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Effect of Weekly Subcutaneous Semaglutide vs Daily Liraglutide on Body Weight in Adults With Overweight or Obesity Without Diabetes: The STEP 8 Randomized Clinical Trial.
Rubino, DM, Greenway, FL, Khalid, U, O'Neil, PM, Rosenstock, J, Sørrig, R, Wadden, TA, Wizert, A, Garvey, WT, ,
JAMA. 2022;(2):138-150
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Abstract
IMPORTANCE Phase 3 trials have not compared semaglutide and liraglutide, glucagon-like peptide-1 analogues available for weight management. OBJECTIVE To compare the efficacy and adverse event profiles of once-weekly subcutaneous semaglutide, 2.4 mg, vs once-daily subcutaneous liraglutide, 3.0 mg (both with diet and physical activity), in people with overweight or obesity. DESIGN, SETTING, AND PARTICIPANTS Randomized, open-label, 68-week, phase 3b trial conducted at 19 US sites from September 2019 (enrollment: September 11-November 26) to May 2021 (end of follow-up: May 11) in adults with body mass index of 30 or greater or 27 or greater with 1 or more weight-related comorbidities, without diabetes (N = 338). INTERVENTIONS Participants were randomized (3:1:3:1) to receive once-weekly subcutaneous semaglutide, 2.4 mg (16-week escalation; n = 126), or matching placebo, or once-daily subcutaneous liraglutide, 3.0 mg (4-week escalation; n = 127), or matching placebo, plus diet and physical activity. Participants unable to tolerate 2.4 mg of semaglutide could receive 1.7 mg; participants unable to tolerate 3.0 mg of liraglutide discontinued treatment and could restart the 4-week titration. Placebo groups were pooled (n = 85). MAIN OUTCOMES AND MEASURES The primary end point was percentage change in body weight, and confirmatory secondary end points were achievement of 10% or more, 15% or more, and 20% or more weight loss, assessed for semaglutide vs liraglutide at week 68. Semaglutide vs liraglutide comparisons were open-label, with active treatment groups double-blinded against matched placebo groups. Comparisons of active treatments vs pooled placebo were supportive secondary end points. RESULTS Of 338 randomized participants (mean [SD] age, 49 [13] years; 265 women [78.4%]; mean [SD] body weight, 104.5 [23.8] kg; mean [SD] body mass index, 37.5 [6.8]), 319 (94.4%) completed the trial, and 271 (80.2%) completed treatment. The mean weight change from baseline was -15.8% with semaglutide vs -6.4% with liraglutide (difference, -9.4 percentage points [95% CI, -12.0 to -6.8]; P < .001); weight change with pooled placebo was -1.9%. Participants had significantly greater odds of achieving 10% or more, 15% or more, and 20% or more weight loss with semaglutide vs liraglutide (70.9% of participants vs 25.6% [odds ratio, 6.3 {95% CI, 3.5 to 11.2}], 55.6% vs 12.0% [odds ratio, 7.9 {95% CI, 4.1 to 15.4}], and 38.5% vs 6.0% [odds ratio, 8.2 {95% CI, 3.5 to 19.1}], respectively; all P < .001). Proportions of participants discontinuing treatment for any reason were 13.5% with semaglutide and 27.6% with liraglutide. Gastrointestinal adverse events were reported by 84.1% with semaglutide and 82.7% with liraglutide. CONCLUSIONS AND RELEVANCE Among adults with overweight or obesity without diabetes, once-weekly subcutaneous semaglutide compared with once-daily subcutaneous liraglutide, added to counseling for diet and physical activity, resulted in significantly greater weight loss at 68 weeks. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04074161.
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Analyses of child cardiometabolic phenotype following assisted reproductive technologies using a pragmatic trial emulation approach.
Huang, JY, Cai, S, Huang, Z, Tint, MT, Yuan, WL, Aris, IM, Godfrey, KM, Karnani, N, Lee, YS, Chan, JKY, et al
Nature communications. 2021;(1):5613
Abstract
Assisted reproductive technologies (ART) are increasingly used, however little is known about the long-term health of ART-conceived offspring. Weak selection of comparison groups and poorly characterized mechanisms impede current understanding. In a prospective cohort (Growing Up in Singapore Towards healthy Outcomes; GUSTO; Clinical Trials ID: NCT01174875) including 83 ART-conceived and 1095 spontaneously-conceived singletons, we estimate effects of ART on anthropometry, blood pressure, serum metabolic biomarkers, and cord tissue DNA methylation by emulating a pragmatic trial supported by machine learning-based estimators. We find ART-conceived children to be shorter (-0.5 SD [95% CI: -0.7, -0.2]), lighter (-0.6 SD [-0.9, -0.3]) and have lower skinfold thicknesses (e.g. -14% [-24%, -3%] suprailiac), and blood pressure (-3 mmHg [-6, -0.5] systolic) at 6-6.5 years, with no strong differences in metabolic biomarkers. Differences are not explained by parental anthropometry or comorbidities, polygenic risk score, breastfeeding, or illnesses. Our simulations demonstrate ART is strongly associated with lower NECAB3 DNA methylation, with negative control analyses suggesting these estimates are unbiased. However, methylation changes do not appear to mediate observed differences in child phenotype.
