Impact of L-Methylfolate Combination Therapy Among Diabetic Peripheral Neuropathy Patients

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At a Glance Practical Implications p 219 Author Information p 225 Full text and PDF www.ajpblive.com Web exclusive eAppendix Original Research Impact of L-Methylfolate Combination Therapy Among Diabetic Peripheral Neuropathy Patients

Rolin L. Wade, RPh, MS; and Qian Cai, MS, MSPH

iabetic peripheral neuropathy (DPN) accounts for ABSTRACT signifi cant morbidity and predisposes the lower Objectives: To evaluate the clinical and economic impacts extremities to debilitating complications such as in- of treatment with L-methylfolate, pyridoxal-5'-phosphate, and D 1 fection, ulceration, and eventually amputation. Nearly 70% methylcobalamin (MPM) among patients with diabetic peripheral of adults with diabetes have some manifestation of neuropa- neuropathy (DPN). thy.2 Diabetic peripheral neuropathy involves progressive Study Design: Retrospective administrative claims analysis of DPN patients. deterioration of nerve fi bers and results in chronic pain in as 3 Methods: Patients aged 18 to 64 years with 2 or more medical many as 16% of patients with diabetes. claims for type 2 diabetes or 1 pharmacy claim for antidiabetic The economic burden of DPN is substantial. Compared agents and with at least 1 medical claim for peripheral neuropa- with patients without neuropathy, patients with DPN have a thy from January 1, 2004, through July 31, 2010, were selected. higher incidence of diabetes-related conditions such as coro- Patients needed a minimum of 12 months preindex and postindex nary artery disease, back pain, limb amputations, depres- continuous eligibility within the study period for baseline and sion, hypertension, valvular or peripheral vascular disease, follow-up evaluations, with no folate-containing prescriptions or se- 4 vere lower limb morbidity at baseline. Propensity scores were used and limb infections. The annual medical costs per patient to match MPM patients to controls. Outcome measures included with DPN were estimated to be $14,062 in 2003, compared all-cause and disease-related hospitalization and healthcare costs. with $6651 per patient with diabetes without DPN.4 The total Multivariable analyses were used to adjust for baseline demo- US annual direct costs of DPN and its complications were graphic and clinical characteristics. estimated to range from $4.6 to $13.7 billion in 2001.5 The sample included 814 MPM patients and 814 Results: Diabetic peripheral neuropathy is associated with pro- matched controls. MPM patients had less risk of all-cause hospi- 6 talization (21.5% vs 25.9%, P = .036) during the follow-up period. longed hyperglycemia and abnormal glucose tolerance. The Following multivariate analysis, MPM patients were less likely than pathophysiologic process of DPN includes increased oxida- the control group to be hospitalized for any reason (odds ratio tive stress, which in conjunction with a hyperglycemic en- 0.74, 95% confi dence interval 0.58-0.94) and had lower disease- vironment leads to the destruction of nerve fi bers.6 A major related costs (−$2258, P <.001). feature of DPN is sensory loss, which may lead to foot ul- Conclusions: MPM use among patients with DPN was associated ceration following even minor trauma as the patient may be with lower hospitalization risk and lower disease-related costs. oblivious to the injury. Such ulcers in the lower extremities These fi ndings should be taken into account when making deci- sions about access to prescription medical foods such as MPM. are common, with the annual incidence of lower extremity ulcers in the population with diabetes being approximately (Am J Pharm Benefi ts. 2012;4(5):218-225) 7%.7 Of every 6 people with diabetes, 1 person will develop a foot ulcer at some point,8 with peripheral neuropathy being a contributing cause in as many as 60% to 70% of all diabetic foot ulcers.9,10 One study identifi ed peripheral neuropathy as a cause in 78% of cases, making it the most common factor leading to ulceration.11 Several classes of pharmacologic agents have been used for symptomatic pain relief or DPN.12 These include

