The effect of obesity pharmacotherapy on body composition, including muscle mass.

Obesity pharmacotherapy represents a promising approach to treating obesity and may provide benefits beyond weight loss alone. Maintaining or even increasing muscle mass during weight loss is important to overall health, metabolic function and weight loss maintenance. Drugs such as liraglutide, semaglutide, tirzepatide, and naltrexone/bupropion have shown significant weight loss effects, and emerging evidence suggests they may also have effects on body composition, particularly a positive influence on muscle mass. However, further research is needed to fully understand the mechanism of action of these drugs and their effects on muscle mass. Clinicians should consider these factors when developing an obesity treatment plan for an individual patient.

Circulating total and H-specific GDF15 levels are elevated in subjects with MASLD but not in hyperlipidemic but otherwise metabolically healthy subjects with obesity.

BACKGROUND: Growth differentiation factor 15 (GDF15) is a mitokine, the role of which, total or H-specific, in modulating energy metabolism and homeostasis in obesity-related diseases, such as metabolic dysfunction associated steatotic liver disease (MASLD), has not been fully elucidated in adult humans. We aimed to investigate the fasting and stimulated levels of GDF15, total and H-specific, glucose-dependent insulinotropic polypeptide (GIP) and C-peptide, in two physiology interventional studies: one focusing on obesity, and the other on MASLD. METHODS: Study 1 investigated individuals with normal weight or with obesity, undergoing a 3-h mixed meal test (MMT); and study 2, examined adults with MASLD and controls undergoing a 120-min oral glucose tolerance test (OGTT). Exploratory correlations of total and H-specific GDF15 with clinical, hormonal and metabolomic/lipidomic parameters were also performed. RESULTS: In study 1, 15 individuals were included per weight group. Fasting and postprandial total and H-specific GDF15 were similar between groups, whereas GIP was markedly higher in leaner individuals and was upregulated following a MMT. Baseline and postprandial C-peptide were markedly elevated in people with obesity compared with lean subjects. GIP was higher in leaner individuals and was upregulated after a MMT, while C-peptide and its overall AUC after a MMT was markedly elevated in people with obesity compared with lean subjects. In study 2, 27 individuals were evaluated. Fasting total GDF15 was similar, but postprandial total GDF15 levels were significantly higher in MASLD patients compared to controls. GIP and C-peptide remained unaffected. The postprandial course of GDF15 was clustered among those of triglycerides and molecules of the alanine cycle, was robustly elevated under MASLD, and constituted the most notable differentiating molecule between healthy and MASLD status. We also present robust positive correlations of the incremental area under the curve of total and H-specific GDF15 with a plethora of lipid subspecies, which remained significant after adjusting for confounders. CONCLUSION: Serum GDF15 levels do not differ in relation to weight status in hyperlipidemic but otherwise metabolically healthy individuals. In contrast, GDF15 levels are significantly increased in MASLD patients at baseline and they remain significantly higher compared to healthy participants during OGTT, pointing to a role for GDF15 as a mitokine with important roles in the pathophysiology and possibly therapeutics of MASLD. Trial registration ClinicalTrials.gov NCT03986684, NCT04430946.

Total and H-specific growth/differentiation factor 15 levels are unaffected by liraglutide or naltrexone/bupropion administration.

AIM: To investigate growth/differentiation factor 15 (GDF-15) levels in response to antiobesity medications, namely, liraglutide (Lira) and naltrexone/bupropion (N/B), in individuals with overweight or obesity. MATERIALS AND METHODS: This was a prospective, non-randomized clinical trial with a two-arm, parallel design. A total of 42 individuals with overweight or obesity without type 1 or type 2 diabetes mellitus were enrolled. The participants received either Lira 3 mg or N/B 32/360 mg, along with diet and exercise, according to comorbidities, cost and method of administration. Participants underwent clinical and laboratory measurements at baseline, as well as at the 3- and 6-month time points. Anthropometric measurements and body composition analysis via bioelectrical impendence analysis were performed. Total blood samples for GDF-15 and H-specific GDF-15 were collected in the fasting state and every 30 min for 3 h after the consumption of a standardized mixed meal. RESULTS: Overall, participants' weight was reduced by 9.29 ± 5.34 kg at Month 3 and 11.52 ± 7.52 kg at Month 6. Total and H-specific GDF-15 levels did not show significant changes during the mixed meal compared to values before the meal when all participants were examined at baseline, and at 3 and 6 month follow-ups. No statistical significance was found when participants were examined by subgroup (Lira vs. N/B). No significant differences between treatment groups in postprandial area under the curve (AUC) or incremental AUC values were found at baseline or in the follow-up months with regard to total and H-specific GDF-15 levels. CONCLUSION: Neither total nor H-specific GDF-15 levels are affected by Lira or N/B treatment in patients with overweight or obesity.

