Therapy duration and improvement of ventricular function in de novo heart failure: the Heart Failure Optimization study.

BACKGROUND AND AIMS: In patients with de novo heart failure with reduced ejection fraction (HFrEF), improvement of left ventricular ejection fraction (LVEF) is expected to occur when started on guideline-recommended medical therapy. However, improvement may not be completed within 90 days. METHODS: Patients with HFrEF and LVEF ≤ 35% prescribed a wearable cardioverter-defibrillator between 2017 and 2022 from 68 sites were enrolled, starting with a registry phase for 3 months and followed by a study phase up to 1 year. The primary endpoints were LVEF improvement > 35% between Days 90 and 180 following guideline-recommended medical therapy initiation and the percentage of target dose reached at Days 90 and 180. RESULTS: A total of 598 patients with de novo HFrEF [59 years (interquartile range 51-68), 27% female] entered the study phase. During the first 180 days, a significant increase in dosage of beta-blockers, renin-angiotensin system inhibitors, and mineralocorticoid receptor antagonists was observed (P < .001). At Day 90, 46% [95% confidence interval (CI) 41%-50%] of study phase patients had LVEF improvement > 35%; 46% (95% CI 40%-52%) of those with persistently low LVEF at Day 90 had LVEF improvement > 35% by Day 180, increasing the total rate of improvement > 35% to 68% (95% CI 63%-72%). In 392 patients followed for 360 days, improvement > 35% was observed in 77% (95% CI 72%-81%) of the patients. Until Day 90, sustained ventricular tachyarrhythmias were observed in 24 wearable cardioverter-defibrillator carriers (1.8%). After 90 days, no sustained ventricular tachyarrhythmia occurred in wearable cardioverter-defibrillator carriers. CONCLUSIONS: Continuous optimization of guideline-recommended medical therapy for at least 180 days in HFrEF is associated with additional LVEF improvement > 35%, allowing for better decision-making regarding preventive implantable cardioverter-defibrillator therapy.

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.

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.

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.

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.

Quantifying Importance of Major Risk Factors for Coronary Heart Disease.

BACKGROUND: To optimize preventive strategies for coronary heart disease (CHD), it is essential to understand and appropriately quantify the contribution of its key risk factors. Our objective was to compare the associations of key modifiable CHD risk factors-specifically lipids, systolic blood pressure (SBP), diabetes mellitus, and smoking-with incident CHD events based on their prognostic performance, attributable risk fractions, and treatment benefits, overall and by age. METHODS: Pooled participant-level data from 4 observational cohort studies sponsored by the National Heart, Lung, and Blood Institute were used to create a cohort of 22 626 individuals aged 45 to 84 years who were initially free of cardiovascular disease. Individuals were followed for 10 years from baseline evaluation for incident CHD. Proportional hazards regression was used to estimate metrics of prognostic model performance (likelihood ratio, C index, net reclassification, discrimination slope), hazard ratios, and population attributable fractions for SBP, non-high-density lipoprotein cholesterol (non-HDL-C), diabetes mellitus, and smoking. Expected absolute risk reductions for antihypertensive and lipid-lowering treatment were assessed. RESULTS: Age, sex, and race capture 63% to 80% of the prognostic performance of cardiovascular risk models. In contrast, adding either SBP, non-HDL-C, diabetes mellitus, or smoking to a model with other risk factors increases the C index by only 0.004 to 0.013. However, primordial prevention could have a substantial effect as demonstrated by population attributable fractions of 28% for SBP≥130 mm Hg and 17% for non-HDL-C≥130 mg/dL. Similarly, lowering the SBP of all individuals to <130 mm Hg or lowering low-density lipoprotein cholesterol by 30% would be expected to lower a baseline 10-year CHD risk of 10.7% to 7.0 and 8.0, respectively (absolute risk reductions: 3.7% and 2.7%, respectively). Prognostic performance decreases with age (C indices for age groups 45-54, 55-64, 65-74, 75-84 are 0.75, 0.72, 0.66, and 0.62, respectively), whereas absolute risk reductions increase (SBP: 1.1%, 2.3%, 5.4%, 10.3%, respectively; non-HDL-C: 1.1%, 2.0%, 3.7%, 5.9%, respectively). CONCLUSIONS: Although individual modifiable CHD risk factors contribute only modestly to prognostic performance, our models indicate that eliminating or controlling these individual factors would lead to substantial reductions in total population CHD events. Metrics used to judge importance of risk factors should be tailored to the research objectives.

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.

Psychometric Evaluation of a Treatment Acceptance Measure for Use in Patients Receiving Treatment via Subcutaneous Injection.

