Effects of Evolocumab on the Postprandial Kinetics of Apo (Apolipoprotein) B100- and B48-Containing Lipoproteins in Subjects With Type 2 Diabetes.

OBJECTIVE: Increased risk of atherosclerotic cardiovascular disease in subjects with type 2 diabetes is linked to elevated levels of triglyceride-rich lipoproteins and their remnants. The metabolic effects of PCSK9 (proprotein convertase subtilisin/kexin 9) inhibitors on this dyslipidemia were investigated using stable-isotope-labeled tracers. Approach and Results: Triglyceride transport and the metabolism of apos (apolipoproteins) B48, B100, C-III, and E after a fat-rich meal were investigated before and on evolocumab treatment in 13 subjects with type 2 diabetes. Kinetic parameters were determined for the following: apoB48 in chylomicrons; triglyceride in VLDL1 (very low-density lipoprotein) and VLDL2; and apoB100 in VLDL1, VLDL2, IDL (intermediate-density lipoprotein), and LDL (low-density lipoprotein). Evolocumab did not alter the kinetics of apoB48 in chylomicrons or apoB100 or triglyceride in VLDL1. In contrast, the fractional catabolic rates of VLDL2-apoB100 and VLDL2-triglyceride were both increased by about 45%, which led to a 28% fall in the VLDL2 plasma level. LDL-apoB100 was markedly reduced by evolocumab, which was linked to metabolic heterogeneity in this fraction. Evolocumab increased clearance of the more rapidly metabolized LDL by 61% and decreased production of the more slowly cleared LDL by 75%. ApoC-III kinetics were not altered by evolocumab, but the apoE fractional catabolic rates increased by 45% and the apoE plasma level fell by 33%. The apoE fractional catabolic rates was associated with the decrease in VLDL2- and IDL-apoB100 concentrations. CONCLUSIONS: Evolocumab had only minor effects on lipoproteins that are involved in triglyceride transport (chylomicrons and VLDL1) but, in contrast, had a profound impact on lipoproteins that carry cholesterol (VLDL2, IDL, LDL). Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02948777.

Impact of proprotein convertase subtilisin/kexin type 9 inhibition with evolocumab on the postprandial responses of triglyceride-rich lipoproteins in type II diabetic subjects.

BACKGROUND: Monoclonal antibodies to proprotein convertase subtilisin/kexin type 9 (PCSK9) significantly lower the levels of low-density lipoprotein and very-low-density lipoproteins (VLDL), but their effect on postprandial lipoprotein metabolism in dyslipidemic subjects is unclear. OBJECTIVE: This study aimed to investigate the effects of evolocumab on postprandial lipid responses, ectopic fat depots, whole-body cholesterol synthesis, hepatic lipogenesis, and fat oxidation in patients with type II diabetes. METHODS: The trial was a single-phase, nonrandomized study of 12-week treatment with evolocumab 140 mg subcutaneously every 2 weeks in 15 patients with type II diabetes on background statin therapy. Cardiometabolic responses to a high-fat mixed meal were assessed before and at the end of the intervention period. RESULTS: Evolocumab treatment reduced significantly postprandial rises in plasma total triglyceride (by 21%; P < .0001) and VLDL1 triglyceride (by 15%; P = .018), but the increase in chylomicron triglyceride after the meal was not significantly perturbed (P = .053). There were reduced postprandial responses in plasma total apolipoprotein C-III (by 14%; P < .0001) and apolipoprotein B-48 concentration (by 17%; P = .0046) and in "remnant-like particles" cholesterol (by 29%; P < .0001) on the PCSK9 inhibitor. Treatment reduced the steady-state (ie, fasting and postprandial) concentrations of VLDL2 cholesterol by 50% (P < .0001) and VLDL2 triglyceride by 29% (P < .0001), in addition to the 78% reduction of low-density lipoprotein cholesterol (P < .001). The changes in apolipoprotein C-III associated significantly with reduction in postprandial responses of remnant-like particles cholesterol and triglyceride-rich lipoprotein cholesterol. Evolocumab therapy did not influence liver fat accumulation, hepatic de novo lipogenesis, or fasting ß-hydroxybutyrate but did increase total body cholesterol synthesis (P < .01). CONCLUSION: Evolocumab treatment improved postprandial responses of triglyceride-rich lipoproteins and measures of cholesterol-enriched remnant particles in type II diabetic subjects. These results indicate that postprandial phenomena need to be taken into account in assessing the full range of actions of PCSK9 inhibitors in dyslipidemic individuals.

