Glucagon-based therapy for people with diabetes and obesity: What is the sweet spot?

People with obesity and type 2 diabetes have a high prevalence of metabolic-associated steatotic liver disease, hyperlipidemia and cardiovascular disease. Glucagon increases hepatic glucose production; it also decreases hepatic fat accumulation, improves lipidemia and increases energy expenditure. Pharmaceutical strategies to antagonize the glucagon receptor improve glycemic outcomes in people with diabetes and obesity, but they increase hepatic steatosis and worsen dyslipidemia. Co-agonism of the glucagon and glucagon-like peptide-1 (GLP-1) receptors has emerged as a promising strategy to improve glycemia in people with diabetes and obesity. Addition of glucagon receptor agonism enhances weight loss, reduces liver fat and ameliorates dyslipidemia. Prior to clinical use, however, further studies are needed to investigate the safety and efficacy of glucagon and GLP-1 receptor co-agonists in people with diabetes and obesity and related conditions, with specific concerns regarding a higher prevalence of gastrointestinal side effects, loss of muscle mass and increases in heart rate. Furthermore, co-agonists with differing ratios of glucagon:GLP-1 receptor activity vary in their clinical effect; the optimum balance is yet to be identified.

Glucagon resistance and metabolic-associated steatotic liver disease: a review of the evidence.

Metabolic-associated steatotic liver disease (MASLD) is closely associated with obesity. MASLD affects over 1 billion adults globally but there are few treatment options available. Glucagon is a key metabolic regulator, and its actions include the reduction of liver fat through direct and indirect means. Chronic glucagon signalling deficiency is associated with hyperaminoacidaemia, hyperglucagonaemia and increased circulating levels of glucagon-like peptide 1 (GLP-1) and fibroblast growth factor 21 (FGF-21). Reduction in glucagon activity decreases hepatic amino acid and triglyceride catabolism; metabolic effects include improved glucose tolerance, increased plasma cholesterol and increased liver fat. Conversely, glucagon infusion in healthy volunteers leads to increased hepatic glucose output, decreased levels of plasma amino acids and increased urea production, decreased plasma cholesterol and increased energy expenditure. Patients with MASLD share many hormonal and metabolic characteristics with models of glucagon signalling deficiency, suggesting that they could be resistant to glucagon. Although there are few studies of the effects of glucagon infusion in patients with obesity and/or MASLD, there is some evidence that the expected effect of glucagon on amino acid catabolism may be attenuated. Taken together, this evidence supports the notion that glucagon resistance exists in patients with MASLD and may contribute to the pathogenesis of MASLD. Further studies are warranted to investigate the direct effects of glucagon on metabolism in patients with MASLD.

Lipid regulation of the glucagon receptor family.

The glucagon receptor family are typical class B1 G protein-coupled receptors (GPCRs) with important roles in metabolism, including the control of pancreas, brain, and liver function. As proteins with seven transmembrane domains, GPCRs are intimately in contact with lipid bilayers and therefore can be putatively regulated by interactions with their lipidic components, including cholesterol, sphingolipids, and other lipid species. Additionally, these receptors, as well as the agonists they bind to, can undergo lipid modifications, which can influence their binding capacity and/or elicit modified or biased signalling profiles. While the effect of lipids, and in particular cholesterol, has been widely studied for other GPCR classes, information about their role in regulating the glucagon receptor family is only beginning to emerge. Here we summarise our current knowledge on the effects of cholesterol modulation of glucagon receptor family signalling and trafficking profiles, as well as existing evidence for specific lipid-receptor binding and indirect effects of lipids via lipid modification of cognate agonists. Finally, we discuss the different methodologies that can be employed to study lipid-receptor interactions and summarise the importance of this area of investigation to increase our understanding of the biology of this family of metabolically relevant receptors.

Bariatric surgery provision in response to the COVID-19 pandemic: retrospective cohort study of a national registry.

