Sustained Reduction In Body Weight Research Articles

Semaglutide outperforms insulin in restoring neutrophil function against implant-related infection in diabetic and obese mice: experimental research.

Bone and joint infections (BJI) are a significant complication after arthroplasty and fracture fixation, particularly challenging in patients with type 2 diabetes mellitus (T2DM) and obesity. Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), have shown efficacy in managing T2DM and obesity. However, its impact on BJI risk and neutrophil function remains unclear. To investigate whether preoperative semaglutide treatment (1) reduces the risk of BJI in diabetic and obese mice undergoing intra-articular implants, and (2) outperforms insulin in restoring neutrophil function to mitigate implant-related infection. A C57BL/6 mouse model of T2DM/obesity was induced using a high-fat diet (HFD) for 12 weeks. Mice received preoperative insulin or semaglutide therapy for 1-28 days. BJI risk was assessed using an intraarticular-implant model challenged with S. aureus or E. coli. Neutrophil function was evaluated through bactericidal activity, superoxide production, and migration ability. Semaglutide treatment led to a significant and sustained reduction in body weight and improved glucose tolerance in HFD mice. Both insulin and semaglutide therapies significantly reduced BJI risk, with semaglutide showing a more pronounced effect over time. Semaglutide therapy also enhanced neutrophil bactericidal activity, superoxide production, and migration ability compared to insulin therapy. Preoperative semaglutide treatment effectively reduces BJI risk and improves neutrophil function in diabetic and obese mouse models. These findings suggest that semaglutide may be a promising pharmacological intervention to mitigate infection risk in orthopedic patients with T2DM or obesity.

Incretin-based investigational therapies for the treatment of MASLD/MASH

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is the most common form of chronic liver disease. It exists as either simple steatosis or its more progressive form, metabolic dysfunction-associated steatohepatitis (MASH), formerly, non-alcoholic steatohepatitis (NASH). The global prevalence of MASLD is estimated to be 32% among adults and is projected to continue to rise with increasing rates of obesity, type 2 diabetes, and metabolic syndrome. While simple steatosis is often considered benign and reversible, MASH is progressive, potentially leading to the development of cirrhosis, liver failure, and hepatocellular carcinoma. Treatment of MASH is therefore directed at slowing, stopping, or reversing the progression of disease. Evidence points to improved liver histology with therapies that result in sustained body weight reduction. Incretin-based molecules, such as glucagon-like peptide-1 receptor agonists (GLP-1 RAs), alone or in combination with glucose-dependent insulinotropic polypeptide (GIP) and/or glucagon receptor agonists, have shown benefit here, and several are under investigation for MASLD/MASH treatment. In this review, we discuss current published data on GLP-1, GIP/GLP-1, GLP-1/glucagon, and GLP-1/GIP/glucagon RAs in MASLD/MASH, focusing on their efficacy on liver histology, liver fat, and MASH biomarkers.

OR10-05 Improved Mental And Psychosocial Patient-Reported Outcomes Among People With Obesity Treated With Tirzepatide: Results From SURMOUNT-1 Study

