A polyphenol fraction from Rosa multiflora var. platyphylala reduces body fat in overweight humans through appetite suppression - a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Rosa species are rich sources of polyphenols with physiological functions. In this study a polyphenol-rich Rosa multiflora (var. platyphylala) petal extract (RoseFit™) was investigated for weight loss in humans. METHODS: In a randomized, placebo-controlled, parallel-group, double-blind clinical trial seventy overweight male and female subjects (20-50 years) with body mass index (BMI) 25-30 kg/m2 were randomly allocated to the active treatment group (RoseFit) and placebo group in a 1:1 ratio. The subjects received 300 mg capsules twice daily for 12 weeks. The primary efficacy outcome measures included body weight, BMI, and body composition, as determined using Dual-energy X-ray absorptiometry (DEXA). Secondary measures consisted of serum lipid profile and appetite marker (leptin and ghrelin) analyses. Safety analyses included biochemical and hematological assessments. RESULTS: At the end of the study, a marked reduction in body weight (-1.20 ± 2.62 kg, p < 0.05) and BMI from baseline was observed in the RoseFit group. In addition, the body fat % (RoseFit = -1.69 ± 2.59%, placebo = 0.96 ± 3.21%; p < 0.001) and fat mass (RoseFit = -1.75 ± 1.80 kg, placebo = 1.61 ± 3.82 kg; p < 0.001) were significantly abated in RoseFit group. Importantly, the lean mass was maintained during the intervention. RoseFit ingestion significantly increased the serum leptin levels compared to the placebo (4.85%; p < 0.05). Further, RoseFit group showed reduction in the hunger hormone ghrelin level (2.27%; p < 0.001) from baseline to the end of study, compared to the placebo. The subjective evaluation of appetite using visual analog scale (VAS) questionnaires further confirmed the appetite-suppression effects of RoseFit. The lipid profile significantly improved in RoseFit-treated subjects. No serious adverse events were observed during the study, indicating the tolerability of RoseFit. CONCLUSIONS: Supplementation with RoseFit significantly impacts body weight management and can thus be a potential nutraceutical ingredient for sustainable weight loss. TRIAL REGISTRATION: CTRI/2019/10/021584 dated 09/10/2019.

Effect of semaglutide 2.4 mg on physical functioning and weight- and health-related quality of life in adults with overweight or obesity: Patient-reported outcomes from the STEP 1-4 trials.

AIMS: To summarize the effects of semaglutide 2.4 mg on weight-related quality of life (WRQOL) and health-related quality of life (HRQOL), focusing on the confirmatory secondary endpoint of physical functioning. MATERIALS AND METHODS: The STEP 1-4 Phase 3a, 68-week, double-blind, randomized controlled trials assessed the efficacy and safety of semaglutide 2.4 mg versus placebo in individuals with overweight/obesity. WRQOL and HRQOL were assessed by change from baseline to Week 68 in two different but complementary measures, the Impact of Weight on Quality of Life-Lite Clinical Trials Version (IWQOL-Lite-CT; STEP 1 and 2) and the SF-36v2 Health Survey Acute (SF-36v2; STEP 1-4). RESULTS: Superiority for semaglutide 2.4 mg over placebo based on IWQOL-Lite-CT and SF-36v2 physical functioning scores was confirmed in STEP 1 and 2 and in STEP 1, 2 and 4, respectively. At Week 68, a greater proportion of participants treated with semaglutide 2.4 mg than with placebo reached meaningful within-person change (MWPC) thresholds for IWQOL-Lite-CT Physical Function scores in STEP 1 (51.8% vs. 28.3%; p < 0.0001) and STEP 2 (39.6% vs. 29.5%; p = 0.0083) and the MWPC threshold for SF-36v2 Physical Functioning in STEP 1 (39.8% vs. 24.1%; p < 0.0001), STEP 2 (41.0% vs. 27.3%; p = 0.0001) and STEP 4 (18.0% vs. 6.6%; p < 0.0001). All other IWQOL-Lite-CT and SF-36v2 scale scores in STEP 1-4 were numerically improved with semaglutide 2.4 mg versus placebo, except for SF-36v2 Role Emotional in STEP 2. CONCLUSIONS: Semaglutide 2.4 mg significantly improved physical functioning, with greater proportions of participants achieving MWPC compared with placebo, and showed beneficial effects on WRQOL and HRQOL beyond physical functioning.

Cost-effectiveness analysis of once-weekly semaglutide vs. once-daily liraglutide administered subcutaneously in patients with overweight and obesity: a decision analysis.

