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Effect of Bimagrumab vs Placebo on Body Fat Mass Among Adults With Type 2 Diabetes and Obesity: A Phase 2 Randomized Clinical Trial.
Heymsfield, SB, Coleman, LA, Miller, R, Rooks, DS, Laurent, D, Petricoul, O, Praestgaard, J, Swan, T, Wade, T, Perry, RG, et al
JAMA network open. 2021;(1):e2033457
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Abstract
IMPORTANCE Antibody blockade of activin type II receptor (ActRII) signaling stimulates skeletal muscle growth. Previous clinical studies suggest that ActRII inhibition with the monoclonal antibody bimagrumab also promotes excess adipose tissue loss and improves insulin resistance. OBJECTIVE To evaluate the efficacy and safety of bimagrumab on body composition and glycemic control in adults with type 2 diabetes and overweight and obesity. DESIGN, SETTING, AND PARTICIPANTS This double-masked, placebo-controlled, 48-week, phase 2 randomized clinical trial was conducted among adults with type 2 diabetes, body mass index between 28 and 40, and glycated hemoglobin (HbA1c) levels between 6.5% and 10.0% at 9 US and UK sites. The trial was conducted from February 2017 to May 2019. Only participants who completed a full treatment regimen were included in analysis. INTERVENTIONS Patients were randomized to intravenous infusion of bimagrumab (10 mg/kg up to 1200 mg in 5% dextrose solution) or placebo (5% dextrose solution) treatment every 4 weeks for 48 weeks; both groups received diet and exercise counseling. MAIN OUTCOMES AND MEASURES The primary end point was least square mean change from baseline to week 48 in total body fat mass (FM); secondary and exploratory end points were lean mass (LM), waist circumference (WC), HbA1c level, and body weight (BW) changes from baseline to week 48. RESULTS A total of 75 patients were randomized to bimagrumab (n = 37; 23 [62.2%] women) or placebo (n = 38; 12 [31.6%] women); 58 (77.3%) completed the 48-week study. Patients at baseline had a mean (SD) age of 60.4 (7.7) years; mean (SD) BMI of 32.9 (3.4); mean (SD) BW of 93.6 (14.9) kg; mean (SD) FM of 35.4 (7.5) kg; and mean (SD) HbA1c level of 7.8% (1.0%). Changes at week 48 for bimagrumab vs placebo were as follows: FM, -20.5% (-7.5 kg [80% CI, -8.3 to -6.6 kg]) vs -0.5% (-0.18 kg [80% CI, -0.99 to 0.63 kg]) (P < .001); LM, 3.6% (1.70 kg [80% CI, 1.1 to 2.3 kg]) vs -0.8% (-0.4 kg [80% CI, -1.0 to 0.1 kg]) (P < .001); WC, -9.0 cm (80% CI, -10.3 to -7.7 cm) vs 0.5 cm (80% CI, -0.8 to 1.7 cm) (P < .001); HbA1c level, -0.76 percentage points (80% CI, -1.05 to -0.48 percentage points) vs -0.04 percentage points (80% CI, -0.23 to 0.31 percentage points) (P = .005); and BW, -6.5% (-5.9 kg [80% CI, -7.1 to -4.7 kg]) vs -0.8% (-0.8 kg [80% CI, -1.9 to 0.3 kg]) (P < .001). Bimagrumab's safety and tolerability profile was consistent with prior studies. CONCLUSIONS AND RELEVANCE In this phase 2 randomized clinical trial, ActRII blockade with bimagrumab led to significant loss of FM, gain in LM, and metabolic improvements during 48 weeks in patients with overweight or obesity who had type 2 diabetes. ActRII pathway inhibition may provide a novel approach for the pharmacologic management of excess adiposity and accompanying metabolic disturbances. TRIAL REGISTRATION ClinicalTrials.gov number: NCT03005288.
