Search

Abstract Background Despite the current trend towards large epidemiological studies of unrelated individuals, linkage studies in families are still thoroughly being utilized as tools for disease gene mapping. The use of the single-nucleotide-polymorphisms (SNP) array technology in genotyping of family data has the potential to provide more informative linkage data. Nevertheless, SNP array data are not immune to genotyping error which, as has been suggested in the past, could dramatically affect the evidence for linkage especially in selective designs such as affected sib pair (ASP) designs. The influence of genotyping error on selective designs for continuous traits has not been assessed yet. Results We use the identity-by-descent (IBD) regression-based paradigm for linkage testing to analytically quantify the effect of simple genotyping error models under specific selection schemes for sibling pairs. We show, for example, that in extremely concordant (EC) designs, genotyping error leads to decreased power whereas it leads to increased type I error in extremely discordant (ED) designs. Perhaps surprisingly, the effect of genotyping error on inference is most severe in designs where selection is least extreme. We suggest a genomic control for genotyping errors via a simple modification of the intercept in the regression for linkage. Conclusion This study extends earlier findings: genotyping error can substantially affect type I error and power in selective designs for continuous traits. Designs involving both EC and ED sib pairs are fairly immune to genotyping error. When those designs are not feasible the simple genomic control strategy that we suggest offers the potential to deliver more robust inference, especially if genotyping is carried out by SNP array technology.

Aims: To describe healthcare resource utilization (HCRU) and associated costs after initiation of injectable glucagon-like peptide-1 receptor agonist (GLP-1 RA) therapy by adult patients with type 2 diabetes (T2D) in the prospective, observational, 24-month TROPHIES study in France, Germany, and Italy., Materials and Methods: HCRU data for cost calculations were collected by treating physicians during patient interviews at baseline and follow-up visits approximately 6, 12, 18, and 24 months after GLP-1 RA initiation with once-weekly dulaglutide or once-daily liraglutide. Costs were evaluated from the national healthcare system (third-party payer) perspective and updated to 2018 prices., Results: In total, 2,005 patients were eligible for the HCRU analysis (1,014 dulaglutide; 991 liraglutide). Baseline patient characteristics were generally similar between treatment groups and countries. The largest proportions of patients using ≥2 oral glucose-lowering medications (GLMs) at baseline (42.9-43.4%) and month 24 (44.0-45.1%) and using another injectable GLM at month 24 (15.3-23.2%) were in France. Mean numbers of primary and secondary healthcare contacts during each assessment period were highest in France (range = 4.0-10.7) and Germany (range = 2.9-5.7), respectively. The greatest proportions (≥60%) of mean annualized costs per patient comprised medication costs. Mean annualized HCRU costs per patient varied by treatment cohort and country: the highest levels were in the liraglutide cohort in France (€909) and the dulaglutide cohort in Germany (€883)., Limitations: Limitations included exclusion of patients using insulin at GLP-1 RA initiation and collection of HCRU data by physician, not via patient-completed diaries., Conclusions: Real-world HCRU and costs associated with the treatment of adults with T2D with two GLP-1 RAs in TROPHIES emphasize the need to avoid generalization with respect to HCRU and costs associated with a particular therapy when estimating the impact of a new treatment in a country-specific setting.