OBJECTIVE: Obesity presents an enduring and multifaceted dilemma that impacts individuals, society, economies, and healthcare systems alike. Glucagon-like peptide-1 (GLP-1) receptor agonists, including liraglutide and semaglutide, have received FDA approval for obesity treatment. This study aims to present a cost-effectiveness analysis to compare the cost and clinical outcomes of semaglutide vs. liraglutide on weight loss in people with overweight and obesity. MATERIALS AND METHODS: A cost-effectiveness analysis was conducted to compare the cost and the clinical outcomes of adding weekly 2.4 mg SC semaglutide vs. daily 3.0 mg SC liraglutide or placebo to physical activity and diet control in overweight and obese patients. A clinical outcome of achieving ≥15% weight loss was chosen. A simple decision analysis model from a third-payer perspective was applied. Drug costs were based on the retail price of the USA market. One-way sensitivity analyses were performed. RESULTS: Results showed that 2.4 mg weekly semaglutide, when added to physical activity and diet control, was the most cost-effective choice in terms of ≥15% weight loss (ICER: $ 7,056/patient/68 weeks). The model was robust against the 50% increase in the unit cost of semaglutide and the 50% decrease in the unit cost of liraglutide, as well as the changes in probabilities by the corresponding 95% confidence intervals across the model. CONCLUSIONS: This cost-effectiveness analysis suggests that employing once-weekly 2.4 mg semaglutide emerges as a remarkably cost-effective option when contrasted with once-daily 3.0 mg liraglutide in patients with overweight and obesity when added to physical activity and diet control.

Effect of liraglutide on thigh muscle fat and muscle composition in adults with overweight or obesity: Results from a randomized clinical trial.

BACKGROUND: Excess muscle fat is observed in obesity and associated with greater burden of cardiovascular risk factors and higher risk of mortality. Liraglutide reduces total body weight and visceral fat but its effect on muscle fat and adverse muscle composition is unknown. METHODS: This is a pre-specified secondary analysis of a randomized, double-blind, placebo-controlled trial that examined the effects of liraglutide plus a lifestyle intervention on visceral adipose tissue and ectopic fat among adults without diabetes with body mass index ≥30 kg/m2 or ≥27 kg/m2 and metabolic syndrome. Participants were randomly assigned to a once-daily subcutaneous injection of liraglutide (target dose 3.0 mg) or matching placebo for 40 weeks. Body fat distribution and muscle composition was assessed by magnetic resonance imaging at baseline and 40-week follow-up. Muscle composition was described by the combination of thigh muscle fat and muscle volume. Treatment difference (95% confidence intervals [CI]) was calculated by least-square means adjusted for baseline thigh muscle fat. The association between changes in thigh muscle fat and changes in body weight were assessed using Spearman correlation coefficients. The effect of liraglutide versus placebo on adverse muscle composition, denoted by high thigh muscle fat and low thigh muscle volume, was explored. RESULTS: Among the 128 participants with follow-up imaging (92.2% women, 36.7% Black), median muscle fat at baseline was 7.8%. The mean percent change in thigh muscle fat over median follow-up of 36 weeks was -2.87% among participants randomized to liraglutide (n = 73) and 0.05% in the placebo group (absolute change: -0.23% vs. 0.01%). The estimated treatment difference adjusted for baseline thigh muscle fat was -0.24% (95% CI, -0.41 to -0.06, P-value 0.009). Longitudinal change in thigh muscle fat was significantly associated with change in body weight in the placebo group but not the liraglutide group. The proportion of participants with adverse muscle composition decreased from 11.0% to 8.2% over follow-up with liraglutide, but there was no change with placebo. CONCLUSIONS: In a cohort of predominantly women with overweight or obesity in the absence of diabetes, once-daily subcutaneous liraglutide was associated with a reduction in thigh muscle fat and adverse muscle composition compared with placebo. The contribution of muscle fat improvement to the cardiometabolic benefits of liraglutide requires further study.

Efficacy and Safety of Once-Weekly Subcutaneous Semaglutide in Overweight or Obese Adults: A Systematic Review with Meta-Analysis.

