A machine-learning algorithm using claims data to identify patients with homozygous familial hypercholesterolemia.

Homozygous familial hypercholesterolemia (HoFH) is an underdiagnosed and undertreated ultra-rare disease. We utilized claims data from the Komodo Healthcare Map database to develop a machine-learning model to identify potential HoFH patients. We tokenized patients enrolled in MyRARE (patient support program for those prescribed evinacumab-dgnb in the United States) and linked them with their Komodo claims. A true positive HoFH cohort (n = 331) was formed by including patients from MyRARE and patients with prescriptions for evinacumab-dgnb or lomitapide. The negative cohort (n = 1423) comprised patients with or at risk for cardiovascular disease. We divided the cohort into an 80% training and 20% testing set. Overall, 10,616 candidate features were investigated; 87 were selected due to clinical relevance and importance on prediction performance. Different machine-learning algorithms were explored, with fast interpretable greedy-tree sums selected as the final machine-learning tool. This selection was based on its satisfactory performance and its easily interpretable nature. The model identified four useful features and yielded precision (positive predicted value) of 0.98, recall (sensitivity) of 0.88, area under the receiver operating characteristic curve of 0.98, and accuracy of 0.97. The model performed well in identifying HoFH patients in the testing set, providing a useful tool to facilitate HoFH screening and diagnosis via healthcare claims data.

Regulation of mast cells by overlapping but distinct protein interactions of Siglec-6 and Siglec-8.

BACKGROUND: Sialic acid-binding immunoglobulin-like lectin (Siglec)-6 and Siglec-8 are closely related mast cell (MC) receptors with broad inhibitory activity, but whose functional differences are incompletely understood. METHODS: Proteomic profiling using quantitative mass spectrometry was performed on primary mouse MCs to identify proteins associated with Siglec-6 and Siglec-8. For functional characterization, each receptor was evaluated biochemically and in ex vivo and in vivo inhibition models of IgE and non-IgE-mediated MC activation in Siglec-6- or Siglec-8-expressing transgenic mice. RESULTS: Siglec-6 and Siglec-8 were found in MCs within large complexes, interacting with 66 and 86 proteins, respectively. Strikingly, Siglec-6 and Siglec-8 interacted with a large cluster of proteins involved in IgE and non-IgE-mediated MC activation, including the high affinity IgE receptor, stem cell factor (SCF) receptor KIT/CD117, IL-4 and IL-33 receptors, and intracellular kinases LYN and JAK1. Protein interaction networks revealed Siglec-6 and Siglec-8 had overlapping yet distinct MC functions, with a potentially broader regulatory role for Siglec-6. Indeed, Siglec-6 preferentially interacted with the mature form of KIT at the cell surface, and treatment with an anti-Siglec-6 antibody significantly inhibited SCF-mediated MC activation more in comparison to targeting Siglec-8. CONCLUSION: These data demonstrate a central role for Siglec-6 and Siglec-8 in controlling MC activation through interactions with multiple activating receptors and key signaling molecules. Our findings suggest that Siglec-6 has a role distinct from that of Siglec-8 in regulating MC function and represents a distinct potential therapeutic target in mast cell-driven diseases.

Rare coding variants in CHRNB2 reduce the likelihood of smoking.

Human genetic studies of smoking behavior have been thus far largely limited to common variants. Studying rare coding variants has the potential to identify drug targets. We performed an exome-wide association study of smoking phenotypes in up to 749,459 individuals and discovered a protective association in CHRNB2, encoding the ß2 subunit of the α4ß2 nicotine acetylcholine receptor. Rare predicted loss-of-function and likely deleterious missense variants in CHRNB2 in aggregate were associated with a 35% decreased odds for smoking heavily (odds ratio (OR) = 0.65, confidence interval (CI) = 0.56-0.76, P = 1.9 × 10-8). An independent common variant association in the protective direction ( rs2072659 ; OR = 0.96; CI = 0.94-0.98; P = 5.3 × 10-6) was also evident, suggesting an allelic series. Our findings in humans align with decades-old experimental observations in mice that ß2 loss abolishes nicotine-mediated neuronal responses and attenuates nicotine self-administration. Our genetic discovery will inspire future drug designs targeting CHRNB2 in the brain for the treatment of nicotine addiction.

Design and synthesis of aminopyridine containing biaryls reducing c-MYC protein levels in cells.

