Antidiabetic drugs Jan Jurica Antidiabetic drugs • Insulin • Drugs used in T2DM Diabetes mellitus chronic multifactorial endocrine and metabolic disease DM I. type (IDDM) absolute deficiency in insulin (10 - 15 %) - infections or toxic effect on pancreas - autoimmune DM II. type (INDDM) relative deficiency in insulin (85 - 90 %) Diabetes Mellitus • = Chronic, metabolic, etiopathogenetically incompatible disease, the underlying feature of hyperglycemia • Due to the insufficient effect of insulin on its absolute or relative deficiency • The genetic predisposition of both forms of DM Types of diabetes Type 2 DM (85-90%) Relative insulin deficiency Damaged insulin secretion in pancreatic beta cells Resistance to insulin in target tissues Both deviations are mutually reinforcing, it is not clear which is the primary one Genetic and exogenous factors - obesity, stress, low physical activity, diet, toxins, changes in immune responses The peak occurrence between 45-65 years, 60-90% with obesity Types of diabetes Secondary DM DM accompanying pancreatic disease (including tumors) DM induced drugs - glucocorticoids, thiazide diuretics Toxins (streptozotocin) Gestational DM - Up to 17% of pregnant women develops in the 2nd trimester (24-28.t.t.) - antiinzulinary action. Of placental hormones ? - risk for the fetus - diabetic fetopathy - large organs, post-partum hypoglycaemia, hyperbilirubinemia, hypokalaemia, weight over 4 kg - Gestational DM = in 20% of non-obese and 60% of obese women with GDM – risk for DM2 in 15yrs, OR = 7 Types of diabetes OGTT 75 g of glucose in 200 ml of water 2 hours after 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 LADA - latent autoimunne diabetes of adults DM I.type manifesting in adults > 35 yrs. normal weight MODY - maturity onset diabetes of the young DM II.type, < 25 yrs, more than 5 yrs treated by OAD/non-insulin Rare subtypes of diabetes 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) lack of insulin Adipose tissue impaired utilisaton of Glc Muscles glucose oxidation  proteosyntheis proteins turnover....  AA HYPERGLYCEMIA OSMOTIC DIURESIS  glucose uptake by insulin – senzitive cells lipolysis  faty acids production ketogenesis acidosis  CNS insult, coma, exitus - dehydration - hypovolemia - impaired renal functions protein catabolism  AA in liver Insulin resistance Hypertension Hypertriglyceridaemia Disorders of glucose tolerance or diabetes Obesity type of apple (male type of obesity) METABOLIC SYNDROME Insulin = lowmolecular protein, 2 chains (A 21 AA, B 30 AA), 2 S-S bonds Synthesis - preproinsulin (107 AA)   proinsulin (82 AA, A,B +C-peptide)insulin marker of endogenous secretion of insulin (is not metabolized by the liver so quickly) Pharmacokinetic parameters • Inter- and intra-individual variability in absorption (25-50 % after s.c., i.m.) - appl. site, vascularity, temperature, massage, sunbathing, vasodilatators • T 1/2 7-10 min. insulin secretagogues glucose glucagon fatty acids OAD amplifiers of glucose-induced I. secretion gastrin, secretin, cholecystokinin GLP1 Beta-adrenergic stimulation AA (Lys, Arg, Leu) Insulin receptor Lincová a kol. 2002 Types of insulin A) Animal insulin - from pork or beef pancreas, highly pure, monocomponent, today only AUV, B) human insulin - produced biosynthetically (synthetically since the 1960s, biosynthetically from 70 years, commercially since 1982) is called HM C) insulin analogues- biosynthetically prepared, spec. Properties length of action (short, prolonged effect) - the production of antibodies to insulin depends on the purity Therapeutical use of insulin - DM I. Type - ketosis, ketonuria or ketoacidosis - patients with serious infetion/gangrene - DM II when blood Glc. not normalized with POAD, diet - DM II patients, use