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A structurally optimized FXR agonist, MET409, reduced liver fat content over 12 weeks in patients with non-alcoholic steatohepatitis.
Harrison, SA, Bashir, MR, Lee, KJ, Shim-Lopez, J, Lee, J, Wagner, B, Smith, ND, Chen, HC, Lawitz, EJ
Journal of hepatology. 2021;(1):25-33
Abstract
BACKGROUND & AIMS The benefits of farnesoid X receptor (FXR) agonists in patients with non-alcoholic steatohepatitis (NASH) have been validated, although improvements in efficacy and/or tolerability remain elusive. Herein, we aimed to assess the performance of a structurally optimized FXR agonist in patients with NASH. METHODS In this 12-week, randomized, placebo-controlled study, we evaluated MET409 - a non-bile acid agonist with a unique chemical scaffold - in patients with NASH. Patients were randomized to receive either 80 mg (n = 20) or 50 mg (n = 19) of MET409, or placebo (n = 19). RESULTS At Week 12, MET409 lowered liver fat content (LFC), with mean relative reductions of 55% (80 mg) and 38% (50 mg) vs. 6% in placebo (p <0.001). MET409 achieved ≥30% relative LFC reduction in 93% (80 mg) and 75% (50 mg) of patients vs. 11% in placebo (p <0.001) and normalized LFC (≤5%) in 29% (80 mg) and 31% (50 mg) of patients vs. 0% in placebo (p <0.05). An increase in alanine aminotransferase (ALT) was observed with MET409, confounding Week 12 changes from baseline (-25% for 80 mg, 28% for 50 mg). Nonetheless, MET409 achieved ≥30% relative ALT reduction in 50% (80 mg) and 31% (50 mg) of patients vs. 17% in placebo. MET409 was associated with on-target high-density lipoprotein cholesterol decreases (mean changes of -23.4% for 80 mg and -20.3% for 50 mg vs. 2.6% in placebo) and low-density lipoprotein cholesterol (LDL-C) increases (mean changes of 23.7% for 80 mg and 6.8% for 50 mg vs. -1.5% in placebo). Pruritus (mild-moderate) occurred in 16% (50 mg) and 40% (80 mg) of MET409-treated patients. CONCLUSION MET409 lowered LFC over 12 weeks in patients with NASH and delivered a differentiated pruritus and LDL-C profile at 50 mg, providing the first clinical evidence that the risk-benefit profile of FXR agonists can be enhanced through structural optimization. LAY SUMMARY Activation of the farnesoid X receptor (FXR) is a clinically validated approach for treating non-alcoholic steatohepatitis (NASH), although side effects such as itching or increases in low-density lipoprotein cholesterol are frequently dose-limiting. MET409, an FXR agonist with a unique chemical structure, led to significant liver fat reduction and delivered a favorable side effect profile after 12 weeks of treatment in patients with NASH. These results provide the first clinical evidence that the risk-benefit profile of FXR agonists can be enhanced.
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A prospective randomized study comparing effects of empagliflozin to sitagliptin on cardiac fat accumulation, cardiac function, and cardiac metabolism in patients with early-stage type 2 diabetes: the ASSET study.