The c-MYC oncogene transcription factor has been implicated in cell cycle regulation controlling cell growth and proliferation. It is tightly regulated in normal cells, but has been shown to be deregulated in cancer cells, and is thus an attractive target for oncogenic therapies. Building upon previous SAR, a series of analogues containing benzimidazole core replacements were prepared and evaluated, leading to the identification of imidazopyridazine compounds that were shown to possess equivalent or improved c-MYC HTRF pEC50 values, lipophilicity, solubility, and rat pharmacokinetics. The imidazopyridazine core was therefore determined to be superior to the original benzimidazole core and a viable alternate for continued lead optimization and medicinal chemistry campaigns.

Tratamiento del tabaquismo guiado por marcadores genéticos

Introducción: Entre las adicciones por drogas, el tabaquismo ocupa el primer lugar como causa de morbimortalidad y es factor de riesgo para seis de las ocho principales causas de muerte en el mundo. La nicotina es el principal componente adictivo del tabaco. En la terapia de reemplazo con nicotina (TRN), la vareniclina y el bupropion son los medicamentos aprobados para tratamiento del tabaquismo, pero los resultados de las clínicas de dejación del tabaquismo sugieren que aún se desconoce muchas variables influyentes en la respuesta al tratamiento. Objetivo: Determinar la adherencia, la tolerabilidad y la efectividad de un programa de dejación de tabaquismo basado en nicotina o bupropion, en pacientes con dependencia al tabaco, seleccionados según los genotipos de las enzimas que metabolizan los dos fármacos. Hallazgos clínicos: Se incluyeron en esta serie 21 fumadores, 67% hombres, con edad promedio de 46,2±11,7 años. Su tabaquismo comenzó a los 17,8±6 años y llevaban fumando 28±13 años. Al inicio del estudio fumaban 17±12 cigarrillos por día (CPD), habían hecho 3,7±2 intentos de dejar de fumar y el puntaje NDSS (escala breve de evaluación de dependencia de la nicotina, por sus siglas en inglés) fue de 22±5 (punto de corte para dependencia a nicotina: 11 o más puntos). Tratamiento: Los pacientes tenían libre acceso telefónico al médico tratante y, cada semana, una consulta consistente en consejería y control del tratamiento farmacológico prescrito según los genotipos CYP2A6 (que codifica la enzima que metaboliza la nicotina) y CYP2B6 (que codifica la enzima que metaboliza el bupropion). Se empleó nicotina en parches transdérmicos de 14 mg el primer mes y luego de 7 mg el segundo mes, complementados con chicles para manejo del síndrome de abstinencia y bupropion en forma de liberación regulada por 300 mg, 1-2 veces al día. Resultados: Después de 8 semanas de tratamiento y 4 de observación, 15 sujetos (71,4%) respondieron en forma parcial/total. El consumo de CPD bajó de 17±12 al inicio del estudio, a 2,2±3,5 al final del estudio, que corresponde a una reducción de 195 cigarrillos/día. Siete de ocho pacientes tratados con bupropion (87,5%) y siete de trece tratados con nicotina (54%) tuvieron respuesta parcial/total. Solo un paciente formulado con nicotina suspendió el medicamento por intolerancia gastrointestinal (náusea y vómito). La tasa de recaídas, evaluada un mes después del tratamiento farmacológico, fue de cero. Se encontró buena correlación genotipo-fenotipo en los individuos tratados con bupropion, pero no en los tratados con nicotina. Relevancia clínica: La inclusión de marcadores farmacogenéticos para la elección de nicotina o bupropion en un programa de dejación de tabaquismo puede mejorar la adherencia, la tolerabilidad al fármaco y la efectividad del tratamiento.

Introduction: Among drug addictions, smoking ranks first as a cause of morbidity and mortality and is a risk factor for six of the eight leading causes of death in the world. Nicotine is the main addictive component of tobacco. In nicotine replacement therapy (NRT), varenicline and bupropion are the approved medications for smoking cessation, but results from smoking cessation clinics suggest that many variables influencing response to treatment remain unknown. Objective: To determine the adherence, tolerability and effectiveness of a smoking cessation program based on nicotine or bupropion, in patients with tobacco dependence, selected according to the genotypes of the enzymes that metabolize the two drugs. Clinical findings: Twenty-one smokers were included in this series, 67% men, with a mean age of 46.2 ± 11.7 years. Their smoking began at 17.8±6 years and they had been smoking for 28±13 years. At baseline, they smoked 17±12 cigarettes per day (CPD), had made 3.7±2 quit attempts, and the NDSS score it was 22±5 (cut-off point for nicotine dependence: 11 or more points). Treatment: The patients had free telephone access to the treating physician and, every week, a consultation consisting of counseling and control of the pharmacological treatment prescribed according to the CYP2A6 genotypes (encoding the enzyme that metabolizes nicotine) and CYP2B6 (coding for the enzyme that metabolizes bupropion). Nicotine was used in transdermal patches of 14 mg the first month and then 7 mg the second month, supplemented with gum to manage the withdrawal syndrome and bupropion in the form of controlled release 300 mg, 1-2 times a day. Results: After 8 weeks of treatment and 4 weeks of observation, 15 subjects (71.4%) responded partially/totally. CPD consumption dropped from 17±12 at the beginning of the study to 2.2±3.5 at the end of the study, which corresponds to a reduction of 195 cigarettes/day. Seven of eight patients treated with bupropion (87.5%) and seven of thirteen treated with nicotine (54%) had a partial/total response. Only one patient receiving nicotine discontinued the medication due to gastrointestinal intolerance (nausea and vomiting). The relapse rate, assessed one month after drug treatment, was zero. Good genotype-phenotype correlation was found in individuals treated with bupropion, but not in those treated with nicotine. Clinical relevance: The inclusion of pharmacogenetic markers for the choice of nicotine or bupropion in a smoking cessation program may improve adherence, drug tolerability, and treatment effectiveness.

