24. Antidiabetic_Drugs_400L.pptx. This slide is created by one of AKTH doctors

*Antidiabetic Therapies*

*Insulin Sensitization*

- Enhance insulin receptor sensitivity
- Improve glucose uptake in peripheral tissues
- Reduce hepatic glucose production

*Insulin Secretion Augmentation*

- Stimulate pancreatic beta-cell insulin release
- Increase insulin availability
- Regulate blood glucose levels

*Carbohydrate Absorption Modulation*

- Delay gastric emptying
- Inhibit intestinal alpha-glucosidases
- Reduce postprandial glucose peaks

*Glucagon-Like Peptide-1 Potentiation*

- Enhance GLP-1 receptor activity
- Increase insulin secretion
- Decrease glucagon release

*Sodium-Glucose Cotransporter 2 Inhibition*

- Reduce renal glucose reabsorption
- Increase urinary glucose excretion
- Lower blood glucose levels

*Key Concepts*

- Pathophysiology of diabetes mellitus
- Therapeutic targets for

1. Pancreatic Hormones & Antidiabetic Drugs By Ramalan MA Clinical Pharmacology Department

2. Diabeted mellitus Two major type of diabetes mellitus Type I Type II Gestational Diabetes Others Require careful monitoring of: Diet, fasting, postprandial blood glucose Hemoglobin A 1c,

3. Insulin Physiology Proinsulin: 86 amino acid C-peptide: 31 amino acid Effects Liver Skeletal muscle Adipose tissue

4. Structure of human proinsulin

5. Glucose transporters. Transporter Tissues Glucose K m (mmol/L) Function GLUT 1 All tissues, especially red cells, brain 1-2 Basal uptake of glucose; transport across the blood-brain barrier GLUT 2 B cells of pancreas; liver, kidney; gut 15-20 Regulation of insulin release, other aspects of glucose homeostasis GLUT 3 Brain, kidney, placenta, other tissues < 1 Uptake into neurons, other tissues GLUT 4 Muscle, adipose »  5 Insulin-mediated uptake of glucose GLUT 5 Gut, kidney 1-2 Absorption of fructose

6. Schematic diagram of the insulin receptor

7. Insulin promotes synthesis

8. Endocrine effects of insulin (1) Effect on liver:       Reversal of catabolic features of insulin deficiency      Inhibits glycogenolysis     Inhibits conversion of fatty acids and amino acids to keto acids     Inhibits conversion of amino acids to glucose   Anabolic action  Promotes glucose storage as glycogen (induces glucokinase and glycogen synthase, inhibits phosphorylase) Increases triglyceride synthesis and very-low-density lipoprotein formation

9. Endocrine effects of insulin (2) Effect on muscle:       Increased protein synthesis      Increases amino acid transport     Increases ribosomal protein synthesis   Increased glycogen synthesis      Increases glucose transport     Induces glycogen synthase and inhibits phosphorylase

10. Endocrine effects of insulin (3) Effect on adipose tissue:       Increased triglyceride storage  Lipoprotein lipase is induced and activated by insulin to hydrolyze triglycerides from lipoproteins Glucose transport into cell provides glycerol phosphate to permit esterification of fatty acids supplied by lipoprotein transport     Intracellular lipase is inhibited by insulin

11. Impact Of Insulin On Life Expectancy By The 1940’s Age at start of diabetes 50 30 10 Avg. age of death in 1897 58.0 34.1 11.3 Avg. age of death in 1945 65.9 60.5 45.0 Years Gained 8 26 34

12. 4. Intracellular accumulation of potassium and phosphate (which are linked to glucose transport in some tissues). 5. Increased cellular amino acid uptake and DNA and RNA synthesis. 6. Increased oxidative phosphorylation.

13. Insulin Kinetics Time (h) Plasma Insulin Level 2 10 6 8 4 12 Lispro Aspart Glulisine Regular NPH Glargine-24 hours inhaled Detemir 12-24 hours DeWitt DE, Hirsch IB. JAMA 289:2254-64, 2003; Chapman TM, Perry CM. Drugs. 2004;64:2577-2595 Rave K. Diabetes Care 28:1077-82, 2005 Deglutec 40 hours Glargine U 300 30 hours

14. Type of Insulin & Brand Names Onset Peak Duration Role in Blood Sugar Management Rapid-Acting Lispro ( Humalog ) 15-30 min. 30-90 min 3-5 hours Rapid-acting insulin covers insulin needs for meals eaten at the same time as the injection. This type of insulin is often used with longer-acting insulin. Aspart ( Novorapid ) 10-20 min. 40-50 min. 3-5 hours Glulisine ( Apidra ) 20-30 min. 30-90 min. 1-2 1/2 hours Short-Acting Regular (R)  or actrapid , humilin R 30 min. -1 hour 2-5 hours 5-8 hours Short-acting insulin covers insulin needs for meals eaten within 30-60 minutes. Velosulin (for use in the insulin pump ) 30 min.-1 hour 1-2 hours 2-3 hours

