Incident Comorbidity, Resource Use, and All-Cause Mortality Associated with Prurigo Nodularis: A United Kingdom Retrospective Database Analysis.

We described comorbidity, resource utilization, and mortality for patients with prurigo nodularis (PN) using data from the Clinical Practice Research Datalink. Patients with incident PN (2008-2018) were selected and matched to controls. Of 2,416 patients with PN, 2,409 (99.7%) were matched to controls. Prevalence of atopic dermatitis (relative risk [RR] = 2.571; 95% confidence interval [CI] = 2.356-2.806), depression (RR = 1.705; 95% CI = 1.566-1.856), anxiety (RR = 1.540; 95% CI = 1.407-1.686), coronary heart disease (RR = 1.575; 95% CI = 1.388-1.787), chronic kidney disease (RR = 1.529; 95% CI = 1.329-1.759), and type 2 diabetes mellitus (RR = 1.836; 95% CI = 1.597-2.111) was significantly higher for patients with PN. Subsequent risk of atopic dermatitis (hazard ratio = 6.58; 95% CI = 5.17- 8.37), depression (hazard ratio = 1.61; 95% CI = 1.30-1.99), and coronary heart disease (hazard ratio = 1.37; 95% CI = 1.09-1.74) were significantly increased. Resource utilization was increased in all settings: incidence rate ratio = 1.48 (95% CI = 1.47-1.49) for primary care, incident rate ratio = 1.80 (95% CI = 1.75-1.85) for inpatients, incident rate ratio = 2.15 (95% CI = 2.13-2.18) for outpatients, and incidence rate ratio = 1.32 (95% CI = 1.27-1.36) for accident and emergency. Respective cost ratios were 1.78 (95% CI = 1.67-1.90), 1.52 (95% CI = 1.20-1.94), 2.34 (95% CI = 2.13-2.58), and 1.55 (95% CI = 1.33-1.80). Total primary and secondary healthcare costs were £2,531 versus £1,333, a cost ratio of 1.62 (95% CI = 1.36-1.94). The adjusted hazard ratio for mortality was 1.37 (95% CI = 1.14-1.66). Patients with PN had significantly increased rates of comorbidity, healthcare resources utilization, and mortality compared with matched controls.

Patient Perspectives on Living With Severe Prurigo Nodularis.

Importance: Because of a paucity of qualitative research on prurigo nodularis (PN), the symptoms and impacts of PN that are most important to patients are poorly understood. Objective: To explore patients' perspectives on their PN symptoms and to understand the impacts of the condition. Design, Setting, and Participants: One-on-one qualitative telephone interviews were held with English-speaking US adults aged 18 years or older with a confirmed diagnosis of PN, severe pruritus, and moderate to severe sleep disturbance. Participants were recruited via patient associations, patient panels, and social media posts. Interviews took place between September 10, 2020, and March 16, 2021. Main Outcomes and Measures: The main symptoms of PN and their impacts on quality of life were identified by content analysis of deidentified interview transcripts. Results: A total of 21 adults with PN (mean [SD] age, 53.1 [11.8] years; 15 [71%] female; 2 African American or Black patients [10%], 1 Asian patient [5%], and 18 White patients [86%]; of these, 1 patient [ 5%] had Hispanic or Latino ethnicity) participated in the interviews. All participants reported itch, pain associated with PN, bleeding or scabbing, and dry skin. Other frequently reported symptoms included lumps or bumps (95%), having a crust on the skin (95%), burning (90%), stinging (90%), lesions or sores (86%), skin discoloration (86%), and raw skin (81%). Of the 17 participants who indicated what their worst symptoms were, 15 (88%) identified itching as the worst or 1 of the worst symptoms. The most frequently reported impacts of PN for quality of life were changes in sleep (100%), daily life (100%), feelings or mood (95%), relationships (95%), social life (81%), and work or school (71%). Overall, the worst impact of PN was its association with impaired feelings or mood. Conclusions and Relevance: This qualitative study suggests the importance of itching, sleep disturbance, and other symptoms and impacts of PN. This information can be used to guide end point selection in clinical trials and to inform patient-centric decision-making in clinical practice.

Assessing Response in Atopic Dermatitis: A Systematic Review of the Psychometric Performance of Measures Used in HTAs and Clinical Trials.

