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High Triglyceride-Glucose Index is Associated with Poor Cardiovascular Outcomes in Nondiabetic Patients with ACS with LDL-C below 1.8 mmol/L.
Zhang, Y, Ding, X, Hua, B, Liu, Q, Gao, H, Chen, H, Zhao, XQ, Li, W, Li, H
Journal of atherosclerosis and thrombosis. 2022;(2):268-281
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Abstract
AIM: To evaluate the prognostic value of triglyceride-glucose (TyG) index in nondiabetic patients with acute coronary syndrome (ACS) with low-density lipoprotein cholesterol (LDL-C) below 1.8 mmol/L. METHODS A total of 1655 nondiabetic patients with ACS with LDL-C below 1.8 mmol/L were included in the analysis. Patients were stratified into two groups. The incidence of acute myocardial infarction (AMI), infarct size in patients with AMI, and major adverse cardiac and cerebral event during a median of 35.6-month follow-up were determined and compared between the two groups. The TyG index was calculated using the following formula: ln [fasting triglycerides (mg/dL)×fasting plasma glucose (mg/dL)/2]. RESULTS Compared with the TyG index <8.33 group, the TyG index ≥ 8.33 group had a significantly higher incidence of AMI (21.2% vs. 15.2%, p=0.014) and larger infarct size in patients with AMI [the peak value of troponin I: 10.4 vs. 4.8 ng/ml, p=0.003; the peak value of Creatine kinase MB: 52.8 vs. 22.0 ng/ml, p=0.006; the peak value of myoglobin: 73.7 vs. 46.0 ng/ml, p=0.038]. Although there was no significant difference in mortality between the two groups, the incidence of revascularization of the TyG index ≥ 8.33 group was significantly higher than that of the TyG index <8.33 group (8.9% vs. 5.0%, p=0.035). A multivariable Cox regression revealed that the TyG index was positively associated with revascularization [hazard ratio, 1.67; 95% confidence interval, 1.02-2.75; p=0.043]. CONCLUSIONS In nondiabetic patients with ACS with LDL-C below 1.8 mmol/L, a high TyG index level was associated with higher incidence of AMI, larger infarct size, and higher incidence of revascularization. A high TyG index level might be a valid predictor of subsequent revascularization.
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LLF580, an FGF21 Analog, Reduces Triglycerides and Hepatic Fat in Obese Adults With Modest Hypertriglyceridemia.
Rader, DJ, Maratos-Flier, E, Nguyen, A, Hom, D, Ferriere, M, Li, Y, Kompa, J, Martic, M, Hinder, M, Basson, CT, et al
The Journal of clinical endocrinology and metabolism. 2022;(1):e57-e70
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Abstract
PURPOSE To evaluate the safety and potential efficacy of LLF580, a genetically engineered variant of human fibroblast growth factor-21, for triglyceride lowering, weight loss, and hepatic fat reduction. METHODS A multicenter, double-blind, parallel design trial in obese, mildly hypertriglyceridemic adults randomized (1:1) to LLF580 300 mg or placebo subcutaneously every 4 weeks for 3 doses. RESULTS Of 64 randomized study participants, 61 (mean ± SD: age 45 ± 11 years, 49% male, 80/15/5% Caucasian/African American/other, body mass index 36.1 ± 3.8 kg/m2) received LLF580 (n = 30) or placebo (n = 31) at 7 research sites in the United States. LLF580 lowered serum triglycerides by 54% (least square mean placebo adjusted change from baseline), total cholesterol 7%, low-density lipoprotein cholesterol 12%, and increased high-density lipoprotein cholesterol 36% compared with placebo (all P < 0.001) over 12 weeks. Substantial reduction of liver fat of 52% over placebo (P < 0.001) was also demonstrated in the setting of improved liver function tests including alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase, the composite enhanced liver fibrosis score, and N-terminal type III collagen propeptide (all P < 0.05). Insulin and C-peptide levels and insulin resistance by homeostatic model assessment for insulin resistance were all lower, and adiponectin higher with LLF580 treatment compared with placebo, whereas fasting glucose and glycated hemoglobin were unchanged. Reductions in biomarkers of bone formation without differences in markers of bone resorption were observed. LLF580 was generally safe and well tolerated, except for higher incidence of generally mild to moderate gastrointestinal adverse effects. CONCLUSIONS In obese, mildly hypertriglyceridemic adults, LLF580 was generally safe and demonstrated beneficial effects on serum lipids, liver fat, and biomarkers of liver injury, suggesting it may be effective for treatment of select metabolic disorders including hypertriglyceridemia and nonalcoholic fatty liver disease. Assessments of longer term safety and efficacy are warranted. CLINICALTRIALS.GOV IDENTIFIER NCT03466203.
