ROLE OF ALPHA CELLS IN DIABETES WITH PATIENT CENTRIC APPROACH OF TREATMENT

The Roger findings suggest that alpha cell function is inappropriately increased in diabetes mellitus and could play a significant role in the diabetic syndrome.2
Roger Unger postulated that diabetes is caused by insulin deficiency (amount or effect) and glucagon presence, or excess.2
Many studies have since demonstrated α-cell dysfunction in diabetes1

1. ROLE OF ALPHA CELLS IN DIABETES WITH PATIENT CENTRIC APPROACH OF TREATMENT   DR. SUDHIR BHANDARI MD, DNB, MNAMS, FRCP ( LONDON) FELLOW AMERICAN COLLEGE OF ENDOCRINOLOGY (FACE) FELLOW AMERICAN COLLEGE OF PHYSICIANS (FACP) FELLOW INDIAN COLLEGE OF PHYSICIANS (FICP) FELLOWSHIP OF RSSDI SR. PROFESSOR OF MEDICINE SMS MEDICAL COLLEGE & HOSPITAL, JAIPUR Hon. Physician to H.E. – The Governor of Rajastha n

2. Flow of presentation

3. BASIC PHYSIOLOGY OF ISLETS OF LANGERHANS

4. Pancreas: Functional components The islets of Langerhans are the endocrine cells of the pancreas. Cells produce and secrete hormones such as insulin and glucagon into the bloodstream. The pancreas. Available at http:// pathology.jhu.edu/pancreas/BasicOverview3.php?area=ba . Accessed on May, 2017. Acinar cells are the exocrine cells of the pancreas.

5. The Islets of Langerhans Types of Cells in the Pancreas. Available at https:// www.boundless.com/physiology/textbooks/boundless-anatomy-and-physiology-textbook/endocrine-system-16/the-pancreas-159/types-of-cells-in-the-pancreas-798-365.Accessed on May, 2017. The pancreatic islets of Langerhans are important components of islet architecture and intercellular communication. 20% 7 0% 5 % 20%

6. Islets alpha and beta cell hormones regulate glucose homeostasis 6 Rhodes C.J. Type 2 diabetes—a matter of beta-cell life and death? Science. 2005;307(5708):380–384

7. Cross-talk mechanisms between alpha and beta cells Moon JS, et al. Pancreatic α-Cell Dysfunction in Type 2 Diabetes: Old Kids on the Block. Diabetes Metab J 2015;39:1-9 Figure A Figure B T2D has been considered as a bi- horrmonal disorder. Glucagon secretion is under paracrine control by insulin (the switch-off hypothesis) for the architectural proximity between α- and β-cell Figure A

8. Alpha cells

9. Alpha cells: Historical background Brereton, et al. Alpha-, Delta- and PP-cells: Are They the Architectural Cornerstones of Islet Structure and Co-ordination? Journal of Histochemistry & Cytochemistry 2015; 63(8) 575– 591.

10. Alpha cells Functions 10 Stanojevic V, et al. Evolving Function and Potential of Pancreatic Alpha Cells . Best Pract Res Clin Endocrinol Metab . 2015 December ; 29(6): 859–871

11. The role of alpha-cell function in diabetes The Roger findings suggest that alpha cell function is inappropriately increased in diabetes mellitus and could play a significant role in the diabetic syndrome. 2 Roger Unger postulated that diabetes is caused by insulin deficiency (amount or effect) and glucagon presence, or excess. 2 Many studies have since demonstrated α- cell dysfunction in diabetes 1 Brereton, et al. Alpha-, Delta- and PP-cells: Are They the Architectural Cornerstones of Islet Structure and Co-ordination? Journal of Histochemistry & Cytochemistry . 2015 , 63(8 ) 575– 591. Unger , R. H., Aquilar-Parado , E., Muller, W. A., and Eisentraut , A. M. (1970). Studies on pancreatic alpha cell function in normal and diabetic subjects.  J. Clin . Invest . 49, 837–848.

12. Glucagon : Synthesis Amélio F. The role of glucagon on type 2 diabetes at a Glance. Diabetology & Metabolic Syndrome 2014, 6:91

13. Organ-specific pharmacological effects of glucagon . Christensen M, et al. The Alpha-Cell as Target for Type 2 Diabetes Therapy . The Review of DIABETIC STUDIES. 2011; 8(4):369-82.

14. The normal reciprocal response of insulin and glucagon regulates postprandial glucose elevations Unger RH. Glucagon and the a Cell — Physiology and Pathophysiology. New England j Med. 1981; 285:443-9.

