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1990

Type 2 Differentiation of by Pathophysiology, LADA Natural History and TypeTyp 1 Prognosis LADA: Latent autoimmune diabetes in adults Diabetes prevalence 3%

Do we know what diabetes is? 2015 1921

Diagnosed by Type 2 ?? Diabetes mellitus measuring one metabolite- LADA

Type 1

Diabetes prevalence 0.1% Diabetes prevalence 7%

1960 Stages of Type 2 Diabetes 100

Adult Onset 75

50

Type 2 Diabetes 25 Phase III Type 2 Type 2 Postprandial IGT Diabetes Diabetes Phase I Phase II Juvenile 0 Onset –12 –10 –6 –2 0 2 6 10 14 Diabetes prevalence 1.5% Years From Diagnosis

Reprinted with permission from Lebovitz H. Diabetes Reviews. 1999;7:139

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Proposed Stage 1 Stage 2 Stage 3 Why Change the T1D Diagnostic Criteria? Nomenclature

Beta Cell Beta Cell Beta Cell  Provides a framework to inform benefit/risk evaluation Phenotypic Autoimmunity Autoimmunity Autoimmunity Characteristics Normoglycemia Dysglycemia Dysglycemia for regulatory, reimbursement, and clinical care with Presymptomatic Presymptomatic Symptomatic Phase in Natural interventions to prevent symptomatic T1D History  Improves the design of prevention trials  Catalyzes risk screening and increases enrollment in natural history and prevention clinical trials  Earlier diagnosis has current benefits – Decreased risk of DKA and hospitalization at diagnosis – Greater levels of residual functional beta cell mass at time of initiation of replacement may lead to long-term benefit

Early Stages of Type 1 Diabetes: + Diagnostic Criteria Environment Genes (e.g. vi ruses, microbiome, epigenetics, physical activity, dietary factors) Stage #1 Stage #2 Stage #3 Stage Autoimmunity Autoimmunity New Onset Normoglycemia Dysglycemia Symptomatic T1D Inflammation and autoimmunity Inflammation and metabolic stress Presymptomatic Presymptomatic

Beta Cell Destruction Beta Cell Dysfunction .Multiple AutoAbs .Dysglycemia: Impaired Glucose Hyperglycemia Tolerance and/or Diabetes (Type 1, Type 2, Other Forms) .Multiple AutoAbs • FPG ≥100 mg/dL or Complications Diagnostic .No impaired ≥110mg/dL .Clinical Symptoms Criteria glucose tolerance • OGTT: 2h PG ≥140mg/dL; 30, or impaired fasting 60, 90 min PG >200 mg/dL glucose • Random plasma glucose >200 mg/dL Microvascular Complications Macrovascular Complications • HbA1c >5.7%; >5.9% Retinopathy Coronary Artery Disease Nephropathy Periperal Arterial Disease • Increasing HbA1c (10%) Neuropathy Stroke 11

T1D incidence is Rising 3-5% per Year Islet Autoantibodies in T1D

Incidence /100,000/ yr in children 0-14 yr 1st generation assays 60 Finland Insulin autoantibodies 50 ICA

40 Sweden

30 Colorado 2nd generation (RIA, ELISA) ZnT8A IA-2A GADA mIAA 20 Germany Poland 10 33rdrdgenerationgeneration ECL ECL-IA-2A ECL-GADA ECL-IAA ElectroChemiLuminescent(ECL, etc. ) 0 1950 1960 1970 1980 1990 2000

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Progression to Stage 3 Symptomatic T1D in At-Risk Children HbA1c increases prior to diagnosis in children Stratified for Number of Islet Autoantibodies with multiple islet autoantibodies.

100 (0)

(1) 80

No. of islet autoantibodies 60 None 1 Islet ibts(%) diabetes 40 2 Islet 3 Islet Proportion without type type 1 Proportionwithout 20 (2)

0 (3)

0 5 10 15 20 No. of events Islet autoantibodies, No. Age (years) 3 Islet 358 250 112 20 2 Islet 227 168 82 19 1 1 Islet 474 430 272 118 9 None 12318 8875 5253 1161 44

JAMA. 2013;309(23):2473-2479 Olli Helminen et al. Diabetes 2015;64:1719-1727

Impact of age on risk for disease progression in antibody-positive relatives participating in TrialNet Pathway to Prevention Study Type 1 Diabetes Risk Screening: Stage 1 to Stage 3 Stage 2 to Stage 3 Screening for Stage 1

