N-3 polyunsaturated fatty acids improve lipoprotein particle size and concentration in Japanese patients with type 2 diabetes and hypertriglyceridemia: a pilot study.
ABSTRACT: Patients with type 2 diabetes are at high risk for cardiovascular disease. Although hydroxymethylglutaryl-CoA reductase inhibitors (statins) can reduce cardiovascular events, residual risk remains even after target low-density lipoprotein cholesterol (LDL-C) levels have been achieved. Lipoprotein particle size and fraction changes are thought to contribute to such risks. The purpose of this study was to evaluate the effects of n-3 polyunsaturated fatty acids (n-3 PUFAs), predominantly eicosapentaenoic acid and docosahexaenoic acid, on lipoprotein particle size, concentration, and glycemic control in Japanese patients with type 2 diabetes and hypertriglyceridemia.This was a multicenter, prospective, open-label, single arm study. We enrolled 14 patients with type 2 diabetes and hypertriglyceridemia treated with statins and dipeptidyl peptidase-4 inhibitors with glycated hemoglobin (HbA1c)?
Project description:Cross-sectional studies have suggested that serum omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) are related to favorable lipoprotein particle concentrations. We explored the associations of serum n-3 and n-6 PUFAs with lipoprotein particle concentrations and sizes in a general population cohort at baseline and after 6 years.The cohort included 665 adults (274 men) with a 6-year follow-up. Nutritional counseling was given at baseline. Serum n-3 and n-6 PUFAs and lipoprotein particle concentrations and the mean particle sizes of VLDL, LDL, and HDL were quantified by nuclear magnetic resonance (NMR) spectroscopy for all baseline and follow-up samples at the same time. Concentrations of n-3 and n-6 PUFAs were expressed relative to total fatty acids. At baseline, n-3 PUFAs were not associated with lipoprotein particle concentrations. A weak negative association was observed for VLDL (P = 0.021) and positive for HDL (P = 0.011) particle size. n-6 PUFA was negatively associated with VLDL particle concentration and positively with LDL (P < 0.001) and HDL particle size (P < 0.001). The 6-year change in n-3 PUFA correlated positively with the change in particle size for HDL and LDL lipoproteins but negatively with VLDL particle size. An increase in 6-year levels of n-6 PUFAs was negatively correlated with the change in VLDL particle concentration and size, and positively with LDL particle size.Change in circulating levels of both n-3 and n-6 PUFAs, relative to total fatty acids, during 6 years of follow-up are associated with changes in lipoprotein particle size and concentrations at the population level.
Project description:Statins decrease levels of low-density lipoprotein (LDL) and triglycerides as well as cardiovascular events but increase the risk for a diagnosis of type 2 diabetes mellitus (T2DM). The risk factors associated with incident T2DM are incompletely characterized.To investigate the association of lipoprotein subclasses and size and a novel lipoprotein insulin resistance (LPIR) score (a composite of 6 lipoprotein measures) with incident T2DM among individuals randomized to a high-intensity statin or placebo.This secondary analysis of the JUPITER trial (a placebo-controlled randomized clinical trial) was conducted at 1315 sites in 26 countries and enrolled 17 802 men 50 years or older and women 60 years or older with LDL cholesterol levels less than 130 mg/dL, high-sensitivity C-reactive protein levels of at least 2 mg/L, and triglyceride levels less than 500 mg/dL. Those with T2DM were excluded. A prespecified secondary aim was to assess the effect of rosuvastatin calcium on T2DM. Incident T2DM was monitored for a median of 2.0 years. Data were collected from February 4, 2003, to August 20, 2008, and analyzed (intention-to-treat) from December 1, 2013, to January 21, 2016.Rosuvastatin calcium, 20 mg/d, or placebo.Size and concentration of lipids, apolipoproteins, and lipoproteins at baseline (11?918 patients with evaluable plasma samples) and 12 months after randomization (9180 patients). The LPIR score, a correlate of insulin resistance, was calculated as a weighted combination of size and concentrations of LDL, very low-density lipoprotein (VLDL), and high-density lipoprotein (HDL) particles.Among the 11 918 patients (4334 women [36.4%]; median [interquartile range] age, 66 [60-71] years), rosuvastatin lowered the levels of LDL particles (-39.6%; 95% CI, -49.4% to -24.6%), VLDL particles (-19.6%; 95% CI, -40.6% to 10.3%), and VLDL triglycerides (-15.2%; 95% CI, -35.9% to 11.3%) and shifted the lipoprotein subclass distribution