Early Diagnosis of T1D Through An3body Screening Andrea Steck, M.D. Barbara Davis Center for Childhood Diabetes Keystone Conference July 15, 2017
Presenter Disclosure Andrea Steck Disclosed no conflict of interest
Outline Stages of type 1 diabetes Immunological markers and risk predic<on Metabolic markers and early diagnosis Studies offering screening and preven<on
Natural History of Type 1 Diabetes PUTATIVE ENVIRONMENTAL TRIGGER CELLULAR (T CELL) AUTOIMMUNITY HUMORAL AUTOANTIBODIES (IAA, GAD 65, IA- 2, ZnT8) BETA CELL MASS GENETIC PREDISPOSITION INSULITIS BETA CELL INJURY LOSS OF FIRST PHASE INSULIN RESPONSE (IVGTT) PRE - DIABETES GLUCOSE INTOLERANCE (OGTT) CLINICAL ONSET DIABETES TIME Eisenbarth, NEJM 1986
T1D Disease Progression Genetic Risk The Stages to Type 1 Diabetes Immune Activation Starting Point If you have a relative: 15x greater risk of developing T1D Immune Activation Beta cells are attacked Immune Response Immune Response Development of single autoantibody STAGE 1 STAGE 2 STAGE 3 STAGE 1 STAGE 2 STAGE 3 Normal Blood Sugar 2 autoantibodies START OF T1D Abnormal Blood Sugar 2 autoantibodies Clinical Diagnosis 2 autoantibodies STAGE 4 STAGE Longstanding T1D
ADA diagnos<c criteria
Tools for monitoring the natural history of prediabetes Markers of immune response to the beta- cell: Autoan<bodies Islet autoan<bodies: insulin, IA- 2, GAD65, ZnT8 T cell response Markers of metabolic changes: Oral glucose tolerance test HbA1c Con<nuous glucose monitoring
Progression to Diabetes in Children with Mul<ple Autoan<bodies Ziegler et al, DAISY, DIPP and BABYDIAB, JAMA 2013
HbA1c at onset is lower (7.2 vs. 10.9%) in DAISY compared to community children 60 50 40 p<0.0001 DAISY Community 30 20 10 0 <6 6-7 7-8 8-9 9-10 10-11 11-12 12-13 13-14 14-15 >15 % HbA1c DAISY, Denver children 0-11 y old, 1999-2002 Barker et al, Diabetes Care 2004
DKA and hospitaliza<on at T1D onset can be prevented by screening for islet autoan<bodies and educa<on! Hospitalization rate 100% 80% 60% DAISY children, age 0-11 years - FDR or pre-screened for HLA-DR,DQ at birth - followed for islet autoantibodies - diabetes education and monitoring - free glucometer, test strips 40% 20% 0% Denver community cases n=101 p < 0.0001 DAISY cases n=30 one 11-month old DAISY child was hospitalized Barker J, et al. DAISY. Diabetes
DKA at diagnosis: a growing problem in CO DKA present in 39% youth at T1D diagnosis Rewers A. et al. JAMA. 2015
Reduc<on of DKA at Onset Study Child < 2 years P value Child < 5 years P value TEDDY 6/40 (15%) 9/79 (11%) Sweden registry 51/129 (40%) 0.02 102/604 (17%) 0.45 SEARCH 29/58 (50%) <0.0001 100/275 (36%) <0.0001 Finland registry 82/183 (45%) <0.0001 138/737 (19%) 0.11 German registry 235/435 (54%) <0.0001 583/1812 (32%) <0.0001 Larsson et al, TEDDY Study, DC 2011
CGM as a marker of early glycemic changes in Ab+ subjects CGM variables: >140: % Time >140 mg/dl; >200: % Time >200 mg/dl OGTT values are baseline and 2- hr glucose values Dx: diagnosis of diabetes SD: standard devia<on Steck et al, Diabetes Care 2014