Hiruma, S, Shigiyama, F, Hisatake, S, Mizumura, S, Shiraga, N, Hori, M, Ikeda, T, Hirose, T, Kumashiro, N
Cardiovascular diabetology. 2021;(1):32
Abstract
BACKGROUND While the cardioprotective benefits of sodium-glucose cotransporter-2 (SGLT2) inhibitors have been established in patients with cardiovascular disease (CVD), their advantages over other anti-diabetic drugs at earlier stages remain unclear. We compared the cardioprotective effects of empagliflozin, an SGLT2 inhibitor, with those of sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, focusing on cardiac fat accumulation, cardiac function, and cardiac metabolism in patients with early-stage type 2 diabetes mellitus (T2DM) without CVD complications. METHODS This was a prospective, randomized, open-label, blinded-endpoint, parallel-group trial that enrolled 44 Japanese patients with T2DM. The patients were randomized for 12-week administration of empagliflozin or sitagliptin. Pericardial fat accumulation and myocardial triglyceride content were evaluated by magnetic resonance imaging and proton magnetic resonance spectroscopy, respectively. Echocardiography, 123I-β-methyl-iodophenyl pentadecanoic acid myocardial scintigraphy, and laboratory tests were performed at baseline and after the 12-week treatment period. RESULTS The patients were middle-aged (50.3 ± 10.7 years, mean ± standard deviation) and overweight (body mass index 29.3 ± 4.9 kg/m2). They had a short diabetes duration (3.5 ± 3.2 years), HbA1c levels of 7.1 ± 0.8%, and preserved cardiac function (ejection fraction 73.8 ± 5.0%) with no vascular complications, except for one baseline case each of diabetic nephropathy and peripheral arterial disease. After the 12-week treatment, no differences from baseline were observed between the two groups regarding changes in pericardial, epicardial, and paracardial fat content; myocardial triglyceride content; cardiac function and mass; and cardiac fatty acid metabolism. However, considering cardiometabolic biomarkers, high-density lipoprotein cholesterol and ketone bodies, including β-hydroxybutyric acid, were significantly increased, whereas uric acid, plasma glucose, plasma insulin, and homeostasis model assessment of insulin resistance were significantly lower in the empagliflozin group than in the sitagliptin group (p < 0.05). CONCLUSIONS Although the effects on cardiac fat and function were not statistically different between the two groups, empagliflozin exhibited superior effects on cardiometabolic biomarkers, such as uric acid, high-density lipoprotein cholesterol, ketone bodies, and insulin sensitivity. Therefore, when considering the primary preventive strategies for CVD, early supplementation with SGLT2 inhibitors may be more beneficial than DPP-4 inhibitors, even in patients with early-stage T2DM without current CVD complications. CLINICAL TRIAL REGISTRATION UMIN000026340; registered on February 28, 2017. https://upload.umin.ac.jp/cgi-open-bin/icdr_e/ctr_view.cgi?recptno=R000030257.
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Individual Response to Standardized Exercise: Total and Abdominal Adipose Tissue.
Brennan, AM, Day, AG, Cowan, TE, Clarke, GJ, Lamarche, B, Ross, R
Medicine and science in sports and exercise. 2020;(2):490-497
Abstract
PURPOSE (1) Determine the effect of exercise amount and intensity on the proportion of individuals for whom the adipose tissue (AT) response is above the minimal clinically important difference (MCID); and (2) Examine whether clinically meaningful anthropometric changes reflect individual AT responses above the MCID. METHODS Men (n = 41) and women (n = 62) (52.7 ± 7.6 yr) were randomized to control (n = 20); low amount low intensity (n = 24); high amount low intensity (n = 30); and high amount high intensity (n = 29) treadmill exercise for 24 wk. The AT changes were measured by MRI. 90% confidence intervals for each individual's observed response were calculated as the observed score ±1.64 × TE (technical error of measurement). RESULTS For visceral AT, HAHI and HALI had a greater proportion of individuals whose AT change and 90% confidence interval were beyond the MCID compared to controls (P < 0.006). For all other AT depots, all exercise groups had significantly more individuals whose changes were beyond the MCID compared with controls. Of those who achieved a waist circumference or body weight reduction ≥ the MCID, 76% to 93% achieved abdominal, abdominal subcutaneous, and visceral AT changes ≥ the MCID. CONCLUSIONS Increasing exercise amount and/or intensity may increase the proportion of individuals who achieve clinically meaningful visceral AT reductions. Waist circumference or body weight changes beyond a clinically meaningful threshold are predictive of clinically meaningful abdominal adiposity changes.
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The causal pathway effects of a physical activity intervention on adiposity in children: The KISS Study cluster randomized clinical trial.
