Substantial Weight Loss Research Articles

Leptin Reduction as a Required Component for Weight Loss.

Partial leptin reduction can induce significant weight loss, while weight loss contributes to partial leptin reduction. The cause-and-effect relationship between leptin reduction and weight loss remains to be further elucidated. Here, we show that FGF21 and the GLP1R agonist liraglutide rapidly induce a reduction in leptin. This leptin reduction contributes to the beneficial effects of GLP1R agonism in metabolic health, as transgenically maintaining leptin levels during treatment partially curtails the beneficial effects seen with these agonists. Moreover, a higher degree of leptin reduction during treatment, induced by including a leptin neutralizing antibody with either FGF21 or liraglutide, synergistically induces greater weight loss and better glucose tolerance in diet-induced obese mice. Furthermore, upon cessation of either liraglutide or FGF21 treatment, the expected immediate weight regain is observed, associated with a rapid increase in circulating leptin levels. Prevention of this leptin surge with leptin neutralizing antibodies slows down weight gain and preserves a better glucose tolerance. Mechanistically, a significant reduction in leptin induces a higher degree of leptin sensitivity in hypothalamic neurons. Our observations support a model that postulates that a reduction of leptin levels is a necessary prerequisite for substantial weight loss and partial leptin reduction is a viable strategy to treat obesity and its associated insulin resistance.

Characterization of non-neutralizing human monoclonal antibodies that target the M1 and NP of influenza A viruses.

Currently, many groups are focusing on isolating both neutralizing and non-neutralizing antibodies to the mutation-prone hemagglutinin as a tool to treat or prevent influenza virus infection. Less is known about the level of protection induced by non-neutralizing antibodies that target conserved internal influenza virus proteins. Such non-neutralizing antibodies could provide an alternative pathway to induce broad cross-reactive protection against multiple influenza virus serotypes and subtypes by partially overcoming influenza virus escape mediated by antigenic drift and shift. Accordingly, more information about the level of protection and potential mechanism(s) of action of non-neutralizing antibodies targeting internal influenza virus proteins could be useful for the design of broadly protective and universal influenza virus vaccines.

Diabetic Markers, Five Years after Bariatric Surgery.

Background: Bariatric surgery delivers substantial weight loss for obese patients with comorbidities like diabetes mellitus. We aimed to investigate the impacts of bariatric surgery on diabetic markers after 5 years of follow-up. Methods: This is a retrospective study on patients with diabetes and a history of bariatric surgery between 2016-2017. The diabetic markers before and 5 years following surgery, including a lipid profile, glucose level, and the required antidiabetic medications, were evaluated. Results: 34 consecutive patients were included, 30 (88.2%) women, with a mean age of 52.71±8.53 years. The majority (65%) of surgeries were Roux-en-Y gastric bypass (RYGB), and the remaining were one anastomosis gastric bypass (OAGB) and sleeve gastrectomy (SG). The serum levels of diabetic markers reduced during follow-up (P=0.001), except for high-density lipoprotein levels and serum total cholesterol, which increased (P=0.011, P=0.838). Low-density lipoprotein levels reduced, but it was insignificant (P=0.194). Surgery types had affected the changes of diabetic markers (P>0.05). Demand for oral medication was reduced significantly, but insulin injection reduction was not significant (P=0.006 and P=0.099, respectively). Conclusion: Our study showed favorable bariatric surgery results on patients with diabetes in long-term follow-up. However, dyslipidemia is still a concern.

Effects of Weight Change and Weight Cycling on Lung Function in Overweight and Obese Adults.

