New in Type 2 Diabetes Mellitus

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  • PDY10931
  • New in Type 2 Diabetes Mellitus

    1. 1. What is NEW in T2DM? Anil Bhansali Department of Endocrinology PGIMER, Chandigarh
    2. 2. Recents in T2DM Prevalence Pathogenesis Diagnosis Treatment -Targets - Incretins - Novel Insulin - Newer Drugs Novel therapies Conclusions
    3. 3. Prevalence of DM Rank 2000 2030 1 India 31.7 India 79.4 2 China 20.8 China 42.3 3 US 17.7 US 30.3 4 Indonesia 8.4 Indonesia 21.3 5 Japan 6.8 Pakistan 13.9 6 Pakistan 5.2 Brazil 11.3 7 Russian Fed. 4.6 Bangladesh 11.1 8 Brazil 4.6 Japan 8.9 9 Italy 4.3 Philippines 7.8 10 Bangladesh 3.2 Egypt 6.7 Wild et al Diabetes Care 2004China 2010- 92.4 million adults Wang et al NEJM 2010
    4. 4. State Pre-diabetes DiabetesMaharashtra 12.8 8.4Tamilnadu 8.3 10.4Jharkhand 8.1 5.3Chandigarh 14.6 13.6
    5. 5. PATHOPHYSIOLOGY
    6. 6. Two Defects of T2DM Insulin resistance Insulin deficiency AJM 2000
    7. 7. Three Defects of T2DM Insulin resistance Insulin deficiency Incretin deficiency -Impaired insulin secretion -Impaired glucose-glucagon axis
    8. 8. Glucose concentration Iso-glycaemic profiles Glucose given orally Glucose given intravenously to achieve the same profile 0 10 20 30 40 50 60 70 80 90 minutes
    9. 9. Iso-glycaemic profiles Incretin effectInsulin concentration Glucose given orally Glucose given intravenously to achieve the same profile 0 10 20 30 40 50 60 70 80 90 minutes
    10. 10. Incretins Enteroendocrine cells (K/L cells): GIP and GLP-1 Released in response to mixed meal/ glucose Potentiate the glucose induced insulin secretion Insulin secretion is glucose dependent Contributes 60% of prandial insulin release Inhibits glucagon
    11. 11. Glucose-Glucagon Axis Normally rising glucose levels inhibits glucagon and vice versa In T2DM, glucose mediated inhibition of α- cells is impaired GLP-1 -Stimulating insulin (Intra-islet insulin) -Direct inhibition of α-cells -Restores glucose sensitivity to α-cells
    12. 12. Insufficient Insulin and Elevated Glucagon in T2DM ( Insulin/Glucagon Ratio) CHO meal 400 300 mg/dL NGT 200 T2DM 100 Glucose 0 150 μU/mL 100 NGT 50 Insulin T2DM 0 150 125 Glucagon pg/mL 100 NGT T2DM 75 -60 0 60 120 180 240 Time (min)CHO=carbohydrate; NGT=normal glucose tolerance; T2DM=type 2 diabetes mellitusAdapted from Müller WA, et al. N Engl J Med. 1970; 283: 109–115.
    13. 13. Pancreatic Islet Dysfunction Leads to Hyperglycemia in T2DM Fewer -cells -cells Hypertrophy Insufficient Excessive Insulin Glucagon + – + ↑ Glucose↓ Glucose ↑ HGO Uptake
    14. 14. The Ominous Octet Islet -cell Decreased Increased Impaired Incretin Effect Lipolysis Insulin SecretionIslet -cell Increased GlucoseIncreased ReabsorptionGlucagon Secretion Increased HGP Decreased Glucose Uptake Neurotransmitter Dysfunction
    15. 15. Diagnosis of DM
    16. 16. Diagnosis FPG 126 mg/dl 2h PG 200 mg/dl (75 gm anhydrous glucose) RPG 200 mg/dl with symptoms Reconfirmation on subsequent daysLimitations Ensure fasting Influenced by exercise and activity Analytical variability Intra-individual variations
    17. 17. Glycated Hb (HbA1c) Diagnosis of DM- HbA1c  6.5%- FPG ≥126mg/dl, RPG > 200 mg/dl with symptoms- Confirm with a repeat HbA1c Prediabetes (IFG, IGT)- HbA1c 5.7 - 6.4%
    18. 18. Glycated Hb (HbA1c) Single estimation Any time of the day Better index of overall glycemic exposure Substantially less biologic variability Better pre-analytic stability Denotes risk of long term complications Standardized and aligned to the DCCT/UKPDS
    19. 19. Total no. people approached -2368 123 (non responders), Refused = 48 Out of station = 64, Sickness = 9 Pregnancy = 2 Included in the study - 2245 18 Excluded – 2hr PG-Not available Refused to take glucose = 7, Taken tea/food and later refused = 5 Under took physical activity = 3Finally evaluable in the study - 2227 - 2245 Not available on 2 consecutive visits = 2 HbA1c not available = 255 HbA1c available - 1972 Flow summary of study subjects JCEM, Bhansali et al 2010
    20. 20. HbA1c for diagnosis of diabetesCut-off level Sensitivity Specificity5.7 92 635.8 92 686.0 83 776.1 81 816.2 76 846.3 73 866.4 70 876.5 65 886.6 62 896.9 47 917.0 42 92 JCEM, Bhansali et al 2010
    21. 21. SE
    22. 22. HbA1c and Pre-diabetes Both the ADA and IEC HbA1c cut-offs under-diagnosed the presence of pre-diabetes in 38% and 64% of these subjects Bhansali et al. Diab Med Dec 2012
    23. 23. Management Algorithms
    24. 24. Standard Approaches to Therapy Result in Prolonged Exposure to Elevated Glucose 10% Diet/Exercise Sulfonylurea or Combination Insulin Metformin Therapy Monotherapy 9.6%Mean A1C at Last 9% 9.0% 8.6% Visit 8% 7% ADA Goal <7% 6% Diagnosis 2 3 4 5 6 7 8 9 10 Years At insulin initiation, the average patient had:  5 years with A1C >8%  10 years with A1C >7% Brown JB, et al. Diabetes Care. 2004;27:1535-1540.
