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Intermittent Fasting Improves Cardiometabolic Risk Factors and Alters Gut Microbiota in Metabolic Syndrome Patients.
Guo, Y, Luo, S, Ye, Y, Yin, S, Fan, J, Xia, M
The Journal of clinical endocrinology and metabolism. 2021;(1):64-79
Abstract
CONTEXT Intermittent fasting (IF) is an effective strategy to improve cardiometabolic health. OBJECTIVE The objective of this work is to examine the effects of IF on cardiometabolic risk factors and the gut microbiota in patients with metabolic syndrome (MS). DESIGN AND SETTING A randomized clinical trial was conducted at a community health service center. PATIENTS Participants included adults with MS, age 30 to 50 years. INTERVENTION Intervention consisted of 8 weeks of "2-day" modified IF. MAIN OUTCOME MEASURE Cardiometabolic risk factors including body composition, oxidative stress, inflammatory cytokines, and endothelial function were assessed at baseline and at 8 weeks. The diversity, composition, and functional pathways of the gut microbiota, as well as circulating gut-derived metabolites, were measured. RESULTS Thirty-nine patients with MS were included: 21 in the IF group and 18 in the control group. On fasting days, participants in the IF group reduced 69% of their calorie intake compared to nonfasting days. The 8-week IF significantly reduced fat mass, ameliorated oxidative stress, modulated inflammatory cytokines, and improved vasodilatory parameters. Furthermore, IF induced significant changes in gut microbiota communities, increased the production of short-chain fatty acids, and decreased the circulating levels of lipopolysaccharides. The gut microbiota alteration attributed to the IF was significantly associated with cardiovascular risk factors and resulted in distinct genetic shifts of carbohydrate metabolism in the gut community. CONCLUSION IF induces a significant alteration of the gut microbial community and functional pathways in a manner closely associated with the mitigation of cardiometabolic risk factors. The study provides potential mechanistic insights into the prevention of adverse outcomes associated with MS.
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Effect of Moderate Hepatic Impairment on the Pharmacokinetics of Vadadustat, an Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor.
Chavan, A, Burke, L, Sawant, R, Navarro-Gonzales, P, Vargo, D, Paulson, SK
Clinical pharmacology in drug development. 2021;(8):950-958
Abstract
Vadadustat is a hypoxia-inducible factor prolyl hydroxylase inhibitor in development for the treatment of anemia of chronic kidney disease. This phase 1, open-label, parallel-group, single-dose study evaluated the pharmacokinetics of 450-mg vadadustat in adults with moderate hepatic impairment (Child-Pugh class B) vs those with normal hepatic function. Primary end points were area under the plasma concentration-time curve (AUC) from dosing to last concentration and to infinity, as well as maximum concentration (Cmax ); additional pharmacokinetic parameters included time to Cmax (Tmax ) and half-life. Safety and tolerability were also assessed. All enrolled participants (n = 16) completed the study. Demographics were similar in both groups (overall, 100% White; 62.5% female; mean age, 59.2 years). Vadadustat plasma exposure was higher in the moderate hepatic impairment group, whereas maximum concentration was similar between groups. Point estimates of the hepatic impairment : normal geometric mean ratios (90% confidence interval) for AUC from dosing to last concentration, AUC from dosing to infinity, and Cmax were 1.05 (0.82-1.35), 1.06 (0.82-1.36), and 1.02 (0.79-1.32), respectively. Mean elimination half-life was 5.8 and 7.8 hours in the normal and hepatic impairment groups, respectively. Treatment-emergent adverse events were mostly mild in severity, and vadadustat was generally well tolerated. In conclusion, moderate hepatic impairment did not significantly impact vadadustat systemic exposure, and mild hepatic impairment is unlikely to alter vadadustat exposure.
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Insulin resistance in type 1 diabetes managed with metformin (INTIMET): Study protocol of a double-blind placebo-controlled, randomised trial.
Snaith, JR, Samocha-Bonet, D, Evans, J, Liu, Z, Kowalski, G, Bruce, C, Holmes-Walker, DJ, Greenfield, JR
Diabetic medicine : a journal of the British Diabetic Association. 2021;(9):e14564
Abstract
BACKGROUND Insulin resistance is an under-recognised metabolic defect and cardiovascular risk factor in Type 1 diabetes. Whether metformin improves hepatic, muscle or adipose tissue insulin sensitivity has not been studied in adults with Type 1 diabetes. We initiated the INTIMET study (INsulin resistance in Type 1 diabetes managed with METformin), a double-blind randomised, placebo-controlled trial to measure the effect of metformin on tissue-specific insulin resistance in adults with Type 1 diabetes. METHODS We will study 40 adults aged 20-55 years with Type 1 diabetes (HbA1c ≤ 80 mmol/mol [9.5%], fasting C-peptide <0.3 nmol/L) and 20 age-, gender- and body mass index (BMI)-matched controls. Insulin sensitivity will be determined by the two-step hyperinsulinaemic-euglycaemic clamp method with deuterated glucose to document liver, muscle and adipose insulin sensitivity. Subjects with Type 1 diabetes will be randomised to metformin extended-release 1500 mg daily or matched placebo for 26 weeks. The primary outcome is change in hepatic insulin sensitivity, assessed by change in basal rate of appearance (Ra) of glucose and suppression of endogenous glucose production (EGP) during the low-dose stage of the clamp. CONCLUSION The INTIMET study is the first clinical trial to quantify the impact of metformin on liver, muscle and adipose insulin resistance in adults with Type 1 diabetes. This study may identify factors that predict an individual's response to metformin in Type 1 diabetes. TRIAL REGISTRATION ACTRN12619001440112.