INTRODUCTION: Assessing treatment response is key to determining treatment value in atopic dermatitis (AD). Currently, response is assessed using various clinician- or patient-reported measures and response criteria. This variation creates a mismatch of evidence across trials, hindering the ability of clinicians, regulators, and payers to compare the efficacy of treatments. This review identifies which measures and criteria are used to determine response in clinical trials and health technology assessments (HTAs). Moreover, it systematically reviews the psychometric performance of those measures and criteria to understand which perform best in capturing patient-relevant symptoms and treatment benefits. METHODS: A scoping review of clinical trials and HTAs in AD identified the following measures for inclusion: the Eczema Area and Severity Index (EASI), the Investigator's Global Assessment (IGA), the Dermatology Life Quality Index (DLQI) and the Peak Pruritus Numerical Rating Scale (PP-NRS). A systematic search was performed in MEDLINE and Embase to identify studies testing the psychometric performance of these measures in adults or adolescents with AD. RESULTS: A lack of consistency in the assessment of response was observed across clinical trials and HTAs. Important gaps in psychometric evidence were identified. No content validations of the EASI and IGA in AD were found, while some quantitative studies suggested that these measures fail to capture itch, a core symptom. The PP-NRS and DLQI performed well. No studies compared the performance of different response criteria. CONCLUSION: Content validation of the PP-NRS confirmed the importance of itch as a core symptom and treatment priority in AD; however, itch is not well covered in the EASI or IGA. Including the PP-NRS in clinical trials and HTAs will better capture patient-relevant benefit and response. Although various response criteria were used, no studies compared the performance of different criteria to inform which were most appropriate to compare treatments in clinical trials and HTAs.

The assessment of treatment response is important in determining treatment value in atopic dermatitis (AD). This study aimed to identify which outcome measures and criteria are used to determine treatment response in clinical trials and health technology assessments (HTAs). The psychometric performance of identified outcome measures and criteria was then systematically reviewed to understand which perform best in capturing patient-relevant symptoms and treatment benefits in AD. The review identified and included the Eczema Area and Severity Index (EASI), Investigator's Global Assessment (IGA), Dermatology Life Quality Index (DLQI) and Peak Pruritus Numerical Rating Scale (PP-NRS) as response measures. Lack of consistency in how response is assessed across clinical trials and HTAs makes it difficult for clinicians and payers to compare the efficacies and cost-effectivenesses of different treatments and to make optimal treatment decisions. The review found that content validity (the extent to which a measure covers those symptoms and treatment benefits which are important to patients) was not assessed for EASI and IGA. EASI and IGA are often used to assess response in clinical trials and HTAs, but they miss key elements of the patient-relevant disease impact and treatment benefit, including itch. Treatments leading to improvements in missed symptoms (e.g. itch) will be undervalued using EASI and IGA, decreasing the chances of regulatory approval and reimbursement. Moreover, response criteria used in clinical trials and HTAs are sometimes adopted in prescriber settings. Here, if response assessment does not capture patient-relevant benefit, patients' access to tailored treatment may be restricted due to the perceived non-response.

Validation of the Peak Pruritus Numerical Rating Scale as a Patient-Reported Outcome Measure in Prurigo Nodularis.

INTRODUCTION: Validated patient report tools for quantifying patient experiences of itch in prurigo nodularis (PN) are limited. This study aimed to evaluate the validity of the 11-point peak pruritus numerical rating scale (PP NRS) as a single-item patient-reported outcome (PRO) measure for assessing itch severity in PN. METHODS: Content validity of the PP NRS was evaluated through qualitative interviews with adults with PN. The PP NRS was then psychometrically evaluated using data from a placebo-controlled trial of nemolizumab in adults with PN, during which patients completed the PP NRS daily. Meaningful within-patient change was estimated from the qualitative interviews and by anchor- and distribution-based analyses of trial data. RESULTS: The interview participants (N = 21) all understood the PP NRS and reported itch as their worst symptom overall. The PP NRS showed good test-retest reliability and demonstrated convergent validity and known-groups validity. PP NRS scores improved more in patients classified as "improved" on other clinical outcome measures than in those classified as "worsened/unchanged". Triangulation of the different estimates identified a 2- to 5-point decrease in PP NRS score as a meaningful within-patient change threshold. CONCLUSION: The PP NRS is a content-valid and reliable PRO measure for quantifying itch severity in adults with PN in clinical trials. TRIAL REGISTRATION NUMBER: NCT03181503.

Prurigo nodularis is a skin disease where the skin becomes inflamed and very itchy. Itching and scratching can ruin the lives of people with prurigo nodularis. For doctors to know how well treatments for prurigo nodularis are working, they need to be able measure how bad their patients' itching is. Here we tested whether a tool called the peak pruritus numeric rating scale (PP NRS) can be used to reliably measure itching in patients with prurigo nodularis. The PP NRS asks patients to rate their itch "at the worst moment during the previous 24 h" on a scale from 0 ("no itch") to 10 ("worst itch imaginable"). We interviewed 21 patients with prurigo nodularis. Overall, itch was their worst symptom. They were able to use the PP NRS with few or no problems. To further explore whether the PP NRS can be used by patients with prurigo nodularis, we also obtained data from a clinical study. In this clinical study, patients with prurigo nodularis received a drug that might one day be used to treat their disease. They completed the PP NRS daily during the time they received the drug. When we analyzed the data from the clinical study, we found that the PP NRS has the properties a tool like this needs to be useful. We also concluded that a decrease of 2­5 points on the PP NRS scale would be a meaningful improvement in itching for patients with prurigo nodularis.

