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Newer insulins in clinical practice


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Overview of newer insulins in use

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Newer insulins in clinical practice

  1. 1. NEWER INSULINS Dr. Arun Sharma
  2. 2. Overview  Introduction & Journery over the years.  Insulin Preparations.  Insulin Delivery Systems.  Conventional Insulin Problems.  Newer Insulins  Ultrashort / Rapid Acting  Long Acting  Inhaled Insulins  Merits, Demerits & Use in Special Conditions.  New Advances  Conclusion 2
  3. 3.  The most powerful agent we have to control glucose.  Miracle discovery that saved many lives.  Leonard Thompson was the first patient to have effective insulin treatment (1922).  Banting and Macleod : Nobel Prize for Medicine (1923).  Later on 3 more Nobel Prizes : F. Sanger (1958), D. Hodgkins (1964) & Yalow et al (1977) leading to better understanding of structure and mechanism of action. INSULIN 3
  4. 4. Insulin Journey over the years  1921 : Insulin extracted by Banting & Best. Conventional insulin preparations from beef/pork pancreas (antigenic)  1970s : Highly purified porcine insulins. Single peak insulins & monocompetent insulins (greater efficacy & lesser side effects)  1980s : Human insulins by recombinant DNA technology.  1990 : Insulin analogues with novel pharmacokinetics. 4
  5. 5. INSULIN PREPARATIONS & CHEMISTRY  With advent of human insulin, beef/porcine insulin not produced anymore.  Human insulin produced by recombinant DNA technology.  Insulin preparations are expressed in International Units (IU).  One unit of insulin is defined as the amount required to reduce the blood glucose concentration in a fasting rabbit to 45 mg/dL (2.5 mM).  Work is ongoing to develop delivery approaches 5
  6. 6. INSULIN DELIVERY SYSTEMS  A. Standard Delivery :  The standard mode of insulin therapy is s.c. injection using disposable needles and syringes.  B. Portable Pen Injectors  To facilitate multiple s.c. injections of insulin, portable pen-sized injectors have been developed.  These contain cartridges of insulin and 6
  7. 7. INSULIN DELIVERY SYSTEMS  C. Continuous Subcutaneous Insulin Infusion Devices (CSII, Insulin Pumps) :  External open-loop pumps for insulin delivery.  The devices have a user programmable pump that delivers individualized basal and bolus insulin replacement doses based on blood glucose self-monitoring results.  Advanced insulin pumps also have an “insulin on board” feature that adjusts a high blood glucose correction dose to correct dose. 7
  8. 8. INSULIN DELIVERY SYSTEMS  Device is about the size of a pager.  Usually placed on belt or in a pocket, and insulin is infused through thin plastic tubing that is connected to the subcutaneously inserted infusion set.  Programming is done through a hand-held unit that communicates wirelessly with the pump.  CSII delivery is regarded as the most physiologic method of insulin replacement. 8
  9. 9. INSULIN DELIVERY SYSTEMS  D. Insulin Inhalers : Most recent delivery system in which powdered insulin is administered via a whistle sized inhaler.  The powder dissolves immediately when inhaled into the lungs, and the insulin’s then quickly dumped into the bloodstream to start working.  Long term conclusive data however still lacking.  E. Orally Absorbed Insulin (Oralin): Generex is developing Aersol containing insulin for buccal absorption 9
  10. 10. PROBLEMS WITH CONVENTIONAL INSULINS  Normally, insulin concentration peaks at 30-45 minutes after a meal and returns to basal level after 2-3 hrs.  The onset of action of regular insulin is too slow (peak action 1-2 hr) & the duration of action is too long (6 hrs) to mimic the physiological insulin pattern.  This leads to post prandial hyperglycemia and late hypoglycemia.  It is therefore, recommended to administer 10
  11. 11. PROBLEMS WITH CONVENTIONAL INSULINS  Also, intermediate or long acting insulin preparation are unable to provide continuous basal insulin for 24 hrs.  This caused premeal and fasting hyperglycaemia and night hypoglycaemia.  Moreover, conventional human and porcine insulins tend to form hexamer in contact with zinc in the bloodstream.  Insulin in the form of hexamer will not bind to its receptors because, hexamer has to slowly equilibrate back into monomers to be clinically 11
  12. 12.  Regular insulins form hexamers which dissociate slowly into monomers thus delaying absorption.  Delayed onset of action (1/2 -1 hr)  Prolonged time of peak action (2 to 3 hrs)  Duration of action (5 to 8 hrs) Hence regular insulins cause a mismatch between need & availability of bolus insulin and do not ideally mimic physiological bolus secretion of insulin. Post prandial hyperglycemia Late post prandial hypoglycemia