218 The American Journal of Pharmacy Benefi ts • September/October 2012 www.ajpblive.com L-Methylfolate Combination Therapy for Diabetic Peripheral Neuropathy anticonvulsants (eg, gabapentin, pregabalin), some antidepressants (eg, tricyclics, selective serotonin reuptake inhibitors/serotonin-norepinephrine reuptake inhibitors), PRACTICAL IMPLICATIONS opioid analgesics, anxiolytics, and sedative hypnotics.13 This study demonstrated that patients with diabetic peripheral neu- These agents may provide pain relief, but do not address ropathy (DPN) who took L-methylfolate, pyridoxal-5'-phosphate, and methylcobalamin (MPM) had signifi cantly lower all-cause hospitaliza- the underlying pathophysiology of DPN. Side effects and tion risk and healthcare costs than patients who did not take MPM. inadequate response to these agents encourage many pa- I 14 To our knowledge, this is the fi rst study to assess the impact of tients with DPN to explore alternative treatments. MPM in the DPN population using administrative claims from a A product classifi ed by the US Food and Drug Ad- large US insured population. 15 ministration as a prescription medical food containing I These fi ndings, which are based on data from real-world practice, L-methylfolate, pyridoxal-5'-phosphate, and methylcobal- can be used by health plans, patients, and physicians regarding amin (MPM; Metanx, Pamlab LLC, Covington, Louisiana) options for the treatment of DPN. is available. MPM is indicated for the distinct nutritional requirements of patients with endothelial dysfunction who present with loss of protective sensation and neuropathic pain associated with DPN.16 This oral formulation that a waiver of informed consent from an institutional re- has been studied in patients with DPN with sensation loss, view board was not required to conduct this study. neuropathic pain, and lower extremity ulcerations. Clini- cal studies have associated MPM with improved sensory Inclusion and Exclusion Criteria perception, reduced neuropathic pain, and restored sensa- The study population consisted of patients who had at tion in patients with DPN.12,17 A recent placebo-controlled least 2 medical claims for type 2 diabetes (International trial of 214 patients demonstrated a signifi cant improve- Classifi cation of Diseases, Ninth Revision, Clinical Modifi ca- ment on the Neuropathy Total Symptom Score-6 at 16 and tion [ICD-9-CM] code 250.x0 or 250.x2) on different dates 24 weeks in patients with DPN. The rate of adverse events or 1 pharmacy claim for antidiabetic agents (Generic Prod- was comparable to that with placebo.18 uct Identifi er code 27 excluding 2730) during the study pe- Few studies report the impact of treatments for DPN riod of January 1, 2004, through July 31, 2010. Patients were on healthcare costs and hospitalization risk. Previous re- also required to have at least 1 medical claim for periph- search concluded that use of duloxetine in the treatment eral neuropathy (ICD-9-CM codes 250.x6, 337.1x, 355.7x, of DPN was associated with lower total healthcare costs or 357.2x) during the study period. The active treatment than standard-of-care medications.19,20 A preliminary study population consisted of patients with a minimum treatment examining the impact of MPM on prescription drug utili- course of at least 2 pharmacy claims for MPM; other pa- zation and healthcare costs identifi ed a positive trend in tients were available for matching as controls. healthcare costs, and recommended that further research The fi rst pharmacy claim date for MPM was defi ned as be conducted to validate the fi ndings.21 The objective of the index date for MPM users. The index date for the con- this study was to assess the impact of MPM treatment on trol population was randomly assigned within the same hospitalization risk and healthcare costs among patients time period of study claims for MPM. All patients were aged with DPN in a real-world setting. 18 to 64 years as of the index date and had a minimum of 12 months preindex and postindex continuous eligibility METHODS within the study period for baseline and follow-up evalua- Study Design tions. A 12-month washout period of no pharmacy claims This retrospective cohort study used patient-level data for any prescription folate–containing product was used to obtained from the HealthCore Integrated Research Data- select patients for whom MPM was newly initiated. base. This database contains administrative claims data Patients with severe lower limb morbidity in the from 14 commercial health insurance plans geographically 12-month preindex period were excluded. Severe lower dispersed across the United States, representing approxi- limb morbidity included decubitus ulcer (ICD-9-CM code mately 43 million patients. All study data were de-identifi ed 707.0x), gangrene (ICD-9-CM code 785.4 or 440.24), and and complied with regulations set by the Health Insurance amputation (ICD-9-CM code 84.1x or 997.6x, or Current Portability and Accountability Act of 1996. Patient confi den- Procedural Terminology codes 28800-28825, 27880-27889, tiality was preserved, and the anonymity of all patient data or 27590-27598). Patients with claims for unbranded was safeguarded throughout the study. It was determined forms of MPM (National Drug Code 42192-0317-90,

