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Effects of exenatide on measures of diabetic neuropathy in subjects with type 2 diabetes: results from an 18-month proof-of-concept open-label randomized study.

ABSTRACT: Experimental studies have reported potential benefit of glucagon-like peptide-1(GLP-1) receptor agonists in preventing diabetic peripheral neuropathy (DPN). We therefore performed a proof-of-concept pilot study to evaluate the effect of exenatide, a GLP-1 agonist, on measures of DPN and cardiovascular autonomic neuropathy (CAN) in patients with type 2 diabetes (T2D).Forty-six T2D subjects (age 54±10years, diabetes duration 8±5years, HbA1c 8.2±1.3%) with mild to moderate DPN at baseline were randomized to receive either twice daily exenatide (n=22) or daily insulin glargine (n=24). The subjects, with similar HbA1c levels, were followed for 18months. The primary end point was the prevalence of confirmed clinical neuropathy (CCN). Changes in measures of CAN, other measures of small fiber neuropathy such as intra-epidermal nerve fiber density (IENFD), and quality of life were also analyzed.Glucose control was similar in both groups during the study. There were no statistically significant treatment group differences in the prevalence of CCN, IENFD, measures of CAN, nerve conductions studies, or quality of life indices.In this pilot study of patients with T2D and mild to moderate DPN, 18months of exenatide treatment had no significant effect on measures of neuropathy compared with glargine treatment.

SUBMITTER: Jaiswal M

PROVIDER: S-EPMC4656068 | biostudies-literature | 2015 Nov-Dec

REPOSITORIES: biostudies-literature

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Effects of exenatide on measures of diabetic neuropathy in subjects with type 2 diabetes: results from an 18-month proof-of-concept open-label randomized study.

Jaiswal Mamta M Martin Catherine L CL Brown Morton B MB Callaghan Brian B Albers James W JW Feldman Eva L EL Pop-Busui Rodica R

Journal of diabetes and its complications 20150717 8

<h4>Objective</h4>Experimental studies have reported potential benefit of glucagon-like peptide-1(GLP-1) receptor agonists in preventing diabetic peripheral neuropathy (DPN). We therefore performed a proof-of-concept pilot study to evaluate the effect of exenatide, a GLP-1 agonist, on measures of DPN and cardiovascular autonomic neuropathy (CAN) in patients with type 2 diabetes (T2D).<h4>Research design and methods</h4>Forty-six T2D subjects (age 54±10years, diabetes duration 8±5years, HbA1c 8.2 ...[more]

PMID: 26264399

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Project description:BackgroundPainful diabetic peripheral neuropathy (PDPN) affects up to 26% of patients with diabetes mellitus, with major impacts on their general health and well-being. Most available drugs fail to deliver acceptable pain reduction in the majority of patients and are often poorly tolerated. NRD.E1 is a novel product that has shown anti-nociceptive preclinical effects and good tolerability in healthy volunteer studies.MethodsThis phase 2a, randomized, dose-finding, Proof of Concept study enrolled patients with PDPN of ≥3 months duration. After at least one treatment-free week (WO week), 88 patients entered a 1-week single-blind (SB)-placebo run-in period, followed by 3 weeks' double-blind (DB) treatment, during which they received NRD.E1 at 10, 40 or 150 mg/day or placebo.ResultsThe primary endpoint (change from SB-placebo run-in week to week 3 in weekly mean of daily average numerical rating scale [NRS] pain intensity) showed clinically relevant placebo-corrected treatment effect pain reductions at 40 mg and 150 mg/day of 0.82 (95% CI: 0.07, 1.58, p = 0.034) and 0.66 (95% CI: -0.03, 1.35; p = 0.061) NRS points, respectively, though did not meet the pre-specified value of p = 0.016 required due to multiplicity. An additional post hoc endpoint looking at the change from WO baseline to week 3 in weekly mean of daily average NRS showed the placebo-corrected treatment effect was 1.46 (95% CI: 0.26, 2.66), and 1.20 (95% CI: 0.10, 2.29) NRS points, respectively. Secondary and post hoc analyses of NRS pain data (including 30 & 50% responder rate and NNT), sleep interference, Short-form McGill pain questionnaire (especially pain intensity assessed on Visual Analogue Scale), Patient's and Clinician's Global Impression of Change showed effects consistent with the primary findings. NRD.E1 was well tolerated, with only headache reported in more than two patients and more frequently on NRD.E1 than placebo.ConclusionsThe data suggest that NRD.E1 potentially represents a novel non-opioid therapeutic option for patients with PDPN, with at least similar efficacy and better tolerability than available therapies, justifying its further evaluation in larger-scale confirmatory studies.SignificanceNRD.E1 is a novel non-opioid therapeutic which is being developed for the treatment of PDPN. In this randomized, controlled, dose-finding, Proof of Concept study, NRD.E1 induced a clinically relevant pain reduction and it was well tolerated. Available data suggest that NRD.E1 has at least similar efficacy and better tolerability than the currently available therapies, potentially offering a promising new therapeutic option to patients with PDPN and possibly other neuropathic pain indications.

Project description:IntroductionPeople with diabetic peripheral neuropathy (DPN) and limited joint mobility syndrome (LJMS) can experience increased forefoot peak plantar pressures (PPPs), a known risk factor for ulceration. The aim of this study was to investigate whether ankle and 1st metatarsophalangeal (MTP) joint mobilisations and home-based stretches in people with DPN improve joint range of motion (ROM) and reduce forefoot PPPs.Design and methodsSixty-one people with DPN (IWGDF risk 2), were randomly assigned to a 6-week programme of ankle and 1st MTP joint mobilisations (n = 31) and home-based stretches or standard care only (n = 30). At baseline (T0); 6-week post intervention (T1) and at 3 months follow-up (T2), a blinded assessor recorded dynamic ankle dorsiflexion range using 3D (Codamotion) motion analysis and the weight bearing lunge test, static 1st MTP joint dorsiflexion ROM, dynamic plantar pressure and balance.ResultsAt T1 and T2 there was no difference between both groups in ankle dorsiflexion in stance phase, plantar pressure and balance. Compared to the control group, the intervention group showed a statistically significant increase in static ankle dorsiflexion range (Left 1.52 cm and 2.9cms, Right 1.62 cm and 2.7 cm) at 6 (T1) and 18 weeks (T2) respectively p < 0.01). Between group differences were also seen in left hallux dorsiflexion (2.75°, p < 0.05) at T1 and in right hallux dorsiflexion ROM (4.9°, p < 0.01) at T2 follow up. Further, functional reach showed a significant increase in the intervention group (T1 = 3.13 cm p < 0.05 and T2 = 3.9 cm p < 0.01). Intervention adherence was high (80%).ConclusionsCombining ankle and 1st MTP joint mobilisations with home-based stretches in a 6-week programme in people with DPN is effective in increasing static measures of range. This intervention may be useful for improving ankle, hallux joint mobility and anteroposterior stability limits in people with diabetes and neuropathy but not for reducing PPP or foot ulcer risk.Trial registrationhttps://classic.Clinicaltrialsgov/ct2/show/NCT03195855 .

Dataset Information

Effects of exenatide on measures of diabetic neuropathy in subjects with type 2 diabetes: results from an 18-month proof-of-concept open-label randomized study.

Publications

Effects of exenatide on measures of diabetic neuropathy in subjects with type 2 diabetes: results from an 18-month proof-of-concept open-label randomized study.

Similar Datasets

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