Combined Hyperlipidemia Research Articles

The genetic architecture of the familial hyperlipidaemia syndromes: rare mutations and common variants in multiple genes.

Genome-Wide Association Studies have provided robust identification of approximately 100 genetic loci determining plasma lipid parameters. Using these multiple common genetic lipid-determining variants in a 'gene score' has thrown new light on the mode of inheritance of familial lipid disorders. Different hypertriglyceridaemia states have been explained by the polygenic coinheritance of triglyceride-raising alleles. Taking this gene score approach with 12 LDL-cholesterol-raising alleles, we reported that for patients with a clinical diagnosis of familial hypercholesterolaemia, but no identified rare mutation in the familial hypercholesterolaemia-causing genes, LDL receptor, apolipoprotein B and PCSK9, the most likely explanation for their elevated LDL-C levels was a polygenic, not a monogenic, cause of the disease. These findings have wider implications for understanding complex disorders, and may very well explain the genetic basis of familial combined hyperlipidaemia, another familial lipid disorder in which the genetic cause(s) has remained elusive.

Hiperlipidemia familiar combinada: documento de consenso

Familial combined hyperlipidemia (FCH) is a frequent disorder associated with premature coronary artery disease. It is transmitted in an autosomal dominant manner, although there is not a unique gene involved. The diagnosis is performed using clinical criteria, and variability in lipid phenotype and family history of hyperlipidemia are necessaries.Frequently, the disorder is associated with type2 diabetes mellitus, arterial hypertension and central obesity. Patients with FCH are considered as high cardiovascular risk and the lipid target is an LDL-cholesterol <100mg/dL, and <70mg/dL if cardiovascular disease or type 2 diabetes are present. Patients with FCH require lipid lowering treatment using potent statins and sometimes, combined lipid-lowering treatment. Identification and management of other cardiovascular risk factors as type 2 diabetes and hypertension are fundamental to reduce cardiovascular disease burden. This document gives recommendations for the diagnosis and global treatment of patients with FCH directed to specialists and general practitioners.

Diabetogenic effects of high intensity statin treatment in heterozygous familial hypercholesterolemia and familial combined hyperlipidemia

Objectives: Many studies over the last years bring up concerns regarding diabetogenic effects of statins. Aim of our study was to assess the potential diabetogenicity of high intensity statin treatment in heterozygous Familial Hypercholesterolemia (hFH) and Familial Combined Hyperlipidemia (FCH) populations.

Impaired glucose metabolism and insulin resistance in patients with familial combined hyperlipidemia

Impaired glucose metabolism and insulin resistance in patients with familial combined hyperlipidemia

SdLDL/LDL ratio in familial combined hyperlipidaemia patients and familial hypercholesterolemia patients

Project grants Science and Technology Foundation [PIC/IC/83333/2007] and Strategic Project Grant [PEst-OE/BIA/UI4046/2011].

Common variants contribute to hypertriglyceridemia without differences between familial combined hyperlipidemia and isolated hypertriglyceridemia

Common variants contribute to hypertriglyceridemia without differences between familial combined hyperlipidemia and isolated hypertriglyceridemia

Impaired incretin secretion in patients with familial combined hyperlipidemia

Impaired incretin secretion in patients with familial combined hyperlipidemia

Weight loss effect on serum lipids and cholesterol metabolism in overweight and obese subjects with genetic hypercholesterolemia

Objectives: o explore the effect of weight loss on lipid profile and cholesterol metabolism, by measuring circulating non-cholesterol sterols, in overweight subjects with familial hypercholesterolemia (FH) and familial combined hyperlipidemia (FCHL).

Cholesteryl ester storage disease: a predominant lipa genotype underlies disease manifestations and progression - A review of 12 french cases.

Objectives: Cholesteryl ester storage disease (CESD) is a rare autosomal recessive disease, due to deficiency of lysosomal acid lipase (LAL) resulting in lysosomal cholesteryl ester and triglyceride accumulation, in liver and macrophages throughout the body. CESD generally manifests with hepatomegaly and liver cytolysis, associated with combined hyperlipidemia.

