newer antidiabetics drugs

1. Dr. Prerna Singh
Junior Resident 3rd 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.

5. NDA
Aleglitazar
Phase 3
Ranolazine
Oral insulin
GPR 40 agonist
Phase 2
Glucokinase activator
PTB1B inhibitor
Phase 1
GPR 119 agonist

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

7. 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

8. 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

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

10. 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• Withdrawn in 2007 because of pulmonary fibrosis and risk of lung cancer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

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

12. 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

13. 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

14. • 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)

15. 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

16. 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

17. • 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)

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

19. • 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)

20. 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

21. • 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)

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

23. Bromocriptine
(1.6 - 4.8 mg)
• Approved in 2009 for diabetes
• D2 agonist
• Effects on blood glucose and may reflect an action in the CNS
Side effects:
• Nausea, vomiting
• Fatigue, headache
• Dizziness
• Orthostatic hypotension

24. 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

25. Newer targets
• PTP-1b inhibitor
• Glycogen synthase kinase 3 inhibitor
• Glucokinase activator
• Fructose 1-6, bis phosphatase inhibitor
• Glycogen phosphorylase inhibitor
• β2 agonist
• Anti CD3 monoclonal antibody- otelixizumab
• Vaccine: recombinant human glutamic acid decarboxylase 65 (rhGAD65)- phase 3

26. Future
 Pancreatic transplant
 Artificial pancreas