  13. 13. Other limitations of regular insulins  Regular insulin has to be administered 30- 45mins before meal - dose of insulin cannot be adjusted according to size of meals.  Time of onset, peak action & duration of action is dose dependent (increases with dose)  Absorption varies with injection site & exercise (variability of absorption as much as 25%)
  14. 14. NEWER INSULINS  Novel long and short acting insulin analogues, the so-called ‘Designer insulins’.  Developed through genetic engineering in the 1990s, paved the way for more physiological insulin therapy.  They made the treatment flexible, safer and simpler.  Theoretically less problematic in terms of hypoglyce-mia and patient satisfaction.  Newer Insulins are faster acting preprandial 14
  15. 15. NEWER INSULINS  Exist as monomers and are absorbed much faster (insulin aspart or lispro) or absorbed very slowly (insulin glargine or detemir).  They have increased stability, less variability and selective action which helps in developing individualized treatment patterns.  The B 26-30 region (critical for insulin receptor recognition) is the site preferred for structural alteration of insulin molecule to design novel insulins.  Risk of carcinogenicity on long term use is major 15
  16. 16. A) Ultrashort/Rapid acting  They have rapid onset and shorter duration of action.  The peak of onset corresponds more closely with the post prandial glucose peak.  Therefore, can be administered immediately before meals.  This avoids post prandial hypoglycaemia that occurs due to long duration of action of soluble insulin.  The shorter duration of action of these 16
  17. 17. A) Ultrashort/Rapid acting 1) Insulin Lispro :  First FDA approved designer insulin (1996).  Developed with the aim of improving glycaemic control at meal times.  There is inversion of proline at position 28 with lysine at position 29.  This allows larger amount of active monomeric insulin to be available postprandial or after meal.  In pregnancy and gestational diabetes, found to be as effective as regular insulin with no 17
  18. 18. A) Ultrashort/Rapid acting 2) Insulin Aspart :  Substitution of proline at 28 position with aspartic acid.  Prevents the formation of hexamers, leading to rapid absorption from subcutaneous tissue.  Its absorption and activity profile are similar to those of insulin lispro.  Similar binding properties and mitogenecity characteristics as regular human insulin and has equivalent immunogenecity. 18
  19. 19. A) Ultrashort/Rapid acting 3) Insulin Glulisine :  Substitution of asparagine at position B3 by lysine and lysine at position B 29 by glutamine.  Exerts its action by causing insulin receptor substrate-2 (IRS-2) phosphorylation.  Has additional antiapoptotic activity, counteracts autoimmune and lipotoxicity induced β-cell destruction.  But insulin glulisine carry the risk of tumorogenecity and increased mitogenic activity. 19
  20. 20. B) Long Acting  Ideal basal insulin has long duration of action and provides 24 hour control with minimum variation.  Traditional intermediate and long acting analogues i.e. isophane, lente and ultralente are unsatisfactory.  Long acting insulin analogues have made significant improvements in the management of type 1 DM.  Developed on two approaches: 20
  21. 21. B) Long Acting 1) Insulin Glargine :  first long acting basal human insulin available in the market (soluble, “peakless” analog).  Less soluble at physiological pH and more soluble at acidic pH.  It precipitates at physiological pH and absorbs slowly from injection site. Thus , it provides basal insulin that mimics insulin profile of healthy individual.  Slow onset of action (1–1.5 hours) and achieves a maximum effect after 4–6 hours. Given once 21
  22. 22. B) Long Acting  Insulin glargine is not to be mixed with other insulin, as it becomes cloudy and results in alteration of pharmacokinetic and pharmacodynamics profile.  Injection site pain is more in patients with insulin glargine than isophane insulin.  The absorption pattern of insulin glargine appears to be independent of the anatomic site of injection.  Associated with less immunogenicity than human insulin. 22
  23. 23. B) Long Acting 2) Insulin Detemir :  Modifying insulin by binding to serum protein albumin prolongs the duration of action.  It is a soluble basal insulin analogue at neutral pH.  Threonine at B30 is removed and myristic acid(14-C fatty acid chain) is attcahed to terminal B29 Lysine.  Its slow dissociation from albumin results in delayed action. 23
  24. 24. B) Long Acting  Given twice daily to obtain a smooth basal insulin level.  Reduction in body weight is an advantage which may be due to direct effect on hypothalamus.  Lower affinity for insulin receptor necessitates higher doses compared to human insulin.  Less potent in binding to IGF-1R therefore, it has reduced risk of inducing tumours.  Shown to be as effective as other long acting analogues i.e. isophane insulin (NPH) in maintaining glycemic control with fewer episodes 24