Lima, RA, Andersen, LB, Soares, FC, Kriemler, S
Scandinavian journal of medicine & science in sports. 2020;(9):1685-1691
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BACKGROUND Very little information on the potential mechanisms of the physical activity interventions effects on adiposity is available. We evaluated the possible mediating factors of a physical activity school-based intervention on the sum of skinfolds in children. METHODS This is a cluster randomized trial, secondary analysis of the KISS study. Children (n = 499) from the first and fifth grades were randomly assigned to intervention or control group. Adiposity was estimated by four skinfolds, aerobic fitness assessed by the shuttle run test, and insulin, triglycerides, total cholesterol, high-density lipoprotein (HDL), and glucose collected via fasting blood samples. RESULTS The intervention affected aerobic fitness (0.140 SD, 95% CI 0.011 to 0.270), triglycerides (0.217 SD, 95% CI -0.409 to -0.025), cholesterol/HDL ratio (-0.191 SD, 95% CI -0.334 to -0.047), glucose (-0.330 SD, 95% CI -0.538 to -0.121), and skinfolds (-0.122 SD, 95% CI -0.189 to -0.056). No intervention effect on insulin was found. We observed that changes in aerobic fitness impacted children's triglycerides and cholesterol/HDL ratio and consecutively the glucose levels mediating 30% of the intervention effect on skinfolds. CONCLUSIONS Our findings provided evidence of the positive metabolic distress caused by a physical activity intervention on adiposity levels in children.
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Empagliflozin Effectively Lowers Liver Fat Content in Well-Controlled Type 2 Diabetes: A Randomized, Double-Blind, Phase 4, Placebo-Controlled Trial.
Kahl, S, Gancheva, S, Straßburger, K, Herder, C, Machann, J, Katsuyama, H, Kabisch, S, Henkel, E, Kopf, S, Lagerpusch, M, et al
Diabetes care. 2020;(2):298-305
Abstract
OBJECTIVE To evaluate whether the sodium-glucose cotransporter 2 inhibitor empagliflozin (EMPA) reduces liver fat content (LFC) in recent-onset and metabolically well-controlled type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS Patients with T2D (n = 84) (HbA1c 6.6 ± 0.5% [49 ± 10 mmol/mol], known disease duration 39 ± 27 months) were randomly assigned to 24 weeks of treatment with 25 mg daily EMPA or placebo. The primary end point was the difference of the change in LFC as measured with magnetic resonance methods from 0 (baseline) to 24 weeks between groups. Tissue-specific insulin sensitivity (secondary outcome) was assessed by two-step clamps using an isotope dilution technique. Exploratory analysis comprised circulating surrogate markers of insulin sensitivity and liver function. Statistical comparison was done by ANCOVA adjusted for respective baseline values, age, sex, and BMI. RESULTS EMPA treatment resulted in a placebo-corrected absolute change of -1.8% (95% CI -3.4, -0.2; P = 0.02) and relative change in LFC of -22% (-36, -7; P = 0.009) from baseline to end of treatment, corresponding to a 2.3-fold greater reduction. Weight loss occurred only with EMPA (placebo-corrected change -2.5 kg [-3.7, -1.4]; P < 0.001), while no placebo-corrected change in tissue-specific insulin sensitivity was observed. EMPA treatment also led to placebo-corrected changes in uric acid (-74 mol/L [-108, -42]; P < 0.001) and high-molecular-weight adiponectin (36% [16, 60]; P < 0.001) levels from 0 to 24 weeks. CONCLUSIONS EMPA effectively reduces hepatic fat in patients with T2D with excellent glycemic control and short known disease duration. Interestingly, EMPA also decreases circulating uric acid and raises adiponectin levels despite unchanged insulin sensitivity. EMPA could therefore contribute to the early treatment of nonalcoholic fatty liver disease in T2D.
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Changes of Branched-Chain Amino Acids and Ectopic Fat in Response to Weight-loss Diets: the POUNDS Lost Trial.
Li, X, Sun, D, Zhou, T, Ma, H, Heianza, Y, Liang, Z, Bray, GA, Sacks, FM, Qi, L
The Journal of clinical endocrinology and metabolism. 2020;(10):e3747-56
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CONTEXT Recent evidence has related circulating branch-chained amino acids (BCAAs) to ectopic fat distribution. OBJECTIVE To investigate the associations of changes in plasma BCAAs induced by weight-loss diet interventions with hepatic fat and abdominal fat, and potential modification by different diets. DESIGN, SETTING, AND PARTICIPANTS The current study included 184 participants from the 2-year Preventing Overweight and Using Novel Dietary Strategies (POUNDS Lost) trial with repeated measurements on plasma BCAAs, hepatic fat, and abdominal fat over 2 years. MAIN OUTCOME MEASURES Repeated measurements of hepatic fat, abdominal fat distribution, including visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and total adipose tissue (TAT). RESULTS Over 2 years, a decrease in total plasma BCAAs was significantly associated with improvement in hepatic density (a marker for hepatic fat; P = 0.02) and reductions in abdominal fat, including VAT, SAT, and TAT (all P < 0.05) in the main analyses. Additionally, we observed that decreases in BCAAs were associated with decreased insulin, homeostasis model assessment of insulin resistance, and triglycerides, independent of weight loss (all P < 0.05). Moreover, we found that dietary protein intake significantly modified the relation between changes in total plasma BCAAs and hepatic density at 6 months (Pinteraction = 0.01). Participants with a larger decrease in total BCAAs showed a greater increase in hepatic density when consuming a high-protein diet, compared with those with a smaller decrease or increase in total BCAAs. CONCLUSIONS Our findings indicate that weight-loss diet-induced decrease in plasma BCAAs is associated with reductions of hepatic and abdominal fat. In addition, dietary protein intake may modify these associations.
