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Cited by 626Lipid metabolism and disordersCancer, Lipids, and MetabolismDiabetes, Cardiovascular Risks, and Lipoproteins

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

Open access
Sandesara, Pratik B, Virani, Salim S, Fazio, Sergio, Shapiro, Michael D·2019·Endocrine Reviews
DOI 10.1210/er.2018-00184PMC PMC6416708
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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.

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Crossref · 10.1210/er.2018-00184

Cites

181 of 181 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

29 of 60 cited sources checked · 14 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    In the Emerging Risk Factors Collaboration analysis, the association between TG levels and coronary heart disease was attenuated after adjustment for HDL-C.

    “However, the association was attenuated after adjustment for HDL-C”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [72] Di Angelantonio, 2009, Major lipids, apolipoproteins, and risk of vascular disease, JAMA source

      The Results (Triglyceride; page not provided) report that the triglyceride–CHD association weakened after adjustment for both HDL-C and non-HDL-C. The passage does not establish that adjustment for HDL-C alone produced the attenuation described in the claim. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Premisecitation

    Do et al. found that the strength of a single-nucleotide polymorphism's effect on TG levels correlated strongly with the magnitude of effect on coronary artery disease after adjustment for the single-nucleotide polymorphism's effects on LDL-C and HDL-C.

    “They found that the strength of an SNP's effect on TG levels correlated strongly with the magnitude of effect on CAD, after adjustment for the SNP's effects on LDL-C and HDL-C”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [116] Do, 2013, Common variants associated with plasma triglycerides and risk for coronary artery disease, Nat Genet source
  • Premisecitation

    Mendelian randomization analyses are susceptible to genetic pleiotropy.

    “a well-known limitation of Mendelian randomization analyses is that they are susceptible to genetic pleiotropy”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [110] Musunuru, 2016, Surprises from genetic analyses of lipid risk factors for atherosclerosis, Circ Res source
  • Premisecitation

    Two large randomized controlled trials of extended-release niacin versus placebo on background statin therapy in individuals with established ASCVD did not demonstrate a reduction in vascular events.

    “Two large randomized controlled trials (RCTs) evaluating the efficacy of extended-release niacin vs placebo on background statin therapy in individuals with established ASCVD did not demonstrate a reduction in vascular events”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [18] Boden, 2011, Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy, N Engl J Med source

      The Study Design and Study Population sections describe a randomized, placebo-controlled trial of 3,414 patients, and the Discussion reports no significant reduction in cardiovascular events with extended-release niacin added to intensive statin therapy. This paper establishes the result for one trial, not two: its Discussion says the other large niacin trial, HPS2-THRIVE, was still in follow-up. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [19] Crosby, 2014, Loss-of-function mutations in APOC3, triglycerides, and coronary disease, N Engl J Med source

      The Discovery Cohorts and APOC3 loss-of-function results sections describe genetic associations with coronary heart disease, not niacin treatment trials. Searches for extended-release niacin, placebo, background statin therapy, and vascular events found no passage in our copy addressing the two claimed randomized trials. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
  • Premisecitation

    Volanesorsen is a second-generation antisense oligonucleotide developed to inhibit apoCIII.

    “Volanesorsen (previously known as ISIS-APOC-III RX ) is a second-generation ASO developed to inhibit apoCIII”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [170] Gaudet, 2015, Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia, N Engl J Med source

      The RESULTS passage describes ISIS 304801 as a second-generation antisense oligonucleotide designed to reduce APOC3 mRNA, supporting the drug class and intended target. Our copy does not identify ISIS 304801 as volanesorsen or ISIS-APOC-III RX, so it does not establish the name equivalence in the citing sentence. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • The quote only partly states this claim. 4
  • May combine two claims. 37
  • Classified as probably not a substantial claim. 16

  • The quote only partly states this claim.

    Premisecitation

    In the Emerging Risk Factors Collaboration analysis, fasting and nonfasting TG levels were associated with increased risk of coronary heart disease after adjustment for nonlipid risk factors.

