February 5, 2023

Oral vitamin D supplementation in diabetic neuropathy


Diabetic neuropathy is without doubt one of the microvascular problems of diabetes mellitus, with as much as 30–50% incidences occurring in all diabetic sufferers.1 This complication is without doubt one of the major causes of morbidity and mortality in diabetic sufferers, resulting in a deterioration of their high quality of life.1,2 A deficiency of vitamin D [25-hydroxyvitamin D, 25(OH) D] is widespread in sufferers with diabetes, and low concentrations are related to the presence and severity of sensory neuropathy in diabetes.2–4 Vitamin D deficiency has been proven to be an unbiased danger issue for diabetic peripheral neuropathy (DPN).2,4,5

Earlier research have reported a big enchancment of the signs and the ache of DPN utilizing vitamin D supplementation.2,6–8 Nevertheless, most research lacked lively comparator teams and utilized inadequate information at therapeutic doses to reveal the advantage of vitamin D supplementation on DPN signs. Vitamin D remedy is present process a restricted variety of scientific trials to find out its potential therapeutic advantages. In 51 people with kind 2 diabetes and extreme neuropathy, an open-label potential trial discovered that taking 2000 IU of vitamin D day by day for 3 months resulted in a 50% discount within the visible analog scale (VAS).7 Equally, a scientific trial indicated a big enchancment of neuropathy signs rating in a bunch supplemented with oral vitamin D3 for eight weeks. The first final result was the advance within the sensation of burning or hyperesthesia.2

Painful diabetic neuropathy is characterised by signs of ache, tingling, burning, and cramps within the decrease legs and ft, considerably lowering the standard of life.9–12 Lately, a earlier examine has proven a big discount within the severity of painful diabetic neuropathy after therapy with vitamin D. Vitamin D3 has been proven to cut back nerve demyelination and enhance axonal regeneration.10,12 The present examine assessed the advantages of oral vitamin D 5000 IU (Hello-D 5000) supplementation on sufferers with diabetic neuropathy.


Examine Design and Setting

This examine was a randomized scientific trial, open-label, managed examine with two examine arms performed at a big tertiary hospital in Yogyakarta, Indonesia. The examine enrolment started in December 2020 and was accomplished in March 2021. The experimental group acquired an oral vitamin D 5000 IU (Hello-D 5000) as soon as day by day over eight weeks along with the usual therapy (pregabalin 1×75 mg, gabapentin 1x100mg, or amitriptyline 1x25mg; the dose was adjusted in line with every sufferers’ symptom) for diabetic neuropathy. The management group acquired commonplace therapy solely over the identical interval.


Contributors had been recruited consecutively from the ache clinic in our neurology division. Eligible individuals had been all sufferers with kind 2 diabetes, aged >18 years, with a vitamin D standing of <30 ng/mL) referred to the neurologist division to complain of diabetic peripheral neuropathy signs (ie, burning, tingling). All sufferers had been assessed by a neurologist from historical past taking and bodily examination. The exclusion standards had been topic to vital renal and liver impairment, topic to recognized hypersensitivity with vitamin D supplementation, being pregnant, breastfeeding sufferers, the affected person enrolled in any scientific trial inside a month, and unwillingness to hitch the examine.

Randomization and Blinding

Following written knowledgeable consent, individuals who fulfilled the standards for the therapy part of the examine had been allotted to 1 of two teams. Randomization was carried out utilizing block randomization with a 1:1 ratio and assigned to the experimental (n = 34) or commonplace care (n = 34) trial group. A randomization checklist was generated by a statistician not concerned with the examine, utilizing blocks of 5 stratifications. Full blinding was thought-about tough and never doable. Contributors had been knowledgeable of key components of the respective intervention and follow-up they had been randomized to, however not on details about the therapy and follow-up options within the different group or the examine’s hypotheses.

Moral Consideration

The authors affirm that each one ongoing and associated trials for this drug/intervention are registered. Moral approval for the examine was obtained from the Bethesda Hospital Ethics Committee with the quantity 120/KEPK-RSB/XII/20 and registered within the Indonesian Scientific Trial Registry with the quantity INA-MEODDY6 and ClinicalTrials.gov with the variety of NCT04689958. All examine individuals gave signed knowledgeable consent in accordance with the Declaration of Helsinki.


Initially, we collected the final traits of all topics: age, heights, weights, gender, marital standing, schooling, occupation, well being financing, length of diabetes, comorbidity, comedication, the baseline rating of NDS (Neuropathy Deficit Rating), and NSS (Neuropathy Signs Rating).

The first final result was the change from baseline within the rating on the Visible Analog Scale (VAS), 0 to 10, with decrease scores indicating lesser ache at a complete of 8 weeks therapy length, the Numerical Score Scale (NRS), 0 to 100, to evaluate various kinds of neuropathic ache together with burning ache, electrical shocks ache, tingling, and numbness with decrease scores indicating lesser ache, in addition to the share modifications within the rating on the Temporary Ache Stock (BPI), for ache impression on the interference on day by day life together with sleep high quality, basic exercise, and temper. We measured the themes BPI scores earlier than and after the trial and categorized it into: vastly improved: >50% enchancment on their rating; improved: 30–50% enchancment on their rating; barely improved: 10–30% enchancment on their rating; no enchancment: <10% enchancment on their rating from the baseline. VAS and NRS scores will probably be examined thrice for baseline, week-4, and week-8.

