Clearance of triglyceride-rich lipoproteins (TRLs) is mediated by several receptors, including heparan sulfate proteoglycans (HSPGs). Sulfate glucosamine-6-O-endosulfatase-2 is a gene related to the ...regulation of HSPG. A variant in this gene, rs2281279, has been shown to be associated with triglycerides and insulin resistance.
To determine the relationship between rs2281279, metabolic parameters and vascular events, and type 2 diabetes mellitus (T2DM) in patients at high cardiovascular risk and whether
genotype modifies this relationship.
Patients (
= 4386) at high cardiovascular risk from the Utrecht Cardiovascular Cohort-Second Manifestations of Arterial Disease study were stratified according to their imputed rs2281279 genotype: AA (
= 2438), AG (
= 1642) and GG (
= 306). Effects of rs2281279 on metabolic parameters, vascular events and T2DM were analyzed with linear regression and Cox models.
There was no relationship between imputed rs2281279 genotype and triglycerides, non-high-density lipoprotein (HDL)-cholesterol, insulin and quantitative insulin sensitivity check index. During a median follow-up of 11.8 (IQR, 9.3-15.5) years, 1026 cardiovascular events and 320 limb events occurred. The presence of the G allele in rs2281279 did not affect the risk of vascular events hazard ratio (HR), 1.03; 95% confidence interval (CI), 0.94-1.14 or limb events (HR, 0.92; 95% CI, 0.77-1.10). The presence of the G allele in rs2281279 did not affect the risk of T2DM (HR, 1.09; 95% CI, 0.94-1.27). The presence of the minor G allele of rs2281279 was associated with a beneficial risk profile in ε2ε2 patients, but not in ε3ε3 patients.
Imputed rs2281279 genotype is not associated with metabolic parameters and does not increase the risk of vascular events or T2DM in patients at high risk for cardiovascular disease.
PCSK9 monoclonal antibodies (mAbs) reduce fasting and post fat load cholesterol in non-HDL and IDL in familial dysbetalipoproteinemia (FD). However, the effect of PCSK9 mAbs on the distribution and ...composition of atherogenic lipoproteins in patients with FD is unknown.
To evaluate the effect of the PCSK9 mAb evolocumab added to standard lipid-lowering therapy in patients with FD on fasting and post fat load lipoprotein distribution and composition.
Randomized placebo-controlled double-blind crossover trial comparing evolocumab (140 mg subcutaneous every 2 weeks) with placebo during two 12-week treatment periods. Patients received an oral fat load at the start and end of each treatment period. (Apo)lipoproteins were measured with ultracentrifugation, gradient gel electrophoresis, retinyl palmitate and SDS-PAGE.
PCSK9 mAbs significantly reduced particle number of all atherogenic lipoproteins, with a stronger effect on smaller lipoproteins than on larger lipoproteins (e.g. IDL-apoB 49%, 95%CI 41-59 and VLDL-apoB 33%, 95%CI 16-50). Furthermore, PCSK9 mAbs lowered cholesterol more than TG in VLDL, IDL and LDL (e.g. VLDL-C 48%, 95%CI 29-63%; and VLDL-TG 20%, 95%CI 6.3-41%). PCSK9 mAbs did not affect the post fat load response of chylomicrons.
PCSK9 mAbs added to standard lipid-lowering therapy in FD patients significantly reduced lipoprotein particle number, in particular the smaller and more cholesterol-rich lipoproteins (i.e. IDL and LDL). PCSK9 mAbs did not affect chylomicron metabolism. It seems likely that the observed effects are achieved by increased hepatic lipoprotein clearance, but the specific working mechanism of PCSK9 mAbs in FD patients remains to be elucidated.
Chylomicronaemia accompanies hypertriglyceridaemia, usually due to a polygenic predisposition in combination with secondary risk factors. Monogenic chylomicronaemia represents a small subgroup of ...patients with hypertriglyceridaemia. This article describes three patients and illustrates the heterogeneity in the presentation of monogenic chylomicronaemia. The first case is a man with mild hypertriglyceridaemia who is a compound heterozygote for two variants in the LMF1 gene, without relevant medical history. The second case is a woman who is a double heterozygote of variants in the LPL and APOA5 genes. She experienced pancreatitis. The third case is a man, with recurrent pancreatitis attributed to severe hypertriglyceridaemia and homozygous for a variant in the APOC2 gene. This article highlights that in patients with hypertriglyceridaemia, the absence of pancreatitis or the presence of mild hypertriglyceridaemia does not exclude monogenic chylomicronaemia. Genetic screening should be considered in patients with unexplained or severe hypertriglyceridaemia, to determine appropriate treatment and follow-up.