Rationale: Epidemiological studies have reported on the detrimental effects on lung function after natural, and thus limited, weight gain in unselected populations. Studies on bariatric surgery, on the contrary, have indicated large improvements in lung function after substantial weight loss. Objectives: To study the associations between profound weight loss or gain and pulmonary function within the same population. A second objective was to investigate the effect of weight cycling on pulmonary function. Methods: From our lung function database, we selected the records of subjects in follow-up for continuous positive airway pressure therapy for sleep apnea with a weight change of ⩾20 kg within 5 years. Lung function (N = 255) at baseline was normal except for a tendency toward mild restriction in morbid obesity. Within this sample, 73 subjects were identified with significant "weight cycling", defined as a ⩾10-kg opposite change in body weight before or after the ⩾20-kg weight change. Results: Weight change affected pulmonary function more in men than in women (P < 0.001). In men, forced vital capacity (FVC) increased an average of 1.4% predicted per unit of body mass index after weight loss and the reverse after weight gain, whereas women exhibited a smaller change of 0.9% predicted per unit of body mass index. Weight loss slightly increased the ratio of forced expiratory volume in 1 second to FVC and decreased the specific airway resistance, whereas the opposite occurred with weight gain. Greater effects of weight change on lung function were observed in leaner subjects (P = 0.02) and in older subjects (P < 0.002). Changes in total lung capacity followed the changes in FVC, with no change in residual volume, and the greatest change was observed in functional residual capacity. In subjects with weight cycling, the improvement in lung function due to weight loss was reversed by subsequent weight gain and vice versa. Conclusions: This study provides evidence that the detrimental effect of obesity on lung function is a passive and reversible process.

Trends in glucagon-like peptide 1 receptor agonist use, 2014 to 2022

BackgroundRecent Food and Drug Administration approvals of glucagon-like peptide 1 (GLP-1) receptor agonists linked to substantial weight loss have generated interest in demand projections. However, a longitudinal analysis in a large, diverse, current, real-world database has not been published. ObjectivesThe study objective was to determine user frequency of GLP-1 receptor agonist products overall and by type 2 diabetes (T2D), cardiovascular disease (CVD), and overweight or obese status. Secondary objective was monthly growth rate estimation by product since first appearance in University of California Health. MethodsThis retrospective cohort study included patients who were dispensed a GLP-1 receptor agonist from 2014 to 2022 in the University of California Health Data Warehouse. Exponential growth rates were estimated using a log-linear regression model. ResultsBetween 2014 and 2018, only Trulicity and Victoza exceeded 5000 annual users. Ozempic users increased from 569 in 2019 to 7667 in 2020. Use accelerated with more than 13,310 users in 2021 to surpass Trulicity. Ozempic count was 22,891 in 2022. Wegovy rose from 989 in 2021 to 2992 in 2022. Mounjaro increased to 1508 users in 2022. Although generally similar trends were observed for T2D, CVD, and overweight or obese subgroups, the ascent of Ozempic as most frequently used was more apparent in the overweight or obese group. The monthly growth rates were 83.9% for Ozempic, 119.2% for Wegovy, 84.8% for Rybelsus, 53.3% for Saxenda, 12.9% for Adlyxin, 78.8% for Trulicity, and 254.3% for Mounjaro. ConclusionThis first cohort study of weight loss–associated GLP-1 receptor agonists in a large, diverse, state-wide health system demonstrated a rapid increased use that represents a clear and likely durable transition in utilization for this category. Informed decision making and longitudinal studies are needed to ensure evidence-concordant prescribing and supply stability.

Cobalt oxide nanoparticles for biological applications: Synthesis and physicochemical characteristics for different natural fuels

Cobalt oxide (Co3O4) nanoparticles were synthesized via a simple combustion process employing natural fuels, and their structural, morphological, thermal, and antibacterial properties were studied. According to XRD measurements, each specimen has a cubic crystalline structure. Co3O4 nanoparticles prepared from natural macromolecules such as cow urine, honey, wine, and tea extract had respective crystallite diameters of 22.9, 31.3, 30.4, and 31.2 nm. According to FESEM and EDAX analyses, the products have stoichiometric shapes such as rice grains, mushrooms, and cluster cavities, and EDX confirmed the presence of the Co and O elements. The FTIR image revealed the presence of various phytochemicals on the surface, and the bands at 400 and 630 cm−1 denoted the distinctive Co–O linkages. The diameters of crystallites and TEM particles are comparable. The thermal properties of Co3O4 nanoparticles synthesized with diverse natural fuels are characterized by substantial weight losses. The particle's colloidal stability has been investigated. It confirms that the use of natural resources influences particle stability. Antibacterial and antifungal activity of green synthesized Co3O4 nanoparticles was evaluated against two distinct bacteria (Gram-positive) Staphylococcus aureus and (Gram-negative) Pseudomonas aeruginosa, as well as two fungi, Candida albicans and Aspergillus niger. It has been discovered that synthetic Co3O4 nanoparticles inhibit microbial and fungal proliferation effectively.

