Stable Dose Research Articles

Proteomics analyses of human plasma reveal triosephosphate isomerase as a potential blood marker of methotrexate resistance in rheumatoid arthritis.

The objective of this study was to assess differentially expressed blood proteins between patients with active RA and patients in remission after MTX treatment, with the aim of identifying a biomarker of MTX resistance (MTXR). Two populations of RA patients treated with a stable dose of s.c. MTX for at least 3 months were constituted according to the DAS28: remission (DAS28 < 2.6; n = 24) and active disease (DAS28 > 3.2; n = 32). The two groups of RA patients were homogeneous regarding their epidemiological characteristics, except for the duration of treatment, which was longer in the remission group. After collection of a blood sample, plasma protein digestion was performed, followed by untargeted proteomics analysis. Then, a targeted analysis was performed to confirm the results of the untargeted approach. Untargeted proteomics analysis revealed eight plasma proteins that were differentially expressed between the two groups of patients. Among them, triosephosphate isomerase (TPI-1) and glucose-6-phosphate isomerase (GPI), which are main actors in glycolysis, were found down-regulated in the active group. This result was confirmed for TPI-1 in the targeted proteomics analysis. A first step was achieved in the search for biomarkers of MTXR, with the identification of two actors in glycolysis (TPI-1 and GPI). The next step will be to confirm these results in a larger cohort, including samples from treatment-naive patients, to assess the predictive potential of these protein markers.

Non-Medical Switching from Tocilizumab to Sarilumab in Rheumatoid Arthritis Patients with Low Disease Activity, an Observational Study.

Tocilizumab and sarilumab are IL-6-receptor antagonists registered for rheumatoid arthritis (RA), with equal effectiveness and safety. Switching from tocilizumab to sarilumab could be a strategy to reduce injection burden, in case of drug shortages, and to reduce costs. This study therefore aims to investigate the effectiveness and safety of switching patients with RA with well-controlled disease under tocilizumab treatment to sarilumab. Patients with RA with low Disease Activity Score 28 (DAS28;-CRP < 2.9 or < 3.5 with clinical judgment), on stable dose tocilizumab (> 6 months) were offered to switch to sarilumab. Patients who switched and consented were followed for 6 months. Sarilumab was started at 200 mg and double the last tocilizumab interval. Co-primary outcomes at 6 months were (i) the 90% confidence interval (CI) of DAS28-CRP change from baseline compared with the non-inferiority margin of 0.6 and (ii) the 90% CI of the proportion of patients persisting with sarilumab, compared with a prespecified minimum of 70%. Of 50 invited patients, 25 agreed to switch to sarilumab, and 23 patients switched and were included. One patient was lost to follow-up immediately after inclusion, therefore 22 patients are included in the analyses. At 6 months, mean change in DAS28-CRP was 0.48 (90% CI: 0.11-0.87), compared with the non-inferiority margin of 0.6. Sarilumab persistence was 68% (90% CI: 51-82%, 15 out of 22 patients), compared with the prespecified minimum of 70%. Non-medical switching from tocilizumab to sarilumab in patients doing well on tocilizumab failed to show non-inferiority regarding disease activity and drug persistence.

Therapeutic Drug Monitoring in Uncontrolled Arterial Hypertension: Result of the Pilot Part of Study

INTRODUCTION: Despite the recently established evidence-based and systemic approach to treatment for arterial hypertension (AH), not in all cases its control can be achieved.&#x0D; AIM: To conduct a comparative analysis of the concentration of antihypertensive drugs (AHTDs) in blood serum of patients with controlled and uncontrolled AH.&#x0D; MATERIALS AND METHODS: Fifty six patients were included. Inclusion criteria: age 18 years, signing of informed consent, established diagnosis of AH, regular intake of any two of study antihypertensive drugs (lisinopril, amlodipine, valsartan) and also of indapamide at stable doses, for women adequate contraception. According to the results of daily monitoring of the arterial pressure (AP), patients were divided into two groups: the first group controlled hypertension (AP 140/90 mmHg; n = 39), the second uncontrolled hypertension (AP 140/90 mmHg; n = 17). The mean age of patients in the first group was 65.03 10.80 years, in the second 63.50 8.31 (p = 0.576). In the first group, women prevailed (64.1% vs. 35.3%, p = 0.047) and the mean body mass index was lower (26.30 1.38 kg/m2 vs. 32.20 4.15 kg/m2, p = 0.02). In patients of both groups, venous blood was taken in fasting condition in the morning and 2 hours after intake of AHTDs to assess their concentration by high-performance liquid chromatography. The analytical range for lisinopril, indapamide, amlodipine was 5500 ng/ml, for valsartan 1010,000 ng/ml.&#x0D; RESULTS: In the first group, equilibrium concentration of lisinopril was 2.67 times higher (p = 0.053), and concentration of indapamide in 2 hours after intake was 1.83 times higher (р = 0,084); when normalized to the dose, the differences were leveled out (p 0.05). Concentrations of amlodipine and valsartan did not differ between the groups both before and 2 hours after intake (p 0.05). In 3 of 39 (7.7%) patients with controlled hypertension and in one of 17 patients (5.9%, p = 1.0) with uncontrolled hypertension, AHTDs were detected in blood serum, which were not administered to them.&#x0D; CONCLUSIONS: Results of the pilot part of the study (n = 56) demonstrated the absence of difference between the mean concentrations of the study AHTDs in the blood serum of patients with controlled and uncontrolled AH, and in some cases the presence of traces of AHTDs not administered by the doctor.