Serum cholesterol and the risk of developing hormonally driven cancers: A narrative review.

Although cholesterol has been hypothesized to promote cancer development through several potential pathways, its role in the risk of developing hormonally driven cancer is controversial. This literature review summarizes evidence from the highest quality studies to examine the consistency and strength of the relationship between serum cholesterol parameters and incidence of hormonally driven cancer. Articles were identified using EMBASE. Longitudinal observational studies published between January 2000 and December 2020 were considered for inclusion. The endpoint of interest was incident prostate, ovary, breast, endometrium, and uterine cancers. In total, 2732 reports were identified and screened; 41 studies were included in the review. No associations were found for ovarian cancer. Most endometrial cancer studies were null. The majority (76.9%) of studies reported no association between cholesterol and prostate cancer. Data on breast cancer were conflicting, associations limited, and effect sizes modest. Our results do not provide evidence for a clear association between cholesterol and different types of incident, hormonally driven reproductive cancers. Future studies should investigate the impact of lipid-lowering therapy.

Real-world effectiveness of casirivimab and imdevimab among patients diagnosed with COVID-19 in the ambulatory setting: a retrospective cohort study using a large claims database.

OBJECTIVE: To assess the real-world effectiveness of casirivimab and imdevimab (CAS+IMD) versus no COVID-19 antibody treatment among patients diagnosed with COVID-19 in the ambulatory setting, including patients diagnosed during the Delta-dominant period prior to Omicron emergence. DESIGN: Retrospective cohort study. SETTING: Komodo Health closed claims database. PARTICIPANTS: 13 273 128 patients diagnosed with COVID-19 (December 2020 through September 2021) were treated with CAS+IMD or untreated but treatment eligible under the Emergency Use Authorization (EUA). Each treated patient was exact and propensity score matched without replacement to up to five untreated EUA-eligible patients. INTERVENTIONS: CAS+IMD. PRIMARY AND SECONDARY OUTCOME MEASURES: Composite endpoint of 30-day all-cause mortality or COVID-19-related hospitalisation. Kaplan-Meier estimators were used to calculate outcome risks overall and across subgroups: age, COVID-19 vaccination status, immunocompromised status, and timing of diagnosis (December 2020 to June 2021, and July to September 2021). Cox proportional hazards models were used to estimate adjusted HRs (aHRs) and 95% CIs. RESULTS: Among 75 159 CAS+IMD-treated and 1 670 338 EUA-eligible untreated patients, 73 759 treated patients were matched to 310 688 untreated patients; matched patients were ~50 years, ~60% were women and generally well balanced across risk factors. The 30-day risk of the composite outcome was 2.1% and 5.2% in the CAS+IMD-treated and CAS+IMD-untreated patients, respectively; equivalent to a 60% lower risk (aHR 0.40; 95% CI, 0.38 to 0.42). The effect of CAS+IMD was consistent across subgroups, including those who received a COVID-19 vaccine (aHR 0.48, 95% CI, 0.41 to 0.56), and those diagnosed during the Delta-dominant period (aHR 0.40, 95% CI, 0.38 to 0.42). CONCLUSIONS: The real-world effectiveness of CAS+IMD is consistent with the efficacy for reducing all-cause mortality or COVID-19-related hospitalisation reported in clinical trials. Effectiveness is maintained across patient subgroups, including those prone to breakthrough infections, and was effective against susceptible variants including Delta. .

The prevalence of low muscle mass associated with obesity in the USA.

