Qian Cai, MS, MSPH

Psoriasis—a chronic, inflammatory skin disease affecting approximately 2.2% of the US population&mdash;is considered the most prevalent immune-mediated inflammatory disease.

Approximately 80% of patients with psoriasis have mild to moderate disease, whereas the remaining 20% have moderate to severe disease.

Mild psoriasis involves itching and burning on affected parts of the body, while severe psoriasis is also frequently associated with joint pain or arthritis.

As a multisystemic disorder, psoriasis is frequently associated with a number of comorbid conditions, including psoriatic arthritis, cardiovascular disorders, hypertension, dyslipidemia, metabolic syndrome, obesity, and diabetes. 

Notably, due to skin lesions, patients with psoriasis also often experience significant psychological comorbidities, such as anxiety and depression.

There is no available cure for psoriasis; therefore, various lines of therapies are used to alleviate disease symptoms, reduce or clear plaques, and induce remission.

 Conventional therapies, including topical agents, phototherapy (such as psoralen plus ultraviolet A or ultraviolet B), and systemic medications (such as methotrexate, retinoids, or cyclosporine) have been used as the mainstay treatments of psoriasis. However, previous studies have shown that, for some patients, these therapies may be limited in the long term due to adverse events (AEs).

 With the increased understanding of the immunology of psoriasis, biologics have emerged as an alternative option with significant impact on providing long-term continuous psoriasis control by interfering with T cell function, by inhibiting tumor necrosis factor-α, or by selectively targeting interleukin-12 (IL-12) and IL-23.

The American Academy of Dermatology (AAD) guidelines recommend biologics in the management of psoriasis when 1 or more conventional systemic medications are not tolerated due to AEs, are unsuitable due to comorbidities, or fail to produce an adequate response.

 Furthermore, the most recent AAD guidelines emphasize that biologics have no relevant drug interactions and have fewer significant safety issues compared with conventional systemic agents; they also highlight the benefits of biologic treatments for patients with complex medical and dermatologic histories on various medications.

Ustekinumab, as the first agent to inhibit IL-12/23, is a novel biologic. It was approved by the FDA in September 2009 for the treatment of moderate to severe psoriasis,

 and has also been recently recommended as a first-line systemic treatment specifically for patients with chronic plaque psoriasis.

The dose of ustekinumab is determined on the basis of patient weight. For patients weighing 100 kg (220 lb) or less, the recommended dose is 1 initial 45-mg dose followed by another dose 4 weeks later, then another 45-mg dose every 12 weeks thereafter. For patients weighing more than 100 kg (220 lb), the recommended dose is 1 initial 90-mg dose followed by another dose 4 weeks later, then a 90-mg dose every 12 weeks thereafter. It is worth noting that 45-mg ustekinumab was also shown to be efficacious in patients weighing more than 100 kg; however, 90-mg ustekinumab resulted in greater efficacy in these patients.

 Clinical trials have demonstrated the safety and efficacy of ustekinumab in improving the symptoms of psoriasis.

 Recently published 5-year efficacy and safety results demonstrate the long-term response associated with ustekinumab as well as the lack of any dose-related or cumulative toxicity with increasing duration of ustekinumab exposure for up to 5 years.

 Additionally, results from a phase 3, doubleblind trial have shown that the efficacy of ustekinumab was superior to that of etanercept in patients with psoriasis. 

 Despite these positive findings on the efficacy and safety of ustekinumab in clinical trials, limited studies are available to quantify the real-world utilization and dosage patterns of ustekinumab. The main objective of this study was to assess the characteristics and dosing patterns of patients with psoriasis initiated on ustekinumab therapy using a large retrospective administrative claims database.

This retrospective analysis used patient-level data from the HealthCore Integrated Research Database (HIRD, HealthCore Inc, Wilmington, DE). HIRD includes longitudinal claims data from 14 geographically dispersed health plans in the United States, covering approximately 44 million insured lives at the time this study was conducted. HIRD consists of integrated medical claims, pharmacy claims, and eligibility files. All study data were de-identified and developed in compliance with the Health Insurance Portability and Accountability Act. It was determined that a waiver of informed consent from an institutional review board was not required to conduct this study.

