Diabetes management


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  • Glucose transporter Insulin dependent and independent glucoseutiliztion, regulation of insulin by chemical. Neuronal and hormonal
  • Already established patients – look for diabetes knowledge, HbA1c level, no. of hypoglycemia episodes, any chronic complications, chronic glucose level SMBG, exercise and nutrtion
  • Special tests – C peptide level ( diagnsis and also suggest insulin requirement), insulin antibodies.
  • 3 principles in management of DM – eliminate symptoms, microvascular and macrovascular complication should be avoided, and achieve normal lifestyle as possible…. 200 mg/dl target
  • Education – SMBG, ketone bodies, insulin administration, signs and treatment of hypoglycemia Nutrition – MNT, type 1 timing, type 2 less calori intake ….Exercise-decrease glucose level and also increase insulin sensitivity.aerobic exercise.
  • CGMS – interstial fluid measurement of glucose ….. Hemoglobinopathie s – Hba1cis not reliable ………
  • Most insulin are formulated as u-100 (100units/ml0 regular insulin U-500 (500units/ml) insulin by bioassay units …. 1 unit rabbit decrease the glucose 45mg/dl after 30 min…. Also quantified by hypoglycemic convulsion in mice …… now purified form… chemcal assay…. 28 units/1mg…..glargine 2 arg. Residue prolong the action…. Detemir fatty acid side chain - prolong the action
  • GLP1 analogue greater effectiveness of reducing glucose excursions and also ass. Weight loss
  • Exenetide – reduce hypoglucemia episodes, asso. With weight loss, actions on glucagon nd other b cellprotective effect
  • Glimipiride – 6-8mg/day, pioglitazone 45mg/day, rosiglitazone – 8 mg/day)
  • 1st generation – no more used so we will discuss about only 1 stgen,bcoz hypoglycemia are more widthem.hypoglycemia – ore common in elderly and hepatic and renal fun. Compromise and taking long acting agents…… other s/e agranulocytosis, rash,
  • *DO NOT EDIT* Note: this slide is animatedInsulin degludec tends to exist as dihexamers in the formulation (in pen). At the injection site, as phenol is rapidly diffuses away, insulin degludec quickly forms multihexamers. The unique properties of the side chain (glutamic acid and fatty acid) facilitates the formation of multihexamers in the presence of zinc ions (contained in the formulation). The multihexamers form a depot at the site of injection and represents the primary mechanism of protraction. With time, the monomers slowly dissociate. The monomers are able to diffuse into the capillary where they bind to albumin (due to the fatty acid side chain). This represents the secondary mechanism of protraction and provides a form for “buffering” of insulin degludec blood levels. At the target organs, the insulin degludec monomers are able to activate the insulin receptors as the affinity for the IR is much higher than for the albumin (which is also present in the interstitial fluid, but at a lower concentration than in blood).
  • Glimipiride can be given …..
