Oral glucagon-like peptide-1 receptor agonists and combinations of entero-pancreatic hormones as treatments for adults with type 2 diabetes: where are we now?

INTRODUCTION: Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) have changed the landscape of type 2 diabetes (T2D) management due to their cardio-renal benefits, their glucose-lowering efficacy and weight loss (WL) maintenance. However, the response to GLP-1 RA monotherapy is heterogeneous. Additionally, the majority of GLP-1 RAs are injectable treatments. Oral GLP-1 RAs and injectable combinations of GLP-1 with other entero-pancreatic hormones (glucose-dependent insulinotropic polypeptide (GIP), glucagon and amylin) are under development for T2D and obesity management. AREAS COVERED: Herein, we review the data on (i) oral GLP-1 RAs (oral semaglutide 25/50 mg and orforglipron) and (ii) dual/triple agonists (tirzepatide, cagrilintide 2.4 mg/semaglutide 2.4 mg, survodutide, mazdutide, retatrutide) that have recently completed phase 3 trials for T2D or are currently in phase 3 clinical trials. Tirzepatide is the first approved dual agonist (GLP-1/GIP) for T2D and obesity management. EXPERT OPINION: We are in a new era in T2D management where entero-pancreatic hormone-based treatments can result in ≥15% WL and euglycemia for many people with T2D. Multiple molecules with different mechanisms of action are under development for T2D, obesity and other metabolic complications. Data on their cardio-renal benefits, long-term efficacy and safety as well as their cost-effectiveness will better inform their position in treatment algorithms.

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.

What is the pipeline for future medications for obesity?

Obesity is a chronic disease associated with increased risk of obesity-related complications and mortality. Our better understanding of the weight regulation mechanisms and the role of gut-brain axis on appetite has led to the development of safe and effective entero-pancreatic hormone-based treatments for obesity such as glucagon-like peptide-1 (GLP-1) receptor agonists (RA). Semaglutide 2.4 mg once weekly, a subcutaneously administered GLP-1 RA approved for obesity treatment in 2021, results in 15-17% mean weight loss (WL) with evidence of cardioprotection. Oral GLP-1 RA are also under development and early data shows similar WL efficacy to semaglutide 2.4 mg. Looking to the next generation of obesity treatments, combinations of GLP-1 with other entero-pancreatic hormones with complementary actions and/or synergistic potential (such as glucose-dependent insulinotropic polypeptide (GIP), glucagon, and amylin) are under investigation to enhance the WL and cardiometabolic benefits of GLP-1 RA. Tirzepatide, a dual GLP-1/GIP receptor agonist has been approved for glycaemic control in type 2 diabetes as well as for obesity management leading in up to 22.5% WL in phase 3 obesity trials. Other combinations of entero-pancreatic hormones including cagrisema (GLP-1/amylin RA) and the triple agonist retatrutide (GLP-1/GIP/glucagon RA) have also progressed to phase 3 trials as obesity treatments and early data suggests that may lead to even greater WL than tirzepatide. Additionally, agents with different mechanisms of action to entero-pancreatic hormones (e.g. bimagrumab) may improve the body composition during WL and are in early phase clinical trials. We are in a new era for obesity pharmacotherapy where combinations of entero-pancreatic hormones approach the WL achieved with bariatric surgery. In this review, we present the efficacy and safety data for the pipeline of obesity pharmacotherapies with a focus on entero-pancreatic hormone-based treatments and we consider the clinical implications and challenges that the new era in obesity management may bring.

Future therapies for obesity.

Obesity is a chronic disease associated with increased morbidity and mortality. Bariatric surgery can lead to sustained long-term weight loss (WL) and improvement in multiple obesity-related complications, but it is not scalable at the population level. Over the past few years, gut hormone-based pharmacotherapies for obesity and type 2 diabetes mellitus (T2DM) have rapidly evolved, and combinations of glucagon-like peptide 1 (GLP1) with other gut hormones (glucose-dependent insulinotropic polypeptide (GIP), glucagon, and amylin) as dual or triple agonists are under investigation to enhance and complement the effects of GLP1 on WL and obesity-related complications. Tirzepatide, a dual agonist of GLP1 and GIP receptors, marks a new era in obesity pharmacotherapy in which a combination of gut hormones could approach the WL achieved with bariatric surgery. In this review, we discuss emerging obesity treatments with a focus on gut hormone combinations and the concept of a multimodal approach for obesity management.