BACKGROUND: Sarcopenia is defined as age-related low muscle mass and function, and can also describe the loss of muscle mass in certain medical conditions, such as sarcopenic obesity. Sarcopenic obesity describes loss of muscle and function in obese individuals; however, as sarcopenia is an age-related condition and obesity can occur in any age group, a more accurate term is obesity with low lean muscle mass (OLLMM). Given limited data on OLLMM (particularly in those aged < 65 years), the purpose of this study was to estimate the prevalence of OLLMM in adults aged ≥ 20 years in the USA. METHODS: Data from the National Health and Nutrition Examination Survey (NHANES) 2017-2018 and 1999-2006 were used. OLLMM was defined as an appendicular lean mass, adjusted for body mass index (BMI), cut-off point < 0.789 for males and < 0.512 for females, measured by dual-energy X-ray absorptiometry (DXA). DXA was only measured in individuals 20-59 years old in NHANES 2017-2018; we therefore utilized logistic regression models to predict OLLMM from NHANES 1999-2006 for those aged ≥ 60 years. The prevalence of OLLMM was estimated overall, and by sex, age, race/ethnicity, and clinical subgroup (high BMI, prediabetes, type 2 diabetes mellitus [T2DM], non-alcoholic fatty liver disease [NAFLD] with fibrosis, or post-bariatric surgery). Prevalence estimates were extrapolated to the USA population using NHANES sampling weights. RESULTS: We estimated that, during 2017-2018, 28.7 million or 15.9% of the USA population had OLLMM. The prevalence of OLLMM was greater in older individuals (8.1%, aged 20-59 years vs 28.3%, aged ≥ 60 years), highest (66.6%) in Mexican-American females aged ≥ 60 years, and lowest (2.6%) in non-Hispanic Black males aged 20-59 years. There was a higher prevalence of OLLMM in adults with prediabetes (19.7%), T2DM (34.5%), NAFLD with fibrosis (25.4%), or post-bariatric surgery (21.8%), compared with those without each condition. CONCLUSIONS: Overall, the burden of OLLMM in the USA is substantial, affecting almost 30 million adults. The prevalence of OLLMM increased with age, and among those with prediabetes, T2DM, NAFLD with fibrosis, or post-bariatric surgery. A unified definition of OLLMM will aid diagnosis and treatment strategies.

Simulation of lipid-lowering therapy (LLT) intensification in very high-risk patients with atherosclerotic cardiovascular disease.

We aim to estimate the number and proportion of very-high risk patients with atherosclerotic cardiovascular disease (ASCVD) who would be able to achieve low-density lipoprotein cholesterol (LDL-C) <70 mg/dL with various lipid-lowering therapies (LLTs), including statins, ezetimibe, bempedoic acid, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and evinacumab, using a Monte Carlo simulation model described previously. With current treatment options for LDL-C lowering, including statin, ezetimibe, bempedoic acid, and PCSK9 inhibitors, it was estimated that most very-high risk patients with ASCVD (99.1%) were able to achieve the LDL-C goal of <70 mg/dL. Nevertheless, approximately 88,715 patients in the USA were estimated to not be able to achieve the LDL-C goal after current available LLTs, thus remaining at elevated risk for recurrent cardiovascular events. Evinacumab may be useful to address such unmet needs effectively, as the majority of those not at goal after PCSK9 inhibitors could achieve the goal of <70 mg/dL after taking evinacumab.

Effectiveness of Subcutaneous Casirivimab and Imdevimab in Ambulatory Patients with COVID-19.

INTRODUCTION: Data on real-world effectiveness of subcutaneous (SC) casirivimab and imdevimab (CAS+IMD) for the treatment of coronavirus disease 2019 (COVID-19) are limited. The objective of this study was to assess the effectiveness of SC CAS+IMD versus no antibody treatment among patients with COVID-19. METHODS: This retrospective cohort study linked Komodo Health and CDR Maguire Health and Medical data. Patients diagnosed with COVID-19 in ambulatory settings (August 1-October 30, 2021) treated with SC CAS+IMD were exact- and propensity score-matched to fewer than five untreated treatment-eligible patients and followed for the composite endpoint of 30-day all-cause mortality or COVID-19-related hospitalization. Kaplan-Meier estimators were used to calculate outcome risk overall and across subgroups. Cox proportional-hazards models were used to estimate adjusted hazard ratios (aHR) and 95% confidence intervals (CI). RESULTS: Of 13,522 patients treated with CAS+IMD, 12,972 were matched to 41,848 untreated patients. The 30-day composite outcome risk was 1.9% (95% CI 1.7-2.2) and 4.4% (95% CI 4.2-4.6) in the treated and untreated cohorts, respectively; treated patients had a 49% lower relative risk of the composite outcome (aHR 0.51; 95% CI 0.46-0.58) and a 67% relative risk of 30-day mortality (aHR 0.33, 95% CI 0.18-0.60). Effectiveness was consistent across vaccination status and various subgroups. DISCUSSION: Patients with COVID-19 benefitted from treatment with SC CAS+IMD versus untreated patients. The results were consistent across subgroups of patients, including older adults, immunocompromised patients, and patients vaccinated against COVID-19. Results were robust across numerous sensitivity analyses. CONCLUSION: SC CAS+IMD is effective in reducing 30-day COVID-19-related hospitalization or mortality in real-world outpatient settings during the Delta-dominant period.