Role of apolipoprotein C-III overproduction in diabetic dyslipidaemia.

AIMS: To investigate how apolipoprotein C-III (apoC-III) metabolism is altered in subjects with type 2 diabetes, whether the perturbed plasma triglyceride concentrations in this condition are determined primarily by the secretion rate or the removal rate of apoC-III, and whether improvement of glycaemic control using the glucagon-like peptide-1 analogue liraglutide for 16 weeks modifies apoC-III dynamics. MATERIALS AND METHODS: Postprandial apoC-III kinetics were assessed after a bolus injection of [5,5,5-2 H3 ]leucine using ultrasensitive mass spectrometry techniques. We compared apoC-III kinetics in two situations: in subjects with type 2 diabetes before and after liraglutide therapy, and in type 2 diabetic subjects with matched body mass index (BMI) non-diabetic subjects. Liver fat content, subcutaneous abdominal and intra-abdominal fat were determined using proton magnetic resonance spectroscopy. RESULTS: Improved glycaemic control by liraglutide therapy for 16 weeks significantly reduced apoC-III secretion rate (561 ± 198 vs. 652 ± 196 mg/d, P = 0.03) and apoC-III levels (10.0 ± 3.8 vs. 11.7 ± 4.3 mg/dL, P = 0.035) in subjects with type 2 diabetes. Change in apoC-III secretion rate was significantly associated with the improvement in indices of glucose control (r = 0.67; P = 0.009) and change in triglyceride area under the curve (r = 0.59; P = 0.025). In line with this, the apoC-III secretion rate was higher in subjects with type 2 diabetes compared with BMI-matched non-diabetic subjects (676 ± 208 vs. 505 ± 174 mg/d, P = 0.042). CONCLUSIONS: The results reveal that the secretion rate of apoC-III is associated with elevation of triglyceride-rich lipoproteins in subjects with type 2 diabetes, potentially through the influence of glucose homeostasis on the production of apoC-III.

ApoA-II HDL Catabolism and Its Relationships With the Kinetics of ApoA-I HDL and of VLDL1, in Abdominal Obesity.

We study the associations between apoA-II fractional catabolic rate (FCR) and the kinetics of VLDL subspecies and apoA-I and show that, in abdominally obese individuals, apoA-II FCR is positively and independently associated with both apoA-I FCR and VLDL1-TG indirect FCR.

Kinetic and Related Determinants of Plasma Triglyceride Concentration in Abdominal Obesity: Multicenter Tracer Kinetic Study.

OBJECTIVES: Patients with obesity and diabetes mellitus have increased risk of cardiovascular disease. A major cause is an atherogenic dyslipidemia related primarily to elevated plasma concentrations of triglyceride-rich lipoproteins. The aim of this study was to clarify determinants of plasma triglyceride concentration. We focused on factors that predict the kinetics of very-low density lipoprotein 1 (VLDL1) triglycerides. APPROACH AND RESULTS: A multicenter study using dual stable isotopes (deuterated leucine and glycerol) and multicompartmental modeling was performed to elucidate the kinetics of triglycerides and apoB in VLDL1 in 46 subjects with abdominal obesity and additional cardiometabolic risk factors. Results showed that plasma triglyceride concentrations were dependent on both the secretion rate (r=0.44, P<0.01; r=0.45, P<0.01) and fractional catabolism (r=0.49, P<0.001; r=0.55, P<0.001) of VLDL1-triglycerides and VLDL1-apoB. Liver fat mass was independently and directly associated with secretion rates of VLDL1-triglycerides (r=0.56, P<0.001) and VLDL1-apoB (r=0.53, P<0.001). Plasma apoC-III concentration was independently and inversely associated with the fractional catabolisms of VLDL1-triglycerides (r=0.48, P<0.001) and VLDL1-apoB (r=0.51, P<0.001). CONCLUSIONS: Plasma triglyceride concentrations in abdominal obesity are determined by the kinetics of VLDL1 subspecies, catabolism being mainly dependent on apoC-III concentration and secretion on liver fat content. Reduction in liver fat and targeting apoC-III may be an effective approach for correcting triglyceride metabolism atherogenic dyslipidemia in obesity.