The secondary final result included the change in vitamin D ranges earlier than and after the eight-week trial. Serum 25(OH)D was measured utilizing an enzyme-linked immunoassay (ELISA) technique. We additionally measured the protection profile by monitoring any antagonistic occasions.

Statistical Evaluation

Numerical information had been reported as imply ± Customary Deviation (SD), a categorical information had been reported utilizing frequency and share. The Chi-square check was used for categorical information. The unbiased t-test or Mann–Whitney check had been used to check the imply scores between the 2 teams. Paired t-test or Wilcoxon signed-rank exams had been additionally used to check imply scores at baseline, week-4, and week-8 after intervention in every group. Spearman’s rho correlation coefficients had been calculated to outline the linear affiliation between Vitamin D degree and ache modifications (VAS). Statistical significance was set at p<0.05, and SPSS model 23 was used for statistical evaluation. Intention to deal with evaluation idea will probably be used for all of the statistical evaluation. Lacking information will probably be imputed.


Knowledge from 68 topics had been collected and analyzed. A complete of 68 topics that fulfilled the inclusion and exclusion standards had been randomly assigned to the experimental and management teams, with every group consisting of 34 topics. Because of being misplaced to follow-up, three topics within the experimental group and one within the management group discontinued the examine on the finish of the follow-up interval. (CONSORT circulation chart of the examine; Determine 1).

Determine 1 CONSORT circulation chart of the examine.

Topics’ Baseline Traits

Desk 1 confirmed the baseline traits of the themes. On this examine, feminine topics outnumbered male topics, with 41 (60.3%) feminine topics and 27 (39.7%) male topics taking part. The themes on this examine had a imply age of 64.96 ± 8.3 years. Diabetes has been current in examine topics for a mean of 9.74 ± 7.79 years, with hypertension (58.8%) being essentially the most frequent comorbidity. Antihypertensive drugs (60.3%) had been essentially the most typically used comedication by examine topics, adopted by vitamin B (51.5%), antiplatelet brokers (44.1%), and statins (19.1%). The experimental group’s imply baseline Neuropathy Deficit Rating (NDS) and baseline Neuropathy Signs Rating (NSS) scores had been 4.15 ± 0.93 and a couple of.12 ± 1.01, respectively, whereas the management group’s imply baseline NDS and baseline NSS scores had been 3.88 ± 0.88 and a couple of.5 ± 0.99, respectively. There was no vital distinction in baseline traits and kind of burn between the 2 teams, aside from marital standing.

Desk 1 Baseline Traits

Ache Severity

The Visible Analog Scale (VAS), 0–10, and the Numerical Score Scale (NRS), 0–100, had been used to evaluate ache severity on this examine, as proven in Desk 2. The outcomes confirmed on the baseline, the imply scores of VAS within the experimental and management teams earlier than the intervention had been 5.74 ± 2.16 and 5.46 ± 2.13, respectively. After eight weeks of therapy, the experimental group confirmed a extra vital VAS rating discount than controls (−3.34 ± 2.03 vs −2.37 ± 2.2, p=0.044). Within the burning kind of ache final result at week-8, the imply scores had been considerably decrease within the experimental group in comparison with controls (1.76 ± 7.16 vs 6.18 ± 13.93, p=0.001). The outcomes additionally confirmed that there was no vital distinction within the severity of electrical shocks ache (p = 0.070), tingling (p = 0.415), and numbness (p = 0.373) between the 2 teams on the change from baseline to week-8. The severity of VAS, burning ache, electrical shocks ache, tingling, and numbness had been measured thrice in the course of the examine interval. The rating modifications within-group for all sorts of ache had been considerably totally different in each experimental and management teams (p<0.05).

Desk 2 Evaluating the Imply Scores of Ache Severity Earlier than and After the Intervention Between Each Teams

Whereas a unfavorable correlation was discovered between vitamin D degree and VAS rating at week-8 with Spearman’s rho (r = −0.403, P = 0.018) [Figure 2] within the intervention group, no correlation was discovered within the management group (P > 0.05) [Figure 3].

Determine 2 Correlation between vitamin D ranges [serum 25(OH) D] and the VAS at week-8 within the experimental group.

Determine 3 Correlation between vitamin D ranges [serum 25(OH) D] and the VAS at week-8 within the management group.

Sleep High quality, Basic Exercise, and Temper

Determine 4 and Desk 3 confirmed the impression of therapy on sleep high quality, basic exercise, and temper measured at week 8 of the examine. At week 8, many of the examine individuals within the experimental group had skilled enchancment (>30% enchancment on their rating) of their sleep high quality (76.5% vs 73.5%), basic exercise (88.2% vs 70.6%), and temper (88.2% vs 70.6%) in comparison with controls. There have been no vital variations in sleep high quality (p=0.885) or basic exercise (p=0.096) between the experimental and management teams. Nevertheless, there have been vital variations in temper modifications (p=0.031) between the 2 teams.