. Relatives: Adults, Children (TrialNet) >20yrs . Universal Childhood Screening >20yrs • 15-19yrs HLA risk screening at birth followed by screening for multiple islet autoantibodies in

10-14yrs HLA at-risk cohort (TEDDY) <5yrs 15-19yrs 10-14yrs 5-9yrs 5-9yrs • Universal screening for multiple islet autoantibodies of population-based young children (FR1DA )

Diane K. Wherrett et al. Dia Care 2015;38:1975-1985 17

Many Type 1 Diabetes Preventions Variables Affecting Rate of Progression from Have Been Successul in NOD Mice Stage 1 to Stage 3

AAV murine IL-10 Gonadectomy AAV rat preproinsulin gene (vLP-1) Mycobacterium avium Guanidinoethyldisulphide Adenovirus expressing mIL-4 Mycobacterium leprae Heat shock protein 65 Aerosol insulin Natural antibodies Heat shock protein peptide (p277) Allogenic thymic macrophages Natural polyreactive autoantibodies Hematopoietic stem cells encoding proinsulin Alpha Galactosylceramide Neuropeptide calcitonin gene-related peptide Housing alone Alpha-interferon (rIFN-alpha) Nicotinamide Human IGF-1 Alpha/beta T cell receptor thymocytes Nicotine . Aminoguanidine I-A beta g7(54-76) peptide Ninjin-to (Ren-Shen-Tang), a Kampo (Japanese traditional) formulation Number of autoantibodies Anti-I-A monoclonal antibodies Androgens NKT cells Anti-ICAM-1 Anesthesia NY4.2 cells IgG2a antibodies Antioxidant MDL 29,311 OK432 Immobilization Antisense GAD mRNA Overcrowding Inomide Azathioprine Pancreatectomy Anti-integrin alpha 4 Anti-B7-1 Pentoxifylline Insulin (intraperitoneal, oral, subcutaneous, nasal) Bacille Calmette Gue’rin (BCG) Pertussigen Insulin B chain (plasmid) Baclofen Poly [I:C] Insulin B chain/B chain amino acids 9-23 (intraperitoneal, oral, subcutaneous, nasal) Bee venom Pregestimil diet . Insulin-like growth factor I (IGF-I) Autoantibody specificities Biolistic-mediated IL-4 Prenatal stress Anti-intercellular adhesion molecule-1 (ICAM-1) Blocking peptide of MHC class II Preproinsulin DNA Bone marrow transplantation Interferon-alpha (oral) Probucol Interferon-gamma Castration Prolactin Anti-CD3 Anti-interferon-gamma Rampamycin Interferon-gamma receptor/IgG1 fusion protein Anti-CD4 Recombinant vaccinia virus expressing GAD CD4+CD25+regulatory T cells Interleukin-1 Reg protein Interleukin-4 Anti-CD8 Reg protein Anti-CD28 MAb Interleukin-4-Ig fusion protein Rolipram Interleukin-4-plasmid . Cholera toxin B subunit-insulin protein Saline (repeated injection) Autoantibody titer Interleukin-10 Class I derived self-I-A beta(g7) (54-76) peptide Schistosoma mansoni Interleukin-10-plasmid DNA Cold exposure Semi-purified diet (e.g., AIN-76) Interleukin-10-viral Anti-complement receptor Short term chronic stress Interleukin 11-human Complete Freund’s adjuvant Silica Anti-CTLA-4 Interleukin-12 Sirolimus/tacrolimus Intrathymic administration of mycobacterial heat shock protein 65 Cyclic nucleotide phosphodiesterases (PDEs) Sodium fusidate Cyclosporin Intrathymic administration of mycobacterial heat shock peptide p277 Soluble interferon-gamma receptor Islet cells-intrathymic Cyclosporin A Somatostatin DC deficient in NF-kappaB L-Selectin (MEL-14) Non-specific pathogen free conditions Lactate dehydogenase virus (LDH) . Age of autoantibody seroconversion (< 3yrs general DC from pancreatic lymph node Streptococcal enterotoxins Large multilamellar liposome DC with IL-4 Streptozotocin Lazaroid Deflazacort Sulfatide (3’sulfogalactosylceramide) Anti-leukocyte function associated antigen (LFA-1) Deoxysperogualin Superantigens Anti-LFA-1 Dexamethasone/progesterone/growth hormone/estradiol Superoxide dismutase-desferrioxamine Linomide (quinoline-3-carboxamide) Diazoxide Anti-T cell receptor Lipopolysaccharide-activated B cells population children; younger vs older relatives) 1,25 dihydroxy Vitamin D3, KH1060 TGF-beta 1 somatic gene therapy Lisofylline 1,25 dihydroxycholecalciferol Th1 clone specific for hsp60 peptide Lymphocyte choriomeningitis virus (LCMV) 1,25 dihydroxyl Vitamin D3 Anti-thy-1 Anti-lymphocyte serum Elevated temperature Thymectomy (neonatal) Lymphoctyte vaccination Emotionality Tolbutamide Encephalomyocarditis virus (ECMV) Lymphocytic choriomeningitis virus Tolerogenic dendritic cells induced by vitamin D receptor ligands Anti-L-selectin Essential fatty acid deficient diets Top of the rack FK506 Lymphotoxin Treatment combined with a 10% w/v sucrose-supplemented drinking water LZ8 FTY720 (myriocin) Tumor necrosis factor-alpha . GAD 65 peptides in utero MC1288 (20-epi-1,25-dihydroxyvitamin D3) TX527 (19-nor-14,20-bisepi-23-yne-1,25(OH)(2)D(3)) HLA (HLA DR3/DR4-DQ8), non-HLA genes MDL 29311 Anti-GAD monoclonal antibody Vitamin E Galactosylceramide Metabolically inactive insulin analog Anti-VLA-4 Glucose (neonatal) Anti-MHC class I Anti-MHC class II Glutamic acid decarboxylase MHC class II derived cyclic peptide (intraperitoneal, intrathymic, intravenous, oral) Glutamic acid decarboxylase 65 Th2 cell clone Mixed allogeneic chimerism Mixed bone marrow chimeras Glutamic acid decarboxylase peptides (intraperitoneal, intrathymic, intravenous, oral) Monosodium glutamate Murine hepatitis virus (MHV) May, 2016 15 Courtesy of Amanda Posgai and Mark Atkinson