toward smaller LDL size (-1.5%; 95% CI, -3.7% to 0.5%), larger VLDL size (2.8%; 95% CI, -5.8% to 12.7%), and lower LPIR score (-3.2%; 95% CI, -20.6% to 16.9%). In analyses adjusted for age, sex, race or ethnic origin, exercise, educational level, family history, and smoking, the hazard ratio (HR) for T2DM per SD of LPIR score in the placebo arm was 1.99 (95% CI, 1.64-2.42); in the rosuvastatin arm, 2.06 (95% CI, 1.74-2.43). After additional adjustment for systolic blood pressure, body mass index, high-sensitivity C-reactive protein, hemoglobin A1c, HDL cholesterol, LDL cholesterol, and triglycerides, the LPIR score remained associated with T2DM in the placebo arm (HR, 1.35; 95% CI, 1.03-1.76) and rosuvastatin arm (HR, 1.60; 95% CI, 1.27-2.03). Similar trends were seen at 12 months. The LPIR score improved the model likelihood ratio (?2?=?18.23; P?<?.001) and categorical net reclassification index (0.039; 95% CI, 0.003-0.072).In apparently healthy people, LPIR score was positively associated with incident T2DM, including during rosuvastatin therapy.clinicaltrials.gov Identifier: NCT00239681.
Project description:Type II diabetes (T2D) is preceded by prolonged insulin resistance and relative insulin deficiency incompletely captured by glucose metabolism parameters, high-density lipoprotein (HDL) cholesterol and triglycerides.Whether lipoprotein insulin resistance (LPIR) score, a metabolomic marker, is associated with incident diabetes and improves risk reclassification over traditional markers on extended follow-up.Among 25,925 nondiabetic women aged 45 years or older, LPIR was measured by nuclear magnetic resonance spectroscopy as a weighted score of very low density lipoprotein, low-density lipoprotein, and HDL particle sizes, and their subsets concentrations. We run adjusted cox regression models for LPIR with incident T2D (20.4 years median follow-up).Adjusting for demographics, body mass index, life style factors, blood pressure, and T2D family history, the LPIR hazard ratio for T2D (hazard ratio [HR] per standard deviation, 95% confidence interval) was 1.95 (1.85, 2.06). Further adjusting for HbA1c, C-reactive protein, triglycerides, HDL and low-density lipoprotein cholesterol, LPIR HR was attenuated to 1.41 (1.31, 1.53) and had the strongest association with T2D after HbA1C in mutually adjusted models. The association persisted even in those with optimal clinical profiles, adjusted HR per standard deviation 1.91 (1.17, 3.13). In participants deemed at intermediate T2D risk by the Framingham Offspring T2D score, LPIR led to a net reclassification of 0.145 (0.117, 0.175).In middle-aged or older healthy women followed prospectively for over 20 years, LPIR was robustly associated with incident T2D, including among those with an optimal clinical metabolic profile. LPIR improved T2D risk classification and may guide early and targeted prevention strategies.
Project description:The associations of serum omega-6 (n-6) fatty acids with lipoprotein subclasses at the population level are uncertain.We aimed to examine associations between major n-6 fatty acids [ie, linoleic acid (LA, 18:2n-6) and arachidonic acid (AA, 20:4n-6)] and the lipoprotein subclasses VLDL, LDL, and HDL.We conducted a cross-sectional study in 1098 participants using population-based data from US white, Japanese American, Japanese, and Korean men aged 40-49 y. Serum fatty acids were analyzed by capillary gas-liquid chromatography. Lipoprotein subclasses were measured by nuclear magnetic resonance spectroscopy. Multiple linear regression models as a function of each fatty acid were used after adjustment for age, population, body mass index, pack-years of smoking, alcohol consumption, diabetes, hypertension, and omega-3 (n-3) and trans fatty acids.Serum LA was inversely associated with large VLDL (beta = -0.62, P < 0.001), total LDL (beta = -22.08, P < 0.001), and small LDL (beta = -31.89, P < 0.001) particle concentrations and VLDL size (beta = -0.72, P < 0.001). Serum LA was positively associated with large HDL particle concentration (beta = 0.21, P < 0.001) and HDL size (beta = 0.03, P < 0.001). The patterns of association of AA with large VLDL and large HDL particle concentrations were comparable with those of LA.At the population level, higher serum concentrations of LA were significantly associated with lower concentrations of total LDL particles. Higher serum concentrations of LA and AA were significantly associated with a lower concentration of large VLDL particles and a higher concentration of large HDL particles. These associations were consistent across the population groups. This trial was registered at clinicaltrials.gov as NCT00069797.