    “fasting and nonfasting TG levels were associated with increased risk of coronary heart disease”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [72] Di Angelantonio, 2009, Major lipids, apolipoproteins, and risk of vascular disease, JAMA source

      The Results > Triglyceride section reports an increased CHD risk with triglycerides after adjustment for nonlipid risk factors (HR 1.37), supporting the overall association. It does not report separate fasting and nonfasting estimates for that adjustment alone; the fasting-status estimates it does report are essentially null after further adjustment for HDL-C and non-HDL-C. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Mendelian randomization is essentially a randomized controlled trial performed by nature because random allocation of alleles to offspring at conception is unaffected by reverse causation and independent of environmental and genetic confounders.

    “Mendelian randomization is essentially an RCT that has been performed by nature, because there is a random allocation of alleles to offspring at the time of conception that is unaffected by reverse causation and independent of environmental and genetic confounders”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [110] Musunuru, 2016, Surprises from genetic analyses of lipid risk factors for atherosclerosis, Circ Res source

      Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    TG lowering by omega-3 fatty acids is linear with a dose-dependent effect such that greater absolute reduction is seen in individuals with higher baseline TG levels.

    “The TG lowering is linear with a dose-dependent effect such that greater absolute reduction is seen in individuals with higher baseline TG levels”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [148] Mozaffarian, 2011, Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events, J Am Coll Cardiol source

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Genetic pleiotropy occurs when the gene variant under study affects more than one pathway, so the observed association between the variant and disease risk may not be due to the biomarker of interest.

    “This phenomenon occurs when the gene variant under study affects more than one pathway; thus, the observed association between the variant and disease risk may not be due to the biomarker of interest”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [110] Musunuru, 2016, Surprises from genetic analyses of lipid risk factors for atherosclerosis, Circ Res source

  • May combine two claims.

    Premisecitation

    Loss-of-function mutations in LPL are associated with increased plasma TG levels and risk of ASCVD.

    “LOF mutations in LPL are also associated with increased plasma TG levels and risk of ASCVD”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [128] Wittrup, 1999, Lipoprotein lipase mutations, plasma lipids and lipoproteins, and risk of ischemic heart disease. A meta-analysis, Circulation source

      The Plasma Triglycerides and Postheparin Plasma Lipoprotein Lipase Activity sections report that three LPL substitutions associated with reduced enzyme activity also increased triglycerides. The Risk of Ischemic Heart Disease and Discussion sections report increased risk for Gly188Glu carriers, but say any increase for Asp9Asn and Asn291Ser carriers was borderline at most. The claim overgeneralizes the cardiovascular-risk association across loss-of-function mutations. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [129] Nordestgaard, 1997, Heterozygous lipoprotein lipase deficiency: frequency in the general population, effect on plasma lipid levels, and risk of ischemic heart disease, Circulation source

  • May combine two claims.

    Premisecitation

    Niacin inhibits adipose tissue lipolysis, which reduces the flux of free fatty acids to the liver and leads to reduced hepatic VLDL synthesis.

    “It inhibits adipose tissue lipolysis, which reduces the flux of FFAs to the liver and, therefore, leads to reduced hepatic VLDL synthesis”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [167] Qin, 2011, Missense mutation in APOC3 within the C-terminal lipid binding domain of human ApoC-III results in impaired assembly and secretion of triacylglycerol-rich very low density lipoproteins: evidence that ApoC-III plays a major role in the formation of lipid precursors within the microsomal lumen, J Biol Chem source

      The Discussion describes excess fatty acid influx and apoC-III’s role in hepatic VLDL assembly, but does not connect either to niacin or inhibition of adipose-tissue lipolysis. Searches for niacin, nicotinic acid, and adipose lipolysis found no passage addressing the claimed mechanism; page numbers were unavailable in our copy. (LLM, conf=0.73)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingcitation

    Despite reductions in LDL-C levels with statins and newer lipid-lowering agents, substantial residual risk persists, with the majority of predicted first and recurrent ASCVD events not being averted.

    “However, despite reductions in LDL-C levels with statins and newer lipid-lowering agents, substantial residual risk persists, with the majority of predicted first and recurrent ASCVD events not being averted”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Triglyceride-rich lipoprotein remnants have been linked to impaired coronary vasomotor function, decreased brachial artery flow-mediated dilatation, and increased carotid intima media thickness.

