Aaditya Recent Advances in Diabetes Mellitus


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Some of the recent advances in diabetes mellitus including newer insulin preparations and other oral hypoglycaemic agents.

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Aaditya Recent Advances in Diabetes Mellitus

  2. 2. Dr Udupa 11/5/2011 INTRODUCTION Definition: “Metabolic disorder characterized by hyperglycemia, glycosuria, hyperlipemia, negative nitrogen balance and sometimes ketonemia.” Classification: ( Expert Committee,2003) Type I - IDDM (Insulin Dependant) Type II - NIDDM (Non- Insulin Dependant) Type III - Others (MODY) Type IV - Gestational 2
  3. 3. Dr Udupa 11/5/2011PHARMACOTHERAPY OF DM Non-pharmacologic Rx:  Diet  Exercise Pharmacological Rx:  Insulins  Oral anti-diabetic drugs  Recent developments Emerging non-pharmaco. Rx:  Islet cell transplant  Gene therapy 3
  4. 4. Dr Udupa 4 11/5/2011CURRENT THERAPY OF DIABETES MELLITUS Drugs increase insulin release OR reduce glucose absorption/increase utilisation. Don’t alter overactivity of glucagon & other hormones that increase hepatic glucose output. Insulin. OHA  Insulin secretogogues- sulfonylureas & meglitinides  Biguanides  Thiazolidinediones  α-glucosidase inhibitors
  5. 5. Dr Udupa 5 11/5/2011NEED FOR NEWER THERAPIES Inadequate control of post prandial hyperglycemia(with sulfonylureas, metformin, TZDs ) Weight gain( sulfonylureas, meglitinides, TZDs & insulin ) Loss of efficacy ( all agents ) Pathophysiology of insulin resistance remains unaltered Insulin- Hypoglycemia , Resistance
  7. 7. Dr Udupa 11/5/2011LIMITATIONS OF REGULAR HUMAN INSULIN Slower onset of activity Patient inconvenience Safety concerns Prolonged duration of action Late post-prandial hypoglycemia Risk of hyperinsulinemia 7
  8. 8. Dr Udupa 11/5/2011HIGHLY PURIFIED INSULIN PREPARATIONS Why purified ? Single peak Insulins: 50-200 ppm proinsulin Actrapid, Lentard Monocomponent Insulins: 20 ppm proinsulin Actrapid MC, Monotard MC Advantages of Monocomponent Insulins: Immunogenicity similar to human insulin greater stability less allergic 8
  9. 9. Dr Udupa 11/5/2011HUMAN INSULINS By recombinant DNA technology Benefits- more water soluble more rapid absorption Special indications- insulin resistance allergy inj. site lipodystrophy short time crisis during pregnancy Examples: Human Actrapid, Human Insulitard. 9
  10. 10. Preparation Source Dr Udupa 11/5/2011Rapid-acting insulins Insulin Lispro, Human analog Insulin Aspart Human analog Insulin Glulisine Human analogShort-acting insulins Regular Human Insulin HumanIntermediate-acting insulins NPH Humulin HumanPremixed insulins (% NPH/ % regular) Humulin 70/30 and 50/50 Human (Lilly) 50/50 NPL, Lispro (Lilly) Human analogLong-acting insulins Insulin detemir, Human analog 10 Insulin glargine, Human analog
  11. 11. NEWER INSULINSInsulin Onset peak DurationRapid acting: 5-15 min 30-90 min 5 hrs-lispro-aspart-glulisineShort acting: 30-60 min 2-3 hrs 5-8 hrs-Reglar ins.Long acting: 2-4 hrs peakless 20-24 hrs-glargineInhaled insulinOral / rectal insulin 11/5/2011 Dr Udupa 11
  12. 12. Dr Udupa 11/5/2011 INSULIN LISPRO (HUMALOG) Ist commercially available analogue At posn 28 of β-chain– lysine At posn 29 of β-chain– proline By s.c., 15 min before meal Rapid absorption from s.c. due to dissociation into monomers –shorter duration Glucose control significantly improved Available as 100 U/ ml. 12
  13. 13. Dr Udupa 11/5/2011INSULIN ASPART (NOVOLOG) At position 28 of β-chain – aspartate replaces proline Produced by rDNA from saccharomyces cerevisiae Similar effects as that of lispro Faster onset & shorter duration Given 10 min before meal by s.c. C/I: hypoglycemia & hypersensitivity. 13
  14. 14. Dr Udupa 11/5/2011INSULIN GLULISINE (APIDRA) By rDNA technology from E. coli (k-12). At position 29 – glutamate for lysine At position 3 - lysine for asparagine Given 15 min before meal by s.c. , peak in 1 hr. ADR: gen. well tolerated hypoglycemia, comprised cardiac disease. Approved for use in type 1 & 2 DM. Used in combination with basal insulin 14
