autoimmune form with antibodies B - idiopatic form no antibodies DM II. type • (cca90%) • Relative lack of insulin due to • damaged production in beta cells • insulin resistance in peripheral tissues • both conditions are mutually potentiating • genetic and exogenous factors - obesity, stress, low physical activity • peak between 45-65 years, 60-90 % with obesity Metabolic syndrome Insulin resistance Hypertension • Hypertriglyceridaemia • Disorders of glucose tolerance or diabetes • Obesity type of apple (male type of obesity) PANCREAS □ (3- cell growth □ P-cell survival □ Glucose sensing LIVER > t FFA,TG secretion 11 Glucose production 11 Lipoprotein uptake BRAIN □ 4 Appetite 0 t Sympathetic tone MYOCARDIUM ?output / HTGIucose oxidation 134- FFA oxidation ARTERIES I Plaque formation MACROPHAGES □ t Survival MACROPHAGES 0T Fat infiltration RESISTANCE VESSELS 0 Vasodilation 0 Vasoconstriction CAPILLARIES t Capillary recruitment t Transendothelial insulin transport Insulin Sensitive© ; Insulin Resistant Clinical symptoms - l.type - more pronounced symptoms, fast onset (weeks) - polyuria, polydypsia, nycturia, loss of bodyweight when eating normally, tiredness, weakness, loss of consciousness or coma (in children) - 2.type - less apparent symptoms, slow onset (months, years) - others - organ complications - itching, impairs in vision, pain or formication*, neuralgias, problems with healing wounds, skin affections, bad teeth, loss of teeth, loss of erection, low libido... * Formication is the sensation resembling that of small insecj crawling on (or under) the skin when nothing is actually therS Gestational DM • (3-5 % pregnant women) —► in 20 % non-obese and 60 % obese women develope DM type 2 in 15 - 20 years • peak between 24.-28.week - anti-insulinary effects of placental hormones • risks for foetus - diabetic foetopathy - large organs, high birth weight, hypoglycaemia after delivery, hyperbilirubinemia, hypocalcemia big i- developed! OGTT 75 g of glucose in 200 ml of water 2 hours later sample collection and determination of glycemia in venous plasma Interpretation • < 7.8 mmol /L DM excluded • 7.8-11 mmol / L - Impaired glucose tolerance • > 11.1 mmol / L Diabetes mellitus In pregnancy is cut-off value more strict: 8,5 mmol/l after 2 hours Secondary DM • DM accompanying • pancreatic diseases • tumors of adrenal gland • hyperthyreosis • chronic renal insuficience • Drug induced DM - glucocorticoids, thiazide diuretics, MAb (Pd-L, PD-1L, CTLA4) • Toxins (streptozotocin) Rare subtypes of diabetes LADA - latent autoimunne diabetes of adults DM I. type manifesting in adults > 35 yrs, with normal weight and insulin sensitivity MODY - maturity onset diabetes of the young DM II. type, < 25 yrs, more than 5 yrs treated by OAD/non-insulin monogenous forms of diabetes (insulin transporter or insulin synthesis) Treatment of diabetes Q Diabetes Treatment 5 mmol/L mg/dL Interpretation 2.0 35 Extremely low 3.0 55 Low 4.0 75 Slightly low 4.4 80 Normal 5.5 100 Normal 5 to 6 90-110 Normal before meal in nondiabetics 8.0 150 Normal After meal in nondiabetics 10.0 180 Maximum After meal in nondiabetics 15.0 270 A little high to very high depending on patient 20.0 360 Very high • Lifestyle and regimen, diet, exercise • Pharmacotherapy with insulin or GLDs • Concomitant metabolic and CV disorders HbAlc 4 Insulin MUNI E D History • 1869 - medicine student Paul Langerhans (Berlin) discovered unknown inslets of tissue • 1889 - Minkowski - connection between panceras and diabetes in dog Further work was interruped by the 1st world war (Paulescu - Budapest) • 1921 - Banting + Best + Marjorie, Toronto • Leonard Thompson - 14 ys, the 1st injection of insulin to a human patient 11.1.1922, died at 27 • Elizabeth Hughes Gösset - the first US pacient, 14 ys, 23,5 kg; died in 1981 • The first producer Eli Lilly and Company C. H. Best and F. G. Banting ca. 1924 1921 - Banting + Best + Marjorie, Toronto Insulin - physiology MUNI E D Regulation of blood glucose 1. hormonal - antagonism with glucagon in the liver, Cortisol muscle tissue, aldosterone and growth hormone 2. autoregulation - glycaemia works back to secretion - Glc penetrates into B cells and opens Ca channel, signal for insulin release 3. nervous system - PS has a hypoglycemizing effect, S hyper. Insulin is produced at a dose of 20-40 IU / day -1/2 continuous, 1/2 pulse <®> Insulin is rapidly metabolised by proteases