The economic burden of obesity in 4 south-eastern European countries associated with obesity-related co-morbidities.

OBJECTIVE: To provide an assessment of the cost burden of obesity across a spectrum of obesity-related comorbidities (ORCs) for four countries in South-Eastern Europe (SEE). METHODS: A micro-costing analysis from the public payer perspective was conducted to estimate direct healthcare costs associated with ten obesity-related comorbidities (ORCs) in Czech Republic, Greece, Hungary, and Romania. A survey was administered to obtain healthcare resource use and unit cost data. Cost estimates were validated by local steering committees which comprised at least one public sector clinician and a panel of independent industry experts. RESULTS: Chronic kidney disease and cardiovascular diseases were the costliest ORCs across all 4 countries, where annual cost burden per ORC exceeded 1,500 USD per patient per year. In general, costs were driven by the tertiary care resources allocated to address treatment-related adverse events, disease complications, and associated inpatient procedures. CONCLUSIONS: Our findings confirm that the high prevalence of obesity and its comorbidities result in substantial financial burden to all 4 SEE public payers. By quantifying the burden of obesity from a public healthcare perspective, our study aims to support policy efforts that promote health education and promotion in combating obesity in the region.

Circulating levels of proglucagon-derived peptides are differentially regulated by the glucagon-like peptide-1 agonist liraglutide and the centrally acting naltrexone/bupropion and can predict future weight loss and metabolic improvements: A 6-month long interventional study.

AIM: To investigate the changes of circulating levels of all proglucagon-derived peptides (PGDPs) in individuals with overweight or obesity receiving liraglutide (3 mg) or naltrexone/bupropion (32/360 mg), and to explore the association between induced changes in postprandial PGDP levels and body composition, as well as metabolic variables, after 3 and 6 months on treatment. MATERIALS AND METHODS: Seventeen patients with obesity or with overweight and co-morbidities, but without diabetes, were assigned to receive once-daily oral naltrexone/bupropion 32/360 mg (n = 8) or once-daily subcutaneous liraglutide 3 mg (n = 9). Participants were assessed before treatment initiation and after 3 and 6 months on treatment. At the baseline and 3-month visits, participants underwent a 3-hour mixed meal tolerance test to measure fasting and postprandial levels of PGDPs, C-peptide, hunger and satiety. Clinical and biochemical indices of metabolic function, magnetic resonance-assessed liver steatosis and ultrasound-assessed liver stiffness were measured at each visit. RESULTS: Both medications improved body weight and composition, carbohydrate and lipid metabolism, and liver fat and function. Naltrexone/bupropion produced a weight-independent increase in the levels of proglucagon (P < .001) and decreases in glucagon-like peptide-2 (GLP-2), glucagon and the major proglucagon fragment (P ≤ .01), whereas liraglutide markedly upregulated total glucagon-like peptide-1 (GLP-1) levels in a weight-independent manner (P = .04), and similarly downregulated the major proglucagon fragment, GLP-2 and glucagon (P < .01). PGDP levels at the 3-month visit were positively and independently correlated with improvements in fat mass, glycaemia, lipaemia and liver function, and negatively with reductions in fat-free mass, at both the 3- and 6-month visits. CONCLUSIONS: PGDP levels in response to liraglutide and naltrexone/bupropion are associated with improvements in metabolism. Our study provides support for the administration of the downregulated members of the PGDP family as replacement therapy (e.g. glucagon), in addition to the medications currently in use that induced their downregulation (e.g. GLP-1), and future studies should explore whether the addition of other PGDPs (e.g. GLP-2) could offer additional benefits.