BACKGROUND: When surgery resumed following the outbreak of the COVID-19 pandemic, guidelines recommended the prioritization of patients with greater obesity-related co-morbidities and/or higher body mass index. OBJECTIVE: The aim of this study was to record the effect of the pandemic on total number, patient demographics, and perioperative outcomes of elective bariatric surgery patients in the United Kingdom. SETTING AND METHODS: The United Kingdom National Bariatric Surgical Registry was used to identify patients who underwent elective bariatric surgery during the pandemic (1 yr from April 1, 2020). Characteristics of this group were compared with those of a pre-pandemic cohort. Primary outcomes were case volume, case mix, and providers. National Health Service cases were analyzed for baseline health status and perioperative outcomes. Fisher exact, χ2, and Student t tests were used as appropriate. RESULTS: The total number of cases decreased to one third of pre-pandemic volume (8615 to 2930). The decrease in operating volume varied, with 36 hospitals (45%) experiencing a 75%-100% reduction. Cases performed in the National Health Service fell from 74% to 53% (P < .0001). There was no change in baseline body mass index (45.2 ± 8.3 kg/m2 from 45.5 ± 8.3 kg/m2; P = .23) or prevalence of type 2 diabetes (26% from 26%; P = .99). Length of stay (median 2 d) and surgical complication rate (1.4% from 2.0%; relative risk = .71; 95% CI .45-1.12; P = .13) were unchanged. CONCLUSIONS: In the context of a dramatic reduction in elective bariatric surgery due to the COVID-19 pandemic, patients with more severe co-morbidities were not prioritized for surgery. These findings should inform preparation for future crises.

Sleeve gastrectomy causes weight-loss independent improvements in hepatic steatosis.

BACKGROUND AND AIMS: Sleeve gastrectomy (VSG) leads to improvement in hepatic steatosis, associated with weight loss. The aims of this study were to investigate whether VSG leads to weight-loss independent improvements in liver steatosis in mice with diet-induced obesity (DIO); and to metabolically and transcriptomically profile hepatic changes in mice undergoing VSG. METHODS: Mice with DIO were treated with VSG, sham surgery with subsequent food restriction to weight-match to the VSG group (Sham-WM), or sham surgery with return to unrestricted diet (Sham-Ad lib). Hepatic steatosis, glucose tolerance, insulin and glucagon resistance, and hepatic transcriptomics were investigated at the end of the study period and treatment groups were compared with mice undergoing sham surgery only (Sham-Ad lib). RESULTS: VSG led to much greater improvement in liver steatosis than Sham-WM (liver triglyceride mg/mg 2.5 ± 0.1, 2.1 ± 0.2, 1.6 ± 0.1 for Sham-AL, Sham-WM and VSG respectively; p = 0.003). Homeostatic model assessment of insulin resistance was improved following VSG only (51.2 ± 8.8, 36.3 ± 5.3, 22.3 ± 6.1 for Sham-AL, Sham-WM and VSG respectively; p = 0.03). The glucagon-alanine index, a measure of glucagon resistance, fell with VSG but was significantly increased in Sham-WM (9.8 ± 1.7, 25.8 ± 4.6 and 5.2 ± 1.2 in Sham Ad-lib, Sham-WM and VSG respectively; p = 0.0003). Genes downstream of glucagon receptor signalling which govern fatty acid synthesis (Acaca, Acacb, Me1, Acly, Fasn and Elovl6) were downregulated following VSG but upregulated in Sham-WM. CONCLUSIONS: Changes in glucagon sensitivity may contribute to weight-loss independent improvements in hepatic steatosis following VSG.

Hepatocyte cholesterol content modulates glucagon receptor signalling.