corticosteroids, liver or kidney impairment Principles of therapy with insulines • prevent fluctuation in Glc levels in plasma • tight glycemic control • control of glycated hemoglobin (Hb1Ac) -indicator of long-term and actual compensation Insulin preparations solutions/suspensions of insulin suspesions of „zinc-insulin“ suspensions „protamin-zinc-insulin“  insulin as a mixture of mono-/di-/tetra-/hexamers + pH, stability, isotonicity adjusted Insulin preparations Short acting A) insulin analogues: insulin lispro, aspart, glulisine Can be administered intravenously Start of operation 0-15 min. Maximum of effect - 30-45 min after admin. Effective for 2 - 5 hours. B) neutral aqueous solutions of insulins (Crystalline insulin, soluble insulin) Can be administered intravenously Start of action 30 min. Maximum 1 - 3 hours. Effective for 4 - 6 hours. Intermediate acting NPH (Neutral Protamine Hagedorn) Protamine insulins or mixtures of amorphous and crystalline forms of insulin in a ratio of 30:70 Start of action 1 - 2.5 hours Maximum 4 - 8 hours. Action 12 - 24 hours. Insulin preparations Long acting Crystalline suspensions of large crystals with very slow absorption Analogs and their conjugates (glargin, detemir, degludec) Onset of effect 2 - 3 hours Maximum 10-18 h (not apparent in degludec) Effective for 24 - 36 hours. Steady state after 3 days (3 doses) Less hypoglycemia than NPH, less weight gain Insulin preparations Long acting insulins Biosimilars of glargine – Abasaglar Glargin U300 – slow release from s.c. depo,longer halflife lower variability less hypoglycemia during night PEG lispro- long acting insulin (!) - polyethylenglycol, ↑ hydrodynamic size, slow absorption, degradation Degludec Solution of degludec subQ depo absorption Insulin preparations solutions/suspensions of insulin suspesions of „zinc-insulin“ suspensions „protamin-zinc-insulin“  insulin as a mixture of mono-/di-/tetra-/hexamers + pH, stability, isotonicity adjusted Complications of insulin therapy - hypoglycaemia - allergy - lipodystrophy Insulin resistance - spec. antibodies Weight gain Treatment strategies - the lowest total daily dose monitoring of glycaemia more doses, the tighter compensation and the lower total dose - intensified regimens Insulin pump Delivery systems (self-administration) 1) Insulin pen - cartridge with extendable needle; In the form of a fountain pen 2)Insulin pumps - continuous infusion s.c. (better compensation, less infectious risk) 3)Insulin syringes - with a sealed needle, calibrated per unit 4) Inhalation (USA) / transnasal ? Hypoglycaemia - below 2.8 mmol / l Causes : - overdose with insulin - delayed food intake, vomiting, diarrhea - excessive physical load (delayed hypoglycaemia) In the elderly, liver, kidney, cardial insufficiency Rapid onset of symptoms: nervousness, tremor, palpitations restlessness, hunger, sweating, consciousness disorders, changes in EEG, coma, exitus Therapy: Saccharide / glucose delivery p.o./i.v. (40% glucose, 30-50 ml or more) Glucagon, followed by glucose Glucagon effects - increases glycemia - positive inotropic (beta rcp. stimulation) - positive chronotropic effect decreases - gastric and panceratic secretion - smooth muscle relaxation (cAMP) Clinical use - limited - severe hypoglycemia - endocrine dg - insulinoma, medullary carcinoma - beta adrenergic blocker - poisoning - reversal cardiac effect Antidiabetics (GLD = glucose lowering drugs) Criteria for initiation of pharmacotherapy of DM II type and suitable selection of drug • OAD do not replace regimen (diet) • age, weight, blood insulin level • glycemia (fasting and postprandial) • comorbidities, metabolic syndrome (Oral) antidiabetics (AOD) The effect of most OAD is boubd to the ability of insulin secretion Most OAD are