The Sleep Disturbance Numerical Rating Scale: Content Validity, Psychometric Validation, and Meaningful Within-Patient Change in Prurigo Nodularis.

INTRODUCTION: Sleep is often disturbed in patients with prurigo nodularis (PN). To address the lack of validated patient-reported outcome (PRO) measures for quantifying sleep disturbance in PN, we evaluated the Sleep Disturbance Numerical Rating Scale (SD NRS) as a single-item PRO measure for quantifying sleep disturbance in PN. METHODS: Adults with PN participated in qualitative interviews, which included concept elicitation and cognitive debriefing of the SD NRS. The SD NRS was evaluated psychometrically using data from a phase 2 randomized trial in adults with PN (NCT03181503). Other PRO assessments included the Average Pruritus (AP) NRS, AP Verbal Rating Scale (VRS), peak pruritus (PP) NRS, PP VRS, and Dermatology Life Quality Index (DLQI). Reliability, validity, and responsiveness of the SD NRS were evaluated, and meaningful within-patient change was estimated from qualitative interview responses and quantitative trial data. RESULTS: All interview participants (N = 21) experienced sleep disturbance and most (95%) understood the SD NRS as intended. The SD NRS demonstrated test-retest reliability based on intra-class correlation coefficients for itch-stable participants of 0.87 for the AP VRS and 0.76 for the PP VRS. At baseline, Spearman's rank-order correlation coefficients were moderate to strong (0.3-0.8) between the SD NRS and the AP NRS, AP VRS, PP NRS, PP VRS, and DLQI. Known-groups validity was demonstrated by higher (worse) SD NRS scores in participants with worse scores on the AP NRS, AP VRS, PP VRS, and DLQI. Improvements in SD NRS scores were greater in participants classified as "improved" versus "worsened/unchanged" on the anchor PROs. A 2- to 4-point decrease on the 11-point SD NRS scale was identified as a meaningful within-patient change. CONCLUSION: The SD NRS is a well-defined, reliable, and valid PRO measure that can be used in daily practice and clinical trials to capture sleep disturbance in adults with PN.

Patients with the skin disease prurigo nodularis often sleep badly because their skin is very itchy in the evening and at night. In assessing the effectiveness of new treatments for prurigo nodularis, it is useful to know whether patients sleep better when taking them. Here, we tested whether the "Sleep Disturbance Numerical Rating Scale" (SD NRS), a tool for measuring sleep, can be used by patients with prurigo nodularis. The SD NRS asks patients to score their sleep loss during the previous night on a scale of 0 ("no sleep loss") to 10 ("I did not sleep at all"). When we interviewed 21 patients with prurigo nodularis, 19 of them had problems falling asleep and 18 of them woke up every night. Most of the patients found the SD NRS easy to use. To further explore whether the SD NRS is suitable for patients with prurigo nodularis, we also analyzed data from a European clinical study in which patients with prurigo nodularis received nemolizumab, a new treatment being developed for the disease. Patients completed the SD NRS each morning during the clinical study. We found that the SD NRS has the necessary properties to be useful for assessing sleep on a daily basis. We also determined that a 2- to 4-point decrease on the SD NRS scale would represent a meaningful improvement in sleep for patients with prurigo nodularis. We conclude that the SD NRS is a useful tool for assessing sleep in prurigo nodularis patients participating in clinical studies.

An explanatory sequential mixed-methods design to establish thresholds of within-individual meaningful change on a sleep disturbance numerical rating scale score in atopic dermatitis.

PURPOSE: Establishing a meaningful within-individual change (MWIC) threshold is a key aspect for interpreting scores used as endpoints for evaluating treatment benefit. A new patient-reported outcome (PRO), a sleep disturbance numerical rating scale (SD NRS), was developed in adults and adolescents with moderate-to-severe atopic dermatitis (AD). This research aims to establish a MWIC threshold of the SD NRS score in the context of a drug development program. METHODS: An explanatory sequential mixed-methods design was used to address the research objective. This mixed-methods design used phase IIb data and a stand-alone qualitative study. Quantitative anchor-based and distribution-based approaches supported by qualitative-based approaches were conducted, and results were triangulated to determine preliminary MWIC thresholds of the SD NRS score. RESULTS: Triangulation of results from both quantitative and qualitative approaches suggested that a 2- to 6-point decrease in the SD NRS score change constitutes a preliminary range of MWIC threshold estimates. CONCLUSION: This research determined MWIC threshold estimates for the SD NRS score in both adolescents and adults with moderate-to-severe AD using an explanatory sequential mixed-methods design. This mixed-methods design provides interesting insights for establishing MWIC thresholds of a PRO score in the context of a drug development program.