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Order of same-day concurrent training influences some indices of power development, but not strength, lean mass, or aerobic fitness in healthy, moderately-active men after 9 weeks of training.
Lee, MJ, Ballantyne, JK, Chagolla, J, Hopkins, WG, Fyfe, JJ, Phillips, SM, Bishop, DJ, Bartlett, JD
PloS one. 2020;(5):e0233134
Abstract
BACKGROUND The importance of concurrent exercise order for improving endurance and resistance adaptations remains unclear, particularly when sessions are performed a few hours apart. We investigated the effects of concurrent training (in alternate orders, separated by ~3 hours) on endurance and resistance training adaptations, compared to resistance-only training. MATERIALS AND METHODS Twenty-nine healthy, moderately-active men (mean ± SD; age 24.5 ± 4.7 y; body mass 74.9 ± 10.8 kg; height 179.7 ± 6.5 cm) performed either resistance-only training (RT, n = 9), or same-day concurrent training whereby high-intensity interval training was performed either 3 hours before (HIIT+RT, n = 10) or after resistance training (RT+HIIT, n = 10), for 3 d.wk-1 over 9 weeks. Training-induced changes in leg press 1-repetition maximal (1-RM) strength, countermovement jump (CMJ) performance, body composition, peak oxygen uptake ([Formula: see text]), aerobic power ([Formula: see text]), and lactate threshold ([Formula: see text]) were assessed before, and after both 5 and 9 weeks of training. RESULTS After 9 weeks, all training groups increased leg press 1-RM (~24-28%) and total lean mass (~3-4%), with no clear differences between groups. Both concurrent groups elicited similar small-to-moderate improvements in all markers of aerobic fitness ([Formula: see text] ~8-9%; [Formula: see text] ~16-20%; [Formula: see text] ~14-15%). RT improved CMJ displacement (mean ± SD, 5.3 ± 6.3%), velocity (2.2 ± 2.7%), force (absolute: 10.1 ± 10.1%), and power (absolute: 9.8 ± 7.6%; relative: 6.0 ± 6.6%). HIIT+RT elicited comparable improvements in CMJ velocity only (2.2 ± 2.7%). Compared to RT, RT+HIIT attenuated CMJ displacement (mean difference ± 90%CI, -5.1 ± 4.3%), force (absolute: -8.2 ± 7.1%) and power (absolute: -6.0 ± 4.7%). Only RT+HIIT reduced absolute fat mass (mean ± SD, -11.0 ± 11.7%). CONCLUSIONS In moderately-active males, concurrent training, regardless of the exercise order, presents a viable strategy to improve lower-body maximal strength and total lean mass comparably to resistance-only training, whilst also improving indices of aerobic fitness. However, improvements in CMJ displacement, force, and power were attenuated when RT was performed before HIIT, and as such, exercise order may be an important consideration when designing training programs in which the goal is to improve lower-body power.
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Changes in Metabolic Parameters and Body Weight in Patients With Major Depressive Disorder Treated With Adjunctive Brexpiprazole: Pooled Analysis of Phase 3 Clinical Studies.