Pleurotus eryngii improves postprandial glycaemia, hunger and fullness perception, and enhances ghrelin suppression in people with metabolically unhealthy obesity.

The aim of this study was to examine potential postprandial benefits of Pleurotus eryngii in nineteen volunteers with metabolically unhealthy obesity. An acute, randomized, crossover-designed trial comparing a meal with Pleurotus eryngii and a control meal was performed. The two meals matched in macronutrient and caloric content. Participants consumed both meals in random order after an overnight fast. Blood samples were drawn before and 30, 60, 90, 120, 150 and 180 min after meal consumption (in total 266 samples) to determine glucose, insulin, ghrelin, peptide YY, glucagon-like peptide-1 and glicentin. Visual analog scales measuring the subjective perception of hunger and fullness were completed at the same time points. The test meal resulted in lower glucose incremental area under the curve (iAUC). Additionally, the iAUC of the ghrelin response over time was substantially lower after the test meal (p = 0.033). Lower desire to eat and higher fullness was reflected by significantly lower hunger iAUC (p = 0.046) and higher fullness iAUC (p = 0.042) after the test meal. No differences in insulin, PYY, GLP-1 and glicentin were observed. Pleurotus eryngii can ameliorate postprandial glycaemia, appetite and regulate ghrelin levels at the postprandial state. This effect is attributed to the bioactive polysaccharides that inhibit the activity of enzymes catalysing carbohydrate hydrolysis, cause a delayed gastric emptying and glucose absorption.

The beneficial short-term effects of a high-protein/low-carbohydrate diet on glycaemic control assessed by continuous glucose monitoring in patients with type 1 diabetes.

AIM: To compare the effects of three different but isocaloric dietary patterns, high-protein/low-carbohydrate (HPD) with 20% of calories as carbohydrates, Mediterranean/low glycaemic index (MED) with 40% carbohydrates, and a reference diet (REF) with 50% carbohydrates, in patients with type 1 diabetes (T1D). MATERIALS AND METHODS: In a randomized crossover study, 15 patients with T1D were assigned to the three dietary patterns for three separate weeks, with 7-day washout periods in between. Continuous glucose monitoring was applied during the intervention periods. The primary outcome was glycaemic control, as measured by the percentage of time patients spent within the euglycaemic range (TIR70-140 mg/dl ). Other key glycaemic metrics were also investigated as secondary outcomes. RESULTS: TIR70-140 was not statistically different between HPD, MED and REF (p = .105). Pairwise analysis revealed a statistically significant difference between HPD and REF at the .05 level, which was not retained after applying Bonferroni correction (54.87% ± 14.11% vs. 48.33% ± 13.72%; p = .018). During the HPD period, 11 out of 15 participants spent more time within TIR70-140 compared with either the REF or MED. The HPD performed significantly better than the REF in terms of TIR70-180 (74.33% ± 12.85% vs. 67.53% ± 12.73%; p = .012), glycaemic variability (coefficient of variation: 36.18% ± 9.30% vs. 41.48% ± 8.69%; p = .016) and time spent in the hypoglycaemic range (TBR70 mg/dl ; median: 12, IQR: 16 vs. median: 14, IQR: 20; p = .007), whereas no statistically significant differences were observed between MED and HPD or REF. CONCLUSIONS: Compared with REF and MED, an HPD plan may have a positive impact on glycaemic control in patients with T1D. During the HPD, patients spent a shorter time in hypoglycaemia and exhibited lower glycaemic variability.

Motives for weight loss and weight loss maintenance: results from the MedWeight study.