Epidemiology of prurigo nodularis in England: a retrospective database analysis.

BACKGROUND: Prurigo nodularis is a debilitating skin condition that is classified as rare by the Genetic and Rare Diseases Information Center (GARD) and the National Organization for Rare Diseases (NORD). There are currently no estimates of the prevalence of prurigo nodularis in England. OBJECTIVES: We aimed to address this data gap by describing the epidemiology of prurigo nodularis in a representative dataset derived from the English National Health Service. METHODS: The study utilized data from the Clinical Practice Research Datalink linked to Hospital Episode Statistics inpatient data. Patients with a diagnosis of prurigo nodularis were selected by clinical code in the primary care or inpatient datasets. Case definition was based on a minimum of two distinct diagnoses to maximize specificity. Point prevalence was calculated for the midpoint of 2018 and incidence rates from 2008 to 2018 were presented. For those classified as incident cases, demographic and clinical characteristics were reported. In sensitivity analyses the case definition was modified to relax the multiple diagnosis criteria and to restrict cases to those diagnosed within a maximum of 4 or 10 years of the midpoint prevalence date. RESULTS: Overall, 11 656 patients within the dataset had at least one prurigo nodularis diagnosis. Following application of the relevant inclusion criteria, 2743 patients formed the point prevalent cohort; the estimated prevalence was 3·27 patients per 10 000 population [95% confidence interval (CI) 3·15-3·40]. In sensitivity analyses the estimated prevalence ranged from 2·24 (95% CI 2·14-2·34) to 6·98 (95% CI 6·80-7·16). Incidence over the study period was 2·88 per 100 000 patient-years. Comorbidity was relatively high in this population, notably for atopic dermatitis (52·2%), depression (41·1%) and anxiety (35·4%). CONCLUSIONS: This study supports the NORD/GARD classification of prurigo nodularis as a rare disease with a prevalence of 3·27 patients per 10 000 population, which equates to 18 471 patients living with the disease in England in 2018. The relatively high prevalence of comorbidity observed for these patients may increase the complexity of management.

Content validity of a sleep numerical rating scale and a sleep diary in adults and adolescents with moderate-to-severe atopic dermatitis.

BACKGROUND: The intense itching associated with atopic dermatitis (AD) often causes patients to experience severe sleep disturbance. Here, we describe the results of a two-phase concept elicitation and cognitive interview study to establish the content validity of a sleep disturbance numerical rating scale (SD NRS) and a Consensus Sleep Diary adapted for adults and adolescents with moderate-to-severe AD (CSD-AD©). RESULTS: In phase I, a concept elicitation conducted in 20 adults and 10 adolescents with moderate-to-severe AD revealed that the following sleep-related issues were important and relevant: nighttime awakening (87%), trouble falling asleep (73%), feeling unrested (53%), daytime fatigue or sleepiness (53%), and feeling as if they did not get enough sleep (33%). The frequency and extent of sleep disturbance varied substantially from day to day due to varying degrees of itching and flares, medication use, and changes in the weather. All participants understood the SD NRS question, with most finding it easy or very easy to understand (100% of adults and 90% of adolescents) and most understanding the anchors as intended (95% of adults, and 100% of adolescents). Most participants (94% of adults, and 90% of adolescents) indicated that they would consider a one- or two-point change meaningful on the SD NRS. The CSD-AD© was revised based on participant feedback, and tested during phase II in a convenience sample of six adults and four adolescents from phase I. The changes made to the CSD-AD© were confirmed to be relevant and understandable. All patients were able to provide an answer to each item in the CSD-AD©, and most were able to estimate the duration of nighttime awakenings, daytime naps, and dozing. CONCLUSIONS: The study supported the content validity of the SD NRS and CSD-AD© in adults and adolescents with moderate-to-severe AD. It also emphasized the importance of using these instruments daily when assessing the benefit of a new treatment on sleep quality in this population.

Early-stage Mycosis Fungoides: Epidemiology and Prognosis.

Most patients with mycosis fungoides are diagnosed with early-stage disease. However, prevalence of early-stage disease is unknown, and evidence of its burden is scarce. The aim of this study is to estimate the prevalence of early-stage mycosis fungoides, how long patients live with early-stage disease and to characterise these patients. Data were obtained from 4 key publications and from US cancer registries (Surveillance, Epidemiology and End Results Program; SEER). The derived incidence of early-stage mycosis fungoides was 0.26/100,000 (UK), 0.29/100,000 (US) and 0.38/100,000 (US-SEER) and the prevalence was 4.8/100,000 (UK), 5.2/100,000 (US) and 6.6/100,000 (US-SEER). Early-stage disease may last for 18 years. From SEER registries, 3,132 were diagnosed at early stage (mostly stage IA). Median age at diagnosis was 58 years. Compared with stage IA, the relative risk of death was 1.3 for stage IB and 3.5 for stage IIA. We confirm the rarity of early-stage mycosis fungoides, a differential prognosis and the potential for elevated burden of disease.