  15. 15. Dr Udupa 11/5/2011INSULIN GLARGINE (LANTUS) First long acting insulin analogue approved At position 21 of A-chain- asparagine by glycine 2 arginine added to c- terminus of β-chain Has acidic pH of 4 Results in less hypoglycemia & sustained “peakless” absorption profile No effect of exercise & site of injection on absorption C/I: hypersensitivity 15
  16. 16. Dr Udupa 11/5/2011 16
  17. 17. Dr Udupa 11/5/2011 NEWER INSULIN DELIVERY DEVICES Insulin syringes Pen devices Jet injectors Insulin pumps-CSII Implantable pumps Buccal insulin Insulin patch External artificial pancreas Inhaled insulin Liposome entrapped insulin 17
  18. 18. Dr Udupa 11/5/2011 INHALED INSULIN (EXUBERA) Inhalable insulin was available from September 2006 to October 2007 in the United States Pharmacological properties:  more rapid increase in insulin conc.  faster onset than s.c. peak at 2 hrs: duration  6 hrs- intraindividual reproducibility of glycemic response  decrease in s. triglyceride levels 18
  19. 19. Dr Udupa 11/5/2011EFFICACY & SAFETY HbA1c values < 8% in 83% pts Mean HbA1c values were reduced & maintained Hypoglycemia Weight gain Greater decline in pulmonary function Cough within seconds of inhalation Lung Cancer concerns 19
  20. 20. Dr Udupa 11/5/2011 20
  21. 21. Dr Udupa 11/5/2011NEWER INSULIN DELIVERY METHODS Jet Injector: High-pressure narrow jet of the injection liquid instead of a hypodermic needle to penetrate the epidermis. Buccal spray launched in India in 2009. Claims to get absorbed through the buccal mucosa. 21
  22. 22. Dr Udupa 11/5/2011NEWER INSULIN DELIVERY METHODS Insulin patch 22
  23. 23. Dr Udupa 11/5/2011INSULIN PUMPS 23
  24. 24. Dr Udupa 11/5/2011RA IN ORAL HYPOGLYCAEMIC THERAPY 24
  25. 25. Dr Udupa 11/5/2011INCRETIN MIMETICS Insulin has been shown to be released more effectively through an oral glucose load than intravenously and this is known as the incretin effect. Enhance the incretin pathway in two ways  ↑ Glucagon-like Polypeptide 1 (GLP-1)  ↓Dipeptidyl peptidase (DPP-IV) 25
  27. 27. Dr Udupa 11/5/2011Human ileum, GLP-1producing L-cells Capillaries, DPP-IV (Di- Peptidyl Peptidase-IV) 27
  28. 28. Dr Udupa 11/5/2011 GLUCAGON-LIKE POLYPEPTIDE 1 ANALOGUES Exenatide:  Saliva of the Gila monster  1 st Incretin therapy. Approved as SC injection, to treat Metformin/sulfonylurea treated T2DM, getting suboptimal response  Suppresses high glucagon  suppress hepatic glucose output  Preserves β-cell reserves  Central loss of appetite. Control of bodyweight  Reduces HbA1c by 1-1.3% S.C. inj. b.d. for 1 year 28
  29. 29. Dr Udupa 11/5/2011EXENATIDE- A D R Nausea in 44%, Vomiting, Diarrhea. Combination with Insulin/secretogogue leads to Hypoglycemia. C/I : T1DM, T2DM with Beta Cell Failure, Diabetic ketoacidosis , Renal impairment , GIT disease , Pregnancy , Lactation. Pancreatitis . 29
  30. 30.  National Institute for Health and Clinical Dr Udupa 11/5/2011 Excellence (NICE) Guidelines:  Exenatide is not recommended for routine use in T2DM Individual Fulfils One Of The Following Criteria:  Has a body mass index (BMI) > 35 kg/m2  Has specific problems of a psychological, biochemical or physical nature arising from high body weight  Has inadequate glucose control (HbA1c >7.5%) with conventional oral agents  If another high cost medication such as a TZD or insulin would otherwise be started. 30
  31. 31. Dr Udupa 11/5/2011PRAMLINTIDE- GLP-1 AGONIST Synthetic analogue of a Gut Hormone, Amylin Pramlintide suppresses Glucagon release. Approved Pre-Prandially [with Insulin] in T1&T2, is a PP Glucose modulator. Delays Gastric Emptying. Central Anorectic effects. Reduces HbA1c by 0.39-0.62% [6 weeks] Peak action 20 Min. Duration-150 Min. Mealtime Insulin Dose reduced by 50%. 31
