Aims
To evaluate the effects of dulaglutide vs placebo on liver and glycaemic/metabolic measurements in a population with Type 2 diabetes and in a subgroup with non‐alcoholic fatty ...liver/non‐alcoholic steatohepatitis.
Methods
A total of 1499 participants from AWARD‐1, AWARD‐5, AWARD‐8 and AWARD‐9 clinical trials were included in this analysis (dulaglutide 1.5 mg, n=971 and placebo, n=528). Thresholds of alanine aminotransferase levels ≥30 IU/l in men and ≥19 IU/l in women were used to determine the subgroup who had non‐alcoholic fatty liver/non‐alcoholic steatohepatitis. Objectives included changes from baseline to 6 months in: (1) alanine aminotransferase, aspartate transaminase and gamma‐glutamyl transpeptidase levels in the overall population and (2) alanine aminotransferase, aspartate transaminase, gamma‐glutamyl transpeptidase and glycaemic/metabolic measurements (e.g. HbA1c, fasting serum glucose, body weight, lipids and homeostatic model assessment) in the non‐alcoholic fatty liver/non‐alcoholic steatohepatitis subgroup.
Results
In the overall population at 6 months, dulaglutide significantly reduced alanine aminotransferase, aspartate transaminase and gamma‐glutamyl transpeptidase levels vs placebo least squares mean treatment differences: –1.7 IU/l (95% CI –2.8, –0.6), P=0.003; –1.1 IU/l (95% CI –2.1, –0.1), P=0.037; –6.6 IU/l (95% CI –12.4, –0.8), P=0.025, respectively. In the subgroup with non‐alcoholic fatty liver/non‐alcoholic steatohepatitis (alanine aminotransferase levels greater than or equal to the upper limit of normal), mean baseline liver enzyme values were 38.0 IU/l, 27.8 IU/l and 43.9 IU/l for alanine aminotransferase, aspartate transaminase and gamma‐glutamyl transpeptidase, respectively. In this population, more pronounced reductions from baseline in alanine aminotransferase were observed with dulaglutide vs placebo (–8.8 IU/l vs –6.7 IU/l). In the subgroup of people with alanine aminotransferase levels less than the upper limit of normal, changes from baseline in alanine aminotransferase did not significantly differ between treatment groups (0.0 IU/l vs 0.7 IU/l).
Conclusions
Once‐weekly dulaglutide improved alanine aminotransferase, aspartate transaminase and gamma‐glutamyl transpeptidase levels compared with placebo in a pattern consistent with liver fat reductions. Our results add further weight to the notion that glucagon‐like peptide‐1 receptor agonists may provide benefit in lowering liver fat in addition to their other metabolic actions.
What's new?
Non‐alcoholic fatty liver disease is present in >75% of people with Type 2 diabetes.
Dulaglutide is a once‐weekly glucagon‐like peptide‐1 receptor agonist approved for the treatment of Type 2 diabetes.
This analysis evaluated the effects of dulaglutide on liver and glycaemic/metabolic measurements in a subgroup of people with non‐alcoholic fatty liver/non‐alcoholic steatohepatitis and Type 2 diabetes.
Treatment response of dulaglutide in the subgroup was similar to that in the overall population.
Dulaglutide improved plasma aminotransferases and gamma‐glutamyl transpeptidase in a pattern consistent with liver fat reductions.
This substudy of the AWARD‐3 trial evaluated the effects of the once‐weekly glucagon‐like peptide‐1 receptor agonist, dulaglutide, versus metformin on glucose control, pancreatic function and insulin ...sensitivity, after standardized test meals in patients with type 2 diabetes. Meals were administered at baseline, 26 and 52 weeks to patients randomized to monotherapy with dulaglutide 1.5 mg/week (n = 133), dulaglutide 0.75 mg/week (n = 136), or metformin ≥1500 mg/day (n = 140). Fasting and postprandial serum glucose, insulin, C‐peptide and glucagon levels were measured up to 3 h post‐meal. β‐cell function and insulin sensitivity were assessed using empirical variables and mathematical modelling. At 26 weeks, similar decreases in area under the curve for glucose AUCglucose (0–3 h) were observed among all groups. β‐cell function AUCinsulin/AUCglucose (0–3 h) increased with dulaglutide and was unchanged with metformin (p ≤ 0.005, both doses). Dulaglutide improved insulin secretion rate at 9 mmol/l glucose (p ≤ 0.04, both doses) and β‐cell glucose sensitivity (p = 0.004, dulaglutide 1.5 mg). Insulin sensitivity increased more with metformin versus dulaglutide. In conclusion, dulaglutide improves postprandial glycaemic control after a standardized test meal by enhancing β‐cell function, while metformin exerts a greater effect on insulin sensitivity.