    “TGRL remnants have been linked to impaired coronary vasomotor function, decreased brachial artery flow-mediated dilatation, and increased carotid intima media thickness”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingcitation

    In pregnancy, plasma triglyceride levels can increase two- to fourfold during the third trimester owing to physiologic hormonal changes and are generally not clinically important.

    “In pregnancy, plasma TG levels can increase two-to fourfold during the third trimester owing to physiologic hormonal changes and are generally not clinically important”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    Mendelian randomization suggests a causal association of elevated nonfasting remnant cholesterol with low-grade inflammation and ischemic heart disease, whereas elevated LDL-C associates with ischemic heart disease but not inflammation.

    “Interestingly, Mendelian randomization suggests a causal association of elevated nonfasting RC with low-grade inflammation and ischemic heart disease (IHD), whereas elevated LDL-C associates with IHD but not inflammation”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Postprandial changes in triglycerides depend on baseline triglyceride levels, fat load in the meal, and time since the last meal.

    “These postprandial changes in TGs depend on baseline TG levels, fat load in the meal, and time since the last meal”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    Triglycerides are catabolized by macrophages and therefore do not accumulate in atherosclerotic plaque.

    “However, the TGs are catabolized by macrophages and therefore do not accumulate in atherosclerotic plaque.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Findingnone given

    Many novel drugs are in development and have shown impressive efficacy in lowering triglyceride levels.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    Early epidemiologic studies demonstrated that fasting triglyceride levels independently associated with cardiovascular disease and correlated well with nonfasting triglyceride levels.

    “Early epidemiologic studies demonstrated that fasting TG levels independently associated with cardiovascular disease (CVD) and correlated well with nonfasting TG levels”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Other secondary causes of hypertriglyceridemia include pregnancy, hypothyroidism, chronic kidney disease, poorly controlled diabetes and/or metabolic syndrome, and medications.

    “Other secondary causes of hypertriglyceridemia include pregnancy, hypothyroidism, chronic kidney disease, poorly controlled diabetes and/or metabolic syndrome, and medications”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    ApoCIII inhibits hepatic lipase activity and inhibits hepatic triglyceride-rich lipoprotein remnant clearance.

    “These include inhibition of hepatic lipase activity and inhibition of hepatic TGRL remnant clearance”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Collectively, these processes lead to enhanced platelet aggregation and clot formation.

    “Collectively, these processes lead to enhanced platelet aggregation and clot formation”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Hypertriglyceridemia is frequently associated with concomitant lipoprotein alterations such as decreased HDL cholesterol, elevated non-HDL-C, small dense and total LDL particles, intermediate-density lipoprotein, and total apolipoprotein CIII, all of which are associated with increased ASCVD risk.

    “Hypertriglyceridemia is frequently associated with concomitant lipoprotein alterations such as decreased high-density lipoprotein (HDL) cholesterol (HDL-C) levels and elevated levels of non-HDL-C; small, dense and total LDL particles; intermediate-density lipoprotein (IDL); and total apolipoprotein CIII (apoCIII), all of which are associated with increased ASCVD risk”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    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 atherosclerotic cardiovascular disease (ASCVD).

    “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.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Several current recommendations support the use of a random, nonfasting lipid profile in clinical practice for cardiovascular risk prediction, although it is not clear how to use nonfasting lipids once treatment is started with lipid-lowering therapy.

    “Accordingly, several current recommendations support the use of a random, nonfasting lipid profile in clinical practice for CV risk prediction”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    At triglyceride levels above 1000 mg/dL, chylomicrons are usually the main carriers of triglyceride in plasma.

    “At these levels, chylomicrons are usually the main carriers of TG in plasma.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Moderately elevated triglyceride concentrations are commonly due to suboptimal lifestyle habits, including diets enriched in simple carbohydrates and/or saturated fats, excess alcohol consumption, obesity, and sedentary behavior.

    “Moderately elevated TG concentrations are commonly due to suboptimal lifestyle habits, including diets enriched in simple carbohydrates and/or saturated fats, excess alcohol consumption, obesity, and sedentary behavior.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Thyroid hormone is an important regulator of lipoprotein lipase activity, and elevated triglyceride levels in hypothyroidism are due to decreased lipoprotein lipase activity.