Introduction: This study aimed to describe utilization patterns, persistence, resource utilization and costs in patients with type 2 diabetes mellitus initiating treatment with glucagon-like peptide 1 receptor agonists in routine clinical practice in Spain., Methods: This retrospective study of medical records in the Big-Pac database identified adults starting treatment with once-weekly (QW) dulaglutide, exenatide-QW or once-daily liraglutide between 1 November 2015 and 30 June 2017. Patients were followed for up to 18 months from treatment initiation. Data on clinical characteristics of patients, treatment patterns, average daily dose and costs were obtained for the three cohorts. Persistence over the 18-month period was evaluated using Kaplan-Meier curves. All analyses were descriptive., Results: A total of 1402 patients were included in this study (dulaglutide [n = 492], exenatide-QW [n = 438] or liraglutide [n = 472]); 52.8% were men, and the mean (SD) age was 62 (11) years, glycated haemoglobin (HbA1c) was 8.1% (1.2) and body mass index was 35.5 (3.2) kg/m 2 at treatment initiation. Persistence at 18 months was 59.1% (95% confidence interval [CI] 54.8-63.4) for dulaglutide, 45.7% (95% CI 41.0-50.4) for exenatide-QW and 46.6% (95% CI 42.1-51.1) for liraglutide. The average (SD) dose was 1.2 (0.4) mg/week for dulaglutide, 1.9 (0.3) mg/week for exenatide-QW and 1.1 (0.3) mg/day for liraglutide. The average reduction in HbA1c levels at 1 year was - 0.68% for patients who initiated dulaglutide, - 0.54% for patients who initiated exenatide-QW and - 0.50% for patients who initiated liraglutide. The mean (SD) total annual health care costs were €4072 (1946) for dulaglutide, €4418 (2382) for exenatide-QW and €4382 (2389) for liraglutide., Conclusion: Results suggest that patients who started treatment with dulaglutide had higher persistence over 18 months, presented lower HbA1c levels at 12 months and incurred lower annual total healthcare costs than patients who initiated exenatide-QW or liraglutide.

Introduction: In type 2 diabetes (T2D), persistence with injectable glucose-lowering therapy is associated with better outcomes. This study used real-world pharmacy data to report on persistence with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in patients with T2D in France., Methods: This retrospective cohort analysis presents longitudinal data from approximately 7500 French retail pharmacies that filled GLP-1-RA prescriptions for GLP-1 RA-naïve patients with T2D ('index therapy': dulaglutide; once-weekly exenatide [exenatide QW]; twice-daily exenatide [exenatide BID]; liraglutide) between January 2015 and December 2016 (follow-up ≥ 12 months). The main outcome was treatment persistence (absence of discontinuation [gap following index therapy prescription ≥ 2-fold the expected duration of that prescription] or switch [new non-index glucose-lowering prescription issued ≤ 30 days before/after index therapy discontinuation]). Persistence was calculated as the median duration through Kaplan-Meier survival analysis over the variable follow-up period and as the proportion of patients persistent at 12 months. In addition to persistence outcomes (discontinuation/switch), three other treatment modifications were assessed: augmentation/intensification with a new non-index glucose-lowering therapy; off-label dose increase (daily dose > 20 μg for exenatide BID; two consecutive prescriptions with daily dose > 1.8 mg for liraglutide); and off-label dose decrease (two consecutive prescriptions with average daily dose lower than the index dose). Off-label dose changes were not assessed for dulaglutide or exenatide QW (as single-dose, prefilled pens)., Results: Median persistence was longest for dulaglutide (373 days) versus liraglutide (205 days), exenatide QW (184 days) and exenatide BID (93 days). Twelve months after treatment initiation, the percentage of persistent patients ranged from 51% (dulaglutide) to 21% (exenatide BID). Overall, treatment modification occurred less commonly for dulaglutide than for the other index GLP-1 RAs., Conclusion: This analysis revealed marked differences in persistence among GLP-1 RAs, which was highest for dulaglutide and lowest for exenatide BID. The prospective TROPHIES study will provide additional information about persistence with dulaglutide and liraglutide, including reasons for treatment modifications.

