Association of Triglyceride-Lowering LPL Variants and LDL-C–Lowering LDLR Variants With Risk of Coronary Heart Disease
Open accessAbstract
Importance: Triglycerides and cholesterol are both carried in plasma by apolipoprotein B (ApoB)-containing lipoprotein particles. It is unknown whether lowering plasma triglyceride levels reduces the risk of cardiovascular events to the same extent as lowering low-density lipoprotein cholesterol (LDL-C) levels. Objective: To compare the association of triglyceride-lowering variants in the lipoprotein lipase (LPL) gene and LDL-C-lowering variants in the LDL receptor gene (LDLR) with the risk of cardiovascular disease per unit change in ApoB. Design, Setting, and Participants: Mendelian randomization analyses evaluating the associations of genetic scores composed of triglyceride-lowering variants in the LPL gene and LDL-C-lowering variants in the LDLR gene, respectively, with the risk of cardiovascular events among participants enrolled in 63 cohort or case-control studies conducted in North America or Europe between 1948 and 2017. Exposures: Differences in plasma triglyceride, LDL-C, and ApoB levels associated with the LPL and LDLR genetic scores. Main Outcomes and Measures: Odds ratio (OR) for coronary heart disease (CHD)-defined as coronary death, myocardial infarction, or coronary revascularization-per 10-mg/dL lower concentration of ApoB-containing lipoproteins. Results: A total of 654 783 participants, including 91 129 cases of CHD, were included (mean age, 62.7 years; 51.4% women). For each 10-mg/dL lower level of ApoB-containing lipoproteins, the LPL score was associated with 69.9-mg/dL (95% CI, 68.1-71.6; P = 7.1 × 10-1363) lower triglyceride levels and 0.7-mg/dL (95% CI, 0.03-1.4; P = .04) higher LDL-C levels; while the LDLR score was associated with 14.2-mg/dL (95% CI, 13.6-14.8; P = 1.4 × 10-465) lower LDL-C and 1.9-mg/dL (95% CI, 0.1-3.9; P = .04) lower triglyceride levels. Despite these differences in associated lipid levels, the LPL and LDLR scores were associated with similar lower risk of CHD per 10-mg/dL lower level of ApoB-containing lipoproteins (OR, 0.771 [95% CI, 0.741-0.802], P = 3.9 × 10-38 and OR, 0.773 [95% CI, 0.747-0.801], P = 1.1 × 10-46, respectively). In multivariable mendelian randomization analyses, the associations between triglyceride and LDL-C levels with the risk of CHD became null after adjusting for differences in ApoB (triglycerides: OR, 1.014 [95% CI, 0.965-1.065], P = .19; LDL-C: OR, 1.010 [95% CI, 0.967-1.055], P = .19; ApoB: OR, 0.761 [95% CI, 0.723-0.798], P = 7.51 × 10-20). Conclusions and Relevance: Triglyceride-lowering LPL variants and LDL-C-lowering LDLR variants were associated with similar lower risk of CHD per unit difference in ApoB. Therefore, the clinical benefit of lowering triglyceride and LDL-C levels may be proportional to the absolute change in ApoB.
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Claims the paper makes
17 of 31 cited sources checked · 6 supported · 2 flagged · accuracy not yet measured
- Premisecitation
In the fibrate trials, the mean reduction in plasma triglyceride concentration was only 20 mg/dL to 50 mg/dL, a fraction of what would be needed to significantly reduce major vascular event risk in a short-term trial.
“However, the mean reduction in plasma triglyceride concentration in the fibrate trials was only 20 mg/dL to 50 mg/dL, a fraction of what would be needed to significantly reduce the risk of major vascular events within a shortterm trial.”
Quote in the paperSubstantial claim1 of 3 sources checked- cites [29] Frick, 1987, Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia: safety of treatment, changes in risk factors, and incidence of coronary heart disease., N Engl J Med source
- cites [30] Rubins, 1999, Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol., N Engl J Med source
The Effects on Lipid Levels section reports triglycerides of 115 mg/dL with gemfibrozil versus 166 mg/dL with placebo, a 51 mg/dL difference. Contrary to the claim that a reduction of roughly this size was too small to yield a significant benefit in a trial, the Outcomes section reports a significant reduction in coronary death or nonfatal myocardial infarction, and the paper reports a significant reduction in the combined outcome including stroke. The paper does not isolate triglyceride lowering from the treatment’s other lipid effects as the cause of that benefit. (LLM, conf=0.86)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured - cites [31] Bezafibrate Infarction Prevention (BIP) Study, 2000, Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease., Circulation source
- Interpretationreasoning
If all ApoB-containing particles have approximately the same atherogenic effect, then to reduce cardiovascular event risk by 20% (as achieved by lowering LDL-C by 40 mg/dL), triglyceride levels must be reduced by approximately 200 mg/dL to achieve the same reduction in ApoB-containing lipoproteins.
“Therefore, if all ApoB-containing particles have approximately the same atherogenic effect as suggested by this study, then to reduce the risk of cardiovascular events by 20% as can be achieved by lowering LDL-C levels by 40 mg/dL, 3,4 triglyceride levels must be reduced by 5-fold this quantity, or approximately 200 mg/dL, to achieve the same corresponding reduction in ApoB-containing lipoproteins”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [3] Baigent, 2010, Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials., Lancet source
- cites [4] Silverman, 2016, Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions: a systematic review and meta-analysis., JAMA source
- Premisecitation
Rare loss-of-function mutations in APOC3, ANGPTL3, and ANGPTL4 are associated with lower triglyceride levels and a corresponding lower risk of cardiovascular disease.
“while rare, loss-of-function mutations in the APOC3, ANGPTL3, and ANGPTL4 genes, which encode for natural inhibitors of LPL, are associated with lower triglyceride levels and a corresponding lower risk of cardiovascular disease.[9][10][11][12][13]”
Quote in the paperSubstantial claim3 of 5 sources checked- cites [9] Nordestgaard, 1997, Heterozygous lipoprotein lipase deficiency: frequency in the general population, effect on plasma lipid levels, and risk of ischemic heart disease., Circulation source
- cites [10] Jørgensen, 2014, Loss-of-function mutations in APOC3 and risk of ischemic vascular disease., N Engl J Med source
The Results and Discussion report that APOC3 loss-of-function mutations are associated with lower nonfasting triglycerides and reduced risk of ischemic cardiovascular disease. The paper also describes apolipoprotein C3 as inhibiting lipoprotein lipase, but the passages do not establish the claimed associations for ANGPTL3 or ANGPTL4. Page numbers were not available in our copy. (LLM, conf=0.90)
Experimental — accuracy not yet measured - cites [11] Khera, 2017, Association of rare and common variation in the lipoprotein lipase gene with coronary artery disease., JAMA source
The Discussion (page not available in our copy) identifies APOC3 and ANGPTL4 as LPL inhibitors and says rare inactivating mutations in those genes confer substantial vascular protection. It does not make the corresponding claim about ANGPTL3 or establish lower triglyceride levels for mutations in all three genes; its triglyceride analysis concerns variants in LPL. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [12] Dewey, 2016, Inactivating variants in ANGPTL4 and risk of coronary artery disease., N Engl J Med source
- cites [13] Stitziel, 2016, Coding variation in ANGPTL4, LPL, and SVEP1 and the risk of coronary disease., N Engl J Med source
The ANGPTL4 Loss-of-Function Mutations section (page unavailable) reports lower triglyceride levels and lower coronary artery disease risk in ANGPTL4 mutation carriers. The Discussion and Figure 2 caption also describe APOC3 as an LPL inhibitor and discuss its loss-of-function variants, but identify ANGPTL3 only as an LPL regulator; they do not report the claimed triglyceride and disease-risk associations for ANGPTL3. (LLM, conf=0.87)
Experimental — accuracy not yet measured
- Interpretationreasoning
The current study's results may help explain why prior randomized trials of fibrates have failed to consistently show that lowering triglyceride levels reduces cardiovascular events.
