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      The Forgotten Lipids: Triglycerides, Remnant Cholesterol, and Atherosclerotic Cardiovascular Disease Risk

      Author(s): 1 , 2 , 3 , 4 , 4
      Publication date Created:
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      Journal: Endocrine Reviews
      Publisher: The Endocrine Society

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          Abstract

          Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of death worldwide. Low-density lipoprotein cholesterol (LDL-C) is a well-established mediator of atherosclerosis and a key target for intervention for the primary and secondary prevention of ASCVD. However, despite substantial reduction in LDL-C, patients continue to have recurrent ASCVD events. Hypertriglyceridemia may be an important contributor of this residual risk. Observational and genetic epidemiological data strongly support a causal role of triglycerides (TGs) and the cholesterol content within triglyceride-rich lipoproteins (TGRLs) and/or remnant cholesterol (RC) in the development of ASCVD. TGRLs are composed of hepatically derived very low-density lipoprotein and intestinally derived chylomicrons. RC is the cholesterol content of all TGRLs and plasma TGs serve as a surrogate measure of TGRLs and RC. Although lifestyle modification remains the cornerstone for management of hypertriglyceridemia, many novel drugs are in development and have shown impressive efficacy in lowering TG levels. Several ongoing, randomized controlled trials are underway to examine the impact of these novel agents on ASCVD outcomes. In this comprehensive review, we provide an overview of the biology, epidemiology, and genetics of TGs and ASCVD; we discuss current and novel TG-lowering therapies under development.

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          Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies.

          J Hokanson, M. Austin (1996)
          Despite nearly 40 years of research, the role of plasma triglyceride as a risk factor for cardiovascular disease remains elusive. The objectives of the present study were to quantify the magnitude of the association between triglyceride and cardiovascular disease in the general population, and to determine whether this relationship is independent of high-density lipoprotein (HDL) cholesterol, using the semi-quantitative techniques of metaanalysis. Seventeen studies were selected for the analysis based on published reports of population-based, prospective studies, including 46413 men and 10864 women. To insure comparability, only studies reporting the association between fasting triglyceride levels and incident cardiovascular endpoints were included. Using standard meta-analysis calculations, relative risks (RR) and 95% confidence intervals (CI) were calculated and standardized with respect to a 1 mmol/l increase in triglyceride. Multivariable-adjusted RRs were determined for the six studies in men and two studies in women that reported adjustments for HDL cholesterol. For men and women, the univariate RRs for triglyceride were 1.32 (95% Cl 1.26-1.39) and 1.76 (95% Cl 1.50-2.07), respectively, indicating an approximately 30% increased risk in men and a 75% increase in women. Adjustment of HDL cholesterol and other risk factors attenuated these RRs to 1.14 (95% Cl 1.05-1.28) and 1.37 (95% Cl 1.13-1.66), respectively, which were still statistically significant values. Based on combined data from prospective studies, triglyceride is a risk factor for cardiovascular disease for both men and women in the general population, independent of HDL cholesterol. These finding demonstrate the necessity for clinical trials to evaluate whether lowering plasma triglyceride decreases the risk of cardiovascular disease.
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            Cardiovascular and Metabolic Effects of ANGPTL3 Antisense Oligonucleotides.

            Mark J. Graham, Richard Lee, Teresa A Brandt … (2017)
            Background Epidemiologic and genomewide association studies have linked loss-of-function variants in ANGPTL3, encoding angiopoietin-like 3, with low levels of plasma lipoproteins. Methods We evaluated antisense oligonucleotides (ASOs) targeting Angptl3 messenger RNA (mRNA) for effects on plasma lipid levels, triglyceride clearance, liver triglyceride content, insulin sensitivity, and atherosclerosis in mice. Subsequently, 44 human participants (with triglyceride levels of either 90 to 150 mg per deciliter [1.0 to 1.7 mmol per liter] or >150 mg per deciliter, depending on the dose group) were randomly assigned to receive subcutaneous injections of placebo or an antisense oligonucleotide targeting ANGPTL3 mRNA in a single dose (20, 40, or 80 mg) or multiple doses (10, 20, 40, or 60 mg per week for 6 weeks). The main end points were safety, side-effect profile, pharmacokinetic and pharmacodynamic measures, and changes in levels of lipids and lipoproteins. Results The treated mice had dose-dependent reductions in levels of hepatic Angptl3 mRNA, Angptl3 protein, triglycerides, and low-density lipoprotein (LDL) cholesterol, as well as reductions in liver triglyceride content and atherosclerosis progression and increases in insulin sensitivity. After 6 weeks of treatment, persons in the multiple-dose groups had reductions in levels of ANGPTL3 protein (reductions of 46.6 to 84.5% from baseline, P<0.01 for all doses vs. placebo) and in levels of triglycerides (reductions of 33.2 to 63.1%), LDL cholesterol (1.3 to 32.9%), very-low-density lipoprotein cholesterol (27.9 to 60.0%), non-high-density lipoprotein cholesterol (10.0 to 36.6%), apolipoprotein B (3.4 to 25.7%), and apolipoprotein C-III (18.9 to 58.8%). Three participants who received the antisense oligonucleotide and three who received placebo reported dizziness or headache. There were no serious adverse events. Conclusions Oligonucleotides targeting mouse Angptl3 retarded the progression of atherosclerosis and reduced levels of atherogenic lipoproteins in mice. Use of the same strategy to target human ANGPTL3 reduced levels of atherogenic lipoproteins in humans. (Funded by Ionis Pharmaceuticals; ClinicalTrials.gov number, NCT02709850 .).
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              Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia.

              Kiran Musunuru, James Pirruccello, Ron Do … (2010)
              We sequenced all protein-coding regions of the genome (the "exome") in two family members with combined hypolipidemia, marked by extremely low plasma levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides. These two participants were compound heterozygotes for two distinct nonsense mutations in ANGPTL3 (encoding the angiopoietin-like 3 protein). ANGPTL3 has been reported to inhibit lipoprotein lipase and endothelial lipase, thereby increasing plasma triglyceride and HDL cholesterol levels in rodents. Our finding of ANGPTL3 mutations highlights a role for the gene in LDL cholesterol metabolism in humans and shows the usefulness of exome sequencing for identification of novel genetic causes of inherited disorders. (Funded by the National Human Genome Research Institute and others.).
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                Author and article information

                Journal
                Title: Endocrine Reviews
                Publisher: The Endocrine Society
                ISSN (Print): 0163-769X
                ISSN (Electronic): 1945-7189
                Publication date Created: April 2019
                Publication date Created: April 01 2019
                Publication date Created: October 11 2018
                Publication date Other: April 2019
                Publication date (Print): April 01 2019
                Publication date (Electronic): October 11 2018
                Volume: 40
                Issue: 2
                Pages: 537-557
                Affiliations
                [1 ]Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia
                [2 ]Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
                [3 ]Baylor College of Medicine, Houston, Texas
                [4 ]Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon
                Article
                DOI: 10.1210/er.2018-00184
                PMC ID: 6416708
                PubMed ID: 30312399
                SO-VID: bfda89a1-3693-4327-8881-84cdd4428f49
                Copyright © © 2018
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