Mean Change In Body Weight Research Articles

Investigation of setmelanotide, an MC4R agonist, for obesity in individuals with Smith-Magenis syndrome

BackgroundSmith Magenis Syndrome (SMS) is a rare genetic disorder caused by RAI1 haploinsufficiency. Obesity in people with SMS is believed partially due to dysfunction of the proximal melanocortin 4 receptor (MC4R) pathway. We therefore studied effects of treatment with the MC4R agonist setmelanotide on obesity and hunger, as well as metabolic, cardiac and safety, in individuals with SMS. MethodsPeople with SMS received once-daily setmelanotide injections, with the dose titrated bi-weekly to a maximum of 3 mg over ∼1 month; and a full-dose treatment duration of 3mo. The primary outcome was percent change in body weight. Secondary outcomes included hunger, waist circumference, body composition, and safety. Results12 individuals, ages 11–39 y, enrolled and 10 completed the full-dose treatment phase. Mean percent change in body weight at end-treatment was − 0.28 % [(95 % CI, −2.1 % to 1.5 %; n = 12; P = 0.66]. Participants experienced a significant decrease in total cholesterol associated with a significant decrease in HDL-cholesterol and a trend for lower LDL-cholesterol. Self-reported hunger was reduced at end-treatment (p = 0.011). All participants reported adverse events (AEs), most commonly injection-site reactions and skin hyperpigmentation. No AEs led to withdrawal or death. ConclusionsIn this trial, setmelanotide did not significantly reduce body weight in participants with SMS. Participants reported significant differences in hunger, but such self-reports are difficult to interpret without a placebo-treated group. The changes in lipid profiles require further investigation. Results of this study do not suggest that dysfunction of the proximal MC4R pathway is the main etiology for obesity in people with SMS.

Tirzepatide for Weight Reduction in Chinese Adults With Obesity

Obesity has become a global public health concern and China has the largest number of affected people worldwide. To assess the efficacy and safety of treatment with tirzepatide for weight reduction in Chinese adults with obesity or overweight and weight-related comorbidities. This randomized, double-blind, placebo-controlled, phase 3 clinical trial conducted at 29 centers in China from September 2021 to December 2022 included Chinese adults (aged ≥18 years) with a body mass index (BMI) greater than or equal to 28 or greater than or equal to 24 and at least 1 weight-related comorbidity, excluding diabetes. Participants were randomly assigned (1:1:1) to receive once-weekly, subcutaneous 10-mg (n = 70) or 15-mg (n = 71) tirzepatide or placebo (n = 69), plus a lifestyle intervention, for 52 weeks. Co-primary end points were the percent change in body weight from baseline and weight reduction of at least 5% at week 52. Efficacy and safety analyses were performed on an intention-to-treat population. Of 210 randomized participants (103 [49.0%] female; mean [SD] age, 36.1 [9.1] years; body weight, 91.8 [16.0] kg; BMI, 32.3 [3.8]), 201 (95.7%) completed the trial. The mean change in body weight at week 52 was -13.6% (95% CI, -15.8% to -11.4%) with tirzepatide 10 mg, -17.5% (95% CI, -19.7% to -15.3%) with tirzepatide 15 mg, and -2.3% with placebo (difference between 10 mg and placebo, -11.3% [95% CI, -14.3% to -8.3%; P < .001]; difference between 15 mg and placebo, -15.1% [95% CI, -18.2% to -12.1%; P < .001]). The percentage of participants achieving body weight reductions of 5% or greater was 87.7% with tirzepatide 10 mg, 85.8% with tirzepatide 15 mg, and 29.3% with placebo (P < .001 for comparisons with placebo). The most frequent treatment-emergent adverse events with tirzepatide were gastrointestinal. Most were mild to moderate in severity, with few events leading to treatment discontinuation (<5%). In Chinese adults with obesity or overweight, once-weekly treatment with tirzepatide 10 mg or 15 mg resulted in statistically significant and clinically meaningful weight reduction with an acceptable safety profile. ClinicalTrials.gov Identifier: NCT05024032.

Healthy Outcomes through Peer Educators: Feasibility of a peer support diabetes prevention programme for African-American grandmother caregivers.

To assess the protocol feasibility and intervention acceptability of a community-based, peer support diabetes prevention programme (DPP) for African-American (AA) grandmother caregivers at risk for diabetes. Grandmother caregivers were randomized in a 2:1 ratio to DPP (active comparator) or DPP plus HOPE (Healthy Outcomes through Peer Educators; intervention). DPP + HOPE incorporated support from a peer educator who met with participants in person or by telephone every week during the 1-year intervention. Outcomes included: (1) recruitment rates, outcome assessment, and participation adherence rates assessed quantitatively; and (2) acceptability of the programme assessed through end-of-programme focus groups. We successfully consented and enrolled 78% (n = 35) of the 45 AA grandmothers screened for eligibility. Eighty percent of participants (aged 64.4 ± 5.7 years) were retained up to Week 48 (74% for DPP [n = 17] and 92% for DPP + HOPE [n = 11]). All grandmothers identified social support, neighbourhood safety, and access to grocery stores as influences on their health behaviours. At Month 12, the active comparator (DPP) group and the intervention group (DPP + HOPE) had a mean change in body weight from baseline of -3.5 ± 5.5 (-0.68, -6.29) kg and - 4.4 ± 5.7 (-0.59, -8.2) kg, respectively. This viable study met the aim of educating and equipping AA grandmothers with the practical and sustained support needed to work toward better health for themselves and their grandchildren, who may be at risk for diabetes. The intervention was both feasible and acceptable to participating grandmothers and their organizations.