    “Thyroid hormone is an important regulator of LPL activity and elevated TG levels in hypothyroidism are due to decreased LPL activity”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Circulating plasma apoB-containing lipoproteins penetrate the endothelial cell lining of the artery wall in susceptible regions and enter the intimal space, where they may be trapped by interaction with subendothelial proteoglycans.

    “Circulating plasma apoB-containing lipoproteins penetrate the endothelial cell lining of the artery wall in susceptible regions and enter the intimal space, where they may be trapped by interaction with subendothelial proteoglycans”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Triglyceride-rich lipoproteins can readily penetrate the arterial wall and are susceptible to retention by connective tissue matrix through interaction of positively charged residues on apoB with negatively charged sulfate groups of subendothelial proteoglycans, similar to LDL.

    “TGRLs can readily penetrate the arterial wall and are susceptible to retention by connective tissue matrix through interaction of the positively charged residues (arginine and lysine) on apoB with the negatively charged sulfate groups of subendothelial proteoglycans, similar to LDL.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Endothelial dysfunction often precedes the development of atherosclerosis.

    “Endothelial dysfunction often precedes the development of atherosclerosis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Incomplete lipidation of apoB by microsomal triglyceride transport protein leads to its proteasomal degradation with subsequent decrease in VLDL production.

    “Incomplete lipidation of apoB by MTP leads to its proteasomal degradation with subsequent decrease in VLDL production.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Hypertriglyceridemia is a well-known cause of acute pancreatitis.

    “Hypertriglyceridemia is a well-known cause of acute pancreatitis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Increase in estrogen levels during the third trimester stimulates hepatic VLDL secretion and reduces the clearance of triglycerides by lipoprotein lipases in the liver and adipose tissues, resulting in elevated triglyceride levels.

    “Increase in estrogen levels during the third trimester stimulates hepatic VLDL secretion and reduces the clearance of TGs by lipoprotein lipases (LPLs) in the liver and adipose tissues resulting in elevated TG levels”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Hypertriglyceridemia occurs because of increased triglyceride production, altered processing and catabolism of triglyceride-rich lipoproteins, or reduced clearance.

    “Hypertriglyceridemia occurs because of increased TG production, altered processing and catabolism of TGRLs, or reduced clearance.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Although apoCIII is a potent inhibitor of lipoprotein lipase activation, recent studies have shown that it has a pleiotropic role in the regulation of triglyceride-rich lipoprotein metabolism independent of lipoprotein lipase pathways.

    “It is important to note that although apoCIII is a potent inhibitor of LPL activation, recent studies have shown that it has a pleiotropic role in the regulation of TGRL metabolism independent of LPL pathways.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The cholesterol content in triglyceride-rich lipoproteins, rather than the triglycerides, may be more important in atherogenesis because it accumulates in atherosclerotic plaque and is in the causal pathway of atherosclerosis.

    “This suggests that the cholesterol content in TGRLs (e.g., RC), rather than the TGs, may be more important in atherogenesis, because it accumulates in atherosclerotic plaque and is in the causal pathway of atherosclerosis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    More commonly, the genetic basis for moderate to severe hypertriglyceridemia is polygenic, which can synergize with environmental factors to profoundly alter triglyceride/VLDL production and clearance.

    “More commonly, the genetic basis for moderate to severe hypertriglyceridemia is polygenic, which can synergize with environmental factors to profoundly alter TG/VLDL production and clearance”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The epidemics of obesity, metabolic syndrome, and diabetes are associated with a dramatic increase in the prevalence of hypertriglyceridemia and its potential intersection with ASCVD.

    “This notion is of particular interest because the burgeoning epidemics of obesity, metabolic syndrome, and diabetes are associated with a dramatic increase in the prevalence of hypertriglyceridemia and its potential intersection with ASCVD”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Impairment of endothelium-dependent vasodilation and increased oxidative stress may also play a role in promoting endothelial dysfunction.

