Disclosures SUCCESFUL INSULIN THERAPY DISCOVERY OF INSULIN 9/28/2017 THE HORROR OF DIABETES

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1 Disclosures Innovations in the Treatment of Diabetes Dennis G. Karounos, M.D. Associate Professor of Internal Medicine, Immunology, Physiology, Graduate Center of Nutrition UKMC & VAMC Grants/research supported by: NIH, Department of Veterans Affairs, Novo Nordisk A/S, Eli Lilly, Amylin Pharmaceuticals, Astra/Zenaca, Bristol-Myer Squib, Peptor Ltd, Diamyd, Osiris, Spherix Consultant: Viacyte Objectives 1. Discuss new therapies of diabetes 2. Report on the development of an artificial pancreas 3. Review strategies to prevent diabetes THE HORROR OF DIABETES Pre-Insulin Era: 50% Children die within 1yr of diagnosis Case Presentation: J.L. age 3, Weight 15# dehydration, emaciation (Dec. 15, 1922) Treatment options Starvation therapy Insulin DISCOVERY OF INSULIN SUCCESFUL INSULIN THERAPY Dr. Frederick Banting & Charles Best (medical student) Bantings Plan: ligate pancreatic duct... isolate internal secretion (of islet)... to relieve glycosuria Notebook with experimental idea Oct. 31, days after insulin therapy, Jan Wt. Increased to 29 # JAMA Feb. 15,

2 Growing Prevalence of Diabetes 2016 National Diabetes Fact Sheet, CDC (current) 29 million (7.8% population) 25% undiagnosed 86 million w/ prediabetes Age > 65 yrs: 21.5% Year 2050: 1:3 Americans with diabetes 33% with diabetes!!!!! 2016 CDC Diabetes Fact Sheet Source: DANGEROUS TOLL: Diabetes in Kentucky Over 424,670 (12.5%) adult Kentuckians have diabetes (national rate 8.1%) nearly doubled from 2000 to 2014 Kentucky ranked in the top 10 in US (unfortunately we are not talking about basketball) An additional 138,000 are undiagnosed CDC estimates that 1.1 million adults in KY have prediabetes (37%, 1 in 3) DM is seventh leading cause of death in Kentucky Source: Kentucky Cabinet for Health and Family Services Etiologic Classification Type 1 diabetes Immune mediated Idiopathic Latent Autoimmune Diabetes of Adults Type 2 diabetes Other specific types Genetic defects of beta cell Genetic defects in insulin action Endocrinopathies Gestational diabetes T1DM Pathogenesis: chronic autoimmune disease Insulitis: Lymphocytic Infiltration & Destruction of Islets in Type 1 Diabetes resulting in severe insulin deficiency Normal Islet Insulitis: arrow marks the ENEMY location Pre-diabetes in Type 1 Diabetes Plasma glucose level and oral glucose tolerance test are normal Decrease insulin secretion when measured with an intravenous glucose tolerance test Islet cell antibodies are detected: GAD antibodies, ICA512, & Insulin autoantibodies (miaa) Candidates for Diabetes Prevention Trials 2010 Criteria for Diagnosis of Diabetes 1. A1C 6.5%. The test should be performed in a laboratory using a method that is NGSP certified and standardized to the DCCT assay.* OR 2. FPG 126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at least 8 h.* OR 3. Two-hour plasma glucose 200 mg/dl (11.1 mmol/l) during an OGTT. The test should be performed as described by the World Health Organization, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.* OR 4. In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose 200 mg/dl (11.1 mmol/l). *In the absence of unequivocal hyperglycemia, criteria 1-3 should be confirmed by repeat testing Source: American Diabetes Assoc. 2

