Food Intake and Eating Behavior After Bariatric Surgery.

Obesity is an escalating global chronic disease. Bariatric surgery is a very efficacious treatment for obesity and its comorbidities. Alterations to gastrointestinal anatomy during bariatric surgery result in neurological and physiological changes affecting hypothalamic signaling, gut hormones, bile acids, and gut microbiota, which coalesce to exert a profound influence on eating behavior. A thorough understanding of the mechanisms underlying eating behavior is essential in the management of patients after bariatric surgery. Studies investigating candidate mechanisms have expanded dramatically in the last decade. Herein we review the proposed mechanisms governing changes in eating behavior, food intake, and body weight after bariatric surgery. Additive or synergistic effects of both conditioned and unconditioned factors likely account for the complete picture of changes in eating behavior. Considered application of strategies designed to support the underlying principles governing changes in eating behavior holds promise as a means of optimizing responses to surgery and long-term outcomes.

Duodenal-Jejunal Bypass Liner for the management of Type 2 Diabetes Mellitus and Obesity: A Multicenter Randomized Controlled Trial.

OBJECTIVE: The aim of this study was to examine the clinical efficacy and safety of the duodenal-jejunal bypass liner (DJBL) while in situ for 12 months and for 12 months after explantation. SUMMARY BACKGROUND DATA: This is the largest randomized controlled trial (RCT) of the DJBL, a medical device used for the treatment of people with type 2 diabetes mellitus (T2DM) and obesity. Endoscopic interventions have been developed as potential alternatives to those not eligible or fearful of the risks of metabolic surgery. METHODS: In this multicenter open-label RCT, 170 adults with inadequately controlled T2DM and obesity were randomized to intensive medical care with or without the DJBL. Primary outcome was the percentage of participants achieving a glycated hemoglobin reduction of ≥20% at 12 months. Secondary outcomes included weight loss and cardiometabolic risk factors at 12 and 24 months. RESULTS: There were no significant differences in the percentage of patients achieving the primary outcome between both groups at 12 months [DJBL 54.6% (n = 30) vs control 55.2% (n = 32); odds ratio (OR) 0.93, 95% confidence interval (CI): 0.44-2.0; P = 0.85]. Twenty-four percent (n = 16) patients achieved ≥15% weight loss in the DJBL group compared to 4% (n = 2) in the controls at 12 months (OR 8.3, 95% CI: 1.8-39; P = .007). The DJBL group experienced superior reductions in systolic blood pressure, serum cholesterol, and alanine transaminase at 12 months. There were more adverse events in the DJBL group. CONCLUSIONS: The addition of the DJBL to intensive medical care was associated with superior weight loss, improvements in cardiometabolic risk factors, and fatty liver disease markers, but not glycemia, only while the device was in situ. The benefits of the devices need to be balanced against the higher rate of adverse events when making clinical decisions. TRIAL REGISTRATION: ISRCTN30845205. isrctn.org; Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership reference 12/10/04.

Fat free mass is positively associated with hunger and energy intake at extremes of obesity.

Fat mass (FM) has been shown to be negatively associated with energy intake (EI) in lean individuals but in overweight and Class I obese individuals this relationship is poorly understood. Fat free mass (FFM) is positively associated with EI in lean, overweight and Class I obese individuals. To date, the relationships between FFM, FM, hunger and EI have not been investigated in patients with a body mass index (BMI) > 35 kg/m2. The aim of the present study was to examine the associations between FFM, FM, BMI, hunger and EI in individuals with severe (BMI > 35 kg/m2) obesity. In total, 43 subjects (52% male) with a mean (±standard deviation) BMI of 44.5 ±â€¯6.2 kg/m2 were recruited for this cross-sectional analysis. Dual energy x-ray absorptiometry and an ad libitum food buffet were used to measure body composition and EI respectively, and hunger was measured using a visual analogue scale (0-100 mm). BMI (p = 0.02; p < 0.01) and FFM (p < 0.01; p = 0.02), but not FM (p = 0.18; p = 0.71), were positively associated with both EI and pre-buffet hunger, respectively, on multivariable regression using the general linear model. These findings suggest that in extremes of obesity FFM continues to promote hunger and EI, but the inhibitory effect of FM on EI that has been observed in lean populations was not present in this cohort suffering from severe obesity.