  32. 32. Dr Udupa 11/5/2011 LIRAGLUTIDE EXENATIDE Once daily Twice daily Peakless PeakGood effect on HbA1c & FBG Good effect on HbA1c & FBG Weight loss Weight loss No antibodies antibodies No inj site reactions Inj site reactions 32
  33. 33. Dr Udupa 11/5/2011DIPEPTIDYL PEPTIDASE INHIBITORS This class of agent works by enhancing the sensitivity of β-cells to glucose, which causes enhanced glucose dependent insulin secretion. It has also been shown to improve markers of β cell function. Can be used in combination with metformin, sulfonylureas, or even as monotherapy 33
  34. 34. Dr Udupa 11/5/2011VILDAGLIPTIN Expands β-cell mass Decreases fasting & PP BGL Reduces HbA1c in T2DM by 0.50-1% & controls Glucose Levels in poorly controlled Addition of Insulin can lead to Hypoglycemia. Single dose reduces Glucose by inhibiting EGP [Endogenous glucose production] . 34
  35. 35. Dr Udupa 11/5/2011VILDAGLIPTIN Absorbed rapidly [Tmax = 1Hr ] Bioavailability 85% T1/2=90 Min But DPP- 4 Inhibition continued for 10 Hrs , Hence OD/BD administration. Glucose Excursions significantly reduced with Vildagliptin & Insulin levels increased. ADR  Headache , Dizziness , Increased sweating , Nasopharingitis ,Cough .  Hyperinsulinemic hypoglycemia .  Nesidioblastosis 35
  36. 36. Dr Udupa 11/5/2011GLP-1 AGONISTS VS DPP-4 INHIBITORS  Parenteral .Twice daily  Oral , Once daily .  Alternative to Insulin  1st line/Add on  HbA1c Reduction  HbA1c Reduction.  Weight loss  Prevent Weight gain ,independent  Predominantly Nausea  Nausea Absent  GLP-1 R stimulation  All above due to depends on Agonist modest stabilisation of [Exenatide] level PP levels of GLP-  Slow Gastric Emtying 1[Vildagliptin]  No Effect 36
  37. 37. Dr Udupa 11/5/2011 CANNABINOID-1 RECEPTOR BLOCKERS Cannabinoid-1 receptors appear to regulate energy balance and body composition Blocking the action of these receptors is an attractive target for treating obesity, diabetes, and the metabolic syndrome Jbilo O, et al, Faseb J, 2005;19:1567-1569 37
  38. 38. Dr Udupa 11/5/2011RIMONABANT Weight loss and improved insulin sensitivity 20 mg once a day before breakfast Phase 3 trials and is licensed for use in patients who have a BMI >30 kg/sqm or BMI >27 kg/sqm with an additional risk factor such as dyslipidaemia 38
  39. 39. Dr Udupa 11/5/2011PPAR MODULATORS PPAR alpha- increases HDL cholesterol PPAR gamma- insulin sensitization PPAR beta/delta- inflammation/ obesity Dual PPAR agonists:  Muraglitazar  Naveglitazar  Tesaglitazar  Farglitazar Pan- PPAR Activator- Bezafibrate 39
  40. 40. RATIONALE FOR DUAL PPAR -α/γ Dr Udupa 11/5/2011 AGONISTS Muraglitazar TZDs : Rosiglitazone; ; Pioglitazone Tesaglitazar PPARgPPARa(liver, vascular wall) (fat, muscle)  “Master Regulation: of Reduced triglycerides adipocyte differentiation Increases circulating HDL  Modulates glucose Improved LDL buoyancy metabolism & insulin sensitivity Glucose intolerance Dyslipidemia and Type 2 diabetes 40
  41. 41. Dr Udupa 11/5/2011DUAL PPAR AGONISTS: SAFETY ISSUES  Several earlier glitazars were discontinued because of serious safety issue  Includes ragaglitazar and farglitazar, among others  Safety issues were different for each drug1  Muraglitazar  Increased risk of death, nonfatal MI, and nonfatal stroke2  Unlikely that further studies will be done  Tesagalitazar  Increased serum creatinine and decreased glomerular filtration rate  Development discoutinued May 2006 41
  42. 42. Dr Udupa 11/5/2011SGLT2 INHIBITORS Sodium Glucose Co-transporter (SGLT)-2 inhibitors SGLT2 mediates 90% of filtered glucose reabsorption in the convoluted segment of the proximal renal tubule Dapagliflozin Canagliflozin Remogliflozin etabonate Sergliflozin 42
  43. 43. Dr Udupa 11/5/2011 Potential Clinical Advantages  SGLT2 is expressed exclusively in the kidney  SGLT2 function is independent of insulin  Increased GLUCOSE EXCRETION Negative energy balance Weight loss  Improvement in both FBG and PPB  Low incidence of hypoglycemia Predicted Clinical Limitations  Increasedurine volume  Sodium loss  Long-term safety not yet studied 43
