SAT-544 - Secondary Prevention of Diabetes Type 1 with Oral Paricalcitol: The PRECAL Study

Type 1 diabetes (T1D) hits about 1:300 with rising incidence in younger children. Population screening at 2, 6 and even 10 yrs with T1D associated autoantibodies (T1AB) has been proven sensitive. 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. Awaiting specific monoclonal antibodies and stem cell/B-cell immunotolerant regeneration therapies we could actively pursue primary prevention with vitamin D and expand research into potent calcitriol analogues for secondary prevention https://pubmed.ncbi.nlm.nih.gov/39834215/.
After demonstrating negativation of T1Abs within 0.6yrs (0.4-2.1) under oral calcitriol in 12 children https://pubmed.ncbi.nlm.nih.gov/23302101/, a prospective interventional non-randomized clinical trial, the PRECAL study (ISRCTN17354692) was initiated. In 2023, 10-year data on 50 children were published https://pubmed.ncbi.nlm.nih.gov/37238410/. Now we present 15-yr data on 103 children aged 0.65-16.37 yrs identified as at high risk for T1D were included: 97 were positive for T1Abs and 6 with negative T1Abs had predisposing HLA A DQ DR haplotypes and genotypes. 9 were diagnosed with varied impaired glucose tolerance (IGT) (T1Ab+), 4 with pre-T1D (3 T1Ab+ and 1 HLA+), and 10 had new-onset T1D (T1Ab+). 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 U/S 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 or, paricalcitol 0.15 mcg/k/day p.o.
Available data on 81 (18 dropouts, 4follow-up < 3 m). 54 negativized T1Abs (43IAA, 3IA2, 4ICA, 2GAD, 1IAA/GAD, 1ICA/GAD) within 0.56 (0.32-1.9) yrs. 5 +HLA did not progress to T1D, follow-up 3 (3-6) yrs]. From 4 pre-T1D, 1 negativized T1Abs (follow-up 3 yr), 1 with +HLA did not progress to T1D (follow-up 5.3 yrs) and 2 with +T1Ab developed T1D in 6m/3yrs. 3 out of 10 children with T1D at presentation progressed immediately to overt disease, 6 showed complete remission for 1yr (1 m - 2 yrs), and 1 is still on remission , even 4 antibodies are still positive for 2.9 yrs. 12 children Τ1Αb has not negativized yet and are still on paricalcitol 1.4 yrs median (0.4-1.8yrs).
7 with +T1Ab relapsed and negativized again after resuming therapy. 4( < 3 yrs) negativized anti-TPO/TG, and two ttg-IgA. 10 presented hypercalciuria/hypercalcemia, 1 nephrocalcinosis, resolving with dose titration/discontinuation.
Calcitriol, and paricalcitol were effective and reasonably safe in negativizing T1Abs in healthy children, possibly preventing the otherwise probably inevitable evolution towards clinical development of T1D, at least if started soon enough after seroconversion.

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