Water Conservation Overrides Osmotic Diuresis During SGLT2 Inhibition in Patients With Heart Failure.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors are believed to improve cardiac outcomes due to their osmotic diuretic potential. OBJECTIVES: The goal of this study was to test the hypothesis that vasopressin-driven urine concentration overrides the osmotic diuretic effect of glucosuria induced by dapagliflozin treatment. METHODS: DAPA-Shuttle1 (Hepato-renal Regulation of Water Conservation in Heart Failure Patients With SGLT-2 Inhibitor Treatment) was a single-center, double-blind, randomized, placebo-controlled trial, in which patients with chronic heart failure NYHA functional classes I/II and reduced ejection fraction were randomly assigned to receive dapagliflozin 10 mg daily or placebo (1:1) for 4 weeks. The primary endpoint was change from baseline in urine osmolyte concentration. Secondary endpoints included changes in copeptin levels and solute free water clearance. RESULTS: Thirty-three randomized, sodium-glucose cotransporter 2 inhibitor-naïve participants completed the study, 29 of whom (placebo: n = 14; dapagliflozin: n = 15) provided accurate 24-hour urine collections (mean age 59 ± 14 years; left ventricular ejection fraction 31% ± 9%). Dapagliflozin treatment led to an isolated increase in urine glucose excretion by 3.3 mmol/kg/d (95% CI: 2.51-4.04; P < 0.0001) within 48 hours (early) which persisted after 4 weeks (late; 2.7 mmol/kg/d [95% CI: 1.98-3.51]; P < 0.0001). Dapagliflozin treatment increased serum copeptin early (5.5 pmol/L [95% CI: 0.45-10.5]; P < 0.05) and late (7.8 pmol/L [95% CI: 2.77-12.81]; P < 0.01), leading to proportional reductions in free water clearance (early: -9.1 mL/kg/d [95% CI: -14 to -4.12; P < 0.001]; late: -11.0 mL/kg/d [95% CI: -15.94 to -6.07; P < 0.0001]) and elevated urine concentrations (late: 134 mmol/L [95% CI: 39.28-229.12]; P < 0.01). Therefore, urine volume did not significantly increase with dapagliflozin (mean difference early: 2.8 mL/kg/d [95% CI: -1.97 to 7.48; P = 0.25]; mean difference late: 0.9 mL/kg/d [95% CI: -3.83 to 5.62]; P = 0.70). CONCLUSIONS: Physiological-adaptive water conservation eliminated the expected osmotic diuretic potential of dapagliflozin and thereby prevented a glucose-driven increase in urine volume of approximately 10 mL/kg/d · 75 kg = 750 mL/kg/d. (Hepato-renal Regulation of Water Conservation in Heart Failure Patients With SGLT-2 Inhibitor Treatment [DAPA-Shuttle1]; NCT04080518).

From Brownian to Deterministic Motor Movement in a DNA-Based Molecular Rotor.

Molecular devices that have an anisotropic periodic potential landscape can be operated as Brownian motors. When the potential landscape is cyclically switched with an external force, such devices can harness random Brownian fluctuations to generate a directed motion. Recently, directed Brownian motor-like rotatory movement was demonstrated with an electrically switched DNA origami rotor with designed ratchet-like obstacles. Here, we demonstrate that the intrinsic anisotropy of DNA origami rotors is also sufficient to result in motor movement. We show that for low amplitudes of an external switching field, such devices operate as Brownian motors, while at higher amplitudes, they behave deterministically as overdamped electrical motors. We characterize the amplitude and frequency dependence of the movements, showing that after an initial steep rise, the angular speed peaks and drops for excessive driving amplitudes and frequencies. The rotor movement can be well described by a simple stochastic model of the system.

UPDATE trial: investigating the effects of ultra-processed versus minimally processed diets following UK dietary guidance on health outcomes: a protocol for an 8-week community-based cross-over randomised controlled trial in people with overweight or obesity, followed by a 6-month behavioural intervention.