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Human T1D Prevention Studies Have Had Very Limited Impact Other Studies in Recent-Onset T1D

• DPT-1 Parenteral Insulin No effect Metabolic Control Study No effect • DPT-1 Oral Insulin No effect** DPP-4 Inhibitor + PPI No effect • TrialNet Oral Insulin Ongoing • ENDIT Nicotinamide No effect Pilot Studies: • DIPP Nasal Insulin No effect Low Dose IL-2 Safe • INIT-II Nasal Insulin Ongoing Plasmid-Encoded Proinsulin Safe • TRIGR Casein hydrolysate No effect on abs T-regs Safe • NIP Docosahexaenoic Acid No effect Dendritic Cells Safe • PRE-Point Oral Insulin Immunologic hints

** Post-hoc analysis identified subgroup with benefit

Antigen-Based New Onset Use of Presymptomatic Stages of Type 1 Diabetes to Studies Design Type 1 Diabetes Prevention Clinical Trials • Oral Insulin France No effect Pre-Stage 1: Individuals at-risk for T1D General population – 0.4%; Individuals with high-risk genes – 4%; • Oral Insulin Italy No effect First-degree relatives – 3-8% • Oral Insulin US No effect Interventions at birth/universal interventions • GAD Pilot No effect (? subgroup) Interventions during pregnancy • TrialNet GAD No effect Childhood interventions in highest-risk individuals Stage 1: Autoimmunity/Normoglycemia/Presymptomatic T1D • Diamyd EU GAD No effect Multiple T1D-associated islet autoantibodies with normal glycemic control • Diamyd US GAD No effect TrialNet Oral Insulin Prevention Trial • Neurocrine Altered Peptide No effect TrialNet Abatacept Prevention Trial • DiaPep-277 Heat Shock Protein No effect (papers Stage 2: Autoimmunity/Dysglycemia/Presymptomatic T1D Multiple T1D-associated islet autoantibodies with glucose intolerance or dysglycemia retracted for fraud) TrialNet Teplizumab Prevention Trial Stage 3: Symptomatic T1D

23

Immunomodulatory New Onset A Combination Therapy Approach May Be Studies Required – One Potential Program  Cyclosporin France Transient effect Anti-Inflammatory Agents (e.g. Targeting IL1β or TNFα)  Cyclosporin Canada/EU Transient effect Immunomodulation  Teplizumab Anti-CD3 Pilot Transient effect (e.g. Anti-CD3 or  Otelixizumab Anti-CD3 Pilot Transient effect Anti-CD20 or  Abate Teplizumab Transient effect Co-Stimulation  Protégé Teplizumab Transient effect Blockade or (2°endpoint) ATG)  DEFEND Otelixizumab (2 trials) No effect Drive T-regs  Etanercept ? Effect (e.g. IL-2 or GCSF  Mycophenylate+Anti-CD25 No effect or T-reg infusion)  Rituximab Anti-CD20 Transient effect Diabetes-Related Antigen (e.g. Oral Insulin or GAD  Abatacept CTLA4-Ig Transient effect vaccine)  Canakinumab Anti-IL1-β No effect Preserve Beta-Cell Health (e.g. GLP-1 Receptor  Anakinra IL-1 trap No effect Agonist)  Thymoglobulin No effect °  Alefacept CTLA4-Ig Potential effect (2 endpoint) Time Skyler. Diabetes Care 2015;38:997-1007