and glutathione insulin transhydrogenases (plasma half-life of 3-5 min) Insulin secretagogues Amplifiers of glucose-induced insulin secretion glucose gastrin, secretin, cholecystokinin glucagon GLP1 fatty acids beta-adrenergic stimulation ((32, (3^ GLDs AA (Lys, Arg, Leu) Factors decreasing insulin secretion somatostatin insulin (negative feedback) a-activation of sympathetic n. s. (adrenalin) galanin (neuropeptide) Insulin receptor Lincová a kol. 2002 Insulin receptor GLUT4—i Glucose molecules . ° * 0 O O V o Outside Insulin molecule— Insulin receptor Cell membrane Inside cell (cytoplasm) Translocation of GLUT-4-vesicle to cell membrane Insulin signal pathway Effects on lipid metabolism Effects on growth Effects on protein metabolism 1— GLUT-4-containing vesicle Insulin lowmolecular protein, 2 chains (A 21 AA, B 30 AA), 2 S-S bonds, 5808 Da Synthesis - preproinsulin (107 AA) proinsulin (82 A + B + C-peptide)^insulin marker of endogenous secretion of insulin + signalling activity Pharmacokinetic parameters A: inter- and intra-individual variability in absorption (25-50 % after s.c, i.m.) application site, vascularity, temperature, massage, sunbathing, vasodilatators D: no binding to plasmatic proteins, Vd = EC water M: fast metabolisation by proteases and transhydrogenases, in diabetics also degradation in kidneys T 1/2 7-10 min. Therapeutical use of insulin • must be administered in . IDDM (DM I. Type) ketosis, ketonuria nebo ketoacidosis • patients with serious infection/gangrene • patients younger than 30 years • DM II where blood Glc. not normalized with POAD, diet • DM II patients, corticosteroids use, liver or kidney impairment Types and origin of insulin a) animal insulins • from porcine or bovine pancreas • different primary structure • purified but immunogenic • monocomponent • used till the 1980s, today only AUV Insulins produced by recombinant techonology (since 1980s): b) human insulin • designation HM, identical structure c) insulin analogues • the primary structure of the protein is specifically altered to modify the pharmacokinetics ^ Classification of insulins Short or rapid acting • clear solutions without adjuvants or modifications slowing absorption • possible i.v. application (the only type) Neutral aqueous solutions of HM insulins (crystalline insulin, soluble insulin) disadvantage - formation of hexameres in site of application onset 30 min. maximum 1 - 3 h Ienght4 - 6 h Insulin analogues: insuliny lispro, aspart, glulisin more rapid action disadvantage - in monotherapy is neccessary often administration onset 10-20 min. aspart, 15-30 lispro maximum 1 - 2 h lenght 2-5 hod. (according to the dose) Classification of insulins Intermediate - acting insulins • modifications of physical and chemical characteristics of preparation decrease its solubility and slow absorption • only for s.c, i.m. admin onset 1 - 2,5 h maximum 4 - 8 h lenght 12-24h Isophan (NPH*) - mixture insulin + protamin + zinc - cloudy solution due to crystals of protamin with insulin Semilente, Lente (mixture of semilente + ultralente** in 30:70 ratio) - cloudy zinc suspensions of insulin Disadvantages • when used on night, maximum of the effect is at 4-6 am, risk of hypoglycaemia • absorption may interindividually vary Neutral Protamine Hagedorn *slow onset and prolonged duration, poorly soluble crystalised insulin Classification of insulins Long - acting insulins Cloudy suspensions of large zinc-insulin crystals with very slow absorption, sc. administration ultralente - poorly soluble crystalline insulin with slow onset and prolonged duration of action onset 2 - 3 h maximum 10-18 h lenght 24 - 36 h Analogues - clear appearance, less AE, lower weight gain detemir (Levemir) = predictable insulin" - small interindividual variability glargin (Lantus, Abasaglar) = „peakless insulin" - even longer effect, flat curve action/time degludec (Tresiba) = ultralong acting onset 1-2 h maximum 6 - 8 h detemir, no peak for glargin 0 lenght up to 24 h, 42 h for degludec Protraction mechanism for Degludec B chain L-7-Glu Hexadecandioyl Cell MembFane nzz|| II Insulin preparations Aqeous solutions - only short acting i.v. Suspensions of insulin, suspensions of „zinc-insulin", suspensions „protam zinc-insulin" - never i.v. Powder for inhalation stabilised mixtures of insulin in different ratios humánni inzulín tispro (výměna poradí B28 a B29) aspart (B28 kys. asparagová) TypeS