Therapeutic administration of peptides may result in anti‐drug antibody (ADA) formation, hypersensitivity adverse events (AEs) and reduced efficacy. As a large peptide, the immunogenicity of ...once‐weekly glucagon‐like peptide‐1 (GLP‐1) receptor agonist dulaglutide is of considerable interest. The present study assessed the incidence of treatment‐emergent dulaglutide ADAs, hypersensitivity AEs, injection site reactions (ISRs), and glycaemic control in ADA‐positive patients in nine phase II and phase III trials (dulaglutide, N = 4006; exenatide, N = 276; non‐GLP‐1 comparators, N = 1141). Treatment‐emergent dulaglutide ADAs were detected using a solid‐phase extraction acid dissociation binding assay. Neutralizing ADAs were detected using a cell‐based assay derived from human endothelial kidney cells (HEK293). A total of 64 dulaglutide‐treated patients (1.6% of the population) tested ADA‐positive versus eight (0.7%) from the non‐GLP‐1 comparator group. Of these 64 patients, 34 (0.9%) had dulaglutide‐neutralizing ADAs, 36 (0.9%) had native‐sequence GLP‐1 (nsGLP‐1) cross‐reactive ADAs and four (0.1%) had nsGLP‐1 neutralization ADAs. The incidence of hypersensitivity AEs and ISRs was similar in the dulaglutide versus placebo groups. No dulaglutide ADA‐positive patient reported hypersensitivity AEs. Because of the low incidence of ADAs, it was not possible to establish their effect on glycaemic control.
Evidence from mouse chronic viral infection models suggests that CD8
T cell subsets characterized by distinct expression levels of the receptor PD-1 diverge in their state of exhaustion and potential ...for reinvigoration by PD-1 blockade. However, it remains unknown whether T cells in human cancer adopt a similar spectrum of exhausted states based on PD-1 expression levels. We compared transcriptional, metabolic and functional signatures of intratumoral CD8
T lymphocyte populations with high (PD-1
), intermediate (PD-1
) and no PD-1 expression (PD-1
) from non-small-cell lung cancer patients. PD-1
T cells showed a markedly different transcriptional and metabolic profile from PD-1
and PD-1
lymphocytes, as well as an intrinsically high capacity for tumor recognition. Furthermore, while PD-1
lymphocytes were impaired in classical effector cytokine production, they produced CXCL13, which mediates immune cell recruitment to tertiary lymphoid structures. Strikingly, the presence of PD-1
cells was strongly predictive for both response and survival in a small cohort of non-small-cell lung cancer patients treated with PD-1 blockade. The characterization of a distinct state of tumor-reactive, PD-1-bright lymphocytes in human cancer, which only partially resembles that seen in chronic infection, provides potential avenues for therapeutic intervention.
Since the onset of the COVID-19 pandemic, increasing cases with variable outcomes continue globally because of variants and despite vaccines and therapies. There is a need to identify at-risk ...individuals early that would benefit from timely medical interventions. DNA methylation provides an opportunity to identify an epigenetic signature of individuals at increased risk. We utilized machine learning to identify DNA methylation signatures of COVID-19 disease from data available through NCBI Gene Expression Omnibus. A training cohort of 460 individuals (164 COVID-19-infected and 296 non-infected) and an external validation dataset of 128 individuals (102 COVID-19-infected and 26 non-COVID-associated pneumonia) were reanalyzed. Data was processed using ChAMP and beta values were logit transformed. The JADBio AutoML platform was leveraged to identify a methylation signature associated with severe COVID-19 disease. We identified a random forest classification model from 4 unique methylation sites with the power to discern individuals with severe COVID-19 disease. The average area under the curve of receiver operator characteristic (AUC-ROC) of the model was 0.933 and the average area under the precision-recall curve (AUC-PRC) was 0.965. When applied to our external validation, this model produced an AUC-ROC of 0.898 and an AUC-PRC of 0.864. These results further our understanding of the utility of DNA methylation in COVID-19 disease pathology and serve as a platform to inform future COVID-19 related studies.
Aim
To examine the generalizability of results from glucagon‐like peptide‐1 receptor agonist (GLP‐1 RA) cardiovascular outcome trials (CVOTs) in the US type 2 diabetes (T2D) population.
Materials and ...methods
Patients enrolled or eligible for inclusion in four CVOTs (EXSCEL, LEADER, REWIND, and SUSTAIN‐6) were examined in reference to a retrospective clinical database weighted to match the age and sex distribution of the US adult T2D population. We descriptively compared key baseline characteristics of the populations enrolled in each trial to those of the reference population and estimated the proportions of individuals in the reference population represented by those in the trials for each characteristic. We also estimated the proportions of individuals in the reference population that might have been enrolled in each trial based upon meeting the trial inclusion and exclusion (I/E) criteria.
Results
No trial's enrolled population perfectly matched the reference population in key characteristics. The EXSCEL population most closely matched in mean age (62.7 vs. 60.5 years) and percentage with estimated glomerular filtration rate <60 (18.6 vs. 17.3%), while REWIND most closely matched in HbA1c, sex distribution, and proportion with a prior myocardial infarction. Based on I/E criteria, 42.6% of the reference population were eligible for enrolment in REWIND, versus 15.9% in EXSCEL, 13.0% in SUSTAIN‐6, and 12.9% in LEADER.