Abstract Disclosure: J. Poon: Employee; Self; Eli Lilly & Company. Stock Owner; Self; Eli Lilly & Company. S. Zhang: Employee; Self; Eli Lilly & Company. Stock Owner; Self; Eli Lilly & Company. H. Kan: Employee; Self; Eli Lilly & Company. Stock Owner; Self; Eli Lilly & Company. M.C. Bunck: Employee; Self; Eli Lilly & Company. Stock Owner; Self; Eli Lilly & Company. J. Dunn: Employee; Self; Eli Lilly & Company. Stock Owner; Self; Eli Lilly & Company. A. Stefanski: Employee; Self; Eli Lilly & Company. Stock Owner; Self; Eli Lilly & Company. M. Murphy: Employee; Self; Eli Lilly & Company. Stock Owner; Self; Eli Lilly & Company. Background: Living with obesity negatively impacts a person’s mental health and psychosocial function, leading to impaired health-related quality of life (HRQoL). Tirzepatide resulted in clinically sustained reductions in body weight among participants with obesity in SURMOUNT-1, a Phase 3 randomized clinical trial. To determine the impact of tirzepatide treatment on mental health and psychosocial function, changes in HRQoL were assessed in SURMOUNT-1 using the Short Form 36 health survey version 2 acute form (SF-36v2) and the Impact of Weight on Quality of Life-Lite Clinical Trials Version (IWQOL-Lite-CT). Methods: A total of 2,539 participants were included in the study (tirzepatide 5 mg, N=630; 10 mg, N=636; 15 mg, N=630; placebo, N=643). The SF-36v2 (36 items) and IWQOL-Lite-CT (20 items) were collected at both baseline and endpoint of primary treatment period (week 72 or early discontinuation, where last observation was carried forward (LOCF)). The SF-36v2 assesses eight domains of HRQoL including role-emotional and mental health, and yields two additional summary scores, including the Mental Component Summary (MCS) score. SF-36v2 scores are norm-based with mean (SD) 50 (10). IWQOL-Lite-CT assesses three primary composites, including 13-item psychosocial composite score. IWQOL-Lite-CT composite scores were transformed to a scale of 0 to 100. Higher scores of both SF-36v2 and IWQOL-Lite-CT indicates better levels of health and psychosocial function. Estimated mean change from baseline to week 72 for SF-36v2 (norm-based) and IWQOL-Lite-CT composite (transformed) scores were analyzed using an analysis of covariance (ANCOVA) model. Results: Mean scores at baseline for tirzepatide 5, 10, 15 mg doses and placebo for SF-36v2 role-emotional were 50.7, 51.0, 50.5, and 50.8, respectively, and for mental health were 53.4, 54.0, 53.4, and 53.4, respectively. Mean MCS scores at baseline for tirzepatide 5, 10, 15 mg doses and placebo were 53.3, 53.8, 53.4, and 53.5, respectively. Mean scores at baseline for tirzepatide 5, 10, 15 mg doses and placebo for IWQOL-Lite-CT psychosocial composite score were 64.3, 62.1, 63.2, and 63.2, respectively. All doses of tirzepatide showed significant improvements at week 72 compared to placebo for both SF-36v2 and IWQOL-Lite-CT scores (p<0.05). Estimated mean change from baseline to week 72 with tirzepatide 5, 10, 15 mg doses versus placebo were as follows: SF-36v2 role-emotional scores, 1.7, 1.3, and 1.8, versus 0.3 (p<0.05); SF-36v2 mental health scores 0.8, 0.8, and 1.1, versus -0.2 (p<0.05); SF-36v2 MCS scores were 0.7, 0.4, and 0.7 versus -0.5 (p<0.05); IWQOL-Lite-CT psychosocial scores 19.6, 22.1, and 23.6 versus 11.0 (p<0.001). Conclusion: In SURMOUNT-1, tirzepatide demonstrated statistically significant improvements in patient-reported mental health and psychosocial function as assessed by SF-36v2 and IWQOL-Lite-CT, compared to placebo. Presentation: Friday, June 16, 2023

SAT658 Tirzepatide Reduces The Predicted Risk Of Developing Atherosclerotic Cardiovascular Disease: A Post-hoc Analysis Of The Surmount-1 Trial