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Circulating levels of cell adhesion molecules and risk of cardiovascular events in obstructive sleep apnea.
Peres, BU, Hirsch Allen, AJ, Daniele, P, Humphries, KH, Taylor, C, Laher, I, Almeida, F, Jen, R, Sandford, AJ, van Eeden, SF, et al
PloS one. 2021;(7):e0255306
Abstract
BACKGROUND Obstructive sleep apnea (OSA) patients are at increased risk of cardiovascular disease (CVD). Cell adhesion molecules (CAM) are increased in OSA and CAM are also implicated in the development of CVD. RESEARCH QUESTION Do CAM (ICAM-1, VCAM-1 and E-selectin) have prognostic value in identifying risk of cardiovascular events in OSA? STUDY DESIGN AND METHODS Patients with suspected OSA referred for a polysomnogram provided a fasting blood sample. Plasma levels of ICAM-1, VCAM-1 and E-selectin were determined by multiplex Luminex Assay (Milliporesigma ON, Canada). Cardiovascular events were determined by deterministic linkage to provincial health databases. RESULTS 418 patients were included in the analysis. Mostly male (68.2%), mean age of 50.7 yrs, median AHI 16.5 events/hour, and mean BMI of 31.7 kg/m2. 36 cardiovascular events occurred in 8-yrs of follow up. Higher levels of ICAM-1 were associated with developing CVD (HR = 3.65 95% CI 1.40-9.53, 2nd and 3rd tertiles vs. 1st tertile), including in patients with OSA (HR = 3.1 95% CI 1.16-8.25). E-selectin was significantly associated with cardiovascular events in patients with moderate to severe OSA (HR = 3.31 95% CI 0.94-11.72, 2nd and 3rd tertiles vs. 1st tertile) but not in patients without moderate to severe OSA (HR = 0.67 95% CI 0.19-2.38), p-value for interaction = 0.07. INTERPRETATION In a suspected OSA cohort, patients with higher levels of ICAM-1 (>816 ng/ml) were significantly more likely to experience a cardiovascular event within 8 years after PSG. In moderate to severe OSA patients, a higher E-selectin (>36.4 ng/ml) was significantly associated with cardiovascular events.
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Real-world safety and effectiveness of insulin glargine 300 U/mL in participants with type 2 diabetes who fast during Ramadan: The observational ORION study.
Hassanein, M, Buyukbese, MA, Malek, R, Pilorget, V, Naqvi, M, Berthou, B, Shaltout, I, Kumar Sahay, R
Diabetes research and clinical practice. 2020;:108189
Abstract
AIMS: ORION evaluated the safety and effectiveness of Gla-300 in insulin-treated people with T2DM before, during and after Ramadan, in a real-world setting. METHODS This prospective, observational study across 11 countries included participants with T2DM treated with Gla-300 in pre-Ramadan, Ramadan and post-Ramadan periods. The primary endpoint was the percentage of participants experiencing ≥1 event of severe and/or symptomatic documented hypoglycaemia with self-monitored plasma glucose (SMPG) ≤70 mg/dL during Ramadan. Secondary endpoints included change in HbA1c and insulin dose and adverse events (AEs). RESULTS The mean ± SD number of fasting days was 30.1 ± 3.2. The percentage of participants experiencing ≥1 event of severe and/or symptomatic documented hypoglycaemia (SMPG ≤70 [<54] mg/dL) was low in the pre-Ramadan (2.2% [0.8%]), Ramadan (2.6% [0%]) and post-Ramadan (0.2% [0%]) periods. No participants reported severe hypoglycaemia during Ramadan or post-Ramadan; one participant reported severe hypoglycaemia in pre-Ramadan. HbA1c fell pre- to post-Ramadan, and Gla-300 daily dose (mean ± SD) was reduced pre-Ramadan to Ramadan (from 25.6 ± 11.9 U/0.32 ± 0.14 U/kg to 24.4 ± 11.5 U/0.30 ± 0.13 U/kg). Incidence of AEs was 5.5%. CONCLUSIONS In ORION, people with T2DM treated with Gla-300 who fasted during Ramadan had a low risk of severe/symptomatic hypoglycaemia and improved glycaemic control.