OBJECTIVE: To determine whether glucagon receptor (GCGR) actions are modulated by cellular cholesterol levels. METHODS: We determined the effects of experimental cholesterol depletion and loading on glucagon-mediated cAMP production, ligand internalisation and glucose production in human hepatoma cells, mouse and human hepatocytes. GCGR interactions with lipid bilayers were explored using coarse-grained molecular dynamic simulations. Glucagon responsiveness was measured in mice fed a high cholesterol diet with or without simvastatin to modulate hepatocyte cholesterol content. RESULTS: GCGR cAMP signalling was reduced by higher cholesterol levels across different cellular models. Ex vivo glucagon-induced glucose output from mouse hepatocytes was enhanced by simvastatin treatment. Mice fed a high cholesterol diet had increased hepatic cholesterol and a blunted hyperglycaemic response to glucagon, both of which were partially reversed by simvastatin. Simulations identified likely membrane-exposed cholesterol binding sites on the GCGR, including a site where cholesterol is a putative negative allosteric modulator. CONCLUSIONS: Our results indicate that cellular cholesterol content influences glucagon sensitivity and indicate a potential molecular basis for this phenomenon. This could be relevant to the pathogenesis of non-alcoholic fatty liver disease, which is associated with both hepatic cholesterol accumulation and glucagon resistance.

Outcomes of bariatric surgery in extreme obesity: results from the United Kingdom National Bariatric Surgery Registry for patients with a body mass index >70 kg/m2.

BACKGROUND: Bariatric and metabolic surgery (BMS) is an established safe, effective, and durable treatment for obesity and its complications. However, there is still a paucity of evidence on surgery outcomes in patients suffering from extreme obesity. OBJECTIVES: This study aimed to evaluate outcomes of BMS in weight loss and the resolution of co-morbidities in patients with a body mass index (BMI) ≥70kg/m2. SETTING: National Health Service and private hospitals in the United Kingdom. METHODS: This cohort study analyzed prospectively collected records from the UK National Bariatric Surgery Registry of patients with a BMI ≥70 kg/m2 undergoing Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), or adjustable gastric band (AGB) between January 2009 and June 2014. RESULTS: There were 230 patients (64% female) eligible for inclusion in the study: 22 underwent AGB; 102 underwent SG, and 106 underwent RYGB. Preoperative weight and BMI values were comparable (76 ± 7 kg/m2 for AGB; 75 ± 5 kg/m2 for SG; 74 ± 5 kg/m2 for RYGB). The median postoperative follow-up was 13 months for AGB (10-22 mo), 18 for SG (6-28 mo), and 15 for RYGB (6-24 mo). Patients undergoing RYGB and SG exhibited the greatest postoperative total body weight loss (35 ± 13% and 31 ± 15%, respectively; P = .14), which led to postoperative BMIs of 48 ± 10 kg/m2 and 51 ± 11 kg/m2, respectively (P = .14). All procedures conferred a reduction in the incidence of co-morbidities, including type 2 diabetes, and led to improved functional statuses. The overall complication rate was 7%, with 3 deaths (1%) within 30 days of surgery. CONCLUSION: This study found that primary BMS in patients with a BMI >70kg/m2 has an acceptable safety profile and is associated with good medium-term clinical outcomes. RYGB and SG are associated with better weight loss and great improvements in co-morbidities than AGB. Given the noninferiority of SG outcomes and SG's potential for further conversion to other BMS procedures if required, SG may be the best choice for primary BMS in patients with extreme obesity.

Receptor Activity-Modifying Protein 2 (RAMP2) alters glucagon receptor trafficking in hepatocytes with functional effects on receptor signalling.

