Clinical and Translational Science

Metabolomics is an emerging and powerful molecular profiling method supporting clinical investigations. For clinical metabolomics studies, serum is commonly used. Serum is collected after blood coagulation, a complex biochemical process involving active platelet metabolism. This may proof relevant as platelet counts and function may vary substantially in individuals. Applying a multi-omics analysis strategy comprising proteins and metabolites with a focus on lipid mediators, we systematically investigated serum and plasma obtained from the same healthy donors. While Biocrates MxP Quant 500 results correlated well (n=461, R2=0.991), lipid mediators (n=77, R2=0.906) and proteins (n=322, R2=0.860) differed substantially between serum and plasma. Actually, secretome analysis of activated platelets identified all proteins and most lipid mediators significantly enriched in serum when compared to plasma. Furthermore, a prospective, randomized, controlled parallel group metabolomics trial was performed, monitored by serum and plasma analyses. Healthy individuals received either acetylsalicylic acid, affecting platelets, or omega-3 fatty acids, hardly affecting platelets, for a period of seven days. In the acetylsalicylic acid group, serum analysis apparently demonstrated a significant drug-induced downregulation of the lipid mediators TXB2 and 12-HETE. The absence of these observation in plasma analyses suggested that these drug effects took place only during blood coagulation. Other effects of acetylsalicylic acid on alpha-linolenic acid and the fatty acid composition of triglycerides were detected both in serum and plasma. In the omega-3 fatty acid group, serum and plasma analysis results did not differ. These data strongly support the hypothesis that the serum metabolome is substantially confounded by platelets. Key pointsO_LISerum metabolomics data are confounded by platelets C_LIO_LIClinical evaluation of drug effects should be based on plasma metabolomics C_LI

The rapid adoption of digital health technologies (DHT) in clinical trials promises to enhance trial representativeness by eliminating geographical barriers and reducing participant burden. However, their actual impact on participant representation remains poorly understood. Our analysis of 68,206 US-based trials from ClinicalTrials.gov uncovers gaps in participant representation in trials utilizing DHT for data collection (DHTcd). While DHTcd trials achieved overrepresentation of female participants (+1.7% versus US Census data and +5.5% vs. non-DHT trials) and reduced underrepresentation of Black participants by 4.2% (vs. non-DHT trials), they showed underrepresentation of adults aged 65 years and older (-8.8% vs. non-DHT trials). These effects vary by therapeutic area. We furthermore find that DHTcd trials report group-specific sample compositions less frequently than non-DHT trials, suggesting that growing DHTcd adoption has not been systematically used to improve trial representativeness. We conclude that evidence-based and indication-specific implementation strategies are needed to enhance standards for DHT-based data collection in clinical trials and to prevent a widening digital divide in trial participation.

ObjectiveIn spite of evidence and recommendations reflecting the importance of pharmacogenomic testing, most prescriptions are still given without testing. We demonstrate the real world implications of the use of testing and evaluate adverse events and outcomes in individuals who did not receive pharmacogenomic testing for clopidogrel. MethodsWe analyzed ~100K individuals with paired EHR and exome sequencing data from population health studies administered at multiple medical centers using the Helix Exome+(R) assay. We inferred clopidogrel dosage by processing the prescription with an LLM. We identified all instances of individuals with at least one prescription that is not in concordance with their CYP2C19 genotype. Lastly, we identify instances of thrombosis using a comprehensive codeset based on ICD9, ICD10, and SNOMED terms. ResultsWe identified 16,140 prescriptions of clopidogrel given to 3,853 participants. We found that 29% of these individuals have a mismatch between the recommended clopidogrel dosage guideline based on their CYP2C19 genotype and their actual prescribed daily dosage. 25% of poor metabolizers experienced thrombosis, with 40% occurring within 2 months of treatment. Poor and intermediate metabolizers receiving clopidogrel are much more likely to experience thrombosis and myocardial infarction (binomial p-value = 0.001). ConclusionsWe estimate a 38% excess of adverse events occur in poor and intermediate metabolizers relative to normal and rapid metabolizers. The lack of testing may be responsible for 1 thrombosis event per every ~30 people prescribed clopidogrel.