BACKGROUND: To evaluate the efficacy and safety of once-weekly subcutaneous semaglutide treatment in overweight or obese patients without type 2 diabetes. METHODS: Randomized clinical trials that assessed the impact of once-weekly semaglutide on body weight and safety outcomes in overweight or obese patients were retrieved from PubMed, EMBASE, and Lilacs up to November 2023. Risk of bias was assessed with RoB 2.0, and certainty of evidence (CoE) with GRADE. A random-effects meta-analysis was conducted. RESULTS: Ten publications, with 22.155 patients, were included. Semaglutide decreased relative body weight (MD: -11.80; 95%CI: -13.53 to -10.07; CoE: High), absolute body weight (MD: -11.58; 95%CI: -13.25 to -9.90; CoE: High) and BMI (MD: -4.15; 95%CI: -4.85 to -3.45; CoE: High). Semaglutide also increased the proportion of patients who achieved 5%, 10%, and 15% of weight loss ([weight loss≥5%: RR 2.29, 95% CI: 1.88 to 2.80; CoE: High]; [weight loss≥10%: RR 4.54, 95% CI: 3.45 to 5.98; CoE: High]; [weight loss≥15%: RR 8.29, 95%CI: 5.54 to 12.39; CoE: High]). Semaglutide leads to small risk to adverse events (RR: 1.03; 95%CI: 1 to 1.06; CoE: High), no difference in the serious adverse events (RR: 1.07; 95%CI: 0.70 to 1.62; CoE: Low), but increases in the risk to discontinued treatment (RR: 2.03; 95%CI: 1.87 to 2.20; CoE: High) and gastrointestinal adverse events (RR: 3.26; 95%CI: 1.99 to 5.34; CoE: Moderate). CONCLUSION: This up-to-date systematic review highlights that once-weekly semaglutide treatment resulted in clinically important weight loss, becoming a promising adjuvant therapy for obesity.

Alpha lipoic acid administration improved both peripheral sensitivity to insulin and liver clearance of insulin reducing potential risk of diabetes and nonalcoholic fatty liver disease in overweight/obese PCOS patients.

OBJECTIVE: To evaluate the effects of alpha lipoic acid (ALA) on hormonal and metabolic parameters in a group of overweight/obese Polycystic Ovary Syndrome (PCOS) patients. METHODS: This was a retrospective study in which thirty-two overweight/obese patients with PCOS (n = 32) not requiring hormonal treatment were selected from the database of the ambulatory clinic of the Gynecological Endocrinology Center at the University of Modena and Reggio Emilia, Italy. The hormonal profile, routine exams and insulin and C-peptide response to oral glucose tolerance test (OGTT) were evaluated before and after 12 weeks of complementary treatment with ALA (400 mg/day). Hepatic Insulin Extraction (HIE) index was also calculated. RESULTS: ALA administration significantly improved insulin sensitivity and decreased ALT and AST plasma levels in all subjects, though no changes were observed on reproductive hormones. When PCOS patients were subdivided according to the presence or absence of familial diabetes background, the higher effects of ALA were observed in the former group that showed AST and ALT reduction and greater HIE index decrease. CONCLUSION: ALA administration improved insulin sensitivity in overweight/obese PCOS patients, especially in those with familial predisposition to diabetes. ALA administration improved both peripheral sensitivity to insulin and liver clearance of insulin. Such effects potentially decrease the risk of nonalcoholic fat liver disease and diabetes in PCOS patients.

A systematic review of the effect of semaglutide on lean mass: insights from clinical trials.

INTRODUCTION: Semaglutide, a glucagon-like peptide-1 receptor agonist, is associated with significant weight loss, yet its impact on lean body mass remains insufficiently understood. This review investigates the effect of semaglutide on lean mass in the context of obesity management. METHODOLOGY: This study investigates through different databases (PubMed, Elsevier, and Google Scholar) from 2016 for randomized control trials (RCTs) or observational studies that assessed the use of semaglutide in overweight or obese patients, regardless of whether they have type 2 diabetes or not. The studies compared semaglutide to a placebo or alternative medications. RESULTS: Six studies with 1,541 overweight or obese adults were included, and significant weight reductions were observed primarily due to fat mass loss. While the lean mass remained stable in some cases, notable reductions ranging from almost 0% to 40% of total weight reduction were observed in others. Noteworthy decreases in lean mass were particularly evident in larger trials, yet the proportion of lean mass relative to total body mass increased, suggesting a positive overall outcome. CONCLUSION: Semaglutide displays potential for weight loss primarily through fat mass reduction. However, concerns arise from notable reductions in lean mass, especially in trials with a larger number of patients.

Efficacy and Safety of Tirzepatide in Overweight and Obese Adult Patients with Type 1 Diabetes.