The study population consisted of patients 18 years or older who received ustekinumab and had at least 1 medical claim for psoriasis (

International Classification of Diseases, Ninth Revision, Clinical Modification

] code of 696.1x) during the study period of September 1, 2009, through November 30, 2010. Ustekinumab was identified from medical claims using the Healthcare Common Procedure Coding System code C9261, or any of the following National Drug Codes ([NDCs]: 57894006002, 57894006003, 57894006103) from pharmacy claims. The date of the first medical or pharmacy claim for ustekinumab was designated as the index date.

All patients included in the analysis were required to have at least 12 months of continuous health plan enrollment prior to the index date. Due to the recent availability of ustekinumab and its early uptake at the time of the study, limited follow-up data were available for the study patients. Therefore, no minimum follow-up period was required and variable follow-up was allowed; however, patients were followed through the latest date of their continuous eligibility after the index date. Patients were excluded from the study if they had a claim for another biologic (ie, adalimumab, alefacept, etanercept, or infliximab) on the index date (

. Patient characteristics were evaluated during 12 months prior to the index date. Demographic characteristics included age, gender, geographic region (as determined by the US Census classification), and type of health insurance plan (preferred provider organization [PPO], health maintenance organization [HMO], or other insurance plan type). Patients’ comorbidity burden was measured using the Deyo-Charlson Comorbidity Index (DCI)

 and specific psoriasis-related comorbid conditions during the pre-index period. The DCI consists of 19 diagnoses identified by 

codes, with a scoring weight from 1 to 6 identified for each diagnosis. The final summary DCI score consists of a sum of weighted values for existing comorbidities, ranging from 0 to 33, with higher scores indicating a greater comorbidity burden. Additionally, the use of various psoriasis- related treatments during the 12-month pre-index period was assessed. Pre-index all-cause and psoriasisrelated healthcare resource utilization and costs, including inpatient admissions, emergency department (ED) visits, physician office visits, and pharmacy fills, were presented. Pre-index costs were calculated using health plan allowed amounts, which are the full fees contractually allowed by health plans (inclusive of the amount paid by the health plan and the patient), and were adjusted for 2010 dollars using the medical care consumer price index from the Bureau of Labor Statistics.

. Observing ustekinumab dosing patterns required methodological considerations as a result of how the drug was packaged and supplied after FDA approval, while accounting for typical reimbursement and practice patterns. Initially, a 45-mg ustekinumab vial could be used in patients with either dose requirement, whereby a patient requiring a 45-mg dose would be prescribed 1 vial and a patient requiring a 90-mg dose would be prescribed 2 vials. The 45-mg vial was subsequently replaced by 45-mg and 90-mg prefilled syringes (PFSs) in February 2010, allowing for more convenient administration options. Preliminary analyses conducted by the authors found that health plans would reimburse for the first 2 doses of ustekinumab in a single prescription. Indicators in the administrative claims of this type of reimbursement practice included the cost of the fill and the time interval between fills.

In determining the index ustekinumab dose, patients with a single claim of 45-mg or 90-mg PFSs were categorized as having received the 45-mg or 90-mg dose, respectively. For patients who had a second fill within 98 to 125 days (ie, 16 weeks ± 2 weeks) between the index date and the next fill date, the index dose was determined using the wholesale acquisition cost ± 15% along with the allowed cost amounts in the claims. For these patients, the second fill was coded as the third dose to account for the first claim including doses 1 and 2, and all subsequent doses were recoded forward thereafter. For all other patients, second and third doses were determined by the dose shown in the claim.

Intervals between fills were calculated as the days between observed ustekinumab fills. Interval patterns were assessed based on a window around the recommended fill intervals per prescribing information (ie, 28 ± 7 days for the interval of index to second dose, and 84 ± 14 days for interval of second and third dose). Patients were then categorized as having fills “expected,” “later than expected,” or “earlier than expected” by comparing the observed fill intervals against the FDA label-recommended fill intervals.