Clinical PGx practice guidelines (PGx guidelines) may have limited generalizability for "marginalized" groups. We proposed the five-step Real-World Data for Genome-Guided Prescribing (ReGGRx) framework and, using All of Us research program (AoU) data, examined its ability to estimate disparities in concordance with and benefit from PGx guidelines for CYP2C19 testing when choosing antiplatelet and antidepressant drugs. The selected measures were intended to identify disparities in avoiding drug failure independent of following PGx guidelines, the odds of avoiding drug failure with PGx concordant treatment, and the degree to which "marginalized" groups (i.e., groups underrepresented in biomedical research [UBR] and with indeterminate CYP2C19 phenotypes) benefit from PGx concordant treatment, when compared with "non-marginalized" groups (i.e., non-UBR and known CYP2C19 phenotypes). Our findings identified disparities in the antidepressant cohort with UBRs (32% of cohort) having a lower odds of avoiding drug failure. For both cohorts, a lower probability of avoiding drug failure was observed in the indeterminate phenotype group (1% of cohorts) than in the known phenotype group, indicating a need to better characterize rare or ancestry-specific risk alleles. With PGx concordant treatment, negative equal opportunity difference values suggested that the UBR group was less likely to avoid drug failure than the non-UBR group. Overall, our findings illustrate the promise of the ReGGRx framework to assess PGx guideline generalizability and produce evidence for use in drug policy decisions.

Glucagon-like peptide-1 receptor agonists (GLP1RAs) are transformative therapies for diabetes and obesity, yet their long-term clinical effects are incompletely understood. To address this, we conducted a phenome-wide association study (PheWAS) to assess potential therapeutic and adverse effects of GLP1RAs using genetic drug proxies near the GLP1R locus. Fifteen variants associated with GLP1R expression in the Genotype-Tissue Expression (GTEx) project were tested against 1,204 phecodes in the Million Veteran Program (MVP, n = 464,626), with replication and meta-analysis within the UK Biobank (n = 449,349) and the Vanderbilt BioVU (n = 118,130). In the MVP, GLP1RA proxies showed expected metabolic benefits, including lower risk of type 2 diabetes (OR = 0.966, 95% CI [0.957-0.974], p = 4.55 x 10-14] and obesity (OR = 0.978, 95% CI [0.969-0.986], p = 6.94x10-7). Protective effects were also found for chronic venous insufficiency, obstructive sleep apnea, cancer of the esophagus, orthopnea, and diabetes complications (retinopathy, nephropathy, retinopathy). However, associations with mental health disorders were cohort-dependent (anxiety disorders in MVP OR = 1.02, 95% CI [1.012-1.0316], p = 1.07 x 10-5, BioVU OR = 0.960, 95% CI [0.938-0.981], p = 3.12 x 10-4). The results reinforce the therapeutic promise of GLP1RAs for metabolic diseases while underscoring the need for cautious monitoring of potential mental health effects.

Glucagon/glucagon-like peptide-1 (GLP-1) receptor co-agonists may provide greater weight loss than agonists targeting the GLP-1 receptor alone. We report results from three phase 1 trials investigating the glucagon/GLP-1 receptor co-agonist NNC9204-1177 (NN1177) for once-weekly subcutaneous use in adults with overweight or obesity. Our focus was a 12-week multiple ascending dose (MAD), placebo-controlled, double-blind trial in which adults (N=99) received NN1177 (dose-escalated to treatment doses of 200, 600, 1,300, 1,900, 2,800, 4,200, and 6,000 g) or placebo. Two other trials also contribute to the findings in this report: a first human dose (FHD) / single ascending dose (SAD), placebo-controlled, double-blind trial in which adults (N=49) received NN1177 (treatment doses of 10, 40, 120, 350, 700 and 1,100 g) or placebo, and a drug-drug interaction (DDI), open-label, single-sequence trial in which adults (N=45) received a 4,200 g dose of NN1177. Pharmacokinetic, safety and tolerability, and pharmacodynamic endpoints were assessed. For the MAD and FHD/SAD trials, baseline characteristics were generally balanced across groups. The half-life of NN1177 was estimated at between 77.3 and 111 hours. NN1177 appeared tolerable across trials; however, a number of safety concerns were observed, including an increase in heart rate (range 5-22 beats per minute) and decrease in reticulocyte count, which were both dose dependent, and increased markers of inflammation (fibrinogen and C-reactive protein), hepatic disturbances (increased aspartate aminotransferase and alanine aminotransferase), impaired glucose tolerance (dose groups 2,800-6,000 ug) and reduced blood levels of some amino acids. Clinically relevant weight loss was achieved (up to 12.6% at week 12; 4,200 ug in the MAD trial), but this was not accompanied by cardiometabolic improvements. In conclusion, although treatment with NN1177 was associated with dose-dependent and clinically relevant weight loss, unacceptable safety concerns precluded further clinical development.