Interpretation of GFR slope in untreated and treated adult Fabry patients.

Nephropathy is one of the main features of Fabry disease (FD) that leads, in untreated patients with classical mutations, to end-stage renal disease (ESRD) from the third to the fifth decade of life. The availability of a specific treatment modified the natural history of FD; in particular, it was widely reported that enzyme replacement therapy (ERT) is able to slow the progression of the disease. Regarding Fabry nephropathy, several reports have documented an elevated estimated glomerular filtration rate (eGFR) slope in untreated patients as expression of a rapid disease progression towards ESRD. Otherwise, the prompt start of treatment may be beneficial in stabilizing renal function or slowing its decline. Therefore, based on data in the literature about the effects of ERT on eGFR decline and on the evidence supporting the role of eGFR slope as a surrogate endpoint for chronic kidney disease progression, we suggest, in this 'Expert Opinion', that a treatment should be defined effective when eGFR decline is <1ml/min/1.73m2/year and not effective when eGFR loss remains ≥3ml/min/1.73m2/year (≥2.5ml/min/1.73m2/year in females). Moreover, practical clinical recommendations and guidance for Fabry patients suggests that a change in treatment may be appropriate if individualized therapeutic goals are not achieved. Since a dose-dependent efficacy has been demonstrated for ERT, we suggest considering a switch to a higher dose of ERT in symptomatic adult Fabry patients (ages 18-60years) with an eGFR of 45-90ml/min/1.73m2 and treated with a stable dose of ERT for at least 1year, in which a linear negative slope of eGFR of 3ml/min/1.73m2/year for males (2.5ml/min/1.73m2/year for females) was observed.

Defect Induced MgO: Li, Sm nanophosphor as a new highly sensitive material for thermoluminescence dosimetry

MgO is drawing considerable attention owing mainly due to its tissue equivalency (Zeff = 10.8) and excellent luminescence response. In this work, we report the synthesis and investigation of a highly sensitive MgO: Li, Sm phosphor in nanocrystalline form for TL dosimetry application. The structural and morphological study has been done using X-ray diffraction (XRD) and Transmission Electron Microscopy (TEM). TL intensity of gamma irradiated MgO nanophosphor increases with doping of Li and further improves by co-doping with Sm. The MgO: Li, Sm nanophosphor exhibit TL glow curve structure having isolated single peak at 169 °C and linearity in the low dose (13 mGy-5 Gy) as well as high dose range (10–1000 Gy). The TL structure and peak position remains stable at all doses. The phosphor shows excellent stability (low fading rate) and repeatability. TL intensity of MgO: Li, Sm is 12 times higher than that of commercially available LiF: Mg, Ti (TLD 100) and almost equivalent to LiF: Mg, Cu, P (TLD-700 H). This may be attributed to the formation of greater number of density of traps and suitable trapping levels with optimum dopant selection in MgO nanophosphor. The incorporation of the Sm3+ has improved the TL intensity manifold with appearance of desired isolated single peak. The photoluminescence (PL) spectra confirm the Sm3+ emission at 566, 603, 651 and 708 nm with an excitation wavelength of 315 nm. Further the role of dopants has been discussed on the basis of charge transfer mechanism and corelated with associated kinetic parameters for better understanding of TL process. The newly explored MgO: Li, Sm nanophosphor has shown attractive TL dosimetry properties owing to its high sensitivity, stable glow curve structure, dose linearity, low fading and repeatability which meet all the requirement to establish this as a next generation TL phosphor for medical and personal dosimetry application.