Of iľlSUlin analouges glulisin (B28 kys. glutamová, B3 lysin) glargin (adice 2 argininů k B řetězci + A21 giycin) detemir (B29 kys. myristová, B30 odstraněn) INZULÍN A NOVINKY V LÉČBĚ INZULÍNEM, MUDr. Pavlína Piťhová, 4 / 2006 INTERNÍ MEDICÍNA PRO PRAXI Type of Insulin Appearance Action times after injection (in hours) Rapid-acting ■ Lispro (Humalog) ■ Glulisine (Apidra) ■ Aspart (NovoRapid) C :iea n r 6 8 12: 14 161 18: 20: 22: 24 Onset: 10 to 15 mins Peak: 1 to 2 hours Duration: 3 to 5 hours Intermediate-acting ■ NPH (Humulin-N, Novolin-NPH) c ouc n iy 10 12: 14: 16: 18: 20: 22: 24 Onset: 1 to 3 hours Peak: 5 to 8 hours Duration: up to 18 hours Slow or long-acting ■ Glargine (Lantus) ■ Detemir (Levemir) c Ilea ň r 2 4 6 8 10 12 j 14 16: 18 20 22: 24 Onset: 90 mins Peak: None Duration: up to 24 hours Rapid (Lispro, Aspart, Glulisine) > m o 6 8 10 12 14 16 18 20 Time [Hours] Insulin RMP labeling „PUR" - chromatophically purified „monocomponent" - highly purified without contaminating impurities (proinsulin, ins. fractions) - animal / human „HM" - human Lenght of action: 1) short acting - „rapid" 2) intermediate - acting - „Dep" (D) - Semilente 3) intermediate - acting with prolonged duration of action - „interdep" (ID) - lente 4) long - acting - „superdep" (SD) - ultralente Delivery systems (self-administration) « & s I* S 1) Insulin injections - calibrated by IU 2) Insulin pens - pen-sized injectors, + blood glucose detectors 3) Insulin pumps - automated administration of insulin (s.c. / i.v.) according to glycemia 4) Nasal insulin delivery, insulin inhalations Treatment strategies • the lowest total daily dose • monitoring of glycaemia • intensified regimens = more doses lower total dose and tighter compensation • insulin pump Breakfast Lunch Dinner Bedtime Insulin Effect Long acting basal insulin 6 AM Insulin Pump continuous sc insulin infusion Breakfast Lunch Dinner Bedtime snack Rapid or Short-acting insulin Insulin Effect B Lispro or Aspart Lispro or Aspart Lispro or Aspart 6 AM (24 hrs) Insulin Effect Bolus Bolus Bolus Smaller Bolus Intermediate (NPH) insulin used as a basal insulin /__ Í NPH Lispro or Aspart Lispro or Aspart Í Lispro NPH or Aspart Basal infusion Examples of physiologic insulin delivery. A) Once-daily glargine serves as a basal insulin that is typically given at bedtime. Rapidly acting insulin are used as prandial insulins. This allows patients to change meal times at will. B) Intermediate-acting NPH, given twice daily, can be used as a basal insulin, and can be combined with a rapid-acting "prandial" insulin. This regimen (shown as a 50:50 dosage ratio) is more difficult to adjust because NPH has a 2 hour delay, limited duration of action, and a time course that gives it "prandial-like" properties. Figure adapted from DeWitt & Hirsch (2003) https://tmedweb.tulane.edu/pharmwiki/doku.php/insulin_regimens 4 Complications of insulin therapy • hypoglycaemia • allergy • lipodystrophy • insulin resistance - spec, antibodies • weight gain Hypoglycaemia Plasma glucose under 2,8 mmol/l Causes • Insulin overdose • Vomiting, diarrhoea, delayed eating • Physical strain • Concomitant liver, heart or kidney insufficency Symptoms - fast onset • Agitation • Tremor, sweating • Hunger • EEG changes, loss of conscousness, coma, death Therapy: • fast intake of sacharides/glucose i.v. (40% glukose 30-50 ml or more) • glucagon + following glucose Increases glycaemia, heart contractility and heart rate Decreases gastric and pancreatic secretion and smooth muscle tone Therapeutical use • Hypoglycaemia in DM (condition of glycogen reserves) - pen (s.c./i.m. transanasal) • Diagnostics in endrocrinology AE - rare • Nausea, vomiting • Allergic reactions Antidiabetics = GLD (glucose lowering drugs) N I D (Oral) antidiabetics (OAD, GLD) The effect of most GLDs is bound to preserved insulin secretion Most GLDs are contraindicated in pregnancy (metformin may be used) Indications: • T2DM - if not properly compensated with diet • T1DM with a high insulin resistance, when insulin does not lead to a sufficient decrease in blood glucose Classical approach in type 2 DM 1. Regimen changes : diet + exercise 2. GLD monotherapy 3. Combined GLD or GLD + insulin 4. Insulin Drugs do not replace changes in lifestyle!!! • age, weight, blood insulin level • glycemia (fasting and postprandial) • comorbidities, metabolic syndrome GLDs 1. Biguanides (metformin) 