BackgroundHealth care inequity includes the lack of adequate representation of various populations in clinical trials. Government, academic and industry organizations have highlighted these issues and committed to actions to improve. In order to assess the current status and future success of these initiatives a quantitative objective measure to assess the state of clinical trial diversity is needed. MethodsFDA review documents for all novel drug approvals from January 2022 through February 16, 2023 were assessed using a scorecard that considers diversity across different demographic subgroups including age (>65 yo), sex (female), race (Black and Asian) and ethnicity (Hispanic/Latino). The scorecard assigns each drug a letter grade, between A and F, for each subgroup (and overall) based on 1) the percent of each sub-population included in the trials and grades relative to the percent of the US population, 2) the number of participants from each subpopulation that received the novel new drug in the trials, 3) the incidence or prevalence of the disease/condition in each of the sub-populations. ResultsThe FDA approved 43 novel new drugs for 44 indications (one drug was simultaneously approved for two indications). The three drugs with A Grades reflecting the best diversity in their registration trials were tapinarof (Vtama from Dermavant), daprodustat (Jesduvroq from GlaxoSmithKline) and eflapegrastim (Rolvedon from Spectrum Pharmaceuticals.) There was good representation of elderly and females with only two drugs receiving a D grade in either of these sub-populations. In contrast, Black and Hispanic representation was often inadequate with 4 drugs receiving F grades. There were 9 drugs (20%) where there were no Black participants receiving the novel new drug and an additional 14 approvals where there were <10 Black participants receiving the novel drug. The median number of Black participants receiving the investigational drug was 9. In the Hispanic/Latino population there were 2 approvals with no Hispanic participants receiving the novel drug and 14 approvals where there were < 10 Hispanic participants receiving the drug. The median number of Hispanic participants receiving the novel drug was 12.5. ConclusionsThis newly developed scorecard provides an objective quantitative approach to assess the current state of diversity in clinical trials supporting new drug approvals. Substantial improvement in racial and ethnic representation is needed. Meaningful change will require actions and cooperation amongst all stakeholders to address this multifaceted issue and will take commitment, perseverance, and appropriate incentives.

STRUCTURED ABSTRACTO_ST_ABSObjectivesC_ST_ABSTo expose the potential impact of residual confounding in common observational study designs investigating metformin using a type 2 diabetes cohort; to propose a more robust study design for future observational studies of metformin. DesignRetrospective cohort studies using a prevalent user design conducted in two distinct cohorts: individuals with type 2 diabetes and individuals with prediabetes. SettingInsurance claims database for Medicare Advantage beneficiaries in the United States, 2018-2019. An identical analysis of commercial insurance beneficiaries appears in the supplement. Participants404,765 individuals with type 2 diabetes, 81,791 individuals with prediabetes. Main outcome measuresTotal inpatient admission days in 2019, total medical spend (excluding prescription drugs) in 2019. Each of these measures is treated as a binary outcome: greater than zero inpatient days and top 10% medical spend. ResultsWe implement a common observational study design and observe a strong metformin effect estimate associated with reduced inpatient admissions and reduced medical expenditures; we also implement a more robust study design that suggests any estimated effect is attributable to residual confounding related to individuals overall health. ConclusionsCommon observational study designs examining metformin in a type 2 diabetes population are likely impacted by significant residual confounding. By additionally considering numerous negative control outcomes and a complementary prediabetes cohort, the study design proposed here demonstrates efficacy at exposing residual confounding related to overall health, nullifying the claim derived from a standard study design. Trial registrationPreregistration available at https://osf.io/qf49p.

IntroductionThe efficacy and safety of elexacaftor/tezacaftor/ivacaftor (ETI) have been established in prospective clinical trials. Liver function test elevations were observed in a greater proportion of patients receiving ETI compared with placebo; however, the relatively small number of patients and short duration of study preclude detection of rare but clinically significant associations with drug-induced liver injury (DILI). To address this gap, we assessed the real-world risk of DILI associated with ETI through data mining of the FDA Adverse Event Reporting System (FAERS). MethodsDisproportionality analyses were conducted on FAERS data from the fourth quarter of 2019 through the third quarter of 2022. Comparative patient demographics, onset time and outcomes for ETI-DILI were also obtained. Results452 reports of DILI associated with ETI were found, representing 2.1% of all adverse event reports for ETI. All disproportionality measures were significant for ETI-DILI at p < 0.05; the reporting odds ratio (ROR) was comparable to that of drugs classified by FDA as "Most-DILI concern". The most notable demographic finding was a male majority for ETI-DILI compared to a female majority for non ETI-DILI. Median ETI-DILI onset time was 50.5 days, and hospitalization was the second most common complication. ConclusionUsing FAERS data, ETI was found to be disproportionality associated with DILI. Future research is needed to investigate the hepatotoxic mechanisms and assess potential mitigation strategies for ETI-induced hepatotoxicity. Article HighlightsO_LIUsing the FDA Adverse Event Reporting System database, ETI and DILI were found to be significantly associated (p < 0.05) for all disproportionality measures (PRR, ROR, IC, EGBM, Yates chi-squared). C_LIO_LIThe ROR for ETI-DILI is greater than that of many "Most-DILI concern" drugs in the FDA DILIRank dataset but is not within the top 20 drugs associated with DILI. C_LIO_LIPatient reports for ETI-DILI were predominately male, in contrast to patient reports for other drugs and DILI. C_LIO_LI"Hospitalization" was the second most common patient outcome for ETI-DILI after "other serious outcomes". C_LIO_LIMost patients had onset times within 3 months of initiation, several patients had an onset time greater than 1 year. C_LIO_LIOnset times indicate that liver function test monitoring should be initiated earlier than 3 months and potentially extend beyond 1 year in some patients. C_LI