contraindicated in pregnancy (metformin may be used) - indication: - 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 Antidiabetics • biguanides • sulfonylurea derivatives (SU) • thiazolidindiones • alpha-glucosidase inhibitors • meglitinides • GLP1 analogues • Inhibitors of DPP IV • SGLT2 (sodium-glucose cotransporter) inhibitors Biguanides N H NH2 N NHNH CH3 CH3 metformin fenformin buforminMechanism of action • increase sensitivity of peripheral tissues to insulin • increase insulin binding to its receptor • reduce hepatic gluconeogenesis • decrease glucose absorption from GIT Do not affect insulin secretion, function of B cells → no hypoglycemia „euglycemic agents“ Further benefits: Direct stimulation of glycolysis in the periphery Reduce hepatic gluconeogenesis Delay Glc absorption from GIT Decrease plasma glucagon levels Increase the proportion of HDL Chol. → improve lipid profile Improve rheological properties of blood Are not metabolized, low protein binding Side effects Lactic acidosis Nausea, GIT problems about 20% of people (diarrhea) Reduced absorption vit. B12 Weight loose disulfiram effect Contraindications: Kidney disease (creatinine above standard, 130 μmol / l) Alcoholism, liver disease - because of a higher risk of lactic acidosis Therapeutic Use Type 2 DM, drug of choice (especially in obese patients) Non-obese in combinations (with insulin, glitazones, analogues, SU, incretins, gliflozines) OFF label indication: PCOS (polycystic ovary syndrome) anticancer effect (AMPK / mTOR) Metformin sulfonylurea derivatives (SU) mechanism of action 1) pancreatic – release of I. from beta - cell 2) extrapankreatic - potentiation of endogenous I effect on the target tissue - reduction of hepatal glucose production - reduction of hepatal Insulin degradation - reduction of serum glucagon levels Tolbutamide N H C O N H SO2CH3 SU derivatives I. Generation - chlorpropamide tolbutamide II. Generation - glibenclamide (gliburide) glipizide gliclazide gliquidone III. Generation - glimepiride Therapeutic use: not drugs of choice, 2nd line treatment Adverse effects • increased appetite • metal taste in mouth • Hypoglycemia •headaches, nausea (5 %) • fluids retention • allergy, fotosensitivity Contraindications DM Type 1 monotherapy, hypoglycemia, ketoacidosis, kidney or liver failure pregnancy, hypersensitivity Thiazolidinediones NHS O OH O N CH3 N rosiglitazone rosiglitazon pioglitazon troglitazon Mechanism of action • increase the sensitivity of periphery to insulin • ligands of PPAR (part of the steroid and thyroid superfamily of nuclar receptors) modulate the expression of the genes involved in the metabolism of lipids and glucose Thiazolidinediones NHS O OH O N CH3 N rosiglitazone Mechanism of action • increase the sensitivity of periphery to insulin • ligands of PPAR (part of the steroid and thyroid superfamily of nuclar receptors) modulate the expression of the genes involved in the metabolism of lipids and glucose Thiazolidindiones • Lowering blood glucose by the primary effect on insulin resistance - in diabetic and pre-diabetic patients • Does not cause hypoglycemia, scavengers •Increase glycogen synthesis and glycolysis in muscles •Stimulating glucose oxidation and lipogenesis in adipose tissue and reducing gluconeogenesis in the liver ... optimal metabolic effects 2010 referral – rosiglitazone withdrawn from registration - CVS AE Therapeutic use Sensitizers of insulin receptors The onset of effect in 4 weeks Side effects Hepatotoxicity Fluid retention Increase TAG Contraindications Hypersensitivity Predisposition to heart failure Liver damage Pregnancy, lactation Inhibitors of intestinal glucosidaseOH OH CH2OH OH OH CH3 O O CH2OH O OOH OH CH2OH O OOH OH acarbose Mechanism of the action • reduce sacharides absorption