Interrelationships between the kinetics of VLDL subspecies and HDL catabolism in abdominal obesity: a multicenter tracer kinetic study.

CONTEXT: Low plasma high-density lipoprotein (HDL) cholesterol is a major abnormality in abdominal obesity. This relates due to accelerated HDL catabolism, but the underlying mechanism requires further elucidation. The relationships between HDL catabolism and other variables that may be modified in abdominal obesity, such as very low-density lipoprotein (VLDL) subspecies (VLDL1, VLDL2) kinetics, liver fat, or visceral adiposity, remain to be investigated. OBJECTIVES: Our aim was to study the associations between HDL apolipoprotein (apo)-A-I fractional catabolic rate (FCR) and the kinetics of VLDL subspecies and estimates of liver and visceral and sc fat. DESIGN: We carried out a multicenter in vivo kinetic study using stable isotopes (deuterated leucine and glycerol) in 62 individuals with abdominal obesity. RESULTS: In a multivariate analysis, among the morphological and biological parameters that may predict apoA-I FCR, liver fat (ß = .400, P = .003), and VLDL1-apoB (ß = .307, P = .020) were independently associated with apoA-I FCR. In a multivariate analysis, among the kinetic parameters, VLDL1-triglycerides (TGs) indirect FCR (ß = -.357, P = .001), VLDL1-TG production rate (ß = 0.213, P = .048), and apoA-II FCR (ß = .667, P < .0001) were independently associated with apoA-I FCR. After adjustment for VLDL1-TG production rate, liver fat was no more correlated with apoA-I FCR. No association between apoA-I FCR and visceral fat was observed. CONCLUSIONS: We show that VLDL1 is an important independent determinant of apoA-I FCR and more precisely that apoA-I FCR is independently associated with both catabolism and the production of VLDL1-TG. In addition, we show an association between liver fat and apoA-I FCR that is mostly mediated by VLDL1-TG production. These data indicate that, in abdominal obesity, dysfunctional VLDL1 metabolism is an important modulator of HDL apoA-I catabolism.

[Statin therapy--for whom?]. / Kenelle aloitan statiinilääkityksen?

For patients with cardiovascular disease, statins belong to routine medical treatment irrespective of blood lipid levels. In primary prevention also, statins have been found to prevent cardiovascular diseases, associated deaths and decrease overall mortality. In previously healthy persons the use of statins should be based on the assessment of total risk--mere cholesterol level does not usually constitute an indication for treatment. The use of statins may lead to adverse effects, the major one being myopathy, for which an elevated risk is associated with increasing statin dosages.

Dual metabolic defects are required to produce hypertriglyceridemia in obese subjects.

OBJECTIVE: Obesity increases the risk of cardiovascular disease and premature death. However, not all obese subjects develop the metabolic abnormalities associated with obesity. The aim of this study was to clarify the mechanisms that induce dyslipidemia in obese subjects. METHODS AND RESULTS: Stable isotope tracers were used to elucidate the pathophysiology of the dyslipidemia in hypertriglyceridemic (n=14) and normotriglyceridemic (n=14) obese men (with comparable body mass index and visceral fat volume) and in normotriglyceridemic nonobese men (n=10). Liver fat was determined using proton magnetic resonance spectroscopy, and subcutaneous abdominal and visceral fat were measured by magnetic resonance imaging. Serum triglycerides in obese subjects were increased by the combination of increased secretion and severely impaired clearance of triglyceride-rich very-low-density lipoprotein(1) particles. Furthermore, increased liver and subcutaneous abdominal fat were linked to increased secretion of very-low-density lipoprotein 1 particles, whereas increased plasma levels of apolipoprotein C-III were associated with impaired clearance in obese hypertriglyceridemic subjects. CONCLUSIONS: Dual metabolic defects are required to produce hypertriglyceridemia in obese subjects with similar levels of visceral adiposity. The results emphasize the clinical importance of assessing hypertriglyceridemic waist in obese subjects to identify subjects at high cardiometabolic risk.

