Liraglutide treatment reduced interleukin-6 in adults with type 1 diabetes but did not improve established autonomic or polyneuropathy

Abstract

Aims: Type 1 diabetes can be complicated with neuropathy that involves immune-mediated and inflammatory pathways. Glucagon-like peptide-1 receptor agonists such as liraglutide, have shown anti-inflammatory properties, and thus we hypothesized that long-term treatment with liraglutide induced diminished inflammation and thus improved neuronal function.

Methods: The study was a randomized, double-blinded, placebo-controlled trial of adults with type 1 diabetes and confirmed symmetrical polyneuropathy. They were randomly assigned (1:1) to receive either liraglutide or placebo. Titration was 6 weeks to 1.2-1.8 mg/d, continuing for 26 weeks. The primary endpoint was change in latency of early brain evoked potentials. Secondary endpoints were changes in proinflammatory cytokines, cortical evoked potential, autonomic function and peripheral neurophysiological testing.

Results: Thirty-nine patients completed the study, of whom 19 received liraglutide. In comparison to placebo, liraglutide reduced interleukin-6 (-22.6%; 95% confidence interval [CI]: -38.1, -3.2; P = .025) with concomitant numerical reductions in other proinflammatory cytokines. However neuronal function was unaltered at the central, autonomic or peripheral level. Treatment was associated with -3.38 kg (95% CI: -5.29, -1.48; P < .001] weight loss and a decrease in urine albumin/creatinine ratio (-40.2%; 95% CI: -60.6, -9.5; P = .02).

Conclusion: Hitherto, diabetic neuropathy has no cure. Speculations can be raised whether mechanism targeted treatment, e.g. lowering the systemic level of proinflammatory cytokines may lead to prevention or treatment of the neuroinflammatory component in early stages of diabetic neuropathy. If ever successful, this would serve as an example of how fundamental mechanistic principles are translated into clinical practice similar to those applied in the cardiovascular and nephrological clinic.

Trial registration: ClinicalTrials.gov NCT02138045.

Keywords: anti-inflammation; diabetic neuropathy; glucagon-like peptide-1 agonist; interleukin-6; liraglutide.

Figure 1

The consort flow chart shows the progress through this prospective, randomized, double‐blind, parallel‐group, placebo‐controlled trial

Figure 2

Grand mean averages of the cortical evoked potentials from 3 different electrodes, representing the subcortical activation (Oz), the early cortical activation (CP5) and the late cortical activation (C1). It can be seen that there is no difference between liraglutide and placebo in latencies and amplitudes

Figure 3

Liraglutide reduced systemic proinflammatory markers, here shown as relative differences in comparison to placebo. The reduction reached significance for interleukin (IL)‐6; however, a similar numerical trend was present for other proinflammatory cytokines, suggesting a potential systemic anti‐inflammatory effect of the glucagon‐like peptide‐1‐agonist. The error bars illustrate the 95% confidence intervals. IFN = interferon; TNF = tumour necrosis factor