AimSGLT2 inhibitors provide multiple benefits to patients with type 2 diabetes - including improved glycemic control and decreased risks of cardiorenal disease. Because drug responses vary among individuals, we initiated investigations to identify genetic variants associated with the magnitude of drug responses. MethodsCanagliflozin (300 mg) was administered to 30 healthy volunteers. Several endpoints were measured to assess clinically relevant responses - including drug-induced increases in urinary excretion of glucose, sodium, and uric acid. ResultsThis pilot study confirmed that canagliflozin (300 mg) triggered acute changes in mean levels of several biomarkers: fasting plasma glucose (-4.1 mg/dL; p=6x10), serum creatinine (+0.05 mg/dL; p=8x10-4), and serum uric acid (-0.90 mg/dL; p=5x10-10). The effects of sex on glucosuria depended upon how data were normalized. Whereas males responses were [~]60% greater when data were normalized to body surface area, males and females exhibited similar responses when glucosuria was expressed as grams of urinary glucose per gram-creatinine. The magnitude of glucosuria was not significantly correlated with fasting plasma glucose, estimated GFR, or age in these healthy non-diabetic individuals with estimated GFR>60 mL/min/1.73m2. ConclusionsNormalizing data relative to creatinine excretion will facilitate including data from males and females in a single analysis. Furthermore, because our ongoing pharmacogenomic study (NCT02891954) is conducted in healthy individuals, this will facilitate detection of genetic associations with limited confounding by other factors such as age and renal function. RegistrationNCT02462421 (clinicaltrials.gov) FundingResearch grants from the National Institute of Diabetes and Digestive and Kidney Diseases: R21DK105401, R01DK108942, T32DK098107, and P30DK072488.

IntroductionTrans sodium crocetinate (TSC) is a synthetic carotenoid with a unique mechanism of action that improves the diffusion of oxygen by reducing oxygen transfer resistance within plasma, and it is currently being developed to enhance oxygen delivery to hypoxic tissues in multiple conditions. The goals of this study were to evaluate safety, pharmacokinetics, and pharmacodynamic properties of escalating doses of TSC on peripheral oxygenation utilizing transcutaneous oxygen measurements, when administered to healthy subjects breathing supplemental oxygen. MethodsThis was a dose-escalation, single-center, randomized, phase 1 study aimed at assessing the safety, pharmacokinetic and pharmacodynamic properties of TSC at doses of 0.5, 1.0, 1.5, 2.0, or 2.5 mg/kg as an intravenous bolus. Thirty healthy adult subjects of 18 to 55 years of age were enrolled and allocated to one of the five dose groups or placebo. Venous blood samples were collected for pharmacokinetic evaluations of TSC at 1, 10, 30 minutes, and 1.5 hours after the start of injection of the study drug. Pharmacodynamic assessment of tissue oxygenation was performed while the subjects breathed supplemental oxygen at 6 L/minute for 70 minutes prior to study drug administration: the first 10 minutes was to allow for equilibration, and the subsequent 60 minutes served as a baseline period (Period 1), followed by a time-matched 60-minute intervention period (Period 2). Tissue oxygenation readings were obtained by transcutaneous oximetry (TcpO2) measurement using four TcpO2 sensors placed on the lower limbs of subjects lying in a supine or semi-recumbent position. TcpO2 values were recorded over a 2-hour time period: 60 minutes prior to study drug administration (Period 1) and 60 minutes post administration of the study drug (Period 2). ResultsTSC was safe and well tolerated at all doses tested. The pharmacokinetic analyses demonstrated that clearance decreased at escalating doses of TSC. The results of the primary pharmacodynamic analysis revealed high levels of variability in the 60-minute baseline TcpO2 levels, however despite such variability, time-matched TcpO2 measurements demonstrated observed increases in median TcpO2 values in subjects who received TSC, relative to those who received a placebo. The high variability observed across the four sensors suggested that the data could not be pooled across all four sensors, therefore, additional supplemental analyses were performed. The results of the supplemental analyses indicated that the TcpO2 intra-subject slopes of the TSC treatment groups were consistently positive during the study intervention period, and therefore suggestive of an increase in TcpO2 levels. This was not observed in the placebo group. Based on this analysis, all TSC dose groups had a greater increase in TcpO2 levels than the placebo group, with the 2.5 mg/kg dose demonstrating the most notable increase over the 1-hour intervention period (Period 2). ConclusionsTSC administered as a single IV bolus dose ranging from 0.5 mg/kg to 2.5 mg/kg to healthy subjects breathing supplemental oxygen, was safe and well tolerated. Pharmacokinetic assessments demonstrated that TSC plasma concentrations increased with escalating dose and that increasing TSC dose was associated with a decrease in clearance. The high levels of variability in TcpO2 levels did not allow for pooling of sensor measurements for primary analysis; however, supplemental analysis of individual sensor measurements demonstrated an observed dose effect of TSC on peripheral tissue oxygenation relative to placebo.