Desk 3 Evaluating the Enchancment of Sleep High quality, Basic Exercise, and Temper Between Each Teams at Week 8 (Go to 3)

Determine 4 Distribution of sleep high quality, basic exercise, and temper enchancment at week 8 within the experimental and management teams.

Vitamin D Ranges

Desk 4 and Determine 5 symbolize the imply vitamin D ranges from baseline to week 8 and a comparability of the experimental and management teams. Vitamin D ranges elevated considerably in each teams from baseline to week 8, earlier than and after the intervention (p<0.001). Between the experimental and management teams, there have been vital variations in vitamin D ranges within the experimental and management teams at week 8 (40.02 ± 15.33 vs 18.73 ± 6.88; p<0.001) in addition to vitamin D ranges’ modifications from baseline to week 8 (+24.14 ± 13.68 vs +3.10 ± 4.20; p<0.001), respectively.

Desk 4 Comparability of Vitamin D Ranges [Serum 25(OH) D] Between the Experimental and Management Teams

Determine 5 Change from baseline in imply vitamin D ranges [serum 25(OH) D], earlier than and after the intervention between each teams (in ng/mL).

Antagonistic Occasions

There have been no antagonistic occasions reported in both the experimental or management teams on this examine.


Vitamin D [25-hydroxyvitamin D, 25(OH) D] deficiency is widespread in diabetic sufferers, and low ranges have been linked to the presence and severity of sensory neuropathy.2–4 A serum 25(OH) D degree of lower than 20 ng/mL is taken into account vitamin D deficiency, whereas a serum degree of greater than 30 ng/mL is important to optimize vitamin D’s medical advantages.13,14 This examine aimed to check the ache impression and vitamin D ranges after including oral vitamin D 5000 IU to plain therapy in sufferers with diabetic neuropathy.

Including oral vitamin D 5000 IU to plain therapy was demonstrated higher in modifications of VAS, burning ache, electrical shocks ache, tingling, numbness scores, and vitamin D ranges after eight weeks of therapy in comparison with commonplace therapy alone. A potential observational examine of 51 type-2 diabetic sufferers with neuropathic ache reported that three months of oral vitamin D3 supplementation improved visible analog scale scores considerably from 3.3 to 17.7.7 Moreover, in a placebo-controlled examine involving 112 sufferers with kind 2 diabetes who had been randomly assigned to obtain 50,000 IU of vitamin D as soon as weekly for eight weeks, there was a big enhance in 25(OH)D and an enchancment within the neuropathy symptom rating.2

Vitamin D supplementation is important for sufferers with peripheral neuropathy because it promotes the synthesis of neurotrophins and neurotransmitters. Nociceptive calcitonin gene related peptide (CGRP)-positive neurons have a definite vitamin D phenotype with hormonally managed ligand and receptor ranges, suggesting a mechanistic affiliation between vitamin D and neuropathic ache.15 Vitamin D deficiency causes a rise within the variety of axons expressing CGRP, and vitamin D receptor (VDR) expression is elevated in development cones in tradition, suggesting that VDR-mediated fast response signaling pathways management sprouting.16 Vitamin D supplementation additionally will increase nerve development issue (NGF), a protein wanted for nerve development and upkeep within the peripheral nervous system.17 Moreover, vitamin D deficiency has been attributed to a decrease ache tolerance, which improves when the deficiency is resolved.8

Vitamin D’s pleiotropic profit, which incorporates improved glycemic regulation, is changing into extra extensively recognized. Enhancements in serum vitamin D ranges have been associated to decrease HbA1c ranges, lowered insulin resistance, and enchancment in insulin sensitivity. Vitamin D can also be unlikely to have any antagonistic implications. Thus, vitamin D not solely relieves ache but in addition improves glycemic regulation.10,18–21 Not solely is vitamin D helpful for neuropathy in kind 2 diabetes sufferers, the earlier examine has proven that vitamin D additionally improves neuropathy signs in kind 1 diabetes sufferers.8

Our examine has some limitations. Since this examine was an open-label design, the doable impact of therapy particulars on outcomes needs to be thought-about. The unblinding nature of the examine can also impression the end result. Furthermore, the vitamin D dosage and potential dose adjustment weren’t analyzed and in contrast. Future research with a double-blind design evaluating numerous dosages and adjustment of vitamin D supplementation are wanted to attain the most effective therapeutic choices.


The addition of oral vitamin D 5000 IU to plain therapy considerably improves ache, temper and will increase vitamin D ranges extra successfully than commonplace therapy alone in diabetic neuropathy. Our findings help using vitamin D dietary supplements for the therapy of diabetic neuropathy sufferers.

Knowledge Sharing Assertion

The information supporting the findings of this examine can be found from the primary creator, Rizaldy Taslim Pinzon, on request Kindly contact [email protected] for any queries.


The authors funded this examine.


The authors declare no conflicts of curiosity.


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