Abstract Disclosure: E.R. Hankosky: Employee; Self; Eli Lilly & Company. Stock Owner; Self; Eli Lilly & Company. H. Wang: Other; Self; Eli Lilly & Company. N.M. Lisa: Employee; Self; Eli Lilly & Company. Stock Owner; Self; Eli Lilly & Company. H. Kan: Employee; Self; Eli Lilly & Company. Stock Owner; Self; Eli Lilly & Company. F. Wang: Employee; Self; Eli Lilly & Company. Stock Owner; Self; Eli Lilly & Company. N.N. Ahmad: Employee; Self; Eli Lilly & Company. Stock Owner; Self; Eli Lilly & Company. A. Stefanski: Grant Recipient; Self; Eli Lilly & Company. Employee; Self; Eli Lilly & Company. Stock Owner; Self; Eli Lilly & Company. W. Garvey: Consulting Fee; Self; Eli Lilly & Company, Novo Nordisk, Boehringer Ingelheim, Pfizer, Inc., Fractyl Laboratories, Merck. Grant Recipient; Self; Eli Lilly & Company, Novo Nordisk, Pfizer, Inc. Background: Tirzepatide (TZP) resulted in substantial and sustained body weight reduction among participants with obesity or overweight in SURMOUNT-1, a phase 3 randomized clinical trial. Using predictive modelling, the current study assessed the impact of TZP treatment on the 10-year risk of developing atherosclerotic cardiovascular disease (ASCVD) among SURMOUNT-1 participants. Methods: The American College of Cardiology/American Heart Association (ACC/AHA) risk engine was applied to data from SURMOUNT-1 participants free of ASCVD at baseline. ASCVD risk scores were calculated at baseline, 24, and 72 weeks. The model inputs were age, total cholesterol, high density lipoprotein, systolic blood pressure, hypertension treatment, diabetes, and smoking status. Mean percent change in the 10-year risk score from baseline to week 72 was compared between TZP groups and placebo (PBO) using Mixed Model for Repeated Measures (MMRM), adjusted for baseline risk scores and country; risk scores were analyzed on log-scale. Since the risk score was low in the overall SURMOUNT-1 population, a subgroup analysis was conducted in participants with higher ASCVD risk at baseline (score≥7.5%, ACC/AHA intermediate-to-high risk). Results: A total of 2461 participants (TZP 5 mg, n=614; 10 mg, n=616; 15 mg, n=609; PBO, n=622) were included (mean age=45 years; female=68%; White=70%). At baseline, the median 10-year predicted risk score ranged from 1.5%–1.6% and did not differ across treatment groups. Median absolute risk scores for TZP 5/10/15 mg and PBO groups were 1.4%, 1.2%, 1.3%, and 1.6% at week 24, and 1.3%, 1.2%, 1.1%, and 1.7% at week 72, respectively. At week 72, MMRM-estimated relative change in risk from baseline was -16.4%, -23.5%, -22.4%, and 12.7% for TZP 5/10/15mg and PBO, leading to significantly greater reduction for TZP groups compared to PBO (TZP 5 mg: -25.8%; 10 mg: -32.1%; 15 mg: -31.1%; p≤0.001). Among 272 participants (TZP 5 mg, n=83; 10 mg, n=66; 15 mg, n=55; PBO, n=68) with intermediate-to-high baseline ASCVD risk, median risk scores for TZP 5/10/15 mg and PBO groups were: baseline: 11.3%, 10.5%, 10.9%, 10.1%; week 72: 11.3%, 9.0%, 10.3%, 11.7%, respectively. MMRM-estimated relative risk reduction at week 72 was -10.3%, -20.6%, -16.1%, and 6.4% for TZP 5/10/15 mg and PBO groups, respectively. Consistent with the primary analysis, relative risk reduction was significantly greater in TZP groups compared to PBO (TZP 5 mg = -15.7%; 10 mg = -25.3%; 15 mg = -21.1%; p≤0.01). Conclusion: TZP treatment significantly reduced the 10-year predicted risk of developing ASCVD compared to PBO, though the magnitude of reduction in absolute risk scores was small due to low baseline risk in the overall population. Among participants with higher ASCVD risk at baseline, TZP treatment resulted in larger absolute reductions in risk along with significant relative risk reduction consistent with the primary analysis. Presentation: Saturday, June 17, 2023

Tirzepatide - a novel dual GLP-1 and GIP receptor agonist used in pharmacotherapy of obesity: A literature review

Background: Obesity is a chronic disease, which along with its complications, poses a huge threat to both our health as individuals and our healthcare as a community.
 Objective: The aim of this work is to review efficacy and safety of Tirzepatide, a novel dual GIP/GLP-1 receptor agonist in the treatment of obesity
 Method: A literature review was conducted on databases such as PubMed and Google Scholar using terms “obesity”, “obesity treatment”, “glucagon-like peptide 1”, “Glucose-dependent insulinotropic polypeptide”, “Tirzepatide” as keywords. The review was performed in accordance with the PRISMA guidelines.
 Results: Administration of tirzepatide once weekly provides a substantial and sustained reduction in bodyweight with little side effects.
 Conclusions: Clinical trials showed both high efficacy and safety of Tirzepatide in management of obesity. Due to its novel, broadened mechanism of action it seems to be the most effective drug for reducing bodyweight available on the market. Tirzepatide could be our answer to tackling the problem of world-wide obesity epidemic.