Moderately severe and severe acute pancreatitis : a systematic review of the outcomes in the USA and European Union-5.

BACKGROUND AND OBJECTIVES: The global incidence of hospitalisation due to acute pancreatitis (AP) has been rising in the recent decades. In the USA alone, there was a 13.2% increase between 2009 and 2012 compared with 2002-2005. There remains a lack of approved treatments to prevent disease progression, leaving many liable to developing complications that include multisystem organ failure (OF) and death. This therapeutic deficit raises questions about the scale of the current burden of illness (BOI) associated with severe forms of AP. The aim of the systematic literature review (SLR) was to assess clinical, humanistic, and economic outcomes associated with moderately severe AP (MSAP) and severe AP (SAP) in the USA and the European Union-5 (EU-5). METHODS: Systematic searches were conducted in MEDLINE and Embase to identify studies published in English (between 2007 and 2017) that reported on the BOI of MSAP and/or SAP. Manual searches of 'grey' literature sources were also conducted. RESULTS: The SLR identified 19 studies which indicated that 15%-20% of patients with AP progress to more severe forms of the disease, up to 10.5% of those with SAP require surgery for complications, and up to 40% die during hospitalisation. By contrast, there appears to be a lack of data on the extent to which SAP affects patients' quality of life. CONCLUSION: The available evidence clearly demonstrates that the current management for MSAP and SAP in the USA and EU-5 does not adequately meet patients' needs. Early identification and intervention for AP is crucial, given the evidence of high rates of morbidity and an associated economic burden that is considerable. Since many patients with the condition present to hospitals at a point when multisystem OF or death is highly likely, there is a particularly urgent need for effective treatment options to prevent disease progression.

The American neurogastroenterology and motility society gastroparesis cardinal symptom index-daily diary (ANMS GCSI-DD): Psychometric evaluation in patients with idiopathic or diabetic gastroparesis.

BACKGROUND: The purpose of this study was to evaluate the measurement properties of the American Neurogastroenterology and Motility Society Gastroparesis Cardinal Symptom Index-Daily Diary, a patient-reported outcome instrument developed to meet US FDA recommendations for a symptom-based clinical trial endpoint in gastroparesis. The ANMS GCSI-DD assesses nausea, early satiety, postprandial fullness, and upper abdominal pain on a severity score from none (0) to very severe (4) and number of vomiting episodes during the past 24 hours. The composite score includes the first four symptoms, the core symptom score includes all five symptoms. METHODS: Seventy-one patients diagnosed with idiopathic or diabetic gastroparesis were recruited for a four-week observational study. Patients completed the ANMS GCSI-DD at home between Baseline and Week 4. Statistical analyses included confirmatory factor analysis, item response theory analysis, internal consistency, test-retest reliability, and construct and known-groups validity. KEY RESULTS: Unidimensionality for the composite and core symptom scores was supported, and items exhibited good fit. Internal consistency (Cronbach's alpha =0.85 and 0.83) and test-retest reliability were 0.89 and 0.88, for composite and core symptom scores, respectively. Convergent validity was supported by strong correlations with patient-reported and clinician measures. Baseline and Week 4 scores differed for three measures used to define disease severity status (P < 0.0001), supporting known-groups validity. CONCLUSIONS & INFERENCES: The ANMS GCSI-DD has excellent reliability and validity, supporting its use to assess symptom-based endpoints in gastroparesis clinical studies. Further analyses will be conducted using clinical trial data to ascertain treatment responsiveness and define a responder.

The content validity of the ANMS GCSI-DD in patients with idiopathic or diabetic gastroparesis.

BACKGROUND: The American Neurogastroenterology and Motility Society Gastroparesis Cardinal Symptom Index-Daily Diary (ANMS GCSI-DD) was developed to meet Food and Drug Administration (FDA) recommendations for patient-reported outcome (PRO) endpoints in gastroparesis studies, including therapeutic trials. The current version of the ANMS GCSI-DD contains five items pertaining to nausea, early satiety, post-prandial fullness, upper abdominal pain, and vomiting. The specific aims of this study were to determine if the appropriate symptoms are included in the ANMS GCSI-DD and to assess the content validity in patients with idiopathic (IG) and diabetic gastroparesis (DG). METHODS: Patients diagnosed with IG or DG were recruited by five clinical sites in the United States for a cross-sectional, qualitative study involving one-on-one in-person concept elicitation and cognitive debriefing interviews. Concept elicitation included open-ended questions to elicit patients' symptoms and impacts of gastroparesis, while cognitive debriefing was designed to assess the comprehensiveness of the ANMS GCSI-DD and clarity of the instructions, items, and response scales. The interviews were audio-recorded and transcribed. Transcripts were analyzed using a content analysis approach with ATLAS.ti. RESULTS: Of 25 patients interviewed, 15 (60%) had IG and 10 (40%) DG. Mean age of the sample was 42.3 years (range: 20-70 years), and most patients were female (n = 19, 76%) and white (n = 19, 76%). During concept elicitation, patients endorsed the following signs and symptoms as relevant and important to their condition: early satiety (n = 25, 100%), post-prandial fullness (n = 25, 100%), nausea (n = 22, 88%), upper abdominal pain (n = 18, 72%), vomiting (n = 15, 60%), and bloating (n = 11, 44%). Many patients (n = 20, 80%) experienced day-to-day symptom change. During cognitive debriefing, patients confirmed the ANMS GCSI-DD content was comprehensive and reflective of their gastroparesis experience. Patients could easily select a response option and describe how they arrived at their answers. Overall, patients found the instrument's instructions, recall period, items, and response options clear and understandable. CONCLUSIONS: The ANMS GCSI-DD was easily understood, found to contain the most important symptoms for patients with IG and DG, and no changes were recommended. Results support the content validity of the ANMS GCSI-DD for clinical trials and clinical care among IG or DG patients.