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Triglyceride/High-Density Lipoprotein Cholesterol Ratio: A Clue to Metabolic Syndrome, Insulin Resistance, and Severe Atherosclerosis.
Azarpazhooh, MR, Najafi, F, Darbandi, M, Kiarasi, S, Oduyemi, T, Spence, JD
Lipids. 2021;(4):405-412
Abstract
High serum levels of triglycerides (Tg) and low levels of high-density lipoprotein cholesterol (HDL-C) are characteristic of the Metabolic Syndrome (MetS). We assessed the ratio of Tg to HDL-C as a way to identify MetS and insulin resistance. We also evaluated its association with severity of carotid atherosclerosis. Data were analyzed from three cohorts totaling 13,908 participants. MetS was defined according to the International Diabetes Federation criteria. Optimal cut-off for Tg/HDL-C ratio was obtained using Youden's index in receiver-operating characteristic (ROC) curve analyses. The risk of MetS and IR in those with a Tg/HDL-C ratio above the optimum cutoff was evaluated by logistic regression analysis. A Tg/HDL-C ratio above the optimal cutoff level significantly increased the odds ratio for MetS in the three cohorts (OR 6.00, 4.04, and 3.50, least in the healthy population), identified insulin resistance defined by the homeostatic model of insulin resistance (HOMA-IR) (p < 0.0001), and was strongly associated with atherosclerosis severity (p = 0.0001). Tg/HDL-C ratio identifies persons with MetS, insulin resistance, and severe atherosclerosis. It should be used more widely to identify patients at high risk. This is clinically important because insulin resistance is treatable.
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Capillary Triglycerides in Late Pregnancy-Challenging to Measure, Hard to Interpret: A Cohort Study of Practicality.
Barrett, HL, Dekker Nitert, M, D'Emden, M, Lingwood, B, de Jersey, S, McIntyre, HD, Callaway, LK
Nutrients. 2021;(4)
Abstract
BACKGROUND Maternal triglycerides are increasingly recognised as important predictors of infant growth and fat mass. The variability of triglyceride patterns during the day and their relationship to dietary intake in women in late pregnancy have not been explored. This prospective cohort study aimed to examine the utility of monitoring capillary triglycerides in women in late pregnancy. METHODS Twenty-nine women (22 with gestational diabetes (GDM) and 7 without) measured capillary glucose and triglycerides using standard meters at home for four days. On two of those days, they consumed one of two standard isocaloric breakfast meals: a high-fat/low-carbohydrate meal (66% fat) or low fat/high carbohydrate meal (10% fat). Following the standard meals, glucose and triglyceride levels were monitored. RESULTS Median capillary triglycerides were highly variable between women but did not differ between GDM and normoglycaemic women. There was variability in capillary triglycerides over four days of home monitoring and a difference in incremental area under the curve for capillary triglycerides and glucose between the two standard meals. The high-fat standard meal lowered the incremental area under the curve for capillary glucose (p < 0.0001). Fasting (rho 0.66, p = 0.0002) and postpradial capillary triglycerides measured at home correlated with venous triglyceride levels. CONCLUSIONS The lack of differences in response to dietary fat intake and the correlation between capillary and venous triglycerides suggest that monitoring of capillary triglycerides before and after meals in pregnancy is unlikely to be useful in the routine clinical practice management of women with gestational diabetes mellitus.