2. Sulphonylurea derivatives 3. Thiazolidindiones 4. Inhibitors of intestinal glucosidases 5. Meglitinides 6. GLP1 (incretine) analoges 7. Inhibitors of DPP IV 8. SGLT2 (sodium-glucose cotransporter) inhibitors 1. Biguanides = metformin „euglycemic agents metformin - buformin, fenformin MoA: H2N N / \ N NH NH CK CK • increase sensitivity of peripheral tissues to insulin • increase insulin binding to its receptor Do not affect insulin secretion, functions of B cells —► no hypoglycemia They need preserved insulin secretion for their effect 4 Other effects: • reduce hepatic gluconeogenesis • decrease glucose absorption from GIT • decrease LDL, VLDL, FFA, TAG • increase fibrinolytic activity (inhibition PAI-1) AE lactic acidosis in renal insufficiency (excreted by the kidneys as the active compound) • nausea, GIT problems cca 20 % patients • anemia (absorption of B12) • reduction of bodyweight • disulfiram effect Kl: • Kidney diseases (GF under 60 ml/min/1,73 m2) • alcoholism • liver diseases Therapeutic use • DM type 2 - 1st choice drug in obese patients • In all combinations (+ insulin, glitazones, SU, incretines. • Off-label - PCOS, anticancer effect (AMPK / mTOR) Kl: Home Journals Specialties The Lancet Clinic GlobalHealth Multimedia Campaigns ■ Kidney diseases (G THE LANCET Oncology alcoholism Online First Current Issue All Issues Multimedia ~ About the Journal liver diseases Therapeutic use All Content t search Advanced Search < Previous Article I Comment Volume 17, No. 4, p407-4O9, April 2016 Next Article > Published. Q2 March 2016 • DM type 2 - 1st ch( • In all combinations i ! — DDI: http ://dx.doi .org/1 0.1016/S1470-2045 (16) 00006-1 Metformin for cancer prevention: a reason for optimism An drew T Chan1=1 □ □□□□ • Off-label - PCOS, a l±l Article Ififo Summary Full Text Tables and Figures References COVID-19 is an emerging, rapidly evolving situation. Get the latest public health information from CDC: https://www.coronavirus.gov. Get the latest research information from NIH: https://www.nih.gov/coronavirus. U.S. National Library of Medicine Clin ical Trials.gov Find Studies ▼ About Studies ▼ Submit Studies ▼ Resources w About Site ▼ PRS Login Home > Search Results > Study Record Detail Save this study A Phase III Randomized Trial of Metformin vs Placebo in Early Stage Breast Cancer The safety and scientific validity of this study is the ^ responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. ClinicalTrials.gov Identifier: NCT01101438 Recruitment Status © : Active, not recruiting First Posted© : April 12, 2010 Last Update Posted © : April 2, 2020 Sponsor: Canadian Cancer Trials Group Collaborators: »■ i _ i_r___I /-\_____I__i!L^. / *. I I \ 2. Sulfonylurea derivatives (SU) 1) pancreatic - increase insulin release, but NOT synthesis 2) extrapancreatic • potentiation of endogenous insulin effect on the target tissue • reduction of hepatal glucose production • reduction of hepatal insulin degradation • reduction of serum glucagon levels • increase the number of insulin receptor on ERYS, adipocytes, monocytes o p \>'/ 3 R1"S-N'R 1 2 R Sulfonamide functional group Hydrochlorthiazide Furosemid Sulfonylurea Calcium channel—[b] Sulphonyturea receptor ATP-sensitive K* channel Glucose transporter (GLUT.2) Ceil membrane ATP/ADP Mitochondria ■ ■ 1 Giucose-6-phosphate f Glucokinase Glucose Membrane Repolarisation OUTSIDE Positive charge 4i 2. Sulfonylurea derivatives (SU) I. generation - II. generation - III. generation - chlorpropamid tolbutamid glibenklamid glipizid gliklazid glikvidon glimepirid 2nd line of treatment, only exceptionally 1st choice in thin patients 2. Sulfonylurea derivatives (SU) Adverse effects Contraindications • hypoglycemia • increased appetite • metal taste in mouth • headaches • nausea (5 %) • fluids retention • allergy, fotosensitivity • hypoglycemia • ketoacidosis • renal/hepatal impairment • pregnancy • age • hypersensitivity 3. Thiazolidindiones (glitazones) Drugs: rosiglitazon f^\\ ?