Efficacy and Safety of Tirzepatide in Type 2 Diabetes and Obesity Management.

The combination of glucagon-like peptide-1 (GLP-1) with other gut hormones including the glucose-dependent insulinotropic polypeptide (GIP) has been explored to complement and enhance further the GLP-1 effects on glycemia and weight loss. Tirzepatide is the first dual GLP-1/GIP receptor co-agonist which has been approved for treatment of type 2 diabetes mellitus (T2DM) based on the findings from the SURPASS program. The SURPASS trials assessed the safety and efficacy of tirzepatide in people with T2DM, from monotherapy through to insulin add-on in global populations, with another two trials dedicated to Japanese population. Over periods of treatment up to 104 weeks, once weekly tirzepatide 5 to 15 mg reduced glycosylated hemoglobin (1.87% to 3.02%), body weight (5.4 to 12.9 kg) and improved multiple cardiometabolic risk factors (including reduction in liver fat, new-onset macroalbuminuria, blood pressure, and lipids) across the T2DM spectrum. Tirzepatide provided better efficacy than placebo and other commonly used glucose-lowering medications such as semaglutide 1 mg, dulaglutide, insulin degludec, and glargine. All tirzepatide doses were well tolerated with similar side-effect profile to the GLP-1 receptor analogues. In people without diabetes, tirzepatide 5 to 15 mg once weekly for the treatment for obesity (SURMOUNT-1) resulted in substantial reductions in body weight (16.5% to 22.4%) over 72 weeks. Overall, the SURPASS program and SURMOUNT-1 study suggest that tirzepatide is marking a new era in T2DM and/or obesity management through dual agonism of gut hormones.

New therapies for obesity.

Obesity is a chronic disease associated with serious complications and increased mortality. Weight loss through lifestyle changes results in modest weight loss long-term possibly due to compensatory biological adaptations (increased appetite and reduced energy expenditure) promoting weight gain. Bariatric surgery was until recently the only intervention that consistently resulted in ≥ 15% weight loss and maintenance. Our better understanding of the endocrine regulation of appetite has led to the development of new medications over the last decade for treatment of obesity with main target the reduction of appetite. The efficacy of semaglutide 2.4 mg/week - the latest glucagon like peptide-1 (GLP-1) receptor analogue - on weight loss for people with obesity suggests that we are entering a new era in obesity pharmacotherapy where ≥15% weight loss is feasible. Moreover, the weight loss achieved with the dual agonist tirzepatide (GLP-1/glucose-dependent insulinotropic polypeptide) for people with type 2 diabetes and most recently also obesity, indicate that combining the GLP-1 with other gut hormones may lead to additional weight loss compared to GLP-1 receptor analogues alone and in the future, multi-agonist molecules may offer the potential to bridge further the efficacy gap between bariatric surgery and the currently available pharmacotherapies. This article provides a review of the currently available interventions for weight loss and weight maintenance with a focus on pharmacological therapies for obesity approved over the last decade, as well as the emerging development of new obesity pharmacotherapies.

Do Gut Hormones Contribute to Weight Loss and Glycaemic Outcomes after Bariatric Surgery?

Bariatric surgery is an effective intervention for management of obesity through treating dysregulated appetite and achieving long-term weight loss maintenance. Moreover, significant changes in glucose homeostasis are observed after bariatric surgery including, in some cases, type 2 diabetes remission from the early postoperative period and postprandial hypoglycaemia. Levels of a number of gut hormones are dramatically increased from the early period after Roux-en-Y gastric bypass and sleeve gastrectomy-the two most commonly performed bariatric procedures-and they have been suggested as important mediators of the observed changes in eating behaviour and glucose homeostasis postoperatively. In this review, we summarise the current evidence from human studies on the alterations of gut hormones after bariatric surgery and their impact on clinical outcomes postoperatively. Studies which assess the role of gut hormones after bariatric surgery on food intake, hunger, satiety and glucose homeostasis through octreotide use (a non-specific inhibitor of gut hormone secretion) as well as with exendin 9-39 (a specific glucagon-like peptide-1 receptor antagonist) are reviewed. The potential use of gut hormones as biomarkers of successful outcomes of bariatric surgery is also evaluated.