Introduction: The glucagon-like peptide-1 receptor agonist (GLP-1 RA) class is evolving and expanding. This retrospective database study evaluated recent real-world treatment and dosing patterns of patients with type 2 diabetes (T2D) initiating GLP-1 RAs in Belgium (BE), France (FR), Germany (DE), Italy (IT), the Netherlands (NL), and Canada (CA)., Methods: Adult T2D patients initiating GLP-1 RA therapy (dulaglutide [DULA], exenatide twice daily [exBID], exenatide once weekly [exQW], liraglutide [LIRA], or lixisenatide [LIXI]) from 2015 to 2016 were identified using the IQVIA (IQVIA, Durham, NC, and Danbury, CT, USA) Real-World Data Adjudicated Pharmacy Claims. The therapy initiation date was termed the 'index date.' Eligible patients had ≥ 180 days pre-index and ≥ 360 days post-index. Persistence (until discontinuation or switch) was evaluated over the variable follow-up using Kaplan-Meier (KM) survival analysis. Average daily dose (ADD) was calculated until discontinuation or switch., Results: A total of 34,649 DULA, 3616 exBID, 11,138 exQW, 48,317 LIRA, and 2,204 LIXI patients were included in the analysis (34.9-63.2% female; median age range 53-62 years; median follow-up 16-30 months). Proportion persistent at 1-year post-index was 36.8-67.2% for DULA, 5.9-44.4% for exBID, 24.7-44.2% for exQW, 22.2-57.5% for LIRA, and 15.5-40.0% for LIXI. Median time persistent (days) was 245-381 for DULA, 62-243 for exBID, 121-319 for exQW, 103-507 for LIRA, and 99-203 for LIXI. Mean ADD was 13.21-20.43 µg for exBID, 1.44-1.68 mg for LIRA, and 19.88-20.54 µg for LIXI. Mean average weekly dose (AWD) ranged from 2.03 to 2.14 mg for exQW. Mean AWD for DULA was 1.25 mg in Canada and ranged from 1.43 to 1.53 mg in the other countries., Conclusion: Across six countries, persistence was highest among DULA patients and generally lowest among exBID patients. ADD/AWD for all GLP-1 RAs was in line with the recommended label. Longer-term data would be useful to obtain a better understanding of GLP-1 RA treatment patterns over time., Funding: Eli Lilly and Company, Indianapolis, IN, USA.

Objectives: To quantify the incremental burden of patients with type 2 diabetes mellitus (T2DM) and a hypoglycemic event in Taiwan using the National Health Insurance Research Database., Methods: Data from 2000 through 2013 with an index period of 2001 through 2012 from the National Health Insurance Research Database's 2-million-patient sample were used. Using a nested case-control study design, patients were indexed if they reported a diagnosis of T2DM during the index period. Patients with T2DM with a hypoglycemic event (defined by International Classification of Diseases, Ninth Revision, Clinical Modification codes) during the index period were identified. Patients with T2DM without a hypoglycemic event were included to form a 4:1 (controls to cases) matched cohort on the basis of age, sex, the Charlson Comorbidity Index, and the T2DM diagnosis date. Both cohorts were followed up for 1 year after the hypoglycemic event and had their treatment utilization, resource utilization, and healthcare costs measured., Results: A total of 144 213 patients with T2DM were identified, with 3 651 (2.5%) recording a hypoglycemic event. Before matching, patients with T2DM with a hypoglycemic event were, on average, older (64.2 vs 56.6) and had higher mean CCI scores (2.4 vs 1.9) than did patients with T2DM without a hypoglycemic event. After matching, patients with T2DM and a hypoglycemic event incurred an additional $1353 in average direct healthcare costs during the 1 year of follow-up compared with the matched cohort. Patients with T2DM with hypoglycemia also spent an additional 5.9 days in the hospital during the follow-up period compared with the matched cohort., Conclusions: Patients with hypoglycemic events, on average, experienced a substantially higher economic burden than did their counterparts without a hypoglycemic event during the same period., (Copyright © 2019 ISPOR--The professional society for health economics and outcomes research. Published by Elsevier Inc. All rights reserved.)