Long-term weight outcomes in patients treated with liraglutide 3.0 mg in real-world clinical practice.

Long-term weight outcomes reflect the success of obesity treatment. Weight regain during treatment for obesity is a biologically maladaptive response that can be considered a central feature of the disease. This phenomenon has been well documented in patients treated with lifestyle changes and bariatric surgery. In patients treated with liraglutide 3.0 mg this has been documented in randomized control trials, but real-world analysis is lacking. The aim of this retrospective observational study was to explore the long-term weight outcomes in patients treated with liraglutide 3.0 mg in a real-world clinical practice. The association between body composition changes and weight outcomes was also explored. The study included 25 patients treated with multi-modal care that included liraglutide 3.0 mg over a period of 78 weeks. Body composition was examined via dual x-ray absorptiometry at 16 and 32 weeks, with body weight captured up until 78 weeks for all patients. Weight loss (R2 = 0.39, p < .001), fat mass loss (R2 = 0.32, p = .003) and fat-free mass loss (R2 = 0.19, p = .03) were all associated with weight change from artificial nadir, which was, on average, 3.8 kg. For body composition, after adjustment, only fat mass loss was associated weight regain (R2 = 0.32, p = .01). In conclusion, in patients with clinical obesity treated with liraglutide 3.0 mg in a real-world clinical setting, fat mass loss was associated with weight regain. Whilst weight regain occurred on average, the magnitude was less than that observed in patients treated with lifestyle alone and weight loss remained clinically significant for most patients.

Obesity Treatments to Improve Type 1 Diabetes (OTID): a randomized controlled trial of the combination of glucagon-like peptide 1 analogues and sodium-glucose cotransporter 2 inhibitors-protocol for Obesity Treatments to Improve Type 1 Diabetes (the OTID trial).

BACKGROUND: The guidelines of the American Diabetes Association and European Association for the Study of Diabetes suggest that patients with obesity type 2 diabetics and chronic kidney disease need either glucagon-like peptide 1 receptor analogues or sodium-glucose cotransporter-2 inhibitors. If neither achieve metabolic control, then the recommendation is to combine both drugs. The evidence base for combining glucagon-like peptide 1 receptor analogues and sodium-glucose cotransporter-2 inhibitors is not well researched, and hence, the impact of the guidelines is limited. The aim of this randomized controlled trial is to test the impact of the combination of glucagon-like peptide 1 receptor analogues/sodium-glucose cotransporter-2 inhibitors on body weight and kidney damage, in patients with type 1 diabetes and chronic kidney disease. In addition, we will explore the associated changes in the metabolic pathways with each of the treatments used in this randomized controlled trial. METHODS: In this 6-month randomized control trial, 60 participants aged between 21 and 65 years, with a body mass index above 25 kg/m2, and type 1 diabetics with chronic kidney disease will be randomized to receive 1 of 5 possible treatments: (1) standard care (control), (2) glucagon-like peptide 1 receptor analogues alone, (3) sodium-glucose cotransporter-2 inhibitors alone, (4) combination of glucagon-like peptide 1 receptor analogues and sodium-glucose cotransporter-2 inhibitors and (5) combination of glucagonlike peptide 1 receptor analogues and sodium-glucose cotransporter-2 inhibitors with intensive lifestyle advice. The primary objective will be the percentage change in total body weight from baseline at 6 months. The secondary objectives are to compare the change in glycaemia; blood pressure; dyslipidaemia; albuminuria; proportion of participants reaching weight loss of ≥ 5%, ≥ 10% and ≥ 15%; and change in BMI (kg/m2) from baseline and change in waist circumference (cm). All the experiments will be conducted at the Dasman Diabetes Institute after approval from the local research and ethics committee. DISCUSSION: The present randomized controlled trial aims to investigate the impact of the combination of glucagon-like peptide 1 receptor analogues and sodium-glucose cotransporter-2 inhibitors on body weight and kidney damage in patients with type 1 diabetes mellitus and chronic kidney disease, as well as exploring the associated changes in the metabolic pathways with each of the treatments used. This study addresses the current gap in the evidence base regarding the combination of these two drugs, which is particularly relevant given the American Diabetes Association and European Association for the Study of Diabetes guidelines recommending their combined use for patients with obesity, type 2 diabetes, and chronic kidney disease who do not achieve metabolic control with either drug alone. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05390307 Trial registration date - 25th May 2022.