Qualitative interviews in patients with lipodystrophy to assess the patient experience: evaluation of hunger and other symptoms.

BACKGROUND: New treatments are being evaluated for lipodystrophy; however, limited information is available on the patient experience. Results of a prior patient panel showed that hunger and temperature-related symptoms were an issue for participants. Therefore, evaluation of any changes in these symptoms is recommended for inclusion in new treatment options. The objective of this study was to further understand the patient experience and to evaluate newly developed items of hunger and temperature regulation. METHODS: Individual, in-depth telephone interviews were conducted via semi-structured discussion guide. Telephone interviews were conducted with 21 US patients with generalized lipodystrophy (GLD) or partial lipodystrophy (PLD). Eligibility requirements included self-reported PLD or GLD. Interviews included open-ended concept elicitation followed by a review of newly developed items assessing hunger, temperature sensations, and patient globals. Interviews were conducted in two rounds, with the newly developed items assessing hunger revised after each round of interviews based on participant feedback. RESULTS: Results indicated that hunger-related symptoms were considered a current issue for greater than half (N = 11) of participants, and all but one reported this as an issue at some point in their lives. Specifically, participants most often reported symptoms of increased appetite and not feeling full. The cognitive debriefing process indicated that the hunger-related symptoms, temperature, and global impression of change and severity items were correctly interpreted and easily completed by the participants. While not a focus of the interviews, the concept elicitation results demonstrated that pain was a frequently reported and bothersome symptom in this patient population. CONCLUSIONS: This qualitative research provided evidence to support the use of clinical outcomes assessments such as hunger and temperature-related items in clinical trials.

Lipid treatment status and goal attainment among patients with atherosclerotic cardiovascular disease in the United States: A 2019 update.

Objective: To update the prevalence of atherosclerotic cardiovascular disease (ASCVD) in the United States (US) and re-evaluate lipid-lowering therapies (LLT) utilization and low-density lipoprotein cholesterol (LDL-C) goal attainment among ASCVD patients after proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have become available using data from 2019. Methods: ASCVD patients with at least 1 valid LDL-C measurement from the 2019 Truven MarketScan Research Database were included and stratified into hierarchical cardiovascular risk groups. The number of patients in each group was extrapolated to approximate national figures based on national demographic and ASCVD prevalence numbers. Descriptive statistics on demographic and clinical characteristics, treatment status and LDL-C for each hierarchical category were reported. Results: The overall prevalence of ASCVD in the US in 2019 was 24.0 million, approximately 10% of the total US population above 21 years old. We found heavy comorbidity burden among ASCVD patients and 31.2% were at very high risk for recurrent events. The majority of ASCVD patients were not at guideline-recommended LDL-C goal. Although there was a significant increase in the use of LLTs (especially of high-intensity statins) in 2019 compared to 2014, overall LLT utilization remained low, with only 3.8% of ASCVD patients on ezetimibe, less than 1% on PCSK9 inhibitors and over 40% on no LLTs. We also found higher utilization of LLTs among patients who were at goal of < 70 or < 55 mg/dL vs. those not at goal. Conclusion: Despite an increase in high-intensity statins use since 2014, there was still an underutilization of LLTs in spite of evidence of their efficacy in LDL-C lowering and ability to reduce the risk of coronary heart disease. Increased awareness of guidelines by healthcare providers and urgency to treat ASCVD is needed in order to improve LLT utilization and help more patients reach the LDL-C goal.

"I Can't Take off My Shirt or Do My Own Hair"-A Qualitative Investigation of the Symptoms and Impact Experience of Children and Adolescents with Fibrodysplasia Ossificans Progressiva (FOP).

