Metanx in Type 2 Diabetes with Peripheral Neuropathy:A Randomized TrialVivian A. Fonseca, MD,a,b Lawrence A. Lavery, DPM, MPH,c Tina K. Thethi, MD,a,b Yahya Daoud, PhDC,d
Cyrus DeSouza, MD,e Fernando Ovalle, MD,f Douglas S. Denham, DO,g Teodoro Bottiglieri, PhD,h Peter Sheehan, MD,i
Julio Rosenstock, MDj
aTulane University Health Sciences Center, New Orleans, La; bSoutheast Louisiana Veterans Health Care System, New Orleans; cScott& White Memorial Hospital, Temple, Tex; dBaylor Health Care System, Department of Quantitative Sciences, Dallas, Tex; eOmaha VA
edical Center, Omaha, Neb; fUniversity of Alabama at Birmingham School of Medicine, Birmingham; gdgd Research, Inc., Sanntonio, Tex; hBaylor Research Institute, Dallas, Tex; iSheehan Health Management Consulting, LLP, New York, NY; jDallas Diabetes
and Endocrine Center at Medical City, Dallas, Tex.
PURPOSE: To determine whether a combination of L-methylfolate, methylcobalamin, and pyridoxal-5=-phosphate (LMF-MC-PLP [Metanx; Pamlab LLC, Covington, La]) improves sensory neuropathy.RESEARCH DESIGN AND METHODS: This multicenter, randomized, double-blind, placebo-controlled trial in-volved 214 patients with type 2 diabetes and neuropathy (baseline vibration perception threshold [VPT]: 25-45volts), who were randomly assigned to 24 weeks of treatment with either L-methylfolate calcium 3 mg,methylcobalamin 2 mg, and pyridoxal-5=-phosphate 35 mg or placebo. The primary end point was effect onVPT. Secondary end points included Neuropathy Total Symptom Score (NTSS-6) and Short Form 36 (SF-36),as well as plasma levels of folate, vitamins B6 and B12, methylmalonic acid (MMA), and homocysteine.ESULTS: There was no significant effect on VPT. However, patients receiving LMF-MC-PLP consistentlyeported symptomatic relief, with clinically significant improvement in NTSS-6 scores at week 16 (P � .013 vslacebo) and week 24 (P � .033). Improvement in NTSS scores was related to baseline MMA and inverselyelated to baseline PLP and metformin use. Quality-of-life measures also improved. Homocysteine decreased by.7 � 3.0 �mol/L with LMF-MC-PLP versus an increase of 0.5 � 2.4 �mol/L with placebo (P � .0001).dverse events were infrequent, with no single event occurring in �2% of subjects.ONCLUSIONS: LMF-MC-PLP appears to be a safe and effective therapy for alleviation of peripheraleuropathy symptoms, at least in the short term. Additional long-term studies should be conducted, as therial duration may have been too short to show an effect on VPT. In addition, further research on the effectsn patients with cobalamin deficiency would be useful.
2013 Elsevier Inc. All rights reserved. • The American Journal of Medicine (2013) 126, 141-149
KEYWORDS: Diabetic peripheral neuropathy; Symptomatic treatment; Vitamin B complex
SEE RELATED EDITORIAL p. 95
Diabetic peripheral neuropathy results from prolonged hy-perglycemia through multiple complex mechanisms andcauses debilitating neuropathic pain or loss of sensation in
Funding: Supported by Pamlab LLC.Conflict of Interest: VAF, TKT, PS, and TB have received research
upport or consulting fees from Pamlab LLC. VAF is supported in part byhe Tullis-Tulane Alumni Chair in Diabetes supporting diabetes research atulane University Health Sciences Center.
Authorship: VAF served as principal investigator, and all other au-hors were involved in conducting the study or analysis of the data. The full
vailable at Pamlab. All authors interpreted the data and
the extremities.1,2 Controlling hyperglycemia may preventthis condition, but treatment options are limited. Duloxetineand pregabalin are approved in the US for treatment of
were involved in the drafting or critical review of the manuscript, and eachauthor approved the final manuscript content.
Requests for reprints should be addressed to Vivian Fonseca, MD,Department of Medicine and Pharmacology, Tullis-Tulane Alumni Chairin Diabetes, Section of Endocrinology, Tulane University Health SciencesCenter, 1430 Tulane Avenue - SL 53, New Orleans, LA 70112.