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Association Between Fasting Glucose Variability in Young Adulthood and the Progression of Coronary Artery Calcification in Middle Age.
Feng, W, Li, Z, Guo, W, Fan, X, Zhou, F, Zhang, K, Ou, C, Huang, F, Chen, M
Diabetes care. 2020;(10):2574-2580
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Abstract
OBJECTIVE To investigate whether intraindividual variability of fasting glucose (FG) in young adulthood is associated with coronary artery calcification (CAC) progression in middle age. RESEARCH DESIGN AND METHODS We included 2,256 CARDIA (Coronary Artery Risk Development Study in Young Adults) participants with CAC assessment by computed tomography scanner at baseline (2000-2001) and 10 years later (2010-2011). CAC progression was assessed for each individual as the difference of logarithmic CAC scores at follow-up and baseline (log[CAC (follow-up) + 1] - log[CAC (baseline) + 1]). FG variability was defined by the coefficient of variation about the mean FG (FG-CV), the SD of FG (FG-SD), and the average real variability of FG (FG-ARV) during the 10-year follow-up. We investigated the association between FG variability and CAC progression with adjustment for demographics, clinical risk factors, mean FG level, change in FG level, diabetes incidence, and medication use. RESULTS After multivariable adjustment, 1-SD increment in FG-CV was associated with worse progression of CAC as demonstrated as percent change in CAC, with incident CAC 5.9% (95% CI 1.0, 10.7) and any CAC progression 6.7% (95% CI 2.3, 11.1) during 10 years. Similar findings were also observed in FG-SD and FG-ARV. CONCLUSIONS Higher FG variability during young adulthood was associated with greater CAC progression in middle age, suggesting its value in predicting risk for subclinical coronary artery diseases.
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Fasting and Non-Fasting Triglycerides and Risk of Cardiovascular Events in Diabetic Patients Under Statin Therapy.
Tada, H, Nomura, A, Yoshimura, K, Itoh, H, Komuro, I, Yamagishi, M, Takamura, M, Kawashiri, MA
Circulation journal : official journal of the Japanese Circulation Society. 2020;(3):509-515
Abstract
BACKGROUND Few data specifically investigate associations between fasting/non-fasting triglycerides (TG) and cardiovascular (CV) events under statin therapy among Japanese diabetic patients.Methods and Results:We recruited 4,988 participants with diabetes from the EMPATHY study. Median follow-up was 3 years. We evaluated associations between serum fasting/non-fasting TG and first CV events in Cox-regression hazard models adjusted by classical risk factors. CV events were defined as (1) major adverse cardiac events (MACE) including myocardial infarction, stroke, or cardiac death; and (2) CV diseases (CVD) including myocardial infarction, unstable angina, ischemic stroke, or large artery disease or peripheral arterial disease. Fasting as well as non-fasting TG were associated with MACE (adjusted hazard ratio [HR]: 1.017 per 10 mg/dL; 95% confidence interval [CI]: 1.000-1.037; P=0.046, adjusted HR: 1.028 per 10 mg/dL; 95% CI: 1.006-1.050; P=0.0091) and CVD (adjusted HR: 1.024 per 10 mg/dL; 95% CI: 1.011-1.038; P=4.4×10-3, adjusted HR: 1.028 per 10 mg/dL; 95% CI: 1.010-1.046; P=4.9×10-3). Comparing the top quartile with the bottom quartile of non-fasting TG, adjusted HR significantly increased 5.18 (95% CI: 1.38-18.3, P=0.014) for MACE, and 2.40 (95% CI: 1.11-4.75, P=0.021) for CVD, while adjusted HR did not change when divided into quartile of fasting TG. CONCLUSIONS Non-fasting TG could be considered as a substitute for fasting TG as a risk stratification for future CV events among Japanese diabetic patients.
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Overnight fasting before lapatinib administration to breast cancer patients leads to reduced toxicity compared with nighttime dosing: a retrospective cohort study from a randomized clinical trial.