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Immune Reset, Anti-Inflammatory and Stem Conclusions Cell Mobilization Trial in New Onset T1DM . T1D, a disease continuum, progresses through distinct presymptomatic stages . Stage 1 ( multiple islet autoantibodies) Anti-Inflammatory Agent – Etanercept and Anakinra . Stage 2 (islet autoantibodies with dysglycemia) Immunomodulation . Stage 3 (symptomatic disease) Alemtuzumab . Relative rate of progression to symptomatic T1D can be predicted Mobilize Stem with appreciable accuracy but needs to be further refined Cells for Beta Cell Repair . Screening and staging prior to symptomatic T1D: Plerixafor . Provides a framework to inform benefit/risk evaluation for regulatory, reimbursement, and clinical care Preserve Beta-Cell Health – Liraglutide . Catalyzes risk screening and will increase enrollment in natural history and prevention clinical trials . Will provide a window of opportunity to delay, and ultimately

Time prevent, symptomatic T1D 28 Courtesy of James Shapiro; Healthg Canada HC6-024-c188081

Diabetes Islet Preservation Immune Treatment (DIPIT) Trial

Anti-Inflammatory Agent - Etanercept

Immunomodulati onATG

Drive Module_1 MDSCs and Module_3 T-regs Module_2 GCSF Module_4 Drive T-regs – IL2

Preserve Beta-Cell Health – Exenatide-QW

Time ClinicalTrials.gov NCT 02586831

Heterogeneity of T2DM Within Populations: the Belfast Diet Study 2–4 years Time to need glucose- lowering medication 5–7 years 8–10 years

60 60

40 40 -Cell Insulin

function 20 Sensitivity (%) 20

0 0 0 2 4 6 0 2 4 6

Years from diagnosis *-cell function determines onset and progression of secondary dietary failure in DM2 Levy J, et al. Diabet Med. 1998;15(4):290-296.

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What determines disease progression in T2DM? DPP Study Treatment Groups Accelerators Screen (158,177 people)

Randomize (3,819 people) Aim of Glucose/ therapy HbA1c Brakes Standard lifestyle teaching

Normal / no progression Intensive Placebo Troglitazone Lifestyle (1073 people) (1082 people) 585 people (1079 people) Until 6/98 Years

DPPPercent Incidence developing diabetes of Diabetes What does the Future Hold? Placebo (n=1082) All participants Metformin (n=1073, p<0.001 vs. Placebo) Lifestyle (n=1079, p<0.001 vs. Met , p<0.001 vs. Plac ) 40 MetforminLifestyle (n=1079,(n=1073, p<0.001 vs. Plac)Metformin, Placebo (n=1082) p<0.001 vs. Placebo) Risk reduction 30 31% by metformin 58% by lifestyle 20

10 Cumulative incidence (%) incidence Cumulative

0 0 1 2 3 4 Years from randomization

Huang ES, et al. Diabetes Care 32:2225, 2009

What does the Future Hold? DPPOS Incidence of Diabetes

Placebo Metformin

Lifestyle

Cumulative Incidence (%) Incidence Cumulative

02 04 060 50 40 30 20 10 0

0 2 4 6 8 10 Huang ES, et al. Diabetes Care 32:2225, 2009 Year since DPP Randomization

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Regression vs. Progression Change from Baseline By Glucose Tolerance Category 20 NGT IGT Diabetes Normal Glucose RegulationPre-diabetes Diabetes B. Triglyceride (mg/dl) (NGR) (IFG/IGT) 10