    25. 25. American Association of Clinical Endocrinologists: algorithm for patients with T2DM Drug-naïve patients Initiate monotherapy HbA1c 6%–7% Metformin, TZD, secretagogues, DPP-4 inhibitors, α-glucosidase inhibitors HbA1c 7%–8% Initiate combination therapy Secretagogue + metformin, TZD, or α-glucosidase inhibitor Lifestyle Changes TZD + metformin DPP-4 + metformin or TZD Secretagogue + metformin + TZD Fixed-dose combinations Insulin HbA1c 8%–10% Intensify combination therapy To address fasting and postprandial glucose levels HbA1c >10% Initiate / intensify insulin therapy Patients currently As above pharmacologically Exenatide may be combined with oral therapies in patients treated not achieving goalsDPP-4=dipeptidyl peptidase-4; T2DM=type 2 diabetes mellitus; TZD=thiazolidinedioneAACE Diabetes Mellitus Clinical Practice Guidelines Task Force. Endocr Pract. 2007; 13 (Suppl 1): 16–34.
    26. 26. WHAT SHOULD BE TARGETED ? Fasting plasma glucose Post prandial glucose
    27. 27. Basal vs Post-Prandial Hyperglycemia – A1c Uncontrolled Diabetes HbA1c 8% Basal hyperglycaemia 300 contributes ~2% Post-prandial Plasma glucose (mg/dL) hyperglycaemia contributes HbA1c ~1% 200 Post-prandial hyperglycaemia Fasting hyperglycaemia 100 Normal HbA1c ~5% 0    6 B 12 L 18 D 24 6 Time of day (h)B=breakfast; L=lunch; D=dinner.Adapted from Riddle MC. Diabetes Care. 1990;13:676-686.
    28. 28. INCRETINS
    29. 29. DPP-IV Inhibitors Vildagliptin Sitagliptin SaxagliptinIC50DPPIV 3nmol/L 18 nmol/L 26 nmol/LDPPIV specificity 32-250 >2600 NAGlucagon ↓↓↓ ↓↓ ↓↓Intact GLP-1 levels ↑↑ ↑ ↑T½ 3 hrs 12.4 hr 2 hrMetabolism 85%hydrolyzed 80% excreted 33-60% by kidney in liver by kidneys 40 -67% hepaticHbA1c reduction 0.4-0.9% 0.4-0.9% 0.43 – 0.54 %Infections ↑ ↑ ↑With insulin Approved Not approved Not approvedRenal insufficiency Moderate to severe Mild to moderate Mild to moderateHepatic dysfunction Caution Use with caution Use with caution
    30. 30. Linagliptin New class of DPP-IV inhibitor Exclusively metabolized through entero- hepatic route Safe in renal and liver failure HbA1c reduction by 0.6-0.8% Reduces albuminuria independent of glycemic control Can be given OD or BID
    31. 31. All GLP-1 Analogues are Same !