INTRODUCTION: Obesity increases the risk of morbidity and mortality. A major driver has been the increased availability of ultra-processed food (UPF), now the main UK dietary energy source. The UK Eatwell Guide (EWG) provides public guidance for a healthy balanced diet but offers no UPF guidance. Whether a healthy diet can largely consist of UPFs is unclear. No study has assessed whether the health impact of adhering to dietary guidelines depends on food processing. Furthermore, our study will assess the impact of a 6-month behavioural support programme aimed at reducing UPF intake in people with overweight/obesity and high UPF intakes. METHODS AND ANALYSIS: UPDATE is a 2×2 cross-over randomised controlled trial with a 6-month behavioural intervention. Fifty-five adults aged ≥18, with overweight/obesity (≥25 to <40 kg/m2), and ≥50% of habitual energy intake from UPFs will receive an 8-week UPF diet and an 8-week minimally processed food (MPF) diet delivered to their home, both following EWG recommendations, in a random order, with a 4-week washout period. All food/drink will be provided. Participants will then receive 6 months of behavioural support to reduce UPF intake. The primary outcome is the difference in weight change between UPF and MPF diets from baseline to week 8. Secondary outcomes include changes in diet, waist circumference, body composition, heart rate, blood pressure, cardiometabolic risk factors, appetite regulation, sleep quality, physical activity levels, physical function/strength, well-being and aspects of behaviour change/eating behaviour at 8 weeks between UPF/MPF diets, and at 6-month follow-up. Quantitative assessment of changes in brain MRI functional resting-state connectivity between UPF/MPF diets, and qualitative analysis of the behavioural intervention for feasibility and acceptability will be undertaken. ETHICS AND DISSEMINATION: Sheffield Research Ethics Committee approved the trial (22/YH/0281). Peer-reviewed journals, conferences, PhD thesis and lay media will report results. TRIAL REGISTRATION NUMBER: NCT05627570.

KCNQ5 Controls Perivascular Adipose Tissue-Mediated Vasodilation.

BACKGROUND: Small arteries exhibit resting tone, a partially contracted state that maintains arterial blood pressure. In arterial smooth muscle cells, potassium channels control contraction and relaxation. Perivascular adipose tissue (PVAT) has been shown to exert anticontractile effects on the blood vessels. However, the mechanisms by which PVAT signals small arteries, and their relevance remain largely unknown. We aimed to uncover key molecular components in adipose-vascular coupling. METHODS: A wide spectrum of genetic mouse models targeting Kcnq3, Kcnq4, and Kcnq5 genes (Kcnq3-/-, Kcnq4-/-, Kcnq5-/-, Kcnq5dn/dn, Kcnq4-/-/Kcnq5dn/dn, and Kcnq4-/-/Kcnq5-/-), telemetry blood pressure measurements, targeted lipidomics, RNA-Seq profiling, wire-myography, patch-clamp, and sharp-electrode membrane potential measurements was used. RESULTS: We show that PVAT causes smooth muscle cell KV7.5 family of voltage-gated potassium (K+) channels to hyperpolarize the membrane potential. This effect relaxes small arteries and regulates blood pressure. Oxygenation of polyunsaturated fats generates oxylipins, a superclass of lipid mediators. We identified numerous oxylipins released by PVAT, which potentiate vasodilatory action in small arteries by opening smooth muscle cell KV7.5 family of voltage-gated potassium (K+) channels. CONCLUSIONS: Our results reveal a key molecular function of the KV7.5 family of voltage-gated potassium (K+) channels in the adipose-vascular coupling, translating PVAT signals, particularly oxylipins, to the central physiological function of vasoregulation. This novel pathway opens new therapeutic perspectives.

Reversible Self-Assembly of Nucleic Acids in a Diffusiophoretic Trap.

The formation and dissociation of duplexes or higher order structures from nucleic acid strands is a fundamental process with widespread applications in biochemistry and nanotechnology. Here, we introduce a simple experimental system-a diffusiophoretic trap-for the non-equilibrium self-assembly of nucleic acid structures that uses an electrolyte gradient as the driving force. DNA strands can be concentrated up to hundredfold by a diffusiophoretic trapping force that is caused by the electric field generated by the electrolyte gradient. We present a simple equation for the field to guide selection of appropriate trapping electrolytes. Experiments with carboxylated silica particles demonstrate that the diffusiophoretic force is long-ranged, extending over hundreds of micrometers. As an application, we explore the reversible self-assembly of branched DNA nanostructures in the trap into a macroscopic gel. The structures assemble in the presence of an electrolyte gradient, and disassemble upon its removal, representing a prototypical adaptive response to a macroscopic non-equilibrium state.