Acute Inhalation Toxicity Study of 3-Methoxybutyl Acetate in Sprague-Dawley Rats

3-Methoxybutyl acetate is an organic solvent used in a wide range of industrial and consumer applications, such as coatings, adhesives, chemical intermediates, paints, and washing products. We conducted an acute inhalation toxicity study of 3-Methoxybutyl acetate using an inhalation exposure system (nose-only) in Sprague-Dawley rats. Male and female rats were exposed to 3-Methoxybutyl acetate for 4 h/day. The tests were conducted according to the Organisation for Economic Cooperation and Development Guidelines for the Testing of Chemicals (OECD TG) 436. The analytical concentrations of the exposure chamber were 9.76 ± 0.51 mg/L. Clinical signs, mean body weight changes, and gross necropsy results were observed. No deaths, abnormal clinical signs, gross findings at necropsy, or abnormal mean body weight changes related to exposure to the test substance were observed in either sex. Based on these results, we suggested that 3-Methoxybutyl acetate does not have acute toxic effects at the technically acceptable concentration of 10 mg/L.

Abstract MP07: Body Weight Change Mediates the Relationship Between Alcohol Intake and Incidence of Hypertension in Japanese Men

Background: Heavy drinking is a risk factor for hypertension. Alcohol consumption is also associated with weight changes. Therefore, the purpose of this study is to examine the mediating effect of weight change on the incidence of hypertension depending on the level of alcohol consumption in a cohort study of Japanese men. Methods: The participants were 2,137 non-hypertensive male employees (18-61 years old, mean age 38.3) of a metal products factory in Japan. BMI and blood pressure (BP) were measured during a health examination in 2009. BP was measured twice after resting, and the means of BP values were analyzed. Types of alcohol, amount and frequency of drinking were evaluated using a self-administered questionnaire. Follow-up body weight and BP were measured during a health examination in 2014. The incidence of hypertension was defined as systolic BP 130 or higher, diastolic BP 80 or higher, or oral antihypertensive medication. We investigated the mediating effect of BMI on the relationship between alcohol consumption and blood pressure. Associations were adjusted for baseline age, BMI, and systolic BP. Results: The mean values (standard deviations, SD) of baseline BMI (kg/m 2 ), systolic and diastolic BP (mmHg) were 22.6 (2.7), 111.6 (9.2), 67.0 (7.3), respectively. During the 5-year follow-up, 429 incident case of hypertension were identified. The mean body weight change (kg) over 5 years for each alcohol consumption category (non-drinker, &lt;20g ethanol/day, 20-39 g/day, and ≥40 g/day) was 0.8 (4.4), 0.7 (4.0), 0.0 (3.8), and -0.4 (4.4), and the incidence rates (%) of hypertension were 16.0, 17.7, 28.0, and 32.1, respectively. The multivariate-adjusted odds ratios (95% confidence intervals) for incident hypertension were 1.00 (reference), 1.22 (0.90-1.64), 1.71 (1.19-2.47), and 2.06 (1.37-3.09); ORs were significantly higher for those with 20-39g/day and ≥40g/day groups compared to non-drinkers. In the mediation analysis, the odds ratios for the direct effect of each alcohol consumption group on the development of hypertension were 1.00 (reference), 1.27 (0.94-1.73), 1.91 (1.39-3.44), 2.36 (1.56-3.58), and those for indirect effect mediated by body weight change were 1.00 (reference), 0.99 (0.95-1.04), 0.96 (0.90-1.01), and 0.93 (0.85-0.99), respectively. Conclusion: Alcohol consumption was inversely associated with body weight change and positively associated with the incidence of hypertension. Among heavy drinkers, there was a significant indirect effect mediated by body weight, and weight loss due to heavy drinking lowered the risk of developing hypertension. When evaluating the relationship between alcohol consumption and the risk of hypertension for heavy drinkers, the risk due to alcohol drinking may be underestimated through changes in body weight.

Semaglutide 2.4mg clinical outcomes in patients with obesity or overweight in a real-world setting: A 6-month retrospective study in the United States (SCOPE).

