Hydroxychloroquine in Stage 1 Type 1 Diabetes

Abstract

Objective: Innate immune responses may be involved in the earliest phases of type 1 diabetes (T1D).

Research design and methods: To test whether blocking innate immaune cells modulated progression of the disease, we randomly assigned 273 individuals with stage 1 T1D to treatment with hydroxychloroquine (n = 183; 5 mg/kg per day to a maximum of 400 mg) or placebo (n = 90) and assessed whether hydroxychloroquine treatment delayed or prevented progression to stage 2 T1D (i.e., two or more islet autoantibodies with abnormal glucose tolerance).

Results: After a median follow-up of 23.3 months, the trial was stopped prematurely by the data safety monitoring board because of futility. There were no safety concerns in the hydroxychloroquine arm, including in annual ophthalmologic examinations. Preplanned secondary analyses showed a transient decrease in the glucose average area under the curve to oral glucose in the hydroxychloroquine-treated arm at month 6 and reduced titers of anti-GAD and anti-insulin autoantibodies and acquisition of positive autoantibodies in the hydroxychloroquine arm (P = 0.032).

Conclusions: We conclude that hydroxychloroquine does not delay progression to stage 2 T1D in individuals with stage 1 disease. Drug treatment reduces the acquisition of additional autoantibodies and the titers of autoantibodies to GAD and insulin.

Graphical abstract

Figure 1

CONSORT diagram showing study conduct.

Figure 2

Effects of hydroxychloroquine treatment on primary study outcome. Time to the first consecutively confirmed AGT or stage 3 T1D diagnosis is shown for the two treatment arms. Unadjusted HR, describing time to confirmed abnormal OGTT or T1D, was 0.95 (95% CI 0.56–1.61; P = not significant).

Figure 3

Effects of hydroxychloroquine treatment on metabolic and immunologic measures. A: Glucose mean AUC (MAUC) was analyzed by linear mixed model. MAUC increased significantly over 24 months in the hydroxychloroquine and placebo groups (slope for placebo 0.054 mg/dL per month; P < 0.0001; hydroxychloroquine 0.0334; P = 0.0003; comparison P = 0.199). Individual time points were compared based on likelihood ratio tests. B: C-peptide levels were unchanged over course of the study (slope for placebo 0.0041 pmol/mL per month; P = 0.688; hydroxychloroquine −0.0073 pmol/mL per month; P = 0.31; comparison P = 0.362). C: HbA_1c levels increased in both groups over time (slope for placebo 0.15% per month; P < 0.0001; hydroxychloroquine 0.136% per month; P < 0.0001), but slopes were not significantly different between the treatment arms (comparison P = 0.552). The number of participants in each treatment arm is shown. For all measures, mean ± 95% CI is shown. D: The number of positive autoantibodies at each study visit was determined. Slope describing change in the number of positive autoantibodies increased in placebo group (0.042 per month) but declined in hydroxychloroquine group (−0.090; P = 0.032). The number of participants at each study time point is reported at bottom of the graph. For each graph, red = drug and blue = placebo. *P = 0.034, **P = 0.002.