ADAM19 cleaves the PTH receptor and associates with brachydactyly type E.

Brachydactyly type E (BDE), shortened metacarpals, metatarsals, cone-shaped epiphyses, and short stature commonly occurs as a sole phenotype. Parathyroid hormone-like protein (PTHrP) has been shown to be responsible in all forms to date, either directly or indirectly. We used linkage and then whole genome sequencing in a small pedigree, to elucidate BDE and identified a truncated disintegrin-and-metalloproteinase-19 (ADAM19) allele in all affected family members, but not in nonaffected persons. Since we had shown earlier that the extracellular domain of the parathyroid hormone receptor (PTHR1) is subject to an unidentified metalloproteinase cleavage, we tested the hypothesis that ADAM19 is a sheddase for PTHR1. WT ADAM19 cleaved PTHR1, while mutated ADAM-19 did not. We mapped the cleavage site that we verified with mass spectrometry between amino acids 64-65. ADAM-19 cleavage increased Gq and decreased Gs activation. Moreover, perturbed PTHR1 cleavage by ADAM19 increased ß-arrestin2 recruitment, while cAMP accumulation was not altered. We suggest that ADAM19 serves as a regulatory element for PTHR1 and could be responsible for BDE. This sheddase may affect other PTHrP or PTH-related functions.

Calcineurin inhibition, cardiovascular consequences, vascular resistance, and potential responses.

AIM: To place the consequences of calcineurin inhibition in a cardiovascular context. METHODS: Literature review coupled with personal encounters. RESULTS: Calcineurin is a calcium-binding and calmodulin-binding protein that is conserved across evolution from yeast to mammals. The enzyme functions as a calcium-dependent, calmodulin-stimulated protein phosphatase. Its role in regulating physiology has largely been elucidated by observing calcineurin inhibition. Calcineurin inhibition transformed organ transplantation from an experiment into a therapy and made much of general immunotherapy possible. The function of this phosphatase and how its inhibition leads to toxicity concern us to this date. Initial research from patients and animal models implicated a panoply of factors contributing to hypertension and vasculopathy. Subsequently, the role of calcineurin in regulating the effective fluid volume, sodium reabsorption, and potassium and hydrogen ion excretion was elucidated by investigating calcineurin inhibition. Understanding the regulatory effects of calcineurin on endothelial and vascular smooth muscle cell function has also made substantial progress. However, precisely how the increase in systemic vascular resistance arises requires further mechanistic research. CONCLUSION: Calcineurin inhibition continues to save lives; however, options to counteract the negative effects of calcineurin inhibition should be vigorously pursued.

Protocol for assessing myogenic tone and perfusion pressure in isolated mouse kidneys.

The isolated perfused kidney is a classic ex vivo preparation for studying renal physiology in general and vascular function. Here, we present a protocol for assessing myogenic tone in isolated mouse kidneys as well as vasodilatory and vasoconstrictive responses, expressed as perfusion pressure. We describe steps for pre-operative preparation, kidney and renal artery isolation, and connection of renal artery with glass cannula. We then detail how to measure pressure changes in perfused kidneys and the myogenic tone. For complete details on the use and execution of this protocol, please refer to Cui et al.1.

Sodium as an Important Regulator of Immunometabolism.

Salt sensitivity concerns blood pressure alterations after a change in salt intake (sodium chloride). The heart is a pump, and vessels are tubes; sodium can affect both. A high salt intake increases cardiac output, promotes vascular dysfunction and capillary rarefaction, and chronically leads to increased systemic vascular resistance. More recent findings suggest that sodium also acts as an important second messenger regulating energy metabolism and cellular functions. Besides endothelial cells and fibroblasts, sodium also affects innate and adaptive immunometabolism, immune cell function, and influences certain microbes and microbiota-derived metabolites. We propose the idea that the definition of salt sensitivity should be expanded beyond high blood pressure to cellular and molecular salt sensitivity.

Electrokinetic Torque Generation by DNA Nanorobotic Arms Studied via Single-Molecule Fluctuation Analysis.