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Stress is Associated with Adiposity in Parents of Young Children.
Hruska, V, Ambrose, T, Darlington, G, Ma, DWL, Haines, J, Buchholz, AC, ,
Obesity (Silver Spring, Md.). 2020;(3):655-659
Abstract
OBJECTIVE This study investigated associations between stress (general stress, parenting distress, and household chaos) and adiposity among parents of young children. METHODS The sample consisted of 49 mothers and 61 fathers from 70 families with young children living in Ontario, Canada. Linear regression using generalized estimating equations was used to investigate associations between stress measures and BMI, waist circumference (WC), waist to height ratio (WHtR), and percent fat mass. RESULTS General stress was significantly associated with BMI ( β^ = 0.54; 95% CI: 0.04-1.03) and WC ( β^ = 1.44; 95% CI: 0.10-2.77). Parenting distress was significantly associated with BMI ( β^ = 0.16; 95% CI: 0.02-0.31), WC ( β^ = 0.39; 95% CI: 0.04-0.75), and WHtR ( β^ = 0.003; 95% CI: 0.001-0.005). Household chaos was significantly associated with all adiposity measures (BMI: β^ = 0.20 [95% CI: 0.08-0.33]; WC: β^ = 0.48 [95% CI: 0.21-0.75]; WHtR: β^ = 0.003 [95% CI: 0.001-0.005]; percent fat mass: β^ = 0.29 [95% CI: 0.08-0.49]). CONCLUSIONS General stress, parenting distress, and household chaos are associated with adiposity among parents of young children. Future research should elucidate mechanisms by which this occurs and elucidate how this risk may be mitigated.
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Starch Digestion-Related Amylase Genetic Variants, Diet, and Changes in Adiposity: Analyses in Prospective Cohort Studies and a Randomized Dietary Intervention.
Heianza, Y, Zhou, T, Yuhang, C, Huang, T, Willett, WC, Hu, FB, Bray, GA, Sacks, FM, Qi, L
Diabetes. 2020;(9):1917-1926
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Salivary amylase, encoded by the AMY1 gene, is responsible for the digestion of carbohydrates. We investigated associations of AMY1 genetic variations with general and central adiposity changes considering dietary carbohydrate intake among 32,054 adults from four prospective cohort studies. A genetic risk score (GRS) was calculated based on nine AMY1 single-nucleotide polymorphisms, with higher AMY1-GRS indicating higher activity of salivary amylase. We meta-analyzed interactions between AMY1-GRS and dietary intake for changes in general and central adiposity over 5.5-10 years. We found that carbohydrate food intake significantly altered associations of AMY1-GRS with changes in BMI (P interaction = 0.001) and waist circumference (P interaction < 0.001). Results were consistent and significant in female cohorts rather than in male cohorts. Among women, higher AMY1-GRS was associated with more increases in adiposity if dietary carbohydrate food intake was high, while higher AMY1-GRS was associated with less gains in adiposity when the dietary intake was low. Also, in a 2-year randomized dietary intervention trial, associations of AMY1-GRS with changes in weight (P interaction = 0.023) and waist circumference (P interaction = 0.037) were significantly modified by carbohydrate intake. Our results suggest the importance of precision nutrition strategies considering participants' genetic adaptation to carbohydrate-rich diets in regulating general and central adiposity.
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Dietary Intake of Carotenoid-Rich Vegetables Reduces Visceral Adiposity in Obese Japanese men-A Randomized, Double-Blind Trial.
