The hypolipidemic effects of lovastatin and clofibrate alone and in combination in patients with type III hyperlipoproteinemia

doi:10.1016/0026-0495(90)90256-C

Metabolism

Volume 39, Issue 4, April 1990, Pages 403-409

https://doi.org/10.1016/0026-0495(90)90256-C Get rights and content

Abstract

The hypolipidemic effects of lovastatin and clofibrate have been evaluated in 12 patients with type III hyperlipoproteinemia. In these patients plasma concentrations of total cholesterol decreased from 500 ± 56 mg/dL (mean ± SEM) at baseline to 278 ± 23 mg/dL on lovastatin (20 mg twice daily), and were 299 ± 15 mg/dL during treatment with clofibrate (1 g twice daily). Nine patients were treated sequentillly with lovastatin at doses of 20 and 40 mg twice daily and clofibrate; in these patients total plasma cholesterol concentrations decreased from 549 ± 67 mg/dL at baseline to 291 ± 24 mg/dL on lovastatin (20 mg twice daily), 247 ± 20 mg/dL (40 mg twice daily) and were 297 ± 18 mg/dL on monotherapy with clofibrate. Concentrations of very-low-density lipoprotein (VLDL) cholesterol were similar on clofibrate and the higher dose of lovastatin, whereas concentrations of low-density lipoprotein (LDL) cholesterol were significantly lower on lovastatin. In six patients who remained hyperlipidemic on monotherapy with either drug, combination drug therapy with lovastatin (20 mg twice daily) plus clofibrate reduced plasma concentrations of total cholesterol from 635 ± 79 mg/dL to 205 ± 11 mg/dL. No patients were discontinued from single or combined drug therapy and no significant biochemical abnormalities were observed. The results of this study demonstrate the potential usefulness of lovastatin in the therapy of type III hyperlipoproteinemia and indicate that, in selected patients who remain hypercholesterolemic on monotherapy with either clofibrate or lovastatin, combination drug therapy with both of these drugs is effective in further reducing plasma concentrations of total, VLDL, and LDL cholesterol. Although none of the six patients treated with lovastatin plus clofibrate developed myopathy, we would urge caution in the use of this combination in view of the known increased risk of myopathy associated with the use of lovastatin plus gemfibrozil.