DNA nanotechnology has enabled the creation of supramolecular machines, whose shape and function are inspired from traditional mechanical engineering as well as from biological examples. As DNA inherently is a highly charged biopolymer, the external application of electric fields provides a versatile, computer-programmable way to control the movement of DNA-based machines. However, the details of the electrohydrodynamic interactions underlying the electrical manipulation of these machines are complex, as the influence of their intrinsic charge, the surrounding cloud of counterions, and the effect of electrokinetic fluid flow have to be taken into account. In this work, we identify the relevant effects involved in this actuation mechanism by determining the electric response of an established DNA-based nanorobotic arm to varying design and operation parameters. Borrowing an approach from single-molecule biophysics, we determined the electrical torque exerted on the nanorobotic arms by analyzing their thermal fluctuations when oriented in an electric field. We analyze the influence of various experimental and design parameters on the "actuatability" of the nanostructures and optimize the generated torque according to these parameters. Our findings give insight into the physical processes involved in the actuation mechanism and provide general guidelines that aid in designing and efficiently operating electrically driven nanorobotic devices made from DNA.

Weight-loss Independent Clinical and Metabolic Biomarkers Associated with Type 2 Diabetes Remission Post-bariatric/metabolic Surgery.

PURPOSE: Remission of type 2 diabetes (T2D) can be achieved by many, but not all, people following bariatric/metabolic surgery. The mechanisms underlying T2D remission remain incompletely understood. This observational study aimed to identify novel weight-loss independent clinical, metabolic and genetic factors that associate with T2D remission using comprehensive phenotyping. MATERIALS AND METHODS: Ten patients without T2D remission (non-remitters) were matched to 10 patients with T2D remission (remitters) for age, sex, type of surgery, body weight, BMI, post-operative weight loss, duration from surgery and duration of T2D. Detailed body composition assessed using magnetic resonance imaging, gut hormones, serum metabolomics, insulin sensitivity, and genetic risk scores for T2D and anthropometric traits were assessed. RESULTS: Remitters had significantly greater ß-cell function and circulating acyl ghrelin levels, but lower visceral adipose tissue (VAT): subcutaneous adipose tissue (SAT) ratio than non-remitters. Branched-chain amino acids (BCAAs) and VLDL particle size were the most discriminant metabolites between groups. A significant positive correlation between, VAT area, VAT:SAT ratio and circulating levels of BCAAs was observed, whereas a significant negative correlation between BCAAs and ß-cell function was revealed. CONCLUSION: We highlight a potentially novel relationship between VAT and BCAAs, which may play a role in glucoregulatory control. Improvement in ß-cell function, and the role ghrelin plays in its recovery, is likely another key factor influencing T2D remission post-surgery. These findings suggest that adjunctive approaches that target VAT loss and restoration of BCAA metabolism might achieve higher rates of long-term T2D remission post-surgery.

Microrobots powered by concentration polarization electrophoresis (CPEP).

Second-order electrokinetic flow around colloidal particles caused by concentration polarization electro-osmosis (CPEO) can result in a phoretic motion of asymmetric particle dimers in a homogeneous AC electrical field, which we refer to as concentration polarization electro-phoresis (CPEP). To demonstrate this actuation mechanism, we created particle dimers from micron-sized silica spheres with sizes 1.0 µm and 2.1 µm by connecting them with DNA linker molecules. The dimers can be steered along arbitrarily chosen paths within a 2D plane by controlling the orientation of the AC electric field in a fluidic chamber with the joystick of a gamepad. Further utilizing induced dipole-dipole interactions, we demonstrate that particle dimers can be used to controllably pick up monomeric particles and release them at any desired position, and also to assemble several particles into groups. Systematic experiments exploring the dependence of the dimer migration speed on the electric field strength, frequency, and buffer composition align with the theoretical framework of CPEO and provide parameter ranges for the operation of our microrobots. Furthermore, experiments with a variety of asymmetric particles, such as fragmented ceramic, borosilicate glass, acrylic glass, agarose gel, and ground coffee particles, as well as yeast cells, demonstrate that CPEP is a generic phenomenon that can be expected for all charged dielectric particles.

Circular single-stranded DNA as switchable vector for gene expression in mammalian cells.