Effectiveness of integrating a pragmatic pathway for prescribing liraglutide 3.0 mg in weight management services (STRIVE study): a multicentre, open-label, parallel-group, randomized controlled trial.

Background: An effective prescribing pathway for liraglutide 3 mg, an approved obesity pharmacotherapy, may improve treatment access. This trial compared a targeted prescribing pathway for liraglutide 3 mg with multiple stopping rules in specialist weight management services (SWMS) to standard SWMS care. Methods: This phase four, two-year, multicentre, open-label, parallel-group, real-world randomized clinical trial (ClinicalTrials.gov: NCT03036800) enrolled adults with BMI ≥35 kg/m2 plus prediabetes, type 2 diabetes, hypertension or sleep apnoea from five SWMS in Ireland and UK. Participants were randomly allocated (2:1, stratified by centre and BMI) to SWMS care plus a targeted prescribing pathway for once daily subcutaneous liraglutide 3 mg (intervention) with stopping rules at 16 (≥5% weight loss, WL), 32 (≥10% WL) and 52 weeks (≥15% WL) or to SWMS care alone (control) through an online randomization service. The primary outcome was WL ≥15% at 52 weeks, assessed by complete cases analysis. All randomized participants were included in safety analysis. Findings: From November 28, 2017 to February 28, 2020, 434 participants were screened, and 392 randomized (260 intervention; 132 control), while 294 (201 intervention; 93 control) included in the 52 weeks complete case analysis. More intervention than control participants achieved WL ≥15% at 52 weeks [51/201 (25.4%) vs 6/93 (6.5%); odds ratio 5.18; 95% CI 2.09, 12.88; p < 0.0001]. More adverse events occurred in the intervention (238/260, 91.5%; two deaths) than control (89/132, 67.4%; no deaths) group. Interpretation: A targeted prescribing pathway for liraglutide 3 mg helps more people achieve ≥15% WL at 52 weeks than standard care alone. Funding: Novo Nordisk A/S.

Food preferences after bariatric surgery: a review update.

Obesity is a serious and global health problem. The multiple complications of obesity reduce quality of life and increase mortality. Bariatric surgery is one of the best treatment options for obesity management. Bariatric surgery helps people reduce their caloric intake by treating the disease of obesity effectively, in part by increasing signaling from the gut to the brain. The most frequent surgical options are Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG). There is controversy regarding changes in food preferences and selection after bariatric surgery. In this review, we aim to outline the changes in food intake and selection, clarify the behavior changes in food intake, and assess the potential mechanisms responsible for these changes in patients after bariatric surgery.

Stratification of obesity phenotypes to optimize future therapy (SOPHIA).

INTRODUCTION: Obesity is considered a poor lifestyle choice. 'Obesity' is not a sufficient definition for patients, any more than 'cancer' or 'arthritis' would be. A major obstacle is the lack of understanding of pathogenesis. The disease of obesity is considered homogenous, while response to treatment is thought of as heterogeneous. This can change if pathogenesis, risk profiles for complications, and treatment responses are viewed within the context of obesity consisting of several subsets of disease. AREAS COVERED: The European Union-funded Innovative Medicine Initiative project Stratification of Obesity Phenotypes to Optimize Future Obesity Therapy is part of a momentum shift. Operational variables are being used to develop tests and therapies which may allow the prediction of risk of obesities and the prediction of response to obesity treatments. However, changing stakeholder perspectives on obesity may require more than high-quality data and analysis. EXPERT OPINION: For patients to benefit, clinicians need to integrate evidence-based treatments and payers need to reimburse the management of the disease of obesity. This will generate commercial opportunities for industry. We need to involve stakeholders (patients, clinicians, regulators, payer, patient organisations) to create a shared value for mutual gain.