OBJECTIVES: Receptor Activity-Modifying Protein 2 (RAMP2) is a chaperone protein which allosterically binds to and interacts with the glucagon receptor (GCGR). The aims of this study were to investigate the effects of RAMP2 on GCGR trafficking and signalling in the liver, where glucagon (GCG) is important for carbohydrate and lipid metabolism. METHODS: Subcellular localisation of GCGR in the presence and absence of RAMP2 was investigated using confocal microscopy, trafficking and radioligand binding assays in human embryonic kidney (HEK293T) and human hepatoma (Huh7) cells. Mouse embryonic fibroblasts (MEFs) lacking the Wiskott-Aldrich Syndrome protein and scar homologue (WASH) complex and the trafficking inhibitor monensin were used to investigate the effect of halted recycling of internalised proteins on GCGR subcellular localisation and signalling in the absence of RAMP2. NanoBiT complementation and cyclic AMP assays were used to study the functional effect of RAMP2 on the recruitment and activation of GCGR signalling mediators. Response to hepatic RAMP2 upregulation in lean and obese adult mice using a bespoke adeno-associated viral vector was also studied. RESULTS: GCGR is predominantly localised at the plasma membrane in the absence of RAMP2 and exhibits remarkably slow internalisation in response to agonist stimulation. Rapid intracellular accumulation of GCG-stimulated GCGR in cells lacking the WASH complex or in the presence of monensin indicates that activated GCGR undergoes continuous cycles of internalisation and recycling, despite apparent GCGR plasma membrane localisation up to 40 min post-stimulation. Co-expression of RAMP2 induces GCGR internalisation both basally and in response to agonist stimulation. The intracellular retention of GCGR in the presence of RAMP2 confers a bias away from ß-arrestin-2 recruitment coupled with increased activation of Gαs proteins at endosomes. This is associated with increased short-term efficacy for glucagon-stimulated cAMP production, although long-term signalling is dampened by increased receptor lysosomal targeting for degradation. Despite these signalling effects, only a minor disturbance of carbohydrate metabolism was observed in mice with upregulated hepatic RAMP2. CONCLUSIONS: By retaining GCGR intracellularly, RAMP2 alters the spatiotemporal pattern of GCGR signalling. Further exploration of the effects of RAMP2 on GCGR in vivo is warranted.

Obstructive sleep apnea remission following bariatric surgery: a national registry cohort study.

BACKGROUND: Obstructive sleep apnea (OSA) is strongly associated with metabolic syndrome. Bariatric surgery is an effective available treatment for OSA; however, limited research predicts which patients undergoing bariatric surgery will undergo OSA resolution. OBJECTIVES: To determine perioperative predictors for OSA resolution following bariatric surgery using a national database. SETTING: United Kingdom national bariatric surgery database. METHODS: The UK National Bariatric Surgery Registry (NBSR) was interrogated to identify all patients with OSA that underwent primary bariatric surgery between January 2009 and June 2017. Those with at least 1 follow-up recording postoperative OSA status were selected for further analysis. Demographic, pre- and postoperative outcomes were collected and analyzed. Poisson multivariate regression was conducted to identify predictors of OSA remission. RESULTS: A total of 4015 bariatric cases were eligible for inclusion: 2482 (61.8%) patients underwent laparoscopic Roux-en-Y gastric bypass (LRYGB), 1196 (29.8%) sleeve gastrectomy (LSG), and 337 (8.4%) adjustable gastric banding (LAGB). Overall, the mean excess weight loss (EWL) % for the whole group was 61.2 (SD ± 27.2). OSA resolution was recorded in 2377 (59.2%) patients. Following Poisson regression, LRYGB (risk ratio [RR], 1.49 confidence interval [CI] 1.25-1.78) and LSG (RR, 1.46 [CI 1.22-1.75] were associated with approximately 50% increased likelihood of OSA remission compared with LAGB. Greater weight loss following intervention was associated with greater likelihood of OSA remission, while both greater age and greater preoperative body mass index (BMI) were associated with reduced likelihood of OSA remission (P < .001). CONCLUSION: This study demonstrated that metabolic surgery results in OSA remission in the majority of patients with obesity. Younger age, lower BMI preprocedure, greater %EWL and the use of LSG or LRYGB positively predicted OSA remission.