from GIT • competitive inhibition of the gut α - glucosidases (inhibits the cleavage of the polysacharides from the meal) acarbose miglitol voglibose • decrease postprandial glycemia • do not affect monosacharides absorption • acarbosis do not rech the systemic blood, miglitol does • „educative drugs“- consequences in bad compliance In hypoglycemia and the simultaneous treatment with other POADs can not be administered sucrose (monosacharide necessary - Glu, Fru) or Glucagon Inhibitors of intestinal glucosidase Meglitinides N H CH3 CH3 N H O OH N H CH3 O repaglinide Mechanism of the action similar to SU-derivatives: block ATP- sensitive K+ channel in membrane of beta-cells, depolarisation of membrane, activation of voltage-gated Ca2+ channel, influx Ca2+ , insulin release through different receptor at K+ channel repaglinid nateglinid meglitinid repaglinid nateglinid meglitinide Pharmacokinetics: • good bioavailibility • extensive protein binding (up to 98 %) • metabolized - inactive compounds • excreted mainly in faeces Meglitinides Clinical use • combined with metformin - esp. if patient not suffciently compensed • alternative of the SU medication in patients with renal impariment (excreted into bile) Contraindications: • hypersensitivity • DM I. type • diabetic ketoacidosis • pregnancy, lactation AE: Hypoglycemia Nausea, diarrhea, joint pain GLP1 – Glucagon-like peptide 1 + analogues „EXENDIN, EXENATIDE“ • exenatide, liraglutide lixisenatid, albiglutide s.c. administration Heloderma suspectum; Gila Monster • GLP1-physiologically secreted postprandially, in DM II insufficiently • stimulate insulin secretion (dependent on glycemia) inhibit glucagon secretion, prolong stomach content evacuation i DPP IV : inhibitors of dipeptidyl peptidase 4; syn. „Gliptins“ • Advantages: no hypoglycemia, stops progressin of ilness • Nowadays: in combinatin with others (POADs) better glycemic control than conventional drugs DPP IV GLP-1 metabolites ↑ Insulin secretion ↓secr. of Glucagon ↓GLC •24-hour effect - 2-3-fold increase in GLP-1 concentrations • Protects B cells • fixed combinations (eg with metformin) • linagliptin, sitagliptin, vildagliptin, aloglitpin • For the treatment of T2DM fixed combination with metformin/SU glitazone/statin i DPP IV : inhibitors of dipeptidyl peptidase 4; syn. „Gliptins“ SGLT2 (sodium-glucose cotransporter) Inhibitors • Increased reabsorbtion in kidney in DM2 • Inhibition SGLT2 = controlled glucosuria • Cardioprotective, renoprotective !! Convincing data from large studies • dapagliflozin, canagliflozin, empagliflozin • Hb1Ac decrease by 0.8% • BMI decrease (negative energy Bilance) AE: thirst, hypoglycemia, genital infections CI: over 75 years, concurrent loop diuretics, pioglitazone DM - Complications 1) hypoglycemia - (< 3,5 mmol/l) consciousness - sweet (sacharide) drink, meal unconsciousness - i.v. Glu 20-40% - u DM I. type i.v. glucagon 2) allergy (hypersensitivity IgE) corticosteroids, adrenalin i.v. 3) insulin resistance - IgG against insulin (animal insulins), change insulin preparation, POAD 4) lipodystrophy - change application sites (scheme), esthetic surgery DM - Complications Diabetic nefropathy - hypertrophy, hyperfiltration;  nefropathy, blood pressure (ACEi), microalbuminuria, insufficiency Diabetic neuropathy – gabapentin, pregabaline, carbamazepine, TCA, duloxetine Hyperlipoproteinemia - diet, statins, fibrates, probucol, nicotinic acid.. DM - Complications Diabetic foot - micro- and macrovascular impairments, a) neuropatic - warm, non-sensitive, dry, complicated with neuropathic ulcer, oedema b) ischemic - cold, without pulsations c) neuroischemic - ulcerations, gangrene Diabetic retinopathy - protein glycation, small vessels collagenisation; microangiopathy DM - Complications