BACKGROUND: Alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, significantly reduces low-density lipoprotein cholesterol, but requires subcutaneous injections rather than oral pills. To measure patients' acceptance of this treatment modality, a new patient-reported outcome, the Injection-Treatment Acceptance Questionnaire (I-TAQ), was developed. OBJECTIVES: To psychometrically evaluate the I-TAQ with patients at high risk of cardiovascular events receiving alirocumab. METHODS: The 22-item, 5-domain I-TAQ was administered cross-sectionally to 151 patients enrolled in alirocumab clinical trials. Item response distributions, factor and multitrait analyses, interitem correlations, correlations with an existing measure of acceptance (convergent validity), and comparison of known-groups were performed to assess the I-TAQ's psychometric properties. RESULTS: Completion rates were high, with no patients missing more than two items and 91.4% missing no data. All items displayed high ceiling effects (>30%) because of high treatment acceptance. Factor analysis supported the a priori hypothesized item-domain structure with good fit indices (root mean square error approximation = 0.070; comparative fit index = 0.988) and high factor loadings. All items demonstrated item convergent validity (item-scale correlation ≥0.40), except for the side effects domain, which was limited by small numbers (n = 46). Almost all items correlated most highly with the domain to which they were assigned (item discriminant validity). Internal reliability was acceptable for all domains (Cronbach α range 0.72-0.88) and convergent validity was supported by a logical pattern of correlations with the Chronic Treatment Acceptance Questionnaire. CONCLUSIONS: These findings provide initial evidence of validity and reliability for the I-TAQ in patients treated with subcutaneous alirocumab. The I-TAQ could prove to be a valuable patient-reported outcome for therapies requiring subcutaneous injection.

The Statin-Associated Muscle Symptom Clinical Index (SAMS-CI): Revision for Clinical Use, Content Validation, and Inter-rater Reliability.

PURPOSE: The Statin-Associated Muscle Symptom Clinical Index (SAMS-CI) is a method for assessing the likelihood that a patient's muscle symptoms (e.g., myalgia or myopathy) were caused or worsened by statin use. The objectives of this study were to prepare the SAMS-CI for clinical use, estimate its inter-rater reliability, and collect feedback from physicians on its practical application. METHODS: For content validity, we conducted structured in-depth interviews with its original authors as well as with a panel of independent physicians. Estimation of inter-rater reliability involved an analysis of 30 written clinical cases which were scored by a sample of physicians. A separate group of physicians provided feedback on the clinical use of the SAMS-CI and its potential utility in practice. RESULTS: Qualitative interviews with providers supported the content validity of the SAMS-CI. Feedback on the clinical use of the SAMS-CI included several perceived benefits (such as brevity, clear wording, and simple scoring process) and some possible concerns (workflow issues and applicability in primary care). The inter-rater reliability of the SAMS-CI was estimated to be 0.77 (confidence interval 0.66-0.85), indicating high concordance between raters. With additional provider feedback, a revised SAMS-CI instrument was created suitable for further testing, both in the clinical setting and in prospective validation studies. CONCLUSIONS: With standardized questions, vetted language, easily interpreted scores, and demonstrated reliability, the SAMS aims to estimate the likelihood that a patient's muscle symptoms were attributable to statins. The SAMS-CI may support better detection of statin-associated muscle symptoms in clinical practice, optimize treatment for patients experiencing muscle symptoms, and provide a useful tool for further clinical research.

Development and Content Validity Testing of a Patient-Reported Treatment Acceptance Measure for Use in Patients Receiving Treatment via Subcutaneous Injection.

BACKGROUND: New therapies in development for lowering low-density lipoprotein cholesterol, such as alirocumab, require administration by subcutaneous injections. There is a need to assess the acceptance of such treatments and their mode of administration. OBJECTIVES: To develop a novel patient-reported outcome measure, the Injection-Treatment Acceptance Questionnaire (I-TAQ), and assess its content validity using qualitative methods. METHODS: Concepts generated from a literature and instrument review informed the initial drafting of 17 items in the I-TAQ, with item wording adapted from three existing instruments. Three rounds of qualitative interviews were conducted with 29 US-English speaking patients at high cardiovascular risk. Concept elicitation questioning was used to explore patients' treatment experiences followed by cognitive debriefing of the I-TAQ using "think-aloud" methods. Verbatim transcripts were analyzed using thematic analysis. RESULTS: Qualitative analysis of concept elicitation data identified the following relevant concepts: perceived efficacy, side effects, self-efficacy, convenience, and overall acceptance. Seven (24%) patients discussed an initial fear of needles, but described this as subsiding with no impact on adherence. Five items were added after round one interviews, three of which were retained after round two testing in which two further items were added, forming the conceptually comprehensive 22-item I-TAQ. Patients demonstrated good understanding of item wording, instructions, response scales, and recall period. CONCLUSIONS: Successive rounds of in-depth interviews resulted in a treatment acceptance measure with strong content validity. Pending demonstration of its psychometric properties, the I-TAQ may prove to be a valuable measure of patients' perspectives toward being treated with low-density lipoprotein cholesterol-lowering therapies requiring subcutaneous injections.

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.

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.

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.

Synthesis and structure-activity relationships of imidazo[1,2-a]pyrimidin-5(1H)-ones as a novel series of beta isoform selective phosphatidylinositol 3-kinase inhibitors.