. Descriptive statistics were calculated for all study measures and outcomes. Mean (± SD) and median were calculated for continuous variables and frequency (percentage) was used for categorical variables. All the statistical analyses were conducted using SAS Version 9.1 (SAS Institute, Inc, Cary, North Carolina).

Of the 563 patients with at least 1 medical or pharmacy claim for ustekinumab during the study period, 374 met all study criteria and were included in the analysis (

). The mean (± SD) age was 48.0 (± 11.9) years, 43.6% were female, and 74.9% were primarily covered by PPO health insurance plans (

). Approximately 70% of the study patients resided in the West and Southeast regions of the United States. On average, study patients had a 6-to-7- month follow-up period with a median of 209 follow-up days after the index fill.

At baseline, the mean DCI score was 0.6 (SD ± 0.9), indicating low burden of comorbid conditions. The most commonly occurring comorbid conditions were dyslipidemia (46.3%), hypertension (43.3%), psoriatic arthritis (22.2%), diabetes (16.3%), and anxiety (12.0%). A total of 217 patients (58.0%) used topical steroids during the pre-index period while 36.4% used non-biologic systemic medications (Table 1). Methotrexate (19.3%) and prednisone (13.1%) were the most commonly administered nonbiologic systemic medications.

In terms of healthcare resource utilization, about 9.1% of study patients had at least 1 hospital admission for any cause within the 12-month pre-index period before receiving ustekinumab (Table 1), for which the average length of stay was 4 days. A few patients (2.7%) had 1 or more psoriasis-related hospital admission, with an average length of stay of 3 days, and only 7 patients (1.9%) had 1 or more psoriasis-related ED visit during the preindex period. Within the pre-index period, study patients had an average of 10 all-cause physician office visits and 4 psoriasis-related physician office visits. During the preindex period, the average all-cause costs were $22,495 (± $19,978) and the average psoriasis-related costs were $17,560 (± $26,031), more than half of which were due to prescriptions.

The majority of study patients (69.5%) used at least 1 biologic agent prior to ustekinumab initiation. Of those with pre-index biologic experience, 22.3% had a history of using 2 or more biologics. Adalimumab and etanercept were the most frequently used biologics, with 38.8% and 40.0% of the biologic-experienced patients, respectively, using them immediately prior to initiating ustekinumab (

). In addition, the average time lapse between the last etanercept fill and the index ustekinumab fill was 77.5 days (± 74.3); similarly, the time lapse between the last adalimumab fill and the index ustekinumab fill was 76.8 days (± 85.2).

In the analysis of ustekinumab dosing patterns, all patients who met the study criteria of having 1 fill or more for ustekinumab were included. Overall, 83.8% (284 of 339 who were followed up for 4 weeks or more) of patients had a second ustekinumab fill and 87.7% (207 of 236 who were followed up for 16 weeks or more) had a third ustekinumab fill after the index fill. On the index date, most patients (n = 294, 78.6%) received a 45-mg ustekinumab dose while the remaining 80 patients (21.4%) received a 90-mg dose (

). During the postindex period, the majority of the study patients remained on the 45-mg dose of ustekinumab, although a few patients switched to a 90-mg dose. Specifically, at the time of the second fill, 8 of 284 patients (2.8%) received a higher dose and only 1 patient received a lower dose than their index dose. By the third fill, 13 of 207 patients (6.9%) received a higher ustekinumab dose, while 5 patients (2.7%) received a lower dose than their previous fill. The median number of days was 28 days between the index and the second ustekinumab fill, and 85 days between the second and the third ustekinumab fills (Table 3). These findings are very much in line with the recommended dosing regimen for ustekinumab, in that the second dose should be administered 4 weeks (28 days) after the first dose and the following doses should be administered every 12 weeks (84 days) thereafter.