“The results of this study may also help to explain why prior randomized trials evaluating fibrates, which lower plasma triglyceride levels at least partially through the LPL pathway, have failed to consistently demonstrate that lowering triglyceride levels reduces the risk of cardiovascular events.[29][30][31][32][33]”
Quote in the paperSubstantial claim1 of 3 sources checked- cites [29] Frick, 1987, Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia: safety of treatment, changes in risk factors, and incidence of coronary heart disease., N Engl J Med source
- cites [30] Rubins, 1999, Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol., N Engl J Med source
- cites [31] Bezafibrate Infarction Prevention (BIP) Study, 2000, Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease., Circulation source
- Interpretationcitation
The current study's results are consistent with a recent mendelian randomization study showing that the causal effect of LDL particles on cardiovascular disease risk is determined by circulating ApoB concentration rather than by LDL-C mass.
“Furthermore, the results of this study are consistent with a recent mendelian randomization study that demonstrated that the causal effect of LDL particles on the risk of cardiovascular disease appears to be determined by the concentration of circulating LDL particles as measured by ApoB rather than by the mass of cholesterol carried by those particles as measured by LDL-C.23”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [23] Ference, 2017, Association of genetic variants related to CETP inhibitors and statins with lipoprotein levels and cardiovascular risk., JAMA source
- Interpretationown data
Triglyceride-rich remnant particles have approximately the same effect on the risk of cardiovascular disease as LDL particles, as suggested by the current study's results extending prior findings.
“The results of the current study extend those findings by suggesting that triglyceride-rich remnant particles have approximately the same effect on the risk of cardiovascular disease as LDL particles.”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [27] Varbo, 2013, Remnant cholesterol as a causal risk factor for ischemic heart disease., J Am Coll Cardiol source
- cites [28] Sarwar, 2010, Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies, Lancet source
The Discussion (page unavailable) describes VLDL and remnant lipoproteins as potentially proatherogenic, and reports findings consistent with a causal role for triglyceride-mediated pathways in coronary heart disease. It does not compare the effect of remnant particles with that of LDL particles or establish approximately equal effects; its reported outcome is coronary heart disease rather than cardiovascular disease broadly. (LLM, conf=0.85)
Experimental — accuracy not yet measured
- Findingown data
The LPL and LDLR scores were associated with similar lower risk of CHD per 10-mg/dL lower level of ApoB-containing lipoproteins (OR, 0.771 for LPL and OR, 0.773 for LDLR).
“Despite these differences in associated lipid levels, the LPL and LDLR scores were associated with similar lower risk of CHD per 10-mg/dL lower level of ApoB-containing lipoproteins (odds ratio [OR], 0.771 [95% CI, 0.741-0.802],P = 3.9 × 10 -38 for the LPL score and OR, 0.773 [95% CI, 0.747-0.801],P = 1.1 × 10 -46 for the LDLR score).”
Quote in the paperSubstantial claim - Findingown data
In multivariable mendelian randomization analyses, the associations between plasma triglyceride and LDL-C levels with risk of CHD became null after adjusting for differences in ApoB.
“In multivariable mendelian randomization analyses, the associations between triglyceride and LDL-C levels with the risk of CHD became null after adjusting for differences in ApoB”
Quote in the paperSubstantial claim - Findingown data
For each 10-mg/dL lower level of ApoB-containing lipoproteins, the LDLR score was associated with 1.9-mg/dL lower plasma triglyceride level.
“and 1.9-mg/dL (95% CI, 0.1-3.9;P = .04)lower plasma triglyceride level”
Quote in the paperNot a substantial claim - Findingown data
For each 10-mg/dL lower level of ApoB-containing lipoproteins, the LPL score was associated with 69.9-mg/dL lower plasma triglyceride levels.
“For each 10-mg/dL lower level of ApoB-containing lipoproteins, the LPL score was associated with 69.9-mg/dL (95% CI, 68.1-71.6;P = 7.1 × 10 -1363 ) lower plasma triglyceride levels”
Quote in the paperNot a substantial claim - Findingown data
For each 10-mg/dL lower level of ApoB-containing lipoproteins, the LPL score was associated with 0.7-mg/dL higher plasma LDL-C level.
“and 0.7-mg/dL (95% CI, 0.03-1.4;P = .04)higher plasma LDL-C level”
Quote in the paperSubstantial claim - Findingown data
In multivariable mendelian randomization analyses, ApoB remained associated with lower risk of CHD after adjustment (OR, 0.761).
“ApoB: OR, 0.761 [95% CI, 0.723-0.798],P = 7.51 × 10 -20 ).”
Quote in the paperSubstantial claim - Findingown data
For each 10-mg/dL lower level of ApoB-containing lipoproteins, the LDLR score was associated with 14.2-mg/dL lower plasma LDL-C level.
“the LDLR score was associated with 14.2-mg/dL (95% CI, 13.6-14.8;P = 1.4 × 10 -465 ) lower plasma LDL-C level”
Quote in the paperNot a substantial claim - Findingown data
Each LDLR exposure allele was associated with 2.40-mg/dL lower level of ApoB-containing lipoproteins.
“and a 2.40-mg /dL (95% CI, 2.02-2.79;P = 3.9 × 10 -34 ) lower level of ApoB-containing lipoproteins.”
Quote in the paperNot a substantial claim - Findingown data
Each LDLR exposure allele was associated with 0.48-mg/dL lower plasma triglyceride level.
“0.48-mg/dL (95% CI, 0.03-0.93;P = .04)lower plasma triglyceride level”
Quote in the paperNot a substantial claim - Findingown data
In stratified analyses, the associations of the LPL and LDLR scores with plasma lipids, lipoproteins, and risk of CHD appeared to be independent of each other.
“In stratified analyses, the associations of the LPL and LDLR scores with plasma lipids, lipoproteins, and the risk of CHD appeared to be independent of each other”
Quote in the paperSubstantial claim - Findingown data
Variants in genes encoding targets of potential therapies that lower triglycerides through the LPL pathway and variants in genes encoding targets of current therapies that lower LDL-C through the LDLR pathway were associated with similar lower risk of CHD per unit difference in ApoB as the LPL and LDLR scores and the APOB score.
“variants in the genes that encode the targets for several potential therapies that lower triglycerides through the LPL pathway, and variants in the genes that encode the targets of several current therapies that lower LDL-C through the LDLR pathway, were also associated with similar lower risk of CHD per unit difference in ApoB as compared with the LPL and LDLR scores and as compared with an APOB”
Quote in the paperNot a substantial claim - Findingown data
Each LDLR exposure allele was associated with 3.42-mg/dL lower plasma LDL-C level.
“each exposure allele in the LDLR score was associated with an inverse variance-weighted mean of 3.42-mg/dL (95% CI, 3.27-3.57;P = 2.3 × 10 -464 ) lower plasma LDL-C level”
Quote in the paperSubstantial claim - Findingown data
The associated lower CHD risk for each of these variants and genetic scores was log-linearly proportional to their associated absolute lower level of ApoB-containing lipoproteins.
“the associated lower CHD risk for each of these variants and genetic scores was log-linearly proportional to their associated absolute lower level of ApoBcontaining lipoproteins”
Quote in the paperSubstantial claim - Findingown data
Each LPL exposure allele was associated with 0.11-mg/dL higher plasma LDL-C level.