BACKGROUND: The relationship of weight loss motives with long-term outcomes is equivocal. We aimed to examine differences in weight loss motives of maintainers and regainers, as well as explore associations between motives and successful maintenance. METHODS: The study sample includes 607 adults, with a history of overweight/obesity and self-reported ≥10% voluntary weight loss, 12 months before study entry. Participants were classified as maintainers (weighing ≤90% maximum weight) or regainers. Volunteers identified possible motives for weight loss and maintenance (maintainers only), from a specific list. RESULTS: Both maintainers and regainers were predominantly motivated by physical appearance (38.6% versus 39.9%, P > 0.05) and self-esteem (26.8% versus 32.0%, P > 0.05) for weight loss. Compared to regainers, more maintainers reported weight reduction driven by social purposes (16.6% versus 9.4%, P = 0.022) and less were prompted by friends/family to lose weight (21.1% versus 31.7%, P = 0.005). In maintainers, shifts in motives from weight loss to maintenance phase were found, including an increased prevalence of health motives (6.4% versus 9.6%, P < 0.001) and decreased physical appearance motives (38.6% versus 30.3%, P < 0.001). Reporting physical appearance as main maintenance motive was inversely associated with maintained weight loss, after adjusting for age, sex and years of education (B = -3.49 [1.07], P = 0.001); maintainers reporting physical appearance as the main motive maintained 3.5% less weight loss compared to those who did not (P = 0.001). CONCLUSIONS: The present study has highlighted motivational influences associated with weight loss outcomes. Future studies should explore the ability of people with overweight/obesity to act upon motives for long-term weight management, as well as the impact of shifting through motives on the magnitude of maintenance.

Obesity and COVID-19: immune and metabolic derangement as a possible link to adverse clinical outcomes.

Recent reports have shown a strong association between obesity and the severity of COVID-19 infection, even in the absence of other comorbidities. After infecting the host cells, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may cause a hyperinflammatory reaction through the excessive release of cytokines, a condition known as "cytokine storm," while inducing lymphopenia and a disrupted immune response. Obesity is associated with chronic low-grade inflammation and immune dysregulation, but the exact mechanisms through which it exacerbates COVID-19 infection are not fully clarified. The production of increased amounts of cytokines such as TNFα, IL-1, IL-6, and monocyte chemoattractant protein (MCP-1) lead to oxidative stress and defective function of innate and adaptive immunity, whereas the activation of NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome seems to play a crucial role in the pathogenesis of the infection. Endothelial dysfunction and arterial stiffness could favor the recently discovered infection of the endothelium by SARS-CoV-2, whereas alterations in cardiac structure and function and the prothrombotic microenvironment in obesity could provide a link for the increased cardiovascular events in these patients. The successful use of anti-inflammatory agents such as IL-1 and IL-6 blockers in similar hyperinflammatory settings, like that of rheumatoid arthritis, has triggered the discussion of whether such agents could be administrated in selected patients with COVID-19 disease.

Metabolic regulation of activins in healthy individuals and in obese patients undergoing bariatric surgery.

OBJECTIVE: Follistatin binds and inactivates activins, which are potent inhibitors of muscle growth and metabolism and are currently being developed for the treatment of obesity and type 2 diabetes (T2D). We have recently reported that follistatin is regulated by glucose (and not lipids) and can prospectively predict the metabolic improvements observed after bariatric surgery. We utilized novel assays herein to investigate whether activins are regulated by glucose or lipids, whether their circulating levels change after bariatric surgery and whether these changes are predictors of metabolic outcomes up to 12 months later. DESIGN AND METHODS: Activin A, B, AB and their ratios to follistatin were measured in (a) healthy humans (n = 32) undergoing oral or intravenous lipid or glucose intake over 6 h, (b) morbidly obese individuals with or without type 2 diabetes undergoing three different types of bariatric surgery (gastric banding, Roux-en-Y bypass or sleeve gastrectomy) in two clinical studies (n = 14 for the first and n = 27 for the second study). RESULTS: Glucose intake downregulates circulating activin A, B and AB, indicating the presence of a feedback loop. Activin A decreases (~30%), activin AB increases (~25%) and activin B does not change after bariatric surgery. The changes in activin AB and its ratio to follistatin 3 months after bariatric surgery can predict the BMI reduction and the improvement in insulin and HOMA-IR observed 6 months postoperatively. CONCLUSION: Activins are implicated in glucose regulation in humans as part of a feedback loop with glucose or insulin and predict metabolic outcomes prospectively after bariatric surgery.