3 Objective 1: Discuss new therapies of diabetes Late-stage Investigational: - Basal Insulins - Rapid Acting Insulins Islet Implants Artificial Pancreas A-CHAIN Gly SUBSTITUTION Asn B-CHAIN EXTENSION Arg Arg Newly approved: -Basal Insulins -Degludec -U-300 glargine insulin A-CHAIN Asn SUBSTITUTION B-CHAIN Gly EXTENSION Arg Arg Basal Insulin: Mechanism for Prolongation of Action: - Decrease solubility: protamine (NPH) or zinc: (UL) variable absorption - ph dependent precipitation (glargine) - Local albumin binding (detemir)-<24h duration - Multiple hexamer complexes but Gly soluble (degludec) Asn Arg Basal Insulins: : Basal Insulin Degludec Multiple Highly Complexed Hexamers New/ Investigational Basal Insulins Insulin lispro protamine suspension (ILPS) Pegylated insulin lispro ((LY )* Administration Status Peak Effective Duration QD or BID Approved 3 h 24 h outside USA < once daily Phase 3 Peakless h Degludec (NN1250) QD or 3x/wk FDA Approval 2015 Peakless >24 h *Bergenstal et al: Diabetes Care (2012) 35: Five ongoing Phase 3 IMAGINE trials T1DM/T2DM Gly Asn Arg Jonassen et al: Pharm Res (2012) 29:

4 : Basal Insulin Degludec -similar glycemic control -decreased nocturnal hypoglycemia Basal Insulin Degludec -similar glycemic control -decreased nocturnal hypoglycemia FDA Approval: Sep 2015: - degludec (Tresiba) & degludec/aspart 70/30 (Ryzodeg) Heller et al: Lancet (2012) 379:1494 FDA.gov Late-stage Investigational: -Ultra-Rapid Acting Insulins Ultra-Rapid Acting Insulins: Formulations to accelerate effect: - EDTA Zn chelation(decrease hexamers - Citrate masks charge (BIOD-238 & BIOD-250) - Hyaluronidases increase dispersion & absortpion - Nicotinamide+Arginine (FIAsp) Are New Basal Insulins Better? Are New Meal-time Insulins Better? Ultra-long-acting Basal Insulin - Evidence of reduced nocturnal hypoglycemia and decreased weight gain at comparable A1c lowering - Large phase 3 clinical trials underway to confirm hepatic and cardiovascular safety - Concentrated formulations (U-200, U-300) so reduced volume of administration Ultra-rapid-acting Bolus Insulin - Evidence for reduced postprandial hyperglycemia and potentially more convenient dosing - Larger phase 2 and 3 clinical trials underway to confirm efficacy, site tolerability and cardiovascular safety Ratner, RE: American Diabetes Association, Alexandria, VA 4

5 Islet Transplantation for Hypoglycemia Unawareness/Severe Hypoglcemia Islet Implants David M. Harlan Dia Care 2016;39: Caveat Emptor Pros - Improved glycemic control > 2yrs - Some with insulin indepencence (~40%) - Less traumatic procedure than whole pancreas transplant Cons - Procedure-related bleeds - Immunosupressionrelated complications (e.g. renal) - Malignancy risk - Cost - Most still require insulin - No clear survival benefit - Limited islet supply Islet Implants Chamber system for macroencapsulation of islets. Ludwig B et al. PNAS 2013;110: by National Academy of Sciences Islet Implants Bioartificial pancreas for transplantation without immunosuppression Islets isolated from donor pancreas Persistent graft function for ten months (stimulated C-peptide from 0.04 to 0.8 nmol/l) Improvement in A1c with reduction in insulin requirements (52 units to 43 units) Oxygen replenished by daily sc injection via oxygen port Stem cell-derived Islet Implants Bio-artificial pancreas for transplantation without immunosuppression Islet derived from embryonic stem cells- culture conditions optimized 5