142 The American Journal of Medicine, Vol 126, No 2, February 2013
painful neuropathy but do not address the underlying pa-thology of the disease or improve sensation. The magnitudeof the problem and the paucity of treatments call out foralternative approaches.
One possible novel tactic is to use a combination ofL-methylfolate, methylcobalamin,and pyridoxal-5=-phosphate, thebiologically active and immedi-ately bioavailable forms of folate,vitamin B12, and vitamin B6, re-spectively. Deficiencies of vita-mins B12 and B6 may contribute toeurologic deficits, and folate im-roves vascular function.3-10
Based on these observations, thisstudy was designed to determinewhether the medical food L-meth-ylfolate calcium 3 mg, methylco-balamin 2 mg, and pyridoxal-5=-phosphate 35 mg (LMF-MC-PLP[Metanx; Pamlab LLC, Coving-ton, La]) improves sensory neu-ropathy in patients with type 2diabetes.
METHODSPatients aged 25 to 80 years withtype 2 diabetes and neuropathy (baseline vibration percep-tion threshold [VPT]: 25-45 volts at hallux on either leg)were recruited at 6 research clinics and hospitals throughoutthe US. Patients were randomly assigned to treatment withLMF-MC-PLP or placebo for 24 weeks. Opiates were notpermitted, but other neuropathy medications (eg, pregaba-lin, gabapentin, duloxetine) could be used as long as ther-apies had been initiated for painful diabetic neuropathymore than 2 months before screening and doses were keptconstant during the study. Dose modifications of currentantidiabetic, lipid, and blood pressure medications wereallowed at the discretion of the investigator, but no newtreatments could be started during the trial or within the 2months before screening. The protocol was approved by theinstitutional review board at each site, and all participantsgave informed written consent before participation. Thetrial was conducted from June 2008 to May 2010.
Exclusion criteria included peripheral vascular disease (pal-pable pedal pulse in both feet, no intermittent claudication, nohistory of lower extremity vascular bypass surgery or angio-plasty); amputation or ulceration within 2 years before screen-ing; Charcot neuroarthropathy; previous surgery to spine orlower extremity with residual pain or impaired mobility; severearthritis causing pain upon walking; A1C �9% at screening;blood pressure �160/90 mm Hg or uncontrolled asthma orhortness of breath in the 2 months before screening; advancedenal disease (serum creatinine �2.5 times the upper limit oformal); pregnant or nursing; and history of alcohol or drug
CLINICAL SIGNIF
● Approximately 3abetes have pleading to debiltion loss and po
● Available treatmadverse effects aunderlying pathripheral neuropa
● Vitamin B deficienparticularly with m
● A specific vitamrepresent a safeperipheral neuro
buse within the past 3 years. The following additional restric-
ions were placed on supplement and medication usage: no�-lipoic acid or B12 injection within 2 months before screen-ng; no more than 10 mg of B6 or 800 �g of folate within 2
onths before screening; maximum dose of any anticonvul-ant and no current treatment with systemic steroids, immuno-
suppressives, or radiotherapy.Randomization schedules were
generated 1:1 separately for eachof the 6 sites, with 50% assign-ment to either LMF-MC-PLP orplacebo using a computer-gener-ated randomization number list.The study medication and placebowere identical in appearance andwere administered as 1 tablettaken twice daily.
Outcomes were assessed at base-line and weeks 8, 16, and 24, and allassessment tools were used con-sistently across all sites and studypopulations. The primary endpoint of the study was VPT asmeasured by the VPT Meter (Dia-betica Solutions, San Antonio,Tex) on the great toe of each foot.Secondary end points includedneuropathic symptoms as evalu-
ted by a modified 6-item Neuropathy Total Symptomcore (NTSS-6) and disability as measured by the Neurop-thy Disability Score (NDS), as well as plasma levels ofolate and its active form, 5-methyltetrahydrofolate (5-
THF), PLP, vitamin B12 and its metabolite methylmaloniccid (MMA), and homocysteine. Additional secondary endoints included health-related quality of life as determinedy the Medical Outcomes Study Short-Form 36-Item Healthurvey (SF-36) and participants’ lower-extremity pain per-eption measured using a 10-point visual analog scale. Ex-loratory end points included plasma levels of high-sensi-ivity C-reactive protein, interleukin 6, malondialdehyde,otential antioxidant, tumor necrosis factor �, 3-nitroty-
rosine, S-adenosylmethionine (SAM), and S-adenosylho-mocysteine (SAH). Depression also was evaluated as anexploratory outcome using the Hospital Anxiety and De-pression Scale (HADS) question inventory.