Follistatins in glucose regulation in healthy and obese individuals.

AIMS: It has been suggested recently that follistatin (FST) and its homologous protein, follistatin-like 3 (FSTL3), may be a therapeutic target in the treatment of type 2 diabetes because of their glucose-regulatory effects in rodents. MATERIALS AND METHODS: We investigated this hypothesis in humans by studying the physiology of a possible glycaemia-follistatin feedback loop, that is, whether glucose, but not lipid intake (oral or intravenous), can regulate circulating FST and FSTL3 in healthy humans (n = 32), whether the levels of follistatins change in response to various types of bariatric operation in morbidly obese individuals, with or without type 2 diabetes (n = 41), and whether such changes are associated prospectively with improvement of glucose homeostasis/insulin sensitivity. RESULTS: In healthy individuals, circulating FST decreases after intravenous or oral glucose intake compared to controls, indicating the presence of a negative feedback mechanism. In morbid obesity, insulin resistance, glycaemia, circulating FST and FSTL3 are all reduced (by 22%-33%) after Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy. Importantly, the changes in circulating FST 3 months after bariatric surgery are associated prospectively with the changes in glucose, insulin, HOMA-IR and HbA1c observed 6 months postoperatively in individuals with and without type 2 diabetes. CONCLUSIONS: Our findings provide evidence of an important role of FST in glucose homeostasis in healthy individuals as well as in severely obese individuals with insulin resistance and type 2 diabetes. Our data extend recent results from animal studies to humans and support the need for further evaluation of FST inactivation strategies for targeting hyperglycaemia and insulin resistance.

The role of bariatric surgery to treat diabetes: current challenges and perspectives.

Bariatric surgery is emerging as a powerful weapon against severe obesity and type 2 diabetes mellitus (T2DM). Given its role in metabolic regulation, the gastrointestinal tract constitutes a meaningful target to treat T2DM, especially in light of accumulating evidence that surgery with gastrointestinal manipulations may result in T2DM remission (metabolic surgery). The major mechanisms mediating the weight loss-independent effects of bariatric surgery comprise effects on tissue-specific insulin sensitivity, ß-cell function and incretin responses, changes in bile acid composition and flow, modifications of gut microbiota, intestinal glucose metabolism and increased brown adipose tissue metabolic activity. Shorter T2DM duration, better preoperative glycemic control and profound weight loss, have been associated with higher rates of T2DM remission and lower risk of relapse. In the short and medium term, a significant amount of weight is lost, T2DM may completely regress, and cardiometabolic risk factors are dramatically improved. In the long term, metabolic surgery may achieve durable weight loss, prevent T2DM and cancer, improve overall glycemic control while leading to significant rates of T2DM remission, and reduce total and cause-specific mortality. The gradient of efficacy for weight loss and T2DM remission comparing the four established surgical procedures is biliopancreatic diversion >Roux-en-Y gastric bypass >sleeve gastrectomy >laparoscopic adjustable gastric banding. According to recently released guidelines, bariatric surgery should be recommended in diabetic patients with class III obesity, regardless of their level of glycemic control, and patients with class II obesity with inadequately controlled T2DM despite lifestyle and optimal medical therapy. Surgery should also be considered in patients with class I obesity and inadequately controlled hyperglycemia despite optimal medical treatment.

The effect of consumption of low-glycemic-index and low-glycemic-load desserts on anthropometric parameters and inflammatory markers in patients with type 2 diabetes mellitus.