15. Incretin effect in normal subjects Drucker DJ . Enhancing Incretin Action for the Treatment of Type 2 Diabetes. Diabetes Care. 2003;26:2929-2949

16. Glucagon is a major contributor to hepatic glucose output Somatostatin and insulin induced  glycogenolysis that maintains our fasting blood glucose level and decreased hepatic glucose production by 75 % Diabetes: Scope of the Problem. Available at http://www.medscape.org/viewarticle/551055 . Accessed on May, 2017.

17. Major incretin release and action of GLP-1 Drucker DJ . Enhancing Incretin Action for the Treatment of Type 2 Diabetes. Diabetes Care. 2003;26:2929-2949 Most of the beneficial GLP-1 properties are negated, because 80% of it is inactivated in 2 minutes.

18. Insulin and GLP-1 response to meal in normal condition This illustrates what happens when food is eaten. In normal people, insulin goes up, GLP-1 goes up, and even though it is largely deactivated, it is present in increased levels.

19. Dysregulation of α-cell function in type 2 diabetes

20. Changing concepts of diabetes Unger RH. Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover J Clin Invest . 2012;122(1):4–12.

21. Alpha cells mediated dysregulations in patients with T2DM

22. Insulin and glucose patterns: Normal and type 2 diabetes Polonsky KS, et al. Abnormal patterns of insulin secretion in non-insulin-dependent diabetes mellitus. N Engl J Med . 1988 May 12;318(19):1231-9.

23. T2DM is marked by blunted insulin response and inadequate glucagon suppression after meals Spellman C. Islet Cell Dysfunction in Progression to Diabetes Mellitus. J Am Osteopath Assoc . 2007;107( suppl 3): S1-S5.

24. Glucagon-like Peptide-1 in Type 2 Diabetes In type 2 diabetes, patients have reduced secretion of GLP-1 in response to a meal

25. Glucagon is very important in the progression of hyperglycemia DeFronzo RA. Lilly lecture 1987. The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM.  Diabetes . 1988;37:667-687.

26. Summary

27. Drugs affecting alpha-cells

28. Metformin, Sulfonylureas and Suppress hepatic glucagon signaling by decreasing production of cyclic AMP Metformin Insulin and Sulphonylureas Partially inhibit glucagon secretion Moon JS, et al. Diabetes Metab J 2015;39:1-9

29. Glucagon antagonist Moon JS, et al. Diabetes Metab J 2015;39:1-9 Increase risk of iatrogenic hypoglycemia Ongoing attempts to develop potent and selective glucagon receptor antagonists for over decades Concerns about safety Lack of specificity or efficacy Potential for induction of immune responses Side effects such as pancreatic α-cell hyperplasia Limitations Improved drug delivery systems renew hope for therapeutic use of peptide-based glucagon receptor antagonist Under research & development, not approved in India

30. CONCLUSIONS In patients with type 2 diabetes, glucagon receptor antagonist treatment significantly lowered HbA 1c and glucose levels with good overall tolerability and a low risk for hypoglycemia . Modest, reversible increases in serum aminotransferases were observed.

31. Conclusions Statistically significant increases in BP, MAP, and serum lipid levels were observed with LY2409021 treatment at a dose that lowered HbA1c and glucose levels. These effects may limit the clinical utility of LY2409021 as a chronic treatment for type 2 diabetes.

32. Other Concerns Glycogen storage disease Seen in rodent not humans Malignant transformation of alpha cells Theoretical possibility Not yet reported in rodent models

33. Type 1 DM Antibodies against glucagon receptor Improved glycemic control far better than insulin monotherapy Glycaemia variability reduced Reduced the doses of Insulin

34. Glucagon like peptide -1 (GLP-1) agonists Enhancing glucose-dependent insulin secretion from β-cell Reducing the plasma glucagon GLP-1 is a product of proglucagon that has nearly 50% homology to glucagon GLP-1 regulates hyperglycemia through a variety of mechanisms Moon JS, et al. Diabetes Metab J 2015;39:1-9

35. GLP-1 agonists – Type 2 diabetes Improved the 24-h glucose profiles, alpha and beta cell function, as well as reduced endogenous glucose release Significant reductions were seen in plasma glucagon, both in the fasting state and after meal stimulation Liraglutide – 1 week treatment Eliminates the inappropriate post meal increase in plasma glucagon levels Exenatide – 5 day treatment GLP-1: Glucagon like peptide -1 Dunning BE, et al. Endocrine Reviews 2007;28(3):253–283; Lund A, et al. Curr Diab Rep (2014) 14:555