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.

Cardiovascular, cancer and mortality events after bariatric surgery in people with and without pre-existing diabetes: A nationwide study.

BACKGROUND: Bariatric surgery reduces cardiovascular events and mortality risk in obese individuals. However, it is unclear whether diabetes modifies this effect. This study examined mortality, cardiovascular, and cancer risk following bariatric surgery in adults with and without pre-existing diabetes. METHODS: Using mortality-linked Hospital Episodes Statistics (2006-14) from England, the risk of death, myocardial infarction, stroke, unstable angina, heart failure, and cancer following bariatric surgery was examined; the risk of death in people undergoing surgery was also compared with mortality rates of the general population. RESULTS: Of the 35 887 people undergoing bariatric surgery, 9175 (25.6%) had pre-existing diabetes. During a mean follow-up of 5.3 years, 801 people died, of whom 293 (36.6%) had pre-existing diabetes. The risk of all-cause mortality was 26% higher in people with than without diabetes (adjusted hazard ratio [aHR] 1.26, 95% confidence interval [CI] 1.08-1.46), whereas the risk of cancer was 21% higher (aHR 1.21; 95% CI 1.14-1.77). The risk of cardiovascular events was higher for patients with than without diabetes (aHRs [95% CIs] 2.08 [1.42-3.05], 1.80 [1.29-2.52], 1.61 [1.18-2.19], and 1.42 [1.14-1.77] for myocardial infarction, unstable angina, stroke, and heart failure, respectively). Compared with the general population, the age-standardized mortality rate ratio was 1.70 (1.52-1.91) and 1.35 (1.23-1.48) in people with and without pre-existing diabetes, respectively. CONCLUSIONS: For patients with pre-existing diabetes, the risk of death, cardiovascular events, and cancer after bariatric surgery was higher than for those without diabetes, whose mortality risk after surgery remains 35% higher than that of the general population.

Esophageal motility after laparoscopic sleeve gastrectomy.

BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) modifies the upper gastrointestinal tract motility. Controversial data currently exist. The aim of the study was to evaluate esophageal motility before and after LSG. PATIENTS AND METHODS: Morbid obese patients scheduled for LSG underwent reflux symptoms evaluation and manometry preoperatively and postoperatively. The preoperative and postoperative results were compared and analyzed. RESULTS: Eighteen patients were enrolled. Heartburn and regurgitation improved in 38.9% and 11.1% of the patients, but deteriorated in 11.1% and 27.8% of the patients, respectively. Lower esophageal sphincter (LES) total length decreased postoperatively (p=0.002). Resting and residual pressures tended to decrease postoperatively (mean difference [95% confidence interval]: -4 [-8.3/0.2] mmHg, p=0.060; -1.4 [-3/0.1] mmHg, p=0.071, respectively). Amplitude pressure decreased from 95.7±37.3 to 69.8±26.3 mmHg at the upper border of LES (p=0.014), and tended to decrease at the distal esophagus from 128.5±30.1 to 112.1±35.4 mmHg (p=0.06) and mid-esophagus from 72.7±34.5 to 49.4±16.7 mmHg (p=0.006). Peristaltic normal swallow percentage increased from 47.2±36.8 to 82.8±28% (p=0.003). Postoperative regurgitation was strongly negatively correlated with LES total length (Spearman's r=-0.670). When groups were compared according to heartburn status, statistical significance was observed between the groups of improvement and deterioration regarding postoperative residual pressure and postoperative relaxation (p<0.002, p<0.002, respectively). With regard to regurgitation status, there was statistically significant difference between groups regarding preoperative amplitude pressure at the upper border of LES (p<0.056). CONCLUSION: Patients developed decreased LES length and weakened LES pressure after LSG. Esophageal body peristalsis was also affected in terms of decreased amplitude pressure, especially at the upper border of LES. Nevertheless, body peristalsis was normalized postoperatively. LSG might not deteriorate heartburn. Regurgitation might increase following LSG due to shortening of LES length, particularly in patients with range of preoperative amplitude pressure at the upper border of LES of 38.9-92.6 mmHg.