Introduction: Real-world evidence on glucagon-like peptide-1 receptor agonist (GLP-1 RAs) usage is emerging in different European countries but is lacking in Italy. This retrospective cohort study aimed to describe the real-world drug utilization patterns in patients initiating GLP-1 RAs for treating T2DM in Italy., Methods: Adults aged ≥ 20 years and with ≥ 1 oral antidiabetic drug (alone or in combination with insulin) other than GLP-1 RAs in the 6 months prior to initiating exenatide twice daily (exBID), exenatide once weekly (exQW), dulaglutide once weekly (DULA), liraglutide once daily (LIRA) or lixisenatide once daily (LIXI) between March and July 2016 were retrospectively identified in the Italian IMS LifeLink™ longitudinal prescriptions database (retail pharmacy data). Patients with ≥ 6-month follow-up (defined as evidence of any prescription activity) were included. Proportions of patients who remained persistent (continued treatment until discontinuation/switch) in the first 6 months and of those who discontinued or switched to a different GLP-1 RA over the entire follow-up were recorded. For each treatment, the average daily/weekly dosage (ADD/AWD) while persistent during the available follow-up was calculated., Results: We identified 7319 patients: 92 exBID, 970 exQW, 3368 DULA, 2573 LIRA and 316 LIXI. Across treatments, 89% patients were ≥ 50 years old, 54% were males, and the median follow-up duration ranged between 8.1 and 8.7 months. At 6 months, 35% exBID, 47% exQW, 62% DULA, 50% LIRA and 40% LIXI patients remained persistent. Over the entire follow-up, median persistence days varied from 73 (exBID) to > 300 days (DULA). The mean ± SD ADD/AWD was exBID: 17.7 ± 2.1 µg/day; exQW: 2.1 ± 0.1 mg/week; DULA: 1.5 ± 0.2 mg/week; LIRA: 1.5 ± 0.2 mg/day; LIXI: 21.0 ± 5.5 µg/day., Conclusions: This real-world analysis suggests differences exist in persistence between patients treated with various GLP-1 RAs. Among the investigated treatments, patients prescribed exBID recorded the lowest and those prescribed DULA the highest persistence with therapy., Funding: Eli Lilly and Co., Indianapolis, IN, USA.

Background: Given the high costs associated with the care of those with Alzheimer's disease (AD) dementia, we examined the likely impact of a reduction in the rate of cognitive decline upon cost outcomes associated with this disease., Methods: Using the group of patients with mild AD dementia from the GERAS study, generalised linear modelling (GLM) was used to explore the relationship between change in cognition as measured using the Mini-Mental State Examination (MMSE) and UK overall costs (health care and social care costs, and total societal costs) associated with AD dementia., Results: A total of 200 patients with mild AD dementia were identified. Least squares mean (LSM) ± standard error (SE) reduction in MMSE score was 3.6 ± 0.4 points over 18 months. Using GLM it was possible to calculate that this worsening in cognition was associated with an 8.7% increase in total societal costs, equating to an increase of approximately £2200 per patient over an 18-month period. If the rate of decline in cognition was reduced by 30% or 50%, the associated savings in total societal costs over 18 months would be approximately £670 and £1100, respectively, of which only £110 and £180, respectively, could be attributed to a saving of health care costs., Conclusion: This study demonstrates that there are potential savings to be made in the care of patients with AD dementia through reducing the rate of cognitive decline. A reduction in wider societal costs is likely to be the main contributor to these potential savings, and need to be further evaluated when intervention costs and cost offsets can be measured.

Background/aims: We assessed whether cognitive and functional decline in community-dwelling patients with mild Alzheimer disease (AD) dementia were associated with increased societal costs and caregiver burden and time outcomes., Methods: Cognitive decline was defined as a ≥3-point reduction in the Mini-Mental State Examination and functional decline as a decrease in the ability to perform one or more basic items of the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory (ADCS-ADL) or ≥20% of instrumental ADL items. Total societal costs were estimated from resource use and caregiver hours using 2010 costs. Caregiver burden was assessed using the Zarit Burden Interview (ZBI); caregiver supervision and total hours were collected., Results: Of 566 patients with mild AD enrolled in the GERAS study, 494 were suitable for the current analysis. Mean monthly total societal costs were greater for patients showing functional (+61%) or cognitive decline (+27%) compared with those without decline. In relation to a typical mean monthly cost of approximately EUR 1,400 at baseline, this translated into increases over 18 months to EUR 2,254 and 1,778 for patients with functional and cognitive decline, respectively. The number of patients requiring supervision doubled among patients showing functional or cognitive decline compared with those not showing decline, while caregiver total time increased by 70 and 33%, respectively and ZBI total score by 5.3 and 3.4 points, respectively., Conclusion: Cognitive and, more notably, functional decline were associated with increases in costs and caregiver outcomes in patients with mild AD dementia.