Pharmacogenomics (PGx) testing improves medication safety and efficacy by identifying genetic variants that affect drug response. However, current technologies often fail to resolve complex loci, detect structural variants, or phase alleles accurately. Here, we present an end-to-end PGx workflow based on Targeted Adaptive Sampling-Long Read Sequencing (TAS-LRS), integrating a streamlined laboratory protocol with a bioinformatics pipeline that includes a novel CYP2D6 caller. Using 1,000 ng of DNA and three-sample multiplexing on a single PromethION flow cell, the assay achieves consistent on-target (25x) and off-target (3x) coverage, enabling accurate, haplotype-resolved testing of 35 pharmacogenes alongside genome-wide genotyping from off-target reads. We further developed the workflow into a clinically ready service and validated its performance across 17 reference and clinical samples. The assay demonstrated high concordance for small variants (99.9%) and structural variants (>95%), with phased diplotypes and metabolizer phenotypes reaching 97.7% and 98.0% concordance, respectively. Improved calls were observed in 12 genes due to enhanced genotyping, phasing, or novel allele detection. In addition, off-target reads supported accurate genome-wide imputation, comparable to short-read sequencing and superior to microarrays. These results establish the feasibility of long-read sequencing for clinical PGx testing and position TAS-LRS as a scalable solution combining both targeted and genome-wide utility.

Pharmacological stimulation of human brown adipose tissue (BAT) has been hindered by either ineffective activation or undesirable off-target secondary effects. Oral administration of the maximal allowable dose of mirabegron (200 mg), a {beta}3-adrenergic receptor ({beta}3-AR) agonist, has been effective in stimulating BAT thermogenesis and whole-body energy expenditure. However, this too has been accompanied by undesirable cardiovascular effects. Combining mirabegron with a cardio-selective {beta}1-AR antagonist could not only suppress these unwanted effects, but potentially increase the sensitivity of the {beta}3-AR and {beta}2-AR in WAT and BAT. Here we report that co-ingesting a high dose of the {beta}1-AR antagonist bisoprolol with mirabegron suppresses the increase in heart rate, systolic blood pressure and myocardial oxygen consumption. However, it also blunted the mirabegron-stimulated increase in BAT lipolysis, thermogenesis and glucose uptake. Whether the attenuation in BAT blood flow induced by the large dose of bisoprolol limited BAT thermogenesis remains to be determined. clinicaltrials.gov (NCT04823442)

BackgroundOver the past two decades, the Food and Drug Administration (FDA) has significantly increased the approval of anti-obesity medications (AOMs) for obesity management. Both FDA-approved AOMs (F-AOMs) and Off-label AOMs (O-AOMs) have gained popularity and demonstrated promising results in randomized clinical trials (RCTs). However, their effectiveness in real-world settings remains less understood. In this study, we evaluated population-level responses to AOMs and individual variability, leveraging electronic health records (EHRs) as real-world data sources for a comprehensive analysis of obesity relevant metabolic metrics. MethodsEHRs of patients with obesity or overweight diagnosis were retrieved from the University of Texas Physician (UT-Physician) and EPIC COSMOS database. F-AOMs and O-AOMs were analyzed for their effects on obesity relevant metrics including body weight, body mass index (BMI), blood pressure (BP), high-density lipoprotein (HDL), low-density lipoprotein (LDL), HbA1c, and triglyceride levels. ResultsFrom the UT-Physician (U) and COSMOS (C) datasets, we identified 610K (2015-2025) and 3.6M (2018-2024) patients as obese or overweight, and 71,318 (11.7%) and 1M (27.9%) with AOM exposures, respectively. During the study period, [U:72%; C:67%] of patients experienced more than one treatment session. The median exposure durations were [U:2.7; C:2.7] months for FDA-approved AOMs (F-AOMs) and [U:.3.0; C:3.1] months for off-label AOMs (O-AOMs). Across both cohorts, F-AOMs generally demonstrated greater weight-loss effects than O-AOMs. Tirzepatide and semaglutide were the most effective F-AOMs. Tirzepatide achieved 10% weight loss target in [U:42%; C:48%] of patients with long-term exposure (65-66 weeks), while semaglutide achieved this threshold in [U:23%; C:33%] of patients with long-term exposure (70-72 weeks). Both medications were also associated with improvements in blood pressure, HDL, LDL, triglycerides, and HbA1c. Among O-AOMs, topiramate demonstrated the most favorable long-term (84-86 weeks) outcomes, with 13% of patients achieving 10% weight loss in both cohorts. Substantial interindividual variability in treatment response was observed across all AOMs, regardless of diagnosis type or exposure duration. Notably, weight gain was observed for all AOMs, ranging from [U:8%; C:12%] for long-term tirzepatide exposure to [U:57%; C:53%] for long-term lisdexamfetamine exposure. Weight regain following AOM discontinuation was consistently observed across both cohorts for both O-AOMs (e.g., lisdexamfetamine) and F-AOMs (e.g., phentermine w/wo topiramate). Interestingly, the combination of metformin with semaglutide or tirzepatide was associated with attenuated weight regain after treatment discontinuation compared with semaglutide or tirzepatide monotherapy. ConclusionsOur findings demonstrate real-world effectiveness of AOMs, particularly FDA-approved AOMs, in a subset of patients, while revealing substantial interindividual variability and notable discrepancies between EHR-based evidence and clinical trial results. These findings highlight the challenges of translating trial outcomes to routine practice and underscore the need for personalized obesity pharmacotherapy to improve effectiveness, adherence, and long-term sustainability of care.