INTRODUCTION: Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare, severely disabling, autosomal dominant, congenital disease characterized by progressive multi-focal heterotopic ossification (HO) of skeletal muscle, ligaments, tendons, and fascia. Past FOP studies have focused on the clinical aspects of the disease; therefore, there is a paucity of qualitative research on the patient experience. Our objective was to better understand the experience of children and adolescents living with FOP from their and their parents' perspectives. METHODS: We conducted a qualitative research study comprising in-depth, open-ended interviews with children and adolescents with FOP and their parents. Semi-structured interviews were conducted via phone call or Microsoft Teams with parent-child dyads (n = 11), adolescents (n = 6), and two clinicians. Children/adolescents and their parents were asked open-ended questions to elicit their daily experience of FOP. RESULTS: Concepts were organized into two major themes: symptoms of FOP and the impact of FOP on daily life. Symptoms of FOP reported by children/adolescents, parents, and clinicians were pain, swelling, redness, and stiffness. Functional impacts of flares and FOP in general included accommodations, mobility, activities of daily living, daily activities, and social activities. Impacts were attributed to the difficulties children and adolescents faced living with a disease that prohibited common activities. CONCLUSIONS: This research documented the experience of children and adolescents with FOP and its effects on their daily lives. It provides a conceptual model for further exploration of the symptoms and impacts important to children and adolescents with FOP and their parents. Children and adolescents and their parents offered novel insights into life with the disease that have not previously been discussed in published literature. Future studies should build upon our conceptual model to create a holistic view of the patient experience of FOP, to inform clinical practice, and the assessment of the patient experience in clinical trials for the disease.

Increased Quality of Life Among Newly Diagnosed Patients With Heart Failure With Reduced Ejection Fraction in the Months After Initiation of Guideline-Directed Medical Therapy and Wearable Cardioverter Defibrillator Prescription.

BACKGROUND: The patient experience of heart failure involves a multi-impact symptom response with functional limitations, psychological changes, and significant treatment burden. OBJECTIVE: The aim of this study was to examine the change in patient-reported outcomes in newly diagnosed patients with heart failure and reduced ejection fraction (HFrEF) prescribed a wearable cardioverter defibrillator. METHODS: Adults hospitalized for new-onset heart failure, due to ischemic or nonischemic cardiomyopathy, and prescribed a wearable cardioverter defibrillator within 10 days post discharge were approached for inclusion. Participants completed the Kansas City Cardiomyopathy Questionnaire at 3 time points: baseline, day 90, and day 180. RESULTS: A total of 210 patients (26% female) were included. All Kansas City Cardiomyopathy Questionnaire subscales (physical limitation, symptom frequency, quality of life, and social limitation) showed improvement from baseline to day 90 (all Ps < .001). Only quality of life continued to improve from day 90 to day 180 (P < .001). By day 90, nearly 70% of patients showed an improvement in quality of life (67.9%, n = 91), and by day 180, more than 80% (82.8%, n = 111) reported a net improvement. Five patients (3.7%) reported a net decrease, and 18 patients (13.4%) had no net change in quality of life during the 180-day period. CONCLUSION: Patient-reported quality of life improved significantly among patients newly diagnosed with HFrEF and prescribed a wearable cardioverter defibrillator. These results suggest that pursuing guideline-directed medical therapy for HFrEF, while being protected by the wearable cardioverter defibrillator, is likely to provide symptom relief and improve quality of life.

The association of triglyceride levels with the incidence of initial and recurrent acute pancreatitis.

BACKGROUND: This retrospective cohort study assessed the annualized incidence rate (IR) of acute pancreatitis (AP) in a nationally representative US adult population, as well as the variation in the risk of AP events across strata of triglyceride (TG) levels. METHODS: Data were obtained from IQVIA's US Ambulatory Electronic Medical Records (EMR) database linked with its LRxDx Open Claims database. Inclusion criteria included ≥1 serum TG value during the overlapping study period of the EMR and claims databases, ≥1 claim in the 12-month baseline period, and ≥ 1 claim in the 12 months post index. All TG measurements were assigned to the highest category reached: < 2.26, ≥2.26 to ≤5.65, > 5.65 to ≤9.94, > 9.94, and > 11.29 mmol/L (< 200, ≥200 to ≤500, > 500 to ≤880, > 880, and > 1000 mg/dL, respectively). The outcome of interest was AP, defined as a hospitalization event with AP as the principal diagnosis. RESULTS: In total, 7,119,195 patients met the inclusion/exclusion criteria, of whom 4158 (0.058%) had ≥1 AP events in the prior 12 months. Most patients (83%) had TGs < 2.26 mmol/L (< 200 mg/dL), while < 1% had TGs > 9.94 mmol/L (> 880 mg/dL). Overall, the IR of AP was low (0.08%; 95% confidence internal [CI], 0.08-0.08%), but increased with increasing TGs (0.08% in TGs < 2.26 mmol/L [< 200 mg/dL] to 1.21% in TGs > 11.29 mmol/L [> 1000 mg/dL]). In patients with a prior history of AP, the IR of AP increased dramatically; patients with ≥2 AP events at baseline had an IR of 29.98% (95% CI, 25.1-34.9%). CONCLUSION: The risk of AP increases with increasing TG strata; however, the risk increases dramatically among patients with a recent history of AP.