\ troglitazon s\ /NH pioglitazon chs ^^^^h o MoA • ligands of PPARy (part of the steroid and thyroid superfamily of nuclear receptors) modulate the expression of the genes involved in the metabolism of lipids and glucose increase the sensitivity of periphery to insulin 3. Thiazolidindiones (glitazones) Adipose O FA storage (FABP) O FA oxidaton (UCP3) Muscle O glucose oxidation (PDK4) O FA oxidaton (UCP3) Liver O gluconeogenesis (PEPCK) insulin sensitization glucose lowering triglyceride lowering antiatherosclerotic antihypertensive Macrophage QoxLDL uptake (CD36) OCH of flux (LXRa and ABCA1) 3. Thiazolidindiones (glitazones) • decrease glycemia by positive effect on insulin resistance, important in pre-diabetic state • better glucose utilisation in the muscle (| glycogen synthesis and glycolysis) • some positive metabolic effects I production of FFA, TAG, peroxidation of LDL, f HDL i TNFa, resistin (causes IR in peripheral tissues) I gluconeogenesis in liver t glucose oxidation and lipogenesis in adipose tissue • CVS AE (rosiglitazone, 2010) !!! 3. Thiazolidindiones (glitazones) Therapeutic use • sensitizers of insulin receptors • the onset of effect in 4 weeks • not 1st line, used in combinations (metformin, SU) Side effects • Rosiglitazone increased risk of heart attack and stroke • Troglitazone was withdrawn for hepatotoxicity • Fluid retention • Osteoporosis • Weight gain „euglycemic drugs" - do not act hypoglycemic on euglycemic individuals Contraindications • Hypersensitivity • Predisposition to heart failure Liver damage Pregnancy, lactation 4 4. Inhibitors of intestinal glucosidases Drugs acarbose miglitol voglibose MoA CH2OH acarbose CH2OH CH2OH OH O reduce sacharides absorption from GIT competitive inhibition of the gut a - glucosidases (inhibits the cleavage of the polysacharides from the meal) Suitable for monotherapy and combinations 4. Inhibitors of intestinal glucosidases • decrease postprandial glycemia • do not affect monosacharides absorption • acarbosis does not reach the systemic blood, miglitol does • ^educative drugs"- consequences in bad compliance In case of hypoglycemia sucrose can not be administered orally (necessary are monosacharides - Glu, Fru) / or Glucagon 5. Meglitinides Drugs: repaglinid nateglinid (STARLIX, TRAZEC) meglitinid MoA similar to SU-derivatives (bind to SUR, but different receptor site), fast onset through different receptor at K+ channel block ATP- sensitive K+ channel in membrane of beta-cells -voltage-gated Ca2+ channel —► influx Ca2+—► insulin release depolarisation of membrane —► activation of 4 5. Meglitinides Pharmacokinetics: • good bioavailibility, fast effect!! - no meal, no tablet • extensive protein binding (up to 98 %) • metabolized - inactive compounds • excreted mainly in faeces 5. Meglitinides Clinical use: • 2nd line, often combined with metformin - esp. if patient not sufficiently compensed • alternative of the SU medication in patients with renal impairment (excreted into bile) • administration before meals - rapid onset and fading effect for 4 hours • skipping a meal = skipping a dose (risk of hypoglycaemia if taken) 5. Meglitinides AE: • hypoglycemia • nausea • diarrhea • joint pain Contraindications: • hypersensitivity • DM I. type • diabetic ketoacidosis • pregnancy, lactation DPP-4 enzyme inactivates GLP-1 DPP-4 inhibitors (drugs) block DPP-4 and decrease glucose 6. GLP1 - Glucagon-like peptide 1 analogues exenatide, liraglutide lixisenatid, semaglutide, albiglutide s.c. administration !!! GLP1 is physiologically secreted postprandially, in DM2 not sufficient levels MoA: • | insulin secretion (dependent on glycemia) • i glucagon secretion, • prolong stomach content evacuation Heloderma suspectum, Gila Monster Registered also as antiobesitics (liraglutide, semaglutide) ■ 7. DPP-IV inhibitors = Gliptins dipeptidyl peptidase 4 Food Intake Gl Tract Release of active GLP-1 and GlPln response to an increased concentration of glucose in the digestive trad lumen DPP-4 rapidly degrades increuns (wilhln few mmutes). DPP-4 Inhibitor Incretin Effect Insulin release Glucagon DPP-4 inhibttDT blacks incretin degradation Key: 0 GLP-1 Q GIP Inactive Incretins 9 —. Increbns stimulate ^ V_) A insulin secretion O Potentiates Incretin Effect » Insulin release -Glucagon 7. DPP-IV inhibitors = Gliptins MoA: • inhibition of degradation of incretins (GLP1) • effect lasts for 24 hod - 2-3x higher levels of GLP1 Advantages: • no hypoglycemia • stop progress of DM • protection of B-cells • better glycemic control than conventional drugs 7. DPP-IV inhibitors = Gliptins dipeptidyl peptidase 4 Therapeutic use: DM 2 in combinatin with other GLDs linagliptin • + metformin - 1st choice in insufficient compensation • + sulfonylurea derivate - in Kl of metformin sitagliptin • + thizolidindione - in Kl of metformin ..iu^^ii^^ vildaqliptin • + statin * K aloglitpin AE: pancreatitis, hypoglycaemia (in combination with Insulin/SU) ^ ^ ^ B ...... . . sodium-glucose 8. SGLT2 inhibitors = glycosunc drugs co-transporter • SGLT2 is selectively exprimed in kidneys responsible for reabsorption of Glc from the filtrate back to circulation (even in hyperglycaemia) • glykosuric effect is apparent after a single dose and lasts for 24 hours • size of glycosuric effect depends on Glc concentration and GFR, NOT levels of insulin • glycosuria leads to loss of energy —► reduced bodyweight mild increase of diuresis and natriuresis • Hb1 Ac decrease by 0.8% 8. SGLT2 inhibitors = glycosuric drugs Therapeutic use: Suitable for monotherapy as well as combinations CAVE hypoglyceamia in combination with insulin / SU Cardioprotective (AIM, stroke, renoprotective !! Convincing data from large studies CI, caveats: over 75 years, kidney dysfunctions, concurrent loop diuretics, hypotension, electrolyte dysbalance AE: ertugliflozin thirst genital infections risk of lower limb amputations (mainly of the toe) hypoglycemia - in monotherapy the risk is minimal; in combination with insulin / der. SU risk high 4 dapagliflozin canagliflozin empagliflozin Start with Monotherapy unless: A1C Is greater than or equal to 9%. consider Dual Therapy. A1C is greater than or equal to 10%, blood glucose is greater than or equal to 300 mg/dL, or patient is markedly symptomatic, consider Combination Injectable Therapy (See Figure 8.2}. CHESS Metformin Lifestyle Management EFFICACY* HYPO RISK WEIGHT SIDE EFFECTS COSTS* high low risk neutral/loss Gl/lactic acidosis low If A1C target not achieved after approximately 3 months of monotherapy, proceed to 2-drug combination (order not meant to denote any specific preference — choice dependent on a variety of patient- 5 disease-specific factors]: Metformin Lifestyle Management EFFICACY* HYPO RISK WEIGHT SIDE EFFECTS COSTS* Sulfonylurea high moderate risk gain hypoglycemia Thiazoildinediorte high low risk gain edema, HF, fxs low DPP-4 Inhibitor Intermediate low risk neutral rare high SGLT2 Inhibitor intermediate low risk loss <3U, dehydration, fxs high GLP-1 receptor aponist high low risk loss (51 high Insulin (basal) highest high risk gain hypoglycemia high If A1C target not achieved after approximately 3 months of dual therapy, proceed to 3-drug combination (order not meant to denote any specific preference — choice dependent on a variety of patient- & disease-specific factors): Lifestyle Management Thiazolidinedione + SU or DPP-4-i or SGLT2-I or GLP-l-RA or Insulin (basal) * If A1C target not achieved after approximately 3 months of triple therapy and patient (1) on oral combination, move to basal Insulin or GLP-1 RA, (2) on GLP-1 RA, add basal Insulin, or (3) on optimally titrated basal Insulin, add GLP-1 RA or mealtime insulin. Metformin therapy should be maintained, while other oral agents may be discontinued on an Individual basis to avoid unnecessarily complex or costly regimens (i.e.,adding a fourth antihyperglycemic agent). Combination Injectable Therapy (See Figure 8.2) 71 TTJAYTJE \ CLINICAL IfiERTU A REASSESS AND MODIFY TREATMENT V MONTHS) / GLUCOSE-LOWERING MEDICATION IN TYPE 2 DIABETES: OVERALL APPROACH ESTABLISHED ASGVD OR CKD FIRST-LINE THERAPY IS METFORMIN AND COMPREHENSIVE LIFESTYLE (INCLUDING WEIGHT MANAGEMENT AND PHYSICAL ACTIVITY) JF HhA, ABOVE TARGET PROCEED AS BELOW GLf-1 RA with praven DIU benefit' SGLT2Í with proven CVD benefit', if eíf R adequate' if HbA, above target If further intensification is required or patient is am unable so tolerate GLP-1 RA andlor fäGLT2i. cheese agents demonstrating CV safely: ■ insider adding the direr class (GLP-1 RA üi 5GLT?i) with proven CVD benefit ■ if notun GLP-1 RA. ■ Bass [insulin' - TZC ■ SU.1 HF OR :K[i PREDOMINATES PREFERABLY 5GLT?i with evident* of reducing MF andfor CUD progression in CYOTs if eGFR adequate1 ........OR........ If SGLTJr not loNialedci contraindicated Dr if«GFR less 1ban adequate'add GLP-1 RA with proven CYD benefit' COMPELLING NEED TD MINIMISE HYPOGLYCEMIA COMPELLING MEED TO MINIMISE WEIGHT GAIN OR PROMOTE WEIGHT LOSS J L If HbA, above target ■ Avoid [ZD in the selling Df HF Choose ag 5 nts demonstrating CV safety: ■ Consider adding the other elsss with proven CVD benefit1 * DPP-4i (not saiagliplin) in the setting of HF (if not on GLP-1 RAI ■ Basal insulin* ■ Slf OPP-Ai GLP-1 HA rzc 4, 4, II HbA . above tätiget If HbA ibúvfi Ur^0t IF W)A._ above target ltHbA1; above target 4, 4, 4, J, CLP-1 RA 5GLT2i! SGLTři1 SGLT2iř Ort OR OR DR DPP-4i DPP-4i TZD TZC OR T7D OR GLP-1 RA 4, Ar If HbA, abffvi target Continue with addition of other agents as outlined above If HbA, above target i '.a 11 si J ■: r. he ad d il \e n of SLT 0 R basal id sulk > Choose later generation 5J wift lower risk of hypoglycemia • Consider basal insulin with lower risk of hypoglycemia' 1. Presen GVP Lenrfil means it hss label indication a? reducing CVtJ events. Far ELP 1 RA strongest ivideiro for lirajliilidrj > stmagtulids > eieiatiite ejleride.it release, For SSLTii evidence modestly ttron-jertor empaglilldiT *tuiaqlifioiin. 1. be aware'hat SGLHi varv" by reajen and individual agent with regard le indicated level of eGFR 5. L bw dose may le ostler Merited tr n ugh list weil itudtei fůr Ciffl effects 1. ChiíiSi later generation St) (villi low» risk nl hypoglycaemia ?. Dígluta i rjfarglne Ißt« - gtirjine UHO I delmlir HPK insolin rj. Semagjuude =■ tiragtudde * djlaglutide > ejrenatide = ioasetialtie GLP^I RA with good efficacy for weight toss' SC."2 If HbA, above target SGLlíi1 GLP-1 RA with good elfkacy lor weight loss' If HbA, above target 4, 4 If triple therapy re qui red or SGLI2i and.'or GLP-1 FtA not tolerated cr rontrainditated use regimen with lowest risk (rl weight gain PREFERABLY DPP-4r (ifnoldflULP-IRAJ based an weight neutrality If DPP-4mot tolerated or contraindtcated or patientalteady on GLP-1 RA. cautious addition of: . Stt! ■ TZQS - Basal insulin COST 15 A MAJOR l5SUE,!a If HbA, above target mV If HbA, above target Insulin therapy basal insulin with l»west acquisition test OR Consider DPP-fiiDR SGLT2i with lowest acquisition cost1' Patients with high CV risk A Type 2 DM - Drug naive patients B Type 2 DM - On metformin ASCVD, or high / very high CV risk (target organ damage or multiple risk factors)1 SGLT2 inhibitor or GLP-I RA Monotherapy" If HbAic above target Add Metformin If HbAit above target Consider adding the other class (GLP-I RA or SGLT2i) with proven CVD benefit DPP-4i if not on GLP-I RA Basal insulin TZD (not in HF pat) SU Metformin Monotherapy If HbAic above target H Add! o 1 r 1 1 Y 1 r DPP-4i GLP-I RA . t SGLT2i if eGFR adequate i TZD i r i r r If HbAit above target I I i SGLT2I or TZD T 1 SGLT2i GLP-I RA or or DPP-4i TZD II or TZD SGLT2i or DPP-4i or GLP-I RA If HbAic above target 1 Continue with addition of other agents as outlined above 1 If HbAic above target i Consider the addition of SU OR basal insulin: • Choose later generation SU with lower risk of hypoglycaemia " Consider basal insulin with lower risk of hypoglycaemia ASCVD, or high / very high CV risk (target organ damage or multiple risk factors)1 SGLT2 inhibitor r GLP-I RAb ■ If HbAic above target 1 Consider adding the other class (GLP-I RA or SGLT2i) with proven CVD benefit • DPP-4i if not on GLP-I RA ■ Basal insulin • TZD (not in HF pat) ■ SU Continue Metformin Monotherapy If HbAic above target 1 r i DPP-41 GLP-I RA SGLT2i if eGFR adequate 1 TZD > > r r If HbAic above target i 1 I SGLT2i or TZD SGLT21 or TZD GLP-1 RA or DPP^i or TZD SGLT2I or DPP-4i or GLP-I RA J If HbAic above target 1 Continue with addition of other agents as outlined above If HbAic above target 1 Consider the addition of SU OR basal insulin: • Choose later generation SU with lower risk of hypoglycaemia • Consider basal insulin with lower risk of hypoglycaemia Useful links American Diabetes Association http://www.diabetes.org/ Drugs used in gastric ulcer disease 80 Gastric ulcer disease Peptic ulcers - result of dysbalance between protective and harmfull factors 81 Dull pain Weight loss Burning II___Ll____ Burping Fatigue Heartburn Bloating Loss of appetite *wW Vomitin9 Nausea 82 Main goals of the treatment supress pain improve healing (mucosa reparation) prevent relapses supress harmfull factors antacids neutralization nhibition of HCl secretion H2 antagonists eradication of H. pylori H+ pump antagonists anticholinergic drugs 83 increase mucosa resistence 4 Antacids • symptomatic therapy to reduce pain • HCI neutralisation in stomach = increase in pH —► decrease in pepsin activity (pH optimum 2) • NaHC03 (strong, rapid relief from pain) • CaC03 (strong, rapid relief from pain, not for chronic treatment absorption of Ca2+) • MgO / Mg(OH)2 (laxative) Mg [AI02(OH)] J Al203 (gel, long-lasting eff., constipation) Bi(OH)2N03 (weak