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Figure 1. Population Selection Flow Chart and variables associated with disease severity such as diabetic comorbidi- Patients with at least 2 medical claims for type 2 diabetes ties, preindex medication burden, and on different dates or at least 1 pharmacy claim for the Deyo-Charlson Comorbidity Index antidiabetic agents during the study period (DCI) were included as covariates in (N = 1,956,632) the propensity score model. Matched cases (MPM group) and controls (non- MPM group) with the highest digit on Patients with at least 1 medical claim for peripheral neuropathy the propensity score were selected for during the study period (N = 200,135) analysis. Figure 1 shows the study cohort construction.

Study Measures Patients with a minimum of 24 months continuous eligibility (12 months preindex and postindex) The primary outcomes of interest (N = 153,074) in this study were hospitalization risk (all cause and disease related) and direct healthcare costs (all cause and

Excluding patients with pharmacy claims for other prescription disease related) during the 12-month folate–containing products within the 12-month preindex period postindex period. All-cause hospital- (N = 146,464) ization was defi ned as any inpatient admission, whereas disease-related hospitalization was defi ned as an in- Excluding patients with medical claims for decubitus ulcer, gangrene, or amputation patient admission containing at least within the 12-month preindex period 1 billing code indicating diabetic neu- (N = 143,623) ropathy or severe lower extremity morbidity (see the eAppendix at www. ajpblive.com). Hospitalization risk was Excluding patients with claims for NDC codes 42192-0317-90, 13925-0144-90, defi ned as the probability of 1 or more or 13925-0144-50 during the study period hospitalizations during the postindex (N = 142,448) period. The baseline (preindex period) was defi ned as the 12 months prior to the < Excluding patients aged 18 years or >64 years on the index date index date; the follow-up (postindex (N = 81,898) period) was defi ned as the 12-month period after the index date, including

1:1 Propensity score matching the index date. Age, sex, region of residence, insurance plan type, and clinical characteristics were assessed MPM group Control group for study patients. Patients’ comorbid (N = 814) (N = 814) conditions as well as their DCI score were determined during the baseline NDC indicates National Drug Code. period.23 Medications (nonnarcotic analgesics, nonsteroidal anti-infl amma- 13925-0144-90, or 13925-0144-50) during the study pe- tory drugs [NSAIDs], opioid analgesics, antidepressants, riod were excluded. anticonvulsants, anxiolytics or sedative hypnotics, anti- The control population was matched 1:1 to patients in biotics, and insulin) were assessed during the 12-month the MPM treatment group using a greedy match propen- preindex period for the MPM and control groups. sity score algorithm.22 Propensity scores were generated Total all-cause costs were defi ned as the 12-month using multivariate logistic regression predicting probabil- postindex sum of all medical and pharmacy claim costs. ity of MPM use. All available demographic characteristics Disease-related costs were defi ned as those associated with

