Charlotte Koopal

Vascular risk factors, vascular disease, lipids and lipid targets in patients with familial dysbetalipoproteinemia: A European cross- sectional study

BACKGROUND Familial dysbetalipoproteinemia (FD), also known as type III hyperlipoproteinemia, is a genetic dyslipidemia characterized by elevated very low density lipoprotein (VLDL) and chylomicron remnant particles that confers increased risk of cardiovascular disease (CVD). The objective of this study was to evaluate the prevalence of vascular risk factors, CVD, lipid values, treatment and lipid targets in patients with FD across Europe. METHODS This cross-sectional study was performed in 305 patients with FD from seven academic hospitals in four European countries. Information was collected from clinical records. RESULTS Patients mean (±standard deviation) age was 60.9±14.4 years, 201 (66%) were male, 69 (23%) had diabetes mellitus (DM) and 87 (29%) had a prior history of CVD. Mean body mass index was 28.5±5.0 kg/m2. Lipid-lowering medication was used by 227 (74%) patients (27% usual dose (theoretical low-density lipoprotein cholesterol (LDL-C) reduction≤40%) and 46% intensive dose (theoretical LDL-C reduction>40%)). Non high-density lipoprotein cholesterol (non-HDL-C) levels below treatment target (<3.3 mmol/L) were present in 123 (40%) patients and 163 patients (53%) had LDL-C levels below target (<2.5 mmol/L). No significant determinants were found for having non-HDL-C levels below target, while a prior history of CVD (OR 1.90, 95%CI 1.05-3.47) and presence of DM (OR 2.00, 95%CI 1.08-3.70) were associated with having LDL-C levels below treatment target. CONCLUSION The majority of FD patients had non-HDL-C levels above the treatment target of 3.3 mmol/L. Intensive dose lipid-lowering medication was used by only half of the patients, leaving them at increased cardiovascular risk.

Influence of APOE-2 genotype on the relation between adiposity and plasma lipid levels in patients with vascular disease

Background:Apolipoprotein E (APOE) genotypes are associated with different plasma lipid levels. People with the APO ɛ2 genotype can develop a disorder called dysbetalipoproteinemia (DBL). A possible predisposing factor for DBL is adiposity. We evaluated whether and to what extent the APOE genotype modifies the relation between adiposity and lipids in patients with manifest arterial disease and we looked at possible determinants of DBL in ɛ2 homo- and heterozygote patients.Methods:This prospective cohort study was performed in 5450 patients with manifest arterial disease from the Secondary Manifestations of ARTerial disease (SMART) study. The APOE genotype was measured in all patients and revealed 58 ɛ2 homozygotes, 663 ɛ2 heterozygotes, 3181 ɛ3 homozygotes and 1548 ɛ4 carriers. The main dependent variable was non-high-density lipoprotein cholesterol (non-HDL-c). The relation between adiposity (including body mass index (BMI), waist circumference (waist), visceral adipose tissue (VAT) and metabolic syndrome (MetS)) and lipids was evaluated with linear regression analyses. Determinants of DBL were evaluated using logistic regression.Results:There was significant effect modification by the APOE genotype on the relation between non-HDL-c and BMI, waist, VAT and MetS. There was an association between BMI and non-HDL-c in ɛ2 homozygotes (β 0.173, 95% confidence interval (CI) 0.031–0.314, P=0.018) and ɛ4 carriers (β 0.033, 95% CI 0.020–0.046, P<0.001). In all genotypes, there was an effect of waist, VAT and MetS on non-HDL-c, but these effects were most distinct in ɛ2 homozygotes (waist β 0.063, 95% CI 0.015–0.110, P=0.011; VAT β 0.580, 95% CI 0.270–0.889, P=0.001; MetS β 1.760, 95% CI 0.668–2.852, P=0.002). Determinants of DBL in ɛ2 homo- and heterozygotes were VAT and MetS.Conclusion:The APOE genotype modifies the relation between adiposity and plasma lipid levels in patients with vascular disease. The relation between adiposity and lipids is present in all patients, but it is most distinct in ɛ2 homozygote patients. Abdominal fat and MetS are determinants of DBL.