Among patients with a second ustekinumab fill (n = 284), most patients (70.1%) had their second prescription filled as expected (within 21-35 days of index fill). Fewer patients (4.2%) got their second fill earlier than expected, while 25.7% had it filled later than expected (

). Among patients with a third ustekinumab fill (n = 207), 75.9% had their third prescription filled as expected (within 71-97 days from the date of the second fill), while the rest had their third filled earlier (8.7%) or later (15.4%) than expected.

This is the first study to provide real-world evidence of the demographic and clinical characteristics, as well as the treatment patterns, of patients with psoriasis who were initiated on ustekinumab. Specifically, this study described the observed dosage patterns of ustekinumab in a large managed care population in the United States.

Results from this study show that approximately 69.5% of patients used at least 1 type of biologic agent, 58.0% used topical steroids, and 36.4% used nonbiologic systemic treatments prior to ustekinumab initiation. Among those who had received other biologics prior to receiving ustekinumab, the majority (78.9%) had used etanercept or adalimumab as the most recent biologic agent, and the average time between switching from etanercept or adalimumab to ustekinumab was quite similar (about 77 days). Previous studies present mixed evidence for patients with psoriasis who were treated with systemic therapy. For example, a claims study found that only 3.1% of patients had used biologic therapy and more than 30% had used 1 type of systemic therapy.

 found that only 26% of respondents had used systemic medication, phototherapy, or both, and 35% received only topical therapy. Consistent with results from another psoriasis administrative claim—based study,

 this study found that dyslipidemia and hypertension were the 2 most prevalent comorbidities for patients with psoriasis. Diabetes, anxiety, and depression were found at baseline in more than 10% of patients in the current study.

This study found that approximately 78.6% of the patients were initiated at a 45-mg dose on the index date and the remaining patients (21.4%) received 90-mg ustekinumab. Fewer than 7% of patients had an increased dose at the third fill, in contrast to a nearly 3% of patients receiving a decreased dose at the third fill. This study also showed that most patients had their second and third prescriptions filled as expected, per the recommended dosing schedule. When ustekinumab was not filled as expected after the index fill, 50.7% and 78.1% had their second and third ustekinumab, fill, respectively, within 30 days of the recommended schedule date.

Information on treatment adherence is important because better treatment adherence has been associated with decreased healthcare resource utilization and decreased other costs for many chronic diseases such as diabetes,

 Although this study did not assess adherence or persistency of ustekinumab due to a limited sample size and follow-up time, this study demonstrated that the majority of patients had their second (83.8%) and third (87.7%) ustekinumab prescriptions filled within the expected time frame, suggesting that adherence with ustekinumab may be promising. However, this hypothesis needs to be confirmed with further research, at which time it would also be worthwhile to examine ustekinumab treatment adherence and the associated economic benefit of adherence among patients with psoriasis.

This study was subject to a few limitations inherent in analyses of retrospective claims data. The existence of a pharmacy claim for a filled prescription does not guarantee that the medication was actually used by the patient, nor does it indicate that the medication was taken as prescribed. Administrative claims data do not typically include clinical data to assist with inferring the effectiveness of a treatment (such as ustekinumab in this study). Study results were derived from a database of members of large commercial health plans in the United States; therefore, results may not be generalizable to people with other types of insurance or those who reside outside the United States. Nonetheless, the data used in this study were derived from a large, geographically diverse population, which enhances the generalizability of the results. In addition, the scope of this study was intended to represent initial ustekinumab dosing patterns, and therefore the results should not be generalized for longer-term maintenance use of the drug.

The findings from this study can offer data to health plans regarding the characteristics of patients with psoriasis who were initiated on ustekinumab. As the first study to investigate the utilization patterns of ustekinumab in a large US managed care population, this study provides insights on the real-world dosage patterns and fill intervals of ustekinumab. The majority of patients with psoriasis in this study received fills per the recommended administration schedule at the 45-mg dose with very few changes in dose following the index administration. Results on ustekinumab dosage and fill patterns have important implications in estimating the cost of ustekinumab from the perspective of healthcare payers. These results may be incorporated in health plan utilization reviews, may be used as part of indirect comparisons with existing data for other biologics, and may offer payers a path to treatment cost predictability.

