Efficacy of Oral Mixed Tocotrienols in Diabetic Peripheral Neuropathy

Abstract

The Vitamin E in Neuroprotection Study (VENUS) Investigators IMPORTANCE Management of painful diabetic peripheral neuropathy remains challenging. Most therapies provide symptomatic relief with varying degrees of efficacy. Tocotrienols have modulatory effects on the neuropathy pathway and may reduce neuropathic symptoms with their antioxidative and anti-inflammatory activities.OBJECTIVE To evaluate the efficacy of oral mixed tocotrienols for patients with diabetic peripheral neuropathy. DESIGN, SETTING, AND PARTICIPANTSThe Vitamin E in Neuroprotection Study (VENUS) was a parallel, double-blind, placebo-controlled trial that recruited participants from January 30, 2011, to December 7, 2014, with 12 months of follow-up. This trial screened 14 289 patients with diabetes from 6 health clinics and ambulatory care units from 5 public hospitals in Malaysia. A total of 391 patients who reported neuropathic symptoms were further assessed with Total Symptom Score (TSS) and Neuropathy Impairment Score (NIS). Patients 20 years or older with a TSS of 3 or higher and an NIS of 2 or higher were recruited.INTERVENTIONS Patients were randomized to receive 200 mg of mixed tocotrienols twice daily or matching placebo for 12 months. Patients with hyperhomocysteinemia (homocysteine level Ն2.03 mg/L) received oral folic acid, 5 mg once daily, and methylcobalamin, 500 μg thrice daily, in both groups. MAIN OUTCOMES AND MEASURESThe primary outcome was patient-reported neuropathy TSS (lancinating pain, burning pain, paresthesia, and asleep numbness) changes at 12 months. The secondary outcomes were NIS and sensory nerve conduction test result. RESULTSOf 391 eligible patients, 300 were recruited (130 [43.3%] male; mean [SD] age, 57.6 [8.9] years; mean [SD] duration of diabetes, 11.4 [7.8] years) and 229 (76.3%) completed the trial. The TSS changes between the tocotrienols and placebo groups at 12 months (−0.30; 95% CI, −1.16 to 0.56; P = .49) were similar. No significant differences in NIS (0.60; 95% CI, −1.37 to 2.65; P = .53) and sensory nerve conduction test assessments were found between both groups. In post hoc subgroup analyses, tocotrienols reduced lancinating pain among patients with hemoglobin A 1C levels greater than 8% (P = .03) and normohomocysteinemia (homocysteine level <2.03 mg/L; P = .008) at 1 year. Serious adverse events in both groups were similar, except more infections were observed in the tocotrienols group (6.7% vs 0.7%, P = .04). Results reported were of modified intention-to-treat analyses.CONCLUSIONS AND RELEVANCE Supplementation of oral mixed tocotrienols, 400 mg/d for 1 year, did not improve overall neuropathic symptoms. The preliminary observations on lancinating pain among subsets of patients require further exploration.

Potential Role of Tocotrienols on Non-Communicable Diseases: A Review of Current Evidence

“…Furthermore, the T3 mixture (100 mg/kg body weight/day) also improved the nociceptive threshold on thermal hyperalgesia, mechanical hyperalgesia, and tactile allodynia by reducing the oxidative stress, inflammation, and cellular damage in the sciatic nerves of diabetic rats [323]. However, oral mixed T3 (400 mg/day) supplementation for 1 year did not significantly reduce neuropathic symptoms among 229 DM patients with diabetic peripheral neuropathy syndromes as reported from VENUS human study [341]. Overall, the effects of T3 on energy metabolism are summarized in Figure 10.…”

“…In addition, supplementation of T3-enriched canola oil (200 mg/day) significantly reduced the fasting blood glucose level among T2DM patients [329]. Similarly, the Vitamin E in Neuroprotection Study (VENUS) also revealed that consumption of oral mixed T3 (400 mg/day) capsule for 12 months resulted in slightly better glycemic control with no adverse effect among DM patients, but failed to reduce the diabetic neuropathic symptoms [341]. On the other hand, Wan Nazaimoon et al reported that Palmvitee did not improve glycemic control of T1DM patients [330].…”

“…T3s (especially γT3 and δT3) were demonstrated to improve glycemic control in in vitro studies [316,318], obese animals [102,103,313,316], diabetic animals [58,318,319,[322][323][324][325]327,328,[337][338][339][340], and human population [329,[341][342][343]. There is a lack of study reported on the hypoglycemic effect of T3 on the obese population.…”

“…The anti-diabetic activities of T3 on human studies are heterogeneous [72,320,329,330,[341][342][343]. A Finnish Mobile Health Examination Survey with 23-years of the follow-up period on 2285 men and 2019 women (free from DM in starting) identified that dietary intake of βT3 was significantly associated with the lower risk of T2DM [343].…”

Rate of neuropathic progression in hereditary transthyretin amyloidosis with polyneuropathy and other peripheral neuropathies: a systematic review and meta-analysis

“…Amongst the 15 studies, four were non-interventional studies [ 30 – 32 ] (Karam Chafic: A registry study of patients with different peripheral neuropathies, unpublished) and the remaining 11 were RCTs [ 6 – 8 , 19 , 28 , 29 , 33 – 37 ]. Eleven studies reported the neuropathic progression measured by the total NIS score, and nine studies reported the change of the total NIS-LL score over time.…”