Tirzepatide Once Weekly for the Treatment of Obesity

BackgroundObesity is a chronic disease that results in substantial global morbidity and mortality. The efficacy and safety of tirzepatide, a novel glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, in people with obesity are not known.MethodsIn this phase 3 double-blind, randomized, controlled trial, we assigned 2539 adults with a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of 30 or more, or 27 or more and at least one weight-related complication, excluding diabetes, in a 1:1:1:1 ratio to receive once-weekly, subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 72 weeks, including a 20-week dose-escalation period. Coprimary end points were the percentage change in weight from baseline and a weight reduction of 5% or more. The treatment-regimen estimand assessed effects regardless of treatment discontinuation in the intention-to-treat population.ResultsAt baseline, the mean body weight was 104.8 kg, the mean BMI was 38.0, and 94.5% of participants had a BMI of 30 or higher. The mean percentage change in weight at week 72 was −15.0% (95% confidence interval [CI], −15.9 to −14.2) with 5-mg weekly doses of tirzepatide, −19.5% (95% CI, −20.4 to −18.5) with 10-mg doses, and −20.9% (95% CI, −21.8 to −19.9) with 15-mg doses and −3.1% (95% CI, −4.3 to −1.9) with placebo (P<0.001 for all comparisons with placebo). The percentage of participants who had weight reduction of 5% or more was 85% (95% CI, 82 to 89), 89% (95% CI, 86 to 92), and 91% (95% CI, 88 to 94) with 5 mg, 10 mg, and 15 mg of tirzepatide, respectively, and 35% (95% CI, 30 to 39) with placebo; 50% (95% CI, 46 to 54) and 57% (95% CI, 53 to 61) of participants in the 10-mg and 15-mg groups had a reduction in body weight of 20% or more, as compared with 3% (95% CI, 1 to 5) in the placebo group (P<0.001 for all comparisons with placebo). Improvements in all prespecified cardiometabolic measures were observed with tirzepatide. The most common adverse events with tirzepatide were gastrointestinal, and most were mild to moderate in severity, occurring primarily during dose escalation. Adverse events caused treatment discontinuation in 4.3%, 7.1%, 6.2%, and 2.6% of participants receiving 5-mg, 10-mg, and 15-mg tirzepatide doses and placebo, respectively.ConclusionsIn this 72-week trial in participants with obesity, 5 mg, 10 mg, or 15 mg of tirzepatide once weekly provided substantial and sustained reductions in body weight. (Supported by Eli Lilly; SURMOUNT-1 ClinicalTrials.gov number, NCT04184622.)

Review article: role of glucagon-like peptide-1 receptor agonists in non-alcoholic steatohepatitis, obesity and diabetes-what hepatologists need to know.

SummaryBackgroundNon‐alcoholic steatohepatitis (NASH) is characterised by hepatic lipid accumulation, cell injury, inflammation and fibrosis. Insulin resistance, a hallmark of type 2 diabetes (T2D) and obesity, is a key pathogenic driver of NASH. Other than difficult‐to‐maintain lifestyle changes, there are no approved treatments for NASH. Due to their effects on multiple pathophysiological processes, glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) have been tested in disorders related to insulin resistance and metabolic defects.AimsTo summarise studies of GLP‐1RAs relevant to the treatment of NASH.MethodsPubMed searches were performed and results were compiled.ResultsLarge trials with GLP‐1RAs in T2D demonstrate highly effective glucose lowering, with body weight loss, and in some cases, reduced cardiovascular events and improved liver transaminases. The GLP‐1RAs, liraglutide and semaglutide, were associated with clinically relevant, sustained body weight reduction in individuals with overweight or obesity and without T2D. In a phase II trial in NASH, liraglutide reduced metabolic dysfunction, insulin resistance and lipotoxicity in key organs associated with NASH pathogenesis. Furthermore, liraglutide and semaglutide led to histological resolution of NASH in ~40% to 60% of patients, although a statistically significant effect on fibrosis has not been confirmed. Regarding safety, GLP‐1RAs are associated with gastrointestinal and gallbladder‐related adverse events, with the latter perhaps related to weight loss. Meta‐analyses do not indicate increased risk of acute pancreatitis, pancreatic cancer or other malignancies with GLP‐1RAs.ConclusionsThese studies support the use of GLP‐1RAs for the improvement of underlying metabolic dysfunction observed in NASH and suggest further long‐term phase III trials are warranted.

Use of sodium-glucose co-transporter-2 inhibitors in Asian patients with type 2 diabetes and kidney disease: An Asian perspective and expert recommendations.

Early onset of type 2 diabetes and a high prevalence of co‐morbidities predispose the Asian population to a high risk for, and rapid progression of, diabetic kidney disease (DKD). Apart from renin‐angiotensin system inhibitors, sodium‐glucose co‐transporter‐2 (SGLT‐2) inhibitors have been shown to delay renal disease progression in patients with DKD. In this review article, we consolidate the existing literature on SGLT‐2 inhibitor use in Asian patients with DKD to establish contemporary guidance for clinicians. We extensively reviewed recommendations from international and regional guidelines, data from studies on Asian patients with DKD, global trials (DAPA‐CKD, CREDENCE and DELIGHT) and cardiovascular outcomes trials. In patients with DKD, SGLT‐2 inhibitor therapy significantly reduced albuminuria and the risk of hard renal outcomes (defined as the onset of end‐stage kidney disease, substantial decline in renal function from baseline and renal death), cardiovascular outcomes and hospitalization for heart failure. In all the cardiovascular and renal outcomes trials, there was an initial decline in the estimated glomerular filtration rate (eGFR), which was followed by a slowing in the decline of renal function compared with that seen with placebo. Despite an attenuation in glucose‐lowering efficacy in patients with low eGFR, there were sustained reductions in body weight and blood pressure, and an increase in haematocrit. Based on the available evidence, we conclude that SGLT‐2 inhibitors represent an evidence‐based therapeutic option for delaying the progression of renal disease in Asian patients with DKD and preserving renal function in patients at high risk of kidney disease.