Comparison of the Lipid-Lowering Effects of Pitavastatin 4 mg Versus Pravastatin 40 mg in Adults With Primary Hyperlipidemia or Mixed (Combined) Dyslipidemia: A Phase IV, Prospective, US, Multicenter, Randomized, Double-blind, Superiority Trial

PurposeResults from a Phase III, European, noninferiority trial in elderly (age ≥65 years) patients with primary hyperlipidemia or mixed (combined) dyslipidemia demonstrated significantly greater reductions in LDL-C for pitavastatin versus pravastatin across 3 pair-wise dose comparisons (1 mg vs 10 mg, 2 mg vs 20 mg, and 4 mg vs 40 mg, respectively). The present study investigated whether pitavastatin 4 mg is superior to pravastatin 40 mg in LDL-C reduction in adults (18–80 years old) with primary hyperlipidemia or mixed (combined) dyslipidemia. MethodsThis was a Phase IV, multicenter, randomized, double-blind, double-dummy, active-control superiority study conducted in the United States. Patients with baseline LDL-C levels of 130 to 220 mg/dL (inclusive) and triglyceride levels ≤400 mg/dL after a 6-week washout/dietary stabilization period were randomized to 12 weeks of once-daily treatment with either pitavastatin 4 mg or pravastatin 40 mg. FindingsA total of 328 subjects (164 per treatment arm) were randomized (mean age, 57.9 years [76% were aged <65 years]; 49.4% women; mean body mass index, 30.2 kg/m2) to treatment. The median percent change in LDL-C from baseline to the week 12 endpoint was –38.1% for pitavastatin 4 mg and –26.4% for pravastatin 40 mg; the difference in median percent change between treatments was –12.5% (P < 0.001). Differences between treatments in median percent reductions from baseline for apolipoprotein B, total cholesterol, and non–HDL-C were also significant in favor of pitavastatin (P < 0.001). Both treatments significantly (P < 0.001) increased HDL-C and decreased triglycerides, but the differences between treatments were not statistically significant. The overall rate of treatment-emergent adverse events was 47.6% (78 of 164) for pitavastatin and 44.5% (73 of 164) for pravastatin. Myalgia was reported by 3 patients (1.8%) in the pitavastatin group and by 4 patients (2.4%) in the pravastatin group. There were no reports of myositis or rhabdomyolysis. ImplicationsPitavastatin 4 mg demonstrated superior LDL-C reductions compared with pravastatin 40 mg after 12 weeks of therapy in adults with primary hyperlipidemia or mixed (combined) dyslipidemia. There were no new safety findings in the trial. Clinical Trials.gov identifier: NCT01256476.

Combinación fija pravastatina/fenofibrato: ¿qué puede aportar?

The treatment of patients with high cardiovascular risk and mixed hyperlipidemia is difficult due to multiple quantitative and qualitative lipid abnormalities. The priority is to reduce LDL-c levels, for which statins are the drug of choice. Despite the benefits of statins, the residual cardiovascular risk is very high in patients with atherogenic dyslipidemia. To reduce this risk, we also need to control non-HDL cholesterol levels, perdecreasing triglyceride levels and increasing HDL-c levels. To achieve these objectives and lifestyle changes, the use of combined therapy is often required. Fibrates are drugs that can be used in combination with statins to reduce this residual risk. Fenofibrate is well tolerated in combination with statins. The fixed combination of pravastatin/ fenofibrate has been shown to have complementary benefits in the atherogenic lipid profile in general. The combination is well tolerated and is indicated in patients with high risk and mixed hyperlipidemia who have controlled or are close to their objectives for LDL-c levels, using 40-mg pravastatin in monotherapy. The beneficial eff ect of the combination on LDL-c levels is minimal and is primarily observed in non-HDL cholesterol, triglycerides and HDL-c. The combination of pravastatin 40 and fenofibrate 160 can provide a considerable clinical benefit to patients with high risk and mixed atherogenic dyslipidemia, to patients with LDL-c levels that are controlled or near the objectives for decreasing their residual risk of lipid origin and is especially useful for patients with type 2 diabetes, obesity and combined metabolic syndrome and familial hyperlipidemia.