Solidification and oral delivery of biologics to the colon- A review

The oral delivery of biologics such as therapeutic proteins, peptides and oligonucleotides for the treatment of colon related diseases has been the focus of increasing attention over the last years. However, the major disadvantage of these macromolecules is their degradation propensity in liquid state which can lead to the undesirable and complete loss of function. Therefore, to increase the stability of the biologic and reduce their degradation propensity, formulation techniques such as solidification can be performed to obtain a stable solid dosage form for oral administration. Due to their fragility, stress exerted on the biologic during solidification has to be reduced with the incorporation of stabilizing excipients into the formulation. This review focuses on the state-of-the-art solidification techniques required to obtain a solid dosage form for the oral delivery of biologics to the colon and the use of suitable excipients for adequate stabilization upon solidification. The solidifying processes discussed within this review are spray drying, freeze drying, bead coating and also other techniques such as spray freeze drying, electro spraying, vacuum- and supercritical fluid drying. Further, the colon as site of absorption in both healthy and diseased state is critically reviewed and possible oral delivery systems for biologics are discussed.

A Transformer-Embedded Multi-Task Model for Dose Distribution Prediction.

Radiation therapy is a fundamental cancer treatment in the clinic. However, to satisfy the clinical requirements, radiologists have to iteratively adjust the radiotherapy plan based on experience, causing it extremely subjective and time-consuming to obtain a clinically acceptable plan. To this end, we introduce a transformer-embedded multi-task dose prediction (TransMTDP) network to automatically predict the dose distribution in radiotherapy. Specifically, to achieve more stable and accurate dose predictions, three highly correlated tasks are included in our TransMTDP network, i.e. a main dose prediction task to provide each pixel with a fine-grained dose value, an auxiliary isodose lines prediction task to produce coarse-grained dose ranges, and an auxiliary gradient prediction task to learn subtle gradient information such as radiation patterns and edges in the dose maps. The three correlated tasks are integrated through a shared encoder, following the multi-task learning strategy. To strengthen the connection of the output layers for different tasks, we further use two additional constraints, i.e. isodose consistency loss and gradient consistency loss, to reinforce the match between the dose distribution features generated by the auxiliary tasks and the main task. Additionally, considering many organs in the human body are symmetrical and the dose maps present abundant global features, we embed the transformer into our framework to capture the long-range dependencies of the dose maps. Evaluated on an in-house rectum cancer dataset and a public head and neck cancer dataset, our method gains superior performance compared with the state-of-the-art ones. Code is available at https://github.com/luuuwen/TransMTDP.

Development of solid lipid nanoparticles of diacerein in a stable oral liquid dosage form using a central composite design

Diacerein (DCN) is used mainly to treat degenerative diseases, such as osteoarthritis. DCN is marketed commercially in solid dosage forms. Liquid formulations of diacerein (DCN) have been hindered by its poor chemical stability in aqueous media. This work aims to develop a novel, stable, oral, liquid preparation of DCN having a concentration of 50 mg/5 ml. Solid lipid nanoparticles (SLNs) of DCN were prepared using cetyl alcohol as the lipid matrix and Tween 80® as a surfactant. A quality-by-design approach was utilized to optimize DCN-SLNs. The optimum DCN-SLNs were dispersed in a structured vehicle to formulate the liquid dosage form. This liquid preparation was subjected to accelerated stability studies at 40 °C and 75% RH for 6 months. The potential of the liquid preparation to minimize the diarrheal effect of DCN was assessed. Optimum concentrations of cetyl alcohol (2%) and Tween 80® (0.9%) were chosen to obtain the desired characteristics of SLNs. Interestingly, we determined that 0.05% of citric acid was the maximum concentration that can be added to the liquid preparation of diacerein to modify its pH without compromising its stability. The results of the stability studies show that the liquid preparation was robust and it withstood storage conditions (40 °C, 75% RH) for 6 months. The encapsulation of diacerein helps to protect it from degradation and significantly reduced the occurrence of diarrhea as a side effect (p < 0.0001). Liquid preparations of DCN-SLNs can thus be marketed as a new dosage form.

Switching from Multiple Insulin Injections to a Fixed Combination of Degludec and Liraglutide in Patients with Type 2 Diabetes Mellitus: Results from the Simplify Study After 6Months.