Introduction and Objective: Most patients with type 1 diabetes (T1D) in the United States are overweight (OW) or obese (OB), contributing to insulin resistance and suboptimal glucose control. The primary Food and Drug Administration-approved treatment for T1D is insulin, which may adversely affect weight. Tirzepatide is approved for managing type 2 diabetes, improves glucose control, facilitates weight loss, and improves cardiovascular disease outcomes. We assessed the use of tirzepatide in OW/OB subjects with T1D. Methods: This was a retrospective single-center real-world study in 62 OW/OB adult patients with T1D who were prescribed tirzepatide (treated group) and followed for 1 year. At least 3 months of use of tirzepatide was one of the inclusion criteria. Based on the inclusion criteria, this study represents 62 patients out of 184 prescribed tirzepatide. The control group included 37 OW/OB patients with T1D (computer frequency matched by age, duration of diabetes, gender, body mass index (BMI), and glucose control) who were not using any other weight-loss medications during the same period. The mean (±standard deviation [SD]) dose of weekly tirzepatide at 3 months was 5.6 ± 1.9 mg that increased to 9.7 ± 3.3 mg at 1 year. Results: The gender, mean baseline age, duration of diabetes, and glycosylated hemoglobin (HbA1c) were similar in the two groups, whereas BMI and weight were higher in the treated group. There were significantly larger declines in BMI and weight in the treated group than in controls across all time points among those in whom data were available. HbA1c decreased in the treated group as early as 3 months and was sustained through a 1-year follow-up (-0.67% at 1 year). As expected, insulin dose decreased at 3 months and throughout the study period. There were no reported hospitalizations from severe hypoglycemia or diabetic ketoacidosis. The mean glucose, time-in-range, time-above-range, SD, and coefficient of variation (continuous glucose monitoring metrics) significantly improved in the treated group. Conclusions: In this pilot (off label) study, we conclude that tirzepatide facilitated an average 18.5% weight loss (>46 pounds) and improved glucose control in OW/OB patients with T1D at 1 year. For safe use of tirzepatide in patients with T1D, we strongly recommend a large prospective randomized control trial in OW/OB patients with T1D.

Acute and two-week effects of neotame, stevia rebaudioside M and sucrose-sweetened biscuits on postprandial appetite and endocrine response in adults with overweight/obesity-a randomised crossover trial from the SWEET consortium.

BACKGROUND: Sweeteners and sweetness enhancers (S&SE) are used to replace energy yielding sugars and maintain sweet taste in a wide range of products, but controversy exists about their effects on appetite and endocrine responses in reduced or no added sugar solid foods. The aim of the current study was to evaluate the acute (1 day) and repeated (two-week daily) ingestive effects of 2 S&SE vs. sucrose formulations of biscuit with fruit filling on appetite and endocrine responses in adults with overweight and obesity. METHODS: In a randomised crossover trial, 53 healthy adults (33 female, 20 male) with overweight/obesity in England and France consumed biscuits with fruit filling containing 1) sucrose, or reformulated with either 2) Stevia Rebaudioside M (StRebM) or 3) Neotame daily during three, two-week intervention periods with a two-week washout. The primary outcome was composite appetite score defined as [desire to eat + hunger + (100 - fullness) + prospective consumption]/4. FINDINGS: Each formulation elicited a similar reduction in appetite sensations (3-h postprandial net iAUC). Postprandial insulin (2-h iAUC) was lower after Neotame (95% CI (0.093, 0.166); p < 0.001; d = -0.71) and StRebM (95% CI (0.133, 0.205); p < 0.001; d = -1.01) compared to sucrose, and glucose was lower after StRebM (95% CI (0.023, 0.171); p < 0.05; d = -0.39) but not after Neotame (95% CI (-0.007, 0.145); p = 0.074; d = -0.25) compared to sucrose. There were no differences between S&SE or sucrose formulations on ghrelin, glucagon-like peptide 1 or pancreatic polypeptide iAUCs. No clinically meaningful differences between acute vs. two-weeks of daily consumption were found. INTERPRETATION: In conclusion, biscuits reformulated to replace sugar using StRebM or Neotame showed no differences in appetite or endocrine responses, acutely or after a two-week exposure, but can reduce postprandial insulin and glucose response in adults with overweight or obesity. FUNDING: The present study was funded by the Horizon 2020 program: Sweeteners and sweetness enhancers: Impact on health, obesity, safety and sustainability (acronym: SWEET, grant no: 774293).

The association between previous use of anti-obesity medication and semaglutide weight loss outcomes.

AIMS: To compare weight loss outcomes between patients starting semaglutide who had previously been on another anti-obesity medication (AOM) compared to those who were AOM-naïve. MATERIALS AND METHODS: We performed a retrospective study in patients with overweight or obesity taking semaglutide for weight loss for a duration of 3 to 12 months. Our primary endpoint was assessment of percentage of total body weight loss (TBWL) in patients who started semaglutide as their first AOM (AOM-naïve) compared to those who started semaglutide and had previously taken another AOM (non-AOM-naïve). The secondary outcome was a comparison of the proportions of patients achieving ≥5%, ≥10%, ≥15% and ≥20% TBWL between the groups. Our endpoints were analysed using independent t-tests and ANOVA/ANCOVA for continuous variables and Pearson's test for categorical variables. RESULTS: This study included 305 patients. Outcomes of semaglutide treatment were superior in AOM-naïve patients (n = 231) compared to non-AOM-naïve patients (n = 74) at 3 (6.3% vs. 3.8%), 6 (10.6% vs. 6.7%), 9 (14.0% vs. 9.1%) and 12 months (14.3% vs. 10.6%; p < 0.0001 at 3, 6 and 9 months, and p = 0.01 at 12 months). A greater proportion of patients in the AOM-naïve group achieved a TBWL ≥ 15% (48% vs 21%; p = 0.02) and ≥20% (27% vs 4% p < 0.01) at 12 months. CONCLUSION: The use of semaglutide in patients with previous intake of other AOMs was associated with inferior weight loss outcomes in comparison to patients who were AOM-naïve.