Conclusions
Although none of the trials are fully representative of the general population, among the four trials examined, results from baseline REWIND were found to be more generalizable to the US adult T2D population than those of other GLP‐1 RA CVOTs.
Vaccination of melanoma patients with tumor-specific antigens recognized by cytolytic T lymphocytes (CTL) produces significant tumor regressions in a minority of patients. These regressions appear to ...occur in the absence of massive CTL responses. To detect low-level responses, we resorted to antigenic stimulation of blood lymphocyte cultures in limiting dilution conditions, followed by tetramer analysis, cloning of the tetramer-positive cells, and T-cell receptor (TCR) sequence analysis of the CTL clones that showed strict specificity for the tumor antigen. A monoclonal CTL response against a MAGE-3 antigen was observed in a melanoma patient, who showed partial rejection of a large metastasis after treatment with a vaccine containing only the tumor-specific antigenic peptide. Tetramer analysis after in vitro restimulation indicated that about 1/40,000 postimmunization CD8+blood lymphocytes were directed against the antigen. The same TCR was present in all of the positive microcultures. TCR evaluation carried out directly on blood lymphocytes by PCR amplification led to a similar frequency estimate after immunization, whereas the TCR was not found among 2.5 × 106CD8+lymphocytes collected before immunization. Our results prove unambiguously that vaccines containing only a tumor-specific antigenic peptide can elicit a CTL response. Even though they provide no information about the effector mechanisms responsible for the observed reduction in tumor mass in this patient, they would suggest that low-level CTL responses can initiate tumor rejection.
Abstract Background Lipoplatin is a new liposomal cisplatin designed to reduce cisplatin toxicities without reducing efficacy. In the present randomized phase II study, we examined the efficacy and ...safety of a Lipoplatin–gemcitabine versus a cisplatin–gemcitabine combination as first line treatment in advanced NSCLC. Patients and methods Patients with advanced (stages IIIB-IV) NSCLC received up to six 21-day cycles of Lipoplatin 120 mg/m2 (days 1, 8, 15) and gemcitabine 1000 mg/m2 (days 1 + 8) (arm A; LipoGem) versus cisplatin 100 mg/m2 (day 1) and gemcitabine 1000 mg/m2 (days 1 + 8) (arm B; CisGem). The primary objective was objective response rate (ORR). Secondary objectives were disease control rate (DCR), progression-free survival (PFS), duration of response and overall survival (OS). Another secondary objective was safety and tolerability of the LipoGem combination. Results Eighty-eight patients ( n = 88) entered the study; 47 patients were treated with LipoGem versus 41 patients treated with CisGem. Efficacy was assessed in patients who completed at least 1 cycle of treatment; ORR was 31.7% in arm A versus 25.6% in arm B and DCR was 70.7% versus 56.4%, respectively. A preliminary efficacy of LipoGem versus CisGem in the adenocarcinoma histological subtype of NSCLC showed 16.7% versus 45.8% PD. Treatment in arm A was better tolerated with myelotoxicity and a transient mild elevation of serum creatinine as the dominant side effects; the only grade 4 adverse event was neutropenia noted in 2% of the patients. There was a significant reduction in nephrotoxicity in the LipoGem arm (0% versus 5% grade III, p -value < 0.001) as well as in nausea vomiting (2% versus 12% grade III, p -value < 0.001). In addition, less antiemetics and G-CSF were administered in arm A. Conclusion Overall, Lipoplatin appears to have lower toxicity, mainly renal toxicity as well as higher efficacy than cisplatin when combined with gemcitabine in advanced NSCLC.
Abstract Objectives Until recently, in-patient NHS hospital care in Greece was reimbursed via an anachronistic and under-priced retrospective per diem system, which has been held primarily ...responsible for continuous budget deficits. The purpose of this paper is to present the efforts of the Ministry of Health (MoH) to implement a new DRG-based payment system. Methods As in many countries, the decision was to adopt a patient classification from abroad and to refine it for use in Greece with national data. Pricing was achieved with a combination of activity-based costing with data from selected Greek hospitals, and “imported” cost weights. Data collection, IT support and monitoring are provided via ESY.net, a web-based facility developed and implemented by the MoH. Results After an initial pilot testing of the classification in 20 hospitals, complete DRG reimbursement data was reported by 113 hospitals (85% of total) for the fourth quarter of 2011. The recorded monthly increase in patient discharges billed with the new system and in revenue implies increasing adaptability by the hospitals. However, the unfavorable inlier vs. outlier distribution of discharges and revenue observed in some health regions signifies the need for corrective actions. Conclusions The importance of this reimbursement reform is discussed in light of the current crisis faced by the Greek economy. There is yet much to be done and many projects are currently in progress to support this effort; however the first cost containment results are encouraging.
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