Indicaciones de la combinación de pravastatina más fenofibrato según el tipo de dislipemia

The combination with fixed doses of pravastatin (40mg) and fenofibrate (160mg) off ers a therapeutic alternative, especially in the comprehensive approach to mixed hyperlipidemia in patients with high cardiovascular risk of metabolic origin. It also ensures the efficacy and safety as a result of the evidence that supports the clinical benefit of both pravastatin in primary and secondary prevention and fenofibrate in patients with atherogenic dyslipidemia. This combination also has few adverse effects, which are similar in all cases to those produced by the isolated monotherapy of each of the drugs.Consequently, the possible indications for this combination include patients with mixed hyperlipidemia, patients with atherogenic dyslipidemia (increased triglyceride levels, reduced HDL-c levels and moderately increased LDL-c levels), patients with hypertriglyceridemia who need to reduce their LDL-c levels, patients with low HDL syndrome who also require a reduction in LDL-c levels, patients with moderate hypercholesterolemia who require an additional reduction of triglyceride levels and especially patients with high atherogenic metabolic risk who require an overall intervention for each of the lipid fractions.

Long-term intake of soyabean phytosterols lowers serum TAG and NEFA concentrations, increases bile acid synthesis and protects against fatty liver development in dyslipidaemic hamsters.

Various human trials and pre-clinical studies have suggested that dietary plant sterols possess hypotriacylglycerolaemic properties apart from their cholesterol-lowering properties. We hypothesised that phytosterols (PS) might attenuate triacylglycerolaemia by interfering with the deleterious effects of cholesterol overload in the liver. In the present study, twenty hamsters (Mesocricetus auratus) with diet-induced combined hyperlipidaemia were fed a high-fat diet (HFD, n 10) or a HFD supplemented with soyabean PS (n 10) for 40 d. In parallel, a healthy group was fed a standard diet (n 10). PS normalised fasting plasma cholesterol concentrations completely after 20 d and were also able to normalise serum TAG and NEFA concentrations after 40 d. HFD feeding caused microvesicular steatosis and impaired the expression of key genes related to fatty acid oxidation such as PPARA, carnitine palmitoyltransferase-Iα (CPT1A) and phosphoenolpyruvate carboxykinase 1 (PCK1) in the liver. PS treatment completely protected against HFD-induced steatosis and resulted in a normalised hepatic gene expression profile. The protection of the hepatic function by PS was paralleled by increased faecal cholesterol excretion along with a 2-fold increase in the biliary bile acid (BA):cholesterol ratio. The present study supports the conclusion that long-term consumption of PS can reduce serum TAG and NEFA concentrations and can protect against the development of fatty liver via different mechanisms, including the enhancement of BA synthesis. The results of the present study place these compounds as promising hepatoprotective agents against fatty liver and its derived pathologies.

Atherosclerosis progression in patients with autosomal dominant hypercholesterolemia in clinical practice

Autosomal dominant hypercholesterolemias (ADH) are associated with high risk of premature cardiovascular disease (CVD). No data on progression of atherosclerosis in ADH population in clinical practice are available. To investigate atherosclerosis progression in ADH patients and its relationship with CVD risk factors. A total of 463 patients, 279 with familial hypercholesterolemia and 184 with familial combined hyperlipidemia, were prospectively followed during a median of 36.5 months. Carotid intima-media thickness (cIMT) was assessed at baseline and at the end of the follow-up by ultrasonography. A total of 259 patients (55.9%) showed cIMT progression and 149 (32.2%) remained within normal age-adjusted cIMT. Baseline cIMT was the variable most inversely associated with cIMT progression (B = -0.313; P < .001). Hypertension, diabetes, and smoking during follow-up were variables positively associated with progression. Patients who began statin treatment during the study period had less progression than former statin users. The 83.7% of ADH with normal baseline cIMT, absence of major CVD risk factors and non-high-density lipoprotein (HDL) cholesterol <190 mg/dL at follow-up remained with normal cIMT at the end of the study. Non-HDL cholesterol concentration reached during the follow-up was associated with cIMT only in subjects with abnormal cIMT at baseline. In this subgroup, cIMT tended to avoid progression with non-HDL cholesterol <130 mg/dL. Atherosclerosis progression varies greatly among ADH patients. cIMT progression was inversely related to baseline cIMT and previous use of statins, and positively with age and CVD risk factors during the follow-up. Patients previously treated with statins may not be the preferred candidates for atherosclerosis regression trials. Treatment recommendations in ADH should be based on baseline risk.