“0.11-mg/dL (95% CI, 0.00-0.21;P = .04)higher plasma LDL-C level”
Quote in the paperSubstantial claim - Findingown data
Each LPL exposure allele was associated with 11.64-mg/dL lower plasma triglyceride level.
“Each exposure allele in the LPL score was associated with an inverse varianceweighted mean of 11.64-mg/dL (95% CI, 10.38-10.90;P = 8.3 × 10 -1365 ) lower plasma triglyceride level”
Quote in the paperSubstantial claim - Findingown data
In multivariable mendelian randomization analyses that included both triglycerides and LDL-C in the same model, the associations between plasma triglycerides and LDL-C with risk of CHD were independent and genome-wide significant.
“In multivariable mendelian randomization analyses that included both triglycerides and LDL-C in the same model, the associations between plasma triglycerides and LDL-C with the risk of CHD were independent and genome-wide significant.”
Quote in the paperSubstantial claim - Findingown data
In a 2 × 2 factorial mendelian randomization analysis, combined exposure to both scores was associated with log-linearly additive decreases in risk of CHD that were proportional to the absolute difference in ApoB but not to differences in either triglycerides or LDL-C.
“as well as a log-linearly ad- ditive decreases in the risk of CHD (LPL score alone: OR, 0.924 [95% CI, 0.889-0.960]; LDLR score alone: OR. 0.921 [95% CI: 0.885-0.958]; combined exposure to both scores: OR, 0.842 [95% CI, 0.811-0.874]) that was proportional to the absolute dif- ference in ApoB but not to differences in either triglycerides or LDL-C”
Quote in the paperSubstantial claim - Findingown data
Each LPL exposure allele was associated with 1.72-mg/dL lower level of ApoB-containing lipoproteins.
“and a 1.72-mg/dL (95% CI, 1.30-2.14;P = 5.5 × 10 -16 ) lower level of ApoB-containing lipoproteins.”
Quote in the paperNot a substantial claim - Findingown data
Despite being associated with different changes in lipids, all genetic scores were associated with similar lower risk of CHD for the same 10-mg/dL lower plasma ApoB concentration.
“Despite being associated with different changes in lipids, all genetic scores were associated with similar lower risk of CHD for the same 10-mg/dL lower plasma ApoB concentration.”
Quote in the paperSubstantial claim - Findingown data
When ApoB was included in the multivariable mendelian randomization analyses, the associations with CHD for both triglycerides (OR, 1.014 per 50-mg/dL lower triglycerides) and LDL-C (OR, 1.010 per 10-mg/dL lower LDL-C) became null.
“By contrast, when ApoB was included in the multivariable mendelian randomization analyses, the associations with CHD for both triglycerides (OR, 1.014 per 50-mg/dL lower triglycerides) and LDL-C (OR, 1.010 per 10-mg/dL lower LDL-C) became null, but the association per”
Quote in the paperSubstantial claim - Findingnone given
The association between lifetime exposure to lower triglycerides and LDL-C on cardiovascular disease risk is approximately the same per unit lower level of ApoB-containing particles.
“However, having first established that the association between lifetime exposure to lower triglycerides and LDL-C on the risk of cardiovascular disease is approximately the same per unit lower level of ApoB-containing particles, it is reasonable to”
Quote in the paperSubstantial claim - Findingown data
The association per 10-mg/dL lower ApoB remained unchanged (OR, 0.761 per 10-mg/dL lower ApoB) when ApoB was included in the multivariable mendelian randomization analyses.
“but the association per 10-mg/dL lower ApoB remained unchanged (OR, 0.761 per 10-mg/dL lower ApoB).”
Quote in the paperSubstantial claim - Interpretationreasoning
The clinical benefit of lowering triglyceride and LDL-C levels may be proportional to the absolute change in ApoB.
“Therefore, the clinical benefit of lowering triglyceride and LDL-C levels may be proportional to the absolute change in ApoB.”
Quote in the paperSubstantial claim- Rests on an assumption: Both triglycerides and cholesterol are carried in plasma by ApoB-containing lipoprotein particles.
- Rests on an assumption: All ApoB-containing lipoproteins have a single ApoB molecule.
- Premisecitation
All ApoB-containing lipoproteins less than 70 nm in diameter, including triglyceride-rich VLDL remnants and LDL particles, freely flux across the endothelial barrier where they can become retained in the artery wall.
“All ApoBcontaining lipoproteins less than 70 nm in diameter, including triglyceride-rich VLDL remnants and LDL particles, freely flux across the endothelial barrier where they can become retained in the artery wall.24”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [24] Borén, 2016, The central role of arterial retention of cholesterol-rich apolipoprotein-B-containing lipoproteins in the pathogenesis of atherosclerosis: a triumph of simplicity., Curr Opin Lipidol source
- Interpretationown data
The effect of ApoB-containing particles on the risk of atherosclerotic cardiovascular disease appears to be determined largely by the concentration of circulating ApoB particles, which in turn determines the number of particles that become retained in the artery wall, regardless of whether those particles principally contain cholesterol or triglycerides.
“The results of this study suggest that the effect of ApoB-containing particles on the risk of atherosclerotic cardiovascular disease appears to be determined largely by the concentration of circulating ApoB particles, which in turn determines the number of particles that become retained in the artery wall, regardless of whether those particles principally contain cholesterol or triglycerides.”
Quote in the paperSubstantial claim- Rests on an assumption: Both triglycerides and cholesterol are carried in plasma by ApoB-containing lipoprotein particles.
- Rests on an assumption: All ApoB-containing lipoproteins have a single ApoB molecule.
- Rests on an assumption: ApoB-containing particles are secreted by the liver as VLDL particles, which principally contain triglycerides, some cholesterol, and 1 molecule of ApoB.
- Rests on an assumption: Lipoprotein lipase removes most of the triglycerides from VLDL particles to convert them into triglyceride-depleted cholesterol-carrying LDL particles, which are then removed from plasma by hepatic LDL receptors.
- Interpretationreasoning
The clinical benefit of lowering triglyceride levels, lowering LDL-C levels, or lowering both may be proportional to the absolute change in ApoB-containing lipoproteins, regardless of the observed changes in plasma triglycerides or LDL-C.
“As a result, the clinical benefit of lowering triglyceride levels, lowering LDL-C levels, or lowering both may be proportional to the absolute change in ApoB-containing lipoproteins, regardless of the observed changes in plasma triglycerides or LDL-C.”
Quote in the paperSubstantial claim- Rests on an assumption: Both triglycerides and cholesterol are carried in plasma by ApoB-containing lipoprotein particles.
- Rests on an assumption: All ApoB-containing lipoproteins have a single ApoB molecule.
- Interpretationreasoning
The fibrate trials' results appear to be explained by the modest reductions in triglyceride levels and the corresponding modest reductions in ApoB-containing lipoproteins observed in those studies.
“Therefore, the results of the fibrate trials appear to be explained by the modest reductions in triglyceride level and therefore the modest corresponding reductions in ApoBcontaining lipoproteins observed in these studies.”
Quote in the paperSubstantial claim - Interpretationown data
The results of this study suggest that all ApoB-containing lipoprotein particles, including triglyceride-rich VLDL particles and their metabolic remnants as well as LDL particles, have approximately the same effect on the risk of cardiovascular disease per particle.
“The results of this study therefore suggest that all ApoBcontaining lipoprotein particles, including triglyceride-rich very-low-density lipoprotein (VLDL) particles and their metabolic remnants as well as LDL particles, have approximately the same effect on the risk of cardiovascular disease per particle.”