Reviewing statin therapy in diabetes--towards the best practise.

Statin therapy is considered critical both in primary and secondary prevention of cardiovascular disease in diabetes. Cholesterol Treatment Trialists' Collaborators meta-analysis of 14 randomised trials of statins in 18686 people with diabetes provides the latest and largest evidence showing a significant 21% reduction in major vascular events per mmol/l reduction in LDL cholesterol. Importantly, the risk reduction was similar in both types of diabetes. Growing evidence supports the view that statin therapy reduces microvascular complications as well. This review updates the current knowledge of statin therapy in preventing micro- and macrovascular complications in both type 1 and type 2 diabetes.

Apolipoprotein E polymorphism is associated with both carotid and coronary atherosclerosis in patients with coronary artery disease.

BACKGROUND AND AIMS: Apolipoprotein E (apoE) polymorphism plays a significant role in the development of atherosclerosis and cardiovascular disease. Therefore, the aim of the present study was to examine the association between apoE polymorphism and carotid intima-media thickness (IMT), and severity and extent of coronary artery disease (CAD). METHODS AND RESULTS: B-mode ultrasound and quantitative coronary angiography (QCA) were used to assess carotid, and coronary artery atherosclerosis in 91 patients with clinically suspected CAD referred for cardiac catheterization. Two apoE phenotype groups were defined: apoE3 (E3/E3) and apoE4 (including E4/E3, E4/E4 phenotypes). Maximum IMT was higher in the apoE4 group than in the apoE3 group (p=0.022). The global atheroma burden index was similarly higher in the apoE4 group than in the apoE3 group (p=0.033). ApoE4 subjects had higher levels of apolipoprotein B (apoB) (p=0.008), triglycerides (p=0.006), remnant lipoprotein-cholesterol (RLP-C) (p=0.023), and lipoprotein(a) [(Lp(a)] (p=0.041) than apoE3 subjects. The mean LDL particle size was smaller in the apoE4 group than in the apoE3 group (p=0.041). CONCLUSIONS: ApoE polymorphism was associated with both carotid and coronary atherosclerosis. Patients with the apoE4 isoform had an increased carotid IMT and a more severe and extensive CAD than patients with the apoE3 isoform.

Insulin resistance as predictor of the angiographic severity and extent of coronary artery disease.

BACKGROUND: Insulin resistance (IR) is frequently observed in patients with coronary artery disease (CAD). Aim. To examine the association between IR and severity and extent of CAD. METHODS: Quantitative coronary angiography (QCA) was used to assess coronary atherosclerosis in 107 patients with clinically suspected CAD. QCA-derived indexes reflecting CAD severity, extent, and overall atheroma burden were calculated for the entire coronary tree, and separately for different coronary segments. IR was quantified using the homeostasis model assessment insulin resistance index (HOMA IR). Nondiabetic subjects (n = 83) were divided into group 1 (n = 41) with HOMA IR <1.8 (the median value), and group 2 (n = 42) with HOMA IR >or=1.8. Group 3 comprised diabetic subjects (n = 24). RESULTS: Global age- and gender-adjusted indexes for severity (P = 0.007), extent (P = 0.038), and atheroma burden (P = 0.035) of CAD were higher in group 2 than in group 1. Similarly, the global severity (P = 0.027), extent (P = 0.090), and global atheroma burden (P = 0.024) indexes were higher in group 3 compared with group 1. IR was correlated with quantitative angiographic indexes for distal segments only, but not for proximal or mid segments of coronary vessels. CONCLUSIONS: Patients with more severe degree of IR have a more severe, extensive, and distal type of CAD than patients with lower degree of IR.