FRI079 Long-term Bone Consequences Of Roux-En-Y Gastric Bypass: A Cross-sectional And Case-Control Study Of Post-menopausal Women

Abstract Disclosure: G. Papadakis: None. E. Gonzalez Rodriguez: None. S. Mantziari: None. J. Pasquier: None. E. Shevroja: None. N. Vionnet: None. L. Favre: None. Bariatric surgery decreases bone mineral density (BMD) due to mechanical unloading (weight loss) and secondary hyperparathyroidism linked to nutrient deficiencies (calcium, vitamin D). Most studies on the bone impact of bariatric surgery have investigated premenopausal women after a follow up of less than 3 years. In the current study, we sought to determine the long-term bone impact of Roux-en-Y gastric bypass (RYGB) on post-menopausal women. A cross-sectional and a case-control study were performed in women for whom a Dual X-ray absorptiometry (DXA) at least 3 years after surgery was available. BMD was measured at lumbar spine (LS), total hip (TH) and femoral neck (FN). Trabecular bone score (TBS) at LS was analyzed after correction for soft tissue thickness. History of fractures was inquired and DXA images were reviewed for vertebral fractures. For patients on anti-osteoporotic drugs, the DXA scan before the onset of therapy was taken into account. One-hundred nineteen women were eligible at a mean 9.0 ± 5.6 years after RYGB. The fracture rate was 12% and 6% for major osteoporotic and vertebral fractures, respectively. As calcium/vitamin D supplements were administered to all patients, serum 25-hydroxyvitamin D levels exceeded the threshold of 75 nmol/l in 77% of participants with insufficient levels (less than 50 nmol/l) only in 3 patients. Serum PTH levels were within the normal range in 87% of participants. A multivariate regression model including BMI, age, time since RYGB, one-year weight loss and serum PTH highlighted higher BMI as the sole significant predictor for better BMD at LS and TH (p=0.001 and p=0.008, respectively). Time since RYGB was the only variable inversely associated with TBS. Plasma levels of bone turnover markers (β-crosslaps, P1NP) exhibited a strong inverse correlation with BMD at all sites. For the case-control substudy, 76 post-RYGB women were age- and BMI-matched to female participants of the OsteoLaus study, a population-based cohort in Lausanne. The patient group had significantly lower BMD at all sites: LS (p=0.03), TH (p=0.01), FN (p=0.007), as well as lower TBS (p=0.003) compared to controls. No statistical difference was observed for fractures, although more major osteoporotic fractures occurred in the post-RYGB group (8 vs 4 in the controls). Possibly contributing to the bone impairment, the post-bariatric cohort had more active smokers (21 vs 7 in the controls, p=0.006) and less hormonal replacement therapy users (2 vs 12 in the controls, p=0.009). In conclusion, post-bariatric BMI is the strongest determinant of long-term BMD levels. Despite satisfactory vitamin D/PTH levels, a history of RYGB several years ago was associated with lower BMD and altered bone structure in this postmenopausal cohort. Long-term bone health monitoring is warranted after RYGB especially in women who are smoking and achieved substantial weight loss. Presentation: Friday, June 16, 2023

FRI078 Real-World Weight Loss Outcomes And Safety Of Tirzepatide, A Novel Dual GIP And GLP-1 Receptor Agonist