BackgroundThe SELECT trial showed cardiovascular benefits of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in obese patients with cardiovascular disease; however, real-world data (RWD) on this benefit remain limited. This study used an artificial intelligence (AI)-generated algorithm and multimodal RWD to evaluate the impact of GLP-1 RAs on cardiovascular disease risk in a population of obese patients with and without preexisting cardiovascular disease. MethodsUsing data from the Dandelion Health RWD library, an Emulated SELECT Cohort was created to include obese patients similar to those in the SELECT trial, but with and without preexisting cardiovascular disease. An AI algorithm developed by Pheiron that used 12-lead electrocardiograms (ECGs) as a predictive biomarker for the risk of major adverse cardiovascular events (MACE) was validated and used to derive MACE risk scores for the Emulated SELECT Cohort. These outcomes were compared over time between patients who used GLP-1 RAs and non-users using inverse-probability weighted linear regression models, adjusting for key covariates. ResultsOut-of-sample validation showed high predictive accuracy of the AI algorithm, with ROC AUCs of 0.81 for myocardial infarction (MI) and 0.75 for stroke. Increased risk scores from the algorithm were correlated with higher MACE incidence in RWD. In the Emulated SELECT Cohort of 20,795 patients, GLP-1 RA use was associated with significant attenuation of MACE risk, with reductions observed in percentile risk score for MI (4%; p<0.001) and stroke (3.6%; p<0.001) per year of use. Differences in GLP-1 RA and non-GLP-1 users were evident as early as 1.7 years, with a 15-20% difference in absolute MACE risk scores between GLP-1 RA users and non-users observed by the end of the study. ConclusionAn AI algorithm using 12-lead ECGs accurately predicted MACE risk and could be used to model risk attenuation associated with GLP-1 RA use. Using this outcome, we find that GLP-1 RA use was associated with significant reductions in MI and stroke risk, in a broader population and within a shorter timeframe than the SELECT trial. These findings suggest potentially significant cardioprotective benefits of GLP-1 RAs in real-world settings and demonstrate a proof-of-concept for utilizing clinical AI to understand these benefits.

ObjectiveTo investigate the effects of sodium fructose diphosphate (FDP) on blood coagulation parameters, including reaction time and plasma coagulation factor activity, in both in vitro and in vivo models. MethodsThree thromboelastography systems (Maiketian, Lepu, Dingrun) were used to assess coagulation parameters (reaction time [R], clotting time [K], -angle, maximal amplitude [MA]) in blood samples spiked with varying FDP concentrations. An automatic coagulation analyzer quantified the activities of coagulation factors II, V, VII, VIII, IX, X, XI, and XII in FDP-treated plasma.Differences between FDP-treated and control groups were statistically compared. Linear regression analyzed correlations between FDP concentrations and coagulation parameters. For in vivo studies, New Zealand white rabbits received intravenous FDP (0.5, 1, 2, or 4 g/kg), and thromboelastography parameters were monitored at multiple time points post-administration (0.5-2 hours). ResultsThromboelastography demonstrated a strong positive correlation between FDP concentration and R values across all systems (P < 0.001; r = 0.988 [Maiketian], 0.999 [Lepu], 0.996 [Dingrun]). No significant associations were observed between FDP and K, -angle, or MA (P > 0.05). In vitro experiments revealed significant negative correlations between FDP concentration and activities of factors V (r = -0.995), VII (r = -0.990), IX (r = -0.989), XI (r = -0.997), and XII (r = -0.995) (P < 0.001), while factors II, VIII, and X remained unaffected (P > 0.05). In vivo administration demonstrated dose-dependent prolongation of R-time, reaching statistical significance (p < 0.05) at:0.5 g/kg: 0.5 hr post-dose,1 g/kg: 0.5-1.5 hr,2 g/kg: 0.5-1.5 hr,4 g/kg: 0.5-2 hr. ConclusionFDP significantly impacts coagulation testing outcomes both in vitro and in vivo, potentially through modulation of intrinsic pathway factors (V, VII, IX, XI, XII) and direct interference with clot initiation. These findings suggest clinically relevant anticoagulant properties that warrant further investigation.