Synthetic gene networks in mammalian cells are currently limited to either protein-based transcription factors or RNA-based regulators. Here, we demonstrate a regulatory approach based on circular single-stranded DNA (Css DNA), which can be used as an efficient expression vector with switchable activity, enabling gene regulation in mammalian cells. The Css DNA is transformed into its double-stranded form via DNA replication and used as vectors encoding a variety of different proteins in a wide range of cell lines as well as in mice. The rich repository of DNA nanotechnology allows to use sort single-stranded DNA effectors to fold Css DNA into DNA nanostructures of different complexity, leading the gene expression to programmable inhibition and subsequently re-activation via toehold-mediated strand displacement. The regulatory strategy from Css DNA can thus expand the molecular toolbox for the realization of synthetic regulatory networks with potential applications in genetic diagnosis and gene therapy.

Sixty Years of Confronting Diabetes and Kidney Disease.

The good old days were not good, at least in terms of treating patients with type 2 diabetes. In the 1960s, the development of a radioimmunoassay for insulin permitted determination of the distinguishing features of type 1 and type 2 diabetes. The latter was treated with sulfonylureas and then phenformin, although the mechanisms of action at the time were unknown. The University Group Diabetes Program was a randomized controlled trial experienced by my medical generation, and the results were dramatic, both medically and legally. Next came the thiazolidinediones. All compounds were associated with weight gain and any end point benefits were uncertain. Nevertheless, basic science explained how glucose is sensed and even found a home for sulfonylureas in some patients. Next came the boom in renin-angiotensin-aldosterone system blockade, sacred ground for many, albeit the benefits were less than astounding. Other wonder drugs came and went. Over the decades, great strides were made in defining the pathology of diabetic renal disease, which is appropriate because the condition has become a primary cause of end-stage renal failure. Nonetheless, recent advances have turned around a depressing situation and are reasons for optimism. We now have compounds that actually could help patients with type 2 diabetes. One hundred years after insulin's introduction, it is high time.

Micro-compartmentalized strand displacement reactions with a random pool background.

Toehold-mediated strand displacement (TMSD) is a widely used process in dynamic DNA nanotechnology, which has been applied for the actuation of molecular devices, in biosensor applications, and for DNA-based molecular computation. Similar processes also occur in a biological context, when RNA strands invade secondary structures or duplexes of other RNA or DNA molecules. Complex reaction environments-inside cells or synthetic cells-potentially contain a large number of competing nucleic acid molecules that transiently bind to the components of the strand displacement reaction of interest and thus slow down its kinetics. Here, we investigate the kinetics of TMSD reactions compartmentalized into water-in-oil emulsion droplets-in both the presence and absence of a random sequence background-using a droplet microfluidic 'stopped flow' set-up. The set-up enables one to determine the kinetics within thousands of droplets and easily vary experimental parameters such as the stoichiometry of the TMSD components. While the average kinetics in the droplets coincides precisely with the bulk behaviour, we observe considerable variability among the droplets. This variability is partially explained by the encapsulation procedure itself, but appears to be more pronounced in reactions involving a random pool background.

Integration of DNA-RNA-triplex-based regulation of transcription into molecular logic gates.

In recent years, increasing numbers of noncoding RNA molecules were identified as possible components of endogenous DNA-RNA hybrid triplexes involved in gene regulation. Triplexes are potentially involved in complex molecular signaling networks that, if understood, would allow the engineering of biological computing components. Here, by making use of the enhancing and inhibiting effects of such triplexes, we demonstrate in vitro the construction of triplex-based molecular gates: 'exclusive OR' (XOR), 'exclusive NOT-OR' (XNOR), and a threshold gate, via transcription of a fluorogenic RNA aptamer. Precise modulation was displayed by the biomolecular-integrated systems over a wide interval of transcriptional outputs, ranging from drastic inhibition to significant enhancement. The present contribution represents a first example of molecular gates developed using DNA-RNA triplex nanostructures.

Effect of cardiopulmonary bypass on plasma and erythrocytes oxylipins.