Partial agonism improves the anti-hyperglycaemic efficacy of an oxyntomodulin-derived GLP-1R/GCGR co-agonist.

OBJECTIVE: Glucagon-like peptide-1 and glucagon receptor (GLP-1R/GCGR) co-agonism can maximise weight loss and improve glycaemic control in type 2 diabetes and obesity. In this study, we investigated the cellular and metabolic effects of modulating the balance between G protein and ß-arrestin-2 recruitment at GLP-1R and GCGR using oxyntomodulin (OXM)-derived co-agonists. This strategy has been previously shown to improve the duration of action of GLP-1R mono-agonists by reducing target desensitisation and downregulation. METHODS: Dipeptidyl dipeptidase-4 (DPP-4)-resistant OXM analogues were generated and assessed for a variety of cellular readouts. Molecular dynamic simulations were used to gain insights into the molecular interactions involved. In vivo studies were performed in mice to identify the effects on glucose homeostasis and weight loss. RESULTS: Ligand-specific reductions in ß-arrestin-2 recruitment were associated with slower GLP-1R internalisation and prolonged glucose-lowering action in vivo. The putative benefits of GCGR agonism were retained, with equivalent weight loss compared to the GLP-1R mono-agonist liraglutide despite a lesser degree of food intake suppression. The compounds tested showed only a minor degree of biased agonism between G protein and ß-arrestin-2 recruitment at both receptors and were best classified as partial agonists for the two pathways measured. CONCLUSIONS: Diminishing ß-arrestin-2 recruitment may be an effective way to increase the therapeutic efficacy of GLP-1R/GCGR co-agonists. These benefits can be achieved by partial rather than biased agonism.

Differential effects of bile acids on the postprandial secretion of gut hormones: a randomized crossover study.

Bile acids (BA) regulate postprandial metabolism directly and indirectly by affecting the secretion of gut hormones like glucagon-like peptide-1 (GLP-1). The postprandial effects of BA on the secretion of other metabolically active hormones are not well understood. The objective of this study was to investigate the effects of oral ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA) on postprandial secretion of GLP-1, oxyntomodulin (OXM), peptide YY (PYY), glucose-dependent insulinotropic peptide (GIP), glucagon, and ghrelin. Twelve healthy volunteers underwent a mixed meal test 60 min after ingestion of UDCA (12-16 mg/kg), CDCA (13-16 mg/kg), or no BA in a randomized crossover study. Glucose, insulin, GLP-1, OXM, PYY, GIP, glucagon, ghrelin, and fibroblast growth factor 19 were measured prior to BA administration at -60 and 0 min (just prior to mixed meal) and 15, 30, 60, 120, 180, and 240 min after the meal. UDCA and CDCA provoked differential gut hormone responses; UDCA did not have any significant effects, but CDCA provoked significant increases in GLP-1 and OXM and a profound reduction in GIP. CDCA increased fasting GLP-1 and OXM secretion in parallel with an increase in insulin. On the other hand, CDCA reduced postprandial secretion of GIP, with an associated reduction in postprandial insulin secretion. Exogenous CDCA can exert multiple salutary effects on the secretion of gut hormones; if these effects are confirmed in obesity and type 2 diabetes, CDCA may be a potential therapy for these conditions.NEW & NOTEWORTHY Oral CDCA and UDCA have different effects on gut and pancreatic hormone secretion. A single dose of CDCA increased fasting secretion of the hormones GLP-1 and OXM with an accompanying increase in insulin secretion. CDCA also reduced postprandial GIP secretion, which was associated with reduced insulin. In contrast, UDCA did not change gut hormone secretion fasting or postprandially. Oral CDCA could be beneficial to patients with obesity and diabetes.

Long-Term Quality of Life Outcomes After Laparoscopic Sleeve Gastrectomy and Roux-en-Y Gastric Bypass-a Comparative Study.

Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) have been shown to improve metabolic comorbidities as well as quality of life (QoL) in the obese population. The vast majority of previous studies have investigated the metabolic effects of bariatric surgery and there is a dearth of studies examining long-term QoL outcomes post bariatric surgery. The outcomes of 43 patients who underwent bariatric surgery were prospectively assessed, using BAROS questionnaires to quantify QoL and metabolic status pre-operatively, at 1 year and at 8 years. Total weight loss and comorbidity resolution were similar between RYGB and SG. The RYGB cohort experienced greater QoL improvement from baseline and had higher BAROS scores at 8 years. RYGB may provide more substantial and durable long-term benefits as compared to SG.

Genetic and biased agonist-mediated reductions in ß-arrestin recruitment prolong cAMP signaling at glucagon family receptors.

Receptors for the peptide hormones glucagon-like peptide-1 (GLP-1R), glucose-dependent insulinotropic polypeptide (GIPR), and glucagon (GCGR) are important regulators of insulin secretion and energy metabolism. GLP-1R agonists have been successfully deployed for the treatment of type 2 diabetes, but it has been suggested that their efficacy is limited by target receptor desensitization and downregulation due to recruitment of ß-arrestins. Indeed, recently described GLP-1R agonists with reduced ß-arrestin-2 recruitment have delivered promising results in preclinical and clinical studies. We therefore aimed to determine if the same phenomenon could apply to the closely related GIPR and GCGR. In HEK293 cells depleted of both ß-arrestin isoforms the duration of G protein-dependent cAMP/PKA signaling was increased in response to the endogenous ligand for each receptor. Moreover, in wildtype cells, "biased" GLP-1, GCG, and GIP analogs with selective reductions in ß-arrestin-2 recruitment led to reduced receptor endocytosis and increased insulin secretion over a prolonged stimulation period, although the latter effect was only seen at high agonist concentrations. Biased GCG analogs increased the duration of cAMP signaling, but this did not lead to increased glucose output from hepatocytes. Our study provides a rationale for the development of GLP-1R, GIPR, and GCGR agonists with reduced ß-arrestin recruitment, but further work is needed to maximally exploit this strategy for therapeutic purposes.

Bariatric surgery for patients with type 2 diabetes mellitus requiring insulin: Clinical outcome and cost-effectiveness analyses.

BACKGROUND: Although bariatric surgery is well established as an effective treatment for patients with obesity and type 2 diabetes mellitus (T2DM), there exists reluctance to increase its availability for patients with severe T2DM. The aims of this study were to examine the impact of bariatric surgery on T2DM resolution in patients with obesity and T2DM requiring insulin (T2DM-Ins) using data from a national database and to develop a health economic model to evaluate the cost-effectiveness of surgery in this cohort when compared to best medical treatment (BMT). METHODS AND FINDINGS: Clinical data from the National Bariatric Surgical Registry (NBSR), a comprehensive database of bariatric surgery in the United Kingdom, were extracted to analyse outcomes of patients with obesity and T2DM-Ins who underwent primary bariatric surgery between 2009 and 2017. Outcomes for this group were combined with data sourced from a comprehensive literature review in order to develop a state-transition microsimulation model to evaluate cost-effectiveness of bariatric surgery versus BMT for patients over a 5-year time horizon. The main outcome measure for the clinical study was insulin cessation at 1-year post-surgery: relative risks (RR) summarising predictive factors were determined, unadjusted, and after adjusting for variables including age, initial body mass index (BMI), duration of T2DM, and weight loss. Main outcome measures for the economic evaluation were total costs, total quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER) at willingness-to-pay threshold of GBP£20,000. A total of 2,484 patients were eligible for inclusion, of which 1,847 had 1-year follow-up data (mean age of 51 years, mean initial BMI 47.2 kg/m2, and 64% female). 67% of patients no longer required insulin at 1-year postoperatively: these rates persisted for 4 years. Roux-en-Y gastric bypass (RYGB) was associated with a higher rate of insulin cessation (71.7%) than sleeve gastrectomy (SG; 64.5%; RR 0.92, confidence interval (CI) 0.86-0.99) and adjustable gastric band (AGB; 33.6%; RR 0.45, CI 0.34-0.60; p < 0.001). When adjusted for percentage total weight loss and demographic variables, insulin cessation following surgery was comparable for RYGB and SG (RR 0.97, CI 0.90-1.04), with AGB having the lowest cessation rates (RR 0.55, CI 0.40-0.74; p < 0.001). Over 5 years, bariatric surgery was cost saving compared to BMT (total cost GBP£22,057 versus GBP£26,286 respectively, incremental difference GBP£4,229). This was due to lower treatment costs as well as reduced diabetes-related complications costs and increased health benefits. Limitations of this study include loss to follow-up of patients within the NBSR dataset and that the time horizon for the economic analysis is limited to 5 years. In addition, the study reflects current medical and surgical treatment regimens for this cohort of patients, which may change. CONCLUSIONS: In this study, we observed that in patients with obesity and T2DM-Ins, bariatric surgery was associated with high rates of postoperative cessation of insulin therapy, which is, in turn, a major driver of overall reductions in direct healthcare cost. Our findings suggest that a strategy utilising bariatric surgery for patients with obesity and T2DM-Ins is cost saving to the national healthcare provider (National Health Service (NHS)) over a 5-year time horizon.