Abstract Disclosure: S. Fansa: None. W. Ghusn: None. B. Nicolalde: None. D. Anazco: None. E. Tama: None. A. Acosta: None. M.D. Hurtado: None. Introduction: The increasing prevalences of obesity and type 2 diabetes (T2D), the “twin epidemics”, have led to the development of drugs targeting both diseases simultaneously. Liraglutide and semaglutide, GLP-1 receptor agonists used for T2DM, are also FDA-approved for weight loss. Tirzepatide, a novel dual GIP/GLP-1 receptor agonist approved for T2D, has shown promising weight loss outcomes in clinical trials. To date, no study has assessed weight loss outcomes of tirzepatide in a real-world setting. Our aim is to assess its efficacy and safety in patients with overweight or obesity. Methods: This is a retrospective cohort study of adults with overweight or obesity taking weekly subcutaneous tirzepatide for T2D or off-label for weight loss. We excluded patients taking tirzepatide for less than one month, prior bariatric procedure, use of any anti-obesity medications, and active malignancy or pregnancy. The primary outcome was total body weight loss percentage (TBWL%) at 3 months. Secondary outcomes included TBWL% at 1 and 2 months; TBWL% difference by T2D status (with and without) and by sex at 3 months; proportion of patients achieving ≥5%, ≥10%, and ≥15% of TBWL% at 3 months; predictors of TBWL% at 3 months; and reported side effects during follow up. We used paired t-test to assess TBWL% compared to baseline, non-paired t-test to compare TBWL% by T2D status and sex, and univariate analyses to estimate the contribution of other variables to TBWL%. Results are presented as mean ± standard deviation. Results: We included 175 participants (81% female, age 49.8±12.2, 91% white, BMI 38.8±7.3 kg/m2). One third of patients had T2D (n=59, 34%). Most patients were on 5mg (39%) or 7.5mg (22%) of tirzepatide weekly. TBWL% at 1, 2, and 3 months was 3.6±2.5% (n=87), 5.8±3.5% (n=100), and 8.4± 4.3% (n=60), respectively (p &amp;lt;0.0001 compared to baseline at all timepoints). Patients with T2D lost less weight at 3 months compared to patients without T2D: 6.9±4.0% vs. 9.1±4.4% (p= 0.03). At 3 months, TBWL% was greater in females, 9.2±4.3% vs. 5.0±2.5% for males, p&amp;lt;0.0001. Greater baseline weight was associated with greater TBWL% (R=0.32, p&amp;lt;0.0001). At 3 months, 60 patients had documented weights with 81.6% achieving ≥ 5%, 30% achieving ≥10%, and 10% achieving ≥15% TBWL. Forty participants (23%) reported side effects. The most frequent were nausea/vomiting (n=27, 15%), constipation (n=6, 3%), and abdominal pain (n=5, 3%). Eight patients (5%) had to either decrease dosage or discontinue the drug due to side effects. Conclusion: In this retrospective cohort study, tirzepatide led to substantial weight loss at 3 months. Patients with T2DM lost less weight than patients without. Further real-world studies with longer follow-up duration and higher tirzepatide doses are needed to establish the long-term efficacy, safety, and tolerability of this drug in this setting. Presentation: Friday, June 16, 2023

Computed tomography in the diagnosis of fever of unknown origin: A case report

Fever of unknown origin can be a symptom of at least 200 diseases. Positron emission tomography-computed tomography, although highly informative, may not be readily available as an imaging tool. We present a clinical case of giant cell arteritis where computed tomography played a key role in arriving at a diagnosis.&#x0D; A 61-year-old woman presented to the hospital with a nocturnal fever up to 39.5С, accompanied by chest and scapular pain, and substantial weight loss (10 kg over 3 months). Lymphoproliferative and infectious diseases were excluded. Baseline colonoscopy had revealed erosions in the colonic mucosa, leading to a preliminary diagnosis of ulcerative colitis, and subsequently, the patient was admitted to the gastroenterology department. Follow-up colonoscopy had excluded this diagnosis. Additional imaging via chest and abdominal computed tomography scan revealed wall thickening of aorta and its branches with subtle contrast enhancement.&#x0D; Conditions, such as tuberculous aortoarteritis and syphilitic aortitis, were excluded. The patient was diagnosed with giant cell arteritis involving brachiocephalic trunk, subclavian arteries, and celiac trunk. Prednisolone was administered with subsequent reduction in symptoms.&#x0D; Although computed tomography may not be regarded as the gold standard for the differential diagnosis of fever of unknown origin, this case underscores its valuable contribution in establishing a definitive diagnosis.

Age-dependent acquisition of pathogenicity by SARS-CoV-2 Omicron BA.5.

Pathology studies of SARS-CoV-2 Omicron variants of concern (VOC) are challenged by the lack of pathogenic animal models. While Omicron BA.1 and BA.2 replicate in K18-hACE2 transgenic mice, they cause minimal to negligible morbidity and mortality, and less is known about more recent Omicron VOC. Here, we show that in contrast to Omicron BA.1, BA.5-infected mice exhibited high levels of morbidity and mortality, correlating with higher early viral loads. Neither Omicron BA.1 nor BA.5 replicated in brains, unlike most prior VOC. Only Omicron BA.5-infected mice exhibited substantial weight loss, high pathology scores in lungs, and high levels of inflammatory cells and cytokines in bronchoalveolar lavage fluid, and 5- to 8-month-old mice exhibited 100% fatality. These results identify a rodent model for pathogenesis or antiviral countermeasure studies for circulating SARS-CoV-2 Omicron BA.5. Further, differences in morbidity and mortality between Omicron BA.1 and BA.5 provide a model for understanding viral determinants of pathogenicity.