BackgroundThe biosimilarity for erythropoietin (EPO) functionality of GBPD002 (test candidate) and Eprex(R) (comparator) has been evaluated by comparing the pharmacokinetic (PK) and pharmacodynamic (PD) properties following subcutaneous injection. MethodsThis was a randomized, double-blinded, two-sequence, crossover clinical trial. Subjects were randomly assigned and received a dose (4,000 IU) of either the test or comparator EPO, and received the alternative formulations after 4-weeks of washout period. ResultsThe PK parameters, viz., maximum observed concentration (Cmax) and area under the curve extrapolated to infinity (AUC0-inf), were calculated with the serum EPO concentrations from blood samples and were found comparable for both formulations. The geometric mean ratios (at 90% CI) of the Cmax and AUCinf were 0.89 and 1.16, respectively, which were within the regulatory range of 0.80 - 1.25. The time-matched serum EPO concentrations and PD markers (reticulocyte, hematocrit, hemoglobin, and red blood cell) denoted a counterclockwise hysteresis, suggesting a time delay between the observed concentration and the response. ANOVA-derived P-values (>0.05) for the effectors clearly revealed the similarity between effects on PD markers for the test and comparator drugs. Both formulations were found tolerated well, and anti-drug antibodies were not observed. ConclusionsThus, the two formulations are projected to be used interchangeably in clinical settings.

BackgroundNicotinamide riboside (NR) is a promising compound for augmenting the intracellular NAD+ pool, potentially mitigating age-related decline and associated conditions. While oral NR supplementation has demonstrated safety and bioavailability in multiple animal and human studies, the effects of intravenous NR (NR IV) are far less understood. Until now, pharmaceutical grade NR was not available for injection research. ObjectivesGiven that intravenous administration may offer advantages in certain conditions and contexts, a systematic investigation of the clinical effects of NR IV is warranted. MethodsThe present randomized, double-blinded, placebo-controlled, pilot clinical study was initiated with the primary aim of investigating the safety, tolerability, and the blood NAD+-boosting efficacy of an acute, single dose of NR IV (500 mg, test), NAD+ IV (500 mg, active comparator), oral NR (500 mg, bridge), and saline IV (placebo control) in generally healthy adult participants. The study consisted of two parts; data from 37 and 16 participants in the first and second phases, respectively, were analyzed. ResultsNo significant differences in vital signs were detected across groups. In comparison to NAD+ IV, NR IV was associated with fewer and less severe adverse experiences during the infusion; no attributable adverse events were reported through the 14-day follow-up period for any treatment groups. Further, the mean tolerable infusion time for NR IV was 75% less than that of NAD+ IV. No clinically meaningful changes in blood chemistry markers were described in the NR IV condition, whereas an increase in white blood cell counts and neutrophils was observed in the NAD+ IV condition, suggesting the presence of an inflammatory response. Finally, NR IV appeared to promote the most robust increases in NAD+ concentration as measured by dried blood spot analyses, with peak NAD+ levels increasing by 20.7% relative to baseline, and acutely outperforming NAD+ IV (p <0.01) and oral NR (p<0.01) at the 3-hr timepoint. ConclusionThis is the first study to clinically evaluate NR IV. Overall, acute intravenous infusions of 500 mg NR were safe in the study participants with no attributable adverse events and only minor and transient infusion-related experiences. In comparison to NAD+ IV, NR IV had a faster infusion time with superior tolerability. At 3 hours post-infusion, blood NAD+ levels were significantly higher in the NR IV group compared to the NAD+ IV group. Future studies in larger populations are needed to validate these results.