  • Diabetes management

    1. 1. Management ofDiabetes mellitus Dr. Kartik Doshi 25.1.2012
    2. 2. Overview• Learning Objectives • Management of type 1 DM• Introduction • Management of type 2• Disease burden DM• Physiology • Recent advances• Pathogenesis • Summary • References
    3. 3. Objective• Types and pathogenesis of DM• Signs, symptoms and laboratory investigations• Management of type 1 and type 2 DM• Recent advances in DM management
    4. 4. History• In 1869 , German medical student – Pancreas has two distinct group of cells. PAUL LANGERHANS• Frederick Banting. J j r Macleod. Charles Best. J b Collip.• Indian physician ( charak and sushruta ) – “mudhumeha”
    5. 5. 1921 – Banting and Best
    6. 6. Introduction • Definition * Diabetes mellitus is a group of metabolic disease characterized by hyperglycemia resulting from defect in insulin secretion, insulin action or both. • 246 million worldwide • Prediabetes – great concern*American diabetic association (ADA) Diabetic Care 28:2005
    7. 7. Spectrum of glucose homeostasis and DM Source : Harrison 18E
    8. 8. Physiology of glucose metabolism
    9. 9. Regulation of insulin secretion
    10. 10. Insulin – tissue level
    11. 11. Pathophysiology of DM
    12. 12. Signs and symptoms• Polyurea – osmotic diuresis• Polydypsia• Weight loss – catabolic state• Fatigue• Weakness• Frequent superficial infections• Blurred vision• Look for complications
    13. 13. Physical examinationWeight / BMI Injection sitesRetinal examination Vibratory sensationFoot examination Tooth examinationOrthostatic blood Peripheral pulsespressure
    14. 14. Diagnosis* Symptom of DM + RBS > 200mg/dl (Random Blood Sugar) FBG (Fasting Blood > 126mg/dl Glucose) HbA1C (glycosylated Hb) > 6.5% PPG (OGTT – 75 gm > 200mg/dl anhydrous glucose)PPG – post prandial glucose *ADA- American Diabetic Association
    15. 15. Categorize into types Type 1 Type 2• Age < 30 years • Age >30 years• Lean body habitus • 80% obese, can be lean• Autoimmune attack on β • Insulin resistance, relative cells or idiopathic insulin deficiency • OHAs + insulin• Require insulin as therapy • HHS, type 2 DKA prone• DKA • Component of metabolic• Other autoimmune disorder disorders • LADA – latent autoimmune diabetes of adult
    16. 16. Laboratory assessmentFBGPPBGGlycosylated Hb (HbA1c )SMBG ( self monitoring of blood glucose) Lipid level TFT Urine for protein Stress testing (in high risk pt.)
    17. 17. Advantages of HbA1C Testing Compared With FPG or 2HPG for the Diagnosis of Diabetes Standardized and aligned to the DCCT/UKPDSBetter index of overall glycemic exposure and risk for long-term complications Substantially less biologic variability Substantially less pre-analytic instability No need for fasting or timed samples Relatively unaffected by acute perturbations in glucose levels
    18. 18. Treatment goals for diabetic adultsGlucemic controlA1c < 7.0%Pre-prandial capillary 70-130mg/dlplasma glucosePeak post prandial <180mg/dlplasma glucoseBP <130/80Lipids (LDL) <100mg/dl
    19. 19. Comprehensive diabetes care nutritionist Endocrinologist patient specialists DM educator
    20. 20. Interlocking ideas Diabetes education Nutrition Exercise
    21. 21. Monitoring level of glycemic control• Short term – SMBG complimentary• Long term – HbA1c to each other• SMBG 3-4 times/day (pt. taking multiple insulin) Site – fingertip• CGMS (continuous glucose monitoring system)• Ketone bodies – β hydroxybuterate in blood• Fructosamine assay - hemoglobinopathies
    22. 22. Management Type 1 DM• Partially or completely lack insulin• INSULIN replacement is essential• Basal, exogenous –prevent glycogen breakdown, gluconeogenesis• Meal time – glucose uptake and storage
    23. 23. What are the types of insulin regimens?• Premixed regimen• Split mix regimen• Basal bolus regime (multidose)• Bedtime dosing alone (detemir/Glargine)• Infusion
    24. 24. Premixed insulinAdvantages• More accurate dosing• Lesser injections• Pen devices administer premixed formsDisadvantages• Fine tuning may not be possible• Strict meal pattern• Nocturnal hypoglycemia• May need “diet changes for insulin” rather than “insulin changes for diet”
    25. 25. Split-mixed insulinAdvantages• Less hypoglycemia, with fine tuning• More physiologic• Adjustable meal patternDisadvantages• More patient education required• Cumbersome mixing• Pen device not feasible if two injections are planned for.