eff., supress H. pylori) 84 Antacids Indications: • dyspepsia, hyperacidity, pyrosis • reflux oesophagitis • symptomatic treatment of GIT disorders • begining of antiulcerous therapy • rapid relief from pain AE: • absorption of Ca, Mg (cardiac complications) • Al - constipation • Mg - laxative effect • decreased absorption of other drugs 85 H2 antihistamines ranitidine famotidine Mechanism of action: • competitive H2 receptor antagonisms • selective supression of HIS-induced secretion • inhibition of intrinsic factor secretion (B12) Indications: • ulcer disease (primary and secondary, prevention of relapse) • Zollinger-Ellison syndrome (tgastrin) • reflux oesophagitis • prophylaxis of gastrotoxicity in NSAIDs treatment Adverse effects: • myalgia, diarrhoea, constipation • CNS - confusion, glossolalia, headache • endocrine - antiandrogenic efect (Cimetidine) - impotence, gynekomastia • blood — granulocytopenia, trombocytopenia, neutropenia..aplastic anemia (ranitidine) • hepatotoxicity - alt, ast 86 Caution: pass placental barrier Proton pump inhibitors omeprazole, esomeprazole pantoprazole, lansoprazole rabeprazole Mo A: irreversible inhibition of PP and supression of HCI secretion regardless the origin of the stimulus (re-synthesis needed for regeneration of activity) r \ ► administered as a pro-drugs » acidic environment in the parietal cells —► active metabolites enterosolvent coating, parenteral Indications: H. pylori eradication in ulcer disease ulcer disease reflux oesophagitis Zollinger-Ellison syndrome (tgastrin) prophylaxis of stress-induced ulcer prophylaxis of NSAIDs- induced gastropathy in risk groups of patients (e.g. lmwh, warfarin) 4 Proton pump inhibitors AE: • dyspepsia, • headache • rarely cytopenia • P450 inhibition Proton pump Cytochrome Interaction inhibitor (PPI) P450 metabolism potential* Omeprazole Major: CYP2C19 Minor: CYP3A4 High Esomeprazole Major: CYP2C19 Minor: CYP3A4 Moderate Pantoprazole Major: CYP2C19 Minor: CYP3A4 Low Lansoprazole CYP2C19 CYP3A4 Moderate Rabeprazole Major: Non-enzymatic Minor: CYP2C19 Minor: CYP3A4 Low Proton Pump Inhibitor Drug Interaction Omeprazole • Clopidogrel (Plavix/Clopiiet/Ceruvin) Esomeprazole • Diazepam (Valium) • Warfarin (Coumadin) • Phenytoin (Dilantin) • Citolopram (Celexa) Ompreazole • Viracept (Nelfinavir) Esomeprazole • Harvoni (Ledipasvir) Lansoprazole • Edurant (Rilpirvine) Rabeprazole • Digoxin (Lanoxin) Pantoprazole • Ketoconazole (Nizoral) Dexlansoprazole • Methotrexate (Trexall) Zegerid 4 Selective parasympatolytics OBSOLETE >---' Mechanism of action: • acetylcholine antagonism in M1/3 receptors • convenient is selective inhibition • supress C02- 3 and mucus secretion • similar action as H2 antagonists pirenzepine Indications: • peptic ulcer disease • dyspepsia after NSAIDs treatment • stress ulcer prevention CI: • glaucoma • prostate hypertrophy • urination disorders Cy to protect i ves protective effect on the stomach mucosa sucralfate bismuth salts alginic acid 90 CH20R 9R Sucralfate = octasulfate of sucrose + aluminium hydroxide • strong mucoprotective eff. • needs acidic pHM • binds pepsin and bile acids • incr. prostaglandins synthesis H OR R0 H R = -S03[AI;!(0H)5] -so; ~J S^ R = -S03[Al2(0H)4)+ AE: • not absorbed • dyspepsia, Al- constipation Sucralfate mechanism of action Sucralfate Conversion in acidic environment pH<4 Cross-linking and formation of paste Coating of mucosal defects — decrease bioavailability Of Other drugs - tetracyclines, Phenytoin, digoxine, Cimetidine. 4 Cy to protect ives Bismuth salts = basic salts of bismuth and citric acid • chelatation of proteins on ulcer surface —► protective barrier • PG secretion stimulation • antibacterial action (eradication of H. pylori) Eicosanoids PGE1, PGI2 = main natural protective factors synthetised in gastric mucosa • increase mucus and HC03 production, perfusion • unstable, only derrivatives administered as prevention of harmfull effects of NSAID • Misoprostol - PGE1 - abortions!!!! Eradication of H. pylori • G- bacteria, over 80 % are asymptomatic • eradication decrease frequency of relapses to 0-10 % • complex therapy - combination of 2 antibiotics - with H+ pump inhibitors for 1 - 2 weeks Tripple therapy: PPI + amoxicilin (2x 1000 mg) + claritromycin/azithromycin (2x 500 mg) or metronidazole (2x 500 mg) ev. sequential In resistant pathogen + tetracyclin or bismuth salts _y Thank you for your attention