FRI608 Secondary Prevention Of Diabetes Type 1 With Oral Calcitriol And Analogs, The Precal Study
Authors: Papadimitriou Dimitrios T , Dermitzaki Eleni , Christopoulos Panagiotis , Papagianni Maria , Kleanthous Kleanthis , Marakaki Chrysanthi , Papadimitriou Anastasios , Mastorakos George 
Published: October 2023

Disclosure: D.T. Papadimitriou: None. E. Dermitzaki: None. P. Christopoulos: None. M. Papagianni: None. K. Kleanthous: None. C. Marakaki: None. A. Papadimitriou: None. G. Mastorakos: None.

Type 1 diabetes (T1D) hits about 1:300 with rising incidence affecting increasingly younger children. Population screening at ages 2 and 6 yrs with T1D associated autoantibodies (T1Ab) has been recently proven sensitive. While potential treatments to prevent or delay T1D are currently in development, a population based cost-effective preventive strategy is still lacking. Hence, 2000 IU cholecalciferol daily in a large birth cohort study published in 2001 reduced by 80% the risk of T1D in 1 yr. A pilot clinical trial 10 yrs ago, demonstrated negativation of T1Ab within 0.6 (0.4-2.1) yrs under oral calcitriol in 12 children. To further pursue this hypothesis, we initiated a prospective interventional non-randomized clinical trial, the PRECAL study (ISRCTN17354692). Between 2010-2022, 50 children (26 boys, 24 girls) aged 0.65-16,37 yrs identified as at high risk for T1D were included: 44 were positive for T1Ab (Insulin auto-antibodies, IAA; anti-tyrosinase abs, IA2, anti-glutamic decarboxylase abs, GAD; islet auto-abs, ICA; anti-Zn8 if available) and 6 with negative T1Abs had predisposing HLA A DQ DR haplotypes and genotypes. Nine were diagnosed with varied impaired glucose tolerance (IGT) ( all T1Ab+), 4 with pre-T1D (3 T1Ab+ and 1 HLA+), and 9 had new-onset T1D (all T1Ab+). Serum T1Ab levels and fasting plasma glucose, HbA1c, c-peptide, Ca (tolerated ≤11.5 mg/dl), P, ALP, Ca/Cr 2-hr urine morning sample, 25(OH)D, 1-25(OH)2D with renal ultrasound in cases with hypercalcemia/hypercalciuria (tolerated ≤50%, or at the upper normal for age) were determined before and q3-6 months after initiation of calcitriol (0.05 mcg/Kg/day) 0.25-0.5 x 1-3/day or its synthetic analogue, paricalcitol (thrice the calcitriol dose) 1-4 mcg x 1-3/day p.o. under cholecalciferol repletion. Measurements are given as median and range. Available data on 42 (7 dropouts, 1 follow-up &lt; 3 m). All 26 without pre-T1D/T1D followed 3.06 (0.5-10) yrs negativized T1Ab (15 IAA, 3 IA2, 4 ICA, 2 GAD, 1 IAA/GAD, 1 ICA/GAD) within 0.57 (0.32-1.3) yrs or did not progress to T1D [5 +HLA, follow-up 3 (1-4) yrs]. From 4 pre-T1D, 1 negativized T1Ab (follow-up 1 yr), 1 with +HLA did not progress to T1D (follow-up 3.3 yrs) and 2 with +T1Ab developed T1D in 6m/3yrs. Three out of 8 children with T1D at presentation progressed immediately to overt disease, 5 showed complete remission for 1 yr (1m-2yrs). Five with +T1Ab relapsed and negativized again after resuming therapy. Four (aged &lt; 3 yrs) negativized anti-TPO/TG, and 2 anti-transglutaminase-IgA. Eight presented mild hypercalciuria/hypercalcemia, resolving with dose titration/discontinuation. Calcitriol, and it’s less-calcemic analogue paricalcitol were 100% effective and reasonably safe in negativizing T1Ab in healthy children, possibly preventing the otherwise probably inevitable evolution towards clinical development of T1D, at least if started soon enough after seroconversion.

Presentation: Friday, June 16, 2023