Newcomer, JW, Eriksson, H, Zhang, P, Meehan, SR, Weiss, C
The Journal of clinical psychiatry. 2019;(6)
Abstract
OBJECTIVE To analyze the effect of adjunctive brexpiprazole on metabolic parameters and body weight in adults with major depressive disorder (MDD) based on pooled data from 4 short-term studies and 1 long-term extension study. METHODS The short-term studies (June 2011 to November 2016) were randomized, double-blind, placebo-controlled studies in outpatients with MDD (DSM-IV-TR criteria) and inadequate response to 1-3 prior antidepressant treatments (ADTs) plus 1 prospective ADT. Patients were randomized to adjunctive brexpiprazole (fixed or flexible doses in the range of 1-3 mg/d; n = 1,032) or placebo (n = 819) for 6 weeks. The long-term study (October 2011 to May 2017) was a 52-week (amended to 26 weeks), open-label, uncontrolled study of adjunctive brexpiprazole 0.5-3 mg/d (flexible dose; n = 2,938). Mean changes from baseline and categorical shifts in fasting metabolic parameters (cholesterol, triglycerides, and glucose) and body weight were analyzed. RESULTS Mean changes from baseline in metabolic parameters were small after 6 weeks (all < 2 mg/dL) and 52 weeks (all < 4 mg/dL, except triglycerides, 15.83 mg/dL) of treatment. In most cases, the incidence of unfavorable shifts in metabolic parameters was lower than the incidence of favorable shifts. Mean body weight increase at last visit in the short-term studies was 1.5 kg with ADT + brexpiprazole and 0.3 kg with ADT + placebo. During long-term treatment, mean body weight increased by 3.8 kg over 58 weeks. CONCLUSIONS Adjunctive brexpiprazole was associated with small changes in metabolic parameters and moderate weight gain during short- and long-term treatment. TRIAL REGISTRATION ClinicalTrials.gov identifiers: NCT01360645, NCT01360632, NCT02196506, NCT01727726, NCT01360866.
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Lean body weight dosing avoids excessive systemic exposure to proton pump inhibitors for children with obesity.
Shakhnovich, V, Abdel-Rahman, S, Friesen, CA, Weigel, J, Pearce, RE, Gaedigk, A, Leeder, JS, Kearns, GL
Pediatric obesity. 2019;(1)
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Abstract
BACKGROUND Children with obesity are more likely to suffer gastroesophageal reflux disease, requiring acid-suppression therapy with proton pump inhibitors (PPIs) and no guidelines regarding dosing. OBJECTIVE To prospectively evaluate lean-body-weight-based (LBW) dosing of the PPI pantoprazole for children with and without obesity. METHODS Methods: Sixty-two children (6-17 years) received a one-time oral dose of liquid pantoprazole (1.2 mg kg-1 LBW). Plasma pantoprazole concentrations were measured at 10 time points over 8 h and pharmacokinetic (PK) profiles generated using non-compartmental techniques, in order to compare PK parameters of interest between children with and without obesity, while accounting for CYP2C19 genotype. RESULTS Adjusted for milligram-per-kilogram total body weight (TBW) pantoprazole received, apparent drug clearance (CL/F) was reduced 50% in children with vs. without obesity (p=0.03). LBW-based dosing compensated for this reduction in CL/F (p = 0.15). CONCLUSION To achieve comparable systemic PPI exposures for children with and without obesity, we recommend using LBW, rather than TBW-based dosing for pantoprazole.
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Glycaemic control, hypoglycaemia, and weight change with insulin glargine 300 U/mL versus insulin glargine 100 U/mL in Japanese adults with type 2 diabetes: A 12-month comparison by concomitant sulphonylurea and/or glinide use.
Terauchi, Y, Riddle, MC, Hirose, T, Koyama, M, Cheng, X, Takahashi, Y, Bolli, GB
Diabetes, obesity & metabolism. 2018;(11):2541-2550
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Abstract
AIM: To explore if clinical effects and hypoglycaemia risks associated with insulin glargine 300 U/mL (Gla-300) and 100 U/mL (Gla-100) differed by sulphonylurea and/or glinide (SU/G) treatment. METHODS A post hoc subgroup analysis of 12-month treatment data from the EDITION Japan 2 trial, a randomized, open-label, phase 3 study of Japanese people with type 2 diabetes receiving once-daily Gla-300/Gla-100 + oral antihyperglycaemic drugs. Participants previously receiving SU/G (+SU/G) were compared with those not taking SU/G (-SU/G). Endpoints included HbA1c, hypoglycaemia and body weight. RESULTS For +SU/G (n = 152, 63%), HbA1c was reduced from baseline to month 12 for Gla-300 (8.1% to 7.6%) and Gla-100 (8.2% to 7.8%). For -SU/G (n = 89, 37%), reductions were 7.8% to 7.4%, and 7.9% to 7.5% for Gla-300 and Gla-100, respectively. A lower annualized rate of hypoglycaemia with Gla-300 versus Gla-100 was observed at night (00:00-05:59 hours; p = 0.0001) and any time of day (24 hour; p = 0.0015). Irrespective of the insulin used, the incidence and rate of confirmed (≤3.9 mmol/L [≤70 mg/dL]) or severe hypoglycaemia appeared higher in +SU/G versus -SU/G; overall, a reduced incidence of nocturnal hypoglycaemia, and rate of hypoglycaemia at any time, was observed in -SU/G versus +SU/G. In the -SU/G subgroup, body weight gain differences were observed between Gla-300 and Gla-100 (p < 0.0001). CONCLUSIONS Participants with prior and continued SU/G use had similar therapeutic responses with basal insulin but greater risk of hypoglycaemia than those not using SU/G; hypoglycaemia risk was lower with Gla-300 than Gla-100 in both subgroups.