Comparison of glucose homeostasis parameters between patients with high and low risk of diabetes at 6 weeks and 6 months after sleeve gastrectomy.

BACKGROUND: The changes in glucose homeostasis after sleeve gastrectomy (SG) for patients with high (HRD) and low risk (LRD) of developing diabetes have not been investigated. OBJECTIVE: To compare the glucose homeostasis parameters between patients with HRD and LRD after SG. SETTING: University hospital in Greece. METHODS: Thirteen patients were categorized as HRD (9 females, mean body mass index 46.3±1.6 kg/m2) and 10 as LRD (8 females, mean body mass index 45.4±1.7 kg/m2) based on a preoperative 2-hour oral glucose tolerance test (OGTT). OGTT was repeated 6 weeks and 6 months postoperatively. OGTT-derived indices of insulin secretion, insulin sensitivity, and ß-cell function (oral disposition index [ODI]) were calculated. RESULTS: Preoperatively, in the HRD group, fasting and postload glucose levels were higher and the ODIs were lower compared with those in the LRD group. Six weeks postoperatively, glucose levels and ODIs were not different between the 2 groups. However, 6 months postoperatively, the HRD group had demonstrated higher postload glucose levels and lower ODI (0-30) and ODI (0-120) compared with the LRD group. Six weeks postoperatively, insulin levels, early insulin secretion, and insulin resistance indices were decreased compared with preoperative levels only in the HRD group. Six months postoperatively, ODIs and insulin sensitivity indices improved in both groups compared with baseline. CONCLUSION: Six months after SG, glucose levels and ODIs improved for both HRD and LRD patients; however, postprandial glucose levels and ODI (0-30) and ODI (0-120) in HRD patients did not return to LRD levels. Moreover, during the first 6 postoperative weeks, the changes in glucose homeostasis parameters compared with preoperative levels were different for HRD and LRD patients.

Efficacy and safety of glucagon-like peptide-1 receptor agonists in type 2 diabetes: A systematic review and mixed-treatment comparison analysis.

AIMS: To compare efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in people with type 2 diabetes. MATERIALS AND METHODS: We electronically searched, up to June 3, 2016, published randomized clinical trials lasting between 24 and 32 weeks that compared a GLP-1RA (albiglutide, dulaglutide, twice-daily exenatide and once-weekly exenatide, liraglutide, lixisenatide, semaglutide and taspoglutide) with placebo or another GLP-1RA. Data on cardiometabolic and safety outcomes were analysed using a mixed-treatment comparison meta-analysis. RESULTS: A total of 34 trials (14 464 participants) met the inclusion criteria; no published data for semaglutide were available. Compared with placebo, all GLP-1RAs reduced glycated haemoglobin (HbA1c) and fasting plasma glucose (FPG) levels (reductions ranged from -0.55% and -0.73 mmol/L, respectively, for lixisenatide to -1.21% and -1.97 mmol/L, respectively, for dulaglutide). There were no differences within short-acting (twice-daily exenatide and lixisenatide) or long-acting (albiglutide, dulaglutide, once-weekly exenatide, liraglutide and taspoglutide) groups. Compared with twice-daily exenatide, dulaglutide treatment was associated with the greatest HbA1c and FPG reduction (0.51% and 1.04 mmol/L, respectively), followed by liraglutide (0.45% and 0.93 mmol/L, respectively) and once-weekly exenatide (0.38% and 0.85 mmol/L, respectively); similar reductions were found when these 3 agents were compared with lixisenatide. Compared with placebo, all GLP-1RAs except albiglutide reduced weight and increased the risk of hypoglycaemia and gastrointestinal side effects, and all agents except dulaglutide and taspoglutide reduced systolic blood pressure. When all GLP-1RAs were compared with each other, no clinically meaningful differences were observed in weight loss, blood pressure reduction or hypoglycaemia risk. Albiglutide had the lowest risk of nausea and diarrhoea and once-weekly exenatide the lowest risk of vomiting. CONCLUSIONS: The RCTs in the present analysis show that all GLP-1RAs improve glycaemic control, reduce body weight and increase the risk of adverse gastrointestinal symptoms compared with placebo. Although there were no differences when short-acting agents were compared with each other or when long-acting agents were compared with each other, dulaglutide, liraglutide and once-weekly exenatide were superior to twice-daily exenatide and lixisenatide at lowering HbA1c and FPG levels. There were no differences in hypoglycaemia between these 3 agents, whilst once-weekly exenatide had the lowest risk of vomiting. These results, along with patient's preferences and individualized targets, should be considered when selecting a GLP-1RA.