This study aimed to evaluate the effectiveness and safety of switching from basal bolus insulin treatment (BBIT) to a fixed combination of insulin degludec and liraglutide (IDegLira) in patients with type 2 diabetes mellitus (T2DM) who had preserved insulin secretion but inadequate glucose control. The study also aimed to assess the feasibility of implementing this therapeutic approach in common clinical practice settings. This was a non-randomized, open-label, multicenter, prospective, single-arm study involving 234 patients with T2DM who were receiving BBIT. Inclusion criteria were duration of diabetes mellitus > 60months, stable total daily dose of insulin (TDDI) ranging from > 20 to < 70IU/day (approx. > 0.3 to < 0.7IU/kg body weight/day), C-peptide levels > 10% above the lower limit, HbA1c levels > 7% and < 10% (Diabetes Control and Complications Trial), and body mass index > 25kg/m2. The primary endpoints were changes in glycated hemoglobin (HbA1c) and body weight at week 28 after treatment switching. Secondary endpoints included changes in the 7-point glycemic profile, hypoglycemia frequency, blood pressure, blood lipids, liver enzymes, insulin dose, and a patient questionnaire focusing on treatment satisfaction, concerns and impact on daily activities. A subgroup of 55 patients underwent continuous glucose monitoring (CGM) with the evaluation of CGM-derived parameters, such as time in range (TIR), time above range (TAR), time below range (TBR), hypoglycemia, and glucose variability. A significant decrease in HbA1c (8.6% vs. 7.6%; p < 0.0001) and body weight (97.8 vs. 94.0kg; p < 0.0001) was observed at week 28 after treatment switching. Significant improvements were also seen in all measurements of the 7-point glycemic profile (p < 0.0001), reduction in the number of hypoglycemia episodes per patient, and the proportion of patients with at least one hypoglycemia event (p < 0.001). Furthermore, there was a significant decrease in daily insulin dose (55.6 vs. 32.7IU/day; p < 0.0001), as well as improvements in blood pressure, blood lipids, and liver enzymes (gamma glutamyl transferase and alanine aminotransferase). The subgroup of patients who underwent CGM showed a significant increase in TIR (57.9% vs. 69.0%; p < 0.01) and a decrease in TAR (40.1% vs. 28.8%; p < 0.01), while TBR, hypoglycemia (number of episodes per patient and proportion of patients), and glucose variability did not change significantly. The results of this study suggest that switching from BBIT to IDegLira in patients with T2DM and preserved insulin secretion can simplify treatment without compromising glycemic control. The switch to IDegLira was associated with significant improvements in various glucose control parameters, including HbA1c, glycemic profile, hypoglycemia, insulin doses, and CGM-derived parameters TIR and TAR. Additionally, it led to significant reductions in body weight, blood pressure, lipid profile, and liver enzyme levels. Switching to IDegLira may be considered a safe and beneficial approach in clinical practice settings, offering metabolic and individual advantages.

Transcranial direct current stimulation as an additional treatment to selective serotonin reuptake inhibitors in adults with major depressive disorder in Germany (DepressionDC): a triple-blind, randomised, sham-controlled, multicentre trial

Transcranial direct current stimulation (tDCS) has been proposed as a feasible treatment for major depressive disorder (MDD). However, meta-analytic evidence is heterogenous and data from multicentre trials are scarce. We aimed to assess the efficacy of tDCS versus sham stimulation as an additional treatment to a stable dose of selective serotonin reuptake inhibitors (SSRIs) in adults with MDD. The DepressionDC trial was triple-blind, randomised, and sham-controlled and conducted at eight hospitals in Germany. Patients being treated at a participating hospital aged 18-65 years were eligible if they had a diagnosis of MDD, a score of at least 15 on the Hamilton Depression Rating Scale (21-item version), no response to at least one antidepressant trial in their current depressive episode, and treatment with an SSRI at a stable dose for at least 4 weeks before inclusion; the SSRI was continued at the same dose during stimulation. Patients were allocated (1:1) by fixed-blocked randomisation to receive either 30 min of 2 mA bifrontal tDCS every weekday for 4 weeks, then two tDCS sessions per week for 2 weeks, or sham stimulation at the same intervals. Randomisation was stratified by site and baseline Montgomery-Åsberg Depression Rating Scale (MADRS) score (ie, <31 or ≥31). Participants, raters, and operators were masked to treatment assignment. The primary outcome was change on the MADRS at week 6, analysed in the intention-to-treat population. Safety was assessed in all patients who received at least one treatment session. The trial was registered with ClinicalTrials.gov (NCT02530164). Between Jan 19, 2016, and June 15, 2020, 3601 individuals were assessed for eligibility. 160 patients were included and randomly assigned to receive either active tDCS (n=83) or sham tDCS (n=77). Six patients withdrew consent and four patients were found to have been wrongly included, so data from 150 patients were analysed (89 [59%] were female and 61 [41%] were male). No intergroup difference was found in mean improvement on the MADRS at week 6 between the active tDCS group (n=77; -8·2, SD 7·2) and the sham tDCS group (n=73; -8·0, 9·3; difference 0·3 [95% CI -2·4 to 2·9]). Significantly more participants had one or more mild adverse events in the active tDCS group (50 [60%] of 83) than in the sham tDCS group (33 [43%] of 77; p=0·028). Active tDCS was not superior to sham stimulation during a 6-week period. Our trial does not support the efficacy of tDCS as an additional treatment to SSRIs in adults with MDD. German Federal Ministry of Education and Research.