6 Islet Implants: Macroencapsulation Bioartificial pancreas for transplantation without immunosuppression Xenotransplantation: Encapsulated porcine islets in patient with T1DM Long-term viability & function of transplanted encapsulated neonatal porcine islets Clinical trials underway 2017: Sentinel impants for safety & implant viability studies: sites: UCSD & U Alberta Xenotransplantation: Microencapsulation Encapsulated porcine islets in patient with T1DM Xenotransplantation: Encapsulated porcine islets in patient with T1DM 2016 Omentum embedded islet nodules: Insulin stain Glucagon stain Long-term viability & function of transplanted encapsulated neonatal porcine islets Long-term viability & function of transplanted encapsulated neonatal porcine islets Xenotransplantation: Encapsulated porcine islets in patient with T1DM 2016 Can Insulin be delivered by a pump? Long-term viability & function of transplanted encapsulated neonatal porcine islets 2 groups of 4 patients each 10,000 islets 20,000 islets First insulin pump - Dr. Arnold Kadish, - Los Angelos, CA

7 Artificial Pancreas - Closed-loop prototypes - Bihormonal therapy (glucagon/insulin) Closed-loop Prototypes: Inpatient & Outpatient Clinic Trials Artificial Pancreas Artificial Pancreas Atkinson et al: Type 1 Diabetes Lancet (2014) 383:69-82 Integrated-closed loop delivery vs conventional insulin pump therapy: closed loop delivery improved overnight control Reduced nocturnal hypoglycemia Tested in closely supervised clinical research facility setting including bihormonal closed-loop system (glucagon/insulin) Also tested ambulatory closed-loop protoype closely-monitored at patient s home in free-living conditions Garg et al: Diabetes Technol. Ther (2012) 14:205-9 Buckingham et al: Diabetes Care (2010) 33: Thabit et al: Curr Opin Endocr Diab Obes (2014) 21(2) Clinical Trials of Hybrid Closed-loop Insulin Delivery Clinical Trials of Hybrid Closed-loop Insulin Delivery Method: - 12 adolescents, two 7 day periods of sensor-augmented insulin pump therapy - Gender (M/F): 8/4 - Age: HbA1c: Duration on pump (years): Total daily insulin: Results: Sensor glucose in target range: - 72% of time Close-loop - vs 53% control period - Mean glucose: 9.4 vs 10.3 mmol/l (169 vs 185 mg/dl) Conclusions: - Unsupervised, day-andnight hybrid closed loop insulin delivery at home is feasible and safe Tauschman et al Diabetes Care 2016 Clinical trial reg. no. NCT : Clinical trial reg. no. NCT : 7

8 Hybrid Closed-loop Insulin Pump Medtronic MiniMed 670G/ Enlite 3 hybrid Closed Loop System - Clinical trial results: single-arm, multi-center home & hotel clinical investigation June 2015-May 2016 Gray: Run-In Red: Study closed loop Hybrid Closed-loop Insulin Pump Medtronic MiniMed 670G/ Enlite 3 hybrid Closed Loop System - Clinical trial results: single-arm, multi-center home & hotel clinical investigation June 2015-May % reduction in hypoglycemia (<70 mg/dl) 40% decline in glucose < 50 mg/dl 0.5% improvement in HbA1c 11% decline in time glucose > 180mg/dl ClinicalTrials.gov Identifier: NCT ClinicalTrials.gov Identifier: NCT First Artificial Pancreas approved by FDA Artificial Pancreas Prototype: Bigfoot Biomedical Pre-filled insulin cartridge Mobile app on smartphone acts as controller & user interface Dexcom G5 CGM glucose sensor Innovative Smart Insulin" Patch PNAS 112: New Technology Blinded Continuous Glucose SensorAbbott s FreeStyle Libre Pro - Approved by FDA - Applied in healthcare providers office - Worn for 2 weeks - Real-time version under FDA review 8

9 New Technology Sensor for carb content - & smart scale for serving size: Long-term Biosensor for continuous monitoring of body chemistry Pathophysiology of Insulin Resistance and Type 2 Diabetes Causes of Hyperglycemia in Type 2 Diabetes C Smoking and Diabetes: Why is there so much diabetes in Kentucky? Physicians Health Study >20 cigarettes/day RR Diabetes > 2 fold cigarettes/d RR Diabetes 1.5 fold Increased Gestational Diabetes in women who smoke Nicotine causes insulin resistance American Journal of Medicine 109(7):538, Am J Epidemiol Dec 15;160(12): How Is Smoking Related to Diabetes? smoking causes type 2 diabetes the more cigarettes you smoke, the higher your risk for type 2 diabetes smoking makes your diabetes harder to control smokers with diabetes have higher risks for serious complications Source: Intensive Therapy A1c goal: <6% The VADT Trial Study Randomization Older individuals with T2DM 1792 Primary Outcomes: Major CV events Amputation Interventions for CAD, PVD Conventional Therapy A1c goal: 8-9% Result: no difference in Major CV between Intensive and Conventional Therapy Groups 9