    “Furthermore, impairment of endothelium-dependent vasodilation and increased oxidative stress may also play a role in promoting endothelial dysfunction”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    The long-term clinical consequences of hepatic steatosis due to pharmacologic apoB or MTP inhibition in humans remain unclear.

    “The long-term clinical consequences of hepatic steatosis due to pharmacologic apoB or MTP inhibition in humans remain unclear”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    The constitutive production and regulation of hepatic apoB plays a key role in VLDL synthesis and secretion, and safeguards against hepatic steatosis.

    “The constitutive production and regulation of hepatic apoB plays a key role in VLDL synthesis and secretion, and safeguards against hepatic steatosis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    In the insulin-resistant state, increased adipocyte lipolysis results in increased free fatty acid flux to the liver, which fuels the lipidation of apoB leading to increased VLDL production and de novo hepatic lipogenesis.

    “Furthermore, in the insulin-resistant state, increased adipocyte lipolysis results in increased FFA flux to the liver, which also fuels the lipidation of apoB leading to increased VLDL production and de novo hepatic lipogenesis”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    At this time, direct assays to measure remnant cholesterol have limited clinical applicability because they do not measure all remnant cholesterol in the plasma and are labor intensive and costly.

    “At this time, these direct assays to measure RC have limited clinical applicability because they do not measure all RC in the plasma and are labor intensive and costly.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Within macrophages, cholesterol cannot be metabolized and thus accumulates, leading to engorged, dysfunctional foam cells.

    “Within macrophages, cholesterol cannot be metabolized; thus it accumulates, leading to engorged, dysfunctional foam cells.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Equivocal clinical trial results of triglyceride-lowering therapies have raised the question whether triglycerides represent a surrogate for other causal mechanisms at play for atherosclerotic disease.

    “In addition, equivocal clinical trial results of TG-lowering therapies have raised the question as to whether TGs represent a surrogate for other causal mechanisms at play for atherosclerotic disease”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Premisecitation

    In 97,962 participants from the Copenhagen City Heart Study and Copenhagen General Population Study, nonfasting calculated remnant cholesterol was associated with a stepwise increase in risk of ischemic heart disease, myocardial infarction, and all-cause mortality.

    “nonfasting calculated RC was associated with a stepwise increase in risk of IHD, MI, and all-cause mortality”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [112] Varbo, 2015, Extreme nonfasting remnant cholesterol vs extreme LDL cholesterol as contributors to cardiovascular disease and all-cause mortality in 90000 individuals from the general population, Clin Chem source

  • May combine two claims.

    Premisecitation

    The FIELD study with fenofibrate did not demonstrate a reduction in the rate of the composite primary outcome of coronary heart disease death and nonfatal myocardial infarction compared with placebo but was associated with a reduction in total cardiovascular events.

    “The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study with fenofibrate did not demonstrate a reduction in the rate of the composite primary outcome (CHD death and nonfatal MI) compared with placebo but was associated with a reduction in total CV events”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [137] Keech, 2005, Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial, Lancet source

  • May combine two claims.

    Premisecitation

    TG reduction by omega-3 fatty acids is mediated by multiple mechanisms, including increased fatty acid catabolism by peroxisomal beta-oxidation, decreased hepatic lipogenesis, and increased clearance of plasma TGs.

    “TG reduction is mediated by multiple mechanisms, including increased FA catabolism by peroxisomal b-oxidation, decreased hepatic lipogenesis, and increased clearance of plasma TGs”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [149] Jacobson, 2012, Effects of eicosapentaenoic acid and docosahexaenoic acid on low-density lipoprotein cholesterol and other lipids: a review, J Clin Lipidol source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Most observational epidemiologic studies of remnant cholesterol and ASCVD were done in the prestatin era.

    “It is important to note that most of these observational epidemiologic studies were done in the prestatin era”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A pooled analysis of the IDEAL and TNT trials demonstrated that increased TG levels were associated with higher risk of cardiovascular disease events in statin-treated patients, although the risk was attenuated after adjustment for HDL-C and apoB-to-apoA-I ratio.