Project description:OBJECTIVE:Metabolic dysfunction characterized by insulin resistance (IR) is an important risk factor for type-2 diabetes and coronary artery disease (CAD). The aim of this study was to determine if clinical lifestyle interventions differing in scope and intensity improve IR, defined by the lipoprotein IR (LPIR) score, in individuals differing in the severity of metabolic dysfunction. METHODS:Subjects with diagnosed type-2 diabetes, CAD or significant risk factors participated in one of two clinical lifestyle modification interventions: (i) intensive non-randomized programme with a strict vegetarian diet (n?=?90 participants, 90 matched controls) or (ii) moderate randomized trial following a Mediterranean-style diet (n?=?89 subjects, 58 controls). On-treatment and intention-to-treat analyses assessed changes over 1?year in LPIR, lipoprotein profiles and metabolic risk factors in intervention participants and controls in both programmes. RESULTS:In the on-treatment analysis, both interventions led to weight loss: [-8.9% (95% CI, -10.3 to -7.4), intensive programme; -2.8% (95% CI, -3.8 to -1.9), moderate programme; adjusted P?<?0.001] and a decrease in the LPIR score [-13.3% (95% CI, -18.2 to -8.3), intensive; -8.8% (95% CI, -12.9 to -4.7), moderate; adjusted P?<?0.01] compared with respective controls. Of the six lipoprotein parameters comprising LPIR, only large very-low-density lipoprotein particle concentrations decreased significantly in participants compared with controls in both programmes [-26.3% (95% CI, -43.0 to -9.6), intensive; -14.2% (95% CI, -27.4 to -1.0), moderate; P?<?0.05]. Intention-to-treat analysis confirmed and strengthened the primary results. CONCLUSION:A stringent lifestyle modification intervention with a vegetarian diet and a moderate lifestyle modification intervention following a Mediterranean diet were both effective for improving IR defined by the LPIR score.
Project description:OBJECTIVE:Metformin affects low density lipoprotein (LDL) and high density (HDL) subfractions in the context of impaired glucose tolerance, but its effects in the setting of acute myocardial infarction (MI) are unknown. We determined whether metformin administration affects lipoprotein subfractions 4 months after ST-segment elevation MI (STEMI). Second, we assessed associations of lipoprotein subfractions with left ventricular ejection fraction (LVEF) and infarct size 4 months after STEMI. METHODS:371 participants without known diabetes participating in the GIPS-III trial, a placebo controlled, double-blind randomized trial studying the effect of metformin (500 mg bid) during 4 months after primary percutaneous coronary intervention for STEMI were included of whom 317 completed follow-up (clinicaltrial.gov Identifier: NCT01217307). Lipoprotein subfractions were measured using nuclear magnetic resonance spectroscopy at presentation, 24 hours and 4 months after STEMI. (Apo)lipoprotein measures were obtained during acute STEMI and 4 months post-STEMI. LVEF and infarct size were measured by cardiac magnetic resonance imaging. RESULTS:Metformin treatment slightly decreased LDL cholesterol levels (adjusted P = 0.01), whereas apoB remained unchanged. Large LDL particles and LDL size were also decreased after metformin treatment (adjusted P<0.001). After adjustment for covariates, increased small HDL particles at 24 hours after STEMI predicted higher LVEF (P = 0.005). In addition, increased medium-sized VLDL particles at the same time point predicted a smaller infarct size (P<0.001). CONCLUSION:LDL cholesterol and large LDL particles were decreased during 4 months treatment with metformin started early after MI. Higher small HDL and medium VLDL particle concentrations are associated with favorable LVEF and infarct size.