Efficacy of Semaglutide in Overweight and Obese Patients with Type 1 Diabetes.

Introduction: More than two-thirds of patients with type 1 diabetes (T1D) are overweight (OW) and/or obese (OB) in the USA and Western Europe, resulting in insulin resistance as in type 2 diabetes. None of the currently available glucagon like polypeptide 1 (GLP-1) analogs are approved for patients with T1D. A higher dose of semaglutide has been approved by the Food and Drug Administration (FDA) for subjects with body mass index (BMI) >27 kg/m2. We evaluated the real-world use of semaglutide in patients with T1D. Methods: This was a retrospective chart review study of 50 OW or OB patients with T1D who were initiated on semaglutide and followed for 1 year. The control group comprised of 50 computer-matched patients (for sex, race, weight, BMI, and diabetes duration) during a similar time period and were not on any weight loss medications. Results: Most patients (92%) were non-Hispanic white in both arms. Mean ± standard deviation (SD) age and duration of diabetes were 42 ± 11 and 27 ± 12 years, respectively. The continuous glucose monitors (CGM), insulin pump use, baseline BMI and body weight were also similar in the two groups. Baseline glycosylated hemoglobin (HbA1c) was insignificantly lower in the semaglutide group (7.6% vs. 8.2%, respectively; P = non-significant [NS]). Total daily insulin dose (TDD) and insulin dose per kg body weight were higher in the semaglutide group at baseline with no difference in basal or prandial insulin dose. There were significantly greater declines in mean (±SD), BMI (7.9% ± 2.6%), body weight (15.9 lbs ± 5.4 lbs), HbA1c, CGM glucose SD and coefficient of variation (CV), and increase in CGM time in range (TIR) in the semaglutide group compared to the control group with no difference in insulin dose changes, time above range (TAR), or time below range (TBR). Conclusions: We conclude that use of semaglutide in patients who are OW and/or OB with T1D was effective in lowering body weight and BMI, and improving glycemic metrics in this pilot real-world study. We strongly recommend performing prospective, large-randomized clinical trials with newer GLP-1 analogs like semaglutide and tirzepatide (twin-cretin) for subjects with T1D associated with OW and/or OB.

In adults with overweight or obesity and CVD, but without diabetes, semaglutide reduced MACE at a mean 40 mo.

SOURCE CITATION: Lincoff AM, Brown-Frandsen K, Colhoun HM, et al; SELECT Trial Investigators. Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023;389:2221-2232. 37952131.

The effect of GnRH analog treatment on BMI in children treated for precocious puberty: a systematic review and meta-analysis.

INTRODUCTION: The purpose of the present meta-analysis was to systematically evaluate the effect of GnRHa treatment on the BMI of children with precocious puberty after GnRHa treatment as compared to before, and to analyze the effect of GnRHa treatment on the body composition of children with precocious puberty at different BMIs by classifying into normal body mass, overweight, and obese groups according to BMI at the time of initial diagnosis. CONTENT: A meta-analysis was performed using Stata 12.0 software by searching PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), Chinese Scientific Journal Database (VIP database), and Wan fang database for relevant literature on standard deviation score of body mass index (BMI-SDS) after GnRHa treatment as compared to before in children with precocious puberty. SUMMARY: A total of eight studies were included with a total sample size of 715 cases, and the results of meta-analysis showed that BMI-SDS increased in children with precocious puberty after GnRHa treatment as compared to before starting [(weighted mean difference (WMD)=0.23, 95 % CI: 0.14-0.33, p=0.000)] and also increased in children with normal body mass [(WMD=0.37, 95 % CI: 0.28-0.46, p=0.000)], and there was no significant change in BMI-SDS in children in the overweight or obese group [(WMD=0.01, 95 % CI: -0.08-0.10, p=0.775)]. OUTLOOK: Overall, there was an observed increase in BMI-SDS at the conclusion of GnRHa treatment in children with precocious puberty. Additionally, it was found that the effect of GnRHa treatment on body composition varied among children with different BMI status. Clinicians should emphasize the promotion of a healthy lifestyle and personalized dietary management for children.