Quote in the paperSubstantial claim- Rests on an assumption: Both triglycerides and cholesterol are carried in plasma by ApoB-containing lipoprotein particles.
- Rests on an assumption: All ApoB-containing lipoproteins have a single ApoB molecule.
- Rests on an assumption: ApoB-containing particles are secreted by the liver as VLDL particles, which principally contain triglycerides, some cholesterol, and 1 molecule of ApoB.
- Rests on an assumption: Lipoprotein lipase removes most of the triglycerides from VLDL particles to convert them into triglyceride-depleted cholesterol-carrying LDL particles, which are then removed from plasma by hepatic LDL receptors.
- Interpretationown data
The present findings and interpretations based on mendelian randomization confirm and extend the initial findings and interpretations in 1980 of Sniderman and colleagues, which were based on cross-sectional coronary angiographic studies.
“The present findings and interpretations based on mendelian randomization confirm and extend the initial findings and interpretations in 1980 of Sniderman and colleagues, 26 which were based on cross-sectional coronary angiographic studies.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Sniderman and colleagues, 26
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Study design and conductown data
The associations of the LPL and LDLR scores with risk of CHD per unit lower ApoB were consistent between studies that contributed individual participant data and studies that contributed summary data.
“The associations of the LPL and LDLR scores with the risk of CHD per unit lower ApoB was consistent between studies that contributed individual participant data and studies that contributed summary data (eTable 6 in the Supplement).”
Quote in the paperNot a substantial claim - Interpretationreasoning
The causal effect of all ApoB-containing lipoprotein particles on cardiovascular disease risk appears to be determined by the circulating concentration of those particles rather than by the mass of cholesterol or triglyceride they carry.
“The results of the current study confirm and extend those findings by suggesting that the causal effect of all ApoB-containing lipoprotein particles on the risk of cardiovascular disease appears to be determined by the circulating concentration of those particles rather than by the mass of cholesterol or triglyceride that they carry.”
Quote in the paperSubstantial claim - Interpretationreasoning
The lower risk associated with lower triglycerides, LDL-C, and ApoB reported in this study is much larger than what has been reported for lipid-lowering therapies in randomized trials.
“As a result, the lower risk associated with lower triglycerides, LDL-C, and ApoB reported in this study is much larger than what have been reported for lipid-lowering therapies in randomized trials.”
Quote in the paperSubstantial claim
- May combine two claims. 11
- Classified as probably not a substantial claim. 8
- The quote only partly states this claim. 1
May combine two claims.
PremisecitationClinical guidelines do not recommend treatment to lower plasma triglyceride levels because randomized trials have not provided consistent evidence that lowering plasma triglyceride levels reduces cardiovascular event risk.
“By contrast, the guidelines do not recommend treatment to lower plasma triglyceride levels because randomized trials have not provided consistent evidence that lowering plasma triglyceride levels reduces the risk of cardiovascular events.1,2”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [1] Catapano, 2016, 2016 ESC/EAS guidelines for the management of dyslipidaemias., Eur Heart J source
Section 7.3 (p. 33) explicitly recommends considering drug treatment to lower triglycerides in high-risk patients with levels above 2.3 mmol/L, contrary to the claim that the guidelines do not recommend such treatment. The same section says evidence for benefit is modest, and section 9.5.2.2 (p. 42) describes mixed trial results; those qualifications do not negate the conditional recommendation. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured - cites [2] Stone, 2014, 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines., J Am Coll Cardiol source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationSeveral novel therapies that potently reduce triglyceride levels are currently in development.
“Several novel therapies that potently reduce triglyceride levels are currently in development.[6][7][8]”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites [6] Dewey, 2017, Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease., N Engl J Med source
- cites [7] Gaudet, 2017, ANGPTL3 inhibition in homozygous familial hypercholesterolemia., N Engl J Med source
- cites [8] Gaudet, 2015, Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia., N Engl J Med source
May combine two claims.
PremisecitationRare loss-of-function mutations in the LPL gene are associated with higher plasma triglyceride levels and a higher risk of cardiovascular disease.
“rare loss-of-function mutations in the lipoprotein lipase (LPL) gene are associated with higher plasma triglyceride levels and a higher risk of cardiovascular disease”
Quote in the paperSubstantial claim3 of 5 sources checked- cites [9] Nordestgaard, 1997, Heterozygous lipoprotein lipase deficiency: frequency in the general population, effect on plasma lipid levels, and risk of ischemic heart disease., Circulation source
- cites [10] Jørgensen, 2014, Loss-of-function mutations in APOC3 and risk of ischemic vascular disease., N Engl J Med source
The Abstract (page unavailable) supports the general association between higher triglyceride levels and greater cardiovascular risk. It does not report an association for loss-of-function mutations in the LPL gene: the mutations studied are in APOC3, and they are associated with lower triglyceride levels and reduced risk. The Discussion mentions lipoprotein lipase as an enzyme inhibited by apolipoprotein C3, not as the mutated gene. (LLM, conf=0.82)
Experimental — accuracy not yet measured - cites [11] Khera, 2017, Association of rare and common variation in the lipoprotein lipase gene with coronary artery disease., JAMA source
The Results (page unavailable) associate rare damaging LPL mutations with higher plasma triglycerides and greater odds of early-onset coronary artery disease (CAD); the CAD association was most pronounced for loss-of-function mutations. However, the triglyceride finding pools loss-of-function and damaging missense mutations, rather than establishing it for loss-of-function mutations alone. The study also assessed early-onset CAD, not cardiovascular disease generally. (LLM, conf=0.84)
Experimental — accuracy not yet measured - cites [12] Dewey, 2016, Inactivating variants in ANGPTL4 and risk of coronary artery disease., N Engl J Med source
- cites [13] Stitziel, 2016, Coding variation in ANGPTL4, LPL, and SVEP1 and the risk of coronary disease., N Engl J Med source
The ‘Coding Variation in LPL and the Risk of Coronary Artery Disease’ section reports that one low-frequency, partial loss-of-function LPL variant (p.D36N) was associated with higher coronary artery disease risk. Figure 2 in the Discussion depicts higher triglycerides as an expected effect of LPL loss of function, but the paper does not report a measured triglyceride association for that variant. The claim presents that expected effect as an observed association and generalizes from one variant to mutations. (LLM, conf=0.86)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationGenetic variants reflect the effect of lifelong changes in ApoB-containing lipoproteins on cardiovascular disease risk, which appear to be cumulative over time.
“Second, genetic variants reflect the effect of lifelong changes in ApoB-containing lipoproteins on the risk of cardiovascular disease, which appear to be cumulative over time.5,34”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [5] Ference, 2017, Low-density lipoproteins cause atherosclerotic cardiovascular disease: 1, Evidence from genetic, epidemiologic, and clinical studies: a consensus statement from the European Atherosclerosis Society Consensus Panel., Eur Heart J source
The sections on Mendelian randomization and cumulative LDL exposure say that LDL-C–associated genetic variants reflect lifetime cardiovascular risk and that the effect depends on the duration of LDL-C exposure (page not available). The paper identifies LDL as an apoB-containing lipoprotein, but its genetic and cumulative-exposure findings concern LDL specifically; they do not establish the same finding for apoB-containing lipoproteins as a whole. (LLM, conf=0.85)
Experimental — accuracy not yet measured - cites [34] Ference, 2012, Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease: a mendelian randomization analysis., J Am Coll Cardiol source
The Discussion (page not provided) says genetically mediated differences in LDL-C reflect the cumulative effect of lifelong exposure, and the study links those differences to coronary heart disease risk. It does not establish the same claim for ApoB-containing lipoproteins as a whole or for cardiovascular disease beyond coronary heart disease. (LLM, conf=0.86)
Experimental — accuracy not yet measured
May combine two claims.