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Sodium-glucose cotransporter 2 inhibitor-induced changes in body composition and simultaneous changes in metabolic profile: 52-week prospective LIGHT (Luseogliflozin: the Components of Weight Loss in Japanese Patients with Type 2 Diabetes Mellitus) Study.
Sasaki, T, Sugawara, M, Fukuda, M
Journal of diabetes investigation. 2019;(1):108-117
Abstract
AIMS/INTRODUCTION It is unclear how changes in body composition induced by sodium-glucose cotransporter 2 (SGLT2) inhibitor treatment correlate with metabolic profile changes. We aimed to clarify how metabolic profile changes correlate with body component changes, and if SGLT2 inhibitor treatment causes sarcopenia and bone mineral content (BMC) loss. MATERIALS AND METHODS Moderately obese Japanese type 2 diabetes patients, treated with luseogliflozin for a year, were observed prospectively and evaluated for body composition changes. We analyzed the changes in the individual body components during treatment, and their correlation with other clinical variables. RESULTS The efficacy analysis set comprised 37 of 43 enrolled patients. The total fat mass significantly decreased early in the treatment at and after week 4, with a mean decrease of -1.97 kg (95% confidence interval -2.66 to -1.28) at week 24. The visceral fat area at week 24 showed an average downward trend, although this was not significant. The changes in visceral fat area in individual patients showed a significant negative correlation with the extent of the baseline visceral fat area (r = -0.399, P = 0.023). The skeletal muscle mass index showed a significant but small change at and after week 36. The BMC profile showed a transient significant decrease only at week 12. No significant change in BMC was noted at other time-points. CONCLUSIONS Luseogliflozin treatment brought about favorable changes in body composition and metabolism of moderately obese Japanese type 2 diabetes patients, accompanied by body fat reduction, and minimal muscle and BMC reduction.
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Effects of canagliflozin on body composition and hepatic fat content in type 2 diabetes patients with non-alcoholic fatty liver disease.
Inoue, M, Hayashi, A, Taguchi, T, Arai, R, Sasaki, S, Takano, K, Inoue, Y, Shichiri, M
Journal of diabetes investigation. 2019;(4):1004-1011
Abstract
AIMS/INTRODUCTION Non-alcoholic fatty liver disease is frequently associated with type 2 diabetes, and constitutes an important risk factor for the development of hepatic fibrosis and hepatocellular carcinoma. Because there remains no effective drug therapy for non-alcoholic fatty liver disease associated with type 2 diabetes, we evaluated the efficacy of sodium-glucose cotransporter 2 inhibitor. METHODS AND MATERIALS In the present pilot, prospective, non-randomized, open-label, single-arm study, we evaluated the effect of 100 mg canagliflozin administered once daily for 12 months on serological markers, body composition measured by bioelectrical impedance analysis method and hepatic fat fraction measured by magnetic resonance imaging in type 2 diabetes patients with non-alcoholic fatty liver disease. RESULTS Canagliflozin significantly reduced body and fat mass, and induced a slight decrease in lean body or muscle mass that did not reach significance at 6 and 12 months. Reductions in fat mass in each body segment (trunk, arms and legs) were evident, whereas those in lean body mass were not. The hepatic fat fraction was reduced from a baseline of 17.6 ± 7.5% to 12.0 ± 4.6% after 6 months and 12.1 ± 6.1% after 12 months (P < 0.0005 and P < 0.005), whereas serum liver enzymes and type IV collagen concentrations improved. From a mean baseline hemoglobin A1c of 8.7 ± 1.4%, canagliflozin significantly reduced hemoglobin A1c after 6 and 12 months to 7.3 ± 0.6% and 7.7 ± 0.7% (P < 0.0005 and P < 0.01). CONCLUSIONS Canagliflozin reduced body mass, fat mass and hepatic fat content without significantly reducing muscle mass.