The Impact Once-Weekly Semaglutide 2.4 mg Will Have on Clinical Practice: A Focus on the STEP Trials.

Obesity is a complex and chronic disease that raises the risk of various complications. Substantial reduction in body weight improves these risk factors. Lifestyle changes, including physical activity, reduced caloric ingestion, and behavioral therapy, have been the principal pillars in the management of obesity. In recent years, pharmacologic interventions have improved remarkably. The Semaglutide Treatment Effect in People with Obesity (STEP) program is a collection of phase-III trials geared toward exploring the utility of once-weekly 2.4 mg semaglutide administered subcutaneously as a pharmacologic agent for patients with obesity. All the STEP studies included diet and exercise interventions but at different intensities. This review paper aims to explore the impact of the behavioral programs on the effect of semaglutide 2.4 mg on weight loss. The results of the STEP trials supported the efficacy of high-dose, once-weekly 2.4 mg semaglutide on body weight reduction among patients with obesity with/without diabetes mellitus. Semaglutide was associated with more gastrointestinal-related side effects compared to placebo but was generally safe and well tolerated. In all the STEP studies, despite the varying intestines of the behavioral programs, weight loss was very similar. For the first time, there may be a suggestion that these behavioral programs might not increase weight reduction beyond the effect of semaglutide. Nevertheless, the importance of nutritional support during substantial weight loss with pharmacotherapy needs to be re-evaluated.

Does Bypass of the Proximal Small Intestine Impact Food Intake, Preference, and Taste Function in Humans? An Experimental Medicine Study Using the Duodenal-Jejunal Bypass Liner.

The duodenal-jejunal bypass liner (Endobarrier) is an endoscopic treatment for obesity and type 2 diabetes mellitus (T2DM). It creates exclusion of the proximal small intestine similar to that after Roux-en-Y Gastric Bypass (RYGB) surgery. The objective of this study was to employ a reductionist approach to determine whether bypass of the proximal intestine is the component conferring the effects of RYGB on food intake and sweet taste preference using the Endobarrier as a research tool. A nested mechanistic study within a large randomised controlled trial compared the impact of lifestyle modification with vs. without Endobarrier insertion in patients with obesity and T2DM. Forty-seven participants were randomised and assessed at several timepoints using direct and indirect assessments of food intake, food preference and taste function. Patients within the Endobarrier group lost numerically more weight compared to the control group. Using food diaries, our results demonstrated similar reductions of food intake in both groups. There were no significant differences in food preference and sensory, appetitive reward, or consummatory reward domain of sweet taste function between groups or changes within groups. In conclusion, the superior weight loss seen in patients with obesity and T2DM who underwent the Endobarrier insertion was not due to a reduction in energy intake or change in food preferences.

Obesity and responsibility: Is it time to rethink agency?