Management guidelines for obesity suggest maintaining a minimum of 5% body weight reduction to help prevent or lower the risk of developing conditions such as hypertension and type 2 diabetes. However, achieving long-term weight control is difficult with lifestyle modification alone, making it essential to combine pharmacotherapy with diet and exercise in individual cases. Semaglutide 2.4mg has demonstrated significant reductions in body weight and cardiometabolic risk factors in clinical trials, but information on outcomes in a real-world setting is limited. To assess changes in body weight and other clinical outcomes at 6-month follow-up among adults on semaglutide 2.4mg in a real-world setting in the United States (US). Observational and retrospective cohort study of patients initiating treatment between 15 June 2021, and 31 March 2022, using a large US claims-linked electronic health record database. Mean (±SD) body mass index (BMI) of the 343 patients included in the analysis was 37.9±5.5kg/m2. After 6months, mean body weight change was -10.5±6.8kg (95% CI: -11.2; -9.8, p<0.001) and mean percentage body weight change was -10.0%±6.6% (95% CI: -10.7; -9.3, p<0.001). Most (79.0%) patients had ≥5% body weight reduction, 48.1% had ≥10% body weight reduction, and 19.0% had ≥15% body weight reduction. Among patients with available data, the mean change in HbA1c (n=30) was -0.6%±1.2% (95% CI: -1.0; -0.1, p=0.016) and nearly two-thirds of patients with prediabetes or diabetes at baseline reverted to normoglycemia. Mean reductions of -4.4±12.3mmHg (95% CI: -5.7; -3.0, p<0.001) and -1.7±8.4mmHg (95% CI: -2.6; -0.7, p<0.001) were observed in systolic and diastolic blood pressure, respectively (n=307). Statistically significant reductions in mean total cholesterol (-12.2±38.8mg/dl [95% CI: -24.3 to -0.06, p<0.049]) and triglycerides (-18.3±43.6mg/dl [95% CI: -4.7; -31.9, p<0.009]) were also observed (n=42). This study demonstrated the effectiveness of semaglutide 2.4mg in reducing body weight and improving cardiometabolic parameters in adults with overweight or obesity in a real-world clinical practice setting, showing a significant mean body weight reduction and improvements in biomarkers like blood pressure and HbA1c over a 6-month period. These findings, aligning with previous clinical trials at comparable time points, highlight the clinical relevance of semaglutide as an effective therapeutic option for obesity.

Semaglutide: The First Anti-Obesity Agent Shown to Decrease Cardiovascular Events

The anti-obesity agent, semaglutide (2.4 mg/week) was evaluated in a large (n=17,604) multinational randomized trial called SELECT to examine its effects on cardiovascular (CV) outcomes in overweight/obese patients with preexisting CV disease and no diabetes. The primary outcome of SELECT trial was a composite of CV death, nonfatal myocardial infarction (MI), and nonfatal stroke. Over a mean duration of follow-up of 39.8 months, a primary CV outcome occurred in 6.5% in the semaglutide group and 8.0% in the placebo group; hazard ratio (HR) 0.80 (95% CI, 0.72 to 0.90; P&lt;0.001). Mean change in body weight over 104 weeks was -9.4% and -0.9% with semaglutide and placebo, respectively; estimated treatment difference (ETT) -8.5% (95% CI, -8.5 to -8.3). There was significant amelioration in blood pressure and plasma levels of lipids, glycated hemoglobin (HbA1c), and C- reactive protein (CRP). The incidences of diabetes and prediabetes were reduced by 73% and 67%, respectively with semaglutide. 16.6% of patients discontinued semaglutide due to adverse effects, mainly gastrointestinal (GI) compared with 8.2% who discontinued placebo (P&lt;0.001). In conclusion, semaglutide is the first anti-obesity agent shown to decrease CV events in overweight/obese subjects with CV disease without diabetes. Further studies are needed to examine the impact of semaglutide on CV events in obese subjects without underlying CV disease.

Validation of an algorithm for sound-based voided volume estimation

A voiding diary is commonly used in clinical practice to monitor urinary tract health. However, manual recording and use of a measuring cup can cause significant inaccuracy and inconvenience. Recently sound-based voided volume estimation algorithms such as proudP have shown potential to accurately measure the voided volumes of patients urination while overcoming these inconveniences. In order to validate the sound-based voided volume estimation algorithm, we chose bodyweight change after urination as a reference value. Total 508 subjects from the United States and Korea were enrolled. 584 data points that have matching bodyweights change data and urination sound data were collected, and fivefold cross validation was performed in order to evaluate the model on all data in the dataset. The mean voided volume estimated by the algorithm was 202.6 mL (SD: ± 114.8) while the mean bodyweight change after urination was 208.0 g (SD: ± 121.5), and there was a strong linear correlation with high statistical significance (Pearson’s correlation coefficient = 0.92, p-value < 0.001). Two paired t-test showed the equivalence with bodyweight change data with 10 mL margin. Additionally, a Bland–Altman plot shows a mean difference of − 5.5 mL with LoA (− 98.0, 87.1). The results support high performance of the algorithm across the large population data from multi-site clinical trials.

Effects of gamal leaf extract (Gliricidia sepium Jacq.) on body weight and internal organ performance of mice (Mus musculus L.)

Gamal leaves (Gliricidia sepium Jacq.) contain toxic compounds that have the potential to act as vegetable rodenticides, such as alkaloids, tannins, dicumerol, and hydrogen cyanic acid (HCN). Coumarin compounds can bind vitamin K, disrupt the circulatory system, and damage liver cells. The compounds dicumerol and warfarin are used as rat poison because of their anticoagulant properties, which prevent blood clots in the heart. Alkaloid and tannin compounds can damage liver cells through liver necrosis and bleeding in the digestive system. This study aims to determine the effect of Gamal leaf extract on body weight and internal organ performance in mice (Mus musculus L.). The experimental research method is based on a Completely Randomized Design (CRD) pattern. A total of 16 mice weighing 20-22 grams consisting of 4 treatments, namely A0 (water control), A1 (extract 10 mg/g BW), A2 (extract 15 mg/g BW) and A3 (extract 20 mg/g BW). The extract was given orally for 14 days, and body weight was measured every 3 days to obtain data on changes in body weight (PBB). At the end of the treatment, the mice were sacrificed using chloroform and then dissected to observe the performance of the liver, kidney and heart organs in color appearance and organ weight. Quantitative data were analyzed using one-way ANOVA and further DMRT test α=0.05. The research showed that mice's mean change in body weight (PBB) decreased significantly as the dose of Gamal leaf extract increased. The percentage of liver organ weight (BOH), kidney organ weight (BOG), and heart organ weight (BOJ) decreased as the dose of Gamal leaf extract increased. The research results concluded that Gamal leaf extract caused color changes in the internal organs of mice and significantly affected the percentage change in body weight (PBB) and internal organ weight (BOD) of mice along with increasing doses of Gamal leaf extract.