•In familial dysbetalipoproteinemia (FD), evolocumab reduced non-HDL-C by 49%.•Non-HDL-C treatment goals were achieved by 89% of patients using evolocumab.•Evolocumab likely results in CVD reduction ...in FD.
Familial dysbetalipoproteinemia (FD) is the second most common monogenic lipid disorder (prevalence 1 in 850-3500), characterized by postprandial remnant accumulation and associated with increased cardiovascular disease (CVD) risk. Many FD patients do not achieve non-HDL-C treatment goals, indicating the need for additional lipid-lowering treatment options.
To evaluate the effect of the PCSK9 monoclonal antibody evolocumab added to standard lipid-lowering therapy on fasting and post fat load lipids and lipoproteins in patients with FD.
A randomized placebo-controlled double-blind crossover trial comparing evolocumab (140 mg subcutaneous every 2 weeks) with placebo during two 12-week treatment periods. At the start and end of each treatment period patients received an oral fat load. The primary endpoint was the 8-hour post fat load non-HDL-C area under the curve (AUC). Secondary endpoints included fasting and post fat load lipids and lipoproteins.
In total, 28 patients completed the study. Mean age was 62±9 years and 93% had an Ɛ2Ɛ2 genotype. Evolocumab reduced the 8-hour post fat load non-HDL-C AUC with 49% (95%CI 42-55) and apolipoprotein B (apoB) AUC with 47% (95%CI 41-53). Other fasting and absolute post fat load lipids and lipoproteins including triglycerides and remnant-cholesterol were also significantly reduced by evolocumab. However, evolocumab did not have significant effects on the rise above fasting levels that occurred after consumption of the oral fat load.
Evolocumab added to standard lipid-lowering therapy significantly reduced fasting and absolute post fat load concentrations of non-HDL-C, apoB and other atherogenic lipids and lipoproteins in FD patients. The clinically significant decrease in lipids and lipoproteins can be expected to translate into a reduction in CVD risk in these high-risk patients.
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A 44-year-old woman was admitted with pancreatitis caused by hypertriglyceridaemia (fasting triglycerides 28 mmol/L). She used oral contraceptives and ezetimibe 10 mg. She was overweight (body mass ...index 29.7 kg/m2). Diabetes mellitus was ruled out, as were nephrotic syndrome, alcohol abuse, hypothyroidism and dysbetalipoproteinaemia. Genetic analysis revealed mutations in two genes involved in triglyceride metabolism (apolipoprotein A5 and lipoprotein lipase LPL). The LPL activity was 45% compared with pooled healthy controls. The post-heparin triglyceride reduction was 6%, compared with a normal reduction of >20%. The patient was initially treated with gemfibrozil, but this was discontinued due to side effects. Dietary triglyceride restriction and discontinuation of the oral contraceptives lowered the plasma triglycerides within 2 weeks to 3.4 mmol/L. Hypertriglyceridaemia is a risk factor for pancreatitis and cardiovascular disease, and has a broad differential diagnosis including genetic causes. Patients can achieve near-normal triglyceride values with a low-fat diet only.
Abstract Introduction Genetic inhibition of Cholesteryl Ester Transfer Protein (CETP) might be associated with insulin resistance and incident type 2 diabetes mellitus (T2DM). This study investigated ...the relation between a genetic variant in the CETP gene and measures of insulin resistance and incident T2DM in patients with manifest cardiovascular disease (CVD). Furthermore the effect on risk of recurrent cardiovascular events was investigated. Methods SMART is a prospective cohort study performed in 5601 patients with clinically manifest CVD. We selected a variant (rs3764261) associated with reduced CETP activity and increased levels of HDL cholesterol (HDL-C). Patients were divided in three groups: 2640 wild type patients (GG), 2420 heterozygotes for rs3764261 (GT) and 541 homozygotes for rs3764261 (TT). Regression analyses were performed using an additive model. Results The study population consisted of 4656 patients without T2DM and 945 patients with T2DM at baseline. Presence of rs3764261 was associated with increased HDL-C in patients without T2DM (β 0.106, 95%CI 0.083–0.128) and with T2DM (β 0.043, 95%CI 0.007–0.078). During a median follow up of 7.2 years (IQR 4.7–10.2) 427 incident T2DM occurred. Presence of rs3764261 was not related to incident T2DM (HR 0.96, 95%CI 0.83–1.11) in patients without T2DM at baseline. Furthermore, presence of rs3764261 was not related to insulin resistance (glucose, insulin, HOMA-IR, HbA1c) or recurrent CVD (HR 0.92, 95%CI 0.84–1.02). Conclusion Presence of CETP SNP rs3764261 is not associated with insulin resistance and incident T2DM in patients with clinically manifest vascular disease. Furthermore, no effect of rs3764261 on the risk of recurrent CVD was observed.