Use of SGLT-2 Inhibitors in Patients with Type 2 Diabetes Mellitus and Abdominal Obesity: An Asian Perspective and Expert Recommendations.

The prevalence of obesity in Asia is of epidemic proportions, with an estimated 1 billion overweight/obese individuals in the region. The majority of patients with type 2 diabetes mellitus (T2DM) are overweight/obese, which increases the risk of cardiorenal outcomes in these patients; hence, sustained reductions in body weight and visceral adiposity are important management goals. However, most of the glucose-lowering therapies such as insulin, sulfonylureas, glinides, and thiazolidinediones induce weight gain, which makes the management of overweight/obese T2DM patients challenging. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are the only oral glucose-lowering agents that have been shown to reduce body weight and visceral adiposity. In addition, SGLT-2 inhibitors therapy reduces ectopic fat deposition and improves adipose tissue function and weight-related quality of life. In this article, we aim to consolidate the existing literature on the effects of SGLT-2 inhibitors in Asian patients with T2DM and to produce clinical recommendations on their use in overweight or obese patients with T2DM. Recommendations from international and regional guidelines, as well as published data from clinical trials in Asian populations and cardiovascular outcomes trials are reviewed. Based on the available data, SGLT-2 inhibitors represent an evidence-based therapeutic option for the management of overweight/obese patients with T2DM.

Pseudomonas aeruginosa-derived pyocyanin reduces adipocyte differentiation, body weight, and fat mass as mechanisms contributing to septic cachexia

Pseudomonas aeruginosa, a leading cause of sepsis, produces pyocyanin, a blue-pigmented virulence factor. Sepsis is associated with cachexia, but mechanisms are unknown and conventional nutrition approaches are not effective treatments. Pyocyanin has affinity for the aryl hydrocarbon receptor (AhR), which is expressed on adipocytes and regulates adipocyte differentiation. The purpose of this study was to define in vitro and in vivo effects of pyocyanin on adipocyte differentiation and body weight regulation as relates to septic cachexia. In 3T3-L1 preadipocytes, pyocyanin activated AhR and its downstream marker CYP1a1, and reduced differentiation. Administration of pyocyanin to male C57BL/6J mice acutely reduced body temperature with altered locomotion, but caused sustained weight loss. Chronic pyocyanin administration to male and female C57BL/6J mice resulted in sustained reductions in body weight and fat mass, with adipose-specific AhR activation. Pyocyanin-treated male mice had decreased energy expenditure and physical activity, and increased adipose explant lipolysis. In females, pyocyanin caused robust reductions in body weight, adipose-specific AhR activation, and increased expression of inflammatory cytokines in differentiated adipocytes. These results demonstrate that pyocyanin reduces adipocyte differentiation and decreases body weight and fat mass in male and female mice, suggesting that pyocyanin may play a role in septic cachexia.

MON-LB020 Compound H Causes a Sustained Reduction in Food Intake and Body Weight in Obese Cynomolgus

Obesity is associated with increased risk of diabetes and cardiovascular disease. Evidence is accumulating that significant WL (>10%) may reduce this risk. GDF15 is a secreted circulating polypeptide associated with energy balance. The receptor for GDF15, Gfral, is expressed in the area postrema and mediates the inhibitory effects of GDF15 on food intake. Compound H (CpdH) is a GDF15 agonist on a half-life extension platform, suitable for once-weekly dosing. We sought to test the durability of the food intake suppression and body weight loss with once weekly dosing of CpdH in the spontaneously obese cynomolgus non-human primate (NHP) model. As a translational control we included dulaglutide (dula), a long-acting GLP-1 agonist, to enable efficacy modeling and validation of the animal model. PK/PD simulations derived from single-dose lean and obese NHP studies were used for dose selection; CpdH or dula was administered SC once weekly in a biologic naïve spontaneously obese cynomolgus (population BMI 46.0±1.0Kg/m2 with 15.1±1.5% total body fat (n=32) at baseline). Chronic treatment of animals with CpdH at 1 and 10nmol/kg once weekly reduced food intake in a dose related manner relative to vehicle. A commensurate, sustained reduction in body weight (up to 16.2±4.9%) was observed at steady state exposures. The injection of dulaglutide control caused rapid, transient reduction in food intake and a 3.8% reduction in vehicle corrected body weight over 12 weeks. A dose-response relationship for CpdH was formally demonstrated. In conclusion, CpdH is a novel agent for the treatment of human obesity and type 2 diabetes. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Nonalcoholic Fatty Liver Disease and Obesity Treatment.