Efficacy and safety of semaglutide 2.4 mg according to antidepressant use at baseline: A post hoc subgroup analysis.

To explore the efficacy and safety of semaglutide 2.4 mg in people with overweight/obesity who were also being treated with antidepressants (ADs). Across the Semaglutide Treatment Effect for People with obesity (STEP) 1-3 and 5 trials, adults with overweight/obesity and type 2 diabetes (STEP 2 only) were enrolled. People with severe major depressive disorder within 2 years prior to screening or with a patient health questionnaire-9 score ≥15 at screening were excluded. Participants were categorized into subgroups according to baseline AD status (on/off ADs) in this post hoc exploratory analysis of the STEP trials. Of 3683 participants randomized, 539 were on ADs at baseline. Mean body weight change from baseline to week 68 was greater for semaglutide versus placebo, regardless of baseline AD use. In STEP 1, for participants on ADs at baseline, mean change from baseline was -15.7% with semaglutide versus -0.2% with placebo and -14.7% versus -2.8% for those not on ADs at baseline. Similar patterns were seen in STEP 2, 3, and 5. The prevalence of adverse events (AEs) was generally similar between semaglutide and placebo in participants on ADs at baseline. In adults with overweight/obesity, semaglutide provided clinically meaningful weight loss regardless of baseline AD use, with an AE profile consistent with previous studies.

Predictors of efficacy of anamorelin in patients with non‑small cell lung cancer and cachexia: A retrospective study.

Anamorelin, a ghrelin receptor agonist, is approved in Japan for the treatment of cachexia in patients with lung and gastrointestinal cancer. However, there is limited research on the usefulness of anamorelin in clinical settings, therefore, the present study evaluated its efficacy using patient characteristics. A total of 40 patients with non-small cell lung cancer and cachexia who were prescribed anamorelin in the Department of Respiratory Medicine, Hirosaki University Graduate School of Medicine (Aomori, Japan) between July 2021 and November 2022, were retrospectively assessed. Anamorelin was prescribed at a dose of 100 mg once daily to patients who had lost >5% of their body weight within 6 months. All patients were weighed before treatment and those who continued anamorelin treatment for 12 weeks were also weighed at 12 weeks. A logistic regression analysis was used to analyze the association between background characteristics and early discontinuation of treatment with anamorelin (within 4 weeks). The median age was 67 years (range, 36-88), and 65% of the patients were male. There were 24 patients (60.0%) with an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) score 1, 11 patients (27.5%) with an ECOG-PS score 2 and five patients (12.5%) with an ECOG-PS score 3. The early discontinuation group included 11 patients (27.5%). An ECOG-PS score ≥2 (odds ratio, 7.85; 95% confidence interval, 1.43-43.21; P=0.018) was associated with early discontinuation. A total of 18/40 patients (45.0%) were able to continue anamorelin treatment for 12 weeks, and the mean change in body weight was +2.31 kg, which was a significant change from the weight recorded at baseline (P=0.027). The mean changes in lean body mass and soft lean mass between baseline and 12 weeks were +1.97 kg (P=0.14) and +1.26 kg (P=0.15), respectively. The results from the present study indicate that anamorelin is unlikely to be useful for patients with a poor general condition (ECOG-PS score ≥2).

Effect of the weight-loss program using daily self-weighing combined with personalized counseling led by village health volunteers in adults with obesity in a rural community, Thailand: a randomized controlled trial

BackgroundIn a remote rural community in central Thailand, obesity prevalence among adults significantly rose from 33.9% in 2012 to 44.8% in 2018. Limited information on weight reduction studies in Thai rural communities was available. The present study aims to evaluate the effect of daily self-weighing combined with personalized counseling in order to reduce body weight (BW) and body mass index (BMI) as well as blood pressure (BP).MethodsA randomized controlled trial was carried out in a rural community in central Thailand.One-hundred and seven adults were randomly allocated (1:2) to intervention and control groups. For 20 weeks, participants in the weight-loss program performed self-weighing twice daily and recorded their weight on the calendar. The program also offers weekly counseling visits by village health volunteers (VHV) who make home visits to participants. The primary outcomes were differences in mean change in BW at 20 weeks from baseline between the intervention and control groups.ResultsA total of 107 participants were initially recruited. Of these, 36 participants were allocated to the intervention group and 57 participants to the control group. Significant differences in mean change in BW and BMI at the twelve-, sixteen-, and twenty-week follow-up from baseline between the two groups were observed. At twenty weeks, the mean change in BW was -1.2 kg (95% CI: -2.2, -0.3) and 0.3 kg (95% CI: -0.3, 0.8) in the intervention and control groups, respectively, with p-value = 0.007. Over 20 weeks of the study period, the estimated mean change in BW among the intervention group was 1.0 kg (95% CI -1.7, -0.2) lower than in the control group, with p-value = 0.015. Furthermore, changes in mean BMI and BP over the 20-week follow-up period in intervention participants were recognized.ConclusionsOur study demonstrates that daily self-weighing combined with personalized counseling led by VHV is feasible and can induce weight loss among adults with obesity in a rural community. In addition, the weight-loss program may be a promising additional tool for reducing BP.Trial registrationTrial identification number was TCTR20201020004; first submitted date: 20/10/2020.