All adverse events were collected and reported using anAdverse Event Case Report Form. They included any unde-sirable sign, symptom, or medical condition occurring afterstarting the study intervention (ie, LMF-MC-PLP or placebo),including those considered unrelated to the intervention. Seri-ous adverse events were identified as those that are fatal orlife-threatening or result in hospitalization, significant disabil-ity, birth defects, or medical or surgical intervention.
Statistical AnalysisThe sample size of 216 subjects was calculated based on ananalysis of variance model, assuming an SD of 16 for the
CE
patients with di-eral neuropathy,g pain or sensa-amputation.
arry a high risk ofo not address the
of diabetic pe-
ommon in diabetes,min treatment.
formulation mayoach for diabeticsymptom relief.
ICAN
5% oferiphitatinssible
ents cnd dologythy.
cy is cetfor
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primary end point of change in VPT, with a significance
tutgtmnWcSp
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143Fonseca et al Metanx in Diabetic Neuropathy
level of 0.05, and assuming a drop-out rate of 20%, suchthat 90 patients per arm would complete the trial. For thepurposes of the statistical analyses, assessments of VPT,visual analog scale, HADS, and the SF-36 had a normaldistribution, while the NDS and NTSS-6 had a multinomialdistribution. Overall and by subgroups, descriptive statisticssuch as means, SDs for continuous measurements, and fre-quencies and percentages for categorical measurementswere summarized in tables. Fisher’s exact test and chi-squared analysis were utilized to evaluate the differencesbetween the 2 groups for categorical variables such as raceand sex; Student’s t test and analysis of variance were usedo evaluate the difference between the 2 groups for contin-ous variables. Generalized linear mixed models were usedo assess baseline for continuous and discrete outcomes, andeneralized linear mixed models differing with respect toheir fixed effects, random effects, and residual covarianceatrix were examined. Type III tests were used to test the
ull hypothesis that a specific fixed effect equals zero, andald z-tests were used to test for significant random inter-
epts. MP (MPSOFTWARE ApS, Helsingør, Denmark) andAS (SAS Institute Inc., Cary, NC) software were used to
Table 1 Baseline Characteristics
Age, mean � SD (years)Male sex, n (%)Race/ethnicity, n (%)
Black/African AmericanOther*WhiteHispanic/Latino
Diabetes duration, mean � SD (years)A1C, mean � SD (%)History of DPN, n (%)DPN duration, mean � SD (years)History of diabetic retinopathy, n (%)Medication usage
*American Indian/Alaska Native, Asian, Native Haw†Glipizide, glimepiride, or glyburide.‡Pioglitazone or rosiglitazone.§Sitagliptin.¶Exenatide.
erform all analyses.
RESULTSOf 373 patients screened, 214 entered the study, and 200completed it. Table 1 shows baseline characteristics forthe study population. The mean age of participants was62.6 � 8.9 years, with a mean duration of diabetes of11.5 � 9.0 years and neuropathy of 6.1 � 6.3 years. Themajority of participants were white men, but there wereno differences between treatment groups in age, race,ethnicity, duration of diabetes or neuropathy, and base-line outcome measures. Mean A1C levels also were sim-ilar at baseline and remained stable throughout the study:at 24 weeks, A1C was 7.0% in both groups. At baseline,mean levels of vitamin B12, MMA, and homocysteine
ere all within normal limits. However, 12 patients in theMF-MC-PLP and 18 in the placebo groups had below-ormal baseline B12 levels, while homocysteine was el-
evated in 8 LMF-MC-PLP and 16 placebo patients, andMMA in 3 LMF-MC-PLP and 4 placebo patients,respectively.
Throughout the study, VPT, the primary outcome,did not differ significantly between the LMF-MC-PLPand placebo groups. Mean baseline VPT ranged from
peptidase; GLP-1 � glucagon-like peptide 1; LMF-MC-sphate.Pacific Islander, or not defined.
eptidyl-5=-phoaiian/
32.16 � 13.00 to 33.88 � 14.24 volts across treatment
cnc
c
s
Sui(
oaDtdtMprLsf
ida
h
144 The American Journal of Medicine, Vol 126, No 2, February 2013
groups and left and right great toes. By week 24, meanVPT (averaged across both toes) had decreased in bothgroups: �1.96 � 13.08 volts with LMF-MC-PLP and�3.27 � 10.32 volts with placebo. The treatment differ-ences at each visit were not statistically significant.