Efficacy and safety of once weekly semaglutide 2·4 mg for weight management in a predominantly east Asian population with overweight or obesity (STEP 7): a double-blind, multicentre, randomised controlled trial.

BACKGROUND: Data on the benefits of the once weekly GLP-1 receptor agonist semaglutide 2·4 mg for weight management in people from east Asia are insufficient. The objective of this study was to determine the efficacy and safety of once weekly semaglutide 2·4 mg versus placebo for weight management in a predominantly east Asian adult population. METHODS: This randomised phase 3a, double-blind multicentre controlled trial (STEP 7) recruited participants from 23 hospitals and trial centres in China, Hong Kong, Brazil, and South Korea. Adults with overweight or obesity, with or without type 2 diabetes, were randomly assigned (2:1) to receive a subcutaneous injection of either semaglutide 2·4 mg or placebo once a week for 44 weeks, plus a diet and physical activity intervention. Randomisation was done in blocks of six with an interactive web response system and was stratified by diagnosis of type 2 diabetes. Participants, investigators, and the trial sponsor were masked to treatment allocation until after database lock. Primary endpoints were percentage change in mean bodyweight and proportion of participants having reached a weight reduction of at least 5% of bodyweight from baseline to week 44. Safety was assessed in all participants who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT04251156, and is now complete. FINDINGS: From Dec 8, 2020, to Aug 23, 2022, 448 participants were screened, of whom 375 were randomly assigned to either the semaglutide 2·4 mg group (n=249) or the placebo group (n=126). Estimated mean percentage change in bodyweight from baseline to week 44 was -12·1% (SE 0·5) with semaglutide 2·4 mg versus -3·6% (0·7) with placebo (estimated treatment difference -8·5 percentage points [95% CI -10·2 to -6·8]; p<0·0001). At week 44, the proportion of participants who lost 5% or more of their bodyweight was higher in the semaglutide 2·4 mg group than in the placebo group (203/238 [85%] vs 36/116 [31%]); odds ratio 13·1 (95% CI 7·4-23·1; p<0·0001). Adverse events were reported by 231 (93%) of 249 participants in the semaglutide 2·4 mg group and 108 (86%) of 126 participants in the placebo group, the most common of which were gastrointestinal disorders (168/249, 67% vs 45/126, 36%). INTERPRETATION: The results of this study support the use of semaglutide 2·4 mg for weight management in people of east Asian ethnicity with overweight or obesity and with or without type 2 diabetes. FUNDING: Novo Nordisk. TRANSLATIONS: For the Mandarin, Portuguese and South Korean translations of the abstract see Supplementary Materials section.

Does metformin reduce the risk of cancer in obesity and diabetes? A systematic review and meta-analysis.

AIM: To evaluate the effect of metformin on cancer incidence in subjects with overweight/obesity and/or prediabetes/diabetes. MATERIALS AND METHODS: We searched MEDLINE, Embase and CENTRAL for randomized controlled trials (RCTs) in adults with overweight/obesity and/or prediabetes/diabetes that compared metformin to other interventions for ≥24 weeks. Independent reviewers selected and extracted data including population and intervention characteristics and new diagnoses of cancer. We used the RoB 2.0 risk-of-bias tool and the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework to assess risk of bias and certainty of evidence. RESULTS: From 14 895 records after removal of duplicates, 27 trials were included, providing a total of 10 717 subjects in the metformin group and 10 003 in the control group, with 170 and 208 new cases of cancer, respectively. Using a random-effects model, the relative risk was 1.07 (95% confidence interval 0.87-1.31), with similar results in subgroup analyses by study duration or effect of control intervention on weight. Risk of bias in most studies was low, and no evidence of publication bias was found. Trial sequential analysis provided evidence that the cumulative sample size was large enough to exclude a significant effect of metformin on cancer incidence. CONCLUSIONS: Metformin did not reduce cancer incidence in RCTs involving subjects with overweight/obesity and/or prediabetes/diabetes.

Comparative effectiveness of biologics in patients with rheumatoid arthritis stratified by body mass index: a cohort study in a Swiss registry.