BACKGROUND: Oxylipins, the oxidative metabolites of polyunsaturated fatty acids (PUFAs), serve as key mediators of oxidative stress, inflammatory responses, and vasoactive reactions in vivo. Our previous work has established that hemodialysis affects both long chain fatty acids (LCFAs) and oxylipins in plasma and erythrocytes to varying degrees, which may be responsible for excess cardiovascular complications in end-stage renal disease. In this study, we aimed to determine changes in blood oxylipins during cardiopulmonary bypass (CPB) in patients undergoing cardiac surgery to identify novel biomarkers and potential metabolites of CPB-related complications. We tested the hypothesis that CPB would differentially affect plasma oxylipins and erythrocytes oxylipins. METHODS: We conducted a prospective observational study of 12 patients undergoing elective cardiac surgery with expected CPB procedure. We collected venous and arterial blood samples before CPB, 15 and 45 min after the start of CPB, and 60 min after the end of CPB, respectively. Oxylipins profiling in plasma and erythrocytes was achieved using targeted HPLC-MS mass spectrometry. RESULTS: Our results revealed that most venous plasma diols and hydroxy- oxylipins decreased after CPB initiation, with a continuous decline until the termination of CPB. Nevertheless, no statistically significant alterations were detected in erythrocytes oxylipins at all time points. CONCLUSIONS: CPB decreases numerous diols and hydroxy oxylipins in blood plasma, whereas no changes in erythrocytes oxylipins are observed during this procedure in patients undergoing cardiac surgery. As lipid mediators primarily responsive to CPB, plasma diols and hydroxy oxylipins may serve as potential key biomarkers for CPB-related complications.

Surgical Myocardial Revascularization with a Composite T-graft from the Left Internal Mammary Artery-Comparison of the Great Saphenous Vein with the Radial Artery.

BACKGROUND: Composite T-grafts between left internal mammary artery (LIMA) and radial artery (RA) are a common concept in complete arterial myocardial revascularization. The aim of the present study was to investigate whether the use of the great saphenous vein (SV) instead of RA leads to comparably good results in terms of outcome in this context. METHODS: Patients who underwent myocardial revascularization with a T-graft using RA or a segment of SV to the right coronary artery or circumflex artery between the beginning of 2014 and the end of 2019 at the Department of Cardiovascular Surgery, University Hospital Schleswig-Holstein, Campus Kiel were included. To minimize surgical variation, only patients were observed by a single senior surgeon in the department. Exclusion criteria were previous cardiac surgery, preoperative extracorporeal circulatory support, off-pump surgery, additional aortocoronary bypasses, and cardiac combination procedures. RESULTS: A total of 115 patients were studied. In 55 patients, the T-graft was placed between the LIMA and SV, and in 60 patients, the T-graft was placed between the LIMA and RA. Patients in the SV group were older (70.6 ± 7.8 vs. 58.5 ± 10.0 years; p < 0.001), suffered more frequently from non-ST elevation myocardial infarction (12.7 vs. 1.7%; p = 0.027), arterial hypertension (83.6 vs. 61.7%; p = 0.009), and atrial fibrillation (18.2 vs. 1.7%; p = 0.003). They were less likely to be active smokers (16.4 vs. 38.3%; p = 0.009) and less likely to have a history of variceal surgery (0 vs. 15.0%; p = 0.003). Calcification of the ascending aorta was also found more frequently in the saphenous group (18.2 vs. 3.3%, p = 0.009). Operative times and number of distal anastomoses did not differ significantly between the two groups. Postoperative deliriums (16.7 vs. 5.0%; p = 0.043) were observed more frequently in venous patients. Wound healing disorders of the leg (11.1 vs. 0%; p = 0.011) did only occur in SV group and wound infections of the arm only in the RA group. Complete follow-up was achieved in 74.8% of cases. Median follow-up was 60.3 (39.6; 73.2) months. Serious adverse cardiac-cerebral events (19.0 vs. 22.7%; p = 0.675) and mortality (14.5 vs. 6.7%; p = 0.167) did not differ significantly between the groups at follow-up. Myocardial infarction (0 vs. 2.5%; p = 1.000) and stroke (0 vs. 7.5%; p = 0.245) were observed exclusively in RA group. Percutaneous coronary intervention was required in single patients of RA group (0 vs. 15.0%; p = 0.028). No patient from either group underwent repeat coronary artery bypass grafting (CABG). The patients of SV group had angiographically competent grafts and open anastomoses. Graft failure was noted in a single patient in RA group, in which case both grafts and native coronary vessels were stented. Kaplan-Meier analysis revealed no significant survival disadvantage for SV group compared with RA group. CONCLUSION: CABG with a composite T-graft between LIMA and a segment of SV may be comparable to bypass surgery with a composite T-graft between LIMA and RA. This might be true in terms of morbidity and mortality over an intermediate-term observation period. The results of our studies give rise to the hypothesis that the decision not to perform aortic bypass anastomosis may be more important than the choice of graft material.