Takagi, T, Hayashi, R, Nakai, Y, Okada, S, Miyashita, R, Yamada, M, Mihara, Y, Mizushima, K, Morita, M, Uchiyama, K, et al
Nutrients. 2020;(8)
Abstract
Metabolic syndrome, whose main diagnostic component is obesity, is a risk factor for lifestyle-related diseases, type 2 diabetes, and cardiovascular disease. Diet is known to affect the prevalence of metabolic syndrome. However, the effect of diet on metabolic syndrome in Japanese subjects has not been thoroughly explored. In the present study, we investigated the effect of carotenoid-rich vegetables, particularly lycopene- and lutein-rich vegetables, on the metabolic syndrome in obese Japanese men. We conducted an 8-week long randomized, double-blinded, controlled clinical trial in which, 28 middle-aged (40 ≤ age < 65) Japanese men with high body mass index (BMI ≥ 25) were randomized into four dietary groups: high lycopene + high lutein (HLyHLu), high lycopene + low lutein (HLyLLu), low lycopene + high lutein (LLyHLu), and low lycopene + low lutein (LLyLLu). Our results showed that daily beverage-intake increased the plasma levels of carotenoids without adverse effects, and the visceral fat level was significantly decreased in all the groups. The waist circumference was significantly decreased only in the HLyLLu group, whereas the CoQ10 oxidation rate was decreased in all the groups. The gene expression profiles of whole blood samples before and after ingestion differed only in the LLyLLu group, indicating the effect of carotenoids on gene expression profile. In conclusion, our results suggest that dietary uptake of carotenoid-rich vegetables increases their concentration in blood and reduces the intra-abdominal visceral fat.
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Body adiposity indicators and cardiometabolic risk: Cross-sectional analysis in participants from the PREDIMED-Plus trial.
Konieczna, J, Abete, I, Galmés, AM, Babio, N, Colom, A, Zulet, MA, Estruch, R, Vidal, J, Toledo, E, Díaz-López, A, et al
Clinical nutrition (Edinburgh, Scotland). 2019;(4):1883-1891
Abstract
BACKGROUND & AIMS Excess adiposity is associated with poor cardiometabolic (CM) health. To date, several techniques and indicators have been developed to determine adiposity. We aimed to compare the ability of traditional anthropometric, as well as standard and novel DXA-derived parameters related to overall and regional adiposity, to evaluate CM risk. METHODS Using the cross-sectional design in the context of the PREDIMED-Plus trial, 1207 Caucasian senior men and women with overweight/obesity and metabolic syndrome (MetS) were assessed. At baseline, anthropometry- and DXA-measured parameters of central, visceral, peripheral and central-to-peripheral adiposity together with comprehensive set of CM risk factors were obtained. Partial correlations and areas under the ROC curve (AUC) were estimated to compare each adiposity measure with CM risk parameters, separately for men and women, and in the overall sample. RESULTS DXA-derived indicators, other than percentage of total body fat, showed stronger correlations (rho -0.172 to 0.206, p < 0.001) with CM risk than anthropometric indicators, after controlling for age, diabetes and medication use. In both sexes, DXA-derived visceral adipose tissue measures (VAT, VAT/Total fat, visceral-to-subcutaneous fat) together with lipodystrophy indicators (Trunk/Legs fat and Android/Gynoid fat) were strongly and positively correlated (p < 0.001) with glycated hemoglobin (HbA1c), the triglyceride and glucose index (TyG), triglycerides (TG), the ratio TG/HDL-cholesterol (TG/HDL-C), and were inversely related to HDL-C levels (p < 0.001). Furthermore, in AUC analyses for both sexes, VAT/Total fat showed the highest predictive ability for abnormal HbA1c levels (AUC = 0.629), VAT for TyG (AUC = 0.626), both lipodystrophy indicators for TG (AUCs = 0.556), and Trunk/Legs fat for HDL-C (AUC = 0.556) and TG/HDL-C (AUC = 0.581). CONCLUSIONS DXA regional adiposity measures offer advantages beyond traditional anthropometric and DXA overall adiposity indicators for CM risk assessment in senior overweight/obese subjects with MetS. In particular, in both sexes, visceral adiposity better stratifies individuals at risk for glucose abnormalities, and indicators of lipodystrophy better predict markers of dyslipidemia.