Reference: N Engl J Med. 2023 Dec 7;389(23):2140
Practice Point: Oral baricitinib is an exciting addition to available therapies for new-onset type 1 diabetes and has the potential to be a game-changer.
EBM Pearl: Unequal randomization is only justified in specific circumstances, but when more people are allocated to the treatment arm, it allows more power to detect harms and may also help with recruitment.
One of the saddest and bravest things you might see as a clinician is a 3-year-old with type 1 diabetes giving themself an insulin shot and stating matter-of-factly their dosing regimen. At present, treatment for type 1 diabetes is focused on insulin replacement after the pancreatic β-cells burn out, in addition to managing complications from end-organ damage and hypoglycemia. Two investigational therapies aimed at T-lymphocytes have shown promise for preservation of β-cells, however they require cycles of IV infusions and are expensive. Recently however, the oral disease-modifying antirheumatic agent (DMARD), baricitinib, which targets JAK 1 and JAK2 and is used to treat RA, alopecia areata, and severe COVID, was evaluated for the treatment of type 1 diabetes in the phase 2 clinical trial BANDIT.
Ninety-one patients aged 10-30 in Australia with a recent diagnosis of type 1 diabetes were randomized 2:1 to receive daily oral baricitinib (4 mg) or placebo for 48 weeks. The primary outcome was mixed-meal C-peptide level, with higher values indicating more endogenous insulin production. At 48 weeks, the median C-peptide level was 0.65 nmol per liter per minute (interquartile range 0.31 to 0.82) in the baricitinib group and 0.43 nmol per liter per minute (interquartile range 0.13 to 0.63) in the placebo group. Secondary outcomes of BANDIT suggested lower insulin requirements, less fluctuation in glucose levels, and possibly even lower A1c in the baricitinib group. Fewer adverse events were reported in the baricitinib group (you read that right), but no p values were reported.
The primary outcome data from BANDIT translate to a 48% relative increase in C-peptide levels in patients who got baricitinib, suggesting preservation of β-cells over time. This is similar to effect sizes seen in other trials of similar investigational therapies such as the monoclonal antibody teplizumab and the DMARD abatacept, however these treatments require cycles of IV infusions, as often as daily for repeated 12-day cycles in the case of teplizumab. As most people with recently-diagnosed type 1 diabetes are children, the option of a safe and effective oral treatment may mean fewer days of missed school and reduced likelihood of vulnerable child syndrome. We do find it curious that the youngest age of enrollment in BANDIT was 10, with a mean age of 19. Other trials have tended to start enrollment at age 6-8. We know that earlier age at diagnosis is generally associated with worse outcomes. If more β-cell destruction were present, would baricitinib be more or less effective? We don’t know yet, but we should definitely try to find out. Who knows, maybe someday more 3-year-olds with diabetes will know how to say “baricitinib” than “insulin”. In addition, reduced fluctuations in blood glucose with baricitinib might eventually translate to fewer complications associated with brittle diabetes, such as hypoglycemic events or ketoacidosis. In any case, it would seem that any amount of clinically meaningful β-cell preservation that comes from an attainable oral medication without significant harms would be a win.
For more information, see the topic Management of Type 1 Diabetes in DynaMed.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by Katharine DeGeorge, MD, MS, Senior Deputy Editor at DynaMed and Associate Professor of Family Medicine at the University of Virginia. Edited by Alan Ehrlich, MD, FAAFP, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School; Dan Randall, MD, MPH, FACP, Deputy Editor at DynaMed; Nicole Jensen, MD, Family Physician at WholeHealth Medical; Vincent Lemaitre, PhD, Medical Editor at DynaMed; Hannah Ekeh, MA, Senior Associate Editor at DynaMed; and Jennifer Wallace, BA, Senior Associate Editor at DynaMed.