36. Dipeptidyl peptidase - IV (DPP-IV) inhibitor Moon JS, et al. Diabetes Metab J 2015;39:1-9 Prolong the activity of GLP-1 & GIP Stimulate insulin secretion and reduce plasma glucagon Improve insulin secretion as well as reduce plasma glucagon

37. DPP-IV inhibitors prolong GLP-1 & GIP 1. Fonseca V, et al. Diabetologia 2007;50:1148–15 2. Christensen M, et al. Diabetes 2011;60:3103–9

38. DPP-IV inhibitors Aschner P. Diabetes care. 2006 Dec 1;29(12):2632-7 . Balas B, et al. J Clin Endocrinol Metab 2007;92:1249–55 Rauch T. Diabetes Therapy. 2012 Dec 1;3(1):1-4. (Seen with Vildagliptin) . Hissa MR. Diabetology & metabolic syndrome. 2015 Jul 11;7(1 ) Reduction in plasma glucagon versus placebo (Sitagliptin 1 , Vildalgiptin 2 , linagliptin 3 ) Significant reduction of plasma glucagon compared to SU 4 38

39. DPP-IV inhibitors . Lunch Dinner Breakfast Lunch Dinner Breakfast Rizzo MR, et al. Diabetes Care. 2012 Oct;35(10):2076-82 Continuous evaluation of plasma glucagon levels : Vildagliptin & Sitagliptin Vildagliptin 50mg BD, Sitagliptin 100mg OD, N=90 Comparative effect on glucagon dynamics

40. Sodium glucose co-transporter (SGLT-2) inhibitor Candelario N, et al. Oxford Medical Case Reports, 2016;7, 144–146;Singh AK. Indian J Endocrinol Metab . 2015 NovDec ; 19(6): 722–730; Bonner C, et al. Nature Medicine 2015;21(5):512-519 Inhibit glucose reabsorption at SGLT2 receptors in the proximal tubule of the kidney. Inducing glucosuria Canagliflozin , dapagliflozin and empagliflozin First class of medications that act on the kidneys to optimize glycemic control However, increase both plasma glucagon and endogenous glucose production

41. SGLT-2 inhibitors – FDA warning Increase in glucagon may play a role in euglycemic ketoacidosis Candelario N, et al. Oxford Medical Case Reports, 2016;7, 144–146 SGLT-2 Inhibitor Decreased glucose Reabsorption in the proximal convoluted tubules Decreased blood glucose Decreased insulin levels (Increased glucagon to insulin ratio) Gluconeogenesis Ketoacidosis Decreased carbohydrate intake/starvation Decreased insulin dose/ Secretagogue dose Pregnancy Accelerated increase in counter regulatory hormones

42. Current Drugs for Diabetes and Glucagon Secretion or Action Insulin : Reproduction of high intra-islet insulin concentrations that allow the achievement of sufficient inhibition of glucagon secretion by subcutaneous insulin administration may induce peripheral tissues over- insulinization and excessively increase the risk of hypoglycemia. Sulphonylureas : By stimulating intra-islet insulin release, S ulphonylureas potentially reduce glucagon secretion. In people with T2DM, with persistent endogenous insulin secretion, oral glibenclamide inhibits glucagon response to insulin-induced hypoglycemia . Ref: Diabetes, Obesity and Metabolism, 2015

43. Current Drugs for Diabetes and Glucagon Secretion or Action Alpha glucosidase inhibitors Significant postprandial increase in active GLP-1 circulating levels, and may contribute to reduced glucagon secretion. Thiazolidinediones or Glitazones : Inhibit glucagon gene transcription in pancreatic alpha cell lines through binding to the nuclear peroxisome proliferator -activated receptor gamma and inhibition of the transcriptional activity of PAX6 that is required for cell-specific activation of the glucagon gene. Ref: Diabetes, Obesity and Metabolism, 2015

44. Novel drugs Hughes DS, et al. Br J Diabetes Vasc Dis 2014;14:45-51 Dual GLP-1/glucagon receptor and GLP-1/GIP receptor targeted peptides Ghrelin antagonists, and with leptin agonists ( metreleptin ) Drugs that target the GPR119 receptor Tocilizumab , an IL-6 receptor monoclonal antibody

45. Conclusion Alpha cells - important in the maintenance of beta cell health and functions Alpha cells being more resistant to metabolic stress lead to increased glucagon in diabetes. Long term glycemic control depends upon effect of an agent on glucagon balance.