Findingown dataThe study included 654,783 participants, including 91,129 cases of CHD, with mean age 62.7 years and 51.4% women.
“A total of 654 783 participants, including 91 129 cases of CHD, were included (mean age, 62.7 years; 51.4% women).”
Quote in the paperNot a substantial claimThe quote only partly states this claim.
Findingown dataIn a 2 × 2 factorial mendelian randomization analysis, combined exposure to both the LPL and LDLR genetic scores was associated with linearly additive lower levels of triglyceride, LDL-C, and ApoB.
“combined exposure to both the LPL and LDLR genetic scores was associated with linearly ad- ditive lower levels of triglyceride”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataFor each 10-mg/dL lower plasma ApoB concentration associated with a genetic score of 51 variants associated with triglycerides but not LDL-C, there was a corresponding 41.3-mg/dL lower triglyceride level, 2.1-mg/dL lower LDL-C level, and a lower risk of CHD (OR, 0.762 [95% CI, 0.724-0.803]).
“For example, for each 10-mg/dL lower plasma ApoB concentration associated with a genetic score consisting of 51 variants associated with triglycerides but not LDL-C at genome-wide level of significance, there was a corresponding 41.3-mg/dL lower triglyceride level, 2.1-mg/dL lower LDL-C level, and a lower risk of CHD (odds ratio [OR], 0.762 [95% CI, 0.724-0.803]).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn multivariable mendelian randomization analyses involving 186 genetic variants, both triglycerides (OR, 0.876 per 50-mg/dL lower triglycerides) and LDL-C (OR, 0.862 per 10-mg/dL lower LDL-C) were independently associated with a lower risk of CHD at genome-wide level of significance.
“For example, in multivariable mendelian randomization analyses involving these 186 genetic variants, both triglycerides (odds ratio [OR], 0.876 per 50-mg/dL lower triglycerides) and LDL-C (OR, 0.862 per 10-mg/dL lower LDL-C) were independently associated with a lower risk of CHD at genome-wide level of significance.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataFor the same 10-mg/dL lower plasma ApoB concentration associated with a genetic score of 168 variants associated with either triglycerides or LDL-C, there was a corresponding 21.6-mg/dL lower triglyceride level, an 11.8-mg/dL lower LDL-C level, and a similar lower risk of CHD (OR, 0.770 [95% CI, 0.757-0.783]).
“Furthermore, for the same 10-mg/dL lower plasma ApoB concentration associated with a genetic score consisting of 168 variants associated with either triglycerides or LDL-C at genome-wide level of significance, there was a corresponding 21.6-mg/dL lower triglyceride level, an 11.8-mg/dL lower LDL-C level, and a similar lower risk of CHD (OR, 0.770 [95% CI, 0.757-0.783]).”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThe associations between lower triglyceride level and lower LDL-C level with risk of CHD due to these variants appeared to be independent, additive, and proportional to the absolute change in ApoB.
“The associations between lower triglyceride level and lower LDL-C level with risk of CHD due to these variants appeared to be independent, additive, and proportional to the absolute change in ApoB.”
Quote in the paperSubstantial claim- Rests on an assumption: Both triglycerides and cholesterol are carried in plasma by ApoB-containing lipoprotein particles.
- Rests on an assumption: All ApoB-containing lipoproteins have a single ApoB molecule.
May combine two claims.
Interpretationown dataThe results of this study suggest that the clinical benefit of lowering triglyceride levels is similar to the clinical benefit of lowering LDL-C levels per unit change in ApoB and is proportional to the net absolute reduction in ApoB-containing lipoproteins.
“The results of this study suggest that the clinical benefit of lowering triglyceride levels is similar to the clinical benefit of lowering LDL-C levels per unit change in ApoB and is proportional to the net absolute reduction in ApoB-containing lipoproteins.”
Quote in the paperSubstantial claim- Rests on an assumption: Both triglycerides and cholesterol are carried in plasma by ApoB-containing lipoprotein particles.
- Rests on an assumption: All ApoB-containing lipoproteins have a single ApoB molecule.
Classified as probably not a substantial claim.
Study design and conductnone givenAll regression analyses were performed separately in each included study adjusting for age, sex, and the first 5 principal components of ancestry.
“All regression analyses were performed separately in each of the included studies adjusting for age, sex, and the first 5 principal components of ancestry.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationThe cholesterol, and perhaps triglyceride, content of the ApoB particles retained in the artery wall provokes an inflammatory response that leads to the initiation and progression of atherosclerotic plaque.
“The cholesterol, and perhaps triglyceride, content of the ApoB particles retained in the artery wall provokes an inflammatory response that leads to the initiation and progression of atherosclerotic plaque.25”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [25] Nordestgaard, 2014, Triglycerides and cardiovascular disease., Lancet source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAll authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.
“All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenThe funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
“Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenDr Ference had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
“Dr Ference had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductnone givenThis study compared triglyceride- and LDL-C-lowering genetic variants, not lipid-lowering therapies.
“First, this study compared triglyceride-and LDL-C-lowering genetic variants not lipidlowering therapies.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenNo other disclosures were reported.
“No other disclosures were reported.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
It is unknown whether lowering plasma triglyceride levels by targeting the LPL pathway will reduce the risk of cardiovascular events.
“However, it is unknown whether lowering plasma triglyceride levels by targeting the LPL pathway will reduce the risk of cardiovascular events.”
The paper relies on this without support.
Both triglycerides and cholesterol are carried in plasma by ApoB-containing lipoprotein particles.
“Both triglycerides and cholesterol are carried in plasma by apolipoprotein B (ApoB)-containing lipoprotein particles.”
The paper relies on this without support.
All ApoB-containing lipoproteins have a single ApoB molecule.
“Because all ApoB-containing lipoproteins, including triglyceriderich lipoprotein particles and LDL particles, have a single ApoB molecule”
The paper relies on this without support.
ApoB-containing particles are secreted by the liver as VLDL particles, which principally contain triglycerides, some cholesterol, and 1 molecule of ApoB.
“These particles are secreted by the liver as VLDL particles, which principally contain triglycerides, some cholesterol, and 1 molecule of ApoB.”
The paper relies on this without support.
Lipoprotein lipase removes most of the triglycerides from VLDL particles to convert them into triglyceride-depleted cholesterol-carrying LDL particles, which are then removed from plasma by hepatic LDL receptors.
“Lipoprotein lipase removes most of the triglycerides from these particles to convert the triglyceride-rich VLDL particles into triglyceridedepleted cholesterol-carrying LDL particles, which are then removed from plasma by hepatic LDL receptors.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Moderate elevations in triglyceride levels are associated with an increased risk of atherosclerotic cardiovascular disease.
“Moderate elevations in triglyceride levels are associated with an increased risk of atherosclerotic cardiovascular disease, 1,2,19,20”
From Targeting <i>APOC3</i> with Olezarsen in Moderate Hypertriglyceridemia (2025) · cites this paper as [20]
The Abstract reports that genetic variants associated with higher triglyceride levels are also associated with higher cardiovascular disease risk. The Discussion links triglyceride-rich ApoB particles to atherosclerotic cardiovascular risk, but it does not specifically establish the association for moderate triglyceride elevations; it emphasizes particle concentration rather than triglyceride level alone. Page numbers are unavailable in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredRecent genetic data show that lower levels of apoB-containing particles, whether cholesterol-rich LDL or triglyceride-rich VLDL, are associated with similar lower risk of major vascular events.
