© 2013 Eli Lilly and Company Managing insulin therapy in Insulin resistance Speaker name and affiliation Prescribing information is available on the last slide. © 2013 Eli Lilly and Company UKDBT01534 September 2013

Company Confidential © 2012 Eli Lilly and Company © 2013 Eli Lilly and Company Back to Basics  What are the clinical indications for insulin therapy in Type 2 diabetes?  Types of insulin at initiation – What are the clinical characteristics of a basal pt – What are the clinical characteristics of a mixture patient – How do you determine regime at initiation – Does one size fit all ?? – Initial regime is vital.... Wrong insulin wrong time and place..... May contribute to insulin resistance. 2

Company Confidential © 2012 Eli Lilly and Company © 2013 Eli Lilly and Company Back to Basics What does insulin do??  Released 1 st acute phase lasts a few minutes followed by a sustained second phrase 1  Increases glucose uptake at cell level by transporting glucose across cell membrane 1  Decreases Glycogenolysis (Glycogen breakdown)  Decreases gluconeogenisis (production of new glucose)  Decreases lipolysis (fat breakdown)  Insulin binds to cell surface receptor  Insulin has many functions primary function is to lower blood glucose level 3 1. Bilous R & Donnelly R 2010, 28:Handbook of diabetes

Company Confidential © 2012 Eli Lilly and Company © 2013 Eli Lilly and Company What is insulin resistance  Defined as early as  Effect on glucose uptake and utilisation that defines insulin resistance 1  The development of insulin resistance is seen as the core defect for the development of type 2 diabetes 2  Insulin resistance + deficient beta cell function = Type 2 diabetes Lebovitz H.E Insulin resistance :definition and consequences: Endocrinology and diabetes 2001 S Schofield & Sutherland 2012 Disordered insulin secretion in the development of insulin resistance and Type 2 diabetes: Diabetic medicine 2012: 1464

Company Confidential © 2012 Eli Lilly and Company © 2013 Eli Lilly and Company The underlying defects: Insulin resistance and  -cell dysfunction 5 5. Ramlo-Halsted BA, et al. Prim Care 1999;26:771–789. Impaired Insulin Production & Secretion Insulin Resistance (IR) - Hyperinsulinaemia - Normal Glucose Tolerance IR + Declining Insulin Levels + Impaired Glucose Tolerance - Failure of β -Cell to Adapt to IR Impaired Responsiveness to Insulin ↑FFA Levels Sedentary Lifestyle Diet Obesity Type 2 Diabetes Glucotoxicity  -Cell Dysfunction Genetic Predispositions

Company Confidential © 2012 Eli Lilly and Company © 2013 Eli Lilly and Company Pathophysiology of type 2 diabetes involves three core defects and multiple organ systems 6 Inzucchi SE. JAMA 2002; 287: 360–372 HYPERGLYCAEMIA Insulin resistance 1. Peripheral tissues Decreased glucose uptake Increased lipolysis 2. Liver Increased glucose production 2. Liver Increased glucose production Combined islet cell dysfunction and insulin resistance 3. Pancreatic beta cells Decreased insulin secretion Pancreatic alpha cells Excessive glucagon secretion 3. Pancreatic beta cells Decreased insulin secretion Pancreatic alpha cells Excessive glucagon secretion Islet cell dysfunction

Company Confidential © 2012 Eli Lilly and Company © 2013 Eli Lilly and Company Insulin resistance and insulin hypersecretion precede type 2 diabetes 7 Adapted from: Beck-Nielsen H, Groop LC. J Clin Invest 1994; 94: 1714–1721. Insulin Insulin Macrovascular secretion resistance disease (+) IGT Impaired glucose metabolism Normal glucose metabolism Type 2 diabetes

Company Confidential © 2012 Eli Lilly and Company © 2013 Eli Lilly and Company What are the clinical characteristics of an insulin resistant patient?  Central obesity 1  Insulin dose >1 unit /kg in weight 1  Continued hyperglycaemia despite increasing insulin doses 1  Weight gain on insulin therapy 1  Hypertension 2  Hyperlipidaemia (especially triglycerides) 2  Increased cvd risk W Crasto et al Insulin U-500 in severe insulin resistance in type 2diabetes mellitus 2.G Reaven; Role of Insulin resistance in human disease (syndrome x): An expanded definition.

Company Confidential © 2012 Eli Lilly and Company © 2013 Eli Lilly and Company Potential causes of Insulin resistance  Central obesity/ visceral adiposity 1  Genetic abnormalities in insulin action cascade 1  Decreased physical activity 1  Foetal malnutrition 1  Exogenous causes 1 – Pregnancy – Cushings – Acromegaly – Polycystic ovaries – Smoking Lebovitz H.E Insulin resistance :definition and consequences: Endocrinology and diabetes 2001 S Evans & Krentz: 2000:Insulin resistance and beta cell dysfunction as therapeutic targets in Type 2 diabetes Diabetes. Obesity and Metabolism, 3, 2001, leading to increase in counter regulatory hormones

Company Confidential © 2012 Eli Lilly and Company © 2013 Eli Lilly and Company Measuring insulin resistance  HOMA ir  All techniques used to measure IR use the relationship between insulin and glucose uptake and utilisation  Homa assessment 1 – Steady state beta cell function (expressed % Bcf) – Insulin sensitivity (expressed % sensitvity) Fasting plasma glucose and fasting plasma insulin PTS MUST BE OFF EXOGENOUS INSULIN FOR 2 WEEKS

Company Confidential © 2012 Eli Lilly and Company © 2013 Eli Lilly and Company Monitoring Insulin Resistance Record progression of doses, weight gain and HbA1C 11  Consider concordance with insulin – Check number of pens or cartridges used  Use of discovery sheets – pre and post prandial monitoring DateInsulin Type and dose Units/kgHbA1Cweight

Company Confidential © 2012 Eli Lilly and Company © 2013 Eli Lilly and Company Treatment of Insulin Resistance in Type 2 diabetes  Lifestyle – Exercise Insulin sensitivity can be improved by exercise independently from weight reduction and changes in body composition 1 – Weight Loss – Consider low carb/low GI diet to reduce post prandial glucose excursions – Stop smoking 12  Pharmacology – Metformin 2 – Reduces effect of insulin resistance – Acarbose 2 – Acts mainly to reduce post prandial glucose excursion – Thiazolidinediones 2 – Increase insulin sensitivity – GLP1’S 2 – Potential for weight loss – Optimise insulin, ensure current regime targets problem blood glucose areas – Pump therapy 3 1. Matthaei S et al : Bailey C J Treating insulin resistance in type 2 diabetes with metformin and thiazolidinediones 7: ; W Crasto et al Insulin U-500 in severe insulin resistance in type 2diabetes mellitus 2009;85:

Company Confidential © 2012 Eli Lilly and Company © 2013 Eli Lilly and Company Treatment of Insulin Resistance in Type 2 diabetes cont  Optimise insulin therapy, ensure current regimen targets problem blood glucose areas  Assess pre and post prandial blood glucose levels  Simply increasing current insulin regime may not address poor control or insulin resistance 13

Company Confidential © 2012 Eli Lilly and Company © 2013 Eli Lilly and Company Conclusion  The development of insulin resistance is seen as the core defect for the development of type 2 diabetes  Treatment strategies need to address - Carbohydrate intake and load - Obesity, lack of physical activity, smoking cessation - Pharmacological interventions to improve insulin sensitivity - Optimising insulin therapy - A consideration of pump therapy 14

UKDBT01534 September 2013