    26. 26. Insulin dosage 0.5-1unit/kg per day in divided doses• 50% - basal insulin• Insulin – sensitive to heat and O2
    27. 27. Insulin regimes
    28. 28. Cont…
    29. 29. cont…B – breakfastL – LunchS –SupperHS – nightNPH – Neutral protein hagedon
    30. 30. CSII
    31. 31. Hypoglycemic drugs in Type 1 DmPramlinitide Amylin analogue, given before meal 15µg start – up to 30-60 µg Reduce gastric emptying, Glucagon ↓Acarbose Alpha glucosidase inhibitor Reduce absorption of glucose Hypoglycemic reaction – Rx Glucose
    32. 32. Diabetic ketoacidosis • Diabetic coma • Its an emergency!!! • s/s – nausea, vomitting, thirst , polyurea • PPt. events • Insulin ↓,glucagon↑↑ • Hyperglucemia, ketosis, acidosis, hyperkelemia, hyponatremia
    33. 33. Point to rememberDKAAlways treat in emergency/ICUsetting in initially 24-48 hours.
    34. 34. Confirm diagnosis (plasma glucose,serum ketones, metabolic acidosis) Assess : serum electrolytes, acid base status, RFT Replace fluids, 2-3 L of 0.9% saline over 1-3 hrs(15-20ml/kg/hr), 0.45% saline at 250-500ml/hr. Short acting insulin IV(0.1units/kg) f/b infusion 0.1units/kg/hr, ↑es 2-4hr- no response Replace K+ . Replace with long acting insulin
    35. 35. Monitor following measures• Assess ppt factor – CXR, culture, USG• Capillary glucose 1-2 hrly• Acid-base status and e - 4 hrly for 24 hr• BP, pulse, respiration, mental status, Urine input-output 1-4 hrly• Measure K+ every 1-2 hourly• Measure PO4• ECG
    36. 36. Hyperglycemic hyperosmolar state (HHS)• Elderly person type 2 DM• Several week H/O polyurea, weight loss,• Hypotension, tachycardia, altered mental status• Relative insulin deficiency and fluid intake ↓• Glucose – 1000mg/dl, osmolarity >350mos/l• Prenatal azotemia• Mortality – 15%
    37. 37. Treatment of HHS• Fluid balance Start with 0.9% NS 1-3L over 1-3 hr Fast Repletion of fluid – neurological dysfunction Na > 150meq/l - 0.45% NS use Hemodynamic stability – 0.5 % dextrose use Glucsoe – insulin infusion after glucose 250mg/dl Insulin – same as DKA
    38. 38. Type 2 DM
    39. 39. Food and exercise • Medical nutrition therapy • Glycemic index ( GI) • 150 min/wk (atleast for 3 days) • Type 2 – resistance training • Exercise – can lead hypo/hyper- glycemia • Pre/inter/after exercise glucose testing
    40. 40. The economic driving factors……> Rs. 70/- per kgRs. 90/-per kg …Consumer Price Index shifts favour unhealthy products Adam Drewnowski and SE Specter. Poverty, obesity, and diet costs. Am J Clin Nutr 2004;79:6 –16
    41. 41. Drug options • Sulfonylureas • Meglitinides • Metformin • Thiazolidinediones• α- glucosidase inhibitors • Peptide analogues • DPP4 inhibitors • Insulin
    42. 42. Different site actions of OHAs AGI, PramlinitideIncretins ,SU,Meglitnides TZDMetformin
    43. 43. Pharmacotherapy of type 2 DM LIFE STYLE MODIFICATION A1c 6.5-7.5 A1c 7.5 - 9 A1c >9 Drug naïve Under treatmentMonotherapyMet/ TZD/DPP4 inh./AGI Symptom free Symptom +nt Dual therapy Triple therapy Insulin /insulin agonist Insulin / insulin agonist No response – after at least 2-3 months therapy
    44. 44. • Mono therapy• Dual therapy Met DPP4/ GLP 1, TZD, Glinide/SU TZD DPP4/GLP 1 Met Colesevalam, AGI• Triple therapy Met + GLP 1 or DPP4 TZD SU or glinide