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Proprotein convertase subtilisin kexin type 9 (PCSK9) monoclonal antibodies (mAbs) reduce fasting and post fat load cholesterol in non-HDL and intermediate density lipoprotein (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. Apolipoproteins (apo) were measured with ultracentrifugation, gradient gel electrophoresis, retinyl palmitate and SDS-PAGE.
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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.
Dietary recommendations for dysbetalipoproteinemia: A need for better evidence
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The increased risk of cardiovascular disease in patients with dysbetalipoproteinemia (DBL) is well documented and is associated with the dysfunctional metabolism of remnant lipoproteins. Although these patients are known to respond well to lipid-lowering medication including statins and fibrates, the best dietary approach to lower remnant lipoprotein accumulation and to prevent cardiovascular outcomes remain unclear. Indeed, current evidence is based on studies published mainly in the 1970s, which comprise small sample sizes and methodological limitations. This review aims to summarize nutritional studies performed in DBL patients to date and to discuss potential avenues in this field and future areas of research.
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
2017, Journal of Lipid Research
Citation Excerpt :
Both statins and fibrates reduce apoB, although statins reduce apoB more effectively (33% vs. 17%) (32). Adding a fibrate to statin therapy in FD patients resulted in improved fasting levels of TC, TG, and HDL-C compared with statin monotherapy, but these changes were nonsignificant (13, 14), which was probably due to insufficient power because fibrate was only added in patients who did not sufficiently respond to statin monotherapy. In general, the European dyslipidemia guideline recommends initiating treatment for hypertriglyceridemia when TG levels are >2.3 mmol/l (10).
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.
Autosomal dominant familial dysbetalipoproteinemia: A pathophysiological framework and practical approach to diagnosis and therapy
2017, Journal of Clinical Lipidology
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Simvastatin (20 or 40 mg per day) in combination with gemfibrozil (450 mg per day) in 19 patients with FD was more effective in lowering fasting plasma lipids (TC, TG, LDL-C, HDL-C, and VLDL-C) than simvastatin alone.117 This was also found for the combination of lovastatin and clofibrate compared to lovastatin alone.118 Postprandial clearance of VLDL and CM remnants is reduced in FD,119 exposing them to postprandial hypercholesterolemia and hypertriglyceridemia that are associated with increased cardiovascular risk.104
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.
Vascular risk factors, vascular disease, lipids and lipid targets in patients with familial dysbetalipoproteinemia: A European cross-sectional study
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Citation Excerpt :
Another cross-over study in patients with FD found that lovastatin and clofibrate lowered non-HDL-C by 50% and 46%. In this study, patients with ongoing hypercholesterolemia after the first treatment phase received a combination of lovastatin and clofibrate, which was effective in further reducing VLDL-C and LDL-C by 27% and 3% compared to lovastatin alone [34]. When cholesterol levels are above target, clinical guidelines recommend to 1.
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.
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.
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.
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.
Disappearance of angina pectoris by lipid-lowering in type III hyperlipoproteinemia
2011, American Journal of Cardiology
Citation Excerpt :
However, neither was enough to meet the criteria for high-risk patients of published guidelines.7 A combination of a statin and a fibrate was shown to be more effective than monotherapy.8,9 In the present case, atorvastatin and fenofibrate, along with diet control, decreased cholesterol and triglyceride levels by 78% and 92%, respectively.
Type III hyperlipoproteinemia is a rare familial disease characterized by marked elevations of serum cholesterol and triglyceride levels caused by an accumulation of remnant lipoproteins in apolipoprotein E2/E2 homozygotes. It is associated with an increased risk for premature atherosclerotic vascular disease. A 55-year-old woman was diagnosed as having type III hyperlipoproteinemia on the basis of skin lesions, serum lipid levels, lipid electrophoresis, and apolipoprotein E genotyping and stable angina pectoris on the basis of typical symptoms and treadmill exercise electrocardiographic results. After 1 year of combination therapy with atorvastatin and fenofibrate, skin xanthomata disappeared, leaving minimal remnants. In addition, there was no exertional chest pain, and treadmill exercise electrocardiographic results were negative. This finding was confirmed by coronary computed tomographic angiography. This case suggests that proper medical therapy can induce the regression of uncomplicated coronary lesions in type III hyperlipoproteinemia.

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^☆: Supported in part by National Institutes of Health Research Grants No. HL28399 and HL37940 and by the General Clinical Research Center's Program (RR334).

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The hypolipidemic effects of lovastatin and clofibrate alone and in combination in patients with type III hyperlipoproteinemia☆

Abstract

Atherosclerosis

Metabolism

Atherosclerosis

Metabolism

Am J Med

Biochemical, clinical and genetic features of type III hyperlipoproteinemia

Ann Intern Med

Type III hyperlipoproteinemia. Recent insights into the genetic defect of familial dysbetalipoproteinemia

Adv Intern Med

Type III hyperlipoproteinemia (dysbetalipoproteinemia): The role of apolipoprotein E in normal and abnormal lipoprotein metabolism

Gemfibrozil in the treatment of resistant familial hypercholesterolemia and type III hyperlipoproteinemia

J R Soc Med

Lovastatin therapy in familial dysbetalipoproteinemia. Effects on kinetics of apolipoprotein B

Atherosclerosis

Lovastatin (Mevinolin) in the treatment of heterozygous familial hypercholesterolemia: A multicenter study

Ann Intern Med

Therapeutic response to lovastatin (Mevinolin) in non-familial hypercholesterolemia

JAMA