Nonalcoholic fatty liver disease (NAFLD), the most prevalent cause of chronic liver disease worldwide, is strongly associated with obesity and insulin resistance. Significant weight loss can improve NAFLD and nonalcoholic steatohepatitis (NASH). Diet and exercise that result in a sustained body weight reduction of 7-10% can improve liver fat content, NASH, and fibrosis. Vitamin E can be considered in patients with biopsy-proven NASH without diabetes, though caution must be used in those with prostate cancer. Pioglitazone improves liver histology, including fibrosis, and can be considered in patients with or without diabetes. Glucagon-like peptide-1 (GLP-1) antagonists may be beneficial in NASH, but more studies are needed before they can be recommended. Bariatric surgery, with resultant weight loss, can result in improvement in liver fat and inflammation. NAFLD treatment includes diet and exercise with a target 7-10% weight reduction. Treatment goals include improvements in liver fat content, liver inflammation, and fibrosis.

Results of VERTIS SU extension study: safety and efficacy of ertugliflozin treatment over 104 weeks compared to glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin

Objective: To assess the safety and efficacy of ertugliflozin over 104 weeks in patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin.Methods: In this double-blind, multicenter, randomized, phase III study (VERTIS SU; NCT01999218), adults with T2DM and glycated hemoglobin (HbA1c) 7.0–9.0% on metformin ≥1500 mg/day received ertugliflozin 5 mg or 15 mg, or glimepiride. The primary efficacy time point was Week 52; double-blinded treatment continued until Week 104.Results: Baseline characteristics of randomized, treated patients (n = 1315) were similar across groups (mean age 58.2 years, HbA1c 7.8%); 76.4% completed the study; 61.6% completed on study medication. Mean glimepiride dose at 104 weeks was 3.5 mg/day. At Week 104, least squares mean change from baseline in HbA1c (95% confidence intervals) were −0.3% (−0.4, −0.2), −0.4% (−0.5, −0.3) and −0.4% (−0.5, −0.3) for ertugliflozin 5 mg, 15 mg, and glimepiride, respectively. Ertugliflozin provided sustained reductions in body weight and systolic blood pressure (SBP) over 104 weeks. The incidence of adverse events (AEs) and serious AEs was similar across groups. The incidence of symptomatic hypoglycemia was 3.8%, 6.4% and 22.1% in the ertugliflozin 5 mg, 15 mg, and glimepiride groups, respectively. Genital mycotic infections were reported in 5.3%, 2.6% and 0% of men, respectively, and 9.2%, 12.3% and 1.4% of women, respectively. The incidence of urinary tract infection and hypovolemia AEs was similar across groups.Conclusions: Ertugliflozin was well tolerated and provided clinically meaningful glycemic control and durable reductions in body weight and SBP over 104 weeks.Trial registration: ClinicalTrials.gov identifier: NCT01999218.

Effectiveness of testosterone therapy in obese men with low testosterone levels, for losing weight, controlling obesity complications, and preventing cardiovascular events: Protocol of a systematic review of randomized controlled trials.

The use of testosterone replacement therapy in obese men with low testosterone levels has been controversial. This review aims to analyze the effectiveness of testosterone therapy for weight loss and preventing cardiovascular complications in obese men with low testosterone levels. We will perform a systematic review according to Cochrane Methodology of randomized studies, including crossover studies, wherein patients are allocated into one of the two groups: testosterone therapy and control (no treatment or placebo). The primary outcomes analyzed will be: weight loss, adverse events, quality of life, improvement of libido, control of obesity complications, frequency of cardiovascular events, and deaths. Four general and adaptive search strategies have been created for the following electronic health databases: Embase, Medline, LILACS, and CENTRAL. Two reviewers will independently select the eligible studies, assess the risk of bias, and extract the data from included studies. Similar outcomes measured in at least two trials will be plotted in the meta-analysis using Review Manager 5.3. The quality of evidence of the effect estimate of the intervention for the outcomes that could be plotted in the meta-analysis will be generated according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group. Although testosterone replacement seems to be an attractive treatment modality for obese men with low testosterone, its potential benefits has been refuted by some studies, whose results have not shown significant differences between treated and untreated patients. For obese men with low testosterone concentrations, the proposed systematic review aims to answer the following questions: When compared with no treatment or placebo: Is testosterone therapy safe? Is testosterone therapy effective in promoting weight loss, a sustained reduction in body weight and changes in body composition? Is testosterone effective in improving quality of life, libido, and erectile function? Is testosterone therapy effective in controlling obesity complications and in preventing cardiovascular events?