15. Intermediate-Acting NPH (N) 1-2 hours 4-12 hours 18-24 hours Intermediate-acting insulin covers insulin needs for about half the day or overnight. This type of insulin is often combined with a rapid- or short-acting type. Long-Acting Insulin glargine (Basaglar, Lantus , Toujeo ) 1-1 1/2 hours No peak time. Insulin is delivered at a steady level. Lantus 20-24 hours Toujeo 30 hs Long-acting insulin covers insulin needs for about one full day. This type is often combined, when needed, with rapid- or short-acting insulin. Insulin detemir ( Levemir ) 1-2 hours 6-8 hours Dose dependent Up to 24 hours Insulin degludec (Tresiba) 30-90 min. No peak time 42 hours

16. Pre-Mixed* Humulin 70/30 30 min. 2-4 hours 14-24 hours These products are generally taken two or three times a day before mealtime. Mixtard 70/30 30 min. 2-12 hours Up to 24 hours Novomix 70/30-50/50 10-20 min. 1-4 hours Up to 24 hours Humalog mix 50/50 30 min. 2-5 hours 18-24 hours Humalog mix 75/25 15 min. 30 min.-2 1/2 hours 16-20 hours *Premixed insulins combine specific amounts of intermediate-acting and short-acting insulin in one bottle or insulin pen. (The numbers following the brand name indicate the percentage of each type of insulin.)

17. Faster Acting Insulin Fiasp Admelog Biochaperone

18. Summary of available insulin preparations Agent Type / Administration Glucose lowering Basal Post-meal NPH Intermediate-acting human Once or twice daily at bedtime ± breakfast  Detemir Long-acting analogue Once or twice daily at bedtime ± breakfast  Glargine 100-300U deglutec Long-acting analogue Once daily at bedtime or before breakfast  Premixed Human or analogue mix Twice daily before breakfast and dinner   Regular Fast-acting human Before meals  Aspart, glulisine, lispro Rapid-acting analogue Before meals  Inhaled insulin Rapid-acting human Before meals  Arab Diabetes Forum. Cairo 2014

19. Action Profiles of Basal Insulins Plasma Insulin Levels Hours Note: Action curves are approximations for illustrative purposes. Actual patient response will vary. NPH 12–20 hours Detemir ~ 6–23 hours (dose-dependent) Glargine ~ 20–26 hours Glargine 300 ~30 h Deglutec ~40 h Adapted from Insulin Therapy for the 21 st Century. American Diabetes Association; information from insulin glargine, insulin detemir, and NPH product monographs Intermediate acting peakless Arab Diabetes Forum. Cairo 2014

20. Pancreatic islet cells and their secretory products Cell Types Approximate Percent of Islet Mass Secretory Products A cell (alpha) 20 Glucagon, proglucagon B cell (beta) 75 Insulin, C-peptide, proinsulin, amylin D cell (delta) 3-5 Somatostatin F cell (PP cell) 1 < 2 Pancreatic polypeptide (PP) 1 Within pancreatic polypeptide-rich lobules of adult islets, located only in the posterior portion of the head of the human pancreas, glucagon cells are scarce (< 0.5%) and F cells make up as much as 80% of the cells.

21. Insulin preparation Rapid-acting Short-acting Intermediate-acting Long-acting Insulin delivery systems

22. Extent and duration of action of various types of insulin

23. Hazards of insulin use Hypoglycemia Insulin induced immunologic complication

24. Abcessess Sup Soft tissue/Skin Infections

25. Stimulants of insulin release       Glucose, mannose    Leucine    Vagal stimulation    Sulfonylureas  Amplifiers of glucose-induced insulin release   Enteric hormones:      Glucagon-like peptide 1(7-37)     Gastrin inhibitory peptide     Cholecystokinin     Secretin, gastrin   Neural amplifiers:      b -Adrenoceptor stimulation   Amino acids:      Arginine Inhibitors of insulin release       Neural: a -Sympathomimetic effect of catecholamines   Humoral: Somatostatin, amylin    Drugs: Diazoxide, phenytoin, vinblastine, colchicine  Regulation of insulin release

26. Non-Insulin antidiabetic Drugs 1) Sulfonylureas, 2) Meglitinides, 3) Metformin (a biguanide), 4) Thiazolidinediones (TZDs), 5) Alpha-glucosidase inhibitors, 6) Dipeptidyl peptidase IV (DPP-4) inhibitors, 7) Bile acid sequestrants, 8) Dopamine agonists, 9) Sodium-glucose transport protein 2 (SGLT2) inhibitors 10) Glucagon-like peptide 1 (GLP-1) receptor agonists

27. Non Insulin antidiabetic drugs Insulin secretagogues Biguanide metformin Thiazolidinediones Alpha-glucosidase inhibitors

28. Insulin secretagogues Group drugs: Sulfunylureas: tolbutamide, chlorpropamide, glyburide, glipizide, glimepride Mechanism of action Closure of potassium channel Toxicity Hypoglycemia, allergic reactions Weight gain

