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

Abstract

AimsType 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.MethodsThe 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.ResultsThirty‐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).ConclusionHitherto, 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.

Effect of treatment with exenatide and pioglitazone or basal-bolus insulin on diabetic neuropathy: a substudy of the Qatar Study

“…However, a study of 39 patients with T1D and established neuropathy randomized to liraglutide or placebo over 26 weeks recently failed to show a benefit on autonomic function or sensory and motor nerve conduction. 36 TZDs have also been reported to have a neuroprotective effect. In preclinical studies, Qiang et al 12 reported that troglitazone prevented nerve conduction slowing and maintained normal myelinated fiber architecture and density in T1D rats.…”

Increased levels of inflammatory factors are associated with severity of polyneuropathy in type 1 diabetes

“…The increasing recognition of neuroinflammation as a potential key player in the pathogenesis of DSPN has recently paved the way for novel experimental therapeutic strategies aimed at dampening inflammatory immune processes 28,29 . Studies conducted in animal models of DSPN have shown promising results including lower circulating levels of pro‐inflammatory cytokines as well as improved nerve conduction velocity after treatment with drugs with anti‐inflammatory properties 30 .…”

Diabetic peripheral neuropathy in people with type 2 diabetes: too little too late

“…The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial showed a significantly lower incidence of ulcer-related foot amputations in participants on liraglutide compared to placebo [37], suggesting a beneficial effect on neuropathy. A study of exenatide [38] showed no benefit on symptoms and deficits or intraepidermal nerve fibre density, and another study of liraglutide [39] showed no benefit with regard to neurophysiology. The Steno-2 trial showed that intensive risk factor management, targeting glucose, blood pressure, lipids, smoking and other lifestyle factors in a group of people with type 2 diabetes and albuminuria, prevented retinopathy and nephropathy but had no effect on vibration perception threshold [40].…”

“…The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial showed a significantly lower incidence of ulcer‐related foot amputations in participants on liraglutide compared to placebo , suggesting a beneficial effect on neuropathy. A study of exenatide showed no benefit on symptoms and deficits or intraepidermal nerve fibre density, and another study of liraglutide showed no benefit with regard to neurophysiology.…”