Despite obesity declared a disease, there still exists considerable weight stigma in both popular culture and health care, which negatively impacts policy making regarding prevention and treatment. While viewed as a choice or a failure of willpower by many, evidence exists to challenge the argument that both weight gain and failure to achieve weight loss maintenance are the individuals' fault due to personal failure or lack of responsibility. In this article, we draw upon literature from obesity treatment, neuroscience, philosophy of mind, and weight stigma to challenge the commonly held beliefs that individuals are free to choose how much they can weigh, and achievement of long-term weight loss maintenance is completely subject to conscious choice. In reality, the regulation of hunger, satiety, energy balance, and body weight takes place in subcortical regions of the brain. Thus, hunger and satiety signals are generated in regions of the brain, which are not associated with conscious experience. This points towards biological determinism of weight and challenges ideas of willpower and resultant moralization regarding body weight regulation. In this article, we will thus argue that in the context of dysregulation of hunger and satiety contributing to the obesity epidemic, a wider discourse related to personal responsibility and the stigma of obesity is needed to enhance understanding, prevention, and treatment of this complex disease. Obesity is a chronic disease requiring personalized treatment. Lifestyle interventions alone may not be enough to achieve medically significant and sustained weight loss for many individuals with obesity. By understanding that obesity is not due to a lack of motivation or willpower, the availability and utilization of additional treatments or combination of treatments such as lifestyle, pharmacotherapy, and surgery are likely to improve the quality of life for many suffering with this disease.

Liraglutide Does Not Adversely Impact Fat-Free Mass Loss.

OBJECTIVES: This study aimed to examine fat-free mass (FFM) loss between successful responders to lifestyle intervention alone compared with lifestyle intervention plus liraglutide 3.0 mg. An additional objective was to examine the effects of varying resistance training frequencies (days per week) on FFM retention. METHODS: This prospective study examined patients with BMI ≥ 35 kg/m2 receiving treatment in a tertiary care obesity clinic. Body composition (dual-energy x-ray absorptiometry) was captured at baseline and after 16 weeks of treatment. Exercise-related data (aerobic minutes per week and resistance training frequency) were captured at week 16. A total of 78 individuals were examined in two groups, the first with lifestyle intervention alone (n = 19) and the second with lifestyle intervention plus liraglutide 3.0 mg (n = 59). Linear mixed-effects models were used to examine between-group differences. RESULTS: Compared with lifestyle intervention alone, participants on liraglutide lost more weight (-12.2 kg vs. -9.7 kg, P = 0.048) and FFM (-2.3 kg vs. -1.5 kg, P = 0.06). After controlling for weight loss, there was no difference in FFM loss between groups (0.14 kg/wk vs. -0.09 kg/wk, P = 0.12). Absolute weight loss (kilograms) was associated with FFM loss (kilograms) (ρ = 0.58, P < 0.0001). Exercise did not increase weight loss, and resistance training frequency (days per week) did not attenuate FFM loss. CONCLUSIONS: Liraglutide does not have effects on FFM beyond what can be expected from total weight loss. Resistance training did not attenuate FFM loss in the liraglutide or lifestyle-alone groups. To ameliorate FFM loss after liraglutide, a new strategy may be needed that may combine exercise with specific nutritional interventions.

The effect of a duodenal-jejunal bypass liner on lipid profile and blood concentrations of long chain polyunsaturated fatty acids.

BACKGROUND & AIMS: Duodenal-jejunal bypass liners (DJBLs) prevent absorption in the proximal small intestine, the site of fatty acid absorption. We sought to investigate the effects of a DJBL on blood concentrations of essential fatty acids (EFAs) and bioactive polyunsaturated fatty acids (PUFAs). METHODS: Sub-study of a multicentre, randomised, controlled trial with two treatment groups. Patients aged 18-65 years with type-2 diabetes mellitus and body mass index 30-50 kg/m2 were randomised to receive a DJBL for 12 months or best medical therapy, diet and exercise. Whole plasma PUFA concentrations were determined at baseline, 10 days, 6 and 11.5 months; data were available for n = 70 patients per group. RESULTS: Weight loss was significantly greater in the DJBL group compared to controls after 11.5 months: total body weight loss 11.3 ± 5.3% versus 6.0 ± 5.7% (mean difference [95% CI] = 5.27% [3.75, 6.80], p < 0.001). Absolute concentrations of both EFAs, linoleic acid and α-linolenic acid, and their bioactive derivatives, arachidonic acid, eicosapentaenoic acid, docosapentaenoic acid and docosahexaenoic acid, were significantly lower in the DJBL group than in the control group at 6 and 11.5 months follow-up. Total serum cholesterol, LDL-cholesterol and HDL-cholesterol were also significantly lower in the DJBL group. CONCLUSION: One year of DJBL therapy is associated with superior weight loss and greater reductions in total serum cholesterol and LDL-cholesterol, but also depletion of EFAs and their longer chain derivatives. DJBL therapy may need to be offset by maintaining an adequate dietary intake of PUFAs or by supplementation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02459561.