Cost-effectiveness of superabsorbent wound dressing versus standard of care in patients with moderate-to-highly exuding leg ulcers.

OBJECTIVE: To determine the cost-effectiveness/utility of a superabsorbent wound dressing (Zetuvit Plus Silicone) versus the current standard of care (SoC) dressings, from the NHS perspective in England, in patients with moderate-to-high exudating leg ulcers. METHOD: A model-based economic evaluation was conducted to analyse the cost-effectiveness/utility of a new intervention. We used a microsimulation state-transition model with a time horizon of six months and a cycle length of one week. The model uses a combination of incidence base and risk prediction approach to inform transition probabilities. All clinical efficiency, health-related quality of life (HRQoL), cost and resource use inputs were informed by conducting a systematic review of UK specific literature. RESULTS: Treatment with the superabsorbent dressing leads to a total expected cost per patient for a six month period of £2887, associated with 15.933 expected quality adjusted life weeks and 10.9% healing rate. When treated with SoC, the total expected cost per patient for a six month period is £3109, 15.852 expected quality adjusted life weeks and 8% healing rate. Therefore, the superabsorbent dressing leads to an increase in quality-adjusted life weeks, an increase in healing rate by 2.9% and a cost-saving of £222 per single average patient over six months. Results of several scenario analyses, one-way deterministic sensitivity analysis, and probabilistic sensitivity analysis confirmed the robustness of base-case results. The probabilistic analysis confirmed that, in any combination of variable values, the superabsorbent dressing leads to cost saving results. CONCLUSION: According to the model prediction, the superabsorbent dressing leads to an increase in health benefits and a decrease in associated costs of treatment.

Candy cane revision after Roux-en-Y gastric bypass.