OBJECTIVES: Obesity is associated with lower treatment response in patients with rheumatoid arthritis (RA). In patients with obesity, abatacept was suggested as a preferable option to tumour necrosis factor-alpha inhibitors. We aimed to assess the comparative effectiveness of etanercept, infliximab and abatacept, compared with adalimumab, in patients with RA with obesity. Secondarily, we also investigated this in patients with overweight and normal weight for completeness. DESIGN: Observational cohort study. SETTING: Swiss Clinical Quality Management in Rheumatic Diseases (SCQM) registry (1997-2019). PARTICIPANTS: Adult patients with RA from the SCQM registry who received etanercept, infliximab, abatacept or adalimumab as their first biological or targeted synthetic disease-modifying antirheumatic drug were classified based on their body mass index (BMI) at the start of that treatment in three cohorts: obese, overweight, normal weight. They were followed for a maximum of 1 year. EXPOSURE: The study exposure of interest was the patients' first biological, particularly: etanercept, infliximab and abatacept, compared with adalimumab. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary study outcome was remission within 12 months, defined as 28-joint Disease Activity Score (DAS28) <2.6. Missingness was addressed using confounder-adjusted response rate with attrition correction. Logistic regression was used to compare the effectiveness of etanercept, infliximab and abatacept versus adalimumab. Each BMI cohort was addressed and analysed separately. RESULTS: The study included 443 obese, 829 overweight and 1243 normal weight patients with RA. There were no statistically significant differences in the odds of DAS28-remission at ≤12 months for etanercept, infliximab and abatacept, compared with adalimumab, in any of the BMI cohorts. CONCLUSIONS: No differences in DAS28-remission were found between the study drugs and adalimumab as first biologic in patients with RA, independently of the BMI cohort. We did not find evidence that treatment with abatacept increased the likelihood of remission compared with adalimumab among obese patients with RA.

Lower body mass and lower adiposity are associated with differential responses to two treatment strategies for rheumatoid arthritis.

PURPOSE: To determine if body mass index (BMI) and adipokine levels identify rheumatoid arthritis (RA) patients most likely to benefit from initiation of tumour necrosis factor inhibitors (TNFi) after methotrexate inadequate response. METHODS: This is a secondary analysis of the Rheumatoid Arthritis Comparison of Active Treatments (RACAT) trial and the (TEAR) trial. Both studies compared treatment strategies starting with conventional disease-modifying anti-rheumatic drugs (DMARDs) (triple therapy) versus etanercept plus methotrexate. We compared response rates between TNFi and triple therapy among patients with different BMI. Adipokines were measured at enrolment and associations with treatment response were examined using regression, adjusting for age, sex, BMI and baseline disease activity. RESULTS: In RACAT (n=306), participants who were normal/underweight were more likely to benefit from TNFi versus triple therapy, with greater change in Disease Activity Score in 28 and greater ACR20 response (ACR 20: 64% vs 23%, p=0.001). In contrast, overweight/obese participants had similar response to TNFi versus triple therapy (p-for-interaction=0.001). Similarly, but modest patterns were observed in TEAR (n=601; ACR20: 67% vs 52%, p=0.05). In RACAT, adipokine scores consistent with lower adiposity also predicted greater response to TNFi (ACR20: 58% vs 37%, p=0.01) with better model fit compared with BMI alone. CONCLUSIONS: Lower BMI and evidence of lower adiposity based on adipokine profiles were associated with a superior response to TNFi compared with triple therapy. There was no difference between treatments among overweight/obese participants. The results support TNFi being a particularly important therapeutic among normal/underweight patients, with implications for clinical decisions and trial design.

Safety and efficacy of glucagon-like peptide-1 receptor agonists on cardiovascular events in overweight or obese non-diabetic patients.

BACKGROUND: Randomized controlled trials (RCTs) have shown variable cardiovascular (CV) outcomes in overweight or obese patients without diabetes mellitus (DM) who are treated with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) vs. placebo. We conducted a meta-analysis of the available studies. METHODS: Online databases were searched for RCTs comparing GLP-1 RA to placebo in overweight or obese non-diabetic patients. The clinical endpoints of interest were major adverse CV events (MACE), CV death, all cause death, myocardial infarction (MI), stroke, revascularization, total adverse events and their subtypes. Pooled odds ratios (OR) and 95 % confidence intervals (CI) were calculated using a random-effects model. RESULTS: A total of 10 RCTs with 29,325 patients (n = 16,900 GLP-1 RA, n = 12,425 placebo) were included. The mean age was 48 years and 34 % of patients were men. As compared with placebo, the GLP-1 RA group was associated with significant reduction of MACE (OR 0.79, 95 % CI 0.71-0.89, p < 0.0001), all cause death (OR 0.80, 95 % CI 0.70-0.92, p = 0.002), MI (OR 0.72, 95 % CI 0.61-0.85, p = 0.0001) and revascularization (OR 0.76, 95 % CI 0.67-0.86, p < 0.0001), without any differences in CV death or stroke. Total adverse events, gastrointestinal and gallbladder-related disorders were higher in the GLP-1 RA group, with a similar rate of renal adverse events, malignant neoplasms and acute pancreatitis to placebo. CONCLUSION: In overweight or obese patients without DM, patients treated with GLP-1 RAs had significantly reduced MACE, all cause death, MI and revascularization when compared with placebo.