    “a pooled analysis of the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) and Treating to New Targets (TNT) trials demonstrated that increased TG levels were associated with higher risk of CVD events in statin-treated patients, although the risk was attenuated after adjustment for HDL-C and apoB-to-apoA-I ratio”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [109] Faergeman, 2009, Plasma triglycerides and cardiovascular events in the Treating to New Targets and Incremental Decrease in End-Points through Aggressive Lipid Lowering trials of statins in patients with coronary artery disease, Am J Cardiol source

  • The quote only partly states this claim.

    Premisecitation

    Niacin reduces plasma TG levels by ≤30%.

    “#30%”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Shapiro, 2016, From lipids to inflammation: new approaches to reducing atherosclerotic risk, Circ Res source

  • May combine two claims.

    Premisecitation

    In clinical trials, intramuscular injection of alipogene tiparvovec was associated with reduction in the incidence of pancreatitis and was well tolerated.

    “In clinical trials, intramuscular injection of alipogene tiparvovec was associated with reduction in the incidence of pancreatitis and was well tolerated”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [172] Gaudet, 2012, Gene therapy for lipoprotein lipase deficiency, Curr Opin Lipidol source

  • The quote only partly states this claim.

    Premisecitation

    Moderate to intense aerobic exercise reduces plasma TG levels by ≤20%.

    “#20% reduction in plasma TG levels with moderate to intense aerobic exercise”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Watts, 2013, Demystifying the management of hypertriglyceridaemia, Nat Rev Cardiol source

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    It is established that LDL is the primary causal factor in the development of atherosclerosis.

    “it is established that LDL is the primary causal factor in the development of atherosclerosis”
    Quote in the paperNot a substantial claim
50 of 50

  • The paper relies on this without support.

    Plasma triglyceride concentrations serve as a surrogate measure of triglyceride-rich lipoproteins and remnant cholesterol.

    “Clinically, plasma TG concentrations serve as a surrogate measure of TGRLs and RC.”

  • The paper relies on this without support.

    Residual confounding can limit the ability to draw causal inference from observational studies linking TGs and remnant cholesterol to ASCVD.

    “However, the possibility of residual confounding limits the ability to draw causal inference from these observational studies”

  • The paper relies on this without support.

    Elevated TG levels are closely linked to non-HDL-C with high intercorrelation between the variables.

    “elevated TG levels are closely linked to non-HDL-C with high intercorrelation between the variables”
3 of 3

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Relatives are described as both wild-type and completely deficient

    Minor

    The imaging statement calls the relatives wild-type while also saying they had complete ANGPTL3 deficiency. The preceding statement attributes complete deficiency to loss-of-function mutations, so the relatives' genetic status is unclear.

1 of 1

Cites

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3 of the 184 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Chait, 2000, Endotext

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Authors
Sandesara, P. B., Virani, S. S., Fazio, S., & Shapiro, M. D.
Affiliations
  • Emory University (US)
  • Michael E. DeBakey VA Medical Center (US)
  • Oregon Health & Science University (US)
Corresponding author
Shapiro, Michael D
ORCID
Venue
Endocrine Reviews
Publisher
The Endocrine Society
Published
2018-10-11
Volume
40
Issue
2
Pages
537-557
ISSN
  • 0163-769X (ISSN-L)
  • 1945-7189
DOI
10.1210/er.2018-00184
PMC
PMC6416708
OpenAlex
W2896008418
Cited by
626
References
184
Citations by year
2026: 79 · 2025: 98 · 2024: 123 · 2023: 118 · 2022: 62 · 2021: 61 · 2020: 30 · 2019: 17 · 2018: 2
FWCI
17.98
Type
journal article
Language
en
Open access
Locations
  • Endocrine Reviews (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (submittedVersion)
  • PubMed Central (submittedVersion)
  • eCommons - AKU (Aga Khan University) (submittedVersion)
Funders
  • National Institutes of Health (5R01HL132985)
  • U.S. Department of Veterans Affairs (09-028)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (K12HD043488)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords
triglycerides, remnant cholesterol, triglyceride-rich lipoproteins, atherosclerotic cardiovascular disease, hypertriglyceridemia, residual cardiovascular risk, VLDL, chylomicrons
MeSH terms
Cholesterol, Humans, Lipoproteins, Triglycerides, Hypertriglyceridemia, Dyslipidemias

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-11.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-11.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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