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Effect of vitamin D supplementation on markers of cardiometabolic risk in children and adolescents: A meta-analysis of randomized clinical trials.
Cai, B, Luo, X, Zhang, P, Luan, Y, Cai, X, He, X
Nutrition, metabolism, and cardiovascular diseases : NMCD. 2021;(10):2800-2814
Abstract
BACKGROUND AND AIMS An increasing attention to the effect of vitamin D supplementation on cardiometabolic risk markers in children and adolescents has been gained recently. However, the results are inconsistent. Therefore, we conducted a meta-analysis to examine the effect of vitamin D supplementation on cardiometabolic risk markers in children and adolescents. METHODS AND RESULTS Eligible randomized controlled trials (RCTs) were identified by searching PubMed, EMBASE and Web of Science. The results of this study are synthetized and reported in accordance with the PRISMA statement. GRADE system was used to assess the certainty of evidence. A total of 9 RCTs were identified and included in the meta-analysis. We found that vitamin D supplementation did not affect the changes of cardiometabolic risk markers including high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglycerides (TG), body mass index (BMI), waist circumferences, systolic blood pressure (SDP) and diastolic blood pressure (DBP). However, vitamin D supplementation showed a beneficial effect on fasting glucose (MD, -1.54 mg/dl, 95% CI -2.98 to -0.10) and TG (MD, -24.76 mg/dl, 95% CI -37.66 to -11.86) in the sub-group analysis of total vitamin D supplementation ≥ 200,000 IU. CONCLUSIONS Vitamin D supplementation appeared to have a beneficial effect on reducing fasting glucose and TG level when total vitamin D supplementation ≥200,000 IU but not HDL-C, LDL-C TC, blood pressure and waist circumferences levels in children and adolescents. Further studies are needed to address this issue.
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Triglycerides and Residual Atherosclerotic Risk.
Raposeiras-Roubin, S, Rosselló, X, Oliva, B, Fernández-Friera, L, Mendiguren, JM, Andrés, V, Bueno, H, Sanz, J, Martínez de Vega, V, Abu-Assi, E, et al
Journal of the American College of Cardiology. 2021;(24):3031-3041
Abstract
BACKGROUND Even when low-density lipoprotein-cholesterol (LDL-C) levels are lower than guideline thresholds, a residual risk of atherosclerosis remains. It is unknown whether triglyceride (TG) levels are associated with subclinical atherosclerosis and vascular inflammation regardless of LDL-C. OBJECTIVES This study sought to assess the association between serum TG levels and early atherosclerosis and vascular inflammation in apparently healthy individuals. METHODS An observational, longitudinal, and prospective cohort study, including 3,754 middle-aged individuals with low to moderate cardiovascular risk from the PESA (Progression of Early Subclinical Atherosclerosis) study who were consecutively recruited between June 2010 and February 2014, was conducted. Peripheral atherosclerotic plaques were assessed by 2-dimensional vascular ultrasound, and coronary artery calcification (CAC) was assessed by noncontrast computed tomography, whereas vascular inflammation was assessed by fluorine-18 fluorodeoxyglucose uptake on positron emission tomography. RESULTS Atherosclerotic plaques and CAC were observed in 58.0% and 16.8% of participants, respectively, whereas vascular inflammation was evident in 46.7% of evaluated participants. After multivariate adjustment, TG levels ≥150 mg/dl showed an association with subclinical noncoronary atherosclerosis (odds ratio [OR]: 1.35; 95% confidence interval [CI]: 1.08 to 1.68; p = 0.008). This association was significant for groups with high LDL-C (OR: 1.42; 95% CI: 1.11 to 1.80; p = 0.005) and normal LDL-C (OR: 1.85; 95% CI: 1.08 to 3.18; p = 0.008). No association was found between TG level and CAC score. TG levels ≥150 mg/dl were significantly associated with the presence of arterial inflammation (OR: 2.09; 95% CI: 1.29 to 3.40; p = 0.003). CONCLUSIONS In individuals with low to moderate cardiovascular risk, hypertriglyceridemia was associated with subclinical atherosclerosis and vascular inflammation, even in participants with normal LDL-C levels. (Progression of Early Subclinical Atherosclerosis [PESA]; NCT01410318).
