Development and Progression of Polyneuropathy Over 5 Years in Patients With Type 2 Diabetes.

BACKGROUND AND OBJECTIVES: There is a need for knowledge regarding the natural course of diabetic polyneuropathy (DPN), a complication in type 2 diabetes (T2D). The aim of this study was to examine the development of DPN over time. METHODS: Patients with newly diagnosed T2D, recruited from a national cohort, and controls without diabetes of similar age and sex, underwent sensory phenotyping in 2016-2018. The Toronto consensus criteria were used to classify patients into possible, probable, and confirmed DPN. For this 5-year, observational, follow-up, cohort study, all participants were invited to a reexamination combining bedside sensory examination, quantitative sensory testing (QST), nerve conduction studies (NCSs), and skin biopsies measuring intraepidermal nerve fiber density (IENFD) in order to compare phenotypic and diagnostic changes over time. RESULTS: Of the baseline 389 patients and 97 controls, 184 patients (median [interquartile range] diabetes duration 5.9 [4.1-7.4] years, mean hemoglobin A1c [HbA1c] 51 ± 11 mmol/mol at baseline) and 43 controls completed follow-up (46.9%). Confirmed DPN was present in 35.8% and 50.3%, probable DPN in 27.2% and 14.6%, possible DPN in 17.2% and 16.6%, and no DPN in 15.2% and 17.9% at baseline and follow-up, respectively. The estimated prevalence (95% CI) of confirmed DPN was 33.5% (24.9-42.1) compared with 22.7% (17.5-28.0) at baseline. During the follow-up period, 43.9% of patients with probable DPN developed confirmed DPN. Progression of neuropathy occurred in 16.5% and 24.7% and regression in 5.9% and 18.6% of patients based on NCS and IENFD, respectively. Progression based on NCS and/or IENFD was associated with higher baseline waist circumference and triglycerides, and regression with lower baseline HbA1c. Patients with at least probable DPN at baseline but neither patients without DPN nor controls developed increased spread of hyposensitivity, more hyposensitivity on QST and lower NCS z-scores at follow-up, and worsening of nerve parameters at follow-up correlated with higher baseline triglycerides. DISCUSSION: In patients with well-regulated T2D, the proportion of patients with confirmed DPN increased over 5 years driven by progression from probable DPN. A large proportion of patients progressed, and a smaller proportion regressed on nerve parameters. Higher triglycerides correlated with this progression and may constitute a risk factor.

The effect of lacosamide in peripheral neuropathic pain: A randomized, double-blind, placebo-controlled, phenotype-stratified trial.

BACKGROUND: Neuropathic pain is common and difficult to treat. The sodium channel blocker lacosamide is efficacious in animal models of pain, but its effect on neuropathic pain in humans is inconclusive. METHODS: In a multicentre, randomized, double-blinded placebo-controlled phenotype stratified trial, we examined if lacosamide produced better pain relief in patients with the irritable nociceptor phenotype compared to those without. The primary outcome was the change in daily average pain from baseline to last week of 12 weeks of treatment. Secondary and tertiary outcomes included pain relief, patient global impression of change and presence of 30% and 50% pain reduction. RESULTS: The study was prematurely closed with 93 patients included and 63 randomized to lacosamide or placebo in a 2:1 ratio, of which 49 fulfilled the per protocol criteria and was used for the primary objective. We did not find a better effect of lacosamide in patients with the irritable nociceptor phenotype, the 95% CI for the primary objective was 0.41 (-1.2 to 2.0). For all patients randomized, lacosamide had no effect on the primary outcome, but significantly more patients were responders to lacosamide than during placebo, with an NNT of 4.0 (95% CI 2.3-16.1) and 5.0 (95% CI 2.8-24.5) for 30% and 50% pain reduction respectively. We did not identify any predictors for response. Lacosamide was generally well tolerated. CONCLUSION: We could not confirm that lacosamide was more efficacious in patients with the irritable nociceptor type, but the study was prematurely closed, so we cannot exclude a small difference. SIGNIFICANCE: Treatment of neuropathic pain is often a trial and error process. Little is known about which patient benefit from which kind of medication. The sodium channel blocker lacosamide shows variable effect on neuropathic pain. Pain sensory phenotype, as defined by quantitative sensory testing, did not predict response to treatment with lacosamide.