  25. 25. B) Long Acting 3) Insulin Degludec :  Newest long acting basal insulin with longer half life (25-40 hr).  Can be given any time of the day or thrice weekly.  Unlike glargine, it is effective at physiological pH.  Following s.c. administration, it forms multihexamers which form “s.c. depots” thereby ensuring slow insulin release into systemic circulation. 25
  26. 26. B) Long Acting  Unlike glargine & detemir, it can be mixed with other insulins.  However, it has shown high incidence of hypoglycemia in CTs.  Currently approved for use in Europe (Tresiba) & will be marketed in US after submitting cardiac studies. 26
  27. 27. C) Inhaled Insulins  Earliest marketed products caused pharyngitis & pulmmonary fibrosis.  Exubera (Pfizer) was approved in 2006 but was discontinued later due to lung complications and inconvenient use reported by users.  Afrezza is a ultarapid acting insulin which is inhaled at beginning of a meal & was approved in 2014 by the FDA.  administered via a whistle-sized inhaler called the ‘Dreamboat’. 27
  28. 28. C) Inhaled Insulins  Afrezza peaks within 12 -15 minutes and is out of the system within an hour.  The Dreamboat is meant to be thrown away after 15 days to prevent any powder buildup inside that could clog the device.  Unlike traditional insulin, it needs no refrigeration, but rather is kept at room temperature.  Each single-use cartridge holds either 4 or 8 units. 28
  29. 29. C) Inhaled Insulins  Not recommended for people with diabetes who smoke, nor for treating diabetic ketoacidosis (DKA).  Can cause bronchospams in asthma/COPD patients.  Hypoglycemia, cough, and throat pain or irritation are the common side effects reported in CTs.  Long term PMS studies are underway to 29
  30. 30. Merits of insulin analogues  Better mimicking of physiological insulin secretion.  Better control of post prandial blood glucose levels  Better control of glucose levels in the fasting, interdigestive period.  Lesser risk of hypoglycemia (esp. nocturnal)  Action profile independent of dose/site of injection/exercise- more predictable action.  Greater flexibility with short acting analogues
  31. 31. Merits of insulin analogues  Compliance is improved with long acting analogues as once a day the insulin  The need for snacks between meal may be reduced with short acting analogues  Advantage in term of weight loss epically with detemir insulin.
  32. 32. DEMERITS  No significantly different adverse effects when compared to standard insulins.  Worsening Retinopathy with Lispro (homologous to IGF-1)  ???Carcinogenicity: Concerns over Glargine carcinogenicity (FDA considers Glargine as a Black triangle drug)  HIGH COST
  33. 33. Insulin analogues are preferred in :  Persons with uncertain lifestyle/qty of meals/time of meals (busy persons) not controlled by std.insulins  High unpredictable FBS/PPBS  Risk of hypoglycemia esp. nocturnal (elderly)  Unexpected exercise (sportsmen/policemen)  Critical patients (hepatic & renal disease, ICU patients shifted from iv to s/c, periop patients)  Weight gain with standard insulins (detemir).
  34. 34. INSULIN ANALOGUES IN SPECIAL SITUATIONS  Diabetic ketoacidosis – Lispro (i.v)  Pregnancy  Lispro & Aspart demonstrated efficacy & safety (Cat B)  Long acting analogues not studied.  Children Data on insulin analogues is limited.  Elderly (at risk of nocturnal hypoglycemia) Insulin analogues preferred.
  35. 35. Newer Advances 35  LY2605541 is a PEGylated basal insulin lispro.  Has completed Phase II clinical trials.  insulin molecule is embedded in a polyethylene glycol (PEG) chain.  The resultant molecule is quite large and absorption from the subcutaneous space is slowed significantly, prolonging the duration of action.  Comparable or better glycaemic control than insulin glargine aswell as reduced weight in patients with T1DM and T2DM.
  36. 36. Conclusion  These analogues have shown equal or superior efficacy and have lower incidence of hypoglycaemia.  But insulin analogues are more expensive than human insulin.  The proper use of insulin analogues will allow the diabetics greater flexibility in the timing of meals, snacks and exercise which will improve their quality of life.  Other newer routes of insulin administration are also showing promise & research is ongoing in 36
  37. 37. References 37  Chapter 41.Pancreatic hormones and antidiabetic drugs. Bertram G. Katzung Basic & Clinical Pharmacology. 12th edition 2012, pp 746-751.  Hirsch IB. Insulin analogues. N Engl J Med 2005; 352 : 174-83.  Setter SM, Corbett CF, Campbell RK, White JR. Insulin aspart: a new rapid – acting insulin analog. Ann Pharmacother 2000;34:1423-31.  Vajo Z, Duckworth W. Genetically engineered insulin
  38. 38. References 38  Zib I, Raskin P. Novel insulin analogues and its mitogenic potential. Diabetes Obes Metab 2006;8:611-20.  Mandal TK. Inhaled insulin for diabetes mellitus. Am J Health Syst Pharm 2005;54:1359-64.  Owens DR, Zinman B, Bolli G. Alternative routes of insulin delivery. Diabet Med 2003;20:886-98.  ucm403122.htm [FDA Approved Afrezza to treat diabetes].