Nonlinear association of BMI with all-cause and cardiovascular mortality in type 2 diabetes mellitus: a systematic review and meta-analysis of 414,587 participants in prospective studies.

AIMS/HYPOTHESIS: The relationship between BMI and mortality has been extensively investigated in the general population; however, it is less clear in people with type 2 diabetes. We aimed to assess the association of BMI with all-cause and cardiovascular mortality in individuals with type 2 diabetes mellitus. METHODS: We searched electronic databases up to 1 March 2016 for prospective studies reporting associations for three or more BMI groups with all-cause and cardiovascular mortality in individuals with type 2 diabetes mellitus. Study-specific associations between BMI and the most-adjusted RR were estimated using restricted cubic splines and a generalised least squares method before pooling study estimates with a multivariate random-effects meta-analysis. RESULTS: We included 21 studies including 24 cohorts, 414,587 participants, 61,889 all-cause and 4470 cardiovascular incident deaths; follow-up ranged from 2.7 to 15.9 years. There was a strong nonlinear relationship between BMI and all-cause mortality in both men and women, with the lowest estimated risk from 31-35 kg/m2 and 28-31 kg/m2 (p value for nonlinearity <0.001) respectively. The risk of mortality at higher BMI values increased significantly only in women, whilst lower values were associated with higher mortality in both sexes. Limited data for cardiovascular mortality were available, with a possible inverse linear association with BMI (higher risk for BMI <27 kg/m2). CONCLUSIONS/INTERPRETATION: In type 2 diabetes, BMI is nonlinearly associated with all-cause mortality with lowest risk in the overweight group in both men and women. Further research is needed to clarify the relationship with cardiovascular mortality and assess causality and sex differences.

Differences in Anthropometric and Metabolic Parameters Between Subjects with Hypoglycaemia and Subjects with Euglycaemia After an Oral Glucose Tolerance Test Six Months After Laparoscopic Sleeve Gastrectomy.

BACKGROUND: Hypoglycaemia after an oral glucose tolerance test (OGTT) can occur in up to 33 % of subjects after laparoscopic sleeve gastrectomy (LSG). The underlying pathophysiology is not well understood. We aimed to compare the anthropometric and metabolic characteristics of subjects with post-OGTT hypoglycaemia (HYPO) to subjects with post-OGTT euglycaemia (EU) 6 months after LSG. METHODS: Eighteen morbidly obese patients with normal glucose tolerance (NGT) were evaluated with an OGTT before and 6 months after LSG. Serum glucose and insulin were measured before and every 30 min after glucose ingestion up to 120'. The patients were categorized as HYPO or EU based on lowest glucose levels 90' to 120' post-OGTT 6 months after LSG (hypoglycaemia defined as glucose levels <60 mg/dl). OGTT derived indices of insulin secretion; insulin sensitivity and beta cell function were also evaluated. RESULTS: Eight patients (44.4 %) were categorized as HYPO. Preoperatively, subjects with HYPO had lower BMI (p = 0.02) compared to that with EU. Postoperatively, subjects with HYPO had lower BMI (p = 0.01), lower weight (p = 0.01), and higher percentage of total weight loss (%TWL) (p = 0.03) compared to that with EU. The beta cell function index was higher in the HYPO group postoperatively compared to EU (p = 0.02)-especially during the latter portion of the OGTT. No difference was detected in insulin secretion and insulin sensitivity indices between the two groups preoperatively or postoperatively. CONCLUSIONS: Subjects with NGT who developed HYPO 6 months after LSG are leaner, with higher TWL% and higher beta cell function at the latter portion of the OGTT compared to those with EU.

