Cyclosporin-induced remission of IDDM after early intervention: association of 1 yr of cyclosporin treatment with enhanced insulin secretion

Abstract

A randomized double-blind placebo-controlled trial was undertaken to determine whether cyclosporin enhances remission of insulin-dependent diabetes mellitus (IDDM) through the 1st yr after diagnosis. Dosage with insulin was minimized with target control of blood glucose levels ≤7.8 mM (140 mg/dl) before meals. Metabolic control was evaluated by serial determinations of glycosylated hemoglobin levels, and endogenous secretion of insulin was evaluated by determination of the levels of glucagon-stimulated insulin-connecting peptide (CP) in the plasma at 3-mo intervals. A compound definition of remission required a glucagon-stimulated CP level in plasma ≥0.6 nM or a non-insulin-receiving state (NIR) in which target control of glycemia was maintained without administration of insulin. A clinical definition of remission required only the NIR state as defined. One hundred eighty-eight patients aged 10–35 yr entered the study within 6 wk of initiation of insulin therapy and within 14 wk of onset of symptoms and were studied for 1 yr. There were no significant differences in metabolic control between the two treatment groups during the study. The anticipated adverse effects of cyclosporin were not more frequent or severe than in other experience with the drug, but histological changes attributable to cyclosporin were present in some kidney biopsies obtained from selected patients after 1 yr. At 1 yr, by the compound definition, 33% of the cyclosporin-group and 21% of the placebo-group patients were in remission, when the corresponding rates for NIR remissions were 24 and 10%. With adjustment for differences in the baseline variables, the differences in rates between the treatment groups were statistically significant in all comparisons, and the relative odds for NIR remission at 1 yr were increased approximately five times in the cyclosporin-treated group. Furthermore, a relatively short duration of diabetes (entry ≤6 wk after onset of symptoms, with ≤2 wk of insulin therapy) was associated with greater efficacy of cyclosporin. The mean glucagon-stimulated CP levels in the plasma in cyclosporin-treated patients exceeded those in placebo-treated patients after 3 mo and were maintained through 12 mo, in contrast to a decline after 3 mo in the placebo group. Thus, the results show that cyclosporin treatment initiated soon after diagnosis increases the rate of remission and enhances β-cell function during the 1st yr of IDDM. We conclude that a continuing search for clinically beneficial immunomodulatory therapies designed to prevent or ameliorate the disease is feasible and worthwhile.