Fasting glucose <100 100-125 >125 mg/dl 0 2h glucose <140 140-200 >200 mg/dl -10

-20

-30

-40 Glucose concentration assessed by annual 2h OGTT All Visits At 3 Years

Goldberg R, et al. Diabetes Care 32:726-734, 2009

Change from Baseline By Regression vs. Progression Glucose Tolerance Category

3 NGT IGT Diabetes Normal Glucose RegulationPre-diabetes Diabetes C. HDL (mg/dl) (NGR) (IFG/IGT) 2

Fasting glucose <100 100-125 >125 mg/dl 1

2h glucose <140 140-200 >200 mg/dl 0 -1

-2 Glucose concentration assessed by annual 2h OGTT -3 All Visits At 3 Years

Goldberg R, et al. Diabetes Care 32:726-734, 2009

Risk Factor Change from Baseline Change from Baseline By By Glucose Tolerance Category in Placebo Group Glucose Tolerance Category NGT IGT Diabetes 1 NGT IGT Diabetes 3 D. LDL size (Rf) A. SBP (mmHg) 0.6 2 0.2 1

0 -0.2

-1 -0.6 -2 -1 -3 All visits At 3 years All Visits At 3 Years

Goldberg R, et al. Diabetes Care 32:726-734, 2009 Goldberg R, et al. Diabetes Care 32:726-734, 2009

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Delay and Prevention of Diabetes

Variables associated with regression:

• Lower baseline fasting and 2h glucose • Younger age • Higher insulin response • Greater weight loss • ILS Diabetes Care 2009 Herman, et al. Ann Int Med 144:66-67, 2006.

Diabetes Incidence in DPPOS: Cumulative, Undiscounted, Per-participant Effect of Achieving NGR Direct Medical Costs

0.45 DPP/DPPOS Interventions Medical Care Received Outside

0.40 the DPP/DPPOS

0.35

0.30 Never reached NGR in DPP

0.25

0.20

0.15 p<0.0001 0.10

Reached NGR at least once in DPP

Diabetescumulativeincidence 0.05

0.00 01234567 Year in DPPOS Perrault L, et al. Lancet 379:2243, 2012 Herman et al. Diabetes Care 35:723-30, 2012

Diabetes Incidence in DPPOS: Effect of Achieving NGR by Treatment Discounted Incremental Cost- Effectiveness Ratios over 10 Years by 0.45 Lifestyle Pre-Diabetes Intervention Group – 0.40 Metformin Pre-Diabetes Health System Perspective Placebo Pre-Diabetes 0.35 Lifestyle NGR Lifestyle Metformin Placebo 0.30 Metformin NGR Placebo NGR Total direct medical costs 25,456 24,071 24,229 0.25 QALYs 5.99 5.88 5.87 0.20  Cost v placebo 1,226 -159 — 0.15

0.10  QALY v placebo 0.12 0.02 —

DiabetesCumulative Incidence 0.05  Cost /  QALY 10,037 Cost-saving

0.00 01234567 Year in DPPOS Perrault L, et al. Lancet 379:2243, 2012 Herman et al. Diabetes Care 35:723-30, 2012

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“Real-World Translation” • FOR IMMEDIATE RELEASE March 23, 2016 • [email protected] • Independent experts confirm that diabetes prevention model supported flickr:peppergrasss' Kurt Nordstrom) by the Affordable Care Act saves money and improves health • First ever preventive service model eligible for expansion under Medicare holds promise for employers, private insurers and patients

w:User:Ross Uber

Translating the DPP/DPPOS • Secretary Sylvia M. Burwell announced Experience that the independent Office of the Actuary in the Centers for Medicare & to the “Real World” Medicaid Services (CMS) certified that  Can we take what we know from DPP and bring it expansion of the Diabetes Prevention into many communities? Program, a model funded by the Affordable Care Act, would reduce net  What types of programs or treatments can and Medicare spending. The expansion should be offered? was also determined to improve the quality of patient care without limiting Who will deliver these programs?  coverage or benefits. This is the first  Who will pay for them? time that a preventive service model from the CMS Innovation Center has become eligible for expansion into the Medicare program.

Action on Capitol Hill • Medicare beneficiaries enrolled in the program lost about five percent of their body • Franken-Lugar Health Reform Bill weight, which is enough to substantially “Diabetes Prevention Amendment” reduce the risk of future diabetes. Average weight loss was 4.73 percent of body weight • This amendment will authorize the Centers for for participants attending at least four weekly Disease Control and Prevention (CDC) to train, sessions. Participants who attended at least recognize, and fund community based diabetes nine weekly sessions lost an average of 5.17 prevention programs. percent of their body weight. • Over 80 percent of participants recruited attended at least four weekly sessions. • When compared with similar beneficiaries not it the program, Medicare estimated savings of $2,650 for each enrollee in the Diabetes Prevention Program over a 15-month period, more than enough to cover the cost of the program.

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We must prevent diabetes or our health system will be consumed by it

10