Treatment choice, medication adherence and glycemic efficacy in people with type 2 diabetes: a UK clinical practice database study.

OBJECTIVE: Using primary care data obtained from the UK Clinical Practice Research Datalink, this retrospective cohort study examined the relationships between medication adherence and clinical outcomes in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Data were extracted for patients treated between 2008 and 2016, and stratified by oral antihyperglycemic agent (OHA) line of therapy (mono, dual or triple therapy). Patients were monitored for up to 365 days; associations between medication possession ratio (MPR) and outcomes at 1 year (glycated hemoglobin A1c (HbA1c), weight and hypoglycemia incidence) were assessed using linear regression modeling and descriptive analyses. RESULTS: In total, 33 849 patients were included in the study (n=23 925 OHA monotherapy; n=8406 OHA dual therapy; n=1518 OHA triple therapy). One-year change in HbA1c was greater among adherent (-0.90 to -1.14%; -9.8 to -12.5 mmol/mol) compared with non-adherent patients (-0.49 to -0.69%; -5.4 to -7.5 mmol/mol). On average, adherent patients had higher hypoglycemia event rates than non-adherent patients (rate ratios of 1.24, 1.10 and 2.06 for OHA mono, dual and triple therapy cohorts, respectively) and experienced greater weight change from baseline. A 10% improvement in MPR was associated with -0.09% (-1.0 mmol/mol), -0.09% (-1.0 mmol/mol) and -0.21% (-2.3 mmol/mol) changes in HbA1c for OHA mono, dual and triple therapy cohorts, respectively. CONCLUSIONS: For patients with type 2 diabetes, increasing medication adherence can bring about meaningful improvements in HbA1c control as the requirement for treatment escalation increases. Regimens associated with weight loss and the avoidance of hypoglycemia were generally associated with better medication adherence and improved glycemic control.

Impact of treatment with pioglitazone on stroke outcomes: A real-world database analysis.

AIMS: Randomized controlled trials have reported an association between pioglitazone and reduced incidence of stroke in type 2 diabetic (T2DM) and insulin-resistant populations. We investigated this association within a real-world database. MATERIALS AND METHODS: T2DM patients who initiated pioglitazone between 2000 and 2012 were extracted from the Clinical Practice Research Datalink (CPRD), a UK routine data source. Two non-exposed control cohorts were matched according to age, gender, HbA1c, diabetes duration, stroke history, co-morbidities and prior T2DM regimen. Control cohort-1 comprised patients initiating a new T2DM therapy as their respective case initiated pioglitazone. Control cohort-2 maintained the same T2DM regimen as their respective case prior to the case initiating pioglitazone. Primary outcome was incident stroke; other outcomes included mortality, length of hospital stay and stroke recurrence. RESULTS: A total of 4234 patients initiating pioglitazone were matched to controls in cohort-1 and 3604 in cohort-2. For the primary outcome there were significantly reduced hazard ratios (HRs) for cases: controls. For cohort 1, the HR was 0.666 (95% CI, 0.466-0.952) during the therapy period and was 0.750 (0.612-0.919) over the entire observation period; for cohort 2, respective HRs were 0.516 (0.336-0.794) and 0.773 (0.611-0.978). There was no significant difference in 30-day mortality rate or rate of recurrent stroke. For stroke events that required hospitalization, there was a significant difference in length of stay for patients discharged to usual residence (median, 3.0 days vs 7.0 days; P = .008) for control cohort-2 while undergoing treatment. CONCLUSIONS: In support of evidence from 2 large randomized trials, these observational data show that pioglitazone has a potent effect in reducing stroke events in patients with type 2 diabetes.

Relationship between initial therapy and blood pressure control for high-risk hypertension patients in the UK: a retrospective cohort study from the THIN general practice database.