Dapagliflozin once daily plus exenatide once weekly in obese adults without diabetes: Sustained reductions in body weight, glycaemia and blood pressure over 1 year

AimsDapagliflozin and exenatide reduce body weight by differing mechanisms. Dual therapy with these agents reduces body weight, adipose tissue volume, glycaemia and systolic blood pressure (SBP) over 24 weeks. Here, we examined these effects over 1 year in obese adults without diabetes.Materials and methodsObese adults without diabetes (N = 50; aged 18‐70 years; body mass index, 30‐45 kg/m2) were initially randomized to double‐blind oral dapagliflozin 10 mg once daily plus subcutaneous long‐acting exenatide 2 mg once weekly or to placebo. They entered an open‐label extension from 24 to 52 weeks during which all participants received active treatment.ResultsOf the original 25 dapagliflozin + exenatide‐treated and 25 placebo‐treated participants, respectively, 21 (84%) and 17 (68%) entered the open‐label period and 16 (64%) and 17 (68%) completed 52 weeks of treatment. At baseline, mean body weight was 104.6 kg, and 73.5% of participants had prediabetes (impaired fasting glucose or impaired glucose tolerance). Reductions with dapagliflozin + exenatide at 24 weeks were sustained at 52 weeks, respectively, for body weight (−4.5 and −5.7 kg), total adipose tissue volume (−3.8 and −5.3 L), proportion with prediabetes (34.8% and 35.3%), and SBP (−9.8 and −12.0 mm Hg). Effects on body weight, SBP and glycaemia at 52 weeks with placebo → dapagliflozin + exenatide were similar to those observed with continuation of dapagliflozin + exenatide. Nausea and injection‐site reactions were more frequent with dapagliflozin + exenatide than with placebo and diminished over time. Safety and tolerability were similar to that in previous diabetes trials with these agents. No clear difference in adverse event‐related withdrawals between placebo and active treatment periods was observed.ConclusionsDapagliflozin + exenatide dual therapy produced sustained reductions in body weight, prediabetes and SBP over 52 weeks and was well tolerated in obese adults without diabetes.

Repeated restraint stress lowers the threshold for response to third ventricle CRF administration

Rats and mice exposed to repeated stress or a single severe stress exhibit a sustained increase in energetic, endocrine, and behavioral response to subsequent novel mild stress. This study tested whether the hyper-responsiveness was due to a lowered threshold of response to corticotropin releasing factor (CRF) or an exaggerated response to a standard dose of CRF. Male Sprague–Dawley rats were subjected to 3h of restraint on each of 3 consecutive days (RRS) or were non-restrained controls. RRS caused a temporary hypophagia but a sustained reduction in body weight. Eight days after the end of restraint, rats received increasing third ventricle doses of CRF (0–3.0μg). The lowest dose of CRF (0.25μg) increased corticosterone release in RRS, but not control rats. Higher doses caused the same stimulation of corticosterone in the two groups of rats. Fifteen days after the end of restraint, rats were food deprived during the light period and received increasing third ventricle doses of CRF at the start of the dark period. The lowest dose of CRF inhibited food intake during the first hour following infusion in RRS, but not control rats. All other doses of CRF inhibited food intake to the same degree in both RRS and control rats. The lowered threshold of response to central CRF is consistent with the chronic hyper-responsiveness to CRF and mild stress in RRS rats during the post-restraint period.

