Scope. History. History. Incretins. Incretin-based Therapy and DPP-4 Inhibitors

Transcription

1 Plasma Glucose (mg/dl) Plasma Insulin (pmol/l) Incretin-based Therapy and Inhibitors Scope Mechanism of action ผศ.ดร.นพ.ว ระเดช พ ศประเสร ฐ สาขาว ชาโภชนว ทยาคล น ก ภาคว ชาอาย รศาสตร คณะแพทยศาสตร มหาว ทยาล ยขอนแก น Pharmacological profile of insulin enhancer 192 : mechanism of pancreatic secretion nature of signal of pancreas chemical stimulus extracts from intestinal wall after stimulated by acid = secretin 196 : 1 st attempt at extracts of intestinal mucosa therapies for treating diabetes 1921 : different results of extracts of duodenal mucosa on fasting blood glucose and/or on hyperglycemia 1932 : incretin = an extract from upper gut mucosa that produces hypoglycemia but does not induce exocrine secretion 1964 : incretin effect Pharmacol Rev. 8 December ; 6(4): Pharmacol Rev. 8 December ; 6(4): Incretin Effect Different Responses to Oral vs IV Glucose Oral Glucose Tolerance Test and Matched IV Infusion 4 5 g Glucose 15 3 Incretins : Glucagon-like Peptide-1 A E G T F T S D V S S Y L E G A A K L A I F K G R G V W E =6 Oral IV J Clin Endocrinol Metab. 1986; 63: : Glucose-dependent Insulinotropic Peptide Y A E G T F S I D Y I S A M D K I K A L L W V F W D K G K D K I T Amino acids shown in orange are homologous with the structure of glucagon. 1

2 C-Peptide (pmol/l) and are Synthesized and Secreted from the Gut in Response to Food Intake Function of & L-cell (ileum) Pro Proglucagon [7 37] [1 42] [ ] K-cell (jejunum) Comaparison Between and Stimulate insulin release from β-cell Significant effects on β-cell growth and survival Potent inhibition of gastric emptying Potent inhibition of glucagon secretion Reduction of food intake and body weight Stimulate insulin release from β-cell Potential effects on β-cell growth and survival Modest effects on gastric emptying o significant inhibition of glucagon secretion o significant effects on satiety or body weight Incretin Effect in ealthy Participants and in Patients with Type 2 DM J Am Pharm Assoc. 9;49(suppl 1):S16 S29 Different Insulinotropic Effects of and in Patients with T2DM Saline yperglycemic Clamp Saline or or Diabetologia. 2; 45: = Restores Insulin and Glucagon Responses in a Glucose-sensitive Manner in Patients with T2DM 5 Glucose (mg/dl) infusion Placebo C-peptide (nmol/l) infusion Glucagon (pmol/l) infusion Diabetologia. 1993; 36:

3 Physiology of Secretion and Action on Receptors Stomach gastric emptying decelerated acid secretion Endocrine pancreas: Secretion β cells: insulin secretion α cells: glucagon secretion δ cells: somatostatin secretion Biosynthesis (Pro-) insulin β-cell mass growth, regeneration, neogenesis apoptosis Lancet 6; 368: Physiology of Secretion and Action on Receptors Adipose tissue Insulin-like effects: - glucose uptake - glycogen synthesis (? Indirect actions) Muscle Liver Lancet 6; 368: Physiology of Secretion and Action on Receptors Brain/nervous system: ypothalamus appetite, satiety food intake, water intake ucleus tractus solitarii GLP 1 production Access CS: circumventricular organs (circulating ) Autonomic nervous system Afferent vagus ( from GI tract) epatoportal region Lancet 6; 368: Mechanisms of -regulated Glucose omeostasis Sites of action Effect of Pancreatic β cell Enhance insulin secretion May play important role in islet neogenesis and proliferation of β cells apoptosis in β cells in vitro markers of β cell function Pancreatic α cell glucagon secretion Periphery Stomach CS glucose uptake Delays gastric emptying food intake Induces satiety J Am Pharm Assoc. 9;49(suppl 1):S16 S29 Mediated Actions Physiology of Current Opinion in Pharmacology 6, 6: Diabetes Care 9; 32(suppl2): S223-S231 3