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The effects of a 12-week worksite physical activity intervention on anthropometric indices, blood pressure indices, and plasma biomarkers of cardiovascular disease risk among university employees.
Corbett, DB, Fennell, C, Peroutky, K, Kingsley, JD, Glickman, EL
BMC research notes. 2018;(1):80
Abstract
BACKGROUND To determine the effectiveness of a low-cost 12-week worksite physical activity intervention targeting a goal of 10,000 steps per day on reducing anthropometric indices, blood pressure indices, and plasma biomarkers of cardiovascular disease (CVD) risk among the employees of a major university. METHODS Fifty university employees (n = 43 female, n = 7 male; mean age = 48 ± 10 years) participated in the 12-week physical activity intervention (60 min, 3 day/week). Each session included both aerobic (cardiorespiratory endurance) and muscle-strengthening (resistance) physical activity using existing university facilities and equipment. Anthropometric indices, blood pressure indices, and plasma biomarkers of CVD risk assessed included those for obesity (body mass index), hypertension (systolic blood pressure, SBP; diastolic blood pressure, DBP), dyslipidemia (high-density lipoprotein, HDL; low-density lipoprotein, LDL; total serum cholesterol), and prediabetes (impaired fasting glucose, IFG). Steps per day were assessed using a wrist-worn activity monitor. Participants were given the goal of 10,000 steps per day and categorized as either compliers (≥ 10,000 steps per day on average) or non-compliers (< 10,000 steps per day on average) based on their ability to achieve this goal. RESULTS Overall, 34% of participants at baseline were already at an elevated risk of CVD due to age. On average, 28% of participants adhered to the goal of 10,000 steps per day. After 12-weeks, participants in both groups (compliers and non-compliers) had lower BMI scores (p < 0.001), lower HDL scores (p < 0.034), and higher IFG scores (p < 0.001). The non-compliers had a greater reduction of BMI scores than the compliers (p = 0.003). Participants at risk for CVD had greater reductions than those not at risk for several risk factors, including SBP (p = 0.020), DBP (p = 0.028), IFG (p = 0.002), LDL (p = 0.006), and total serum cholesterol (p = 0.009). CONCLUSION While the physical activity intervention showed mixed results overall with both favorable changes in anthropometric indices yet unfavorable changes in plasma biomarkers, it was particularly beneficial in regards to both blood pressure indices and plasma biomarkers among those already at risk of CVD. Trial registration ClinicalTrials.gov NCT03385447; retrospectively registered.
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Changes in Weight Associated With Telotristat Ethyl in the Treatment of Carcinoid Syndrome.
Weickert, MO, Kaltsas, G, Hörsch, D, Lapuerta, P, Pavel, M, Valle, JW, Caplin, ME, Bergsland, E, Kunz, PL, Anthony, LB, et al
Clinical therapeutics. 2018;(6):952-962.e2
Abstract
PURPOSE In the placebo-controlled Phase III TELESTAR (Telotristat Etiprate for Somatostatin Analogue Not Adequately Controlled Carcinoid Syndrome) trial, the oral tryptophan hydroxylase inhibitor telotristat ethyl significantly reduced bowel movement (BM) frequency during a 12-week, double-blind treatment period in 135 patients with metastatic neuroendocrine tumors with carcinoid syndrome and ≥4 BMs per day. Patients (mean [SD] age, 63.5 [8.9] years; mean [SD] body mass index, 24.9 [4.9] kg/m2) received placebo, telotristat ethyl 250 mg, or telotristat ethyl 500 mg 3 times per day (TID) in addition to somatostatin analogue therapy. Weight loss is associated with uncontrolled carcinoid syndrome and may be associated with reduced survival. METHODS Assessment of the occurrence of weight change ≥3% at week 12 was prespecified in the statistical analysis plan. FINDINGS In 120 patients with weight data available, weight gain ≥3% was observed in 2 of 39 patients (5.1%) taking placebo TID, 7 of 41 (17.1%) taking telotristat ethyl 250 mg TID, and 13 of 40 (32.5%) taking telotristat ethyl 500 mg TID (P = 0.0017) at week 12. Weight loss ≥3% was observed in 5 of 39 patients (12.8%) taking placebo TID, 4 of 41 (9.8%) taking telotristat ethyl 250 mg TID, and 6 of 40 (15.0%) taking telotristat ethyl 500 mg TID (P = 0.77). Biochemical and metabolic parameters of serum albumin and cholesterol significantly increased (P = 0.02 and P = 0.001, respectively) in patients gaining weight and decreased in patients who lost weight, suggesting an improvement in overall nutritional status. IMPLICATIONS Up to 32.5% of patients treated with telotristat ethyl experienced significant, dose-dependent weight gain, associated with reduced diarrhea severity and improved biochemical and metabolic parameters. Improved nutritional status could be an additional aspect of telotristat ethyl efficacy among patients with functioning metastatic neuroendocrine tumors. ClinicalTrials.gov identifier: NCT01677910.