A series of PI3K-beta selective inhibitors, imidazo[1,2-a]-pyrimidin-5(1H)-ones, has been rationally designed based on the docking model of the more potent R enantiomer of TGX-221, identified by a chiral separation, in a PI3K-beta homology model. Synthesis and SAR of this novel chemotype are described. Several compounds in the series demonstrated potent growth inhibition in a PTEN-deficient breast cancer cell line MDA-MB-468 under anchorage independent conditions.

Synthesis and structure-activity relationships of 1,2,4-triazolo[1,5-a]pyrimidin-7(3H)-ones as novel series of potent ß isoform selective phosphatidylinositol 3-kinase inhibitors.

A series of 1,2,4-triazolo[1,5-a]pyrimidin-7(3H)-ones with excellent enzyme inhibition, improved isoform selectivity, and excellent inhibition of downstream phosphorylation of AKT has been identified. Several compounds in the series demonstrated potent (∼ 0.100 µM IC(50)) growth inhibition in a PTEN deficient cancer cell line.

Health care costs in patients with fibromyalgia on pregabalin vs. duloxetine.

BACKGROUND: The economic burden associated with fibromyalgia in the U.S. is substantial. The objective of this study was to compare changes in health care costs in fibromyalgia patients initiated on pregabalin and duloxetine in real-world settings. METHODS: Patients (≥ 18 years old) initiating pregabalin or duloxetine between June 1, 2007 and December 31, 2008 were identified using a U.S. managed care database. Patients were selected if they had ≥ 2 medical claims for fibromyalgia (ICD-9-CM, 729.1) at least 90 days apart or ≥ 1 claim for fibromyalgia followed within 30 days by a pharmacy claim for pregabalin. The date of the first pregabalin or duloxetine prescription was defined as the index date, and continuous enrollment for 6-month pre- and postindex periods was required. RESULTS: A total of 1,616 pregabalin and 207 duloxetine patients were identified. Treatment differences between pregabalin and duloxetine in the pre-/postindex change in mean [SD] all-cause total health care costs ($1,307 [16,747] vs. -$158 [17,337]; P = 0.24) or fibromyalgia-related total health care costs ($584 [3,834] vs. $759 [2,133]; P = 0.32) were not significant. Multivariate analysis using difference-in-differences models showed no significant difference in all-cause costs (mean cost ratio = 1.05, 95% CI: 0.84 to 1.31) or fibromyalgia-related costs (0.85, 95% CI: 0.61 to 1.18) between treatments during the postindex period. CONCLUSION: No significant differences were found between pregabalin and duloxetine in the pre- to postindex change in mean all-cause or fibromyalgia-related total health care costs.

Health care costs in patients with painful diabetic peripheral neuropathy prescribed pregabalin or duloxetine.

BACKGROUND: Pregabalin and duloxetine are two FDA-approved medications for the treatment of pain associated with diabetic peripheral neuropathy (pDPN). The objective of this study was to compare changes in all-cause and pDPN-related health care costs in patients with pDPN initiated on pregabalin or duloxetine. METHODS: Patients at least 18 years of age initiating pregabalin or duloxetine between March 1, 2006 and December 31, 2008 were identified from a large U.S. managed care plan database. The date of the first pregabalin or duloxetine prescription was defined as the index date. Patients with claims-based evidence of pDPN and who had continuous enrollment for 6-month pre- and post-index periods were selected for study inclusion. Duloxetine patients with depression or generalized anxiety disorder (GAD) were excluded. All-cause and pDPN-related total health care costs (over 6 month pre-index and post-index periods) were analyzed with difference-in-differences (DiD) models. RESULTS: A total of 2,136 patients (1,785 pregabalin and 351 duloxetine) were identified. No significant differences in gender, age, or pre-index Quan-Charlson comorbidity score were observed between the two cohorts. No significant differences (pregabalin vs. duloxetine) in pre-index to post-index change in mean all-cause health care costs ($1,411 vs. $1,560, P = 0.93) or mean pDPN-related health care costs ($704 vs. -$240, P = 0.22) were found. The DiD models showed no significant difference in all-cause (mean) costs attributable to pregabalin vs. duloxetine therapy between pre-index and post-index periods (mean cost ratio = 0.97, 95% CI: 0.75 to 1.26), but showed that patients receiving pregabalin had a significantly higher increase in pDPN-related costs compared with patients receiving duloxetine (mean cost ratio = 2.35, 95% CI: 1.01 to 5.46). However, the difference (pre- to post-index) in pDPN-related costs attributable to pregabalin vs. duloxetine therapy was nonsignificant (mean cost ratio = 2.30, 95% CI: 0.93 to 5.68) in a sensitivity analysis in which patients with depression and GAD were excluded from both cohorts. CONCLUSION: No differences were noted in all-cause costs attributable to pregabalin or duloxetine. Although patients receiving pregabalin had a significantly greater pre- to post-index increase in pDPN-related health care costs compared with patients receiving duloxetine, this may have been due to an imbalance in patient exclusion criteria between cohorts.

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.

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.