PURPOSE: The aim of the present study was to examine the effects of consumption of desserts with low glycemic index (GI) and low glycemic load (GL), as part of a balanced hypo-caloric diet, on anthropometric and biochemical parameters in patients with type 2 diabetes mellitus (T2DM). METHODS: A total of 61 subjects with T2DM were randomly assigned to the intervention (n = 30) or to the control group (n = 31). Both groups followed the same hypo-caloric (-500 kcal) diet for 12 weeks. Consumption of four portions of low-GI/low-GL desserts/week was included in the diet in the intervention group while one portion of a favorite usual sweet/week was allowed to be consumed in the control group. RESULTS: Thirty subjects in the control and 28 subjects in the intervention group completed the trial. Body weight, body mass index, and waist circumference were reduced significantly in both groups. Arterial blood pressure, fasting blood glucose, glycosylated hemoglobin, insulin, and γ-GT were reduced significantly only in the intervention group; however, there were no significant differences between the two groups at endpoint. C-reactive protein was reduced in the intervention, and HDL cholesterol was also reduced in the control group; the reductions were significantly different at the end of the trial. No significant changes were observed in the other plasma lipids, uric acid, leptin, adiponectin, and interleukin-6 in either study group. CONCLUSIONS: Consumption of desserts with low GI/GL in a balanced hypo-caloric diet has a positive impact on anthropometric and metabolic parameters of patients with T2DM.

Multiple cranial nerve palsies in giant cell arteritis and response to cyclophosphamide: a case report and review of the literature.

Giant cell arteritis (GCA) has been previously associated with cranial mononeuritis (usually optic neuritis). We hereby describe a 68-year-old man who presented due to fever and diplopia of acute onset. Physical examination revealed left abducens nerve palsy and a hearing defect in the right ear. Brain imaging and cerebrospinal fluid analysis were not diagnostic. GCA was suspected, and treatment with high-dose methylprednisolone was initiated, leading to marked improvement. Temporal artery biopsy confirmed the presence of GCA. While considering corticosteroid tapering, the patient experienced hoarseness due to right laryngeal nerve palsy. Addition of cyclophosphamide to the treatment resulted in full response. GCA mainly affects large vessels, but one or more cranial nerve palsies may also occur. Following a review of the literature, this is the first report of three cranial nerve palsies in the setting of histologically proven GCA. The role of cyclophosphamide in this entity is also discussed.

Advances in obesity pharmacotherapy; learning from metabolic surgery and beyond.

Currently, metabolic surgery (MS) constitutes the most effective means for durable weight loss of clinically meaningful magnitude, type 2 diabetes remission and resolution of non-alcoholic steatohepatitis, as well as other obesity-related comorbidities. Accumulating evidence on the mechanisms through which MS exerts its actions has highlighted the altered secretion of hormonally active peptides of intestinal origin with biological actions crucial to energy metabolism as key drivers of MS clinical effects. The initial success of glucagon-like peptide-1 (GLP-1) receptor agonists regarding weight loss and metabolic amelioration have been followed by the development of unimolecular dual and triple polyagonists, additionally exploiting the effects of glucagon and/or glucose-dependent insulinotropic polypeptide (GIP) which achieves a magnitude of weight loss approximating that of common MS operations. Through the implementation of such therapies, the feasibility of a "medical bypass", namely the replication of the clinical effects of MS through non-surgical interventions may be foreseeable in the near future. Apart from weight loss, this approach ought to be put to the test also regarding other clinical outcomes, such as liver steatosis and steatohepatitis, cardiovascular disease, and overall prognosis, on which MS has a robustly demonstrated impact. Besides, a medical bypass as an alternative, salvage, or combination strategy to MS may promote precision medicine in obesity therapeutics.

Effects of Wheat Biscuits Enriched with Plant Proteins Incorporated into an Energy-Restricted Dietary Plan on Postprandial Metabolic Responses of Women with Overweight/Obesity.

This study investigates the effect of daily consumption of wheat biscuits enriched with plant proteins in postprandial metabolic responses of women with overweight/obesity who follow an energy-restricted diet. Thirty apparently healthy women participated in a 12-week randomized controlled trial and were assigned either to a control (CB) or an intervention (PB) group. Participants consumed daily either a conventional (CB) or an isocaloric wheat biscuit enriched with plant proteins (PB) containing high amounts of amino acids with appetite-regulating properties, i.e., BCAAs and L-arg. At baseline and the end of the intervention, a mixed meal tolerance test was performed. The responses of glucose, insulin, ghrelin, GLP-1, and glicentin were evaluated over 180 min. After 12 weeks, both groups experienced significant decreases in body weight, fat mass, and waist circumference. In the PB group, a trend towards higher weight loss was observed, accompanied by lower carbohydrate, fat, and energy intakes (p < 0.05 compared to baseline and CB group), while decreases in fasting insulin and the HOMA-IR index were also observed (p < 0.05 compared to baseline). In both groups, similar postprandial glucose, ghrelin, and GLP-1 responses were detected, while iAUC for insulin was lower (p < 0.05). Interestingly, the iAUC of glicentin was greater in the PB group (p < 0.05 compared to baseline). Subjective appetite ratings were beneficially affected in both groups (p < 0.05). Consumption of wheat biscuits enriched in plant proteins contributed to greater weight loss, lower energy intake, and insulin resistance and had a positive impact on postprandial glicentin response, a peptide that can potentially predict long-term weight loss and decreased food intake.