220 The American Journal of Pharmacy Benefi ts • September/October 2012 www.ajpblive.com L-Methylfolate Combination Therapy for Diabetic Peripheral Neuropathy treatment of diabetic neuropathy Table 1. Demographic and Clinical Characteristics of Study Patients or severe lower extremity mor- Characteristics MPM Group (n = 814) Control Group (n = 814) Pa bidity in all treatment settings, as Age, mean (SD), y 54 (7.01) 55 (7.16) .311 well as prescription costs associ- Sex, n (%) ated with the treatment of DPN Male 460 (56.51) 441 (54.18) .139 (eAppendix). Costs were calcu- Female 354 (43.49) 373 (45.82) lated using the plan-paid amount Geographic region, n (%) and were adjusted to the 2010 Northeast 129 (15.85) 150 (18.43) .088 mid-year Consumer Price Index. Midwest 343 (42.14) 340 (41.77) Statistical Analyses Southeast/mid-Atlantic 242 (29.73) 223 (27.40) For the matched MPM and West 100 (12.29) 101 (12.41) control populations, differ- Insurance plan type, n (%) ences on matched variables HMO 209 (25.68) 247 (30.34) .221 used in propensity scores were PPO 584 (71.74) 543 (66.71) evaluated using the Wilcoxon Other 21 (4.67) 24 (5.41) signed rank test for continuous DCI score, mean (SD) 2.67 (1.76) 2.58 (1.70) .097 data (age, DCI score, number of Comorbid conditions, n (%) unique medications received) Back pain 251 (30.84) 234 (28.75) .359 and the McNemar test for cat- Cellulitis, lower limb 73 (8.97) 54 (6.63) .069 egorical data (sex, region, insurance plan type, presence of Congestive heart failure 50 (6.14) 40 (4.91) .232 specifi c comorbid conditions). Coronary artery disease 165 (20.27) 142 (17.44) .068 Descriptive statistics such as Depression 79 (9.71) 74 (9.09) .669 means (± standard deviation) Diabetic retinopathy 92 (11.30) 84 (10.32) .519 and proportions (frequencies) Dyslipidemia 622 (76.41) 632 (77.64) .070 were used to characterize con- Fibromyalgia 60 (7.37) 60 (7.37) >.99 tinuous and categorical study Hypertension 709 (87.10) 706 (86.73) .174 variables, respectively. The t Lower limb ulcer 96 (11.79) 76 (9.34) .052 test was used to compare the Myocardial infarction 165 (20.27) 142 (17.44) .068 differences between the MPM Osteoarthritis 146 (17.94) 120 (14.74) .087 and control groups for continu- Osteomyelitis, lower limb 11 (1.35) 11 (1.35) >.99 ous variables, the χ2 test was used for categorical variables, Peripheral vascular disease 87 (10.69) 72 (8.85) .203 and the Mann-Whitney test was Renal disease 101 (12.41) 90 (11.06) .337 used for cost data. Rheumatoid arthritis 13 (1.60) 10 (1.23) .513 Multivariable logistic regres- Stroke 31 (3.81) 34 (4.18) .706 sion was conducted to compare Number of unique medications 13.09 (6.75) 13.11 (6.76) .803 hospitalization risk between received, mean (SD) the MPM and matched control DCI indicates Deyo-Charlson Comorbidity Index; HMO, health maintenance organization; MPM, L-methylfolate, pyridoxal-5'- phosphate, and methylcobalamin; PPO, preferred provider organization; SD, standard deviation. groups, controlling for differ- aDifferences between the 2 groups were evaluated with the Wilcoxon signed rank test for continuous variables and the McNemar ences in preindex utilization test for categorical variables. of pain medications. General- ized linear models with gamma distribution were used RESULTS to compare all-cause and disease-related costs between A total of 81,898 patients (814 in the MPM group the 2 groups, adjusting for baseline demographics and and 81,084 in the control group) met all study inclu- clinical characteristics. All descriptive and multivariate sion and exclusion criteria prior to propensity score analyses were conducted with SAS version 9.1 (SAS In- matching (Figure 1). Of those, 814 MPM patients and stitute, Cary, North Carolina). Statistical signifi cance was 814 matched controls were selected for the fi nal study set at P <.05. cohort.

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Figure 2. Baseline Medication Usea group were more likely to use duloxetine (10.69% vs 4.67%, P <.001). Insulin P = .680