Articles

This study is an evaluation of the dosing patterns of ustekinumab among patients with psoriasis in a real-world setting.

Real-World Dosing and Utilization of Ustekinumab Among Patients With Psoriasis

Diabetic peripheral neuropathy (DPN) accounts for significant morbidity and predisposes the lower extremities to debilitating complications such as infection, ulceration, and eventually amputation.

Nearly 70% of adults with diabetes have some manifestation of neuropathy.

 Diabetic peripheral neuropathy involves progressive deterioration of nerve fi bers and results in chronic pain in as many as 16% of patients with diabetes.

The economic burden of DPN is substantial. Compared with patients without neuropathy, patients with DPN have a higher incidence of diabetes-related conditions such as coronary artery disease, back pain, limb amputations, depression, hypertension, valvular or peripheral vascular disease, and limb infections.

 The annual medical costs per patient with DPN were estimated to be $14,062 in 2003, compared with $6651 per patient with diabetes without DPN.

 The total US annual direct costs of DPN and its complications were estimated to range from $4.6 to $13.7 billion in 2001.

Diabetic peripheral neuropathy is associated with prolonged hyperglycemia and abnormal glucose tolerance.

 The pathophysiologic process of DPN includes increased oxidative stress, which in conjunction with a hyperglycemic environment leads to the destruction of nerve fibers.

 A major feature of DPN is sensory loss, which may lead to foot ulceration following even minor trauma as the patient may be oblivious to the injury. Such ulcers in the lower extremities are common, with the annual incidence of lower extremity ulcers in the population with diabetes being approximately 7%.

 Of every 6 people with diabetes, 1 person will develop a foot ulcer at some point,

 with peripheral neuropathy being a contributing cause in as many as 60% to 70% of all diabetic foot ulcers.

 One study identified peripheral neuropathy as a cause in 78% of cases, making it the most common factor leading to ulceration.

Several classes of pharmacologic agents have been used for symptomatic pain relief or DPN.

These include anticonvulsants (eg, gabapentin, pregabalin), some antidepressants (eg, tricyclics, selective serotonin reuptake inhibitors/serotonin-norepinephrine reuptake inhibitors), opioid analgesics, anxiolytics, and sedative hypnotics.

 These agents may provide pain relief, but do not address the underlying pathophysiology of DPN. Side effects and inadequate response to these agents encourage many patients with DPN to explore alternative treatments.

A product classifi ed by the US Food and Drug Administration as a prescription medical food

 containing L-methylfolate, pyridoxal-5'-phosphate, and methylcobalamin (MPM; Metanx, Pamlab LLC, Covington, Louisiana) 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.

 This oral formulation has been studied in patients with DPN with sensation loss, neuropathic pain, and lower extremity ulcerations. Clinical studies have associated MPM with improved sensory perception, reduced neuropathic pain, and restored sensation in patients with DPN.

 A recent placebo-controlled trial of 214 patients demonstrated a signifi cant improvement on the Neuropathy Total Symptom Score-6 at 16 and 24 weeks in patients with DPN. The rate of adverse events was comparable to that with placebo.

Few studies report the impact of treatments for DPN on healthcare costs and hospitalization risk. Previous research concluded that use of duloxetine in the treatment of DPN was associated with lower total healthcare costs than standard-of-care medications.

 A preliminary study examining the impact of MPM on prescription drug utilization and healthcare costs identifi ed a positive trend in healthcare costs, and recommended that further research be conducted to validate the fi ndings.

 The objective of this study was to assess the impact of MPM treatment on hospitalization risk and healthcare costs among patients with DPN in a real-world setting.