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Effects on body composition and handgrip strength of a nutritional intervention for malnourished HIV-infected adults referred for antiretroviral therapy: a randomised controlled trial.
PrayGod, G, Rehman, AM, Wells, JCK, Chisenga, M, Siame, J, Jeremiah, K, Kasonka, L, Woodd, S, Changalucha, J, Kelly, P, et al
Journal of nutritional science. 2019;:e19
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Abstract
Lipid-based nutrient supplements (LNS) may be beneficial for malnourished HIV-infected patients starting antiretroviral therapy (ART). We assessed the effect of adding vitamins and minerals to LNS on body composition and handgrip strength during ART initiation. ART-eligible HIV-infected patients with BMI <18·5 kg/m2 were randomised to LNS or LNS with added high-dose vitamins and minerals (LNS-VM) from referral for ART to 6 weeks post-ART and followed up until 12 weeks. Body composition by bioelectrical impedance analysis (BIA), deuterium (2H) diluted water (D2O) and air displacement plethysmography (ADP), and handgrip strength were determined at baseline and at 6 and 12 weeks post-ART, and effects of LNS-VM v. LNS at 6 and 12 weeks investigated. BIA data were available for 1461, D2O data for 479, ADP data for 498 and handgrip strength data for 1752 patients. Fat mass tended to be lower, and fat-free mass correspondingly higher, by BIA than by ADP or D2O. At 6 weeks post-ART, LNS-VM led to a higher regain of BIA-assessed fat mass (0·4 (95 % CI 0·05, 0·8) kg), but not fat-free mass, and a borderline significant increase in handgrip strength (0·72 (95 % CI -0·03, 1·5) kg). These effects were not sustained at 12 weeks. Similar effects as for BIA were seen using ADP or D2O but no differences reached statistical significance. In conclusion, LNS-VM led to a higher regain of fat mass at 6 weeks and to a borderline significant beneficial effect on handgrip strength. Further research is needed to determine appropriate timing and supplement composition to optimise nutritional interventions in malnourished HIV patients.
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A haplotype of three SNPs in FTO had a strong association with body composition and BMI in Iranian male adolescents.
Kalantari, N, Keshavarz Mohammadi, N, Izadi, P, Doaei, S, Gholamalizadeh, M, Eini-Zinab, H, Salonurmi, T, Rafieifar, S, Janipoor, R, Azizi Tabesh, G
PloS one. 2018;(4):e0195589
Abstract
BACKGROUND Single-nucleotide polymorphisms (SNPs), which are located in the first intron of the FTO gene, are reported to be associated with body weight and the body mass index (BMI). However, their effects on anthropometric measurements in adolescents are poorly understood. OBJECTIVE This study aimed to investigate the association of three adjacent polymorphisms (rs9930506, rs9930501, & rs9932754) in the FTO gene with anthropometric indices in Iranian adolescent males. DESIGN The participants comprised a total of 237 adolescent males who were recruited randomly from two high schools in Tehran, Iran. The DNA samples were genotyped for the FTO gene polymorphisms by DNA sequencing. BMI, body fat percentage (BF%), and body muscle percentage (BM%) were determined using a validated bioelectrical impedance analysis scale. The association of the FTO polymorphisms with weight, height, BMI, BF%, and BM% was investigated. RESULTS A haplotype of rs9930506, rs9930501, and rs9932754 (GGT) in the first intron of the FTO with complete linkage disequilibrium (LD) was found to be significantly associated with higher weight (OR = 1.32), BMI (OR = 5.36) and BF% (OR = 1.46), and lower BM% (OR = 3.59) (all P<0.001). None of the students with GGC genotypes were underweight, while all of the students with AAT genotypes had high muscle mass. CONCLUSIONS A haplotype in the first intron of the FTO gene had a strong association with obesity indices in Iranian adolescent males. The FTO gene polymorphisms might have greater effects on anthropometric indices than what was previously imagined. Moreover, we suggested that the FTO gene exerted their effects on anthropometric measurements through haplotypes (and not single SNPs).