Oral antidiabetic agents P = .005 Hospitalization Risk During the 12-month preindex period, Antibiotics P = .875 the percentage of patients with at least 1 Anxiolytics and sedative hypnotics P >.99 all-cause hospitalization was similar between the 2 groups (20.52% vs 22.11%, Anticonvulsants P <.001 P = .43). However, the postindex differ- Antidepressants P = .262 ence was signifi cant: the percentage was Opioid analgesics P = .620 21.50% for the MPM group and 25.92% for the control group (P = .04). The percent- P = .522 Non-narcotic analgesics and NSAIDs age of patients with disease-related hospi- 0.00 20.00 40.00 60.00 80.00 talizations was similar between the MPM Percentage and control groups during both the preindex (4.79% vs 6.27%, P = .19) and postin- Control group MPM group dex (6.63% vs 7.37%, P = .56) periods. After multivariate adjustment for differences in baseline pain-related medication use, the MPM group had signifi cantly MPM indicates L-methylfolate, pyridoxal-5'-phosphate, and methylcobalamin; NSAID, nonsteroidal anti- infl ammatory drug. lower risk of postindex all-cause hospi- aDifferences in baseline medication use between the 2 groups were evaluated using the 2 test. χ talization (odds ratio [OR] 0.74, 95% confi dence interval [CI] 0.58-0.94) compared The demographic and clinical characteristics were with the control group. Disease-related postindex hospi- similar between the matched treatment groups (Table 1). talization risk was not statistically signifi cantly different Patients’ mean age was 54 years and 55% were male. A between the 2 groups (Figure 3), although the average majority of patients were enrolled in preferred provider length of stay for MPM users was 10.65 (±19.03) days organization insurance plans in both the MPM (71.7%) compared with 20.17 (±39.18) days for the control group. and control (66.7%) groups. Among the study patients, the most frequent comorbidities were hypertension, dys- Healthcare Costs lipidemia, and back pain. The mean DCI score was not Costs increased from the preindex to the postindex signifi cantly different between the groups. period for both the MPM and control groups. All-cause 12-month costs increased by a mean of $4096 in the MPM Baseline Medication Use treatment group from the preindex to the postindex period No difference was found between the MPM and con- (P <.001), whereas in the control population, the costs had trol groups on the use of baseline nonnarcotic analgesics a larger mean increase of $6283 (P = .017). In both the MPM and NSAIDs (32.2% for MPM vs 30.7% for non-MPM, P = and control groups, the increase in mean pre-post disease- .52), opioid analgesics (51.1% for MPM vs 49.9% for non- related costs was signifi cant, again with a greater increase in MPM, P = .62), antidepressants overall (39.4% for MPM the control group than in the MPM group (Table 2). vs 36.7% for non-MPM, P = .26), anxiolytics and sedative Following multivariate analyses, the total adjusted all- hypnotics (25.4% for MPM vs 25.4% for non-MPM, P = cause costs in the MPM group were approximately 9% .99), antibiotics (66.5% for MPM vs 66.8% for non-MPM, lower than those in the control group during the follow- P = .88), and insulin (63.5% for MPM vs 64.5% for non- up period, although the difference was not signifi cant MPM, P = .68) (Figure 2). (Table 3). However, the adjusted disease-related postin- At baseline, a greater proportion of patients in the dex costs were found to be signifi cantly lower in the MPM group used anticonvulsants (34.52% vs 25.18%, MPM group compared with the control group (Table 3). P <.001), the most common being gabapentin (21.38% vs 17.08%, P = .03) and pregabalin (12.41% vs 4.42%, P DISCUSSION <.001). Although overall preindex antidepressant use was We believe this is the fi rst study to use administrative similar between the 2 study groups, patients in the MPM claims from a large US insured population to determine

222 The American Journal of Pharmacy Beneﬁ ts • September/October 2012 www.ajpblive.com L-Methylfolate Combination Therapy for Diabetic Peripheral Neuropathy

Figure 3. Adjusted Odds Ratio for Hospitalization Risk for the MPM Group Compared With the Control Groupa

0.74 All-cause hospitalization

0.83

Disease-related hospitalization

0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 Odds Ratio

MPM indicates L-methylfolate, pyridoxal-5'-phosphate, and methylcobalamin. aAdjusted for baseline pain medication use (duloxetine, gabapentin, pregabalin) and baseline costs. An odds ratio less than 1.0 indicates a lower risk of hospitalization for the MPM group compared with the control group.

