CORE PRINCIPLES OF TREATMENT OF DIABETES MELLITUS.pptx

This lecture was part of a vertical integration program for the Department of Pharmacology prepared and presented by a practicing Diabetologist

1. VERTICAL INTEGRATION Dr Deepak Anand R MBBS, DNB (Med), MRCP, IDCCM Associate Professor Department of General Medicine

2. Management of Diabetes Mellitus Feeling blessed… Thank s to Department of Pharmacology…

3. Management Work up & Treatment

4. Work Up Work Up for Diagnosis/Monitoring Fasting Blood Sugar Postprandial Blood Sugar HbA1C Urine Routine Work up for Complications Biothesiometry Fundus Examination Urine Micralbumin Urea & Creatinine

5. How many of you have watched this movie ???

6. Treatment Before we discuss about

7. Worrying Trend… Kanwal A, Kanwar N, Bharati S, Srivastava P, Singh SP, Amar S. Exploring New Drug Targets for Type 2 Diabetes: Success, Challenges and Opportunities. Biomedicines. 2022 Jan 31;10(2):331. doi : 10.3390/biomedicines10020331. PMID: 35203540; PMCID: PMC8869656

8. The Trend in more detail…

9. The Silver Lining… Remember, we have overtaken China in population this year

10. Why do we need to treat Diabetes Mellitus ??? What are we trying to prevent or Achieve ???

11. Complications aka ATHEROSCLEROSIS aka TRIPATHY

12. Do we need to blood sugar levels to normal levels if at all they get deranged ??? Yes or No ???

13. Treatment Matters T he University Group Diabetes Program (UGDP) – 1960s placebo, tolbutamide, phenformin, or insulin Increase in Cardiovascular deaths Stopped after 8 years

14. Landmark Trials in DM

15. Treatment Matters UKPDS – 1970s Largest and longest of it’s kind Conclusively proven benefits of good glycemic control Median follow up was 10 yrs

16. Treatment Matters DCCT TRIAL : Demonstrated the LEGACY EFFECT OR METABOLIC MEMORY Study Duration : 6.5 yrs

17. Quick Recap on Types of Diabetes

18. Ten Classes – roughly Sixty Medications More than 100 are in TRIALS 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) oral and injectable glucagon like peptide 1 (GLP-1) receptor agonists Also, we have Injectables like Amylin Analogues

19. TRIUMVIRATE TO OMINOUS OCTET Defronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009 Apr;58(4):773-95. doi : 10.2337/db09-9028. PMID: 19336687; PMCID: PMC2661582.

20. Egregious Eleven

21. Sweetening Sixteen Beyond Ominous Octet & Egrigious Eleven Phatak , Sanjeev R.; Saboo , Banshi; Dwivedi, Shivangi; Zinzuwadia , Padmanabh; Panchal, Dharmendra; Ganguli, Abhilasha; Hasnani , Dhruvi Journal of Diabetology12(1):1-9, Jan-Mar 2021. doi : 10.4103/jod.jod_9_20

22. Oral Anti-Diabetics

23. Tablets

24. Tablets

25. Injectable Anti-Diabetics

26. Injections

27. Analogy

28. Analogy

29. BIGUANIDES

30. BIGUANIDES Metformin Sheet Anchor in the management of Diabetes Also approved for use in pregnancy GI side effects – problematic Cannot be used in renal failure

31. AGI

32. Alpha Glucosidase Inhibitors Voglibose & Acarbose Very very relevant for Indian Diabetics Only control post prandial spikes Can only be an add on Can be used in IGT to delay Diabetes onset GI intolerance is the Achilles Heel

33. SECRETOGOGUES

34. Secretogogues Sulphonylureas Glipizide Glibenclamide (Glyburide) Glimepride Gliclazide Meglitinides Nateglinide Repaglinide

35. PPAR AGONISTS

36. PPAR GAMMA AGONISTS Pioglitazone Lobeglitazone Former is controversial Weight Gain, Edema & Fractures are problematic

37. INCRETIN MIMETICS

38. The Incretin effect

39. Incretin effect

40. INCRETIN MIMETICS DPP4i GLIPTINS Lina Sita Vilda Teneli Evo Gemi GLP1 R A GLUTIDES Lira Dula Sema

41. SGLT2i

42. SGLT2i The Gliflozins Are Cardioprotective Can be used in Heart Failure without Diabetes GTI/UTI is their Achilles Heel Dapa , Empa , Cana, Remo

43. Recent Entrants

44. Lobeglitazone The Dust has settled on Pioglitazone Available in Indian Market 0.5 mg per day Monotherapy as well as FDC with Metformin It’s a PPAR Gamma Agonist

45. Imeglimin  first‐in‐class novel oral agent tetrahydrotriazine ‐containing molecule, the class will be called glimins Mechanism of Action : (a) amplification of glucose‐stimulated insulin secretion (GSIS) and preservation of β‐cell mass; (b) enhanced insulin action, including the potential for inhibition of hepatic glucose output and improvement in insulin signaling in both liver and skeletal muscle Aka “ correction of mitochondrial dysfunction ” Available in Indian Market