A Comparison of Total Food Intake at a Personalised Buffet in People with Obesity, before and 24 Months after Roux-en-Y-Gastric Bypass Surgery.

Long-term reductions in the quantity of food consumed, and a shift in intake away from energy dense foods have both been implicated in the potent bariatric effects of Roux-en-Y gastric bypass (RYGB) surgery. We hypothesised that relative to pre-operative assessment, a stereotypical shift to lower intake would be observed at a personalised ad libitum buffet meal 24 months after RYGB, driven in part by decreased selection of high energy density items. At pre-operative baseline, participants (n = 14) rated their preference for 72 individual food items, each of these mapping to one of six categories encompassing high and low-fat choices in combination with sugar, complex carbohydrate or and protein. An 18-item buffet meal was created for each participant based on expressed preferences. Overall energy intake was reduced on average by 60% at the 24-month buffet meal. Reductions in intake were seen across all six food categories. Decreases in the overall intake of all individual macronutrient groups were marked and were generally proportional to reductions in total caloric intake. Patterns of preference and intake, both at baseline and at follow-up appear more idiosyncratic than has been previously suggested by verbal reporting. The data emphasise the consistency with which reductions in ad libitum food intake occur as a sequel of RYGB, this being maintained in the setting of a self-selected ad libitum buffet meal. Exploratory analysis of the data also supports prior reports of a possible relative increase in the proportional intake of protein after RYGB.

Effectiveness and cost of integrating a pragmatic pathway for prescribing liraglutide 3.0 mg in obesity services (STRIVE study): study protocol of an open-label, real-world, randomised, controlled trial.

INTRODUCTION: In the UK and Ireland, severe and complex obesity is managed in specialist weight management services (SWMS), which provide multicomponent lifestyle interventions to support weight loss, and use of medication if available. Liraglutide 3 mg (LIRA 3 mg) is an effective weight-loss medication, but weight loss in individual patients is variable, and its efficacy has not been assessed in SWMS. This study aims to investigate whether a targeted prescribing pathway for LIRA 3 mg with multiple prespecified stopping rules could help people with severe obesity and established complications achieve ≥15% weight loss in order to determine whether this could be considered a clinically effective and cost-effective strategy for managing severe and complex obesity in SWMS. METHODS AND ANALYSIS: In this 2-year, multicentre, open-label, real-world randomised controlled trial, 384 adults with severe and complex obesity (defined as body mass index ≥35 kg/m2 plus either prediabetes, type 2 diabetes, hypertension or sleep apnoea) will be randomised via a 2:1 ratio to receive either standard SWMS care (n=128) or standard SWMS care plus a targeted prescribing pathway for LIRA 3 mg with prespecified stopping rules at 16, 32 and 52 weeks (n=256).The primary outcome is to compare the proportion of participants achieving a weight loss of ≥15% at 52 weeks with a targeted prescribing pathway versus standard care. Secondary outcomes include a comparison of (1) the weight loss maintenance at 104 weeks and (2) the budget impact and cost effectiveness between the two groups in a real-world setting. ETHICS AND DISSEMINATION: The Health Research Authority and the Medicines and Healthcare products Regulatory Authority in UK, the Health Products Regulatory Authority in Ireland, the North West Deanery Research Ethics Committee (UK) and the St Vincent's University Hospital European Research Ethics Committee (Ireland) have approved the study. The findings of the study will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov-Identifier: NCT03036800.European Clinical Trials Database-Identifier: EudraCT Number 2017-002998-20.