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Effect of bimagrumab on thigh muscle volume and composition in men with casting-induced atrophy.
Rooks, DS, Laurent, D, Praestgaard, J, Rasmussen, S, Bartlett, M, Tankó, LB
Journal of cachexia, sarcopenia and muscle. 2017;(5):727-734
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BACKGROUND Patients experiencing disuse atrophy report acute loss of skeletal muscle mass which subsequently leads to loss of strength and physical capacity. In such patients, especially the elderly, complete recovery remains a challenge even with improved nutrition and resistance exercise. This study aimed to explore the clinical potential of bimagrumab, a human monoclonal antibody targeting the activin type II receptor, for the recovery of skeletal muscle volume from disuse atrophy using an experimental model of lower extremity immobilization. METHODS In this double-blind, placebo-controlled trial, healthy young men (n = 24; mean age, 24.1 years) were placed in a full-length cast of one of the lower extremities for 2 weeks to induce disuse atrophy. After cast removal, subjects were randomized to receive a single intravenous (i.v.) dose of either bimagrumab 30 mg/kg (n = 15) or placebo (n = 9) and were followed for 12 weeks. Changes in thigh muscle volume (TMV) and inter-muscular adipose tissue (IMAT) and subcutaneous adipose tissue (SCAT) of the thigh, maximum voluntary knee extension strength, and safety were assessed throughout the 12 week study. RESULTS Casting resulted in an average TMV loss of -4.8% and comparable increases in IMAT and SCAT volumes. Bimagrumab 30 mg/kg i.v. resulted in a rapid increase in TMV at 2 weeks following cast removal and a +5.1% increase above pre-cast levels at 12 weeks. In comparison, TMV returned to pre-cast level at 12 weeks (-0.1%) in the placebo group. The increased adiposity of the casted leg was sustained in the placebo group and decreased substantially in the bimagrumab group at Week 12 (IMAT: -6.6%, SCAT -3.5%). Knee extension strength decreased by ~25% in the casted leg for all subjects and returned to pre-cast levels within 6 weeks after cast removal in both treatment arms. Bimagrumab was well tolerated with no serious or severe adverse events reported during the study. CONCLUSIONS A single dose of bimagrumab 30 mg/kg i.v. safely accelerated the recovery of TMV and reversal of accumulated IMAT following 2 weeks in a joint-immobilizing cast.
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Energy expenditure and body composition changes after an isocaloric ketogenic diet in overweight and obese men.
Hall, KD, Chen, KY, Guo, J, Lam, YY, Leibel, RL, Mayer, LE, Reitman, ML, Rosenbaum, M, Smith, SR, Walsh, BT, et al
The American journal of clinical nutrition. 2016;(2):324-33
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BACKGROUND The carbohydrate-insulin model of obesity posits that habitual consumption of a high-carbohydrate diet sequesters fat within adipose tissue because of hyperinsulinemia and results in adaptive suppression of energy expenditure (EE). Therefore, isocaloric exchange of dietary carbohydrate for fat is predicted to result in increased EE, increased fat oxidation, and loss of body fat. In contrast, a more conventional view that "a calorie is a calorie" predicts that isocaloric variations in dietary carbohydrate and fat will have no physiologically important effects on EE or body fat. OBJECTIVE We investigated whether an isocaloric low-carbohydrate ketogenic diet (KD) is associated with changes in EE, respiratory quotient (RQ), and body composition. DESIGN Seventeen overweight or obese men were admitted to metabolic wards, where they consumed a high-carbohydrate baseline diet (BD) for 4 wk followed by 4 wk of an isocaloric KD with clamped protein. Subjects spent 2 consecutive days each week residing in metabolic chambers to measure changes in EE (EEchamber), sleeping EE (SEE), and RQ. Body composition changes were measured by dual-energy X-ray absorptiometry. Average EE during the final 2 wk of the BD and KD periods was measured by doubly labeled water (EEDLW). RESULTS Subjects lost weight and body fat throughout the study corresponding to an overall negative energy balance of ∼300 kcal/d. Compared with BD, the KD coincided with increased EEchamber (57 ± 13 kcal/d, P = 0.0004) and SEE (89 ± 14 kcal/d, P < 0.0001) and decreased RQ (-0.111 ± 0.003, P < 0.0001). EEDLW increased by 151 ± 63 kcal/d (P = 0.03). Body fat loss slowed during the KD and coincided with increased protein utilization and loss of fat-free mass. CONCLUSION The isocaloric KD was not accompanied by increased body fat loss but was associated with relatively small increases in EE that were near the limits of detection with the use of state-of-the-art technology. This trial was registered at clinicaltrials.gov as NCT01967563.