Impact of perioperative management of glycemia in severely obese diabetic patients undergoing gastric bypass surgery.

BACKGROUND: Roux-en-Y gastric bypass (RYGB) surgery is associated with rapid postsurgical improvement in glycemic control in patients with type 2 diabetes mellitus (T2 DM). However, there is little outcome-based evidence to guide the glycemic management of this patient group preoperatively. OBJECTIVES: We conducted 2 pilot studies randomizing patients to assess the impact of intensive glucose management pre- and post-RYGB on clinical outcomes after surgery. SETTING: University hospital. METHODS: In the GLUCOSURG-pre randomized controlled trial (RCT), 34 obese T2 DM patients with glycated hemoglobin (HbA1 c) ≥8.5% (69 mmol/mol) undergoing RYGB were randomly assigned to receive either glucose optimization or no optimization 3 months preoperatively. In the GLUCOSURG-post RCT, 35 obese T2 DM patients on insulin were randomly assigned to either intensive or conservative glucose management up to 2 weeks post- RYGB. HbA1c at 1 year post-RYGB was the primary outcome. RESULTS: In GLUCOSURG-pre, the HbA1 c at 1 year postsurgery was -3.0% (51.9 mmol/mol) in the optimized and -4.0% (45.4 mmol/mol) in the nonoptimized groups (P = .06). In GLUCOSURG-post, there were no significant differences in HbA1 c at 1 year postsurgery between the intensive and conservative groups [-2.4% (44.3 mmol/mol)] versus [-2.3% (44.3 mmol/mol), P = .73)]. CONCLUSIONS: Our pilot studies suggested that neither intensive management of glycemia in the 3 months pre- RYGB, nor the first 2 weeks post-RYGB resulted in better glycemic control one year after surgery. RYGB has substantial effects on glucose control, and additional intensive glucose-lowering interventions do not confer clinical benefits compared to conservative approaches.

Copper, selenium and zinc levels after bariatric surgery in patients recommended to take multivitamin-mineral supplementation.

BACKGROUND: Bariatric surgery is widely performed to improve obesity-related disorders, but can lead to nutrient deficiencies. In this study we examined serum trace element concentrations before and after bariatric surgery. METHODS: We obtained serum trace element concentrations by inductively coupled plasma-mass spectrometry (ICP-MS) method in 437 patients (82% women, median preoperative body-mass index 46.7 kg/m(2) [interquartile range 42-51]) undergoing either gastric banding (22.7%), sleeve gastrectomy (20.1%), or gastric bypass (57.3%) procedures. Trace element data were available for patients preoperatively (n = 44); and 3 (n = 208), 6 (n = 174), 12 (n = 122), 18 (n = 39), 24 (n = 44) and 36 months (n = 14) post-operatively. All patients were recommended to take a multivitamin-mineral supplement after surgery. RESULTS: Copper deficiency was found in 2% of patients before surgery; and after surgery deficiency rates ranged from 0 to 5% with no significant change in median concentrations during follow-up (p = 0.68). Selenium deficiency was reported in 2% of patients before surgery; and after surgery deficiency rates ranged from 11 to 15% with a near-significant change in median concentrations (p = 0.056). Zinc deficiency was reported in 7% before surgery; and after surgery deficiency rates ranged from 7 to 15% with no significant change in median concentrations (p = 0.39). CONCLUSIONS: In bariatric surgery patients recommended to take multivitamin-mineral supplements, serum copper, zinc and selenium concentrations were mostly stable during the first years after bariatric surgery. There was a possible tendency for selenium concentrations to decline during the early postoperative period.

Complicated gallstones after laparoscopic sleeve gastrectomy.

