Is anti-inflammatory therapy for type 2 diabetes mellitus ready for routine clinical practice?

Abstract

BACKGROUND: Type 2 diabetes mellitus (T2DM) is characterized by a progressive loss of pancreatic function, which results in part from increased β-cell apoptosis. The inflammatory cytokine interleukin 1β (IL-1β) is a putative mediator of apoptosis in this context.

OBJECTIVE: To evaluate the efficacy of a recombinant IL-1-receptor antagonist (anakinra) as a novel therapy for T2DM.

DESIGN AND INTERVENTION: This was a 13-week, double-blind, placebo-controlled study of anakinra in adults with T2DM. Inclusion criteria included age ≥20 years, disease duration >3 months, HbA_1c level >7.5%, BMI >27 kg/m², and stable medication in the 3-month period before enrollment. Exclusion criteria included autoantibody-positivity, HbA_1c >12%, fasting C-peptide level <0.400 nmol/l, current use of anti-inflammatory agents, infection, neutropenia, anemia, liver or renal disease, cancer, and immunodeficiency. Eligible participants were randomly allocated to receive 100 mg anakinra or placebo, self-administered by subcutaneous injection every morning. All other antidiabetic medications or lifestyle interventions remained unchanged. A 2 h oral glucose tolerance test was performed at baseline and week 13 to assess the levels of glucose, proinsulin, insulin, and C-peptide. Insulin sensitivity was assessed by euglycemia–hyperinsulinemia clamp analysis and insulin-regulated gene expression was determined from skeletal muscle biopsies.

OUTCOME MEASURES: The primary outcome measure was the change from baseline in HbA_1c. Secondary outcome measures included β-cell function, insulin sensitivity, insulin-regulated gene expression, and the levels of adipokines and inflammatory markers.

RESULTS: A total of 34 patients received anakinra. The placebo group comprised 35 patients, 2 of whom withdrew before study end. The mean HbA_1c level at baseline was 8.7% in the anakinra group and 8.2% in the placebo group. By week 13, the mean HbA_1c level was reduced by 0.33% in the anakinra group but was increased by 0.13% in the placebo group. The between-group difference in the mean HbA_1c level was 0.46% (95% CI 0.01–0.90%, P = 0.03). Overall, 61.8% of patients in the anakinra group experienced a reduction in HbA_1c, compared with only 30.3% of patients in the placebo group (P <0.001). The effect of anakinra on the HbA_1c level was apparent from 4 weeks of treatment (P = 0.004). When compared with placebo, the ratio of proinsulin to insulin was lower in the anakinra group (P = 0.005). In addition, C-peptide secretion was enhanced (P = 0.04) in the anakinra group. Treatment with anakinra was also associated with reduced levels of inflammatory markers and decreased neutrophil and platelet counts. By contrast, there were no significant differences between the groups in BMI, insulin sensitivity, insulin-regulated gene expression, or adipokine levels. Transient injection-site reactions were reported by 17 patients in the anakinra group.

CONCLUSION: Treatment with anakinra reduced inflammation and improved β-cell function and glycemic control of patients with T2DM.