CGM measures in Ab+ vs Ab- subjects CGM Ab+ subjects (N=14) Ab- subjects (N=9) P value Mean glucose (mg/dl) 117 + 13 109 + 11 0.07 Mean day* glucose (mg/dl) 119 + 13 109 + 11 0.06 Max. day* sensor value (mg/dl) 221 + 53 168 + 31 0.011 Max. night sensor value (mg/ 173 + 35 170 + 44 0.57 dl) SD (mg/dl) 26 + 8 19 + 7 0.039 CV (mg/dl) 22 + 6 17 + 5 0.046 Range (mg/dl) 166 + 53 111 + 43 0.016 % Time > 140 mg/dl 0.18 + 0.15 0.09 + 0.09 0.04 % Time > 200 mg/dl 0.02 + 0.03 0 + 0.01 0.075 AUC (mg/min/dl) 676196 + 72197 627443 + 64823 0.16 AUC day* (mg/min/dl) 514433 + 54758 466436 + 48577 0.06 AUC night (mg/min/dl) 160977 + 22912 158913 + 22308 0.60 *Day: values between 6am and midnight AUC: area under the curve, calculated by the trapezoidal rule
CGM among Ab+ progressors vs. Ab+ non- progressors Variables Ab* positive progressors (N=5) Ab* positive nonprogressors (N=9) P value Mean glucose (mg/dl) 125 + 16 112 + 8 0.19 Mean day glucose (mg/dl) 129 + 15 114 + 8 0.06 Max. day SG value (mg/dl) 241 + 38 210 + 58 0.44 SD (mg/dl) 32 + 7 23 + 7 0.06 CV (mg/dl) 26 + 5 20 + 6 0.15 Range (mg/dl) 182 + 37 157 + 60 0.3 % Time > 140 mg/dl 0.31 + 0.18 0.12 + 0.07 0.04 % Time > 200 mg/dl 0.03 + 0.04 0.01 + 0.01 0.06 AUC (mg/min/dl) 725629 + 91052 648733 + 44149 0.15 AUC day (mg/min/dl) 561040 + 61792 488540 + 29180 0.02 AUC night (mg/min/dl) 164180 + 32128 159198 + 18082 0.52 HbA1c, % (mean) 5.9 + 0.3 5.3 + 0.9 0.16
OGTT or random BG as markers for <me to T1D in children with mul<ple Ab (DIPP study) > 2 Abs IFG Median diabetes free survival <me indicated for each curve IGT BG 140 mg/dl OGTT group: 209/403 (52%) progressed to T1D Random BG group: 204/505 (40%) progressed to T1D (a) > 2 islet autoan<bodies (b) IFG in OGTT (solid line) or not (dashed line) (c) IGT in OGTT (solid line) or not (dashed line) (d) random BG 140 mg/dl (solid) or not (dashed) Helminen et al, Diabetologia 2015
DPTRS: Diabetes Preven<on Trial- Type 1 Risk Score DPTRS <6.5: low risk (<0.2) DPTRS >7.5: high risk (>0.5) The DPTRS includes the glucose sum of 30-, 60-, 90-, and 120- min values divided by 100, the C- pep<de sum of 30-, 60-, 90-, and 120- min values divided by 10, log fas<ng C- pep<de, log BMI, and age. Sosenko et al, Diabetes Care 2011
Residual beta- cell func<on in diabetes children followed prospec<vely TEDDY children iden<fied at birth with high- risk HLA and followed every 3 months un<l diabetes diagnosis were compared to age- matched children diagnosed with diabetes in the community HbA1c and MMTT were performed within 1 month of diabetes onset, then at 3, 6, and 12 months, and biannually thereaoer Steck AK et al, Pediatr Diabetes. 2017
TEDDY (N=43) Community (N=43) P-value Age at Dx, mean (years) 6.0 ± 1.6 6.4 ± 1.8 0.001 Gender Female, N (%) 20 (47) 27 (63) 0.21 BMI 16.0 ± 2.0 15.4 ± 2.5 0.26 Family history of diabetes, N (%) 9 (21) 2 (5) 0.04 Diabetes symptoms, N (%) 18 (42) 42 (98) <0.001 Diabetic ketoacidosis, N (%) 0 (0) 6 (14) 0.03 Hospitalization at diagnosis, N (%) 21 (49) 32 (74) 0.01 HLA-DR3/4,DQB1*0302,N (%) 24 (56) 4 (10) 0.003 # of positive autoantibodies, N (%) 0 /1 / >2 1(4) / 5(19) / 21(78) 1(3) / 10(30) / 22(67) 0.58 Mean GADA level 0.55 + 0.80 0.19 + 0.59 0.07 Mean IA-2A level 1.43 + 0.83 1.35 + 0.85 0.39 Mean ZnT8A level 0.29 + 0.20 0.23 + 0.18 0.81 HbA1c, % (mmol/mol) 6.8 + 1.3 (51 + 14 mmol/mol) 10.5 + 2.1 (91 + 23 mmol/mol) <0.001
C- pep<de AUC during MMTT in TEDDY cases and community controls during the first year aoer onset Box plots with minimum, first quartile, median, third quartile, and maximum values. The line in the box plots indicates the median value, while the mean is denoted by o for cases and + for controls. Outliers are marked as.
