Newer antidiabetic agents

newer antidiabetics drugs

1. Dr. Prerna Singh Junior Resident 3 rd year Department of Pharmacology JNMCH, AMU Newer Antidiabetic Agents

2. INTRODUCTION Diabetes mellitus refers to a group of metabolic disorders that share a common phenotype of hyperglycemia - Harrison’s Principles of internal medicine 4types- Type 1- IDDM Type 2 -NIDDM Type 3- Other specific types Type 4 – Gestational DM Insulin  was the first peptide hormone  discovered . Frederick Banting and Charles Herbert Best , working in the laboratory of J.J.R. Macleod at the University of Toronto, were the first to isolate  insulin  from dog pancreas in 1921.

3. New insulins Detemir Degludec Neutral protamine lispro Hexyl insulin monoconjugate – HIM 2 Oral insulin spray formulation Inhaled insulin : Exubera Aferezza

4. New insulins Detemir: Long acting: DOA <24 Hour Onset: 1-2 hour Less frequent hypoglycemia Minimum weight gain Degludec : Long acting DOA>24 hour; 3times a week

5. New insulins Neutral protamine lispro: Intermediate acting Reported more weight gain and hypoglycemia HIM-2: In phase 3 trails Oral insulin Enhanced stability and resistance to intestinal degradation

6. New insulins Oral insulin spray: In Phase 3 trial Liquid aerosol mist Absorbed through mucus membrane

7. New insulins Bioavailability – 20% Patient training is important Exubera : Withdrawn in 2007 because of pulmonary fibrosis and risk of lung cancer Afrezza : Approved In 2014 Rapid acting inhaled insulin Not suitable for ketoacidosis Side effect : Hypoglycemia, cough, throat pain and irritation

8. New insulin delivery system Pen device Insulin pump Continuous SC insulin infusion

9. New drugs Incretin based therapy: GLP1 analogue- Exenatide, Albiglutide, Liraglutide, Semaglutide DPP4 inhibitor- Sitagliptin, Vildagliptin, Saxagliptin , Alogliptin Amylin mimetics: Pramlintide Dual PPAR agonists: Saroglitazar SGLT 2 inhibitors: Dapagliflozin, Canagliflozin, Empagliflozin Bromocriptine Colesevelam

10. Incretin based therapy Incretin: GI hormone Released after meal; increase insulin biosynthesis and release Examples: GLP1,GIP Metabolized by DPP IV- short half life DPP IV resistant GLP1 agonist are useful for therapy DPP IV inhibitor are useful for therapy

11. Increase glucose dependent insulin secretion Control PP Show good efficacy as monotherapy but are not first line agents Used as adjuvant Incretin mimetics Exenatide (5-10mcg BD), Liraglutide (0.6-1.8mg OD), Albiglutide (30-50 mg weekly), Semaglutide (oral)

12. Mechanism of action: Act on GLP1 receptor (GPCR) Activate cAMP-PKA pathway and also signaling via PKC & PI3K Increase insulin synthesis and release In CNS (GLP1 receptor) - food intake affected, Gastric emptying, nausea GLP1 agonist

13. Side effect Nausea Anorexia – weight loss Pancreatitis Only injectables –SC (except semaglutide-2019) No risk of hypoglycemia Liraglutide: black box warning- risk of thyroid carcinoma Exenatide: avoid in pancreatitis predisposed patients GLP1 agonist

14. Inhibit metabolism of incretins (GLP1, GIP) DPP IV enzyme is responsible for metabolism of incretins which increase insulin release. No effect on weight Increase risk of heart failure with saxagliptin and Alogliptin DPP IV inhibitors Sitagliptin (100mg OD), Vildagliptin (50 mg OD/BD), Saxagliptin (5mg/day), Linagliptin (5mg/day), Alogliptin (25mg/day)

15. DPP IV inhibitors Anagliptin- phase 3 trials Dutogliptin - phase 3 trials

16. Approved in 2005 Act on amylin receptor in hind brain Inhibit glucagon secretion Delay gastric emptying Decrease appetite Subcutaneously before meals Used in both T1 and T2 DM Added to decrease insulin requirement Should not be mixed in same syringe - different pH Risk of hypoglycemia with insulin Pregnancy category C Amylin mimetics Pramlintide (T1: 15-0 mcg/day; T2: 60-120 mcg/day)

17. PPAR  agonist- this increases insulin sensitivity and decrease resistance to insulin (insulin sensitizers) Decrease gluconeogenesis Increase GLUT-4 transporter Onset is slow:1- 3 months to achieve euglycemia PPAR γ agonist Pioglitazone (15- 45 mg/ day OD)

18. Increase HDL Decrease Triglycerides Weight gain and edema (fluid retention) Anemia due to hemodilution Hepatotoxic High incidence of heart failure Pioglitazone is associated with bladder cancer Avoid in osteoporosis PPAR γ agonist Pioglitazone (15- 45 mg/ day OD)

19. Dual PPAR (α+ γ agonists) α- improve lipid profile γ – improve insulin sensitivity Saroglitazar – approved for diabetic dyslipidemia Aleglitazar - in phase 2 trail Tesaglitazar - renal toxicity – discontinued Muraglitazar - MI, stroke – discontinued

20. Inhibit glucose reabsorption thereby increasing glucose excretion Urinary tract infection Sodium loss in urine – decrease BP by 2-4 mm Hg Low risk of hypoglycaemia Increase risk of fracture – affect PTH, vitamin D SGLT 2 inhibitors Dapagliflozin (8-10mg/day), Canagliflozin (100-300mg/day), Empagliflozin (10-25mg/day)

21. SGLT 2 inhibitors Remogliflozin – in phase 2 clinical trials Tofogliflozin – in phase 3 clinical trials

22. Bromocriptine ( 1.6 - 4.8 mg) Approved in 2009 for diabetes D 2 agonist Effects on blood glucose and may reflect an action in the CNS Side effects: Nausea, vomiting Fatigue, headache Dizziness Orthostatic hypotension

23. Colesevelam Approved for Type 2 diabetes as an adjunct to diet and exercise Mechanism: not established Reduce intestinal glucose absorption Dose : 625-mg tablets are available 3 tablets twice daily before lunch and dinner OR 6 tablets prior to the patient’s largest meal

24. Newer targets PTP-1b inhibitor Glycogen synthase kinase 3 inhibitor Glucokinase activator Fructose 1-6, bis phosphatase inhibitor Glycogen phosphorylase inhibitor β 2 agonist Anti CD3 monoclonal antibody- otelixizumab Vaccine: recombinant human glutamic acid decarboxylase 65 (rhGAD65)- phase 3

25. Future Pancreatic transplant Artificial pancreas