Type 1 diabetes

Imatinib may preserve beta-cell function in people with recent-onset type 1 diabetes.

The tyrosine kinase inhibitor imatinib appears to preserve β-cell function in adults with recent-onset type 1 diabetes.

A phase 2 study randomised 64 adults aged 18-45 years, with diabetes diagnosed within the previous 100 days, to either 400 mg daily imatinib or placebo for 26 weeks.

Participants, from eight sites in the US and one site in Australia, were receiving intensive diabetes management with the aim of achieving the HbA1c target ≤7·0%.

The study, published in The Lancet Diabetes Endocrinology, showed that 26 weeks of treatment with imatinib slowed the decrease in β-cell function for up to 12 months.

The primary endpoint, the area under the curve (AUC) mean for stimulated C-peptide in the first 2 hr of a 4-hr mixed meal tolerance test (MMTT) at 12 months was 0·583 nmol L– ¹ for the imatinib group and 0·489 nmol L– ¹ for the placebo group.

“The adjusted mean difference between study groups was 0·095 (90% CI –0·003 to 0·191), and constituted a 19·4% treatment effect,” the study said.

The study noted the effect was not sustained out to 24 months.

Data on 4-hr C-peptide AUC mean were consistent with the 2-hr analyses.

In secondary endpoints, exogenous insulin use was similar at baseline between the two groups, but was notably lower in the imatinib group versus the placebo group at the 3-month and 6- month assessments.

HbA1c was also lower in the imatinib group than in the placebo group during the active treatment phase, with the greatest difference at 3 months and mean difference –0·422%.

β-cell glucose sensitivity improved during imatinib treatment, but diminished after the drug regimen was completed.

“We also found that the proinsulin to C-peptide ratio was low during imatinib therapy, which has been linked with reduced endoplasmic reticulum stress and improved β-cell function,” the investigators said.

Adiponectin markedly increased in the imatinib group during the 6 months on therapy, compared with the placebo group but decreased to baseline levels by 12 months.

There was no apparent effect of imatinib on measures of immune function.

The study found imatinib was relatively well tolerated although 38% of the group had temporary dose modifications and 13% permanently discontinued the drug due to adverse events including neutropenia, rashes, and abnormal liver function tests.

“In planning this study, we were mindful of potential safety issues associated with imatinib, but anticipated that it might be better tolerated than in oncology settings, as we were working with relatively young adults with type 1 diabetes who were otherwise healthy,” they said.

They concluded imatinib might have novel effects on metabolism leading to improved β-cell function and insulin sensitivity.

“These initial observations suggest considerations for future study of imatinib in type 1 diabetes, provided treated participants are closely monitored for possible toxicities.”

A new approach

A Comment article published in the journal said no other intervention has been shown to affect β-cell glucose sensitivity.

Professor Jay Skyler, Deputy Director of the Diabetes Research Institute at the University of Miami, said a combination of drugs might be a worthwhile approach.

“In this context, sustained administration of an anti-inflammatory drug (such as anti-TNF) could also be provided to alter background innate immunity, plus an intervention to directly improve β-cell function (such as a glucagon-like peptide 1 receptor agonist or a tyrosine kinase inhibitor).”

He noted that as in other autoimmune conditions such as rheumatoid arthritis or psoriasis, disease modifying therapies would need to be continued indefinitely.

The Australian investigator on the study, Associate Professor John Wentworth told the limbic the findings hinted at a pathway that might be worth targeting and might deliver massive benefit to diabetes patients generally.

“It was important to do the study because there was a huge weight of animal and preclinical evidence that it was going to be useful,” he said.

“The real outcome of this study and what was slightly surprising was that it looks like the drug helps resuscitate β-cell function but it doesn’t seem to turn off the autoimmunity. That’s interesting,” he said.

“When we finally look at combinations for type 1 diabetes, here’s a non-immune therapy that could be combined with an immune therapy. So it’s something that might show promise then.”

He said it raised questions about whether the same approach might be useful for newly diagnosed type 2 diabetes

“The reasons why I think it is unlikely that people will pursue this in the short term, is that the overall clinical impact was modest and the drug tolerability was not great.”

Associate Professor Wentworth, from the Walter and Eliza Hall Institute and Royal Melbourne Hospital, said the BANDIT trial was currently investigating the JAK inhibitor baricitinib in type 1 diabetes, after compelling animal data showing it was effective.

“The aspiration is that, like cancer, we will get to a stage where if you are diagnosed, the next thing people think of is which trial or which new agent can we offer this person to preserve the β-cell function and decrease insulin requirements.”

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