Table 2 shows the data for all secondary and exploratoryend points. Neuropathy symptoms, as measured by changesin mean NTSS-6 scores, improved significantly in patientsreceiving LMF-MC-PLP: �0.90 � 1.42 at week 16 and�0.96 � 1.54 at week 24, compared with �0.40 � 1.72(P � .013) and �0.53 � 1.69 (P � .033) in the placebogroup at weeks 16 and 24, respectively (Figure 1). LMF-MC-PLP patients also experienced significantly less neu-ropathy-related disability as measured by the NDS at week16 (�0.78 � 2.13 for LMF-MC-PLP vs. �0.18 � 2.24 forplacebo; P � .027), although the difference was no longerstatistically significant at week 24. Patients receiving LMF-MC-PLP also reported modest but significant improvementin quality-of-life measures. Scores on the mental componentsubscale of the SF-36 improved by almost 2 points withLMF-MC-PLP (1.99 � 8.57), compared with a decrease inthe placebo group (�0.29 � 8.48; P � .031).
As expected, plasma levels of folate and 5-MTHF, vitaminB12, and PLP increased significantly, while MMA levels de-reased (Table 2). By week 24, homocysteine decreased sig-ificantly in the LMF-MC-PLP group by 2.68 �2.98 �mol/L,ompared with an increase of 0.48�2.40 �mol/L with pla-
cebo (P� .0001). There were no other statistically significanthanges (Table 2).
As shown in Table 3, improvement in NTSS-6 wasignificantly inversely associated with baseline PLP (P�.003). There also was a significant inverse association withAM (P� .045) and a negative association with metforminse (P� .0215). The same model also showed that the changen quality of life was positively associated with MMAP� .007).
Adverse events were infrequent, with no single eventccurring in �2% of subjects. Table 4 shows rates ofdverse events grouped by categories from the Medicalictionary for Regulatory Activities,11 where the combined
otal occurred in �2% of patients. There were 2 deathsuring the trial, both in the placebo group. In addition, aransient ischemic attack occurred in 1 patient in the LMF-
C-PLP group, and a severe case of dyspnea occurred in 1atient in the placebo group. Neither event was consideredelated to study intervention. There was 1 case of rash in theMF-MC-PLP group that the investigator considered pos-ibly related to study intervention. No patients withdrewrom the study due to adverse events.
DISCUSSIONThe present study is the first randomized, placebo-con-trolled investigation to examine vitamin B in the form ofLMF-MC-PLP. Over 24 weeks, VPT decreased in bothtreatment groups, with no significant between-group differ-
ences. In contrast, relative to placebo, LMF-MC-PLP sig-
nificantly improved neuropathy symptoms at 16 and 24weeks and disability at 16 weeks. Improvement in symp-tom scores was inversely associated with baseline PLP(P � .003) and positively associated with changes in PLP(P � .003) and SAM (P � .045). In addition, metformin usewas associated with less improvement in NTSS-6 score(P � .0215). The mental component of the SF-36 improvedsignificantly, suggesting that patients taking LMF-MC-PLPfelt better. Adverse events were infrequent and mostly mildto moderate, occurred at similar rates in the 2 treatmentgroups, and did not lead to any withdrawals.
The treatment failed to meet the primary end point ofchange in VPT. However, this measure may not be sensitiveenough to detect changes in nerve function attributable toLMF-MC-PLP. This compound has been shown to improvesensory nerve conduction and fiber density in Zucker dia-betic fatty rats.12 Small, uncontrolled, but longer-term pilotstudies of LMF-MC-PLP have shown improvements in tac-tile and discriminatory static test results as well as nervefiber density and symptoms in patients with diabetic neu-ropathy.13,14 These improvements also have been observedn small studies of topiramate (which is not approved foriabetic neuropathy) and ruboxistaurin, an investigationalgent.15,16 Nerve conduction also has improved with the
investigational agents ranirestat, epalrestat, and acto-vegin,17-19 while results with the antioxidant �-lipoic acidave been mixed.20-25 Currently, in the US, the only agents
approved for the treatment of symptomatic diabetic periph-eral neuropathy are duloxetine and pregabalin, which do notaffect nerve conduction, have mechanisms of action unre-lated to the pathophysiology of diabetic neuropathy, and areapproved only for pain relief.19