To estimate the relation between physical exercise volume, type, and intensity with all-cause mortality and recurrent vascular events in patients with cardiovascular disease (CVD) and to quantify to ...what extent traditional cardiovascular risk factors mediate these relations.
In the prospective UCC-SMART cohort (
= 8660), the associations of clinical endpoints and physical exercise volume (metabolic equivalent of task hours per week, METh/wk), type (endurance vs. endurance + resistance), and intensity (moderate vs. vigorous) were estimated using multivariable-adjusted Cox models. The proportion mediated effect (PME) through body mass index, systolic blood pressure, low-density lipoprotein cholesterol, insulin sensitivity, and systemic inflammation was assessed using structural equation models. Sixty-one percent of patients (73% male, age 61 ± 10 years, >70% receiving lipid-lowering and blood pressure-lowering medications) reported that they did not exercise. Over a median follow-up of 9.5 years interquartile range (IQR) 5.1-14.0, 2256 deaths and 1828 recurrent vascular events occurred. The association between exercise volume had a reverse J-shape with a nadir at 29 (95% CI 24-29) METh/wk, corresponding with a HR 0.56 (95% CI 0.48-0.64) for all-cause mortality and HR 0.63 (95% CI 0.55-0.73) for recurrent vascular events compared with no exercise. Up to 38% (95% CI 24-61) of the association was mediated through the assessed risk factors of which insulin sensitivity (PME up to 12%, 95% CI 5-25) and systemic inflammation (PME up to 18%, 95% CI 9-37) were the most important.
Regular physical exercise is significantly related with reduced risks of all-cause mortality and recurrent vascular events in patients with CVD. In this population with high rates of lipid-lowering and blood pressure--lowering medication use, exercise benefits were mainly mediated through systemic inflammation and insulin resistance.
Abnormalities in the lipid profile are common, but it is often not easy to determine their cause. After exclusion of secondary causes, a primary (genetic) cause of dyslipidaemia should be considered. ...The most common monogenic dyslipidaemia is familial hypercholesterolemia (FH), but there are other clinically relevant genetic dyslipidaemias, including familial dysbetalipoproteinaemia (FD), monogenic chylomicronaemia and hypoalphalipoproteinemia. It is important to make a genetic diagnosis because it may influence the prognosis of the patient, for determining appropriate treatment goals and because it is relevant for family members. This clinical viewpoint explains the diagnostic process of genetic dyslipidaemias using two cases.
•In FD, PCSK9 mAbs in particular reduce smaller and cholesterol-rich lipoproteins.•PCSK9 mAbs do not affect CM metabolism.•PCSK9 mAbs probably achieve their effects by increased hepatic clearance.
...PCSK9 monoclonal antibodies (mAbs) reduce fasting and post fat load cholesterol in non-HDL and IDL in familial dysbetalipoproteinemia (FD). However, the effect of PCSK9 mAbs on the distribution and composition of atherogenic lipoproteins in patients with FD is unknown.
To evaluate the effect of the PCSK9 mAb evolocumab added to standard lipid-lowering therapy in patients with FD on fasting and post fat load lipoprotein distribution and composition.
Randomized placebo-controlled double-blind crossover trial comparing evolocumab (140 mg subcutaneous every 2 weeks) with placebo during two 12-week treatment periods. Patients received an oral fat load at the start and end of each treatment period. (Apo)lipoproteins were measured with ultracentrifugation, gradient gel electrophoresis, retinyl palmitate and SDS-PAGE.
PCSK9 mAbs significantly reduced particle number of all atherogenic lipoproteins, with a stronger effect on smaller lipoproteins than on larger lipoproteins (e.g. IDL-apoB 49%, 95%CI 41–59 and VLDL-apoB 33%, 95%CI 16-50). Furthermore, PCSK9 mAbs lowered cholesterol more than TG in VLDL, IDL and LDL (e.g. VLDL-C 48%, 95%CI 29–63%; and VLDL-TG 20%, 95%CI 6.3–41%). PCSK9 mAbs did not affect the post fat load response of chylomicrons.
PCSK9 mAbs added to standard lipid-lowering therapy in FD patients significantly reduced lipoprotein particle number, in particular the smaller and more cholesterol-rich lipoproteins (i.e. IDL and LDL). PCSK9 mAbs did not affect chylomicron metabolism. It seems likely that the observed effects are achieved by increased hepatic lipoprotein clearance, but the specific working mechanism of PCSK9 mAbs in FD patients remains to be elucidated.
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