4 Incretin Mimetics DPP-IV Inhibitor / Incretin Enhancer Diabetes Care 9; 32(suppl2): S223-S231 Diabetes Care 9; 32(suppl2): S223-S231 Inhibition of Increases Active Meal Intestinal release Active inhibitor t ½ =1 2 min inactive (>8% of pool) Diabetes. ; 49 (Suppl 1): A39 Diabetes. 1995; 44: Inhibition Increases Concentrations of Active Incretins Release of active incretins by the intestine a Glucose-dependent Glucagon from α cells epatic glucose production Glucose-dependent Insulin from β cells Peripheral glucose uptake Blood glucose in fasting and postprandial states enzyme Inactive X and inhibitor By increasing and prolonging active incretin levels, inhibitors increase insulin release and decrease glucagon levels in the circulation in a glucosedependent manner. =dipeptidyl peptidase-4; =glucose-dependent insulinotropic peptide; =glucagon-like peptide-1. a Incretin hormones and are released by the intestine throughout the day, and their levels increase in response to a meal. 1. Kieffer 22 TJ et al. Endocr Rev. 1999;2(6): Drucker DJ. Diabetes Care. 3;26(1): olst JJ. Diabetes Metab Res Rev. 2;18(6): Analogues vs Control in Adults With Type 2 Diabetes Inhibitors vs Control in Adults With Type 2 Diabetes JAMA. 7;298(2): JAMA. 7;298(2):

5 A Comparison between Incretin Mimetics and DPP4 Inhibitors Incretin Mimetics DPP4 Inhibitors ausea is often (44%) ausea is rare (1.4%) Gastric emptying delay Weight loss ot recommended for Pt with Cr clearance < 3 ml/min Twice-daily dose Administered by injection GI effects are rare Weight neutral Dose for renal insufficiency Once-daily dose Orally administrated ba1c reduction.8-1% ba1c reduction.6-.85% Inhibitors: Pharmacologic Profiles Adv Ther. 8;25(7): Inhibitors Differ in Molecular Structures and Pharmacologic Properties Chemical Class Generic ame Molecular Structure β-phenethylamines 1 Cyanopyrrolidines Aminopiperidine 8 Xanthine F F Sitagliptin 2 Vildagliptin 3 5 Saxagliptin 3,6,7 Alogliptin 9,1 Linagliptin 11,12 F 2 O Bioavailability ~87% 85% >75 % 4 /A ~3% alf-life 12.4 h ~2 3 h 2 O 3 C C F C O 3 O C O O O 2.5 h (parent) 3 h (metabolite) h Effective t 1/2 ~12 h Terminal t 1/2 > h Absorption 2 h (4 h for active 1 4 h 1.7 h t max (median) metabolite) 1 2 h 1.5 h =dipeptidyl peptidase-4. a Pharmacodynamic studies were performed in different assay systems and should not be compared. 1. Kim D et al. J Med Chem. 5;48: Data on file, MSD. 3. Matsuyama-Yokono A et al. Biochem Pharmacol. 8;76: Villhauer EB et al. J Med Chem. 3;46: EUSPC for Galvus. 6. Augeri DJ et al. J Med Chem. 5;48: EUSPC for Onglyza. 8. Feng J et al. J Med Chem. 7;5: Lee B 28 et al. Eur J Pharmacol. 8;589: Christopher R et al. Clin Ther. 8;3: Thomas L et al. J Pharmacol Exp Ther. 8;325: EUSPC for Trajenta. C 2 O O 2 Pharmacokinetic Properties of Inhibitors Oral administration Therapeutic dose Elimination Dose reduction with renal impairment 29 Sitagliptin (Merck) Vildagliptin (ovartis) Saxagliptin (BMS/AZ) Alogliptin (Takeda) Linagliptin (BI) Once daily 2 times a day Once daily Once daily Once daily mg/day 5 mg bid 5 mg/day Renal 87% (79% Yes (25 5 mg) Renal 85% (23% o Renal 75% (24% as parent; 36% as active metabolite) Yes (2.5 mg) mg/day Renal (6% 71% Probably yes 5 mg/day Feces 8% (9% Renal 5% Probably no Diabetes, Obesity and Metabolism 21; 12: Pharmacokinetic Properties of Inhibitors Distribution Metabolism epatic Insufficiency Drug-drug interactions Sitagliptin (Merck) 1 38% protein bound ~16% metabolized low potential of drug interactions with substrates of CYP3A4, 2C8, and 2C9 o dose Vildagliptin (ovartis) 2 9.3% protein bound 69% metabolized mainly renal (inactive metabolite) ot recommended Saxagliptin (BMS/AZ) 3 Low protein binding epatic (active metabolite) CYP3A4/5 Does in coadministration w CYPenhancers/ suppressors; no in I Alogliptin (Takeda) 5 =dipeptidyl peptidase-4. a Pharmacokinetic studies were performed in different assay systems and should not be compared. 1. Data on file, MSD. 2. EUSPC for Galvus. 3. EUSPC for Onglyza. 4. EPAR for 3 Onglyza. Accessed May 4, Christopher R et al. Clin Ther. 8;3: EUSPC for Trajenta. 7. Blech S et al. Drug Metab Dispos.21;38: Kidney Blood Press Res 212;36:65-84 /A <8% metabolized o dose Linagliptin (BI) 6,7 Concentrationdependent protein binding: 1 nm: 99% () 3 nm: 75% 89% ~13% metabolized o dose o o Yes o o 5