OBJECTIVE: To examine the UK practice patterns in treating newly diagnosed hypertension and to determine whether subgroups of high-risk patients are more or less likely to follow particular therapeutic protocols and to reach blood pressure goals. DESIGN: Retrospective cohort study. SETTING: This study examined adults in The Health Improvement Network (THIN) UK general practice medical records database who were initiated on medication for hypertension. PARTICIPANTS: 48 131 patients with essential hypertension diagnosed between 2008 and 2010 who were registered with a participating practice for a minimum of 13 months prior to, and 6 months following, initiation of therapy. We excluded patients with gestational hypertension or secondary hypertension. Patients were classified into risk groups based on blood pressure readings and comorbid conditions. PRIMARY AND SECONDARY OUTCOME MEASURES: Odds of receiving single versus fixed or free-drug combination therapy and odds of achieving blood pressure control were assessed using multivariable logistic regression. RESULTS: The vast majority of patients (95.8%) were initiated on single drug therapy. Patients with high cardiovascular risk (patients with grade 2-3 hypertension or those with high normal/grade 1 hypertension plus at least one cardiovascular condition pretreatment) had a statistically significant benefit of starting immediately on combination therapy when blood pressure control was the desired goal (OR: 1.23; 95% CI: 1.06 to 1.42) but, surprisingly, were less likely than patients with no risk factors to receive combination therapy (OR: 0.53; 95% CI: 0.47 to 0.59). CONCLUSIONS: Our results suggest that combination therapy may be indicated for patients with high cardiovascular risk, who accounted for 60.6% of our study population. The National Institute for Health and Care Excellence guideline CG34 of 2006 (in effect during the study period) recommended starting with single drug class therapy for most patients, and this advice does seem to have been followed even in cases where a more aggressive approach might have been considered.

Comparative Effectiveness of Adding Alogliptin to Metformin Plus Sulfonylurea with Other DPP-4 Inhibitors in Type 2 Diabetes: A Systematic Review and Network Meta-Analysis.

INTRODUCTION: Alogliptin is an oral antihyperglycemic agent that is a selective inhibitor of the enzyme dipeptidyl peptidase-4 (DPP-4), approved for the treatment of type 2 diabetes mellitus (T2DM). There currently exists no comparative data to support the use of alogliptin in combination with metformin (met) and sulfonylurea (SU). A decision-focused network meta-analysis (NMA) was performed to compare the relative efficacy and safety of alogliptin 25 mg once daily to other DPP-4 inhibitors as part of a triple therapy regimen for patients inadequately controlled on metformin and SU dual therapy. METHODS: A systematic literature review was conducted to identify published papers of randomized controlled trials (RCTs) that compared alogliptin with other DPP-4 inhibitors (linagliptin, saxagliptin, sitagliptin, and vildagliptin) at their Summary of Product Characteristics (SmPC) recommended daily doses, added on to metformin and SU. Comprehensive comparative analysis involving frequentist meta-analysis and Bayesian NMA compared alogliptin to each DPP-4 inhibitor separately and collectively as a group. Quasi-random effect models were introduced when random effect models could not be estimated. RESULTS: The review identified 2186 articles, and 94 full-text articles were assessed for eligibility. Eight RCTs contained appropriate data for inclusion in the NMA. All analyses over all trial population sets produced very similar results, and show that alogliptin 25 mg is as least as effective (as measured by change in HbA1c from baseline, but supported by other outcome measures: change in body weight and FPG from baseline) and safe (as measured by incidence of hypoglycemia and adverse events leading to study discontinuation) as all the other DPP-4 inhibitors in triple therapy. CONCLUSION: This decision-focused systematic review and NMA demonstrated alogliptin 25 mg daily to have similar efficacy and safety compared to other DPP-4 inhibitors, for the treatment of T2DM in adults inadequately controlled on metformin and SU. (Funded by Takeda Development Centre Americas; EXAMINE ClinicalTrials.gov number, NCT00968708).

Managing glycaemia in older people with type 2 diabetes: A retrospective, primary care-based cohort study, with economic assessment of patient outcomes.