From the patient’s perspective, symptom improvementmay be the most important goal of neuropathy management,and the effect of LMF-MC-PLP on symptoms was bothstatistically and clinically significant. The NTSS-6 was cho-sen for this study because it measures sensation (2 items) aswell as pain (4 items). The total score ranges from zero (nosymptoms) to 20 (most severe for all symptoms), and theclinical significance of the change depends on baselinescore and duration of treatment. For example, a small de-crease from a low baseline of 5.7 over 1 year leads tomeaningful changes in other parameters of neuropathy.26
However, a larger decrease from a higher score (eg, 20 to15) might leave patients with moderately severe symptoms.In the present study, patients were selected using VPT withno minimum symptom score required for inclusion. Theresulting study population exhibited only mild symptoms onNTSS, with a mean baseline of 3.6. Thus, the patients in thisstudy had 3-4 mild symptoms or 1-2 moderate symptoms atbaseline. The observed 1-point decrease over the 6 monthsof our trial suggests that at least one mild symptom wascompletely eliminated or one moderate symptom could beclassified as mild in the LMF-MC-PLP patients. The clini-cal significance of this effect is further supported by the
146 The American Journal of Medicine, Vol 126, No 2, February 2013
The exploratory analysis of the relationship betweenbaseline and 24-week levels of the components of LMF-MC-PLP and their associated biologic factors (MMA,SAM, and SAH) suggests that improvements in the NTSS-6and the SF-36 were related to baseline activity of the com-ponents of LMF-MC-PLP as well as changes that occurred
Table 2 Continued
LMF-MC-P
PAO (�mol/L)Baseline 1094.52Change from BL, Week 24 7.95
TNF-� (pg/mL)Baseline 1.69Change from BL, Week 24 0.03
Additional assessments3-NT
Baseline 48.50Change from BL, Week 24 2.04
SAHBaseline 35.93Change from BL, Week 24 3.10
SAMBaseline 103.88Change from BL, Week 24 6.12
SAM-SAH ratioBaseline 3.25Change from BL, Week 24 �0.12
Figure 1 Change in mean Neuropbaseline to 24 weeks. This questionnneuropathic symptoms including vasensation. Each “yes” answer is s
improvement.
on treatment. Whether these improvements would be main-tained in the long term remains unclear.
To date, controlled studies of polyneuropathy treatmentwith vitamin B have been small in scale, with varyingresults.4,27,28 Nevertheless, the individual components of
MF-MC-PLP have been shown to counteract hyperglyce-
Placebo P-Value
83 1102.15 � 250.54 NS36 5.29 � 204.92 NS
2.01 � 2.72 NS�0.04 � 0.54 NS
2 45.65 � 34.68 NS3 �2.61 � 25.21 NS
6 35.81 � 15.15 NS6 3.72 � 16.65 NS
0 105.22 � 37.64 NS9 �2.70 � 30.61 NS
3.35 � 2.08 NS�0.25 � 1.98 NS
d Depression Scale; hs-CRP � high-sensitivity C-reac-late, methylcobalamin, and pyridoxal-5=-phosphate;MMA � methylmalonic acid; 5-MTHF � 5-methyltetra-otyrosine; NTSS-6 � Neuropathy Total Symptom Score;ary; PLP � pyridoxal-5=-phosphate; SAH � S-adenosyl-rm 36; TNF-� � tumor necrosis factor �; VAS � visual
otal Symptom Score (NTSS-6) fromcludes 6 yes-or-no questions about
ypes of pain, tingling, and loss ofas 1 point. Lower scores signify
LP
� 230.� 190.
� 1.25� 0.76
� 33.6� 21.1
� 20.7� 11.4
� 36.9� 30.6
� 1.29� 1.20
iety anethylfoehyde;3-nitr
t summhort Fo
athy Taire in
rious tcored
sw
wsd
147Fonseca et al Metanx in Diabetic Neuropathy
mia-associated oxidative stress, considered a major cause ofdiabetic neuropathy.1 L-methylfolate restores normal cou-pling of endothelial nitric oxide synthase, reversing theproduction of superoxide and oxidative-nitrative stress andrestoring NO synthesis.3,29 These actions may lead to va-odilation and improved endothelial function in patientsith diabetes.30,31 Methylcobalamin also neutralizes super-
oxide and peroxynitrite and restores normal glutathionelevels and has been shown to improve neuropathy symp-toms in both humans and animals.4-6,8,27,32 Finally, pyrox-idal may prevent formation of advanced glycation end prod-ucts (AGEs), possibly via chelation of transition metals.33,34
Table 3 Results from Analyses of Biologic Parameters andTheir Treatment Effects*
Covariant Estimated Effect � SD P-Value
NTSS-6Baseline PLP† �0.005 � 0.002 .003Increase in PLP at 24weeks‡
0.004 � 0.001 .003
Increase in SAM at 24weeks‡
0.011 � 0.005 .045
No metformin‡ �0.325 � 0.140 .022SF-36 MCS
Baseline MMA† 0.015 � 0.005 .007Decrease in MMA at 24weeks‡
�0.027 � 0.008 .002
Increase in SAM at 24weeks‡
0.065 � 0.028 .021
Decrease in SAM-SAH ratioat 24 weeks‡
�1.042 � 0.485 .033
MMA � methylmalonic acid; NTSS-6 � Neuropathy Total SymptomScore; PLP � pyridoxal-5=-phosphate; SAH � S-adenosylhomocysteine;SAM � S-adenosylmethionine; SF-36 MCS � Short Form 36 mental com-ponent summary.
