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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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Effects of curcumin on body weight, glycemic control and serum lipids in women with polycystic ovary syndrome: A randomized, double-blind, placebo-controlled trial.
Jamilian, M, Foroozanfard, F, Kavossian, E, Aghadavod, E, Shafabakhsh, R, Hoseini, A, Asemi, Z
Clinical nutrition ESPEN. 2020;:128-133
Abstract
OBJECTIVE The aim of this study was to evaluate the effect of curcumin on body weight, glycemic control and serum lipids in women suffering from polycystic ovary syndrome (PCOS). METHODS The current randomized, double-blinded, placebo-controlled clinical trial was performed on 60 subjects with PCOS, aged 18-40 years old. Subjects were randomly allocated to take 500 mg/day curcumin (n = 30) or placebo (n = 30) for 12 weeks. Glycemic control and serum lipids were measured at baseline and after the 12-week intervention. Using RT-PCR method, gene expression related to insulin and lipid metabolism was evaluated. RESULTS Curcumin significantly decreased weight (-0.8 ± 0.9 vs. -0.2 ± 0.8 kg, P = 0.03) and BMI (-0.3 ± 0.4 vs. -0.1 ± 0.3 kg/m2, P = 0.03). Curcumin, compared with the placebo, significantly reduced fasting glucose (β -2.63 mg/dL; 95% CI, -4.21, -1.05; P = 0.002), serum insulin (β -1.16 μIU/mL; 95% CI, -2.12, -0.19; P = 0.02), insulin resistance (β -0.26; 95% CI, -0.48, -0.03; P = 0.02), and significantly increased insulin sensitivity (β 0.006; 95% CI, 0.001, 0.01; P = 0.02). In addition, taking curcumin was associated with a significant reduction in total cholesterol (β -15.86 mg/dL; 95% CI, -24.48, -7.24; P = 0.001), LDL-cholesterol (β -16.09 mg/dL; 95% CI, -25.11, -7.06; P = 0.001) and total-/HDL-cholesterol ratio (β -0.62; 95% CI, -0.93, -0.30; P < 0.001), and a significant increase in HDL-cholesterol levels (β 2.14 mg/dL; 95% CI, 0.36, 3.92; P = 0.01) compared with the placebo. Additionally, curcumin administration up-regulated gene expression of peroxisome proliferator-activated receptor gamma (PPAR-γ) (P = 0.03) and low-density lipoprotein receptor (LDLR) (P < 0.001) compared with the placebo. CONCLUSIONS Overall, curcumin administration for 12 weeks to women with PCOS had beneficial effects on body weight, glycemic control, serum lipids except triglycerides and VLDL-cholesterol levels, and gene expression of PPAR-γ and LDLR. Registered under Clinical Trials.gov Identifier no. http://www.irct.ir: IRCT20170513033941N50.
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Attenuation of Weight Loss Through Improved Antilipolytic Effect in Adipose Tissue Via the SGLT2 Inhibitor Tofogliflozin.
Yoshida, A, Matsubayashi, Y, Nojima, T, Suganami, H, Abe, T, Ishizawa, M, Fujihara, K, Tanaka, S, Kaku, K, Sone, H
The Journal of clinical endocrinology and metabolism. 2019;(9):3647-3660
Abstract
CONTEXT Although calorie loss from increased urinary glucose excretion continues after long-term treatment with sodium-glucose cotransporter 2 inhibitors (SGLT2is), the mechanisms of the attenuated weight loss due to SGLT2is are not well known. OBJECTIVE To examine the mechanism of the attenuated weight loss during long-term treatment with an SGLT2i, tofogliflozin, focusing on the antilipolytic effect of insulin on adipose tissue. DESIGN AND PARTICIPANTS An integrated analysis was performed using data from two phase 3 studies of 52 weeks of tofogliflozin administration. The antilipolytic effect was evaluated using adipose tissue insulin resistance (Adipo-IR) calculated from the product of the levels of fasting insulin (f-IRI) and fasting free fatty acids (f-FFAs). RESULTS Data from 774 patients with type 2 diabetes (mean age, 58.5 years; glycosylated hemoglobin, 8.1%; body mass index, 25.6 kg/m2; estimated glomerular filtration rate, 83.9 mL/min/1.73m2; 66% men) were analyzed. Weight loss plateaued between weeks 24 and 52 after decreasing significantly. f-IRI levels decreased significantly from baseline to week 24, and the decrease was maintained until Week 52. f-FFA levels significantly increased, peaked at week 24, then declined from weeks 24 to 52. Adipo-IR levels declined progressively throughout the 52 weeks (-3.6 mmol/L·pmol/L and -6.2 mmol/L·pmol/L at weeks 24 and 52, respectively; P < 0.001 baseline vs weeks 24 and 52 and week 24 vs week 52). Higher baseline Adipo-IR levels were independently associated with greater weight loss at week 52. CONCLUSION The improved antilipolytic effect in adipose tissue may attenuate progressive lipolysis, leading to attenuating future weight loss induced by an SGLT2i in patients with type 2 diabetes.
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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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Weight Evolution During Endocrine Therapy for Breast Cancer in Postmenopausal Patients: Effect of Initial Fat Mass Percentage and Previous Adjuvant Treatments.
Ginzac, A, Thivat, É, Mouret-Reynier, MA, Dubray-Longeras, P, Van Praagh, I, Passildas, J, Abrial, C, Kwiatkowski, F, Boirie, Y, Duclos, M, et al
Clinical breast cancer. 2018;(5):e1093-e1102
Abstract
BACKGROUND Weight changes during adjuvant treatment for early-stage breast cancer has been associated with a poor prognosis. The long-term evolution of body composition during adjuvant treatment for breast cancer, in particular, endocrine therapy, is not well known, and new data on this topic are required. The present study assessed the evolution of weight and body composition among 33 postmenopausal breast cancer patients receiving endocrine therapy after standard adjuvant chemotherapy that included taxanes. PATIENTS AND METHODS Dual-energy x-ray absorptiometry was used to measure the fat and lean body mass. Body water was assessed using multifrequency bioelectrical impedance analysis. The Hospital Anxiety and Depression questionnaire and the short version of the International Physical Activity Questionnaire were also administered. RESULTS During endocrine therapy, 5 of the 33 patients (15.2%) lost weight and 12 (36.4%) gained weight. The overall average gain was 2.0 ± 5.5 kg (P = .04). During this period, the fat mass, lean body mass, and body water increased. The factors linked to fat mass gain included an excess fat mass (≥ 36%) before treatment and weight loss during chemotherapy. In the overall period of adjuvant cancer treatment, 30% of the population gained > 5% of their initial weight. The average gain was the same as that during the endocrine therapy period (2.0 ± 5.4 kg; P = .031) and was characterized by an increase in total lean body mass, mainly localized in the trunk region. CONCLUSION Endocrine therapy appears as a pivotal period in weight and body composition management. Overfat and obese patients and those who lose weight during chemotherapy were more subject to weight and fat mass gain during endocrine therapy.
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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.