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Effects of endogenous GIP in patients with type 2 diabetes.
Stensen, S, Gasbjerg, LS, Krogh, LL, Skov-Jeppesen, K, Sparre-Ulrich, AH, Jensen, MH, Dela, F, Hartmann, B, Vilsbøll, T, Holst, JJ, et al
European journal of endocrinology. 2021;(1):33-45
Abstract
OBJECTIVE The insulinotropic effect of exogenous, intravenously infused glucose-dependent insulinotropic polypeptide (GIP) is impaired in patients with type 2 diabetes. We evaluated the effects of endogenous GIP in relation to glucose and bone metabolism in patients with type 2 diabetes using a selective GIP receptor antagonist and hypothesized that the effects of endogenous GIP were preserved. DESIGN A randomized, double-blinded, placebo-controlled, crossover study. METHODS Ten patients with overweight/obesity and type 2 diabetes (mean±s.d.; HbA1c 52 ± 11 mmol/mol; BMI 32.5 ± 4.8 kg/m2) were included. We infused a selective GIP receptor antagonist, GIP(3-30)NH2 (1200 pmol/kg/min), or placebo (saline) during two separate, 230-min, standardized, liquid mixed meal tests followed by a meal ad libitum. Subcutaneous adipose tissue biopsies were analyzed. RESULTS Compared with placebo, GIP(3-30)NH2 reduced postprandial insulin secretion (Δbaseline-subtracted area under the curve (bsAUC)C-peptide% ± s.e.m.; -14 ± 6%, P = 0.021) and peak glucagon (Δ% ± s.e.m.; -11 ± 6%, P = 0.046) but had no effect on plasma glucose (P = 0.692). Suppression of bone resorption (assessed by circulating carboxy-terminal collagen crosslinks (CTX)) was impaired during GIP(3-30)NH2 infusion compared with placebo (ΔbsAUCCTX; ±s.e.m.; -4.9 ± 2 ng/mL × min, P = 0.005) corresponding to a ~50% reduction. Compared with placebo, GIP(3-30)NH2 did not affect plasma lipids, meal consumption ad libitum or adipose tissue triglyceride content. CONCLUSIONS Using a selective GIP receptor antagonist during a meal, we show that endogenous GIP increases postprandial insulin secretion with little effect on postprandial glycaemia but is important for postprandial bone homeostasis in patients with type 2 diabetes.
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Relationship between triglyceride glucose index, retinopathy and nephropathy in Type 2 diabetes.
Srinivasan, S, Singh, P, Kulothungan, V, Sharma, T, Raman, R
Endocrinology, diabetes & metabolism. 2021;(1):e00151
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AIMS: To explore the relationship between TyG index, diabetic retinopathy (DR) and nephropathy. METHODS This was a cross-sectional observational study that examined 1413 subjects with type 2 diabetes (both known and newly diagnosed). Subjects underwent a detailed standard evaluation to detect diabetic retinopathy (fundus photography) and nephropathy (defined as urinary albumin excretion ≥ 30 mg/24 h). The TyG index was calculated as ln (fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2) and stratified into 4 quartiles (TyG-Q). The baseline characteristics of the study population in the four TyG-Q (Q1 (≤7.3) n = 349, Q2 (>7.3 to ≤ 7.5) n = 358, Q3 (>7.5 to ≤ 8.0) n = 354, and Q4 (>8.0) n = 352) were analysed. Variables associated with the presence of DR and nephropathy were assessed using a stepwise binary logistic regression analysis. RESULTS The presence of DR was associated with higher TyG index (OR = 1.453, P =.001) and longer duration of diabetes (OR = 1.085, P < .001). The presence of nephropathy was associated with a higher TyG index (OR = 1.703, P < .001), greater age (OR = 1.031, P < .001), use of insulin (OR = 1.842, P = .033), higher systolic BP (OR = 1.015, P < .001), and the presence of DR (OR = 3.052, P < .001). Higher TyG-Q correlated with the severity of DR (P = .024), presence of nephropathy (P = .001), age (P < .001) and diastolic blood pressure (P = .006). CONCLUSIONS A higher TyG index is associated with the presence of retinopathy and nephropathy in individuals with diabetes and could be used for monitoring metabolic status in clinical settings.