Association Between Opioid Dose Reduction Rates and Overdose Among Patients Prescribed Long-Term Opioid Therapy.

Tapering long-term opioid therapy is an increasingly common practice, yet rapid opioid dose reductions may increase the risk of overdose. The objective of this study was to compare overdose risk following opioid dose reduction rates of ≤10%, 11% to 20%, 21% to 30%, and >30% per month to stable dosing. We conducted a retrospective cohort study in three health systems in Colorado and Wisconsin. Participants were patients ≥18 years of age prescribed long-term opioid therapy between January 1, 2006, and June 30, 2019. Five opioid dosing patterns and drug overdoses (fatal and nonfatal) were identified using electronic health records, pharmacy records, and the National Death Index. Cox proportional hazard regression was conducted on a propensity score-weighted cohort to estimate adjusted hazard ratios (aHRs) for follow-up periods of 1, 3, 6, 9, and 12 months after a dose reduction. In a cohort of 17 540 patients receiving long-term opioid therapy, 42.7% of patients experienced a dose reduction. Relative to stable dosing, a dose reduction rate of >30% was associated with an increased risk of overdose and the aHR estimates decreased as the follow-up increased; the aHRs for the 1-, 6- and 12-month follow-ups were 5.33 (95% CI, 1.98-14.34), 1.81 (95% CI,1.08-3.03), and 1.49 (95% CI, 0.97-2.27), respectively. The slower tapering rates were not associated with overdose risk. Patients receiving long-term opioid therapy exposed to dose reduction rates of >30% per month had increased overdose risk relative to patients exposed to stable dosing. Results support the use of slow dose reductions to minimize the risk of overdose.

A micro-randomized pilot study to examine the impact of just-in-time nudging on after-dinner snacking in adults with type 2 diabetes: A study protocol.

To determine whether a digital nudge soon after dinner reduces after-dinner snacking events as measured objectively by continuous glucose monitoring (CGM) in patients with type 2 diabetes (T2D). This is a single-site micro-randomized trial (MRT). People with T2D, aged 18-75 years, managed with diet or a stable dose of oral antidiabetic medications for at least 3 months, and who habitual snack after dinner at least 3 nights per week, will be recruited. Picto-graphic nudges were designed by mixed research methods. After a 2-week lead-in phase to determine eligibility and snacking behaviours by a CGM detection algorithm developed by the investigators, participants will be micro-randomized daily (1:1) to a second 2-week period to either a picto-graphic nudge delivered-in-time (Intui Research) or no nudge. During lead-in and MRT phases, 24-hour glucose will be measured by CGM, sleep will be tracked by an under-mattress sleep sensor, and dinner timing will be captured daily by photographing the evening meal. The primary outcome is the difference in the incremental area under the CGM curve between nudging and non-nudging days during the period from 90 minutes after dinner until 04:00 AM. Secondary outcomes include the effect of baseline characteristics on treatment, and comparisons of glucose peaks and time-in-range between nudging and non-nudging days. The feasibility of 'just-in-time' messaging and nudge acceptability will be evaluated, along with the analysis of sleep quality measures and their night-to-night variability. This study will provide preliminary evidence of the impact of appropriately timed digital nudges on 24 -hour intertitial glucose levels resulting from altered after-dinner snacking in people withT2D. An exploratory sleep substudy will provide evidence of a bidirectional relationship between after-dinner snacking behaviour, glycaemia and sleep. Ultimately, this study will allow for the design of a future confirmatory study of the potential for digital nudging to improve health related behaviours and health outcomes.

Predicting successful biologics tapering in patients with inflammatory arthritis: Secondary analyses based on the BIOlogical Dose OPTimisation (BIODOPT) trial.