BACKGROUND: An excessively long-blind end of the alimentary limb following a Roux-en-Y gastric bypass (RYGB), known as a 'candy cane' (CC), may cause symptoms including abdominal pain, regurgitation and vomiting. Very few studies have examined the efficacy of surgical resection of the CC. OBJECTIVES: The aim of this study was to assess sensitivity of preoperative diagnostic tools for CC, as well as perioperative outcomes and symptom resolution after CC revision surgery. SETTING: High volume bariatric centre of excellence, United Kingdom. METHODS: Observational study of CC revisions from 2010 to 2017. RESULTS: Twenty-eight CC revision cases were identified (mean age 45 ± 9 years, female preponderance 9:1). Presenting symptoms were abdominal pain (86%), regurgitation/vomiting (43%), suboptimal weight loss (36%) and acid reflux (21%). Preoperative tests provided correct diagnosis in 63% of barium contrast swallows, 50% of upper gastrointestinal endoscopies and 29% computed tomographies. Patients presenting with pain had significantly higher CC size as compared with pain-free group (4.2 vs. 2 cm, p = 0.001). Perioperative complications occurred in 25% of cases. Complete or partial symptom resolution was documented in 73% of patients undergoing CC revision. Highest success rates were recorded in the regurgitation/vomiting group (67%). CONCLUSION: Surgical revision of CC is associated with good symptom resolution in the majority of patients, especially those presenting with regurgitation/vomiting. However, it carries certain risk of complications. CC diagnosis may frequently be missed; hence more than one diagnostic tool should be considered when investigating symptomatic patients after RYGB.

Adjunctive liraglutide treatment in patients with persistent or recurrent type 2 diabetes after metabolic surgery (GRAVITAS): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Many patients with type 2 diabetes do not achieve sustained diabetes remission after metabolic (bariatric) surgery for the treatment of obesity. Liraglutide, a glucagon-like peptide-1 analogue, improves glycaemic control and reduces bodyweight in patients with type 2 diabetes. Our aim was to assess the safety and efficacy of liraglutide 1·8 mg in patients with persistent or recurrent type 2 diabetes after metabolic surgery. METHODS: In the GRAVITAS randomised double-blind, placebo-controlled trial, we enrolled adults who had undergone Roux-en-Y gastric bypass or vertical sleeve gastrectomy and had persistent or recurrent type 2 diabetes with HbA1c levels higher than 48 mmol/mol (6·5%) at least 1 year after surgery from five hospitals in London, UK. Participants were randomly assigned (2:1) via a computer-generated sequence to either subcutaneous liraglutide 1·8 mg once daily or placebo, both given together with a reduced-calorie diet, aiming for a 500 kcal per day deficit from baseline energy intake, and increased physical activity. The primary outcome was the change in HbA1c from baseline to the end of the study period at 26 weeks, assessed in patients who completed the trial. Safety was assessed in the safety analysis population, consisting of all participants who received either liraglutide or placebo. This trial is registered with EudraCT, number 2014-003923-23, and the ISRCTN registry, number ISRCTN13643081. FINDINGS: Between Jan 29, 2016, and May 2, 2018, we assigned 80 patients to receive either liraglutide (n=53) or placebo (n=27). 71 (89%) participants completed the study and were included in the principal complete-cases analysis. In a multivariable linear regression analysis, with baseline HbA1c levels and surgery type as covariates, liraglutide treatment was associated with a difference of -13·3 mmol/mol (-1·22%, 95% CI -19·7 to -7·0; p=0·0001) in HbA1c change from baseline to 26 weeks, compared with placebo. Type of surgery had no significant effect on the outcome. 24 (45%) of 53 patients assigned to liraglutide and 11 (41%) of 27 assigned to placebo reported adverse effects: these were mainly gastrointestinal and in line with previous experience with liraglutide. There was one death during the study in a patient assigned to the placebo group, which was considered unrelated to study treatment. INTERPRETATION: These findings support the use of adjunctive liraglutide treatment in patients with persistent or recurrent type 2 diabetes after metabolic surgery. FUNDING: JP Moulton Foundation.

Bile acids and the metabolic syndrome.

Bile acids have important roles in the regulation of lipid, glucose and energy metabolism. Metabolic diseases linked to obesity, including type 2 diabetes mellitus and non-alcoholic fatty liver disease, are associated with dysregulation of bile acid homeostasis. Here, the basic chemistry and regulation of bile acids as well as their metabolic effects will be reviewed. Changes in circulating bile acids associated with obesity and related diseases will be reviewed. Finally, pharmaceutical manipulation of bile acid homeostasis as therapy for metabolic diseases will be outlined.