ApoE polymorphism is associated with C-reactive protein in low-HDL family members and in normolipidemic subjects.

The study was aimed to compare inflammatory parameters between carriers of apoE4 isoforms (apoE4/3, apoE4/2, and apoE4/4 phenotypes) and those of carrying apoE3 isoform without apoE4 isoform (apoE3/3 phenotypes and apoE2/3 phenotypes). The concentrations of serum hsCRP, sVCAM-1, sICAM-1, and sE-selectin were measured in 211 subjects from Finnish low-HDL families and in 157 normolipidemic subjects. The subjects with apoE4 isoform had lower concentrations of serum hsCRP both in low-HDL family members (p < 0.05) and in normolipidemic subjects (p < 0.01). The differences in serum CRP values remained significant after adjustment for age, BMI, smoking status, hypertension, gender, lipoprotein variables, and family number. We conclude that apoE phenotype has a strong influence on serum CRP values.

Association of paraoxonase-1 activity and concentration with angiographic severity and extent of coronary artery disease.

OBJECTIVES: The goal of this study was to examine the association between paraoxonase-1 (PON1) activity and concentration and the severity and extent of coronary artery disease (CAD). BACKGROUND: Paraoxonase-1, a high-density lipoprotein-associated enzyme, is proposed to have an antiatherogenic effect by protecting low-density lipoproteins against oxidation. METHODS: We studied PON1 activity and concentration in 107 patients with known or suspected CAD referred for cardiac catheterization. Based on visual estimation of coronary angiograms, subjects were classified as having no or mild CAD (<50% stenosis) and significant CAD (> or =50% stenosis). Quantitative coronary angiography (QCA) was used to estimate the indexes of severity, extent, and overall atheroma burden of CAD. RESULTS: We found lower values of PON1 activity and concentration (p = 0.003 and p = 0.016, respectively) in the group with significant CAD as compared with the group with no or mild CAD. The PON1 activity was significantly inversely correlated with CAD severity (r = -0.364, p < 0.001), extent (r = -0.221, p = 0.022), and atheroma burden (r = -0.277, p = 0.004). Similarly, PON1 concentration correlated with CAD severity (r = -0.306, p = 0.001) and atheroma burden (r = -0.229, p = 0.017). In multiple regression analysis, gender and PON1 activity were significant determinants of the severity of CAD independently of age, hypertension, smoking, abnormal glucose regulation, and high-density lipoprotein cholesterol. CONCLUSIONS: Our results indicate that PON1 activity and concentration are lower in subjects with significant CAD, and that there is a significant relationship between PON1 activity and concentration and CAD assessed by QCA.

Association of carotid intima-media thickness with angiographic severity and extent of coronary artery disease.

The present study examined the association between carotid intima-media thickness (IMT) and severity and extent of coronary artery disease (CAD). B-mode ultrasound and quantitative coronary angiography were used to assess carotid and coronary artery atherosclerosis in 108 patients with known or suspected CAD who had been referred for cardiac catheterization. Maximum and mean IMT values of carotid arteries were measured and expressed as mean aggregate values. To evaluate anatomic severity and extent of CAD, several quantitative coronary angiographically derived parameters were incorporated into indexes. These quantitative coronary angiographic measurements reflected CAD severity, extent, and overall "atheroma burden" and were calculated for the entire coronary tree and separately for different coronary segments (i.e., left main, proximal, mid, and distal segments). Maximum and mean IMT values were significantly correlated with CAD severity (p = 0.004 and 0.005, respectively), extent (p = 0.022 and 0.016, respectively), and atheroma burden (p = 0.008 for the 2 values). Further, carotid IMT was correlated with quantitative angiographic indexes for mid and distal segments but not with the proximal segments of coronary vessels. In conclusion, our study shows an association between carotid IMT and severity and extent of CAD as assessed by quantitative coronary angiography. Carotid IMT seems to be a weaker predictor of coronary atherosclerosis in the proximal parts of the coronary tree than in the mid and distal parts.