To evaluate predictors for successful biologic tapering among patients with inflammatory arthritis using baseline characteristics from the BIODOPT trial. Adult patients with rheumatoid arthritis, psoriatic arthritis or axial spondyloarthritis on stable biologic dose and in low disease activity ≥12 months were enrolled. Participants were randomized (2:1) to disease activity-guided biologic tapering or continuation of baseline biologic. Patients achieving successful tapering reduced their biologic dose by ≥50%, had no protocol deviations and were in low disease activity at 18 months. Modified Poisson regression with robust variance estimator was applied. In total, 142 patients were randomized to tapering (n= 95) or control (n= 47). Successful tapering was achieved by 32 and 2%, respectively. Tapering group was the only statistically significant independent predictor for successful tapering, risk ratio (RR): 14.0 (95% confidence interval [CI]: 1.9 to 101.3, P= .009). However, higher Short Form Health Survey 36 mental component summary (SF-36 MCS) was observed to be a predictor of potential importance, RR: 1.06 (95% CI: 0.99 to 1.13, P= .097). When limiting the analyses to the tapering group only, none of the baseline variables were statistically significant independent predictors but SF-36 MCS was still considered to be of potential importance, RR: 1.05 (95% CI: 0.99 to 1.12, P= .098). Successful tapering is a reachable target for 1 in 3 patients with inflammatory arthritis who are interested in reducing their biological therapy. No statistically significant predictors (besides allocation to tapering) were identified. Future research on mental health and tapering is encouraged.

Efficacy and safety of once-daily oral semaglutide 25 mg and 50 mg compared with 14 mg in adults with type 2 diabetes (PIONEER PLUS): a multicentre, randomised, phase 3b trial

Once-daily oral semaglutide is an effective type 2 diabetes treatment. We aimed to investigate a new formulation of oral semaglutide at higher investigational doses versus the approved 14 mg dose in adults with inadequately controlled type 2 diabetes. This global, multicentre, randomised, double-blind, phase 3b trial, carried out at 177 sites in 14 countries, enrolled adults with type 2 diabetes, glycated haemoglobin (HbA1c) 8·0-10·5% (64-91 mmol/mol), a BMI of 25·0 kg/m2 or greater, receiving stable daily doses of one to three oral glucose-lowering drugs. Participants were randomly assigned (1:1:1), by means of an interactive web response system, to once-daily oral semaglutide 14 mg, 25 mg, or 50 mg for 68 weeks. Investigators, site personnel, trial participants, and trial sponsor staff were masked to dose assignment throughout the trial. The primary endpoint was change in HbA1c from baseline to week 52, evaluated with a treatment policy estimand in the intention-to-treat population. Safety was assessed in all participants who received at least one dose of trial drug. This trial is registered with ClinicalTrials.gov, NCT04707469, and the European Clinical Trials register, EudraCT 2020-000299-39, and is complete. Between Jan 15 and Sept 29, 2021, of 2294 people screened, 1606 (n=936 [58·3%] male; n=670 [41·7%] female; mean [SD] age 58·2 [10·8] years) received oral semaglutide 14 mg (n=536), 25 mg (n=535), or 50 mg (n=535). At baseline, mean (SD) HbA1c was 9·0% (0·8; 74·4 mmol/L [SD 8·3]) and mean bodyweight was 96·4 kg (21·6). Mean changes (SE) in HbA1c at week 52 were -1·5 percentage points (SE 0·05) with oral semaglutide 14 mg, -1·8 percentage points (0·06) with 25 mg (estimated treatment difference [ETD] -0·27, 95% CI -0·42 to -0·12; p=0·0006), and -2·0 percentage points (0·06) with 50 mg (ETD -0·53, -0·68 to -0·38; p<0·0001). Adverse events were reported by 404 (76%) participants in the oral semaglutide 14 mg group, 422 (79%) in the 25 mg group, and 428 (80%) in the 50 mg group. Gastrointestinal disorders, which were mostly mild to moderate, occurred more frequently with oral semaglutide 25 mg and 50 mg than with 14 mg. Ten deaths occurred during the trial; none were judged to be treatment related. Oral semaglutide 25 mg and 50 mg were superior to 14 mg in reducing HbA1c and bodyweight in adults with inadequately controlled type 2 diabetes. No new safety concerns were identified. Novo Nordisk.

Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA

Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA

Solid lipid Lyo-Nanosuspension: A promising stabilized oral delivery system for the antihyperglycemic extract of mistletoe Plicosepalus acacia

The antihyperglycemic effect of Plicosepalus acaciae (P. acaciae) extract was proven, but it still needs to be formulated into a suitable dosage form. We aimed at preparing an oral stabilized SLNs for P. acaciae with high payload, to be used as powder for reconstitution, filled into capsule or compressed into tablet. SLNs were prepared by emulsion solvent evaporation technique. Preliminary characterization was performed followed by full assessment of the optimized SLNs suspension and/or its lyophilized form: particle size, zeta potential, surface morphology, percentage entrapment efficiency (% EE), DSC, FTIR and in vitro release studies. The optimized SLNs lyophilized formula (F3L) exhibited acceptable compressibility and flowability. The reconstituted F3L showed % sedimentation volume of 91.83 %, re-dispersibility of 95%, viscosity of 764.33 cp, uniform particle size of 30.28 nm as shown by TEM, polydispersity index (PDI) of 0.16, zeta potential of −36.4 mV, % EE of 89.64 % and drug content of 97.69 %. The physical mixture and F3L FTIR spectrum indicated compatibility of components. In vitro release study showed a burst release in lyophilized formulations followed by slow-release, calculated as total phenolic content. Our previously reported work revealed that the total extracts of P. acaciae and SLNs formulations with the greatest lipid content F3s, demonstrated a considerable blood glucose-lowering effect in diabetic rats. The obtained lyophilized SLNs is promising for preparation of a suitable stable dosage form for P. acaciae extract to be used in treatment of diabetes.

Right heart catheterization predictors of symptomatic improvement in patients undergoing transcatheter tricuspid valve edge‐to‐edge repair

AbstractBackgroundTranscatheter tricuspid valve edge‐to‐edge repair (TTEER) is associated with improvement in outcomes for symptomatic patients with severe tricuspid regurgitation (TR). However, reliable predictors for clinical success are not yet fully defined. This study aims to describe right heart catheterization (RHC) findings in patients referred for TTEER and identify hemodynamic characteristics of patients who experience immediate symptomatic improvement following successful TR intervention.MethodsPatients who underwent TTEER and had a separate RHC within the preceding 6 months were included. Hemodynamic tracings from the RHC and TTEER procedures were reviewed and recorded. Clinical success was defined as a successful device implant with at least 1‐grade of TR reduction and improvement in NYHA class by 1 or more grades on 30‐day echocardiogram and clinical follow‐up.ResultsThirteen patients underwent an RHC within 6 months of TTEER procedure (median age 76 years [IQR: 73–80]). All patients were on a stable dose of loop diuretics. Baseline right atrial pressure was severely elevated (mean 19 mmHg [IQR: 9–24 mmHg]) with prominent CV waves. Median pulmonary capillary wedge pressure (PCWP) was 20 mmHg (IQR: 14–22) and 70% of patients had a mean PCWP &gt; 15 mmHg at rest. Median PCWP CV‐wave was 34 mmHg (IQR: 23–42). Higher PCWP CV‐wave height (40 mmHg [IQR 33–43] versus 18 mmHg [IQR 17–31]) was associated with lower likelihood of clinical success (OR 0.83, 95% CI: 0.35–0.97,p = 0.04).ConclusionsInclusion of invasive hemodynamics as part of pre‐TTEER evaluation may allow for improved TR phenotyping and patient selection. Patients with a large left atrial CV wave on resting RHC were less likely to experience immediate symptomatic improvement despite procedural success with TTEER.

49-LB: A Low Biologically Available Glucose Diet Reduces Hemoglobin A1c in Type 2 Diabetes Mellitus—A Randomized Controlled Trial

Introduction: The Low Biologically Available Glucose (LoBAG) diet was designed to improve glycemic control of type 2 diabetes mellitus (T2D). This study tested the effectiveness of the diet in free-living participants with T2D. Methods: A 12-week randomized controlled trial in participants with T2D compared the LoBAG30 diet (30% low starch carbohydrate, 30% protein, 40% fat) to a control diet (55% carbohydrate, 15% protein, 30% fat). Participants were taking metformin at a stable dose or no glucose-lowering medication. Diets were prescribed to be weight neutral and participants were asked to keep physical activity level constant. Diet instruction and dietitian support were provided to both study groups; food was not provided. The primary outcome was hemoglobin A1c (HbA1c) at the end of the intervention, compared between groups. Results: Forty-eight participants were enrolled (30 female/18 male; 77% white, 15% Black/African American, 2% Asian, 2% American Indian, 4% not reported; 15% Hispanic/Latino). The majority (88%) took metformin. Baseline characteristics were mean (SD) age 57.4 (10.4) years, HbA1c 7.7 (0.6) %, weight 101.5 (19.7) kg, and BMI 35.4 (5.9) kg/m2 with no significant differences between groups. Thirty-eight participants completed the entire intervention; 4/10 non-completers were withdrawn due to the COVID-19 pandemic. HbA1c decreased in both groups over 12 weeks: mean (SD) -1.0 (0.8) % for the LoBAG diet (p&amp;lt;0.01) and -0.6 (0.7) % for control (p&amp;lt;0.01). The final HbA1c was 6.6 (0.6) % in the LoBAG diet group versus 7.2 (0.8) % for control (p=0.01 for comparison between groups). Both groups lost weight: -6.0 (6.9) kg with the LoBAG diet versus -4.3 (3.5) kg for control (p=0.34 for comparison between groups). Conclusion: Participants with T2D consuming the LoBAG diet had greater reduction in HbA1c over 12 weeks than those consuming a control diet. The LoBAG diet is an effective option for dietary management of blood glucose in patients with T2D. Disclosure J. D. Anderson: None. M. A. Hanson: None. L. F. Lysne: None. L. E. Eberly: None. E. R. Seaquist: Consultant; Zucara Therapeutics. D. Knights: None. L. S. Chow: Research Support; Dexcom, Inc. Q. Wang: None. A. Bantle: None. Funding University of Minnesota Department of Medicine; National Center for Advancing Translational Sciences (UL1TR002494, KL2TR002492); National Institute of Diabetes and Digestive and Kidney Diseases (K23DK115906)