Background: Alzheimer's disease (AD), the commonest cause of dementia, represents a significant cost to UK society. This analysis describes resource utilisation, costs and clinical outcomes in non-institutionalised patients with AD in the UK., Methods: The GERAS prospective observational study assessed societal costs associated with AD for patients and caregivers over 18 months, stratified according to baseline disease severity (mild, moderate, or moderately severe/severe [MS/S]). All patients enrolled had an informal caregiver willing to participate in the study. Healthcare resource utilisation was measured using the Resource Utilization in Dementia instrument, and 18-month costs estimated by applying unit costs of services and products (2010 values). Total societal costs were calculated using an opportunity cost approach., Results: Overall, 526 patients (200 mild, 180 moderate and 146 MS/S at baseline) were recruited from 24 UK centres. Mini-Mental State Examination (MMSE) scores deteriorated most markedly in the MS/S patient group, with declines of 3.6 points in the mild group, 3.5 points in the moderate group and 4.7 points in the MS/S group; between-group differences did not reach statistical significance. Patients with MS/S AD dementia at baseline were more likely to be institutionalised (Kaplan-Meier probability 28% versus 9% in patients with mild AD dementia; p < 0.001 for difference across all severities) and had a greater probability of death (Kaplan-Meier probability 15% versus 5%; p = 0.013) at 18 months. Greater disease severity at baseline was also associated with concomitant increases in caregiver time and mean total societal costs. Total societal costs of £43,560 over 18 months were estimated for the MS/S group, versus £25,865 for the mild group and £30,905 for the moderate group (p < 0.001). Of these costs, over 50% were related to informal caregiver costs at each AD dementia severity level., Conclusions: This study demonstrated a mean deterioration in MMSE score over 18 months in patients with AD. It also showed that AD is a costly disease, with costs increasing with disease severity, even when managed in the community: informal caregiver costs represented the main contributor to societal costs.

Background: Goals of treating major depressive disorder (MDD) include achieving remission and avoiding relapse. It is possible that patients may have a broader view of remission than what is captured via clinician-rated scales. This patient perspective may, in turn, have an impact on treatment outcomes., Methods: The association between a broader conceptualization of remission, based on the Remission from Depression Questionnaire (RDQ) score at baseline, and being in symptomatic remission after 6 months was evaluated in subjects (N = 613) with MDD in symptomatic remission at baseline (17-item Hamilton Rating Scale for Depression [HAMD-17] ≤7). Specific aspects of depression were assessed from physician and patient perspectives as secondary endpoints. A backwards selection strategy was used to statistically model remission status and determine association of factors with potential to influence remission., Results: At month 6, after adjustment for baseline HAMD-17 score, there was no association between baseline RDQ score and symptomatic remission status (HAMD-17), relapse, composite remission status, healthcare resource utilization, or quality of life. There was no association between functional impairment scores at baseline (Sheehan Disability Scale and Social and Occupational Functioning Assessment Scale) and symptomatic remission status (HAMD-17) at month 6., Conclusions: This study indicates that RDQ-constructs are independent from symptomatic remission. Symptom severity at study entry appeared to be the only significant predictor of eventual relapse during the 6-month follow-up period. However, our results also suggest that the current definition of remission that is based on symptom reduction should be further elaborated and that alternative or additional definitions should be considered in determining remission.