Outcome comparison between primary and revisional bariatric surgery: A propensity-matched analysis

BackgroundRevisional bariatric procedures for weight recurrence are rising but are considered higher risk and less effective than primary bariatric procedures. This study aimed to compare clinical outcomes between primary and revisional bariatric surgery for weight recurrence. MethodsProspectively collected data from adult patients who underwent revisional or primary bariatric surgery from 2016 to 2020 in an academic institution were reviewed. Roux-en-Y gastric bypass and sleeve gastrectomy were performed primarily or as conversion procedures after laparoscopic adjustable gastric band, vertical banded gastroplasty, and sleeve gastrectomy. 1:1 propensity score matching was performed between revisional bariatric surgery and primary bariatric surgery, and logistic regression analysis was used to compare up to 2-year weight loss and comorbidity resolution outcomes. ResultsA total of172 cases (86 revisional bariatric surgery versus 86 primary bariatric surgery) were included. Groups were matched for age, sex, preoperative body mass index, bariatric procedure, diabetes, hypertension, and obstructive sleep apnea. Procedure duration (203 ± 78 vs 154 ± 69 minutes; P < .001) and length of stay (2.3 ± 2.1 vs 1.7 ± 1 days; P = .02) were longer for revisional bariatric surgery versus primary bariatric surgery, respectively. Total weight loss was less in revisional bariatric surgery compared with primary bariatric surgery at 1 year (23 ± 10% vs 32 ± 9%; P < .001) and 2 years (21 ± 12.% vs 32 ± 10%; P < .001) of follow-up; however, no differences were detected in postoperative occurrences, emergency department visits, readmissions, reintervention and reoperation rates, and comorbidity resolution. ConclusionAlthough revisional bariatric surgery was associated with longer operation times, prolonged hospitalization, and lower weight loss than primary bariatric surgery, it was accomplished safely and led to substantial weight loss and comorbidity resolution. This information can guide patient counseling before revisional surgery for weight recurrence.

Characterization of the SARS-CoV-2 BA.5.5 and BQ.1.1 Omicron variants in mice and hamsters.

The continued evolution and emergence of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have resulted in challenges to vaccine and antibody efficacy. The emergence of each new variant necessitates the need to re-evaluate and refine animal models used for countermeasure testing. Here, we tested a recently circulating SARS-CoV-2 Omicron lineage variant, BQ.1.1, in multiple rodent models including K18-human ACE2 (hACE2) transgenic, C57BL/6J, and 129S2 mice, and Syrian golden hamsters. In contrast to a previously dominant BA.5.5 Omicron variant, inoculation of K18-hACE2 mice with BQ.1.1 resulted in substantial weight loss, a characteristic seen in pre-Omicron variants. BQ.1.1 also replicated to higher levels in the lungs of K18-hACE2 mice and caused greater lung pathology than the BA.5.5 variant. However, in C57BL/6J mice, 129S2 mice, and Syrian hamsters, BQ.1.1 did not cause increased respiratory tract infection or disease compared to animals administered BA.5.5. Moreover, the rates of direct contact or airborne transmission in hamsters were not significantly different after BQ.1.1 and BA.5.5 infections. Taken together, these data suggest that the BQ.1.1 Omicron variant has increased virulence in rodent species that express hACE2, possibly due to the acquisition of unique spike mutations relative to earlier Omicron variants. IMPORTANCE As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve, there is a need to rapidly assess the efficacy of vaccines and antiviral therapeutics against newly emergent variants. To do so, the commonly used animal models must also be re-evaluated. Here, we determined the pathogenicity of the BQ.1.1 SARS-CoV-2 variant in multiple SARS-CoV-2 animal models including transgenic mice expressing human ACE2 (hACE2), two strains of conventional laboratory mice, and Syrian hamsters. While BQ.1.1 and BA.5.5 infection resulted in similar levels of viral burden and clinical disease in hamsters and the conventional strains of laboratory mice tested, increases in lung infection were detected in hACE2-expressing transgenic mice, which corresponded with greater levels of pro-inflammatory cytokines and lung pathology. Taken together, our data highlight important differences in two closely related Omicron SARS-CoV-2 variant strains and provide a foundation for evaluating countermeasures.