835-P: First-in-Human Duodenal Endoscopic Recellularization via Electroporation Therapy for Type 2 Diabetes—An Interim Report

Background: We evaluated the feasibility and safety of endoscopic re-cellularization via electroporation therapy (ReCET) (Endogenex. Plymouth, MN) in restoring impaired duodenal signaling adversely impacting glucose control in type 2 diabetes (T2D). Method: We enrolled 30 adults with T2D: duration ≤10 years; HbA1c 7.5-11.0%; BMI of 24-40 kg/m2; C-peptide ≥333pmol/L; 1-4 non-insulin glucose-lowering medications (GLMs) at stable dose. Post-procedure GLMs were unchanged. Primary endpoint: Device or procedure-related serious adverse events (SAEs). Secondary endpoints: Changes in metabolic parameters at 24W. Results: The first 12 participants received single energy (Single Tx) then 18 received double energy application (Double Tx) with no device/procedure-related SAEs. Forty-five adverse events were reported in 23/30 participants (sore throat [17/30]; transient diarrhea [9/30]) and 80% were mild. HbA1c reduction at 24W was greater with double vs. single Tx (p&amp;lt;0.05). For double Tx vs. baseline: FPG was 7.5±1.7 mmol/L vs. 9.8±2.2 mmol/L (p&amp;lt;0.01), HOMA-IR 4.5±3.6 vs. 7.4±3.3 (p&amp;lt;0.01), Time-in-range 79.4±18.8 % vs. 59.0±24.2% (p&amp;lt;0.01), triglyceride 2.0±1.2mmol/L vs. 2.9±1.9mmol/L (P&amp;lt;0.05) and Δweight -5.1%±4.1% (p&amp;lt;0.01). Conclusions: Our data suggest that ReCET is safe and associated with clinically meaningful changes in metabolic control in T2D patients on GLMs. Disclosure C.Yuan: None. A.Sartoretto: Advisory Panel; Bariatek, Research Support; Endogenex, Erbe Electromedizin GMBH, Speaker's Bureau; Pfizer Inc., Stock/Shareholder; Apollo Endosurgery. B.Holt: None. G.Cameron: None. G.Marinos: None. F.E.Napier-flood: None. B.K.Abu dayyeh: Advisory Panel; Endogenex, Consultant; Apollo Endosurgery, Boston Scientific Corporation, Medtronic, Research Support; USGI, Endogastric Solutions. D.N.O'neal: None.

Review on Needle Free Injection Technology

Introduction: Needle-free injection technology (NFIT), its advantages, and the different devices and variants available. It highlights the potential of NFIT for painless and effective drug delivery and its use in mass vaccination campaigns.&#x0D; Methods: The primary factors that need to be considered to provide a stable, safe, and effective dose by NFIT. It also explains the classification of NFIT devices based on their working, type of load, mechanism of drug delivery, and site of delivery.&#x0D; Results: The additional benefit of NFIT technology, which is the ability to administer highly viscous medicated formulations that cannot be administered by conventional needle and syringe systems. It also highlights some of the commercially available variants of NFIT devices, such as Bioject®, ZetaJetTM, and Vitajet.&#x0D; Conclusion: The advantages and potential of NFIT for painless and effective drug delivery, particularly in mass vaccination campaigns and the developing world. It emphasizes the need for further research and development in this field to improve the stability, safety, and efficacy of NFIT devices.&#x0D;