    45. 45. Monotherapy for HbA1c 6-7.5%• Metformin (insulin sensitizer) – 1st choice• Except,1. Renal disease2. Hepatic disease3. GI intolerance4. Lactic acidosis• Secretogogues –not preferred
    46. 46. Cont…• TZD – take time to act, remains for long time, associated with bone fractures• Use : metabolic syndrome, NAFLD• Proceed to next step – after max. dose for adequate duration
    47. 47. Dual therapy• Metformin – preferred for 1st line for dual therapy• TZD – after metformin preferred ( central drug for combination)• Met > TZD,• Incretin mimetic > DPP4 inh. > Glinides > SU• GLP-1 analogue – meal induced glucose excursion , weight loss
    48. 48. • Glinides – more helpful in meal induced glucose ↑ ( HbA1c 7.5%)• Standard dual therapy – met + TZD• Other regimeMetformin + colesevalam (safe, LDL ↓es)Metformin + AGI (anti- atherosclerotic actions)
    49. 49. Triple therapy• 6 options available• Metformin 1st agent unless CI• Exenetide – 2nd agent ( or DPP4 inh.)• Exenetide – CI ( pancreatitis)• 3rd agent – glinides/TZD/SU
    50. 50. Insulin• Reason – no b cell reserve• Can be combined with OHAs• Most useful – metformin• Can be with TZD ( CHF)• 3 regime1. Basal insulin ( glargine )2. Pre mixed insulin ( 2 injections )3. Basal + bolus (4 injections)
    51. 51. HbA1c 7.5-9%• Start with dual therapy• Metformin – 1st agent• Combinations1. Metformin + GLP1 analogue2. Metformin + DPP4 inh.3. Metformin + TZD ( wt. gain, edema)4. Metformin + SU ( more glucose lowering action require)5. Metformin + glinides
    52. 52. Triple therapy• Same as above category• Differences1. No use of glinides, AGI, colesevalam2. Metformin +TZD +SU – weight gain, edema, hypoglycemia• Insulin – same as above• Discontinue ≥1 OHAs• Incretins + insulin – NOT APPROVED
    53. 53. HbA1c >9%• Triple therapy• Insulin – should give drug naïve patients• SU – give importanceFaster actionRobust Glucose lowering effect• Insulin – gradually discontinue after HbA1c<6.5%• Give dual/triple therapy
    54. 54. Insulin in type 2 DMDM – not controlled with max. dose (metformin – 2500mg/day)Physiological stress, infectionUse of parentral nutrition/high caloric dietDKA/HHSGestational DMCRFProgressive complication (D. retinopathy)
    55. 55. Selection of drugs Level of hyperglycemia – choice of initial therapy Mild – moderate DM (200-250 mg/dl) – often respond to monotherapy More rapid glucose control – glucose toxicity ↓↓ Fast control – AGI and Insulin secretogogues No single agent – distinct advantage TZD – target basic problem in type 2 Cost effective – metformin, SU
    56. 56. Combination therapy• Same dose as monotherapy• Different M/A – So additive• Eg. SU and Metformin• Insulin + TZD – more chances of hypoglycemia, weight gain
    57. 57. CIs of combination therapy× Complicated DM× DM with sepsis× DM with tissue hypoxia and systemic BP less then 90 mm of Hg× Type 1 DM× DKA× DM with pregnancy× Auto immune DM
    58. 58. Pharmacological agentsBigunides - Metformin, phenformin Most commonly used drug M/A – AMP Protein kinase HGP ↓, peripheral utilization 500mg -1000mg bd/day
    59. 59. Mechanism of action