Project description:In the Multi-Ethnic Study of Atherosclerosis (MESA), we evaluated associations of baseline levels of a lipoprotein-based insulin resistance (IR) index (LP-IR), IR-related lipoprotein particles, mean particle sizes, and lipids, with incident type 2 diabetes, independent of confounders, glucose, insulin, and HOMA-IR.Among 5,314 adults aged 45-84 years without baseline diabetes or cardiovascular disease, 656 cases of diabetes were identified during a mean follow-up of 7.7 years. Lipoprotein particle concentrations, size, and LP-IR were determined by nuclear magnetic resonance spectroscopy of stored baseline plasma. Potential effect modification, by race/ethnicity, sex, baseline use of lipid-lowering medications or hormone therapy, or glucose strata (<90, 90-99, and ? 100 mg/dL), was also evaluated.Higher levels of LP-IR, large VLDL particles (VLDL-P), small LDL particles, triglycerides (TG), and TG-to-HDL cholesterol (HDL-C) ratio and lower levels of large HDL particles, smaller HDL and LDL size, and larger VLDL size were significantly associated with incident diabetes adjusted for confounders and glucose or insulin. These also were similar by race/ethnicity, sex, and treatment group. Associations were similar for LP-IR, large VLDL-P, mean VLDL size, TG, and TG-to-HDL-C ratio; they persisted for LP-IR, large VLDL-P, or mean VLDL size adjusted for HOMA-IR or TG-to-HDL-C ratio and glucose but not for the TG-to-HDL-C ratio adjusted for LP-IR or for HOMA-IR or insulin if adjusted for LP-IR and glucose.Among ethnically diverse men and women, LP-IR, large VLDL-P, large VLDL size, TG, and TG-to-HDL-C ratio were associated with incident diabetes independent of established risk factors, glucose, insulin, or HOMA-IR, as well as the use of lipid-lowering medications or hormone therapy.
Project description:Background:Metabolic alterations correlate with adverse outcomes in type 2 diabetes. Dietary modification serves as an integral part in its treatment. Objective:We examined the relationships among dietary patterns, dietary biomarkers, and metabolic indicators in type 2 diabetes (n = 871). Design:Diabetic patients (n = 871) who provided complete clinical and dietary data in both 2008 and 2009 were selected from a cohort participating in a diabetic control study in Taiwan. Dietary data were obtained using a short, semiquantitative food frequency questionnaires, and dietary pattern identified by factor analysis. Multiple linear regressions were used to analyze the association between dietary biomarkers (ferritin, folate, and erythrocyte n-3 polyunsaturated fatty acids [n-3 PUFAs]) and metabolic control upon adjusting for confounders. Results:Three dietary patterns (high-fat meat, traditional Chinese food-snack, and fish-vegetable) were identified. Ferritin correlated positively with high-fat meat factor scores (P for trend <0.001). Erythrocyte n-3 PUFAs (eicosapentaenoic acid [EPA] + docosahexaenoic acid [DHA], n-3/n-6 PUFA ratio) correlated positively with fish-vegetable factor scores (all P for trends <0.001). Multiple linear regressions revealed a positive relationship between ferritin concentrations and fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), and triglycerides, but a negative relationship with high-density lipoprotein cholesterol (HDL-C). Erythrocyte n-3 PUFA, EPA+DHA, and n-3/n-6 PUFA ratio were negatively linked to FPG, HbA1c, and triglycerides (all P < 0.05) and positively with HDL-C (though n-3/n-6 ratio marginally correlated). Conclusions:Ferritin and n-3 PUFA can serve as valid biomarkers for high-fat meat and fish-vegetable dietary patterns. Unlike ferritin, erythrocyte n-3 PUFA status was related to better glycemic and blood lipid profiles. Our results suggest that habitual consumption of diet pattern rich in fish and vegetables may contribute in part to a healthier metabolic profile in type 2 diabetes.