Serum plant sterols as surrogate markers of dietary compliance in familial dyslipidemias

A well-balanced diet is the first-line treatment in hyperlipidemia. The objective was to study the association between serum phytosterols and dietary patterns to use them as surrogate markers of dietary compliance in primary dyslipidemias. 288 patients with primary hyperlipidemias (192 autosomal dominant hypercholesterolemia (ADH) and 96 familial combined hyperlipidemia (FCHL)) were included. Principal factor analysis identified 2 major dietary patterns using a 137-item food frequency questionnaire. "Vegetable & Fruits pattern" was characterized by higher intake of fruits, green beans, nuts, tomatoes, roasted or boiled potatoes, lettuce and chard and lower of processed baked goods, pizza and beer. "Western pattern" was positively characterized by hamburgers, pasta, sunflower oil, rice, chickpeas, whole milk, veal, red beans and negatively with white fish. Serum non-cholesterol sterols were determined by HPLC-MS/MS. Plant sterols to-total cholesterol (TC) levels were lower with a higher adherence to a "Vegetable & Fruits pattern" (P = 0.009), mainly in ADH subjects (R(2) = 0.019). Their concentration was greater with higher compliance to "Western pattern" especially in FCHL (P = 0.014). Higher levels of synthesis markers-to-TC with a greater adherence to "Vegetable & Fruits pattern" were found (P = 0.001) (R(2) = 0.033 and R(2) = 0.109 in ADH and FCHL respectively). In subjects with primary dislipidemia, dietary patterns associate with serum absorption and synthesis markers, but no with lipid concentrations. The influence of diet on non-cholesterol sterols levels is not powerful enough to use them as subrogate markers.

Control del colesterol-LDL en pacientes con dislipidemias genéticas seguidos en unidades de lípidos y riesgo vascular de la Sociedad Española de Arteriosclerosis

ObjectiveTo evaluate low-density lipoprotein-cholesterol (LDLc) achieved in patients with genetic dyslipidemia treated during one year in Lipid and Vascular Risk Units (LVRU) of the Spanish Society of Arteriosclerosis (SSA). DesignObservational, longitudinal, retrospective, multicenter national study that included consecutive patients of both sexes over 18 years of age referred due to dyslipidemia to LVRU of the SSA. Information was collected from medical records corresponding to two visits in the lipid unit. ResultsA total of 527 patients (mean age 48 years, 60.0% men) diagnosed with genetic dyslipidemia (241 with heterozygous familial hypercholesterolemia, and 286 with familial combined hyperlipidemia) were included. The mean follow-up was 12.9 months. In the last visit, 94% were taking statins, one third combined with ezetimibe, although only 41% were taking a high-intensity hypolipidemic treatment. Overall, 28.5% of patients attained an LDLc level<100mg/dL, 35.8% decreased their LDLc by >50%, and 53.8% achieved one of the two. Predictors of target LDLc levels in the multivariate analysis were age, smoking habit and the presence of vascular disease. ConclusionOver half of the patients with genetic dyslipidemia followed up by LVRU of SSA achieve LDLc objectives after one year of follow-up. The use of high-intensity hypolipidemic treatment could improve these results.

Familial combined hyperlipidemia: from molecular insights to tailored therapy.

This review presents recent basic and clinical developments in familial combined hyperlipidemia (FCHL). A variety of experiments have contributed to the elucidation of this complex disease. They consist of dynamic and gene expression studies in adipocytes, confirming the role of dysfunctional adipose tissue in the pathogenesis of FCHL and identifying potential new pathways, such as complement activation. Whole exome sequencing and classical linkage studies in FCHL pedigrees, some conducted with new traits (e.g. plasma proprotein convertase subtilisin/kexin type 9 [PCSK9] and phospholipid transfer protein activity), have revealed new genes of interest, among which SLC25A40 and LASS4. Finally, gene expression studies in liver biopsies and liver cell culture experiments have gained further insight in the role of upstream stimulatory factor 1, one of the most replicated genes in FCHL, in its pathogenesis.On the basis of these observations and recent phase II clinical trials, PCSK9 antagonizing is the most promising lipid-lowering therapy to be added to our current arsenal of statins and fibrates in FCHL treatment. Ongoing basic research provides a steady growth in our knowledge on the genes that are involved in FCHL as well as their metabolic function(s). This field of research may be enhanced when data are expanded and integrated for systems biology approaches. Our growing insights in the cause of FCHL allow for better, targeted treatment of dyslipidemia and prevention of cardiovascular complications.