*Generalized linear model equation: Y � � � �1X1 � �2X2 � �3X3 �. . . . � �kXk � �, where Y is the outcome (response variable), � is aconstant, X is the covariant, � is the estimated effect of the covariate, and� is any random error.
†Model included baseline data and treatment effect.‡Model included change from baseline and treatment effect.
Table 4 AEs Occurring at a Frequency of �2%
MedDRA Category, n (%)
No AEs reportedInfections and infestationsInjury, poisoning, and procedural complicationsGeneral disorders and administration site conditiMusculoskeletal and connective tissue disordersSkin and subcutaneous tissue disordersSurgical and medical proceduresGastrointestinal disordersMetabolism and nutrition disorders
AE � adverse event; MedDRA � Medical Dictionary for Reg
AGE inhibition by pyroxidal has been shown to reducemicrovascular disease in animal models, although the ef-fects in humans are not well defined.10,35,36 In the presentstudy, however, there was a significant inverse associationbetween baseline pyridoxal levels and NTSS-6 scores, sug-gesting a possible benefit of pyridoxal supplementation.
Mean vitamin B12 and MMA levels were within normallimits at baseline, and neither measure was significantlycorrelated with the NTSS-6 score at 24 weeks. Due to lackof power, we cannot determine whether methylcobalaminsupplementation significantly affected the NTSS-6 scores ofthe patients with below-normal B12 levels. However, thenegative association between NTSS-6 scores and metforminuse suggests that methylcobalamin may have corrected aB12 deficiency. Such deficiency can be undetectable bymeasurement of serum values, and the use of elevated ho-mocysteine and MMA as surrogate measures for vitaminB12 is increasingly recommended.37-39 Metformin interferes
ith the absorption of cobalamin, which can lead to progres-ive deterioration of nerve tissue frequently misdiagnosed asiabetic peripheral neuropathy.7-9,37 Frank cobalamin defi-
ciency increases with age in nondiabetic individuals, whilefunctional deficiency (ie, normal cobalamin but elevatedMMA levels) is increased in patients with type 2 diabetes(regardless of metformin use) and associated with a tripling ofneuropathy frequency.8
Homocysteine, which may contribute to oxidative stress40
and is a useful marker of vascular risk,31,41 is metabolized byboth folate and cobalamin. Whether the significant decrease inhomocysteine observed in our study contributed to symptomimprovement cannot be determined from our results.
This study has several limitations. First, the trial durationmay not have been long enough to demonstrate an effect onVPT. Second, patients with possible cobalamin deficiencywere not excluded—a more robust treatment response insuch patients could have affected the results. Third, becausethe NTSS-6 is a composite tool, it was not possible todetermine whether sensation, pain, or both improved duringour trial. Future studies of LMF-MC-PP using either dulox-etine or pregabalin as an active comparator may help clarifythe compound’s effects on pain.
148 The American Journal of Medicine, Vol 126, No 2, February 2013
In summary, this study of LMF-MC-PLP showed anencouraging and statistically significant impact on neurop-athy symptoms and quality-of-life measurements in patientswith type 2 diabetes and peripheral neuropathy. The rate ofadverse events was low and comparable with placebo.These findings support the use of LMF-MC-PLP as a safeapproach for short-term alleviation of diabetic neuropathysymptoms, although its impact on long-term outcomes isnot known. Additional studies are needed to further definethese effects.
ACKNOWLEDGEMENTSThe authors thank Amanda Justice for assistance in prepa-ration of the manuscript and Matthew Williams, BSc, andErland Arning, PhD (Baylor Research Institute), for tech-nical assistance with the biochemical analysis. This studywas funded and conducted by Pamlab LLC.
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