Background: The burden on caregivers of patients with Alzheimer's disease (AD) is associated with the patient's functional status and may also be influenced by chronic comorbid medical conditions, such as diabetes. This post-hoc exploratory analysis assessed whether comorbid diabetes in patients with AD affects caregiver burden, and whether caregivers with diabetes experience greater burden than caregivers without diabetes. Caregiver and patient healthcare resource use (HCRU) were also assessed., Methods: Baseline data from the GERAS observational study of patients with AD and their caregivers (both n = 1495) in France, Germany and the UK were analyzed. Caregiver burden was assessed using the Zarit Burden Interview (ZBI). Caregiver time on activities of daily living (ADL: basic ADL; instrumental ADL, iADL) and supervision (hours/month), and caregiver and patient HCRU (outpatient visits, emergency room visits, nights hospitalized) were assessed using the Resource Utilization in Dementia instrument for the month before the baseline visit. Regression analyses were adjusted for relevant covariates. Time on supervision and basic ADL was analyzed using zero-inflated negative binomial regression., Results: Caregivers of patients with diabetes (n = 188) were younger and more likely to be female (both p < 0.05), compared with caregivers of patients without diabetes (n = 1307). Analyses showed caregivers of patients with diabetes spent significantly more time on iADL (+16 %; p = 0.03; increases were also observed for basic ADL and total caregiver time but did not reach statistical significance) and had a trend towards increased ZBI score. Patients with diabetes had a 63 % increase in the odds of requiring supervision versus those without diabetes (p = 0.01). Caregiver and patient HCRU did not differ according to patient diabetes. Caregivers with diabetes (n = 127) did not differ from those without diabetes (n = 1367) regarding burden/time, but caregivers with diabetes had a 91 % increase in the odds of having outpatient visits (p = 0.01)., Conclusions: This cross-sectional analysis found caregiver time on iADL and supervision was higher for caregivers of patients with AD and diabetes versus without diabetes, while HCRU was unaffected by patient diabetes. Longitudinal analyses assessing change in caregiver burden over time by patient diabetes status may help clarify the cumulative impact of diabetes and AD dementia on caregiver burden.

Background: Attention-deficit/hyperactivity disorder (ADHD) often persists into adulthood. This study was designed to estimate the prevalence of ADHD in adult psychiatric outpatients in several European countries., Method: ADHD diagnosis was made using the Diagnostic Interview for ADHD in Adults, version 2.0 (DIVA), according to criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) and 5th Edition (DSM-5)., Results: Of 5662 patients present/approached, 2284 (40.3 %) consented, of whom 1986 patients (87.0 %) completed the study. Based on the DIVA, and applying DSM-IV-TR or DSM-5 criteria, 15.8 % (95 % confidence interval [CI] 14.2 %-17.4 %) or 17.4 % (95 % CI 15.7 %-19.0 %) of patients were diagnosed with ADHD, respectively. The prevalence of ADHD was 15.3 % when counting as non-ADHD those patients who screened positive but did not complete the DIVA (DSM-5)., Conclusions: Estimates from this study indicate that a relevant part of the psychiatric outpatient care population suffers from ADHD.

Objective: Hypertension in diabetes is characterized by abnormal sodium homeostasis, suggesting a particular role of natriuretic peptide pathway. Natriuretic peptides can affect blood pressure (BP) through their plasma concentrations, which are dependent on their receptor activities. We thus assessed the association between nine NPR3 gene polymorphisms and BP levels in patients with type 2 diabetes., Research Design and Methods: Nine single nucleotide polymorphisms (SNPs) tagging the haplotype structure of the NPR3 gene were genotyped in the 3,126 French Non-insulin-dependent Diabetes, Hypertension, Microalbuminuria or Proteinuria, Cardiovascular Events, and Ramipril (DIABHYCAR) trial participants. We then used a second population (Diabete de type 2, Nephropathie et Genetique [DIAB2NEPHROGENE]/Survie, Diabete de type 2 et Genetique [SURDIAGENE] study) of 2,452 patients for the purpose of replication. Finally, we separately investigated subjects selected according to their rs 2270915SNP genotypes for their BP response to salt restriction., Results: In DIABHYCAR patients, three SNPs (rs6889608, rs1173773, and rs2270915) were significantly associated with systolic BP (SBP). The effect of the rs2270915 was replicated in the second step population: AA homozygotes had a lower SBP than G carriers (137.4 ± 19.1 vs. 140.0 ± 20.2 mmHg, P = 0.004). The rs2270915 influenced the response of SBP to salt reduction, with AA homozygous patients showing greater reductions after restriction of salt intake compared with G carriers: -20 mmHg (-43 to -8) vs. -3 (-20 to +7); P = 0.006., Conclusions: We found a consistent and significant association between the rs2270915 polymorphism of the NPR3 gene and SBP in diabetic patients. This genetic variation may affect pressure response to changes in dietary sodium.