HbA1c in TEDDY cases and community controls during the first year follow- up aoer diagnosis of diabetes
Insulin dose in TEDDY cases and community controls during the first year follow- up aoer diagnosis of diabetes
IDAA1C in TEDDY cases and community controls during the first year follow- up aoer diagnosis of diabetes IDAA1C: Insulin-dose adjusted A1c: calculated as A1c (%) + [4 x insulin dose (units/kg/day)]
E<ology and Preven<on of T1D 1993-2020 Find the cause of T1D General population cohort Sibling/offspring cohort Develop preven3on Public health screening Rela3ves and General Popula3on 2004-2025 Colorado: 31,881 newborns screened 2,547 general popula3on and first- degree rela3ves followed Mul3na3onal: 424,000 newborns screened 8,677 high- risk children intensively followed omics studies Fr1da study 24
TrialNet Disease Preven<on Genetic Risk Immune Activation Immune Response Using knowledge gained through clinical research, TrialNet s mission is to prevent type 1 diabetes and stop disease progression by preserving insulin produc<on before and aoer diagnosis. STAGE 1 STAGE 2 STAGE 3 STAGE 4 25
TrialNet Pathway to Preven<on P2P Free screening for autoantibodies Anyone between age 1 and 45 with a FDR with T1D Anyone between age 1 and 20 with a 2nd degree rela<ve with T1D Those under 18 who do not have autoan<bodies can be retested yearly Based on results Look to enroll in clinical trial to preserve beta cell func<on Or monitor for disease progression Scott & Adam Pathway to Prevention Participants Keilyn Pathway to Prevention Participant Brooke, Emily & Ava Pathway to Prevention Participants
TrialNet Preven<on Studies Oral Insulin Study TrialNet Pathway to Prevention Study Abatacept Prevention Study Anti-CD3 Prevention Study
Capillary blood islet autoan<body screening The Fr1Da study in Germany is screening general popula<on children age 2 5 years for Ab The study uses capillary blood samples and a mul<plex ELISA assay for GAD, IA- 2, and IAA In the first 10 months, the study screened an average of 2,676 children per month General popula<on screening for Ab through collabora<on with primary care pediatricians is feasible Two pilot studies performed through TrialNet also showed the feasibility of Ab tes<ng by dried blood spots or capillary blood sampling Raab J & al, BMJ Open 2016 Liu Y & al, Diabet Med. 2017
ASK: Autoimmunity Screening for Kids Offer screening for pre- symptoma<c T1D and Celiac Disease Autoimmunity (CDA) to 55,000 Denver Metro Area children 2-17 years old Over a period of 3 years, with an<cipated 30% par<cipa<on rate, iden<fy: ~ 440 children with stage 1 or 2 T1D ~1100 children with confirmed celiac TGA 2
Specific Aims Enroll children with stage 1 or 2 T1D in intensive follow- up to prevent DKA and hospitaliza<on at onset of diabetes Enroll eligible children into preven<on trial to delay progression to diabetes Facilitate referral of children with celiac autoimmunity to pediatric GI services for treatment and follow- up Provide cost- effec<veness analyses of screening 3
Opportuni<es for Preven<on in ASK Par<cipants At diagnosis: 40% in DKA >80% hospitalized Insel R et al. Diabetes Care 2015
Take Away Messages Early diagnosis through prospec<ve studies is feasible (metabolic surveillance once mul<ple an<bodies are present) Subjects from prospec<ve studies have decreased rates of DKA and hospitaliza<ons Predic<on of risk is accurate Ongoing screening and preven<on trials for both rela<ves and general popula<on children
ADA Acknowledgments