Effectiveness of different recruitment strategies in an RCT of a surgical device: experience from the Endobarrier trial.

Recruiting participants into clinical trials is notoriously difficult and poses the greatest challenge when planning any investigative study. Poor recruitment may not only have financial ramifications owing to increased time and resources being spent but could adversely influence the clinical impact of a study if it becomes underpowered. Herein, we present our own experience of recruiting into a nationally funded, multicentre, randomised controlled trial (RCT) of the Endobarrier versus standard medical therapy in obese patients with type 2diabetes. Despite these both being highly prevalent conditions, there were considerable barriers to the effectiveness of different recruitment strategies across each study site. Although recruitment from primary care proved extremely successful at one study site, this largely failed at another site prompting the implementation of multimodal recruitment strategies including a successful media campaign to ensure sufficient participants were enrolled and the study was adequately powered. From this experience, we propose where appropriate the early engagement and investment in media campaigns to enhance recruitment into clinical trials. Trial Registration: ISRCTN30845205.

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.

Effect of Macronutrient Type and Gastrointestinal Release Site on PYY Response in Normal Healthy Subjects.

BACKGROUND AND AIMS: Enteroendocrine L cells release satiety inducing hormones in response to stimulation by luminal macronutrients. We sought to profile the differential effect of macronutrient type and site of release on circulating concentrations of the L cell-derived enteroendocrine hormone peptide tyrosine tyrosine (amino acids 1 to 36) (PYY). MATERIALS AND METHODS: Eight healthy volunteers were recruited to a randomized, double-blinded, six-way crossover study. At each visit, the participants consumed a 500-kcal drink containing carbohydrate, protein, or fat in either gastric or small intestinal release formulations. Plasma PYY concentrations and hunger ratings were assessed for 3 hours after consumption of the test drink. The food intake was recorded thereafter at an ad libitum lunch. RESULTS: Microcapsular formulations targeting the distal small intestinal delivery of fat, but not carbohydrate or protein, markedly enhance PYY release relative to macronutrient delivery in gastric release formulations. Food intake at an ad libitum meal was lowest after consumption of the formulation releasing fat at the distal small intestine. CONCLUSION: Targeting of fat to the distal small intestine in delayed release microcapsules enhanced PYY release and was associated with reductions in food intake.

Current and emerging pharmacotherapy for prediabetes: are we moving forward?

INTRODUCTION: Prediabetes is a state wherein blood glucose levels are above normal but below the diagnostic threshold for diabetes. Seventy percent of patients with prediabetes develop type 2 diabetes in their lifetime. Despite this, prediabetes frequently goes undiagnosed. AREAS COVERED: This review focuses on the pharmacological treatment of prediabetes and the prevention of progression to diabetes. A literature search was carried out on PubMed and Embase to review randomized controlled trials examining treatment of prediabetes. Emerging pharmacological therapies with potential benefit are discussed. EXPERT OPINION: Lifestyle intervention is the cornerstone for preventing progression to diabetes, but metformin remains the first line pharmacological intervention. There appears to be minimal additive effect of combining metformin with lifestyle changes. It would be interesting to assess whether using combination pharmacological approaches plus or minus lifestyle interventions have any additive benefit. Despite the good level of evidence available, the penetrance of any interventions remains very low in part due to the prodromal categorization of the prediabetic state.

Integrated insights into the role of alpha-melanocyte stimulatory hormone in the control of food intake and glycaemia.

Identifying peptide hormones with multipotent actions on both weight and glycaemia can have a significant impact on therapeutic options in the treatment of obesity and diabetes. This has been exemplified by recent advances involving pharmacological exploitation of glucagon-like peptide 1 biology. Herein, we summarise evidence supporting the potential candidacy in this light of alpha-melanocyte stimulatory hormone, an endogenous peptide hormone and a breakdown product of the neuropeptide pro-opiomelanocortin. We reference its well described central actions in the control of food intake and moreover highlight new data pointing to an important role for this peptide hormone in the periphery, in relation to glycaemic control.