    60. 60. Alpha glucosidase inhibitor• Acarbose, voglibose Dose – 25 mg evening meal – 50-100mg/every meal (acarbose) Hypoglycemia – glucose as a treatment Additional actions Anti atherosclerotic Anti platelet Decrease fibrinogen, inflammation Cardio protective in IGT patients
    61. 61. Insulin secretogogues MeglitinideSulfonylurease Glucose , AA analogues GLP-1 receptor DPP4 agonist inhibitors
    62. 62. Modes of action: Glimepiride (SU) Most Sulphonylureas K+ Glimepiride 140 - cell Glimepiride kDa membrane 65 Sulphonylurea kDa Receptor KATP channel K+ GLUT-4 So What ?? 65kDa Component absent in Cardiovascular System Safer to use in patients with a higher cardiovascular risk
    63. 63. Incretins• Entero- insular axis / entero-hypothalamo- insular axis• GIP – glucose dependent insulinotropic peptide• GLP 1 – glucagon like peptide• Preserve B cell mass• Synthetic incretins – use as a drug• “Incretomimetic” and “incretin enhancer”
    64. 64. Incretin hormonesGLP-1 receptor agonist GIP• Secreted by L cells • Secreted K cells• Stimulate – glucose induced • Stimulate – glucose induced• Effect on glucagon • No effect on glucagon• Delay gastric emptying • Does not delay gastric emptying• Circulating level of GLP-1 • Circulating level GIP are reduced normal/high• Enhance B cell proliferation • Same effect• Eg. Exenetide, liraglutide • None
    66. 66. DosesMetformin 0.5-2.5gm 2-3 doses/dayGlimipiride 1-6mg 1Pioglitazone 15-45 mg 1Nateglinide 180-480mg 3-4 doses/dayExenetide (SC) 10-20µg 2 doses/daySitagliptin 100mg 1
    67. 67. Recent advances
    68. 68. Cont…Oral insulin – physiological insulinUse – Ecuador ( india – biocon ) Cortisone Cortisol (active) Enzyme – 11-B hydroxysteroid dehydrogense Activators of glucokinaseStatins – pravastatin (most useful)
    69. 69. Molecular size correlates with rate of absorption Multi-hexamersDuration of Action Di-Hexamer Hexamer Monomer Molecular size
    70. 70. Insulin degludec: Mechanism of protraction Multi-hexamers Subcutaneous tissue Monomers Capillary membrane Insulin degludec in blood Albumin bindingCapillary blood Cell Membrane Insulin Receptors
    71. 71. Gestational and other DM• Intensive treatment required• Fetal macrosomia• Insulin only is used• 30-60% - chance of type 2 DM Pediatric DM• More chances – hypoglycemia, coma• Metformin – only approved (10mg/ml)
    72. 72. Prediabetes : What’s in a Name? Use for IGT and IFG If 50% chance of DM – next 10 years Forerunners of DM, CV risk Life style modification and metformin*1. <60 years of age2. BMI >35kg/m23. Family history4. TG, HDL5. HT6. A1c > 6.0%
    73. 73. References• Harrison 18th edition• Goodman and gillman. Pharmacological basis of therapeutics. 12th edition• KDT 6th edition• Medicine update 2008. Vol.18• An algorithm for glycemic control. AACE/ACE consensus statement. Endocr Pract. 2009;15(No. 6)
    74. 74. 1st – Acetohexamide, Tolbutamide, Chlorpropamide, SULFONYLUREAS Tolzamide. 2nd – Glibenclamide, SECRETAGOGUES K+ATP Glipizide, Gliclazide 3rd – GlimepirideINSULIN MEGLITINIDES/ Nateglinide, PHENYLALANINE Repaglinide GLP -1 Exenatide, Liraglutide ANALOG DPP IV Sitagliptin, Vildagliptin, Saxagliptin INHIBITORS BIGUANIDES Metformin SENSITIZERS TZD (PPAR) Rosiglitazone, Pioglitazone α - GLUCOSIDASE Acarbose, Miglitol, VogliboseOTHERS INHIBITORS AMYLIN ANALOG Pramlintide
    75. 75. Thank you