BACKGROUND: The natural history of gallstone formation after laparoscopic sleeve gastrectomy (LSG), the incidence of symptomatic gallstones, and timing of cholecystectomy are not well established. METHODS: A retrospective review of prospectively collected database of 150 patients that underwent LSG was reviewed. RESULTS: Preoperatively, gallbladder disease was identified in 32 of the patients (23.2%). Postoperatively, eight of 138 patients (5.8%) became symptomatic. Namely, three of 23 patients (13%) who had evident cholelithiasis preoperatively developed complicated cholelithiasis. From the cohort of patients without preoperative cholelithiasis, five of 106 patients (4.7%) experienced complicated gallstones after LSG. Total cumulative incidence of complicated gallstones was 4.7% (95% CI: 1.3-8.1%). The gallbladder disease-free survival rate was 92.2% at 2 years. No patient underwent cholecystectomy earlier than 9 months or later than 23 months indicating the post-LSG effect. CONCLUSION: A significant proportion of bariatric patients compared to the general population became symptomatic and soon developed complications after LSG, thus early cholecystectomy is warranted. Routine concomitant cholecystectomy could be considered because the proportion of patients who developed complications especially those with potentially significant morbidities is high and the time to develop complications is short and because of the real technical difficulties during subsequent cholecystectomy.

Changes in gut hormone profile and glucose homeostasis after laparoscopic sleeve gastrectomy.

BACKGROUND: Changes in glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) levels after bariatric surgery have been proposed as a mechanism for long-term maintenance of weight loss and improvement in glucose homeostasis postoperatively. The objective of the present study was to assess the changes in GLP-1, PYY, insulin, and glucose levels after laparoscopic sleeve gastrectomy (SG). METHODS: Ten morbidly obese patients without type 2 diabetes (3 male, 7 female; body mass index [BMI] 47.92±2.06 kg/m(2)) were evaluated preoperatively and at 6 weeks, 6 months, and 12 months after SG. Total GLP-1, total PYY, insulin, and glucose were measured in fasting state and every 30 minutes after ingestion of 75 g glucose for a total time of 120 minutes. RESULTS: BMI decreased markedly postoperatively (P<.001). Postprandial total GLP-1 and total PYY responses, measured by the area under the curve (AUC), were significantly increased by the sixth postoperative week compared with preoperative period (P<.001). Fasting insulin levels were markedly decreased postoperatively at all time points (all P<.01). Insulin AUC decreased progressively throughout the first postoperative year (P = .04), whereas glucose AUC decreased significantly at 6 and 12 months postoperatively (both P<.01). Insulin sensitivity measured by the Matsuda index increased progressively postoperatively. First phase insulin secretion remained unchanged. CONCLUSION: Postprandial total GLP-1 and total PYY levels increased significantly at 6 weeks post-SG and remained elevated for at least 1 year. These findings may indicate their involvement in better glucose homeostasis and weight loss maintenance after SG.

Dumping symptoms and incidence of hypoglycaemia after provocation test at 6 and 12 months after laparoscopic sleeve gastrectomy.

BACKGROUND: A previous study has demonstrated that symptoms suggestive of dumping syndrome appear after a provocation test early after laparoscopic sleeve gastrectomy (LSG) in 45 % of patients, and these are mainly related to early dumping. The aim of this study is to evaluate the evolution of dumping symptoms during the first postoperative year. METHODS: Twenty-five non-diabetic morbidly obese patients (6 male, 19 female) were evaluated with an oral glucose tolerance test (OGTT) preoperatively, at 6 weeks and at 6 months postoperatively. In addition, 12 of them repeated the OGTT at 12 months after LSG. Sigstad score was used to separate dumpers from non-dumpers and Arts' questionnaire to differentiate between early and late dumping. Insulin and glucose levels were also measured. RESULTS: Sigstad score remained significantly elevated at 6 and 12 months postoperatively compared to preoperative values. Symptoms suggestive of dumping syndrome were recorded in 40 % of patients at 6 months and in 33 % at 12 months postoperatively. Arts' questionnaire demonstrated that early dumping score remained higher compared to baseline at 6 and 12 months postoperatively. Late dumping scores increased gradually during the time and that difference was statistically significant at 12 months after LSG. Hypoglycaemia occurred at 33 % of patients both at 6 and 12 months postoperatively. CONCLUSIONS: Symptoms suggestive of dumping syndrome after provocation still exist at 6 and 12 months in a significant proportion of patients after LSG and include both early and late dumping. These findings are consistent with the high incidence of hypoglycaemia after OGTT at 6 and 12 months after LSG.