Cost-Effectiveness of Alirocumab in Patients With Acute Coronary Syndromes: The ODYSSEY OUTCOMES Trial.

BACKGROUND: Cholesterol reduction with proprotein convertase subtilisin-kexin type 9 inhibitors reduces ischemic events; however, the cost-effectiveness in statin-treated patients with recent acute coronary syndrome remains uncertain. OBJECTIVES: This study sought to determine whether further cholesterol reduction with alirocumab would be cost-effective in patients with a recent acute coronary syndrome on optimal statin therapy. METHODS: A cost-effectiveness model leveraging patient-level data from ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was developed to estimate costs and outcomes over a lifetime horizon. Patients (n = 18,924) had a recent acute coronary syndrome and were on high-intensity or maximum-tolerated statin therapy, with a baseline low-density lipoprotein cholesterol (LDL-C) level ≥70 mg/dl, non-high-density lipoprotein cholesterol ≥100 mg/dl, or apolipoprotein B ≥80 mg/l. Alirocumab 75 mg or placebo was administered subcutaneously every 2 weeks. Alirocumab was blindly titrated to 150 mg if LDL-C remained ≥50 mg/dl or switched to placebo if 2 consecutive LDL-C levels were <15 mg/dl. Incremental cost per quality-adjusted life-year (QALY) was determined with the addition of alirocumab versus placebo and, based on clinical efficacy findings from the trial, was stratified by baseline LDL-C levels ≥100 mg/dl and <100 mg/dl. RESULTS: Across the overall population recruited to the ODYSSEY OUTCOMES trial, using an annual treatment cost of US$5,850, the mean overall incremental cost-effectiveness ratio was US$92,200 per QALY (base case). The cost was US$41,800 per QALY in patients with baseline LDL-C ≥100 mg/dl, whereas in those with LDL-C <100 mg/dl the cost per QALY was US$299,400. Among patients with LDL-C ≥100 mg/dl, incremental cost-effectiveness ratios remained below US$100,000 per QALY across a wide variety of sensitivity analyses. CONCLUSIONS: In patients with a recent acute coronary syndrome on optimal statin therapy, alirocumab improves cardiovascular outcomes at costs considered intermediate value, with good value in patients with baseline LDL-C ≥100 mg/dl but less economic value with LDL-C <100 mg/dl. (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab [ODYSSEY OUTCOMES]; NCT01663402).

Symptoms and Dietary Impact in Hypertriglyceridemia-Associated Pancreatitis: Development and Content Validity of Two New Measures.

BACKGROUND: Severe hypertriglyceridemia (sHTG) is a rare condition, complicated by episodes of acute pancreatitis (AP), which can cause pain and/or life-threatening multi-organ dysfunction. Currently, there are no disease-specific patient-reported outcome (PRO) measures evaluating symptoms or dietary impact for this condition. OBJECTIVE: The objective of this study was to explore patient-reported symptoms and impacts of sHTG and AP and develop new measures to capture the symptoms and dietary impacts of this condition using patient language. METHODS: In-depth, semi-structured concept elicitation interviews were conducted with 12 US-based participants to explore their experience and identify key symptoms and impact on dietary behavior, both during and between episodes of AP. Participants had a range of AP severity with a previous triglyceride reading > 1000 mg/dL, and at least one attack of AP within the last 12 months. Transcripts were coded using thematic analysis. RESULTS: Qualitative data analysis revealed the substantial burden of AP associated with sHTG. Participants reported experiencing symptoms, especially abdominal pain, both during and between attacks of AP, and discussed considerable diet changes to prevent or minimize future attacks. A conceptual model was refined, based on patient input, and reviewed by clinical experts to determine key concepts for inclusion within two PRO measures, one evaluating symptoms and another evaluating impact on dietary behavior. Items were drafted using patient-derived language. A 19-item symptoms measure [Hypertriglyceridemia and Acute Pancreatitis Symptom Scale (HAP-SS)] and a 6-item dietary impact measure (Hypertriglyceridemia and Acute Pancreatitis Dietary Behavior (HAP-DB) measure) were developed, both with a 24-h recall period. CONCLUSIONS: The qualitative analysis confirmed the substantial burden of AP associated with sHTG. This research resulted in development of two disease-specific PRO measures for use during and between attacks of AP. These measures are being utilized in a clinical trial, which will confirm content, structure, and psychometric properties.

Risk of Cardiovascular Events in Patients With Type 2 Diabetes and Metabolic Dyslipidemia Without Prevalent Atherosclerotic Cardiovascular Disease.