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Effects of exenatide on weight and appetite in overweight adolescents and young adults with Prader-Willi syndrome.
Salehi, P, Hsu, I, Azen, CG, Mittelman, SD, Geffner, ME, Jeandron, D
Pediatric obesity. 2017;(3):221-228
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Abstract
BACKGROUND Prader-Willi syndrome (PWS) is associated with hyperphagia and hyperghrelinemia with major morbidity because of obesity without effective medical treatment targeting hyperphagia. Exenatide (Byetta [synthetic Exendin-4]; AstraZeneca, Wilmington DE) is a GLP-1 receptor agonist which reduces appetite and weight and may be an effective treatment in PWS. OBJECTIVE The objective of this study is to determine the effect of a 6-month trial of exenatide on appetite, weight and gut hormones in youth with PWS. METHODS Ten overweight and obese subjects with PWS (13-25 years) were recruited for a 6-month open-label, non-randomized, longitudinal study conducted at Children's Hospital Los Angeles. Exenatide was given using standard diabetes dosing without dietary modifications. Weight, body mass index (BMI), truncal fat, appetite and plasma acylated ghrelin were measured over 6 months. Mixed meal tolerance tests were performed at 0 and 6 months. RESULTS Appetite scores significantly decreased from baseline (32.2 ± 8.7) after 1, 3 and 6 moths of treatment (27.5 ± 8.8, 25.4 ± 9.3, and 25.4 ± 7.2 respectively; p = 0.004). Hemoglobin A1c decreased significantly after treatment, but weight, BMI z-score and adiposity did not. There was no significant change in ghrelin. CONCLUSIONS This is the first longitudinal investigation of the effects of exenatide in subjects with PWS. It was effective in decreasing appetite, without change in weight or BMI in the short term. Larger, controlled, longer-term trials in patients with PWS are needed to confirm the efficacy and safety of exenatide and to evaluate whether its use might induce weight loss when given in conjunction with behavioural modification.
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Higher resting-state activity in reward-related brain circuits in obese versus normal-weight females independent of food intake.
Hogenkamp, PS, Zhou, W, Dahlberg, LS, Stark, J, Larsen, AL, Olivo, G, Wiemerslage, L, Larsson, EM, Sundbom, M, Benedict, C, et al
International journal of obesity (2005). 2016;(11):1687-1692
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Abstract
BACKGROUND In response to food cues, obese vs normal-weight individuals show greater activation in brain regions involved in the regulation of food intake under both fasted and sated conditions. Putative effects of obesity on task-independent low-frequency blood-oxygenation-level-dependent signals-that is, resting-state brain activity-in the context of food intake are, however, less well studied. OBJECTIVE To compare eyes closed, whole-brain low-frequency BOLD signals between severely obese and normal-weight females, as assessed by functional magnetic resonance imaging (fMRI). METHODS Fractional amplitude of low-frequency fluctuations were measured in the morning following an overnight fast in 17 obese (age: 39±11 years, body mass index (BMI): 42.3±4.8 kg m-2) and 12 normal-weight females (age: 36±12 years, BMI: 22.7±1.8 kg m-2), both before and 30 min after consumption of a standardized meal (~260 kcal). RESULTS Compared with normal-weight controls, obese females had increased low-frequency activity in clusters located in the putamen, claustrum and insula (P<0.05). This group difference was not altered by food intake. Self-reported hunger dropped and plasma glucose concentrations increased after food intake (P<0.05); however, these changes did not differ between the BMI groups. CONCLUSION Reward-related brain regions are more active under resting-state conditions in obese than in normal-weight females. This difference was independent of food intake under the experimental settings applied in the current study. Future studies involving males and females, as well as utilizing repeated post-prandial resting-state fMRI scans and various types of meals are needed to further investigate how food intake alters resting-state brain activity in obese humans.