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Insulin-Like Growth Factor-1 and Resistance Exercise in Community Dwelling Old Adults.
Arnarson, A, Gudny Geirsdottir, O, Ramel, A, Jonsson, PV, Thorsdottir, I
The journal of nutrition, health & aging. 2015;(8):856-60
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BACKGROUND Insulin-like growth factor-1 (IGF-1) is related to the preservation of lean body mass. Its decline during ageing is thought to make old adults more susceptible to sarcopenia and functional dependency. The aim of the present study was to investigate circulating total IGF-1 in old adults who engaged in a 12-weeks of progressive resistance training. DESIGN Intervention study. SETTING Community. PARTICIPANTS Old Icelandic adults (N = 235, 73.7 ± 5.7 years, 58.2% female). INTERVENTION Twelve-week resistance exercise program (3 times/week; 3 sets, 6-8 repetitions at 75-80% of the 1-repetition maximum) designed to increase strength and muscle mass of major muscle groups. MEASUREMENTS IGF-1. RESULTS At baseline IGF-1 was significantly associated with lean body mass and appendicular muscle mass (also when corrected for age, gender and various covariates). After the training IGF-1 decreased significantly from 112.1 ± 35.6 to 106.1 ± 35.2 µg/L during the course of the study. On and individual level, IGF-1 decreased in 59% and increased in 39% of the participants. Changes in IGF-1 were inversely related to changes in lean body mass (rho = -0.176, P = 0.013 ) and appendicular muscle mass (rho = -0.162, P = 0.019) also when corrected for protein intake, age, gender, and other covariates. CONCLUSION Serum total IGF-1 decreases after 12 weeks of resistance exercise in community dwelling old adults. When looked at IGF-1 changes for participants individually it becomes clear that IGF-1 response to resistances exercise is highly variable. Changes in IGF-1 are negatively related to changes in lean body mass during training, which supports the hypothesis that IGF-1 is redistributed from circulation into tissue during periods of active muscle building.
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Higher Daily Energy Expenditure and Respiratory Quotient, Rather Than Fat-Free Mass, Independently Determine Greater ad Libitum Overeating.