BACKGROUND: The relationship between achieved low-density lipoprotein cholesterol (LDL-C) levels and risk of incident atherosclerotic cardiovascular disease events among patients with diabetes and metabolic dyslipidemia has not been well described. METHODS: We conducted an observational cohort study of statin-treated adults (ages 21-90 years) with type 2 diabetes without established atherosclerotic cardiovascular disease (as of January 1, 2006) who had metabolic dyslipidemia (elevated triglycerides ≥150 mg/dL and low high-density lipoprotein cholesterol, <50 mg/dL [women] and <40 mg/dL [men]). All subjects were members of Kaiser Permanente Northern California, an integrated health care delivery system. Adjusted multivariable Cox models were specified to estimate hazard ratios (HRs) for incident atherosclerotic cardiovascular disease events by achieved LDL-C levels (<50, 50-<70, 70-<100, and ≥100 mg/dL). Incident atherosclerotic cardiovascular disease events were defined as a composite of nonfatal myocardial infarction, ischemic stroke, or coronary heart disease death through December 31, 2013. RESULTS: A total of 19,095 individuals met the selection criteria. Mean age was 63.4 years, 53.5% were women, and the mean follow-up was 5.9 years. Unadjusted rates of atherosclerotic cardiovascular disease events were not significantly different across specified LDL-C categories. In models adjusted for demographics and clinical characteristics, the risk was significantly lower with decreasing achieved LDL-C levels (P <0.0001 for trend). Relative to achieved LDL-C ≥100 mg/dL, LDL-C <50 mg/dL had an hazard ratio of 0.66 (95% confidence interval [CI] 0.52-0.82). CONCLUSION: In a large, contemporary cohort of statin-treated patients with type 2 diabetes and metabolic dyslipidemia without established atherosclerotic cardiovascular disease, lower achieved LDL-C levels were associated with a monotonically lower risk of incident atherosclerotic cardiovascular disease events. The benefits of achieving very-low LDL-C (<50 mg/dL) in this population requires further evaluation in prospective interventional studies.

Discovery of GSK3527497: A Candidate for the Inhibition of Transient Receptor Potential Vanilloid-4 (TRPV4).

GSK3527497, a preclinical candidate for the inhibition of TRPV4, was identified starting from the previously reported pyrrolidine sulfonamide TRPV4 inhibitors 1 and 2. Optimization of projected human dose was accomplished by specifically focusing on in vivo pharmacokinetic parameters CLu, Vdssu, and MRT. We highlight the use of conformational changes as a novel approach to modulate Vdssu and present results that suggest that molecular-shape-dependent binding to tissue components governs Vdssu in addition to bulk physicochemical properties. Optimization of CLu within the series was guided by in vitro metabolite identification, and the poor FaSSIF solubility imparted by the crystalline properties of the pyrrolidine diol scaffold was improved by the introduction of a charged moiety to enable excellent exposure from high crystalline doses. GSK3527497 is a preclinical candidate suitable for oral and iv administration that is projected to inhibit TRPV4 effectively in patients from a low daily clinical dose.

Simulation of impact on cardiovascular events due to lipid-lowering therapy intensification in a population with atherosclerotic cardiovascular disease.

In patients with atherosclerotic cardiovascular disease (ASCVD), guidelines recommend statins as first-line lipid-lowering therapy (LLT) with addition of nonstatin agents in those with persistently elevated low-density lipoprotein cholesterol levels. METHODS: To estimate the cardiovascular (CV) risk reduction implications of treatment intensification, we used a previously reported simulation model with enhancements. An ASCVD cohort was developed from a US claims database. A Cox model was used to estimate baseline risk of CV events: myocardial infarction, ischemic stroke, unstable angina hospitalization, elective coronary revascularization, or cardiovascular death. Patients were sampled with replacement (bootstrapping) and entered the simulation model, which applied stepwise LLT intensification logic, with a goal of achieving low-density lipoprotein cholesterol less than 70 mg/dL at each step. CV risk reduction assumptions were based on published data. Two treatment intensification scenarios were investigated: ideal and real-world (which accounted for statin intolerance, nonadherence, and payer restrictions). RESULTS: In a cohort of 1,000 patients with ASCVD, approximately 813 (809-818) would require treatment intensification with LLT under an ideal treatment intensification scenario. Before treatment intensification, 183 (179-187) events would be expected to occur over 5 years. With treatment intensification, 40 (34-45) of these events could be avoided. In a real-world scenario, about 818 (813-823) patients require treatment intensification with LLT, resulting in 29 (24-34) events avoided over 5 years. CONCLUSIONS: Intensification of LLT in an ASCVD population translates into a substantial number of CV events avoided. This simulation-based model could assist in assessing the potential benefits of various types of population-level LLT interventions.