This retrospective cohort study used patient-level data obtained from the HealthCore Integrated Research Database. This database contains administrative claims data from 14 commercial health insurance plans geographically dispersed across the United States, representing approximately 43 million patients. All study data were de-identifi ed and complied with regulations set by the Health Insurance Portability and Accountability Act of 1996. Patient confi dentiality was preserved, and the anonymity of all patient data was safeguarded throughout the study. It was determined that a waiver of informed consent from an institutional review board was not required to conduct this study.

The study population consisted of patients who had at least 2 medical claims for type 2 diabetes (

International Classifi cation of Diseases, Ninth Revision, Clinical Modification

] code 250.x0 or 250.x2) on different dates or 1 pharmacy claim for antidiabetic agents (Generic Product Identifier code 27 excluding 2730) during the study period of January 1, 2004, through July 31, 2010. Patients were also required to have at least 1 medical claim for peripheral neuropathy (ICD-9-CM codes 250.x6, 337.1x, 355.7x, or 357.2x) during the study period. The active treatment population consisted of patients with a minimum treatment

course of at least 2 pharmacy claims for MPM; other patients were available for matching as controls.

The first pharmacy claim date for MPM was defi ned as the index date for MPM users. The index date for the control population was randomly assigned within the same time period of study claims for MPM. All patients were aged 18 to 64 years as of the index date and had a minimum of 12 months preindex and postindex continuous eligibility within the study period for baseline and follow-up evaluations. A 12-month washout period of no pharmacy claims for any prescription folate—containing product was used to select patients for whom MPM was newly initiated.

Patients with severe lower limb morbidity in the 12-month preindex period were excluded. Severe lower limb morbidity included decubitus ulcer (

 code 84.1x or 997.6x, or Current Procedural Terminology codes 28800-28825, 27880-27889, or 27590-27598). Patients with claims for unbranded forms of MPM (National Drug Code 42192-0317-90, 13925-0144-90, or 13925-0144-50) during the study period were excluded.

The control population was matched 1:1 to patients in the MPM treatment group using a greedy match propensity score algorithm.

 Propensity scores were generated using multivariate logistic regression predicting probability of MPM use. All available demographic characteristics and variables associated with disease severity such as diabetic comorbidities, preindex medication burden, and the Deyo-Charlson Comorbidity Index (DCI) were included as covariates in the propensity score model. Matched cases (MPM group) and controls (non- MPM group) with the highest digit on the propensity score were selected for analysis. 

The primary outcomes of interest in this study were hospitalization risk (all cause and disease related) and direct healthcare costs (all cause and disease related) during the 12-month postindex period. All-cause hospitalization was defined as any inpatient admission, whereas disease-related hospitalization was defi ned as an inpatient admission containing at least 1 billing code indicating diabetic neuropathy or severe lower extremity morbidity (see the 

). Hospitalization risk was defined as the probability of 1 or more hospitalizations during the postindex period.

The baseline (preindex period) was defined as the 12 months prior to the index date; the follow-up (postindex period) was defined as the 12-month period after the index date, including the index date. Age, sex, region of residence, insurance plan type, and clinical characteristics were assessed for study patients. Patients’ comorbid conditions as well as their DCI score were determined during the baseline period.

 Medications (nonnarcotic analgesics, nonsteroidal anti-infl ammatory drugs [NSAIDs], opioid analgesics, antidepressants, anticonvulsants, anxiolytics or sedative hypnotics, antibiotics, and insulin) were assessed during the 12-month preindex period for the MPM and control groups.

Total all-cause costs were defi ned as the 12-month postindex sum of all medical and pharmacy claim costs. Disease-related costs were defined as those associated with treatment of diabetic neuropathy or severe lower extremity morbidity in all treatment settings, as well as prescription costs associated with the treatment of DPN (eAppendix). Costs were calculated using the plan-paid amount and were adjusted to the 2010 mid-year Consumer Price Index.