Table 2. Unadjusted All-Cause and Disease-Related Preindex and Postindex Cost Difference for the MPM and Control Groups Type of Cost Preindex Postindex Difference Pa All cause MPM group, mean (SD) $14,432 ($19,932) $18,528 ($28,044) $4096 ($27,107) <.001 Control group, mean (SD) $16,992 ($35,486) $23,275 ($79,995) $6283 ($74,713) .017 Disease related MPM group, mean (SD) $1950 ($7500) $3216 ($13,797) $1266 ($14,405) .012 Control group, mean (SD) $2220 ($8982) $6930 ($65,068) $4710 ($63,566) .035

MPM indicates L-methylfolate, pyridoxal-5'-phosphate, and methylcobalamin. aDifference between preindex and postindex costs was evaluated with the Wilcoxon signed rank test. the hospitalization risk associated with and the economic research have shown MPM increases nitric oxide produc- impact of MPM treatment in the DPN population. When tion and reduces homocysteine levels among DPN pa- we applied a propensity score matching using patient tients,12 and MPM has been shown to improve endothelial demographics and disease severity measures as covari- function in patients with type 2 diabetes.27 One study ates and further controlled for remaining differences in has reported that MPM treatment was associated with im- preindex pain medication use between the 2 groups, proved epidermal nerve fi ber density and reduced par- MPM-treated patients were signifi cantly less likely to be esthesias in patients with type 2 diabetes and small-fi ber hospitalized in the postindex period for any cause. The neuropathy.17 In a study using an animal model for type MPM-treated group also had signifi cantly lower disease- 2 diabetes, MPM was associated with alleviations in hind- related costs in the postindex period compared with the limb digital sensory nerve conduction defi cits, induction control population. of small sensory nerve fi ber regeneration, and increases In DPN, hyperglycemia causes oxidative stress and in intra-epidermal nerve fi ber density. It is postulated leads to decreased nitric oxide availability and vasocon- that the mechanisms for these effects involve inhibition striction in the peripheral vasculature,24 and has been of oxidative-nitrosative stress.28 These data suggest that linked to impaired wound healing.25,26 Results of previous MPM has positive effects on the underlying pathology

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Table 3. Adjusted 12-Month Postindex All-Cause and Disease-Related Costsa MPM Group Control Group Type of Cost Mean 95% CI Mean 95% CI P b All cause $16,435 $15,197-$17,773 $18,098 $16,735-$19,572 .091 Disease related $2185 $1834-$2604 $4443 $3729-$5295 <.001