ImportanceGlucagon-like peptide-1 receptor agonists (GLP-1RAs) are fast-growing treatments for type 2 diabetes, obesity, and sleep apnea and are under investigation as potential treatments for many other conditions. The National Institutes of Healths (NIHs) All of Us Research Program offers a robust observational data source for studying questions related to GLP-1RA use in real-world settings. ObjectiveThis article describes key characteristics of All of Us participants who have been prescribed GLP-1RAs. The goals are to present the utility of the All of Us data and describe the strengths and limitations of using this resource for future research on GLP-1RAs. DesignUsing the All of Us Controlled Tier Curated Data Repository version 8 (CDRv8), we provide a descriptive analysis of the cohort with GLP-1RA records using cross-sectional surveys, longitudinal electronic health record (EHR) data, and longitudinal Fitbit data. SettingThe All of Us Research Program is a large, federally funded, longitudinal cohort study established in 2018 by NIH. Recruitment efforts are nationwide and target a range of populations to advance precision medicine for all. ParticipantsParticipants are U.S. residents, aged 18 or older at the time of study consent, who were enrolled between May 6, 2018, and October 1, 2023. ExposuresThe GLP-1RA cohort included participants with at least two GLP-1RA prescription records on different days at any time point based on their EHRs. Main OutcomesFrequencies and medians for a range of sociodemographic characteristics, health care utilization patterns, comorbid conditions, GLP-1RA prescription trends, laboratory and observation availability, and Fitbit data. ResultsThe All of Us GLP-1RA cohort is large (n=15 477), with high data availability across a range of relevant data types. These participants are older and have more comorbid conditions than the entire CDRv8 population. Prescription trends indicate rapid uptake of GLP-1RA drugs since 2014. Conclusions and RelevanceAll of Us CDRv8 is a valuable resource for research on GLP-1RAs across a large, heterogeneous cohort of participants. The variety and availability of data offer many possibilities for future observational, real-world research to address unanswered questions about GLP-1RA use and replicate recent findings generated from other datasets. Key pointsO_ST_ABSQuestionC_ST_ABSWhat data are available and what are the patterns of GLP-1 receptor agonist (GLP-1RA) prescriptions among participants in the All of Us Research Program? FindingsIn this descriptive cohort study of 633 534 All of Us participants, 15 477 participants had at least two records of GLP-1RA prescriptions. These participants tended to be older, have more comorbid conditions, and have higher health care utilization than the All of Us population as a whole. MeaningThe All of Us Research Program has a robust array of data to support observational studies of people receiving GLP-1RA prescriptions.

BackgroundIcosapent ethyl (ICP), an ethyl ester of eicosapentaenoic acid (EPA), and omega-3 acid ethyl esters (DHA/EPA), comprised of ethyl esters of EPA and doxosahexaenoic acid (DHA), are approved as adjunctive therapy to statins for reducing adverse cardiovascular events (CV) in patients with CV risks. However, there are concerns regarding a potential association between ICP and atrial fibrillation (AF). This study evaluated the incidence of AF onset between ICP and DHA/EPA when used as adjuvant therapy with statins. Methods and ResultsThis retrospective study utilized administrative healthcare claims to analyze adult AF-naive patients from one year preceding their first prescription for ICP or DHA/EPA. These patients were followed for two years, spanning from2013-2021. AF incidence was assessed during active treatment with either ICP or DHA/EPA as adjunct statin therapy. A propensity score (PS) matched cohort controlled for baseline characteristics and the effect of calendar year on the use of ICP or DHA/EPA. The cumulative incidence of AF was estimated using a product-limit estimator and compared between groups using a Cox proportional hazards regression model. The PS-matched cohort included 17,638 participants with a mean age 56 years, predominantly male (65.7% ICP vs. 64.5% DHA/EPA). Over two years, the cumulative incidence of AF from ICP and DHA/EPA was 5.32% and 3.99% respectively, resulting in a HR of 1.242 (95% CI: 1.061 to 1.455). ConclusionsIn adult AF-naive patients, ICP, when compared to DHA/EPA in conjunction with statin therapy, was associated with a significantly higher significant risk of developing AF. RESEARCH PERSPECTIVEO_ST_ABSWhat is New?C_ST_ABSO_LIDoes icopasent ethyl (ICP), an ethyl ester of eicosapentaenoic acid (EPA) and omega-3 acid ethyl esters comprised of ethyl esters of EPA and doxosahexaenoic acid (DHA) in atrial fibrillation (AF)-naive patients taking statins increase the incidence of AF? C_LIO_LIOver two years, the cumulative incidence of AF from ICP and DHA/EPA was 5.32% and 3.99% respectively, resulting in a HR of 1.242 (95% CI: 1.061 to 1.455). C_LIO_LIIn adult AF-naive patients, ICP, when compared to DHA/EPA in conjunction with statin therapy was associated with a higher significant risk of developing AF. C_LI What Question Should be Addressed Next?O_LIWhat should be considered as clinical and demographic factors in identifying patients at risk of atrial fibrillation prior to being prescribed ICP or DHA/EPA agents. C_LIO_LIInvestigation into the underlying mechanism of the increase in atrial fibrillation with marine omega-3 ethyl esters should continue. C_LIO_LIUnderstanding AF outcomes from ICP or DHA/EPA use including AF burden, need for AF medical or electrophysiological interventions, and health-care total costs. C_LI