Abstract 396: High Doses of a Novel Niacin Analog Are Devoid of Clinically Relevant Adverse Events in Safety Trials in Healthy Volunteers

Introduction: High doses of niacin has beneficial effects on lipids and coronary outcomes. However, the use is limited due to side effects at higher doses, as shown by trials such as HPS2 THRIVE, including flushing, myopathy and increases in blood glucose. These dose limitations blunt the lipid responses and potential therapeutic effects of niacin in reducing coronary risk. ARI-3037MO is an orally active, novel niacin analog that induces beneficial changes in Low Density Lipoproteins (LDL), Triglycerides (TG) and in High Density Lipoproteins (HDL) in preclinical studies without evidence of flushing, liver toxicity or changes in blood glucose. Additionally, in a single ascending dose clinical trial in healthy volunteers, ARI-3037MO did not provoke flushing and produced significant changes in TGs and HDL at the highest dose. Methods: We evaluated the effect of repeat dosing high doses of ARI-3037MO on safety parameters in two separate studies in healthy volunteers. In the first placebo controlled trial, daily doses of 2g and 3.5g of ARI-3037MO were administered for 14 days to 9 subjects per group with 8 subjects receiving placebo. The 2g cohort was extended to 28 days of dosing. In the second trial, 7 subjects received 3g BID (total daily dose of 6g) administered for 24 days with 6 subjects receiving placebo. Results: In both studies, ARI-3037MO was well tolerated with no flushing or skin changes, no abnormalities in liver function tests or changes in blood glucose. There was also no effect on oral glucose tolerance test after 24 days of dosing with 3g BID. There was a trend toward lipid reduction in both of the studies, with the 3g BID dose showing a reduction of -19% in TGs, -7.4% in LDL-C, and a significant reduction of -8.7% in Apo B (p&lt;0.05). Similarly, the 3g BID dose significantly increased HDL-C by 7.0% (p&lt;0.05). In both studies, the effect of ARI-3037MO on lipids improved with the duration of dosing. Conclusion: The lack of niacin like adverse effects with very high doses of ARI-3037MO indicates that ARI-3037MO has a wide therapeutic index. This safety and tolerability profile with encouraging lipid effects suggest that ARI-3037MO represents a promising therapy for management of mixed hyperlipidemia, especially in the setting of metabolic syndromes and type II diabetes.

The use of the non-fasting lipid profile for lipid-lowering therapy in clinical practice – Point of view

Current guidelines for the management of dyslipidaemias recommend measuring lipid profiles in the fasting state. The primary lipid targets are traditionally plasma total cholesterol and low-density lipoprotein-cholesterol (LDL-C) levels. However, triglycerides, apolipoprotein (apo) B and non-high-density lipoprotein-cholesterol (non-HDL-C) are also suitable parameters to assess cardiovascular risk and to guide lipid-lowering therapy. The advantage of the use of these variables is that they can be used in both the fasting and non-fasting state. In most cases, postprandial lipid profiles in combination with apo B are as useful as fasting lipid profiles for the differentiation between familial lipid disorders, such as heterozygous familial hypercholesterolemia, familial combined hyperlipidemia and familial hypertriglyceridemia. This article will address the interpretation, applications and limitations of a non-fasting lipid profile for daily clinical practice.

A novel missense SMPD1 gene mutation, T460P, and clinical findings in a patient with Niemann–Pick disease type B presenting to a lipid disorders clinic

Niemann-Pick disease, type B (NPD-B; OMIM 607616) is an inborn error of metabolism where reduced concentrations of the enzyme acid sphingomyelinase (ASM; EC 3.1.4.12) lead to multisystem disease though with survival into adulthood. The natural history of NPD-B is one of progressive hypersplenism and gradual deterioration of pulmonary function. We describe a 46-year-old South African man of French Huguenot descent who presented to a lipid disorders clinic with mixed hyperlipidaemia. Clinical examination and imaging findings revealed the presence of massive hepatosplenomegaly, interstitial lung disease and subclinical atherosclerosis; there were no neurological or cognitive abnormalities. Laboratory testing showed thrombocytopaenia, increased liver transaminases and mild hyperbilirubinaemia. Lysosomal enzyme analysis showed markedly reduced ASM activity, suggestive of NPD. DNA sequence analysis of the SMPD1 gene revealed that he was a compound heterozygote for the previously reported c.1829_1831delGCC (ΔR608) mutation and a novel missense mutation c.1378A > C (p.T460P). In conclusion, we describe the clinical findings of a case of NPD-B with mixed hyperlipidaemia, compound heterozygous for the SMPD1 ΔR608 mutation and a novel mutation, T460P.