CI indicates confi dence interval; MPM, L-methylfolate, pyridoxal-5'-phosphate, and methylcobalamin. aAdjusted for baseline pain medication use (duloxetine, gabapentin, pregabalin) and baseline costs using multivariate generalized linear models. bThe adjusted mean difference between the MPM and control groups was evaluated using generalized linear models with gamma distribution. of DPN and that these effects may improve patient out- nonnarcotic analgesics, and NSAIDs.19,30 In this study, comes beyond palliative relief. more than two-thirds of the MPM and control patients This study found that MPM-treated patients were 30% used antibiotics in the preindex period, a potential mark- less likely to be hospitalized for any cause in the postin- er of lower extremity infection. dex period compared with the matched controls. The This study should be interpreted in light of certain postindex mean all-cause cost for the MPM group was limitations. Any retrospective study can only describe the lower than that for the control group by $1663 (P = .09), association between groups, and cannot construe causal- but this difference was not statistically signifi cant. The ity. Medical conditions defi ned in this study were identi- postindex hospitalization costs for the MPM group were fi ed using ICD-9-CM billing codes and were subject to lower than those for the control population, but this dif- miscoding; however, our requirement for multiple claims ference was offset by increased costs in the outpatient reduced the likelihood of false positives when identifying and pharmacy settings. Previous studies reported that the DPN population. Despite propensity score matching, outpatient costs account for a substantial proportion of whether there was unknown or unmeasured selection total healthcare costs associated with DPN.19,20,29 bias in the MPM-treated group cannot be ascertained. Al- Disease-related postindex hospitalization risk was not though the preindex healthcare resource use was similar statistically different between the 2 groups after controlling between the MPM and control populations, there was for baseline characteristics. However, among patients with no practical way to determine whether the actual sever- a disease-related admission, the average length of stay for ity of disease was similar between the groups. Although the control group was longer than that for the MPM group the requirement for at least 2 MPM claims ruled out during the postindex period. In contrast to all-cause costs, patients who immediately discontinued treatment, the disease-related costs were dominated by inpatient utiliza- length of therapy and adherence to treatment with MPM tion, which accounted for more than 50% of total costs for in the postindex period were unknown. Given that this both groups. The higher percentage of patients with at study investigated commercially insured patients, fi nd- least 1 disease-related hospitalization and the longer aver- ings may not be generalizable to other populations. The age length of stay resulted in a mean adjusted postindex cost estimates in this study included only direct plan-paid disease-related cost that was $2258 higher for the control costs, so no data were reported on out-of-pocket costs group than for the MPM group (P <.001). to the patient. Claims data do not capture indirect costs A cost analysis of the diabetic Medicare population incurred by patients, including loss of productivity and found that medical expenditures associated with lower travel expenses, although these costs are relatively higher extremity ulcers were 3 times higher on average than for chronic illnesses such as DPN.2,4,5,31,32 costs for Medicare patients in general. Lower extrem- Despite these limitations, administrative claims data ity ulcer–related costs accounted for 24% of total costs remain a powerful data source and have been used in in these patients, and most of the ulcer-related costs oc- previous studies of the healthcare costs associated with curred in the inpatient setting.7 The current study suggests DPN.19,20,29 The current study used standard techniques to that utilization of MPM in patients with DPN may decrease control for confounders. hospitalization risk for lower extremity causes and may reduce the length of stay should hospitalization occur. CONCLUSIONS This impact appears to be the major factor contributing This study found that commercially insured patients to the disease-related cost benefi t seen in the MPM group. with DPN who had at least 2 prescription claims for MPM Similar to other studies, this study found that DPN had a signifi cantly lower risk of all-cause hospitalization patients had high utilization of palliative therapy such in the 12 months following initiation of treatment com- as opioid analgesics, antidepressants, anticonvulsants, pared with a control population. The mean 12-month