For the matched MPM and control populations, differences on matched variables used in propensity scores were evaluated using the Wilcoxon signed rank test for continuous data (age, DCI score, number of unique medications received) and the McNemar test for categorical data (sex, region, insurance plan type, presence of specific comorbid conditions). Descriptive statistics such as means (± standard deviation) and proportions (frequencies) were used to characterize continuous and categorical study variables, respectively. The

 test was used to compare the differences between the MPM and control groups for continuous variables, the 

test was used for categorical variables, and the Mann-Whitney test was used for cost data.

Multivariable logistic regression was conducted to compare hospitalization risk between the MPM and matched control groups, controlling for differences in preindex utilization of pain medications. Generalized linear models with gamma distribution were used to compare all-cause and disease-related costs between the 2 groups, adjusting for baseline demographics and clinical characteristics. All descriptive and multivariate analyses were conducted with SAS version 9.1 (SAS Institute, Cary, North Carolina). Statistical signifi cance was set at 

A total of 81,898 patients (814 in the MPM group and 81,084 in the control group) met all study inclusion and exclusion criteria prior to propensity score matching (Figure 1). Of those, 814 MPM patients and 814 matched controls were selected for the final study cohort.

The demographic and clinical characteristics were similar between the matched treatment groups (

). Patients’ mean age was 54 years and 55% were male. A majority of patients were enrolled in preferred provider organization insurance plans in both the MPM (71.7%) and control (66.7%) groups. Among the study patients, the most frequent comorbidities were hypertension, dyslipidemia, and back pain. The mean DCI score was not significantly different between the groups.

No difference was found between the MPM and control groups on the use of baseline nonnarcotic analgesics and NSAIDs (32.2% for MPM vs 30.7% for non-MPM, 

 = .52), opioid analgesics (51.1% for MPM vs 49.9% for non- MPM, 

 = .62), antidepressants overall (39.4% for MPM vs 36.7% for non-MPM, 

 = .26), anxiolytics and sedative hypnotics (25.4% for MPM vs 25.4% for non-MPM, 

 = .99), antibiotics (66.5% for MPM vs 66.8% for non-MPM,

 = .88), and insulin (63.5% for MPM vs 64.5% for non- MPM, 

At baseline, a greater proportion of patients in the MPM group used anticonvulsants (34.52% vs 25.18%, 

 <.001), the most common being gabapentin (21.38% vs 17.08%, 

 = .03) and pregabalin (12.41% vs 4.42%, 

 <.001). Although overall preindex antidepressant use was similar between the 2 study groups, patients in the MPM group were more likely to use duloxetine (10.69% vs 4.67%, 

During the 12-month preindex period, the percentage of patients with at least 1 all-cause hospitalization was similar between the 2 groups (20.52% vs 22.11%, 

 = .43). However, the postindex difference was signifi cant: the percentage was 21.50% for the MPM group and 25.92% for the control group (

 = .04). The percentage of patients with disease-related hospitalizations was similar between the MPM and control groups during both the preindex (4.79% vs 6.27%, 

After multivariate adjustment for differences in baseline pain-related medication use, the MPM group had signifi cantly

lower risk of postindex all-cause hospitalization (odds ratio [OR] 0.74, 95% confidence interval [CI] 0.58-0.94) compared with the control group. Disease-related postindex hospitalization risk was not statistically signifi cantly different between the 2 groups (

), although the average length of stay for MPM users was 10.65 (±19.03) days compared with 20.17 (±39.18) days for the control group.

Costs increased from the preindex to the postindex period for both the MPM and control groups. All-cause 12-month costs increased by a mean of $4096 in the MPM treatment group from the preindex to the postindex period (

 <.001), whereas in the control population, the costs had a larger mean increase of $6283 (

 = .017). In both the MPM and control groups, the increase in mean pre-post diseaserelated costs was signifi cant, again with a greater increase in the control group than in the MPM group (

Patients with diabetic peripheral neuropathy taking L-methylfolate, pyridoxal-5'-phosphate, and methylcobalamin (MPM) had lower all-cause hospitalization risk and healthcare costs than patients not taking MPM.