AIMS: To describe the relative health and economic outcomes associated with different second-line therapeutic approaches to manage glycaemia in older type 2 diabetes patients requiring escalation from metformin monotherapy. MATERIALS AND METHODS: The Clinical Practice Research Datalink database was used to inform a retrospective observational cohort study of patients with type 2 diabetes treated with metformin monotherapy requiring escalation (addition or switch) to a second-line oral regimen from January 1, 2008 to December 31, 2014. Primary outcomes included time to first event (any event, myocardial infarction [MI], stroke, or composite of MI/stroke [major adverse cardiovascular event; MACE]) and total event rate. The health economic consequences associated with the choice of second-line treatment in older patients were assessed using the CORE Diabetes Model. RESULTS: A total of 10 484 patients were included; the majority escalated to second-line treatment with metformin + sulphonylurea (SU; 42%) or switched to SU monotherapy (28%). In multivariate adjusted analyses, total event rates for MACE with metformin + dipeptidyl peptidase-4 (DPP-4) inhibitor were significantly lower than with metformin + SU (0.61, 95% confidence interval [CI] 0.39-0.98), driven by a lower MI rate in the metformin + DPP-4 inhibitor group (0.52, 95% CI 0.27-0.99). Economic analyses estimated that metformin + DPP-4 inhibitor treatment was associated with the largest gain in health benefit, and cost-effectiveness ratios were favourable (<£30 000 per quality-adjusted life-year) for all second-line treatment scenarios. CONCLUSIONS: With respect to treatment choice, data from the present study support the notion of prescribing beyond metformin + SU, as alternative regimens have been shown to be associated with reduced outcomes risk and value for money.

The Cost-Effectiveness of Alogliptin Versus Sulfonylurea as Add-on Therapy to Metformin in Patients with Uncontrolled Type 2 Diabetes Mellitus.

INTRODUCTION: ENDURE (ClinicalTrials.gov identifier, NCT00856284), a multicenter, double-blind, active-controlled study of 2639 patients with uncontrolled type 2 diabetes mellitus (T2DM), found that metformin in combination with alogliptin (12.5 and 25 mg doses), when compared to standard add-on therapy (sulfonylurea, SU), exerted sustained antihyperglycemic effects over 2 years. This economic analysis of ENDURE aimed to quantify the relationship between increased glycemic durability and cost-effectiveness of alogliptin in the UK clinical setting, and communicate its sustained glycemic benefit in economic terms. METHODS: Using baseline characteristics and treatment effects from the ENDURE trial population, between-group cost-effectiveness analyses compared the combined use of metformin and alogliptin (MET + ALO12.5/25) in patients with inadequately controlled T2DM, as an alternative to metformin and SU (MET + SU). In scenario analyses, an intragroup cost-effectiveness analysis compared MET + ALO12.5/25 with MET + SU; a between-group cost-effectiveness analysis also compared MET + ALO12.5/25 versus MET + SU within a subpopulation of patients who achieved HbA1c control (<7.5%) at 2 years on study drug. RESULTS: Compared with baseline profiles of patients, combination therapies with alogliptin or SU were associated with improvements in length and quality of life and were cost-effective at established norms. Despite increased drug acquisition costs, alogliptin at 12.5 mg and 25 mg doses resulted in greater predicted lifetime quality-adjusted life year (QALY) gains with associated incremental cost-effectiveness ratios (ICERs) of £10,959/QALY and £7217/QALY compared to SU, respectively. CONCLUSION: The ENDURE trial and the present cost-effectiveness analysis found that the glycemic durability of alogliptin therapy was associated with improved long-term patient outcomes, QALY gains, and ICERs that were cost-effective when evaluated against standard threshold values. Alogliptin therefore represents a cost-effective treatment alternative to SU as add-on therapy to metformin in patients with poorly managed T2DM. FUNDING: Takeda Development Centre Europe Ltd.

Factors Predictive of Weight Gain and Implications for Modeling in Type 2 Diabetes Patients Initiating Metformin and Sulfonylurea Combination Therapy.

INTRODUCTION: The objectives of this study were to (a) assess the factors associated with weight gain in a population of type 2 diabetes patients escalating from metformin (M) to M+ sulfonylurea (M + S) and (b) evaluate whether healthcare resource utilization associated with being overweight or obese is underestimated in typical health economic evaluations. METHODS: The study was a retrospective cohort study using UK Clinical Practice Research Datalink linked to Hospital Episode Statistics (CPRD/HES) data. The association between baseline phenotypic factors and weight gain was assessed using logistic regression. Hospitalization incidence rates per 1000 person-years for major diabetes-related complications according to body mass index (BMI) at baseline were estimated from the data (observed) and compared to those obtained from a validated diabetes model (predicted). RESULTS: 11,071 patients were included in the analysis; approximately 40% gained weight in the first year following escalation to M + S. Baseline age, HbA1c and gender were found to be predictors of weight gain [odds ratios 0.99 (1-year increment), 1.11 (1% increment) and 0.81 (female vs male), respectively, p < 0.001]. Observed vs predicted incidence rates of hospitalization were 265 vs 13 (normal), 297 vs 31 (overweight), 223 vs 50 (obese) and 378 vs 41 (severe obese). CONCLUSION: This analysis suggests there are identifiable patient characteristics predictive of weight gain that may be informative to clinical and economic decision making in the context of patients escalating from M to an M + S regimen. Hospital admissions in people with type 2 diabetes were generally under-predicted. A particular focus of future research should be the need for diabetes models to make the likelihood of experiencing an event conditional on BMI. FUNDING: Takeda Development Centre Europe Ltd., UK.