10 Clinical Implications: T2DM CV Trials Clinical Implications: T2DM CV Trials Control of non-glucose risk factors especially HDL reduce CV events in patients with Type 2 DM. Appropriate management of hypertension, dyslipidemia and other CV risk factors appears to be most effective at reducing cardiovascular morbidity and mortality in individuals with long-standing type 2 diabetes Intensive glucose control is beneficial if begun soon after diagnosis, but may be detrimental in long established Type 2 DM. Severe hypoglycemia is associated with an increase in CV events. Treat To Target: Clinical Inertia Objective 3: Identify current research for the prevention of diabetes Esposito et al: New guidelines for metabolic targets in diabetes Endocrine (2014) doi: /s Path to Type 1 Diabetes Genetic Risk Immune Activation Stage 1 Stage 2 Stage 3 Post- Diagnosis Normal Abnormal Clinical Blood Sugar Blood Sugar diagnosis > 2 Autoantibodies > 2 Autoantibodies > 2 Autoantibodies Battaglia et al: Understanding & Preventing T1DM through the unique working model of TrialNet. Diabetologia

11 TrialNet Sites Clinical Trials to Prevent Diabetes: Type 1 Diabetes TrialNet Study Group Conducting studies to: Test family members of people with type 1 diabetes to determine their risk to develop type 1. Learn more about common risk factors among people who develop type 1 diabetes. Test treatments that could delay or prevent onset of type 1 diabetes. Test treatments that might help people who have recently been diagnosed keep producing their own insulin. TrialNet Studies 1. Studies for people who do not have type 1 diabetes, but are at increased risk because they have a family member with the disease 2. Studies for those recently diagnosed with type 1 diabetes (within 100 days) 3. Studies for participants previously enrolled in TrialNet Studies TrialNet Studies 1. Natural History Study (TN01): Studies for people who do not have type 1 diabetes, but are at increased risk because they have a family member with the disease Over 178,648 relatives screened (as of ) Positive for one autoantibody: 3,273 Positive for 2 or > autoantibodies: 4,888 Progressed to T1DM: 835 Battaglia et al Diabetologia, 2017 TrialNet Interventions New-Onset Diabetes Anti-CD3 (via ITN collaboration) Mycophenolate Mofetil +/- Anti-CD25 Anti-CD20 Anti-CD3 +/- Exenatide Thymoglobulin (via ITN collaboration) IL-2 plus Sirolimus Phase 1 Safety Study (together with ITN) Current TrialNet Studies Pathway to Prevention Study: UK is a site please refer any first degree relative of person with type 1 diabetes to be screened - Call (859) D. Karounos, PI Anti-CD3 mab (Teplizumab) for Prevention Of Diabetes In Relatives At Risk For Type 1 Diabetes Mellitus CTLA4-Ig (Abatacept) for Prevention of Type 1 Diabetes in Relatives At-Risk 11

12 Summary Diabetes Research Group Immune therapy of diabetes will likely involve treatment with multiple agents to try to prevent destruction of islets New ultra-fast and ultra-long acting insulins will improve the therapy of diabetes Glucose sensors and insulin delivery devices now provide us with closed-loop insulin-delivery systems Dennis G. Karounos, M.D. Collaborators: - J. Scott Bryson, Ph.D. - David Randall, Ph.D. - L. Ray Reynolds, M.D. - Nicole C. Dombroski, D.O. - Derick Adams, D.O. - Matt Hager, M.D. - Robert Lodder, Ph.D. Research Coordinators: Ruth Oremus Lyndsey Dye 12