Safety and Efficacy of Liraglutide, 3.0 mg, Once Daily vs Placebo in Patients With Poor Weight Loss Following Metabolic Surgery: The BARI-OPTIMISE Randomized Clinical Trial.

Importance: Metabolic surgery leads to weight loss and improved health, but these outcomes are highly variable. Poor weight loss is associated with lower circulating levels of glucagon-like peptide-1 (GLP-1). Objective: To assess the efficacy and safety of the GLP-1 receptor agonist, liraglutide, 3.0 mg, on percentage body weight reduction in patients with poor weight loss and suboptimal GLP-1 response after metabolic surgery. Design, Setting, and Participants: The Evaluation of Liraglutide 3.0 mg in Patients With Poor Weight Loss and a Suboptimal Glucagon-Like Peptide-1 Response (BARI-OPTIMISE) randomized placebo-controlled trial recruited adult patients at least 1 year after metabolic surgery who had experienced 20% or less body weight loss from the day of surgery and a suboptimal nutrient-stimulated GLP-1 response from 2 hospitals in London, United Kingdom, between October 2018 and November 2019. Key exclusion criteria were type 1 diabetes; severe concomitant psychiatric, gastrointestinal, cardiac, kidney or metabolic disease; and use of insulin, GLP-1 receptor analogues, and medication that can affect weight. The study period was 24 weeks followed by a 4-week follow-up period. Last participant follow-up was completed in June 2020. All participants and clinical study personnel were blinded to treatment allocation. Of 154 assessed for eligibility, 70 met trial criteria and were included in the study, and 57 completed follow-up. Interventions: Liraglutide, 3.0 mg, once daily or placebo as an adjunct to lifestyle intervention with a 500-kcal daily energy deficit for 24 weeks, on a 1:1 allocation by computer-generated randomization sequence, stratified by surgery type (Roux-en-Y gastric bypass [RYGB] or sleeve gastrectomy [SG]) and type 2 diabetes status. Main Outcome and Measures: The primary outcome was change in percentage body weight from baseline to the end of the 24-week study period based on an intention-to-treat analysis. Participant safety was assessed through monitoring of biochemical parameters, including kidney and liver function, physical examination, and assessment for adverse events. Results: A total of 70 participants (mean [SD] age, 47.6 [10.7] years; 52 [74%] female) with a poor weight loss response following RYGB or SG were randomized to receive 3.0-mg liraglutide (n = 35) or placebo (n = 35). All participants received at least 1 dose of the trial drug. Eight participants discontinued treatment (4 per group), and 2 in the 3.0-mg liraglutide group and 1 in the placebo group were lost to follow-up. Due to COVID-19 restrictions, 3 participants in the 3.0-mg liraglutide group and 7 in the placebo group were unable to attend their final in-person assessment. Estimated change in mean (SD) percentage body weight from baseline to week 24 was -8.82 (4.94) with liraglutide, 3.0 mg (n = 31), vs -0.54 (3.32) with placebo (n = 26). The mean difference in percentage body weight change for liraglutide, 3.0 mg, vs placebo was -8.03 (95% CI, -10.39 to -5.66; P < .001). Adverse events, predominantly gastrointestinal, were more frequent with liraglutide, 3.0 mg (28 events [80%]), than placebo (20 events [57%]). There were no serious adverse events and no treatment-related deaths. Conclusion and Relevance: These findings support the use of adjuvant liraglutide, 3.0 mg, for weight management in patients with poor weight loss and suboptimal GLP-1 response after metabolic surgery. Trial Registration: ClinicalTrials.gov Identifier: NCT03341429.