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The Pharmacokinetics of Triheptanoin and Its Metabolites in Healthy Subjects and Patients With Long-Chain Fatty Acid Oxidation Disorders.
Lee, SK, Gupta, M, Shi, J, McKeever, K
Clinical pharmacology in drug development. 2021;(11):1325-1334
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Long-chain fatty acid oxidation disorders (LC-FAODs) are a group of life-threatening autosomal recessive disorders caused by defects in nuclear genes encoding mitochondrial enzymes involved in the conversion of dietary long-chain fatty acids into energy. Triheptanoin is an odd-carbon, medium-chain triglyceride consisting of 3 fatty acids with 7 carbons each on a glycerol backbone developed to treat adult and pediatric patients with LC-FAODs. The pharmacokinetics of triheptanoin and circulating metabolites were explored in healthy subjects and patients with LC-FAODs using noncompartmental analyses. Systemic exposure to triheptanoin following an oral administration was negligible, as triheptanoin is extensively hydrolyzed to glycerol and heptanoate in the gastrointestinal tract. Multiple peaks for triheptanoin metabolites were observed in the plasma following oral administration of triheptanoin, generally coinciding with the time that meals were served. Heptanoate, the pharmacologically active metabolite of triheptanoin supplementing energy sources in patients with LC-FAODs, showed the greatest exposure among the metabolites of triheptanoin in human plasma following oral administration of triheptanoin. The exposure of heptanoate was approximately 10-fold greater than that of beta-hydroxypentoate, a downstream metabolite of heptanoate. Exposure to triheptanoin metabolites appeared to increase following multiple doses as compared with the single dose, and with the increase in triheptanoin dose levels.
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Association of "hypertriglyceridemic waist" with increased 5-year risk of subclinical atherosclerosis in a multi-ethnic population: a prospective cohort study.
Namdarimoghaddam, P, Fowokan, A, Humphries, KH, Mancini, GBJ, Lear, S
BMC cardiovascular disorders. 2021;(1):63
Abstract
BACKGROUND Hypertriglyceridemic waist (HTGW), which incorporates measures of waist circumference and levels of triglyceride in blood, could act as an early-stage predictor to identify the individuals at high-risk for subclinical atherosclerosis. Previous studies have explored the cross-sectional association between HTGW and atherosclerosis; however, understanding how this association might change over time is necessary. This study will assess the association between HTGW with 5-year subclinical carotid atherosclerosis. METHODS 517 participants of Aboriginal, Chinese, European, and South Asian ethnicities were examined for baseline HTGW and 5-year indices of subclinical atherosclerosis (intima media thickness (mm), total area (mm2), and plaque presence). Family history of cardiovascular disease, sociodemographic measures (age, sex, ethnicity, income level, maximum education), and traditional risk factors (systolic blood pressure, smoking status, total cholesterol, high-density lipoprotein cholesterol, body mass index) were incorporated into the models of association. These models used multiple linear regression and logistic regression. RESULTS Baseline HTGW phenotype is a statistically significant and clinically meaningful predictor of 5-year intima media thickness (β = 0.08 [0.04, 0.11], p < 0.001), total area (β = 0.20 [0.07, 0.33], p = 0.002), and plaque presence (OR = 2.17 [1.13, 4.19], p = 0.02) compared to the non-HTGW group independent of sociodemographic factors and family history. However, this association is no longer significant after adjusting for the traditional risk factors of atherosclerosis (p = 0.27, p = 0.45, p = 0.66, respectively). Moreover, change in status of HTGW phenotype does not correlate with change in indices of atherosclerosis over 5 years. CONCLUSIONS Our results suggest that when the traditional risk factors of atherosclerosis are known, HTGW may not offer additional value as a predictor of subclinical atherosclerosis progression over 5 years.