The relation between apolipoprotein E (APOE) genotype and peripheral artery disease in patients at high risk for cardiovascular disease

INTRODUCTION The apolipoprotein E gene (APOE) is associated with coronary heart disease and stroke, but the relation with peripheral artery disease (PAD) is unknown. We investigated the relation of APOE genotype with PAD and other types of vascular disease. METHODS The cross-sectional association between APOE genotype and ankle-brachial index (ABI) and vascular disease prevalence; and the prospective relation with incident PAD and other types of vascular disease (coronary artery disease, stroke and vascular mortality) were evaluated in 7418 patients from the Secondary Manifestations of ARTerial disease (SMART) study. This is a prospective cohort study in patients with cardiovascular disease or a cardiovascular risk factor. Analyses were adjusted for age and sex. RESULTS Mean age was 56.7 ± 12.4 years and 68% of the patients was male. APOE genotype frequencies were ε2ε2 1.3%; ε2ε3 9.9%; ε2ε4 2.4%; ε3ε3 56.9%; ε3ε4 26.7% and ε4ε4 2.8%. Median follow-up time was 8.1 years (IQR 5.4-11.4) in which 452 new PAD events occurred. The ε2ε2 genotype was significantly associated with a lower ABI (regression coefficient -0.04, 95%CI -0.07 to -0.01), increased PAD prevalence (prevalence ratio 1.54, 95%CI 1.01-2.17) and a higher risk of incident PAD (HR 2.31, 95%CI 1.29-4.12) compared with ε3ε3. No relations between APOE genotypes and other vascular disease were observed. CONCLUSION Of the six APOE genotypes, the ε2ε2 variant is associated with an increased risk for PAD in patients at high risk for cardiovascular disease. No association was observed between APOE genotype and coronary artery disease, stroke or vascular mortality in this population.

Association between CETP gene polymorphism, insulin resistance and risk of diabetes mellitus in patients with vascular disease

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.

Autosomal dominant familial dysbetalipoproteinemia: A pathophysiological framework and practical approach to diagnosis and therapy

Familial dysbetalipoproteinemia (FD) is a genetic disorder of lipoprotein metabolism associated with an increased risk for premature cardiovascular disease. In about 10% of the cases, FD is caused by autosomal dominant mutations in the apolipoprotein E gene (APOE). This review article provides a pathophysiological framework for autosomal dominant FD (ADFD) and discusses diagnostic challenges and therapeutic options. The clinical presentation and diagnostic work-up of ADFD are illustrated by two cases: a male with premature coronary artery disease and a p.K164Q mutation in APOE and a female with mixed hyperlipidemia and a p.R154H mutation in APOE. ADFD is characterized by a fasting and postprandial mixed hyperlipidemia due to increased remnants. Remnants are hepatically cleared by the low-density lipoprotein receptor and the heparan sulfate proteoglycan receptor (HSPG-R). Development of FD is associated with secondary factors like insulin resistance that lead to HSPG-R degradation through sulfatase 2 activation. Diagnostic challenges in ADFD are related to the clinical presentation; lipid phenotype; dominant inheritance pattern; genotyping; and possible misdiagnosis as familial hypercholesterolemia. FD patients respond well to lifestyle changes and to combination therapy with statins and fibrates. To conclude, diagnosing ADFD is important to adequately treat patients and their family members. In patients presenting with mixed hyperlipidemia, (autosomal dominant) FD should be considered as part of the diagnostic work up.

Effect of adding bezafibrate to standard lipid-lowering therapy on post-fat load lipid levels in patients with familial dysbetalipoproteinemia. A randomized placebo-controlled crossover trial

Familial dysbetalipoproteinemia (FD) is a genetic disorder associated with impaired postprandial lipid clearance. The effect of adding bezafibrate to standard lipid-lowering therapy on postprandial and fasting lipid levels in patients with FD is unknown. In this randomized placebo-controlled double-blind crossover trial, 15 patients with FD received bezafibrate and placebo for 6 weeks in randomized order in addition to standard lipid-lowering therapy (statin, ezetimibe, and/or lifestyle). We assessed post-fat load lipids, expressed as incremental area under the curve (iAUC) and area under the curve (AUC), as well as fasting levels and safety, and found that adding bezafibrate did not reduce post-fat load non-HDL-cholesterol (non-HDL-C) iAUC (1.78 ± 4.49 mmol·h/l vs. 1.03 ± 2.13 mmol·h/l, P = 0.57), but did reduce post-fat load triglyceride (TG) iAUC (8.05 ± 3.32 mmol·h/l vs. 10.61 ± 5.92 mmol·h/l, P = 0.03) and apoB (0.64 ± 0.62 g·h/l vs. 0.93 ± 0.71 g·h/l, P = 0.01). Furthermore, bezafibrate significantly improved AUC and fasting levels of non-HDL-C, TG, total cholesterol, HDL-C, and apoB. Bezafibrate was associated with lower estimated glomerular filtration rate (78.4 ± 11.4 ml/min/1.73 m2 vs. 86.1 ± 5.85 ml/min/1.73 m2, P = 0.002). In conclusion, in patients with FD, the addition of bezafibrate to standard lipid-lowering therapy resulted in improved post-fat load and fasting plasma lipids. Combination therapy of statin/fibrate could be considered as standard lipid-lowering treatment in FD.