46. Patient Centric Approach Guiding the selection of treatment in Diabetes

47. Management of Hyperglycemia in Type 2 Diabetes, 2015: A Patient-Centered Approach Update to a Position Statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) Diabetes Care 2015;3 8:140–149 Diabetologia 2015;58:429–442

48. Patient-Centered Approach “ ... providing care that is respectful of and responsive to individual patient preferences, needs, and values - ensuring that patient values guide all clinical decisions.” Gauge patient’s preferred level of involvement. Explore, where possible, therapeutic choices. Consider using decision aids. Shared Decision Making – a collaborative process between patient and clinician, using best available evidence and taking into account the patient’s preferences and values F inal decisions regarding lifestyle choices ultimately lie with the patient. ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, 2015 Diabetes Care 2012;35:1364– 1379; Diabetologia 2012;55:1577– 1596

49. 2. BACKGROUND Relationship of glycemic control to microvascular and macrovascular outcomes. ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, 2015 Diabetes Care 2012;35:1364– 1379; Diabetologia 2012;55:1577– 1596

50. SU=sulfonylurea; TZDs=thiazolidinediones; T2DM=type 2 diabetes. Koro CE, et al. Diabetes Care . 2004;27:17-20; Hoerger TJ, et al. Diabetes Care . 2008;31:81-86. NHANES 1988-1994 5 6 7 8 9 10  1980s 1990s 2000s  HbA 1c (%) SU / Insulin Metformin (1995) TZDs (1998) Incretins (2004) Pre-DCCT 9.0% 7.7 NHANES 1999-2000 7.8 NHANES 2001-2002 7.5 NHANES 2003-2004 7.2 Future 6.0% ? 1997: ADA lowered T2DM diagnosis from FPG ≥7.8 mmol/L to ≥7.0 mmol/L 2003: ADA eliminated HbA 1c “action point” of <8% from guidelines 2005: ADA added HbA 1c goal of <6% for “individual patients” to guidelines General ADA Target: <7% 1998: UKPDS results published 2008: ACCORD, ADVANCE, VADT, and UKPDS 80 published 2009: ADA added “less stringent” HbA 1c goal for patients with significant comorbidities or risk of hypoglycemia, or short life expectancy Advances in Therapy, but Falling Short of Goals

51. Impact of Intensive Therapy for Diabetes: Summary of Major Clinical Trials Study Microvasc CVD Mortality UKPDS       DCCT / EDIC*       ACCORD    ADVANCE    VADT    Long Term Follow-up Initial Trial * in T1DM Kendall DM, Bergenstal RM. © International Diabetes Center 2009 UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854. Holman RR et al. N Engl J Med . 2008;359:1577. DCCT Research Group. N Engl J Med 1993;329;977. Nathan DM et al. N Engl J Med . 2005;353:2643. Gerstein HC et al. N Engl J Med. 2008;358: 2545. Patel A et al. N Engl J Med 2008;358:2560. Duckworth W et al. N Engl J Med 2009;360:129 . (erratum: Moritz T. N Engl J Med 2009;361:1024)

52. 2. BACKGROUND Overview of the pathogenesis of T2DM Insulin secretory dysfunction Insulin resistance (muscle, fat, liver) Increased endogenous glucose production Decreased incretin effect Deranged adipocyte biology ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, 2015 Diabetes Care 2012;35:1364– 1379; Diabetologia 2012;55:1577– 1596

53. peripheral glucose uptake hepatic glucose production pancreatic insulin secretion pancreatic glucagon secretion gut carbohydrate delivery & absorption incretin effect HYPERGLYCEMIA ? Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011 Multiple, Complex Pathophysiological Abnormalities in T2DM _ _ + renal glucose excretion

54. peripheral glucose uptake hepatic glucose production pancreatic insulin secretion pancreatic glucagon secretion gut carbohydrate delivery & absorption incretin effect HYPERGLYCEMIA ? Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011 Multiple, Complex Pathophysiological Abnormalities in T2DM _ _ + renal glucose excretion DA agonists T Z D s Metformin S U s Glinides DPP-4 inhibitors GLP-1R agonists A G I s Amylin mimetics Insulin Bile acid sequestrants

55. Pathophysiology of Type 2 Diabetes Insulin resistance. Beta cell dysfunction.

56. Pathophysiology of Type 2 Diabetes Insulin Resistance Insulin Resistance starts very early in the course of the disease. insulin resistance alone will not produce diabetes. If beta-cell function is normal, one can compensate for insulin resistance by increasing insulin secretion.