224 The American Journal of Pharmacy Benefi ts • September/October 2012 www.ajpblive.com L-Methylfolate Combination Therapy for Diabetic Peripheral Neuropathy postindex disease-related cost also was $2258 lower for peripheralneuropathy/detail_peripheralneuropathy.htm#171313208. Revised MPM patients than for controls (P <.001). When used in February 18, 2011. Accessed July 26, 2011. 14. Halat KM, Dennehy CE. Botanicals and dietary supplements in diabetic patients with DPN, MPM may have a favorable clinical peripheral neuropathy. J Am Board Fam Pract. 2003;16(1):47-57. and cost benefi t. 15. Food and Drug Administration. Guidance for industry: frequently asked ques- tions about medical foods. http://www.fda.gov/food/guidancecomplianceregulato- Acknowledgment ryinformation/guidancedocuments/medicalfoods/ucm054048.htm. Revised May Cheryl Jones, BA, and Lisa Kaspin, PhD, provided writing and editing 2007. Accessed July 26, 2011. assistance for this manuscript. 16. Metanx [package insert]. Covington, LA: Pamlab LLC; 2005. http://www Author Affi liations: From Cerner Research (RLW), Culver City, CA; .metanx.com/HCP. Revised February 2010. Accessed July 26, 2011. HealthCore, Inc (QC), Wilmington, DE. 17. Jacobs AM, Cheng D. Management of diabetic small-fi ber neuropathy with Funding Source: Pamlab LLC, Covington, LA. combination L-methylfolate, methylcobalamin, and pyridoxal 5'-phosphate. Rev Author Disclosures: Mr Wade reports employment with Cerner Re- Neurol Dis. 2011;8:39-47. search, which has a consulting contract with Pamlab LLC, the funder of 18. Fonseca VA, Lavery LA, Thethi TK, et al. Effect of combination L-methylfolate, the study. Mr Cai reports no relationship or fi nancial interest with any pyridoxal-5'-phosphate, and methylcobalamin on neuropathy symptoms and entity that would pose a confl ict of interest with the subject matter of infl ammatory biomarkers in patients with diabetic peripheral neuropathy (DPN) this article. [abstract]. Diabetes. 2011;60(suppl 1):A289. Authorship Information: Concept and design (RLW, QC); acquisi- 19. Chen S, Wu N, Fraser K, Boulanger L, Zhao Y. Opioid use and healthcare costs tion of data (RLW, QC); analysis and interpretation of data (RLW, QC); among patients with DPNP initiating duloxetine versus other treatments. Curr Med drafting of the manuscript (RLW, QC); critical revision of the manu- Res Opin. 2010;26(10):2507-2516. script for important intellectual content (RLW, QC); statistical analysis 20. Zhao Y, Wu N, Chen S, Boulanger L, Police RL, Fraser K. Changes in opioid (QC);obtaining funding (RLW); administrative, technical, or logistic sup- use and healthcare costs among U.S. patients with diabetic peripheral neuropa- port (RLW, QC); and supervision (RLW, QC). thic pain treated with duloxetine compared with other therapies. Curr Med Res Address correspondence to: Rolin L. Wade, RPh, MS, Cerner Re- Opin. 2010;26(9):2147-2156. search 600 Corporate Pointe, Ste 320, Culver City, CA 90230. E-mail: [email protected]. 21. Wade RL, Cai Q, Thethi T. Administrative claims analysis of an L-methylfolate combination product in patients with diabetic peripheral neuropathy [abstract PDB6]. Value Health. 2009:12(7):a402. REFERENCES 22. Parsons LS. Reducing bias in a propensity score matched-pair sample using 1. Boulton AJ, Vinik AI, Arezzo JC, et al; American Diabetes Association. Diabetic greedy matching techniques. Paper 214-26. Proceedings of the 26th Annual SAS neuropathies: a statement by the American Diabetic Association. Diabetes Care. Users Group International Conference. http://www2.sas.com/proceedings/sugi26/ 2005;28(4):956-962. p214-26.pdf. Published 2001. Accessed July 22, 2012. 2. Hogan P, Dall T, Nikolov P; American Diabetes Foundation. Economic costs of diabetes in the US in 2002. Diabetes Care. 2003;26(3):917-932. 23. Deyo RA, Cherkin DsC, Ciol MA. 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eAppendix. Codes Used to Identify Disease-Related (DPN-Related) Outcomes Codes Description ICD-9-CM 707.1x, 707.8x, 707.9x Ulcer of lower limbs, excluding decubitus

ICD-9-CM 250.6x, 337.1x, 355.7x, 357.2x Peripheral neuropathy ICD-9-CM 680.7x, 681.1x, 681.9x, 682.7x, 686.0x-686.1x, 686.8x-686.9x, 728.xx, (Infection) Cellulitis, myositis, fascitis, osteomyelitis, periostitis, 729.1x, 729.4x, 730.06-730.09, 730.16-730.19, 730.26-730.29, 730.36-730.39, other bone infections, gangrene, carbuncle 730.86-730.89, 730.96-730.99, 785.4x CPT 12001-12002, 12004-12007, 11040-11044, 27600-27604, 27607-27610, (Procedures, excluding amputation): repair, debridement, incision, 29897-29898, 28001-28008, 28111-28160, 38.08, 38.09, 38.48, 38.49, 29540, excision, revascularization, Unna boot, arthropathy, synovectomy, 29550, 29580, 28020-28024, 28070, 28072, 28086, 28088, 28060 fasciectomy ICD-9-CM 84.1x, 997.6x, or CPT 28800-28825, 27880-27889, 27590-27598 (Amputation) foot, ankle/leg, knee and above, stump complication GPI2: 65; GPI4: 5820; GPI8: 66100525, 58180025, 58180090, DPN-related prescriptions 72600030, 72600057, 72600075, 72500020,72600040, 72600046, 72600020 CPT indicates Current Procedural Terminology; DPN, diabetic peripheral neuropathy; GPI, Generic Product Identifi er; ICD-9-CM, International Classifi cation of Diseases, Ninth Revision, Clinical Modifi cation.

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