Giving weight to incretin-based pharmacotherapy for obesity-related sleep apnea: a revolution or a pipe dream?

Obesity is a chronic disease affecting over 670 million adults globally, with multiple complications including obstructive sleep apnea (OSA). Substantial weight loss in patients with obesity-related OSA can reduce or even eliminate OSA as well as reduce sleepiness and improve cardio-metabolic health. Evidence suggests that these improvements exceed those that occur with device-based OSA therapies like continuous positive airway pressure which continue to be the first-line of therapy. Resistance to weight management as a first-line strategy to combat OSA could arise from the complexities in delivering and maintaining adequate weight management, particularly in sleep clinic settings. Recently, incretin-based pharmacotherapies including glucagon-like peptide 1 (GLP-1) receptor agonists alone or combined with glucose-dependent insulinotropic polypeptide (GIP) receptor agonists have been developed to target glycemic control in type 2 diabetes. These medications also slow gastric emptying and reduce energy intake. In randomized, placebo-controlled trials of these medications in diabetic and non-diabetic populations with obesity, participants on active medication lost up to 20% of their body weight, with corresponding improvements in blood pressure, lipid levels, physical functioning, and fat mass loss. Their adverse effects are predominantly gastrointestinal-related, mild, and transient. There are trials currently underway within individuals with obesity-related OSA, with a focus on reduction in weight, OSA severity, and cardio-metabolic outcomes. These medications have the potential to substantially disrupt the management of OSA. Pending coming data, we will need to consider pharmacological weight loss as a first-line therapy and how that influences training and management guidelines.

Long-term cancer outcomes after bariatric surgery.

Obesity is associated with increased cancer risk. Because of the substantial and sustained weight loss following bariatric surgery, postsurgical patients are ideal to study the association of weight loss and cancer. Retrospectively (1982-2019), 21,837 bariatric surgery patients (surgery, 1982-2018) were matched 1:1 by age, sex, and BMI with a nonsurgical comparison group. Procedures included gastric bypass, gastric banding, sleeve gastrectomy, and duodenal switch. Primary outcomes included cancer incidence and mortality, stratified by obesity- and non-obesity-related cancers, sex, cancer stage, and procedure. Bariatric surgery patients had a 25% lower risk of developing any cancers compared with a nonsurgical comparison group(hazard ratio [HR] 0.75; 95% CI 0.69-0.81; p < 0.001). Cancer incidence was lower among female (HR 0.67; 95% CI 0.62-0.74; p < 0.001) but not male surgery patients, with the HR lower for females than for males (p < 0.001). Female surgerypatients had a 41% lower risk for obesity-related cancers (i.e., breast, ovarian, uterine, and colon) compared with nonsurgical females (HR 0.59; 95% CI 0.52-0.66; p < 0.001). Cancer mortality was significantly lower after surgery in females (HR 0.53; 95% CI 0.44-0.64; p < 0.001). Bariatric surgery was associated with lower all-cancer and obesity-related cancer incidence among female patients. Cancer mortality was significantly lower among females in thesurgical group versus the nonsurgical group.

The Prevalence of Hearing Symptoms Associated With Patulous Eustachian Tube Dysfunction Following Bariatric Surgery at King Khalid University Hospital, Saudi Arabia.

Background A patulous Eustachian tube (PET) is defined as a persistent tubal opening, which affects 0.3-6.6% of the population, with a female preponderance. PET is caused by the loss of subcutaneous adipose tissue enclosing the cartilaginous portion of the Eustachian tube (Ostmann's pad) as a result of acute, rapid, and substantial loss of weight which occurs during bariatric surgery. The most common complaint of PET is autophony, in which patients hear their own voices or breaths, with additional symptoms including crackling sounds, tinnitus, and aural congestion. In this study, we aimed to determine the prevalence of symptoms associated with PET dysfunction subsequent to bariatric surgery at King Khalid University Hospital (KKUH). Methodology A cross-sectional study was conducted at KKUH, Saudi Arabia. The presence of symptoms consistent with the diagnosis of PET dysfunction was assessed through in-person and telephonic interviews of bariatric surgery patients using a standardized questionnaire. Results A total of 450 patients were evaluated. The preoperative body mass index (BMI) of evaluated patients ranged from 28 to 117 kg/m2 (mean = 46.07 kg/m2), with no significant difference between symptomatic and asymptomatic groups (p = 0.303). The postoperative BMI ranged from 16 to 100 kg/m2 (mean = 29.37 kg/m2), with no significant difference between symptomatic and asymptomatic groups (p = 0.263). Hypertension was the most prevalent comorbid condition (12.2%), followed by diabetes (9.3%). In total, 91 (20.22%)patients exhibited symptoms (aural fullness and autophony) compatible with patent auditory tube dysfunction. Conclusions Overall, 20.22% of the bariatric surgery patients in our study sample displayed symptoms consistent with patulous auditory tubal dysfunction. The preoperative and postoperative BMI of symptomatic and asymptomatic patients did not differ significantly. To improve patient outcomes and satisfaction following bariatric surgery hearing symptoms associated with PET need to be included in postoperative follow-ups after bariatric surgery.