Familial dysbetalipoproteinemia : an underdiagnosed lipid disorder

Purpose of review To review pathophysiological, epidemiological and clinical aspects of familial dysbetalipoproteinemia; a model disease for remnant metabolism and remnant-associated cardiovascular risk. Recent findings Familial dysbetalipoproteinemia is characterized by remnant accumulation caused by impaired remnant clearance, and premature cardiovascular disease. Most familial dysbetalipoproteinemia patients are homozygous for apolipoprotein &egr;2, which is associated with decreased binding of apolipoprotein E to the LDL receptor. Although familial dysbetalipoproteinemia is an autosomal recessive disease in most cases, 10% is caused by autosomal dominant mutations. Of people with an &egr;2&egr;2 genotype 15% develops familial dysbetalipoproteinemia, which is associated with secondary risk factors, such as obesity and insulin resistance, that inhibit remnant clearance by degradation of the heparan sulfate proteoglycan receptor. The prevalence of familial dysbetalipoproteinemia ranges from 0.12 to 0.40% depending on the definition used. Clinical characteristics of familial dysbetalipoproteinemia are xanthomas and mixed hyperlipidemia (high total cholesterol and triglycerides); the primary lipid treatment goal in familial dysbetalipoproteinemia is non-HDL-cholesterol; and treatment consists of dietary therapy and treatment with statin and fibrate combination. Summary Familial dysbetalipoproteinemia is a relatively common, though often not diagnosed, lipid disorder characterized by mixed hyperlipidemia, remnant accumulation and premature cardiovascular disease, which should be treated with dietary therapy and statin and fibrate combination.

Tendon xanthomas: Not always familial hypercholesterolemia.

Tendon xanthoma are most commonly associated with Familial Hypercholesterolemia, but the differential diagnosis includes sitosterolemia and cerebrotendinous xanthomatosis (CTX). The case presented here is of a 48-year old male with large tendon xanthomas attributable to CTX. CTX is a rare, recessive disorder caused by mutations in the CYP27A1 gene. The resultant defect in bile acid synthesis leads to cholestanol deposition in different tissues in the body, including tendons. CTX is associated with neurologic symptoms and a reduced life expectancy. Treatment consists of bile acid supplementation in combination with a statin. When patients present with tendon xanthomas and FH is ruled out, clinicians should consider CTX as a possible diagnosis.

Predicting the Effect of Fenofibrate on Cardiovascular Risk for Individual Patients With Type 2 Diabetes

OBJECTIVE In clinical trials, treatment with fenofibrate did not reduce the incidence of major cardiovascular events (MCVE) in patients with type 2 diabetes mellitus (T2DM). However, treatment effects reported by trials comprise patients who respond poorly and patients who respond well to fenofibrate. Our aim was to use statistical modeling to estimate the expected treatment effect of fenofibrate for individual patients with T2DM. RESEARCH DESIGN AND METHODS To estimate individual risk, the FIELD risk model, with 5-year MCVE as primary outcome, was externally validated in T2DM patients from ACCORD and the SMART observational cohort. Fenofibrate treatment effect was estimated in 17,142 T2DM patients from FIELD, ACCORD, and SMART. Individual treatment effect, expressed as absolute risk reduction (ARR), is the difference between treated and untreated MCVE risk. Results were stratified for patients with and without dyslipidemia (i.e., high triglycerides and low LDL cholesterol). RESULTS External validation of the FIELD risk model showed good calibration and moderate discrimination in ACCORD (C-statistic 0.67 [95% CI 0.65–0.69]) and SMART (C-statistic 0.66 [95% CI 0.63–0.69]). Median 5-year MCVE risk in all three studies combined was 6.7% (interquartile range [IQR] 4.0–11.7) in patients without (N = 13,224) and 9.4% (IQR 5.4–16.1%) in patients with (N = 3,918) dyslipidemia. The median ARR was 2.15% (IQR 1.23–3.68) in patients with dyslipidemia, corresponding with a number needed to treat (NNT) of 47, and 0.22% (IQR 0.13–0.38) in patients without dyslipidemia (NNT 455). CONCLUSIONS In individual patients with T2DM, there is a wide range of absolute treatment effect of fenofibrate, and overall the fenofibrate treatment effect was larger in patients with dyslipidemia. The method of individualized treatment effect prediction of fenofibrate on MCVE risk reduction in T2DM can be used to guide clinical decision making.