“Indeed, recent genetic data highlight that lower levels of apoB-containing particles, be it cholesterol-rich LDL or triglyceride-rich VLDL, are associated with similar lower risk of major vascular events.35”
From Association Between Triglyceride Lowering and Reduction of Cardiovascular Risk Across Multiple Lipid-Lowering Therapeutic Classes: A Systematic Review and Meta-Regression Analysis of Randomized Controlled Trials (2019) · cites this paper as [35]
The Discussion reports similar lower coronary heart disease (CHD) risk per unit lower ApoB for triglyceride-lowering and LDL-C-lowering genetic variants, and describes triglyceride-rich VLDL remnants and LDL as ApoB-containing particles. But the Study Outcomes section defines the measured outcome as CHD, not the broader category of major vascular events. (LLM, conf=0.86)
Experimental — accuracy not yet measuredRemnant lipoproteins are causal contributors to atherogenesis.
“Genetic studies and epidemiologic data increasingly implicate remnant lipoproteins as causal contributors to atherogenesis, providing a strong mechanistic and clinical rationale for targeted intervention [8–12].”
From Targeting Triglycerides in Cardiovascular Disease Prevention: Evidence, Mechanisms, and Emerging Therapies (2026) · cites this paper as [12]
Mendelian randomization studies demonstrated that the reduction in cardiovascular risk associated with genetic variation in clearance and processing of apoB-containing lipoproteins, including LDL particles as well as TG-rich VLDL particles and their remnants, was correlated with the change of concentration of these particles as measured by apoB rather than the cholesterol mass carried by those as
“Furthermore, Mendelian randomization studies demonstrated that the reduction in cardiovascular risk associated with genetic variation in clearance and processing of apoB-containing lipoproteins, including LDL particles as well as TG-rich VLDL particles and their remnants, was correlated with the change of concentration of these particles as measured by apoB rather than the cholesterol mass carried”
From Quantifying atherogenic lipoproteins for lipid-lowering strategies: Consensus-based recommendations from EAS and EFLM (2020) · cites this paper as [80]
The number of atherogenic particles may be the driver of cardiovascular risk, rather than cholesterol or triglyceride content per se.
“suggesting that the number of atherogenic particles may be the driver of cardiovascular risk, rather than cholesterol or TG content per se.4,5”
From Association of Apolipoprotein B–Containing Lipoproteins and Risk of Myocardial Infarction in Individuals With and Without Atherosclerosis (2022) · cites this paper as [4]
Mendelian randomization studies have shown that apoB is a better predictor of coronary artery disease risk than serum LDL-C or triglyceride concentration.
“Mendelian randomization studies have shown that apoB is a better predictor of coronary artery disease risk than serum LDL-C or TG concentration”
From Association of Apolipoprotein B–Containing Lipoproteins and Risk of Myocardial Infarction in Individuals With and Without Atherosclerosis (2022) · cites this paper as [4]
Triglyceride-lowering is associated with about half the CV risk reduction per mmol/L and therefore closer to 1⁄4 the benefit per mg/dL compared with LDL-C lowering.
“We demonstrate that triglyceride-lowering is associated with about half the CV risk reduction per mmol/L and therefore closer to ¼ the benefit per mg/dL (1 mmol/L = 38.67 mg/dl of LDL-C and 88.57 mg/dL of TG), a ratio congruent with our Mendelian randomization study data.35”
Triglycerides per se may not be atherogenic, but rather may be a marker for the concentration of atherogenic very low density lipoprotein (VLDL) particles.
“Moreover, triglycerides per se may not be atherogenic, but rather may be a marker for the concentration of atherogenic very low density lipoprotein (VLDL) particles.35”
On a mg/dL basis, the association of triglycerides with major vascular events is less strong than that for LDL-C.
“but also that, on a mg/dL basis, the association of triglycerides with major vascular events is less strong as that for LDL-C.6,8,35”
Lower triglyceride levels, when accompanied by lower apolipoprotein B levels, are associated with lower cardiovascular risk.
“However, genetic studies suggest that lower triglyceride levels, when accompanied by lower apolipoprotein B levels, are associated with lower CV risk”
The authors' recent Mendelian randomization study suggests that the number of atherogenic apoB-containing lipoproteins is the true determinant of cardiovascular risk, not the cholesterol or triglyceride content per se.
“Nonetheless, it is important to note that our recent Mendelian randomization study35 would suggest that it is simply the number of atherogenic apoB-containing lipoproteins that is the true determinant of cardiovascular risk and not the cholesterol or triglyceride content per se, which are surrogate biomarkers.”
Multiple lipoprotein metabolism disturbances in prediabetes and type 2 diabetes arise from the combined effects of insulin deficiency, insulin resistance, and hyperglycemia.
“Multiple disturbances in lipoprotein metabolism in individuals with prediabetes and T2D result from the combined effects of insulin deficiency, insulin resistance, and hyperglycemia.”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [308]
The Discussion describes VLDL-to-LDL metabolism and the relationship between ApoB-containing particles and coronary heart disease, but does not address what causes lipoprotein disturbances in prediabetes or type 2 diabetes. Searches for insulin deficiency, insulin resistance, hyperglycemia, and prediabetes found no passage supporting the claimed combined mechanism; diabetes appears in a baseline table and reference titles. (LLM, conf=0.76)
Experimental — accuracy not yet measuredOver the past three decades, epidemiologic and genetic evidence supports that elevated plasma levels of triglycerides, triglyceride-rich lipoproteins, and triglyceride-rich lipoprotein remnants are causally related to increased risk of atherosclerotic cardiovascular disease-related events, including myocardial infarction, stroke, and aortic valve stenosis, and all-cause mortality.
“Over the past three decades, epidemiologic and genetic evidence has accumulated to support the concept that elevated levels of plasma TG, TRL, and TRL remnants are causally related to an increased risk of ASCVD-related events—myocardial infarction (MI), stroke, and aortic valve stenosis—and all-cause mortality.1,2,17,19,20,24–28”
Recent advances in human genetics, epidemiologic, preclinical, and clinical trial results provide strong support for a causal association between triglycerides, triglyceride-rich lipoproteins, and triglyceride-rich lipoprotein remnants and increased risk of myocardial infarction, ischaemic stroke, and aortic valve stenosis.
“Recent advances in human genetics, together with a large body of epidemiologic, preclinical, and clinical trial results, provide strong support for a causal association between triglycerides (TG), TG-rich lipoproteins (TRL), and TRL remnants, and increased risk of myocardial infarction, ischaemic stroke, and aortic valve stenosis.”
Multiple epidemiological and genetic analyses have demonstrated an independent association between elevated triglycerides and increased cardiovascular risk.
“Multiple epidemiological and genetic analyses have demonstrated an independent association with increased cardiovascular risk (14)”
From Effects of Icosapent Ethyl on Total Ischemic Events (2019) · cites this paper as [14]
ASCVD risk mediated by TRLs appears to be determined by the circulating concentration of apoB-containing particles rather than their TG content, and the clinical benefit of lowering TG correlates with the reduction in apoB rather than the change in plasma TG concentration.
“Atherosclerotic cardiovascular disease risk mediated by TRLs appears to be determined by the circulating concentration of apoB-containing particles rather than their TG content and that the clinical benefit of lowering TG correlates with the reduction in apoB, rather than the change in plasma TG concentration.”
From Clinical review on triglycerides (2020) · cites this paper as [24]
A recent Mendelian randomization study found that all apoB-containing lipoproteins have a similar effect on ASCVD risk.