A crossover randomized controlled trial examining the effects of black seed (Nigella sativa) supplementation on IL-1ß, IL-6 and leptin, and insulin parameters in overweight and obese women.

BACKGROUND: Nigella sativa (NS) oil has been found to have advantageous benefits in the management of inflammation and obesity. This study investigated the effect of NS supplementation on blood mRNA expressions and serum levels of IL-1ß, IL-6, leptin, and insulin concentrations in overweight/obese women. METHODS: In a crossover design, participants were randomized to receive either NS supplements(2000 mg/day) or placebo for 2 durations(8 weeks). With between-subject and within-subject components and interactions, a repeated-measure ANOVA model was used considering the treatment, time, and the carryover effects. Cohen's d(d) was used to measure the magnitude of the effects. RESULTS: Forty-six eligible participants were included. NS supplementation significantly reduced the mRNA expressions(d=-0.68, P = 0.03) and serum levels of IL-1ß with medium-high effect sizes(d=-1.6, P < 0.001). Significant reductions with large effect sizes were observed in the gene expression and serum levels of IL-6(d=-1.8, d=-0.78, respectively; P < 0.01) and Leptin(d=-1.9, d=-0.89, respectively; P < 0.01, serum leptin P carryover < 0.001). Despite the meaningful carryover effect for serum leptin, results remained significant following the first intervention period analysis(P < 0.001). A significant but low effect size decrease in serum insulin was observed(d=-0.3, P = 0.02). CONCLUSIONS: The clinical significance of present findings regarding improvements in obesity-related pro-inflammatory markers must be interpreted with caution due to some observed medium-low effect sizes. TRIAL REGISTRATION: IRCT20180430039475N1 (Date:25/6/2018).

Effects and plasma proteomic analysis of GLP-1RA versus CPA/EE, in combination with metformin, on overweight PCOS women: a randomized controlled trial.

PURPOSE: Polycystic ovary syndrome (PCOS) is characterized by reproductive dysfunctions and metabolic disorders. This study aims to compare the therapeutic effectiveness of glucagon-like peptide-1 receptor agonist (GLP-1RA) + Metformin (Met) versus cyproterone acetate/ethinylestradiol (CPA/EE) + Met in overweight PCOS women and identify potential proteomic biomarkers of disease risk in women with PCOS. METHODS: In this prospective, open-label randomized controlled trial, we recruited 60 overweight PCOS women into two groups at a 1:1 ratio to receive CPA/EE (2 mg/day: 2 mg cyproterone acetate and 35-µg ethinylestradiol,) +Met (1500 mg/day) or GLP-1 RA (liraglutide, 1.2-1.8 mg/day) +Met (1500 mg/day) for 12 weeks. The clinical effectiveness and adverse effects were evaluated, followed by plasma proteomic analysis and verification of critical biomarkers by ELISA. RESULTS: Eighty(80%) patients completed the study. Both interventions improved menstrual cycle, polycystic ovaries, LH(luteinizing hormone) and HbA1c(hemoglobin A1c) levels after the 12-week treatment. GLP-1RA + Met was more effective than CPA/EE + Met in reducing body weight, BMI (Body Mass Index), and waist circumference, FBG(fasting blood glucose), AUCI(area under curve of insulin),TC (Total Cholesterol), IL-6(Interleukin-6) and improving insulin sensitivity, and ovulation in overweight women with PCOS, with acceptable short-term side effects. CPA/EE + Met was more effective in improving hyperandrogenemia, including T(total testosterone), LH, LH/FSH(Luteinizing hormone/follicle-stimulating hormone), SHBG(sex hormone-binding globulin) and FAI (free androgen index). By contract, GLP-1RA+Met group only improved LH. Plasma proteomic analysis revealed that the interventions altered proteins involved in reactive oxygen species detoxification (PRDX6, GSTO1, GSTP1, GSTM2), platelet degranulation (FN1), and the immune response (SERPINB9). CONCLUSIONS: Both CPA/EE+Met and GLP-1RA + Met treatment improved reproductive functions in overweight PCOS women. GLP-1RA + Met was more effective than CPA/EE + Met in reducing body weight, BMI, and waist, and improving metabolism, and ovulation in overweight women with PCOS, with acceptable short-term side effects. CPA/EE + Met was more effective in reducing hyperandrogenemia. The novel plasma biomarkers PRDX6, FN1, and SERPINB9, might be indicators and targets for PCOS treatment. TRIAL REGISTRATION CLINICALTIALS. GOV TRIAL NO: NCT03151005. Registered 12 May, 2017, https://clinicaltrials.gov/ct2/show/NCT03151005 .