46. Newer Drugs in the Horizon for Diabetes Mellitus

47. Icodec The ONWARDS 3 Randomized Clinical Trial No difference in weight change a higher rate of combined level 2 or 3 hypoglycemic events in the context of less than 1 event per patient-year exposure in both groups

48. Cagrilintide S table, lipidated long-acting amylin analogue cagrilintide Amylin is a 37 amino acid peptide, produced in pancreatic beta cells and co-secreted with insulin It has important effects on appetite, glucose management, and gastric emptying that warrant investigation for treatment of diabetes and obesity Human amylin is also involved in the cytotoxic amyloid formation

49. FDC of BASAL INSULIN - GLP1RA IDegLira Sanofi Degludec + Liraglutide Once Daily DUAL II, DUAL V & DUAL VII trials Phase 3 Lower chances of Hypoglycemia than Basal-Bolus

50. CAGRISEMA FDC of 2.4 mg semaglutide and 2.4 mg cagrilintide Viz. GLP1RA & Amylin Analogues Both promote weight loss Weekly once Subcutaneous Injection Completed Phase 2 in August 2022, entering Phase 3 Novo Nordisk

51. FDC OF BASAL INSULIN - GLP1RA IcoSema Icodec + Semaglutide Once Weekly Novo Nordisk

52. RETATRUTIDE Eli Lilly, Phase 2 GLP1+GIP+GLUCAGON GLP1+GIP GLP1

53. PRAMLINTIDE The only anti-diabetic other than insulin approved for use in T1DM Didn ’t gain much fanfare…

54. Eating less & Staying Thin may not be by CHANCE or CHOICE but by TRAIT ROLE OF FECAL MICROBIOTA TRANSPLANT IN DIABETES MELLITUS Chen L, Guo L, Feng S , et al Fecal microbiota transplantation ameliorates type 2 diabetes via metabolic remodeling of the gut microbiota in db / db mice BMJ Open Diabetes Research and Care  2023; 11: e003282.  doi : 10.1136/bmjdrc-2022-003282

55. FMT – FECAL MICROBIOTA TRANSPLANT MICROBIOTA or GUT MICROBIOME The term ‘microbiome’ refers to the collective genomes of these microorganisms. 1100 prevalent species Minimum 160 per individual 10 to 100 trillion individual cells Difficult (read impossible) to isolate and culture Study the 16 S rRNA and metagenomics instead COPROPHAGY IN ANCIENT GREEK

56. Honorary Mention…

57. ORMD – 0801 (aka) ORAL INSULIN Presently in Phase 3 8 mg HS appears to be the most promising dose S afe, well tolerated and not associated with weight gain or hypoglycemia Eldor R, Neutel J, Homer K, Kidron M. Efficacy and safety of 28-day treatment with oral insulin (ORMD-0801) in patients with type 2 diabetes: A randomized, placebo-controlled trial. Diabetes Obes Metab . 2021 Nov;23(11):2529-2538. doi : 10.1111/dom.14499. Epub 2021 Aug 18. PMID: 34310011. Eldor R, Francis BH, Fleming A, Neutel J, Homer K, Kidron M, Rosenstock J. Oral insulin (ORMD-0801) in type 2 diabetes mellitus: A dose-finding 12-week randomized placebo-controlled study. Diabetes Obes Metab . 2023 Apr;25(4):943-952. doi : 10.1111/dom.14901. Epub 2022 Nov 21. PMID: 36281496.

58. Cure for Early Type 1 Diabetes All is not lost ideology Teplizumab – Anti-CD3 Antibody Must be used sufficiently early in the course of Type 1 Diabetes Mellitus Can delay the onset in anti-body positive individuals

59. Transdifferentiation Case for α cells : α and β cell lineages appear to arise from a common precursor Phenomenon already known in mice models B oth cells have common Slc2a2 transporter that allows glucose sensing Anatomically same Blood and Nerve supply 35 % of cells in Islets are α cells Reduction in number of α cells doesn ’t translate to adverse outcomes

60. Transdifferentiation by gene therapy The transcription factors are delivered using Adenovirus vectors into the Pancreatic duct Animal Studies

61. Islet Cell Transplant Islet encapsulation is an active area of research aimed at shielding implanted islets from immunological rejection and inflammation while still allowing for effective insulin and nutrient exchange with donor cells. “H ydrogels” have been a major subject of focus in the field of islet transplantation and encapsulation technology Made of Alginate-Graphene Oxide Xu L, Guo Y, Huang Y, Xu Y, Lu Y, Wang Z. Hydrogel materials for the application of islet transplantation. Journal of Biomaterials Applications. 2019;33(9):1252-1264. doi:10.1177/0885328219831391

62. Encapsulated Islet Cells

63. Thank You Dr Deepak Anand R MBBS, DNB (GM), MRCP (UK), IDCCM Associate Professor General Medicine