“A recent Mendelian randomization study found that all apoB-containing lipoproteins have a similar effect on ASCVD risk.24”
From Clinical review on triglycerides (2020) · cites this paper as [24]
Long-term exposure to lower LDL-C levels is associated with a much lower risk of cardiovascular events than shorter-term exposure to lower LDL-C.
“Furthermore, Mendelian randomization studies have demonstrated that long-term exposure to lower LDL-C levels is associated with a much lower risk of CV events as compared with shorter-term exposure to lower LDL-C (as achieved, for example, in randomized trials) [48,52].”
From 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk (2019) · cites this paper as [52]
Triglyceride elevation is a potent marker of residual cardiovascular risk in patients with well-controlled LDL-C on statin therapy.
“Triglyceride elevation is a potent marker of residual cardiovascular risk in patients with well-controlled low-density lipoprotein cholesterol (LDL-C) on statin therapy, as shown in both randomized statin trials and observational studies.1–3”
From REDUCE-IT USA: Results From the 3146 Patients Randomized in the United States (2020) · cites this paper as [2]
Haemoglobin is a heterotetramer that is made up of alpha and beta globin polypeptides, each encoded by discrete genes.
“For example, haemoglobin is a heterotetramer that is made up of alpha and beta globin polypeptides, each encoded by discrete genes 62 .”
From Integrating genomics with biomarkers and therapeutic targets to invigorate cardiovascular drug development (2021) · cites this paper as [62]
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.
LPL triglyceride estimate falls outside its confidence interval
MinorThe reported estimate of 11.64 mg/dL is above the stated 95% CI upper bound of 10.90 mg/dL. The interval's midpoint is 10.64 mg/dL, not 11.64 mg/dL.
Reported 11.64 · recomputed 10.64
“11.64-mg/dL (95% CI, 10.38-10.90;P = 8.3 × 10 -1365 ) lower plasma triglyceride level”
Triglyceride change for the 51-variant score differs between text and table
MinorThe Table 2 description gives a 41.3-mg/dL reduction for the 51-variant score, whereas the table reports a 43.1-mg/dL reduction.
“there was a corresponding 41.3-mg/dL lower triglyceride level”
“| 51 Variants associated with triglycerides at P < 5.0×10 -8 , | -43.1 (-44.5 to -41.7) | -2.1 (-2.6 to -1.6) | 0.762 (0.724 to 0.803) |”
LDLR-associated LDL-C reduction differs between figure caption and results
MinorThe Figure 1 caption reports a 14.1-mg/dL reduction per 10-mg/dL lower ApoB, while the results report 14.2 mg/dL for the same comparison.
“there is a corresponding 14.1-mg/dL lower LDL-C level”
“the LDLR score was associated with 14.2-mg/dL (95% CI, 13.6-14.8;P = 1.4 × 10 -465 ) lower plasma LDL-C level”
LPL triglyceride confidence-interval bound differs across presentations
MinorThe lower-triglyceride association has a 95% CI endpoint of −68.3 mg/dL in the Figure 1 material, but −68.1 mg/dL in the Figure 2 material.
“-69.9 (-71.6 to -68.3)”
“-69.9 (-71.6 to -68.1)”
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Gaudet, D., Gipe, D. A., Pordy, R., Ahmad, Z., Cuchel, M., Shah, P. K., Chyu, K.-Y., Sasiela, W. J., Chan, K.-C., Brisson, D., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmc1705994 · Cited by 323 · see citing works
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Self-citationAssociation of rare and common variation in the lipoprotein lipase gene with coronary artery disease
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How to use Mendelian randomization to anticipate the results of randomized trials
Ference, B. A. (2018) · European Heart Journal · doi:10.1093/eurheartj/ehx462 · Cited by 96 · see citing works
Self-citationLoss-of-Function Mutations in APOC3 and Risk of Ischemic Vascular Disease
Jørgensen, A. B., Frikke‐Schmidt, R., & Nordestgaard, B. G. (2014) · Journal of Vascular Surgery · doi:10.1016/j.jvs.2014.08.087 · Cited by 41 · see citing works
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Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease
Stitziel, N. O., Stirrups, K. E., Masca, N. G. D., Erdmann, J., Ferrario, P. G., Koenig, I. R., Weeke, P. E., Webb, T. R., Auer, P. L., Schick, U. M., et al. (2016) · New England Journal of Medicine · doi:10.1056/nejmx160012 · Cited by 20 · see citing works
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Heart Disease and Stroke Statistics—2020 Update: A Report From the American Heart Association
Virani, S. S., Alonso, A., Benjamin, E. J., Bittencourt, M. S., Callaway, C. W., Carson, A. P., Chamberlain, A. M., Chang, A. R., Cheng, S., Delling, F. N., et al. (2020) · Circulation · doi:10.1161/cir.0000000000000757 · Cited by 9,175 · see citing works
Heart Disease and Stroke Statistics—2023 Update: A Report From the American Heart Association
Tsao, C. W., Aday, A. W., Almarzooq, Z. I., Anderson, C. A. M., Arora, P., Avery, C. L., Baker-Smith, C. M., Beaton, A. Z., Boehme, A. K., Buxton, A. E., et al. (2023) · Circulation · doi:10.1161/cir.0000000000001123 · Cited by 8,300 · see citing works
Heart Disease and Stroke Statistics—2022 Update: A Report From the American Heart Association
Tsao, C. W., Aday, A. W., Almarzooq, Z. I., Alonso, A., Beaton, A. Z., Bittencourt, M. S., Boehme, A. K., Buxton, A. E., Carson, A. P., Commodore-Mensah, Y., et al. (2022) · Circulation · doi:10.1161/cir.0000000000001052 · Cited by 5,987 · see citing works
Heart Disease and Stroke Statistics—2021 Update: A Report From the American Heart Association
Virani, S. S., Alonso, A., Aparicio, H. J., Benjamin, E. J., Bittencourt, M. S., Callaway, C. W., Carson, A. P., Chamberlain, A. M., Cheng, S., Delling, F. N., et al. (2021) · Circulation · doi:10.1161/cir.0000000000000950 · Cited by 5,784 · see citing works
Mach, F., Baigent, C., Catapano, A. L., Koskinas, K. C., Casula, M., Badimon, L., Chapman, M. J., De Backer, G. G., Delgado, V., Ference, B. A., et al. (2019) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2019.08.014 · Cited by 4,854 · see citing works
Self-citationMartin, S. S., Aday, A. W., Almarzooq, Z. I., Anderson, C. A. M., Arora, P., Avery, C. L., Baker-Smith, C. M., Barone Gibbs, B., Beaton, A. Z., Boehme, A. K., et al. (2024) · Circulation · doi:10.1161/cir.0000000000001209 · Cited by 2,800 · see citing works
Martin, S. S., Aday, A. W., Allen, N. B., Almarzooq, Z., Anderson, C. A. M., Arora, P. K., Avery, C. L., Baker-Smith, C. M., Bansal, N., Beaton, A., et al. (2025) · Circulation · doi:10.1161/cir.0000000000001303 · Cited by 1,206 · see citing works
Ginsberg, H. N., Packard, C. J., Chapman, M. J., Borén, J., Aguilar-Salinas, C. A., Averna, M., Ference, B. A., Gaudet, D., Hegele, R. A., Kersten, S., et al. (2021) · European Heart Journal · doi:10.1093/eurheartj/ehab551 · Cited by 979 · see citing works
Self-citationRichardson, T. G., Sanderson, E., Palmer, T. M., Ala-Korpela, M., Ference, B. A., Davey Smith, G., & Holmes, M. V. (2020) · PLOS Medicine · doi:10.1371/journal.pmed.1003062 · Cited by 843 · see citing works
“This adds further evidence to support the hypothesis that it is the number of atherogenic lipoprotein particles indexed by apolipoprotein B rather than the amount of circulating cholesterol or triglycerides per se that is the important driver of CHD [26].”