Changes in weight, body composition and metabolic parameters after switch to dolutegravir/lamivudine compared with continued treatment with dolutegravir/abacavir/lamivudine for virologically suppressed HIV infection (The AVERTAS trial): a randomised, open-label, superiority trial in Copenhagen, Denmark

IntroductionWith longer life expectancy in people living with HIV (PLWH) on antiretroviral therapy, cardiovascular disease (CVD) has become a common cause of mortality among them. Abacavir has been associated with...

Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial

Weight reduction is essential for improving health outcomes in people with obesity and type 2 diabetes. We assessed the efficacy and safety of tirzepatide, a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, versus placebo, for weight management in people living with obesity and type 2 diabetes. This phase 3, double-blind, randomised, placebo-controlled trial was conducted in seven countries. Adults (aged ≥18 years) with a body-mass index (BMI) of 27 kg/m2 or higher and glycated haemoglobin (HbA1c) of 7-10% (53-86 mmol/mol) were randomly assigned (1:1:1), using a computer-generated random sequence via a validated interactive web-response system, to receive either once-weekly, subcutaneous tirzepatide (10 mg or 15 mg) or placebo for 72 weeks. All participants, investigators, and the sponsor were masked to treatment assignment. Coprimary endpoints were the percent change in bodyweight from baseline and bodyweight reduction of 5% or higher. The treatment-regimen estimand assessed effects regardless of treatment discontinuation or initiation of antihyperglycaemic rescue therapy. Efficacy and safety endpoints were analysed with data from all randomly assigned participants (intention-to-treat population). This trial is registered with ClinicalTrials.gov, NCT04657003. Between March 29, 2021, and April 10, 2023, of 1514 adults assessed for eligibility, 938 (mean age 54·2 years [SD 10·6], 476 [51%] were female, 710 [76%] were White, and 561 [60%] were Hispanic or Latino) were randomly assigned and received at least one dose of tirzepatide 10 mg (n=312), tirzepatide 15 mg (n=311), or placebo (n=315). Baseline mean bodyweight was 100·7 kg (SD 21·1), BMI 36·1 kg/m2 (SD 6·6), and HbA1c 8·02% (SD 0·89; 64·1 mmol/mol [SD 9·7]). Least-squares mean change in bodyweight at week 72 with tirzepatide 10 mg and 15 mg was -12·8% (SE 0·6) and -14·7% (0·5), respectively, and -3·2% (0·5) with placebo, resulting in estimated treatment differences versus placebo of -9·6% percentage points (95% CI -11·1 to -8·1) with tirzepatide 10 mg and -11·6% percentage points (-13·0 to -10·1) with tirzepatide 15 mg (all p<0·0001). More participants treated with tirzepatide versus placebo met bodyweight reduction thresholds of 5% or higher (79-83% vs 32%). The most frequent adverse events with tirzepatide were gastrointestinal-related, including nausea, diarrhoea, and vomiting and were mostly mild to moderate in severity, with few events leading to treatment discontinuation (<5%). Serious adverse events were reported by 68 (7%) participants overall and two deaths occurred in the tirzepatide 10 mg group, but deaths were not considered to be related to the study treatment by the investigator. In this 72-week trial in adults living with obesity and type 2 diabetes, once-weekly tirzepatide 10 mg and 15 mg provided substantial and clinically meaningful reduction in bodyweight, with a safety profile that was similar to other incretin-based therapies for weight management. Eli Lilly and Company.

Oral semaglutide 50 mg taken once per day in adults with overweight or obesity (OASIS 1): a randomised, double-blind, placebo-controlled, phase 3 trial

We assessed the efficacy and safety of the oral glucagon-like peptide-1 analogue, semaglutide 50 mg, taken once per day versus placebo for the treatment of overweight or obesity in adults without type 2 diabetes. This randomised, double-blind, placebo-controlled, phase 3, superiority trial enrolled adults with a BMI of at least 30 kg/m2, or at least 27 kg/m2 with bodyweight-related complications and comorbidities, without type 2 diabetes. The trial was done at 50 outpatient clinics in nine countries across Asia, Europe, and North America. Participants were randomly allocated (1:1) via an interactive web-response system to oral semaglutide escalated to 50 mg, or visually matching placebo, once per day for 68 weeks, plus lifestyle intervention. Group assignment was masked for participants, investigators, and those assessing outcomes. Coprimary endpoints were the percentage change in bodyweight and whether participants reached a bodyweight reduction of at least 5% at week 68 for oral semaglutide 50 mg versus placebo, assessed regardless of treatment discontinuation or use of other bodyweight-lowering therapies (an intention-to-treat analysis). Safety was assessed in participants who received at least one dose of trial drug. This trial, registered with ClinicalTrials.gov (NCT05035095), is now complete. From Sept 13 to Nov 22, 2021, 709 participants were screened, of whom 667 were randomly assigned to oral semaglutide 50 mg (n=334) or placebo (n=333). The estimated mean bodyweight change from baseline to week 68 was -15·1% (SE 0·5) with oral semaglutide 50 mg versus -2·4% (0·5) with placebo (estimated treatment difference -12·7 percentage points, 95% CI -14·2 to -11·3; p<0·0001). More participants reached bodyweight reductions of at least 5% (269 [85%] of 317 vs 76 [26%] of 295; odds ratio [OR] 12·6, 95% CI 8·5 to 18·7; p<0·0001), 10% (220 [69%] vs 35 [12%]; OR 14·7, 9·6 to 22·6), 15% (170 [54%] vs 17 [6%]; OR 17·9, 10·4 to 30·7), and 20% (107 [34%] vs 8 [3%]; OR 18·5, 8·8 to 38·9) at week 68 with oral semaglutide 50 mg versus placebo. Adverse events were more frequent with oral semaglutide 50 mg (307 [92%] of 334) than with placebo (285 [86%] of 333). Gastrointestinal adverse events (mostly mild to moderate) were reported in 268 (80%) participants with oral semaglutide 50 mg and 154 (46%) with placebo. In adults with overweight or obesity without type 2 diabetes, oral semaglutide 50 mg once per day led to a superior and clinically meaningful decrease in bodyweight compared with placebo. Novo Nordisk.