  44. 44. Dr Udupa 11/5/2011CLINICAL DATA FOR DAPAGLIFLOZIN Orally effective SGLT-2 selective Half life= 11.2-16.6hrs…. Suitable for once daily dosing Dose dependent increase in glycosuria BSL and HbA1c reduction comparable to metformin; Weight loss more than metformin Effective in combination with metformin and other antidiabetics 44
  45. 45. Dr Udupa 11/5/2011RUBOXISTAURIN (ARXXANT) Protein kinase C- β inhibitor drug under investigation To reduce occurrence of vision loss in patients with non-proliferative diabetic retinopathy. DRUGS ACTING ON INTERMEDIARY METABOLISM TO ↓ HEP. GLUCOSE OUTPUT: Acipimox, bezafibrate- ↓ FA levels Etomoxir- ↓ FA oxidation 45
  46. 46. Dr Udupa 11/5/2011ALDOSE REDUCTASE INHIBITORS Enhanced polyol pathway – diabetic peripheral neuropathy ARI blocks polyol pathway Delays progression & ameliorate symptoms of diabetic neuropathy Examples :  Epalrestat  Ranirestat  Fidarestat  Zinarestat 46
  47. 47. Dr Udupa 11/5/2011 PEGAPTINIB (MACUGEN) & RANIBIZUMAB Pegaptinib: Selective Vascular Endothelial Growth Factor antagonist (VEGF Antagonist) For Rx of age related macular degeneration associated with diabetes 0.3 mg every 6 weeks intravitreous inj ADR: anterior chamber inflammation, cataract, blurred vision, endophthalmitis Ranibizumab- recombinant humanised monoclonal antibody that neutralizes all active forms of VEGF-A 47
  48. 48. Dr Udupa 11/5/2011OTHER EMERGING DRUGS Glucagon antagonist: skyrin, oxyskyrin, octreotide β-3 adrenoreceptor agonists Endogenous cannabinoid modulator- Rimonabant Protein kinase C inhibitors : Calphostin, staurosporine Insulin like growth factors (IGF) Morpholinoguanidine 48
  49. 49. Dr Udupa 11/5/2011MISCELLANEOUS THERAPIES INGAP (Islet NeuroGenesis Assisted Protein) Thyroxyl insulin Phosphodiesterase inhibitors Growth hormone fragments RXR (Retinoid X Receptor ) agonist Glucose 6 phosphatase inhibitors Trace elements: vanadium (decreases EGF), zinc, chromium, magnesium,selenium 49
  50. 50. Dr Udupa 11/5/2011HERBAL REMEDIES Gymnema sylvestre Pterocarpous marsupium (vijaysar) – trials by ICMR Momordica charantia (karela) Trigonella faenum (methi) Marine product- CDR-MOES-D123 50
  51. 51. Dr Udupa 11/5/2011GYMNEMA SYLVESTRE Indian ayurvedic plant vastly studied Also called gur-mar = sugar destroyer Active ingredient gymnemic acid As sugar controller & insulin secretagogue 51
  53. 53. Dr Udupa 11/5/2011 GENE AND CELL-REPLACEMENT THERAPY IN THE TREATMENT OF TYPE 1 DIABETES Gene Therapy  (Insulin) gene therapy will  introduction of a foreign gene into any cell type in the body, allowing it to produce insulin May be:  insulin gene itself, perhaps under control of a tissue-specific promoter  a gene encoding a factor that in turn activates the insulin gene Induction of stem-cell differentiation into ß-cells by means of molecular intervention 53
  54. 54. Dr Udupa 11/5/2011 GENE AND CELL-REPLACEMENT THERAPY IN THE TREATMENT OF TYPE 1 DIABETES Challenges:  To ensure adequate insulin response after glucose load  Any newly created insulin-secreting cell will have to be able to adapt to alterations in insulin requirements that accompany changes with exercise, body weight, and aging  Ensure that newly created or implanted (surrogate) ß-cells are protected in some way from recognition by the immune system and in particular from autoimmune destruction 54
  55. 55. Dr Udupa 11/5/2011 ISLET CELL TRANSPLANTATION Average-size person (70 kg), a typical transplant requires about one million islets, isolated from two donor pancreases Donor pancreas isolated enzymatically digested purified infused via the portal vein into the liver. Daclizumab, Sirolimus And Tacrolimus Limitations:  Low donor pool  High incidence of failure of immunosuppressive regimen 55
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