29. Insulin secretagogues: Sulfonylureas

30. Insulin secretagogues: Sulfonylureas First-Generation Sulfonylureas Tolbutamide, Chlorpropamide, Tolazamide Second-Generation Sulfonylureas Glyburide, Glipizide, Glimepiride

31. Insulin secretagogues: Meglitinides

32. Biguanides: metformin Mechanism of action Inhibit gluconeogenesis Induction of glucose uptake in periphery Slowing the absorption of glucose Reduction of glucagon level Toxicity Gastrointestinal distress Lactic acid in some patiets

33. Thiazolidinediones Group drugs: rosiglitazone, pioglitazone Mechanism of action Increase target tissue sensivity Activating: peroxisome proliferator-activated receptor-gamma nuclear receptor (PPAR-  receptor) Toxicity Fluid retention, MI, bone fracture Liver enzyme inducers

34. Thiazolidinediones

35. Alpha glucosidase inhibitors: acarbose, miglitol Mechanism of action Inhibit -glucosidase Toxicity Flatulence, diarrhea, abdominal pain

36. Alpha glucosidase inhibitors

37. Miscellaneous Paramlitide Exenatide Sitagliptin

38. Balancing Act Slide 58 of 88

39. Dipeptidyl Peptidase-4 Inhibitor Neumiller JJ et al. J Am  Soc   Nephrol  2017;28 Slide 69 of 88 MOA: protects glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide (GLP-1) from inactivation . ↑ insulin release & ↓ glucagon levels in the circulation Can be used in patients with CKD but lower doses are required for sitagliptin, saxagliptin and alogliptin.  Linagliptin: no dose adjustment needed A reduction in albuminuria has been seen with all DPP-4 inhibitors Generally well-tolerated but may cause headache, pancreatitis, arthralgia and upper respiratory infection

40. Glucagon-like peptide-1 (GLP-1) Glucagon-like peptide-1 (GLP-1) agonists (in type 2 DM): increase pancreatic secretion of insulin: They reduce BMI, HbA1C, and systolic blood pressure, and improves beta cell function of the pancreas. Exenatide Liraglutide (S.C. once a day) Dulaglutide (S.C. once weekly) Semaglutide (Oral once daily)

41. Glucagon-Like Peptide-1 Receptor Agonist Neumiller JJ et al. J Am  Soc   Nephrol  2017;28 Filippatos TD, et al. World J Diabetes. 2013;4(5):190-201.  Slide 70 of 88 MOA: Acts as an incretin mimetic agent to enhance glucose-dependent insulin secretion from the pancreatic beta cells. Benefits: better glycemic control, low hypoglycemia risk and weight loss Concerns - associated with: decreased kidney function (especially with exenatide) acute kidney injury May cause injection site reaction, diarrhea, nausea, upper respiratory infection, appendicitis, pancreatitis, renal failure and pneumonia Monitor for signs or symptoms of pancreatitis and thyroid disease

42. Glucagon-Like Peptide-1 Receptor Agonist Neumiller JJ et al. J Am  Soc   Nephrol  2017;28 Slide 71 of 88 GLP-1 RA Doses for patients with Chronic Kidney Disease Albiglutide No dose adjustment for eGFR > 15 mL/min per 1.73m 2 Dulaglutide No dose adjustment recommended by manufacturer Exenatide Not recommended with eGFR < 30 mL/min per 1.73m 2 Liraglutide No dose adjustment for eGFR > 60 mL/min per 1.73m 2 Lixisenatide Patients should be monitored for adverse events and changes in kidney function. No dose adjustment for eGFR > 30 mL/min per 1.73m 2 Avoid with eGFR < 15 mL/min per 1.73m 2 Semglutide No adjustment necessary

43. SGLT-2 inhibitors Slide 72 of 88 Image source: National Kidney Disease Education Program

44. SGLT-2 inhibitors Slide 73 of 88 Common side effects : May cause hypoglycemia, increased frequency of urination, urinary tract infection, female genital infection Serious side effects : diabetic ketoacidosis, acute kidney injury, pyelonephritis, sepsis  (more common with concurrent diuretic use) Monitor for volume contraction

45. SGLT-2 inhibitors Slide 74 of 88 SGLT-2 inhibitors Doses for patients with Chronic Kidney Disease Canagliflozin No dose adjustment for eGFR > 60 mL/min per 1.73m 2 100 mg daily if eGFR 45-59 mL/min per 1.73m 2 Avoid use with eGFR < 45 mL/min per 1.73m 2 Dapagliflozin Avoid initiating if eGFR < 60 mL/min per 1.73m 2 Not recommended with eGFR 30-60 mL/min per 1.73m 2 Contraindicated with eGFR <30 mL/min per 1.73m 2 Empagliflozin No dose adjustment if eGFR > 45 mL/min per 1.73m 2 Avoid use with eGFR < 45 mL/min per 1.73m 2

46. Thank you