Bariatric surgery, through beneficial effects on underlying mechanisms, improves cardiorenal and liver metabolic risk over an average of ten years of observation: A longitudinal and a case-control study.

BACKGROUND: Bariatric surgery has long-term beneficial effects on body weight and metabolic status, but there is an apparent lack of comprehensive cardiometabolic, renal, liver, and metabolomic/lipidomic panels, whereas the underlying mechanisms driving the observed postoperative ameliorations are still poorly investigated. We aimed to study the long-term effects of bariatric surgery on metabolic profile, cardiorenal and liver outcomes in association with underlying postoperative gut hormone adaptations. METHODS: 28 individuals who underwent bariatric surgery [17 sleeve gastrectomy (SG), 11 Roux-en-Y gastric bypass (RYGB)] were followed up 3, 6 and 12 and at 10 years following surgery. Participants at 10 years were cross-sectionally compared with an age-, sex- and adiposity-matched group of non-operated individuals (n = 9) and an age-matched pilot group of normal-weight individuals (n = 4). RESULTS: There were durable effects of surgery on body weight and composition, with an increase of lean mass percentage persisting despite some weight regain 10 years postoperatively. The improvements in metabolic and lipoprotein profiles, cardiometabolic risk markers, echocardiographic and cardiorenal outcomes persisted over the ten-year observation period. The robust improvements in insulin resistance, adipokines, activin/follistatin components and postprandial gastrointestinal peptide levels persisted 10 years postoperatively. These effects were largely independent of surgery type, except for a lasting reduction of ghrelin in the SG subgroup, and more pronounced increases in proglucagon products, mainly glicentin and oxyntomodulin, and in the cardiovascular risk marker Trimethylamine-N-oxide (TMAO) within the RYGB subgroup. Despite similar demographic and clinical features, participants 10 years after surgery showed a more favorable metabolic profile compared with the control group, in conjunction with a dramatic increase of postprandial proglucagon product secretion. CONCLUSIONS: We demonstrate that cardiorenal and metabolic benefits of bariatric surgery remain robust and largely unchanged ten years postoperatively and are associated with durable effects on gastrointestinal- muscle- and adipose tissue-secreted hormones. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04170010.

Relative Energy Deficiency in sport (REDs): Endocrine manifestations, pathophysiology and treatments.

Research on lean, energy-deficient athletic and military cohorts has broadened the concept of the Female Athlete Triad into the Relative Energy Deficiency in Sport (REDs) syndrome. REDs represents a spectrum of abnormalities induced by low energy availability (LEA), which serves as the underlying cause of all symptoms described within the REDs concept, affecting exercising populations of either biological sex. Both short- and long-term LEA, in conjunction with other moderating factors, may produce a multitude of maladaptive changes that impair various physiological systems and adversely affect health, well-being, and sport performance. Consequently, the comprehensive definition of REDs encompasses a broad spectrum of physiological sequelae and adverse clinical outcomes related to LEA, such as neuroendocrine, bone, immune, and hematological effects, ultimately resulting in compromised health and performance. In this review, we discuss the pathophysiology of REDs and associated disorders. We briefly examine current treatment recommendations for REDs, primarily focusing on non-pharmacological, behavioral, and lifestyle modifications that target its underlying cause - energy deficit. We also discuss treatment approaches aimed at managing symptoms, such as menstrual dysfunction and bone stress injuries, and explore potential novel treatments that target the underlying physiology, emphasizing the roles of leptin and the activin-follistatin-inhibin axis, the roles of which remain to be fully elucidated, in the pathophysiology and management of REDs. In the near future, novel therapies leveraging our emerging understanding of molecules and physiological axes underlying energy availability or lack thereof may restore LEA-related abnormalities, thus preventing and/or treating REDs-related health complications, such as stress fractures, and improving performance.