Efficacy and safety of oral orforglipron in patients with type 2 diabetes: a multicentre, randomised, dose-response, phase 2 study

Orforglipron, an oral, non-peptide glucagon-like peptide-1 (GLP-1) receptor agonist, is in development for type 2 diabetes and obesity. We assessed the efficacy and safety of orforglipron versus placebo or dulaglutide in participants with type 2 diabetes. In this 26-week, phase 2, double-blind, randomised, multicentre study, participants were recruited from 45 centres (private clinics, hospitals, and research centers) in the USA, Hungary, Poland, and Slovakia. Adult participants aged 18 years or older with type 2 diabetes treated with diet and exercise, with or without metformin, and with a glycated haemoglobin (HbA1c) of 7·0-10·5%, and stable BMI of 23 kg/m2 or more, were randomly assigned (5:5:5:5:5:3:3:3:3) via an interactive web-response system to placebo, dulaglutide 1·5 mg once per week, or orforglipron 3 mg, 12 mg, 24 mg, 36 mg (group 1), 36 mg (group 2), 45 mg (group 1), or 45 mg (group 2) once per day with no food or water restrictions. Two different dose escalation regimens were evaluated for each of the 36 mg and 45 mg cohorts. Participants were masked to the study drug, dulaglutide, and placebo. The primary efficacy outcome The primary efficacy outcome was mean change in HbA1c from baseline with orforglipron versus placebo at week 26. Efficacy was analysed in all randomly assigned participants who received at least one dose of study drug and excluded data after the permanent discontinuation of study drug or initiation of rescue medication. Safety was analysed in all participants who received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov (NCT05048719) and is completed. Between Sept 15, 2021, and Sept 30, 2022, 569 participants were screened and 383 were enrolled and randomly assigned to a group. 352 (92%) completed the study and 303 (79%) completed 26 weeks of treatment. At baseline, the mean age was 58·9 years, HbA1c was 8·1%, BMI was 35·2 kg/m2, 226 (59%) were men, and 157 (41%) were women. At week 26, mean change in HbA1c with orforglipron was up to -2·10% (-1·67% placebo adjusted), versus -0·43% with placebo and -1·10% with dulaglutide. HbA1c reduction was statistically superior with orforglipron versus placebo (estimated treatment difference -0·8% to -1·7%). Change in mean bodyweight at week 26 was up to -10·1 kg (95% CI -11·5 to -8·7; 7·9 kg placebo adjusted [-9·9 to -5·9]) with orforglipron versus -2·2 kg (-3·6 to -0·7) for placebo and -3·9 kg (-5·3 to -2·4) for dulaglutide. The incidence of treatment-emergent adverse events ranged from 61·8% to 88·9% in orforglipron-treated participants, compared with 61·8% with placebo and 56·0% with dulaglutide. The majority were gastrointestinal events (44·1% to 70·4% with orforglipron, 18·2% with placebo, and 34·0% with dulaglutide) of mild to moderate severity. Three participants receiving orforglipron and one participant receiving dulaglutide had clinically significant (<54 mg/dL [<3 mmol/L]) hypoglycaemia and no participants had severe hypoglycaemia. One death occurred in the placebo group and was not related to study treatment. In this phase 2 trial the novel, oral, non-peptide GLP-1 receptor agonist orforglipron at doses of 12 mg or greater showed significant reductions in HbA1c and bodyweight compared with placebo or dulaglutide. The adverse event profile was similar to other GLP-1 receptor agonists in similar stage of development. Orforglipron might provide an alternative to injectable GLP-1 receptor agonists and oral semaglutide, with the prospect of less burdensome administration to achieve treatment goals in people with type 2 diabetes. Eli Lilly and Company.

