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

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Impact of L-Methylfolate Combination Therapy Among Diabetic Peripheral Neuropathy Patients 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 an- tidepressants (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 neuro- pathic 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, www.ajpblive.com Vol. 4, No. 5 • The American Journal of Pharmacy Benefi ts 219 I Wade • Cai 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.
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