    32. 32. All GLP-1 receptor agonists are not the same Native human GLP Lixisenatide, exenatide Liraglutide Meier Nat Rev Endocrinol 2012
    33. 33. PDY10931: effects of lixisenatide and liraglutide on post-prandial glucose and insulin Lixisenatide (D-1) Liraglutide (D-1) Lixisenatide (D28) Liraglutide (D28) Glucose (mg/dL) Insulin free (µIU/mL) 70 60 p<0.0001 50 40 30 20 0 0 30 60 90 150 210 270 Time (minutes) Time (minutes) Meal 451 kcal Meal 451 kcal Source: www.clinicaltrial.gov NCT01175473, IDF 2011 D-0740, Sanofi internal data
    34. 34. Newer concepts of GLP-1 analogues Nat.Rev.Endocrinol Sep 2012
    35. 35. Effect of Incretin on Islet cell Mass
    36. 36. Novel Insulin (Degludec) Ultra long acting basal insulin- insulin Degludec Extreme dosing intervals of 8–40 h Daily injection time of IDeg can be varied without compromising glycemic control or safety Less hypoglycemia, particularly nocturnal hypoglycemia Diabetes care Jan 2013 Feb 12, 2013 FDA rejected approval of Degludec Need of additional CVS safety data
    37. 37. SGLT2 Inhibitors Abdul-Ghani ; Endo Rev 2011
    38. 38. SGLT2 Inhibitor (Dapagliflozin) Abdul-Ghani ; Endo Rev 2011
    39. 39. Glucokinase Activator (Piragliatin)
    40. 40. Glucokinase Activator (Piragliatin) Pre-clinical studies  Increases insulin secretion,  Decreases HGO Concerns  Hypoglycemia,  Fatty liver,  Hyperlipidemia Matschinsky F et al Diabetes care 2012
    41. 41. GPR 40 Modulator(TAK 875) TAK-875 50–200-mg OD reduced A1C similar to 1 mg glimepiride OD HbA1c reduction was 0.65%-1.37% with increasing doses Kaku K Diabetes Care 2013
    42. 42. Stem Cells Dev. 2009 Dec;18(10):1407-16Efficacy Of Autologous Bone Marrow Derived StemCell Transplantation In Patients With Type 2 DiabetesMellitus.Bhansali A, Upreti V, Khandelwal N, Marwaha N, Gupta V, Sachdeva N,Sharma RR, Saluja K, Dutta P, Walia R, Minz R, Bhadada S, Das S,Ramakrishnan S.PGIMER , Chandigarh,
    43. 43. BASELINE PARAMETERS N=10 (8 men) Mean age: 57.5 5.9 years Mean duration of DM: 14.6 7.5 years Mean duration of insulin therapy: 5.6 3 years Mean dose of insulin: 69.4 6.6 units/day Mean weight : 74.5 11.6 kg Mean BMI: 26.5 3.4 kg/m2 Mean waist circumference: 93.2 7.8 cm
    44. 44. RESULTS Primary end points  Reduction in insulin requirement by ≥ 50%  Improvement in glucagon stimulated C– peptide levels at the end of 6 months Secondary end points  Change in weight, HbA1c and insulin- glucose homeostasis Responders :7, Nonresponders:3
    45. 45. RESULTSParameters Baseline 6 months p valueINSULIN REQUIREMENT/ DAY (U)*Group 69.4 6.6 28.2 7.4 0.007Responders 75.3 8.2 18.9 7.4 0.02Non-responders 55.7 6.2 50 9.9 0.29FPG (mg/dl)Group 136.5 25.1 119.1 21.3 0.059Responders 133.9 28.8 112.3 4.6 0.063Non-responders 142.7 16.1 134.7 37.8 0.59HbA1c*Group 8.4 0.6 7.3 0.8 0.009Responders 8.1 0.2 7.3 0.4 0.04Non–responders 8.9 0.2 7.5 0.2 0.11
    46. 46. RESULTSParameters Baseline 6 months p valueSTIMULATED C- PEPTIDE (ng/ml)*Group 1.1± 0.2 2.1 0.3 0.03Responders 1.2 0.1 2.6 0.3 0.03Non–responders 0.8 0.7 0.9 0.6 0.99HOMA- BGroup 46.1 14.0 174.5 52.9 0.02Responders 37.7 18.4 154.5 74.3 0.04Non–responders 67.3 9.8 224.5 2.8 0.18HOMA- IRGroup 4.74 1.4 3.37 0.95 0.74Responders 5.14 1.94 3.86 1.27 0.89Non–responders 3.75 1.75 2.15 0.75 0.66
    47. 47. Bariatric surgery- an option or ultimate solutionHbA1c> 7.5% inspite of optimal therapy Endocrine Pract 2013
    48. 48. OutcomesWt LossDiabetesRemissionCo-morbidities
    49. 49.  At 2 years, diabetes remission in no patients in the medical-therapy group 75% in the gastric-bypass group and 95% in the biliopancreatic-diversion group NEJM 2012
    50. 50. Future Motto of ADA “Living with diabetes” With bariatric surgery: “LIVING WITHOUT DIABETES”
    51. 51. Conclusions Enormous advances have been made in understanding of the disease , diagnosis and treatment. Treatment of diabetes should be tailor-made and needs to be individualized Future is pregnant with many possibilities

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