Efficacy and safety of co-administered once-weekly cagrilintide 2·4 mg with once-weekly semaglutide 2·4 mg in type 2 diabetes: a multicentre, randomised, double-blind, active-controlled, phase 2 trial

Combining the GLP-1 receptor agonist semaglutide with the long-acting amylin analogue cagrilintide has weight-loss benefits; the impact on glycated haemoglobin (HbA1c) is unknown. This trial assessed the efficacy and safety of co-administered semaglutide with cagrilintide (CagriSema) in participants with type 2 diabetes. This 32-week, multicentre, double-blind, phase 2 trial was conducted across 17 sites in the USA. Adults with type 2 diabetes and a BMI of 27 kg/m2 or higher on metformin with or without an SGLT2 inhibitor were randomly assigned (1:1:1) to once-weekly subcutaneous CagriSema, semaglutide, or cagrilintide (all escalated to 2·4 mg). Randomisation was done centrally using an interactive web response system and was stratified according to use of SGLT2 inhibitor treatment (yes vs no). The trial participants, investigators, and trial sponsor staff were masked to treatment assignment throughout the trial. The primary endpoint was change from baseline in HbA1c; secondary endpoints were bodyweight, fasting plasma glucose, continuous glucose monitoring (CGM) parameters, and safety. Efficacy analyses were performed in all participants who had undergone randomisation, and safety analyses in all participants who had undergone randomisation and received at least one dose of the trial medication. This trial is registered on ClinicalTrials.gov (NCT04982575) and is complete. Between Aug 2 and Oct 18, 2021, 92 participants were randomly assigned to CagriSema (n=31), semaglutide (n=31), or cagrilintide (n=30). 59 (64%) participants were male; the mean age of participants was 58 years (SD 9). The mean change in HbA1c from baseline to week 32 (CagriSema: -2·2 percentage points [SE 0·15]; semaglutide: -1·8 percentage points [0·16]; cagrilintide: -0·9 percentage points [0·15]) was greater with CagriSema versus cagrilintide (estimated treatment difference -1·3 percentage points [95% CI -1·7 to -0·8]; p<0·0001), but not versus semaglutide (-0·4 percentage points [-0·8 to 0·0]; p=0·075). The mean change in bodyweight from baseline to week 32 (CagriSema: -15·6% [SE 1·26]; semaglutide: -5·1% [1·26]; cagrilintide: -8·1% [1·23]) was greater with CagriSema versus both semaglutide (p<0·0001) and cagrilintide (p<0·0001). The mean change in fasting plasma glucose from baseline to week 32 (CagriSema: -3·3 mmol/L [SE 0·3]; semaglutide: -2·5 mmol/L [0·4]; cagrilintide: -1·7 mmol/L [0·3]) was greater with CagriSema versus cagrilintide (p=0·0010) but not versus semaglutide (p=0·10). Time in range (3·9-10·0 mmol/L) was 45·9%, 32·6%, and 56·9% at baseline and 88·9%, 76·2%, and 71·7% at week 32 with CagriSema, semaglutide, and cagrilintide, respectively. Adverse events were reported by 21 (68%) participants in the CagriSema group, 22 (71%) in the semaglutide group, and 24 (80%) in the cagrilintide group. Mild or moderate gastrointestinal adverse events were most common; no level 2 or 3 hypoglycaemia was reported. No fatal adverse events were reported. In people with type 2 diabetes, treatment with CagriSema resulted in clinically relevant improvements in glycaemic control (including CGM parameters). The mean change in HbA1c with CagriSema was greater versus cagrilintide, but not versus semaglutide. Treatment with CagriSema resulted in significantly greater weight loss versus semaglutide and cagrilintide and was well tolerated. These data support further investigation of CagriSema in this population in longer and larger phase 3 studies. Novo Nordisk.

756-P: A Phase 1c Evaluation of a Novel GLP-1 Analog Ecnoglutide (XW003) for Weight Loss in Adults with Overweight and Obesity

Ecnoglutide (XW003) is a novel, long-acting GLP-1 analog being developed for the treatment of type 2 diabetes and obesity. We conducted a Phase 1c randomized, double-blind, placebo-controlled study of ecnoglutide, which enrolled 60 nondiabetic adults with BMI 24-35 kg/m2. The study was conducted in China. PK, change in mean body weight and BMI, safety, and tolerability were evaluated. Participants received 1.8 or 2.4 mg ecnoglutide or placebo as once weekly injections for 14 weeks, including dose escalation. This core treatment was followed by an open-label extension of the ecnoglutide groups, for a total duration of 26 weeks. At baseline, participants had a mean body weight of 84.61 ± 10.44 kg and BMI of 29.53 ± 1.73 kg/m2. After 14 weeks of core treatment, mean weight reduction from baseline was -8.29 ± 0.52 kg in the 1.8 mg ecnoglutide group and -7.24 ± 0.56 kg in the 2.4 mg group, compared to -0.61 ± 0.82 kg for placebo (P&amp;lt;0.0001 vs placebo for both doses). At Week 14, the proportion of participants achieving ≥5% weight loss from baseline was 87.5% (95% CI, 67.6 to 97.3) and 70.0% (95% CI, 45.7 to 88.1) for 1.8 and 2.4 mg ecnoglutide, respectively, and 22.2% (95% CI, 2.8 to 60.0) for placebo. Continued weight reduction was observed until the end of study at Week 26, with a mean percent change from baseline of -15.0% (95%CI, -16.8 to -13.2) and -13.2% (95% CI, -15.3 to -11.1) for 1.8 and 2.4 mg ecnoglutide, respectively. At Week 26, ≥5% weight loss was observed for 94.7% (95% CI, 74.0 to 99.9) of participants in the 1.8 mg group and 100.0% (95% CI, 75.3 to 100.0) in the 2.4 mg group. At steady state, ecnoglutide showed a mean Cmax of 310 - 468 ng/mL, Tmax of 26 - 29 h, and half-life of 139 - 162 h. Overall, ecnoglutide was safe and well tolerated. The proportion of participants reporting any AE was similar between cohorts (95.2 to 100% for ecnoglutide vs 90% for placebo). The most frequent AEs were gastrointestinal, including diarrhea and vomiting. No drug-related SAE or drug-related AEs ≥Grade 3 were reported. Disclosure G. Wang: None. W. Hu: None. H.H. Qin: Employee; Sciwind Biosciences, Sichuan Anerobic Biotech. Q. Zheng: Employee; Sciwind Biosciences. J. Ning: None. G. Mengying: None. Y. Bu: Employee; Sciwind Biosciences. C. Jones: Employee; Sciwind Biosciences. M. Fenaux: Employee; Sciwind Biosciences. Stock/Shareholder; Terns Pharmaceuticals. S. Xu: Employee; Sciwind. M.K. Junaidi: None. Funding Sciwind Biosciences