Effects of canagliflozin on body weight and body composition in patients with type 2 diabetes over 104 weeks

ABSTRACTObjectives: Canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, has been associated with weight loss in a broad range of patients with type 2 diabetes mellitus (T2DM). This analysis further evaluated changes in body weight and composition with canagliflozin in two 104-week, Phase 3 studies.Methods: In Study 1, patients aged 18–80 years (N = 1,450) received canagliflozin 100 or 300 mg or glimepiride as add-on to metformin for a 52-week core treatment period, followed by a 52-week extension period. In Study 2, patients aged 55–80 years (N = 714) received canagliflozin 100 or 300 mg or placebo added to stable background antihyperglycemic agents for a 26-week core treatment period, followed by a 78-week extension period. Percent change from baseline in body weight; proportion of patients with any weight loss, ≥5% weight loss, and ≥10% weight loss; change in body mass index (BMI) and waist circumference; change in body weight across weight-loss quartiles; and changes in body composition were evaluated in both studies.Results: Canagliflozin 100 and 300 mg provided sustained weight loss versus either glimepiride or placebo over 104 weeks. More patients experienced any weight loss and ≥5% weight loss with canagliflozin versus comparator. Across the 3 highest weight-loss quartiles, canagliflozin provided greater weight loss versus glimepiride or placebo. BMI and waist circumference reductions were observed with canagliflozin 100 and 300 mg versus either glimepiride or placebo over 104 weeks; more patients had BMI or waist circumference reductions with canagliflozin versus comparator. Body composition analysis indicated that the majority of weight loss was due to loss of fat mass. Canagliflozin was generally well tolerated, with increased incidence of adverse events related to the SGLT2 inhibition mechanism.Conclusions: Canagliflozin 100 and 300 mg provided sustained reductions in body weight, BMI, and waist circumference in a greater proportion of patients with T2DM versus glimepiride or placebo over 104 weeks.Trial registration: ClinicalTrials.gov NCT00968812, NCT01106651

Beneficial Effects of a Dietary Weight Loss Intervention on Human Gut Microbiome Diversity and Metabolism Are Not Sustained during Weight Maintenance

Objective: In the present study, we examined the effect of a very low-calorie diet(VLCD)-based obesity program on human gut microbiome diversity and metabolism during weight loss and weight maintenance. Methods: Obese subjects underwent 3 months of VLCD followed by 3 months of weight maintenance. A lean and an obese control group were included. The microbiome was characterized by performing high-throughput dual-indexed 16S rDNA amplicon sequencing. Results: At baseline, a significant difference in the Firmicutes/Bacteroidetes ratio between the lean and obese individuals was observed (p = 0.047). The VLCD resulted in significant alterations in gut microbiome diversity from baseline to 3 months (p = 0.0053). Acinetobacter represented an indicator species for the observed effect (indicator value = 0.998, p = 0.006). Metabolic analyses revealed alterations of the bacterial riboflavin pathway from baseline to 3 months (p_nom = 0.0078). These changes in diversity and bacterial metabolism induced by VLCD diminished during the weight maintenance phase, despite sustained reductions in body weight and sustained improvements of insulin sensitivity. Conclusion: The present data show that a VLCD is able to beneficially alter both gut microbiome diversity and metabolism in obese humans, but that these changes are not sustained during weight maintenance. This finding might suggest that the microbiome should be targeted during obesity programs.

Liraglutide in obesity: a guide to its use in the EU

Liraglutide (Saxenda®; 3 mg dose), a glucagon-like peptide-1 receptor agonist, is indicated as an adjunct to a reduced-calorie diet and increased physical activity for weight management in adult patients with an initial body mass index of ≥30 kg/m2 or ≥27 to <30 kg/m2 in the presence of at least one bodyweight-related co-morbidity (e.g. dysglycaemia, dyslipidaemia, hypertension, obstructive sleep apnoea). Clinical data in these patient populations indicates that subcutaneous liraglutide 3.0 mg once daily provides clinically meaningful (i.e. 5–10 % reduction) and sustained reductions in bodyweight and is generally well tolerated.

The gut sensor as regulator of body weight.

The gastrointestinal (GI) tract comprises a large endocrine organ that regulates not only nutrient sensing and metabolising but also satiety and energy homeostasis. More than 20 hormones secreted from the stomach, intestine, and pancreas as well as signaling mediators of the gut microbiome are involved in this process. A better understanding of how related pathways affect body weight and food intake will help us to find new strategies and drugs to treat obesity. For example, weight loss secondary to lifestyle intervention is often accompanied by unfavorable changes in multiple GI hormones, which may cause difficulties in maintaining a lower body weight status. Conversely, bariatric surgery favorably changes the hormone profile to support improved satiety and metabolic function. This partially explains stronger sustained body weight reduction resulting in better long-term results of improved metabolic functions. This review focuses on GI hormones and signaling mediators of the microbiome involved in satiety regulation and energy homeostasis and summarizes their changes following weight loss. Furthermore, the potential role of GI hormones as anti-obesity drugs is discussed.