57. Glycemic Goals Table 1.  Parameter Normal ADA Goals ACE/AACE Goals Fasting plasma glucose (mg/dL) < 100 90-130 < 110 Postprandial plasma glucose (mg/ dL ) < 120 < 180* < 140** A1C (%) 4-6 < 7*** ≤ 6.5 *1-2 hours post-meal **2 hours post-meal ***as close to normal as possible without undue risk of hypoglycemia

58. 3. ANTI-HYPERGLYCEMIC THERAPY Glycemic targets HbA1c < 7.0% ( mean PG  150-160 mg/ dl [8.3-8.9 mmol/l ] ) Pre -prandial PG <130 mg/ dl (7.2 mmol/l ) Post -prandial PG <180 mg/ dl (10.0 mmol/l ) Individualization is key: Tighter targets (6.0 - 6.5%) - younger, healthier Looser targets (7.5 - 8.0% + ) - older, comorbidities , hypoglycemia prone, etc. Avoidance of hypoglycemia PG = plasma glucose ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, 2015 Diabetes Care 2012;35:1364– 1379; Diabetologia 2012;55:1577– 1596 Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

59. Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442 Figure 1. Modulation of the intensiveness of glucose lowering therapy in T2DM

60. Figure 1. Modulation of the intensiveness of glucose lowering therapy in T2DM Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

61. Figure 1. Modulation of the intensiveness of glucose lowering therapy in T2DM Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

62. Figure 1. Modulation of the intensiveness of glucose lowering therapy in T2DM Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

63. Figure 1. Modulation of the intensiveness of glucose lowering therapy in T2DM Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

64. Figure 1. Modulation of the intensiveness of glucose lowering therapy in T2DM Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

65. Figure 1. Modulation of the intensiveness of glucose lowering therapy in T2DM Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

66. Figure 1. Modulation of the intensiveness of glucose lowering therapy in T2DM Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

67. 3. ANTI-HYPERGLYCEMIC THERAPY Therapeutic options: Lifestyle Weight optimization Healthy diet Increased activity level ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, 2015 Diabetes Care 2012;35:1364– 1379; Diabetologia 2012;55:1577– 1596

68. 3. ANTI-HYPERGLYCEMIC THERAPY Therapeutic options: Oral agents & non - insulin injectables Metformin Sulfonylureas Thiazolidinediones DPP-4 inhibitors SGLT-2 inhibitors GLP-1 receptor agonists Meglitinides a - glucosidase inhibitors Colesevelam Dopamine-2 agonists Amylin mimetics ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, 2015 Diabetes Care 2012;35:1364– 1379; Diabetologia 2012;55:1577– 1596 Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

69. Oral Class Mechanism Advantages Disadvantages Cost Biguanides Activates AMP-kinase (?other)  Hepatic glucose production Extensive experience No hypoglycemia Weight neutral ?  CVD Gastrointestinal Lactic acidosis (rare) B-12 deficiency Contraindications Low Sulfonylureas Closes K ATP channels  Insulin secretion Extensive experience  Microvascular risk Hypoglycemia  Weight Low durability ? Blunts ischemic preconditioning Low Meglitinides Closes K ATP channels  Insulin secretion  Postprandial glucose Dosing flexibility Hypoglycemia  Weight ? Blunts ischemic preconditioning Dosing frequency Mod. TZDs PPAR- g activator  I nsulin sensitivity No hypoglycemia Durability  TGs ( pio )  HDL-C ?  CVD events ( pio )  Weight Edema/heart failure Bone fractures  LDL-C ( rosi ) ?  MI ( rosi ) Low Table 1. Properties of anti-hyperglycemic agents Diabetes Care 2015;38:140-149; Diabetologia 2015;10.1077 /s00125-014-3460-0 Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

70. Oral Class Mechanism Advantages Disadvantages Cost a - Glucosidase inhibitors Inhibits a - glucosidase Slows carbohydrate digestion / absorption No hypoglycemia Nonsystemic  Postprandial glucose ?  CVD events Gastrointestinal Dosing frequency Modest  A1c Mod . DPP-4 inhibitors Inhibits DPP-4 Increases incretin (GLP-1, GIP) levels No hypoglycemia Well tolerated Angioedema / urticaria ? Pancreatitis ?  Heart failure High Bile acid sequestrants Bind bile acids ?  Hepatic glucose production No hypoglycemia  LDL-C Gastrointestinal Modest  A1c Dosing frequency High Dopamine-2 agonists Activates DA receptor Alters hypothalamic control of metabolism  insulin sensitivity No hypoglyemia ?  CVD events Modest  A1c Dizziness, fatigue Nausea Rhinitis High SGLT2 inhibitors Inhibits SGLT2 in proximal nephron Increases glucosuria  Weight No hypoglycemia  BP Effective at all stages GU infections Polyuria Volume depletion  LDL-C  Cr (transient) High Table 1. Properties of anti-hyperglycemic agents Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

71. Case study : Jay 72 Jay is a middle aged businessman and a father of 2 school age children He has been diagnosed with Type 2 Diabetes and has been on metformin (maximum tolerated dose) for about 12 months H e tries to lead a healthy lifestyle and manage his diabetes Despite his best efforts, his HbA1c has recently increased from 7.5% to 8.1 % and he has gained some weight His BMI is 30 kg/m 2 His recent eGFR is 110 mL/min/1.73 m 2 His friend is also affected by Type 2 Diabetes and suffers from frequent hypoglycaemic episodes, which makes it a concern for him. What’s next?