755-P: A Phase 2 Evaluation of a Novel GLP-1 Analog Ecnoglutide (XW003) for Glycemic Control in Adults with Type 2 Diabetes

Ecnoglutide (XW003) is a novel, long-acting GLP-1 analog being developed for the treatment of type 2 diabetes mellitus (T2DM) and obesity. We conducted a Phase 2 randomized, double-blind, placebo-controlled study of ecnoglutide, which enrolled 145 adults at over 20 hospital-based sites in China. Eligible participants had T2DM that was inadequately controlled by lifestyle or a single oral hypoglycemic agent. Participants were randomized to receive 0.4, 0.8, or 1.2 mg ecnoglutide or placebo as once weekly injections for 20 weeks, including dose escalation. Change in mean HbA1c, body weight, and BMI, as well as safety and tolerability were evaluated. At baseline, participants had mean HbA1c of 8.55 ± 0.707 % and BMI of 26.27 ± 3.308 kg/m2. At the end of treatment, participants receiving ecnoglutide achieved significant HbA1c reductions of 1.81% to 2.39% from baseline (P&amp;lt;0.0001 for all cohorts vs placebo). At end of treatment, up to 67% of participants in the ecnoglutide cohorts achieved HbA1c levels ≤6.5% and up to 33% had body weight reductions ≥5% from baseline (Figure). Ecnoglutide was generally safe and well tolerated. There were no treatment-related ≥Grade 3 AEs and no treatment-related SAEs. The proportion of participants reporting any AE ranged from 72.2 to 78.4% for ecnoglutide and 58.3 % for placebo. The most frequently reported AEs were gastrointestinal, including diarrhea and nausea. Disclosure D.Zhu: None. S.Xu: Employee; Sciwind. M.K.Junaidi: None. H.H.Qin: Employee; Sciwind Biosciences, Sichuan Anerobic Biotech. Q.Zheng: Employee; Sciwind Biosciences. J.Ning: None. Z.Zhu: Employee; Sciwind Biosciences. G.Mengying: None. Y.Bu: Employee; Sciwind Biosciences. C.Jones: Employee; Sciwind Biosciences. M.Fenaux: Employee; Sciwind Biosciences, Stock/Shareholder; Terns Pharmaceuticals. Funding Sciwind Biosciences

Neuroprotectant Effects of Hibiscetin in 3-Nitropropionic Acid-Induced Huntington's Disease via Subsiding Oxidative Stress and Modulating Monoamine Neurotransmitters in Rats Brain.

Previously reported data suggest that hibiscetin, isolated from roselle, contains delphinidin-3-sambubioside and cyanidin-3-sambubioside including anthocyanidins and has a broad range of physiological effects. In this study, we aim to analyze the effect of hibiscetin neuroprotective ability in rats against 3-nitropropionic acid (3-NPA)-induced Huntington's disease (HD). To investigate possible toxicities in animals, oral acute toxicity studies of hibiscetin were undertaken, and results revealed the safety of hibiscetin in animals with a maximum tolerated dose. Wistar rats were divided into four groups (n = 6); (group-1) treated with normal saline, (group-2) hibiscetin (10 mg/kg) only, (group-3) 3-NPA only, and (group-4) 3-NPA +10 mg/kg hibiscetin. The efficacy of hibiscetin 10 mg/kg was studied with the administration of 3-NPA doses for the induction of experimentally induced HD symptoms in rats. The mean body weight (MBW) was recorded at end of the study on day 22 to evaluate any change in mean body weight. Several biochemical parameters were assessed to support oxidative stress (GSH, SOD, CAT, LPO, GR, and GPx), alteration in neurotransmitters (DOPAC, HVA, 5-HIAA, norepinephrine, serotonin, GABA, and dopamine), alterations in BDNF and cleaved caspase (caspase 3) activity. Additionally, inflammatory markers, i.e., tumor necrosis factor alpha (TNF-α), interleukins beta (IL-1β), and myeloperoxidase (MPO) were evaluated. The hibiscetin-treated group exhibits a substantial restoration of MBW than the 3-NPA control group. Furthermore, 3-NPA caused a substantial alteration in biochemical, neurotransmitter monoamines, and neuroinflammatory parameters which were restored successfully by hibiscetin. The current study linked the possible role of hibiscetin by offering neuroprotection in experimental animal models.