Tsuda, M, Ishiguro, H, Toriguchi, N, Masuda, N, Bando, H, Ohgami, M, Homma, M, Morita, S, Yamamoto, N, Kuroi, K, et al
Cancer medicine. 2020;(24):9246-9255
Abstract
BACKGROUND The bioavailability of lapatinib is affected by food, even following the 1 hour fast recommended by the package insert. We hypothesized that overnight fasting would minimize food-drug interactions. Here, we investigated if lapatinib administration timing is associated with its tolerability, efficacy, and pharmacokinetics. METHODS This is a retrospective cohort study utilizing the medical records of patients enrolled in the JBCRG-16/Neo-LaTH randomized phase 2 trial for breast cancer patients treated with lapatinib. Lapatinib administration timing was divided into three groups: before breakfast (BB), between meals (BM), and at bedtime (AB). Side effects (SE), treatment discontinuation rate (TDR), relative dose intensity (RDI), pathological complete response (pCR) rate, and lapatinib serum trough concentration were compared between groups. RESULTS About 140 patients were included in this study: BB 15, BM 51, and AB 74. A reduced risk of diarrhea {adjusted hazard ratio (HR), 0.51, 95% confidence interval (CI), 0.27-0.89, p = 0.018}, and rash {adjusted HR, 0.37; 95% CI, 0.17-0.70, p = 0.002} was seen in BB versus AB. Fewer patients with low RDI (< 0.85/<0.6) were in the BB group (BB 13% / 0%, BM 22% / 3.9%, AB 24% / 14%, p = 0.70 / 0.11). pCR was not diminished (p = 0.75). BB group had the lowest serum lapatinib concentration and variability (mean ±SD were 0.35 ± 0.15, 0.65 ± 0.32, 0.96 ± 0.43 µg/ml). CONCLUSIONS Compared to bedtime administration, lapatinib administration after overnight fasting reduces its toxicity without diminishing its therapeutic efficacy.
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Childhood BMI and Fasting Glucose and Insulin Predict Adult Type 2 Diabetes: The International Childhood Cardiovascular Cohort (i3C) Consortium.
Hu, T, Jacobs, DR, Sinaiko, AR, Bazzano, LA, Burns, TL, Daniels, SR, Dwyer, T, Hutri-Kähönen, N, Juonala, M, Murdy, KA, et al
Diabetes care. 2020;(11):2821-2829
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Abstract
OBJECTIVE To examine childhood BMI, fasting glucose, and insulin in relation to incident adult type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS We used data from the International Childhood Cardiovascular Cohort (i3C) Consortium. Data included childhood (age 3-19 years) measurements obtained during the 1970s-1990s; a health questionnaire, including self-report of adult T2DM (occurrence age, medication use) obtained at mean age 40 years; and a medical diagnosis registry (Finland). RESULTS The sample included 6,738 participants. Of these, 436 (6.5%) reported onset of T2DM between ages 20 and 59 (mean 40.8) years, and 86% of them reported use of a confirmed antidiabetic medication. BMI and glucose (age and sex standardized) were associated with incident T2DM after adjustment for cohort, country, sex, race, age, and calendar year of measurement. Increasing levels of childhood BMI and glucose were related to an incrementally increased risk of T2DM beginning at age 30 years, beginning at cut points <95th percentile for BMI and <100 mg/dL for glucose. Insulin was positively associated with adult T2DM after adjustment for BMI and glucose and added to T2DM discrimination. CONCLUSIONS Childhood BMI and glucose are predictors of adult T2DM at levels previously considered to be within the normal range. These easy-to-apply measurements are appealing from a clinical perspective. Fasting insulin has the potential to be an additional predictor.
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Associations between Dietary Glycemic Index and Glycemic Load Values and Cardiometabolic Risk Factors in Adults: Findings from the China Health and Nutrition Survey.
Li, M, Cui, Z, Meng, S, Li, T, Kang, T, Ye, Q, Cao, M, Bi, Y, Meng, H
Nutrients. 2020;(1)
Abstract
Studies investigating the associations between dietary glycemic index (GI) and glycemic load (GL) values and cardiometabolic risk factors (CMRF) among Chinese populations are strikingly limited. To assess the associations between dietary GI and GL values and CMRF, including dyslipidemia, hyperglycemia, and hyperuricemia in Chinese adults, we extracted data of 7886 apparently healthy adults from the 2009 wave of the China Health and Nutrition Survey. Dietary GI and GL values were calculated using data collected from three consecutive 24 h dietary recalls. Fasting lipid, glucose, and uric acid concentrations were measured and CMRF were defined on the basis of established criteria. There were no significant associations between dietary GI values and CMRF, and analyzing the data by age, sex, body mass index (BMI), and region did not alter these results. Dietary GL values were positively associated with prevalence of hyperuricemia in all participants (Q4 compared with Q1: odds ratio (OR) = 1.46; 95% CI: 1.14, 1.87; p-trend = 0.0030) and prevalence of hypercholesterolemia in participants ≥ 60 years old (Q5 compared with Q1: OR = 1.72; 95% CI: 1.11, 2.68; p-trend < 0.0010). Higher dietary GL but not GI values were associated with increased prevalence of hyperuricemia in apparently healthy Chinese adults and hypercholesterolemia in older Chinese adults. Further studies are required to confirm the public health implication of these findings.