Obesity-associated cancer risk reduction after metabolic surgery: insights from the SPLENDID study and the path forward.

Obesity incidence continues to rise globally along with obesity-associated conditions, which heavily burden individuals' quality of life and healthcare systems. Evidence regarding the power of metabolic and bariatric surgery to treat obesity has, fortunately, brought to light how substantial and sustained weight loss can mitigate adverse clinical outcomes of obesity and metabolic disease. Obesity-associated cancer has been an important focus of studies in recent decades to further elucidate what impact metabolic surgery could have on incidence of cancer and cancer-related mortality. The SPLENDID (Surgical Procedures and Long-term Effectiveness in Neoplastic Disease Incidence and Death) study is one of the recent large cohort studies that highlights the power of substantial weight loss and the long-term benefits to patients with obesity in preventing cancer. This review of SPLENDID aims to highlight both consistency of results with prior studies and new findings unexplored previously.

Novel Dual Incretin Receptor Agonists in the Spectrum of Metabolic Diseases with a Focus on Tirzepatide: Real Game-Changers or Great Expectations? A Narrative Review.

The prevalence of metabolic diseases including type 2 diabetes (T2D), obesity and non-alcoholic fatty liver disease (NAFLD) increases globally. This highlights an unmet need for identifying optimal therapies for the management of these conditions. Tirzepatide is a novel dual incretin receptor agonist (twincretin) that activates both glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors. The aim of this narrative review was to examine the impact of novel twincretins, focusing on tirzepatide, on the management of a wide spectrum of metabolic diseases. Data from preclinical and clinical trials have shown that twincretins significantly reduce blood glucose levels in T2D, and tirzepatide is the first agent of this class that has been approved for the management of T2D. Additionally, the beneficial impact of tirzepatide on weight reduction has been corroborated in several studies, showing that this agent can achieve substantial and sustained weight loss in obese patients with or without T2D. Data also suggest that tirzepatide could be a promising drug for hepatic steatosis reduction in individuals with NAFLD. The remarkable effects of tirzepatide on glycaemic control, weight loss and liver-related outcomes have posed new research questions that are likely to lead to further advancements in the treatment of T2D, obesity and related metabolic disorders.

Retatrutide as a Novel Treatment for Obesity and Type 2 Diabetes

Retatrutide is a triple hormone agonist of the receptors of glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide (GIP) and glucagon that can be administered subcutaneously once a week. Different doses and escalation schedules of retatrutide were evaluated in 2 phase 2 American trials of subjects with obesity (n=338) and type 2 diabetes (n=281). In the obesity trial of 48 week-duration, percentage change in body weight from baseline after 24 weeks and 48 weeks were the primary and secondary outcomes respectively. At 24 weeks, the mean percentage decrease in weight ranged from 7.2% to 17.5% across retatrutide groups versus 1.6% with placebo. At 48 weeks, the decrease was 8.7% to 24.2% versus 2.1% with placebo. In the diabetes trial, the primary endpoint was a change in glycated hemoglobin (HbA1c) values from baseline to week 24. This trial included an active treatment group receiving dulaglutide 1.5mg once weekly. Secondary endpoints included change in HbA1c and body weight at 36 weeks. At 24 weeks, mean HbA1c reductions were 0.43% to 2.02% with retatrutide, 1.4% with dulaglutide and 0.01% with placebo. At 36 weeks, mean percentage weight reductions were 3.2% to 16.9% with retatrutide, 2.0% with dulaglutide and 3.0% with placebo. While the decrease in HbA1c levels reached a plateau at 24 weeks, weight loss in the 2 studies was progressive without evidence of attenuation effect up to the end of follow-up at 36-48 weeks. The most common adverse effects of retatrutide were gastrointestinal (GI) such as nausea, diarrhea, vomiting and constipation reported by 13-50% in the retatrutide groups compared with 35% in the dulaglutide group, and 13% in the placebo group. Discontinuation rates due to adverse effects were also higher with retatrutide being 16-17% compared with 2% with dulaglutide and 0-4% with placebo. In summary, retatrutide is highly effective drug in causing substantial weight loss and HbA1c reduction. Yet, tolerance to this drug seems sub-optimal. Phase 3 trials are urgently needed to clarify efficacy and safety of retatrutide.