72. ADA/EASD position statement 2015 Met + Insulin (MDI ) or GLP-1 RA MDI, multiple daily injections; DPP-4i, dipeptidyl peptidase-4 inhibitor; GLP-1RA, glucagon-like peptide-1 receptor agonist; SU, sulphonylurea ; TZD, thiazolidinedione Healthy eating, weight control, increased physical activity Not at target HbA 1c after ~3 months Two-drug combinations Three-drug combinations Metformin SU + TZD DPP-4i GLP-1RA Insulin TZD + SU DPP-4i GLP-1RA Insulin DPP-4i +SU TZD SGLT2i GLP-1RA SGLT2i +TZD DPP-4i GLP-1RA + SU TZD Insulin More complex strategies Initial monotherapy Not at target HbA 1c after 3-6 months combination therapy with insulin Not at target HbA 1c after ~3 months Insulin +SU TZD DPP4i DPP-4i When the goal is avoid hypoglycemia GLP-1RA TZD SGLT2i

73. ADA/EASD position statement 2015 Met + Insulin (MDI ) or GLP-1 RA MDI, multiple daily injections; DPP-4i, dipeptidyl peptidase-4 inhibitor; GLP-1RA, glucagon-like peptide-1 receptor agonist; SU, sulphonylurea ; TZD, thiazolidinedione Healthy eating, weight control, increased physical activity Not at target HbA 1c after ~3 months Two-drug combinations Three-drug combinations Metformin SU + TZD DPP-4i GLP-1RA Insulin TZD +SU DPP-4i GLP-1RA Insulin DPP-4i +SU TZD SGLT2i GLP-1RA SGLT2i +TZD DPP-4i GLP-1RA + SU TZD Insulin More complex strategies Initial monotherapy Not at target HbA 1c after 3-6 months combination therapy with insulin Not at target HbA 1c after ~3 months Insulin +SU TZD DPP4i DPP-4i When the goal is avoid hypoglycemia & weight gain GLP-1RA SGLT2i

74. ADA/EASD position statement 2015 Met + Insulin (MDI ) or GLP-1 RA MDI, multiple daily injections; DPP-4i, dipeptidyl peptidase-4 inhibitor; GLP-1RA, glucagon-like peptide-1 receptor agonist; SU, sulphonylurea; TZD, thiazolidinedione Healthy eating, weight control, increased physical activity Not at target HbA 1c after ~3 months Two-drug combinations Three-drug combinations Metformin SU + TZD DPP-4i GLP-1RA Insulin TZD + SU DPP-4i GLP-1RA Insulin DPP-4i +SU TZD SGLT2i GLP-1RA SGLT2i +TZD DPP-4i GLP-1RA + SU TZD Insulin More complex strategies Initial monotherapy Not at target HbA 1c after 3-6 months combination therapy with insulin Not at target HbA 1c after ~3 months Insulin +SU TZD DPP4i DPP-4i When the goal is avoid hypoglycemia & weight gain with an oral anti-diabetic drug SGLT2i

75. ADA/EASD position statement 2015 Met + Insulin (MDI ) or GLP-1 RA MDI, multiple daily injections; DPP-4i, dipeptidyl peptidase-4 inhibitor; GLP-1RA, glucagon-like peptide-1 receptor agonist; SU, sulphonylurea; TZD, thiazolidinedione Healthy eating, weight control, increased physical activity Not at target HbA 1c after ~3 months Two-drug combinations Three-drug combinations Metformin SU + TZD DPP-4i GLP-1RA Insulin TZD + SU DPP-4i GLP-1RA Insulin DPP-4i +SU TZD SGLT2i GLP-1RA SGLT2i +TZD DPP-4i GLP-1RA + SU TZD Insulin More complex strategies Initial monotherapy Not at target HbA 1c after 3-6 months combination therapy with insulin Not at target HbA 1c after ~3 months Insulin +SU TZD DPP4i DPP-4i When the goal is to avoid hypoglycemia with the added benefit of weight loss with an OAD SGLT2i DPP-4i

76. ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, 2015 3. ANTI-HYPERGLYCEMIC THERAPY Therapeutic option s: Insulins Human Insulins - Neutral protamine Hagedorn (NPH ) - Regular human insulin - Pre-mixed formulations Insulin Analogues - Basal analogues ( glargine , detemir , degludec ) - Rapid analogues ( lispro , aspart , glulisine ) - Pre-mixed formulations Diabetes Care 2012;35:1364– 1379; Diabetologia 2012;55:1577– 1596 Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

77. ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, 2015 Long ( Detemir ) Rapid (Lispro, Aspart, Glulisine) Hours Long (Glargine) 0 2 4 6 8 10 12 14 16 18 20 22 24 Short (Regular) Hours after injection Insulin level ( Degludec ) 3. ANTI-HYPERGLYCEMIC THERAPY Therapeutic option s: Insulins

78. When and why to start Absolute indications All type 1 DM Diabetic Ketoacidosis Serious infections During and after major surgery Pregnancy Failure to achieve control with 2 or 3 OHAs HbA1C >10 Kidney disease and liver disease Acute stroke ,MI

79. When and why to start Relative indications Micro and macrovascular complications Underweight or losing weight without dieting Symptoms from blood sugar >200mg/dl Any hospitalised patients On high dose steroids Onset of DM prior to 30 years or duration over 15 years

80. Why to start All type 1 DM Destruction of beta cells and absolute insulin defeciency Ketoacidosis Absolute or relative insulin deficiency ↑ counter regulatory hormones ↑ hepatic gluconeogeneis ,glycolysis &lipolysis lipid metabolised in liver  ketones Serious infections Gram – ve LPS  Insulin resistance Unable to ↑ endogenous insulin production Can precipitate DKA & HHS Insulin also prevents dehydration

81. Why to start During and after major surgery Metabolic stress response ↓ Insulin secretion ↑insulin resistance Excessive catabolic state Can precipitate DKA or HHS Pregnancy Teratogenecity Cross placenta  fetal hyperinsulinemia  macrosomia and fetal hypoglycemia Postprandial plasma glucose not addressed

82. Why to start Failure to achieve control with 2 or 3 OADDs ↓ β cell function  secondary failure HbA1C >10 , HbA1C>7.5 + FBS>250mg/dl ↓ glucotoxicity  β cell ,and on end organs Insulin can normalise any level of A1c Kidney and liver failure Metformin  acidosis Sulfonylureas  unpredictable can cause hypoglycemia OHAs Contraindicated in liver failure

83. Figure 3. Approach to starting & adjusting insulin in T2DM Diabetes Care 2015;38: 140-149; Diabetologia 2015;58:429-442

84. Figure 3. Approach to starting & adjusting insulin in T2DM Diabetes Care 2015;38: 140-149; Diabetologia 2015;58:429-442

85. Figure 3. Approach to starting & adjusting insulin in T2DM Diabetes Care 2015;38: 140-149; Diabetologia 2015;58:429-442

86. Implications to clinical practice 87

87. EMPA-REG OUTCOME ® : Empagliflozin in 1000 type 2 diabetes on top of standard of care leads to… Based on 1000 T2D patients receiving empagliflozin on top of standard of care for 3 years 88 Risks Benefits

88. 4. OTHER CONSIDERATIONS Age Weight Sex / racial / ethnic / genetic differences Comorbidities Coronary artery disease Heart Failure Chronic kidney disease Liver dysfunction Hypoglycemia-prone ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, 2015 Diabetes Care 2012;35:1364– 1379; Diabetologia 2012;55:1577– 1596

89. What is the individualised approach to treatment ? 90 “ Right treatment for the right patient at the right time ”

90. Type 2 diabetes: selection of glycaemic targets and glucose-lowering treatments S hould be individualised on the basis of patient specific factors age, stage of diabetes, c ardiovascular risk factors, weight, risk associated with hypoglycaemia and of effects on multiple pathophysiological aspects of type 2 diabetes”. DeFronzo RA Diabetes 2009 , 58:773–795 91

91. Combination Therapy of Oral Anti-diabetic Drugs Inzucchi SE, et al. Diabetes Care . 2012;35(6):1364-1379. 92 ADA/EASD Algorithm for Management of T2DM 2015 Efficacy Hypoglycaemia Weight Side Effects Cost Selection of agents are based on Agents that reduce insulin resistance without affecting body weight are already well-defined in the guideline

92. Sequential Insulin Strategies in T2DM Diabetes Care, Diabetologia. 19 April 2012

93. Insulin Therapy: Does not Depend on Phenotype ADA . Diabetes Care 2013;36(1):S11-S66. 94 High HbA1c and severe hyperglycaemic symptoms guide insulin initiation and not the phenotype

94. ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTHER CONSIDERATIONS Age Weight Sex / racial / ethnic / genetic differences Comorbidities Coronary artery disease Heart Failure Chronic kidney disease Liver dysfunction Hypoglycemia Diabetes Care, Diabetologia. 19 April 2012

95. ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTHER CONSIDERATIONS Age: Older adults Reduced life expectancy Higher CVD burden Reduced GFR At risk for adverse events from polypharmacy More likely to be compromised from hypoglycemia Less ambitious targets HbA1c <7.5–8.0% if tighter targets not easily achieved Focus on drug safety Diabetes Care, Diabetologia. 19 April 2012

96. ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTHER CONSIDERATIONS Weight Majority of T2DM patients overweight / obese Intensive lifestyle program Metformin GLP-1 receptor agonists ? Bariatric surgery Consider LADA in lean patients Diabetes Care, Diabetologia. 19 April 2012

97. ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTHER CONSIDERATIONS Sex/ethnic/racial/genetic differences Little is known MODY & other monogenic forms of diabetes Latinos: more insulin resistance East Asians: more beta cell dysfunction Gender may drive concerns about adverse effects (e.g., bone loss from TZDs ) Diabetes Care, Diabetologia. 19 April 2012

98. ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTHER CONSIDERATIONS Comorbidities Coronary Disease Heart Failure Renal disease Liver dysfunction Hypoglycemia Metformin: CVD benefit (UKPDS) Avoid hypoglycemia ? SUs & ischemic preconditioning ? Pioglitazone &  CVD events ? Effects of incretin -based therapies Diabetes Care, Diabetologia. 19 April 2012

99. ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTHER CONSIDERATIONS Comorbidities Coronary Disease Heart Failure Renal disease Liver dysfunction Hypoglycemia Metformin: May use unless condition is unstable or severe Avoid TZDs ? Effects of incretin-based therapies Diabetes Care, Diabetologia. 19 April 2012

100. ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTHER CONSIDERATIONS Comorbidities Coronary Disease Heart Failure Renal disease Liver dysfunction Hypoglycemia Increased risk of hypoglycemia Metformin & lactic acidosis US: stop @SCr ≥ 1.5 (1.4 women) UK:  dose @GFR <45 & stop @GFR <30 Caution with SUs (esp. glyburide) DPP-4-i’s – dose adjust for most Avoid exenatide if GFR <30 Diabetes Care, Diabetologia. 19 April 2012

101. ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTHER CONSIDERATIONS Comorbidities Coronary Disease Heart Failure Renal disease Liver dysfunction Hypoglycemia Most drugs not tested in advanced liver disease Pioglitazone may help steatosis Insulin best option if disease severe Diabetes Care, Diabetologia. 19 April 2012

102. ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. OTHER CONSIDERATIONS Comorbidities Coronary Disease Heart Failure Renal disease Liver dysfunction Hypoglycemia Emerging concerns regarding association with increased mortality Proper drug selection in the hypoglycemia prone Diabetes Care, Diabetologia. 19 April 2012

103. ADA-EASD Position Statement: Management of Hyperglycemia in T2DM 4. FUTURE DIRECTIONS / RESEARCH NEEDS Comparative effectiveness research Focus on important clinical outcomes Contributions of genomic research Perpetual need for clinical judgment! Diabetes Care, Diabetologia. 19 April 2012

104. 4. FUTURE DIRECTIONS / RESEARCH NEEDS Comparative effectiveness research Focus on important clinical outcomes Contributions of genomic research Perpetual need for clinical judgment! ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, 2015 Diabetes Care 2012;35:1364– 1379; Diabetologia 2012;55:1577– 1596

105. Glycemic targets & BG-lowering therapies must be individualized , based on a variety of patient and disease characteristics . Diet, exercise, & education : foundation of any T2DM therapy program. Unless contraindicated, metformin remains the optimal first- line drug. After metformin, data are limited. Combination therapy with 1-2 other oral / injectable agents is reasonable. Try to minimize side effects. Ultimately, many patients will require insulin therapy alone or in combination with other agents to maintain BG control. All treatment decisions should be made in conjunction with the patient ( focusing on his or her preferences , needs & values.) Comprehensive CV risk reduction - a major focus of therapy. ADA-EASD Position Statement Update: Management of Hyperglycemia in T2DM, 2015 KEY POINTS Diabetes Care 2012;35:1364– 1379; Diabetologia 2012;55:1577– 1596 Diabetes Care 2015;38:140-149; Diabetologia 2015;58:429-442

106. Thank you