Project description:<h4>Background & aims</h4>Obeticholic acid (OCA), a farnesoid X receptor agonist, increases total and low-density lipoprotein cholesterol (LDL-C) in patients with non-alcoholic steatohepatitis. In the present study, we aimed to evaluate the impact of OCA therapy on lipoprotein sub-particles.<h4>Method</h4>This study included 196 patients (99 OCA group and 97 placebo group) who were enrolled in the FLINT trial and had samples available for lipid analysis and liver biopsies at enrollment and end-of-treatment (EOT) at 72?weeks. Very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) particles were evaluated at baseline, 12 and 72?weeks after randomization, and 24?weeks following EOT.<h4>Results</h4>Baseline lipoprotein profiles were similar among OCA and placebo groups. OCA did not affect total VLDL particle concentrations, but OCA vs. placebo treatment was associated with decreased large VLDL particle concentration at 12?weeks (baseline-adjusted mean: 6.8 vs. 8.9?nmol/L; p?=?0.002), mirrored by an increase in less atherogenic, small VLDL particle concentration (33.9 vs. 28.0?nmol/L; p?=?0.02). After 12?weeks, total LDL particle concentration was higher in the OCA group than the placebo group (1,667 vs. 1,329?nmol/L; p?<0.0001), characterized by corresponding increases in both less atherogenic, large-buoyant LDL (475 vs. 308?nmol/L; p??0.001) and more atherogenic small-dense LDL particles (1,015 vs. 872?nmol/L; p?=?0.002). The changes in LDL particle concentrations were similar between treatment groups (OCA and placebo) 24?weeks following EOT due to improvement in the OCA cohort. Compared to placebo, a reduction in total HDL particle concentration, particularly large and medium HDL particles, was noted in the OCA-treated patients, but this resolved after drug discontinuation.<h4>Conclusion</h4>OCA therapy is associated with increases in small VLDL particles, large and small LDL particles, and a reduction in HDL particles at 12?weeks. These lipoprotein concentrations reverted to baseline values 24?weeks after drug discontinuation.<h4>Lay summary</h4>Non-alcoholic steatohepatitis is a chronic liver disease that is associated with an increased risk of developing cirrhosis and cardiovascular disease. Recently, obeticholic acid (OCA), a farnesoid X receptor agonist, improved liver disease but led to an increase in cholesterol. However, the impact of OCA on cholesterol is not well understood. In the present study, we show that OCA therapy is associated with a detrimental increase in lipoprotein levels, which improves after drug discontinuation. ClinicalTrials.gov numbers: NCT01265498.
Project description:It is uncertain whether pharmacological reductions in very-low-density lipoproteins (VLDLs), and their component triglyceride and cholesterol could reduce residual risk of atherosclerotic cardiovascular disease (ASCVD) events among individuals in whom low-density lipoprotein cholesterol (LDL-C) has been adequately lowered. We examined whether individuals with greater on-statin reductions in VLDL-related measures-beyond reductions in LDL-C-were at further reduced risk of ASCVD.In 9423 participants in the JUPITER (Justification for the Use of Statins in Prevention) trial (NCT00239681), at baseline and on statin we measured standard lipids, 400-MHz proton nuclear magnetic resonance spectroscopy-measured VLDL particle subclasses (small, medium, and large VLDL lipoprotein particle concentration), and total VLDL cholesterol mass. Compared with individuals allocated to placebo, we examined risk of incident ASCVD (N=211) among statin-allocated participants who achieved minimal (<median) or greater (?median) marker reductions using adjusted Cox models. On-statin changes in VLDL-related markers were only modestly correlated (Spearman r?0.29) with change in LDL-C. On-statin median LDL-C was 54 mg/dL and triglyceride was 101 mg/dL. Dose-response reductions in ASCVD risk were observed for greater reductions in LDL-C, VLDL cholesterol mass, and small VLDL lipoprotein particle concentration; the latter 2 remained significant after incremental adjustment for change in LDL-C (P?0.006). Conversely, there was no further risk reduction with greater reductions in triglycerides or large/medium VLDL lipoprotein particle concentration.Pharmacological reduction in small, cholesterol-enriched, triglyceride-depleted VLDL was associated with reduction in ASCVD risk. Chemically measured triglycerides may not sufficiently capture risk related to VLDL pathways. These findings also support broader profiling of lipid and lipoprotein changes in response to statins as prognostic markers of individual benefit, supporting more precision-medicine, individualized approaches to cardiovascular risk reduction.URL: https://www.clinicaltrials.gov. Unique identifier: NCT00239681.