212-OR: Leptin Reduction as a Required Component for Weight Loss

A significant reduction in circulating leptin levels is well corelated with substantial weight loss. However, it is still not clear whether the observed leptin reduction is a cause or consequence of weight reduction. Here, we showed that FGF21 and liraglutide could rapidly induce leptin reduction, and this reduction contributes to the beneficial effects of FGF21 and liraglutide, as blocking the leptin reduction by a transgenic approach curtails the beneficial effects. Moreover, a higher degree of leptin reduction, induced by combination of leptin neutralizing antibody with either FGF21 or liraglutide, synergistically induced greater weight loss and better glucose tolerance in diet-induced obese mice. Furthermore, after removing liraglutide and FGF21, a significant weight gain is associated with rapid increase in circulating leptin levels and prevention of leptin surge by leptin neutralizing antibody slows down weight gain and preserves a better glucose tolerance. Mechanically, a significant reduction in leptin reduction induces a higher degree of leptin sensitivity in neurons, located in hypothalamic region, other than AP. In conclusion, this study supports a model that leptin reduction is required for substantial weight loss and partial leptin reduction may be a novel strategy to treat obesity and its associated metabolic syndromes. Disclosure S.Zhao: None. P.E.Scherer: None.

CARDIOVASCULAR RISK, METABOLIC PROFILE AND INFLAMMATORY FINGERPRINT OF OBESE SUBJECTS UNDERGOING BARIATRIC SURGERY

Objective: Bariatric surgery has emerged as effective treatment for obesity not only for the substantial and durable weight loss, but also by improving several obesity-related comorbidities, including hypertension. Extracellular vesicles (EVs; membrane nanoparticles released by cells) and their cargo reflect endothelial dysfunction and inflammation, and may be used as indicators of post-surgical outcomes in these patients. The aim of the present study was to exploit an EV signature to assess cardiovascular (CV) risk, metabolic profile, and inflammatory fingerprint before and after bariatric surgery. Design and method: The study cohort was composed by 62 patients (age 39 years; 21% males); for each subject, clinical and biochemical parameters, disease status (including diabetes, dyslipidemia, and hypertension), medications, and EV profiling were evaluated at baseline (T0) and 1-/3-years (T1 and T2, respectively), after surgery (sleeve gastrectomy or Roux-en-Y gastric bypass). EVs were isolated from serum by beads-based immuno-capture and analyzed for the expression of 37 membrane-associated antigens. Results: After bariatric surgery, patients gradually lost weight from a median of 110 Kg at T0 down to 80 Kg at T2 (cumulative weight loss 31 Kg; 29.9% BMI reduction). Accordingly, the overall CV risk and metabolic-inflammatory profile of patients improved: systolic blood pressure, HbA1c, total cholesterol, triglycerides, LDL, uric acid, white blood cells, and C-reactive protein decreased, while HDL and renal function (expressed as eGFR) increased at follow-up (p &lt; 0.05 for all comparisons); prevalence of hypertension, dyslipidemia, and diabetes decreased together with the number of assumed drugs (anti-hypertensives, statins, hypoglycemic, and anti-platelets agents). Consistently, levels of expression of EV specific markers (CD9-CD63-CD81) and 11 out of the 37 evaluated antigens (mainly from endothelium, platelets, and inflammatory cells) decreased at T1/T2, reflecting changes of main CV risk indicators. Interestingly, lower baseline levels of CD4, CD31, CD40, CD42a, and CD62P were associated to a complete post-surgical outcome, defined as no residual disease without medications, with a BMI at T2 lower than 30 Kg/sqm. Conclusions: EV-derived biomarkers reflect the improvement of CV profile in patients who underwent bariatric surgery and may become a new tool to predict post-surgical outcome.