Effect of Semaglutide on Regression and Progression of Glycemia in People With Overweight or Obesity but Without Diabetes in the SELECT Trial.

OBJECTIVE: To determine whether semaglutide slows progression of glycemia in people with cardiovascular disease and overweight or obesity but without diabetes. RESEARCH DESIGN AND METHODS: In a multicenter, double-blind trial, participants aged ≥45 years, with BMI ≥27 kg/m2, and with preexisting cardiovascular disease but without diabetes (HbA1c <6.5%) were randomized to receive subcutaneous semaglutide (2.4 mg weekly) or placebo. Major glycemic outcomes were HbA1c and proportions achieving biochemical normoglycemia (HbA1c <5.7%) and progressing to biochemical diabetes (HbA1c ≥6.5%). RESULTS: Of 17,604 participants, 8,803 were assigned to semaglutide and 8,801 to placebo. Mean ± SD intervention exposure was 152 ± 56 weeks and follow-up 176 ± 40 weeks. In both treatment arms mean nadir HbA1c for participants was at 20 weeks. Thereafter, HbA1c increased similarly in both arms, with a mean difference of -0.32 percentage points (95% CI -0.33 to -0.30; -3.49 mmol/mol [-3.66 to -3.32]) and with the difference favoring semaglutide throughout the study (P < 0.0001). Body weight plateaued at 65 weeks and was 8.9% lower with semaglutide. At week 156, a greater proportion treated with semaglutide were normoglycemic (69.5% vs. 35.8%; P < 0.0001) and a smaller proportion had biochemical diabetes by week 156 (1.5% vs. 6.9%; P < 0.0001). The number needed to treat was 18.5 to prevent a case of diabetes. Both regression and progression were dependent on glycemia at baseline, with the magnitude of weight reduction important in mediating 24.5% of progression and 27.1% of regression. CONCLUSIONS: In people with preexisting cardiovascular disease and overweight or obesity but without diabetes, long-term semaglutide increases regression to biochemical normoglycemia and reduces progression to biochemical diabetes but does not slow glycemic progression over time.

Long-term weight loss effects of semaglutide in obesity without diabetes in the SELECT trial.

In the SELECT cardiovascular outcomes trial, semaglutide showed a 20% reduction in major adverse cardiovascular events in 17,604 adults with preexisting cardiovascular disease, overweight or obesity, without diabetes. Here in this prespecified analysis, we examined effects of semaglutide on weight and anthropometric outcomes, safety and tolerability by baseline body mass index (BMI). In patients treated with semaglutide, weight loss continued over 65 weeks and was sustained for up to 4 years. At 208 weeks, semaglutide was associated with mean reduction in weight (-10.2%), waist circumference (-7.7 cm) and waist-to-height ratio (-6.9%) versus placebo (-1.5%, -1.3 cm and -1.0%, respectively; P < 0.0001 for all comparisons versus placebo). Clinically meaningful weight loss occurred in both sexes and all races, body sizes and regions. Semaglutide was associated with fewer serious adverse events. For each BMI category (<30, 30 to <35, 35 to <40 and ≥40 kg m-2) there were lower rates (events per 100 years of observation) of serious adverse events with semaglutide (43.23, 43.54, 51.07 and 47.06 for semaglutide and 50.48, 49.66, 52.73 and 60.85 for placebo). Semaglutide was associated with increased rates of trial product discontinuation. Discontinuations increased as BMI class decreased. In SELECT, at 208 weeks, semaglutide produced clinically significant weight loss and improvements in anthropometric measurements versus placebo. Weight loss was sustained over 4 years. ClinicalTrials.gov identifier: NCT03574597 .