Piaggi, P, Thearle, MS, Krakoff, J, Votruba, SB
The Journal of clinical endocrinology and metabolism. 2015;(8):3011-20
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CONTEXT Body fat-free mass (FFM), energy expenditure (EE), and respiratory quotient (RQ) are known predictors of daily food intake. Because FFM largely determines EE, it is unclear whether body composition per se or the underlying metabolism drives dietary intake. OBJECTIVE The objective of the study was to test whether 24-hour measures of EE and RQ and their components influence ad libitum food intake independently of FFM. DESIGN AND PARTICIPANTS One hundred seven healthy individuals (62 males/45 females, 84 Native Americans/23 whites; age 33 ± 8 y; body mass index 33 ± 8 kg/m(2); body fat 31% ± 8%) had 24-hour measures of EE in a whole-room indirect calorimeter during energy balance, followed by 3 days of ad libitum food intake using computerized vending machine systems. Body composition was estimated by dual-energy x-ray absorptiometry. MAIN OUTCOME MEASURES FFM, 24-hour EE, RQ, spontaneous physical activity, sleeping EE (sleeping metabolic rate), awake and fed thermogenesis, and ad libitum food intake (INTAKE) were measured. RESULTS Higher 24-hour RQ (P < .001, partial R(2) = 16%) and EE (P = .01, partial R(2) = 7%), but not FFM (P = .65), were independent predictors of INTAKE. Mediation analysis demonstrated that 24-hour EE is responsible for 80% of the FFM effect on INTAKE (44.5 ± 16.9 kcal ingested per kilogram of FFM, P= .01), whereas the unique effect due to solely FFM was negligible (10.6 ± 23.2, P = .65). Spontaneous physical activity (r = 0.33, P = .001), but not sleeping metabolic rate (P = .71), positively predicted INTAKE, whereas higher awake and fed thermogenesis determined greater INTAKE only in subjects with a body mass index of 29 kg/m(2) or less (r = 0.44, P = .01). CONCLUSIONS EE and RQ, rather than FFM, independently determine INTAKE, suggesting that competitive energy-sensing mechanisms driven by the preferential macronutrient oxidation and total energy demands may regulate food intake.
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Differential body composition effects of protease inhibitors recommended for initial treatment of HIV infection: a randomized clinical trial.
Martinez, E, Gonzalez-Cordon, A, Ferrer, E, Domingo, P, Negredo, E, Gutierrez, F, Portilla, J, Curran, A, Podzamczer, D, Ribera, E, et al
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2015;(5):811-20
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BACKGROUND It is unclear whether metabolic or body composition effects differ between protease inhibitor-based regimens recommended for initial treatment of human immunodeficiency virus (HIV) infection. METHODS ATADAR is a phase 4, open-label, multicenter, randomized clinical trial. Stable antiretroviral-naive HIV-infected adults were randomly assigned to atazanavir/ritonavir 300/100 mg or darunavir/ritonavir 800/100 mg in combination with tenofovir/emtricitabine daily. Predefined endpoints were treatment or virological failure, drug discontinuation due to adverse effects, and laboratory and body composition changes at 96 weeks. RESULTS At 96 weeks, 56 (62%) atazanavir/ritonavir and 62 (71%) darunavir/ritonavir patients remained free of treatment failure (estimated difference 8.2%; 95% confidence interval [CI], -.6 to 21.6) and 71 (79%) atazanavir/ritonavir and 75 (85%) darunavir/ritonavir patients remained free of virological failure (estimated difference 6.3%; 95% CI, -.5 to 17.6). Seven patients discontinued atazanavir/ritonavir and 5 discontinued darunavir/ritonavir due to adverse effects. Total and high-density lipoprotein cholesterol similarly increased in both arms, but there was a greater increase in triglycerides in the atazanavir/ritonavir arm. At 96 weeks, body fat (estimated difference 2862.2 gr; 95% CI, 726.7 to 4997.7; P = .0090), limb fat (estimated difference 1403.3 gr; 95% CI, 388.4 to 2418.2; P = .0071), and subcutaneous abdominal adipose tissue (estimated difference 28.4 cm(2); 95% CI, 1.9 to 55.0; P = .0362) increased more in the atazanavir/ritonavir arm than in darunavir/ritonavir arm. Body fat changes in the atazanavir/ritonavir arm were associated with higher insulin resistance. CONCLUSIONS We found no major differences between atazanavir/ritonavir and darunavir/ritonavir in efficacy, clinically relevant side effects, or plasma cholesterol fractions. However, atazanavir/ritonavir led to higher triglycerides and more total and subcutaneous fat than darunavir/ritonavir. Also, fat gains with atazanavir/ritonavir were associated with insulin resistance. Clinical Trials Registration. NCT01274780.