BackgroundResultInfluentialSelf-citationHarrison, S. A., Bashir, M. R., Guy, C. D., Zhou, R., Moylan, C. A., Frias, J. P., Alkhouri, N., Bansal, M. B., Baum, S., Neuschwander-Tetri, B. A., et al. (2019) · The Lancet · doi:10.1016/s0140-6736(19)32517-6 · Cited by 802 · see citing works
Apolipoprotein B Particles and Cardiovascular Disease: A Narrative Review
Sniderman, A. D., Thanassoulis, G., Glavinovic, T., Navar, A. M., Pencina, M., Catapano, A., & Ference, B. A. (2019) · JAMA Cardiology · doi:10.1001/jamacardio.2019.3780 · Cited by 593 · see citing works
Self-citationClinical review on triglycerides
Laufs, U., Parhofer, K. G., Ginsberg, H. N., & Hegele, R. A. (2020) · European Heart Journal · doi:10.1093/eurheartj/ehz785 · Cited by 544 · see citing works
“24 Atherosclerotic cardiovascular disease risk mediated by TRLs appears to be determined by the circulating concentration of apoB-containing particles rather than their TG content and that the clinical benefit of lowering TG correlates with the reduction in apoB, rather than the change in plasma TG…”
BackgroundSelf-citationBlonde, L., Umpierrez, G. E., Reddy, S. S., McGill, J. B., Berga, S. L., Bush, M., Chandrasekaran, S., DeFronzo, R. A., Einhorn, D., Galindo, R. J., et al. (2022) · Endocrine Practice · doi:10.1016/j.eprac.2022.08.002 · Cited by 507 · see citing works
Remnant cholesterol predicts cardiovascular disease beyond LDL and ApoB: A primary prevention study
Quispe, R., Martin, S. S., Michos, E. D., Lamba, I., Blumenthal, R. S., Saeed, A., Lima, J., Puri, R., Nomura, S., Tsai, M., et al. (2021) · European Heart Journal · doi:10.1093/eurheartj/ehab432 · Cited by 441 · see citing works
Self-citationYin, K., Wang, Y., Zhao, H., Wang, D., Guo, M., Mu, M., Liu, Y., Nie, X., Li, B., Li, J., et al. (2021) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2021.145758 · Cited by 437 · see citing works
Using Mendelian Randomization to Improve the Design of Randomized Trials
Ference, B. A., Holmes, M. V., & Smith, G. D. (2021) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a040980 · Cited by 338 · see citing works
Self-citationDuran, E. K., Aday, A. W., Cook, N. R., Buring, J. E., Ridker, P. M., & Pradhan, A. D. (2020) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2020.02.059 · Cited by 336 · see citing works
“RELATIONSHIP WITH Apo B Also relevant to our findings, recent evidence from a large study of LPL and LDLR gene variants suggests that the total Apo B particle concentration may be more influential in the development of CHD than either the triglyceride or cholesterol content of TRL and LDL particles (58).”
BackgroundHDL in the 21st Century: A Multifunctional Roadmap for Future HDL Research
Rohatgi, A. K., Westerterp, M., von Eckardstein, A., Remaley, A. T., & Rye, K. (2021) · Circulation · doi:10.1161/circulationaha.120.044221 · Cited by 333 · see citing works
Richardson, T. G., Leyden, G. M., Wang, Q., Bell, J. A., Elsworth, B., Davey Smith, G., & Holmes, M. V. (2022) · PLOS Biology · doi:10.1371/journal.pbio.3001547 · Cited by 304 · see citing works
Marston, N. A., Giugliano, R. P., Im, K., Silverman, M. G., O’Donoghue, M. L., Wiviott, S. D., Ference, B. A., & Sabatine, M. S. (2019) · Circulation · doi:10.1161/circulationaha.119.041998 · Cited by 301 · see citing works
Self-citationOkamura, T., Tsukamoto, K., Arai, H., Fujioka, Y., Ishigaki, Y., Koba, S., Ohmura, H., Shoji, T., Yokote, K., Yoshida, H., et al. (2023) · Journal of Atherosclerosis and Thrombosis · doi:10.5551/jat.gl2022 · Cited by 317 · see citing works
Evinacumab in Patients with Refractory Hypercholesterolemia
Rosenson, R. S., Burgess, L. J., Ebenbichler, C. F., Baum, S. J., Stroes, E. S. G., Ali, S., Khilla, N., Hamlin, R., Pordy, R., Dong, Y., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa2031049 · Cited by 302 · see citing works
Systems biology in cardiovascular disease: a multiomics approach
Joshi, A., Rienks, M., Theofilatos, K., & Mayr, M. (2020) · Nature Reviews Cardiology · doi:10.1038/s41569-020-00477-1 · Cited by 305 · see citing works
Apolipoprotein B and Cardiovascular Disease: Biomarker and Potential Therapeutic Target
Behbodikhah, J., Ahmed, S., Elyasi, A., Kasselman, L. J., Leon, J. D., Glass, A. D., & Reiss, A. B. (2021) · Metabolites · doi:10.3390/metabo11100690 · Cited by 284 · see citing works
“in 2019 [212] shed light on the importance of apoB particle number in determining CHD risk.”
BackgroundApolipoproteins in vascular biology and atherosclerotic disease
Mehta, A., & Shapiro, M. D. (2022) · Nature Reviews Cardiology · doi:10.1038/s41569-021-00613-5 · Cited by 273 · see citing works
Marston, N. A., Giugliano, R. P., Melloni, G. E. M., Park, J.-G., Morrill, V., Blazing, M. A., Ference, B., Stein, E., Stroes, E. S., Braunwald, E., et al. (2022) · JAMA Cardiology · doi:10.1001/jamacardio.2021.5083 · Cited by 262 · see citing works
Self-citationGenome-wide characterization of circulating metabolic biomarkers
Karjalainen, M. K., Karthikeyan, S., Oliver‐Williams, C., Sliz, E., Allara, E., Fung, W. T., Surendran, P., Zhang, W., Jousilahti, P., Kristiansson, K., et al. (2024) · Nature · doi:10.1038/s41586-024-07148-y · Cited by 268 · see citing works
“We therefore used the number of PCs (28) explaining >95% variation in the metabolic traits defined in the largest cohort, INTERVAL, to correct for multiple-testing, and our genome-wide significance threshold was set to p < 1.”
MethodSelf-citationEffects of Icosapent Ethyl on Total Ischemic Events
Bhatt, D. L., Steg, P. G., Miller, M., Brinton, E. A., Jacobson, T. A., Ketchum, S. B., Doyle, R. T., Juliano, R. A., Jiao, L., Granowitz, C., et al. (2019) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2019.02.032 · Cited by 259 · see citing works
Self-citationHandelsman, Y., Jellinger, P. S., Guerin, C. K., Bloomgarden, Z. T., Brinton, E. A., Budoff, M. J., Davidson, M. H., Einhorn, D., Fazio, S., Fonseca, V. A., et al. (2020) · Endocrine Practice · doi:10.4158/cs-2020-0490 · Cited by 248 · see citing works
“Hypertriglyceridemia may present with increased numbers or concentrations of atherogenic small, dense LDL particles and apo B-100-associated triglyceride-rich lipoprotein remnant cholesterol particles, which increase ASCVD risk (92).”
Triglycerides and residual atherosclerotic risk
Raposeiras-Roubin, S., Rosselló, X., Oliva, B., Fernández-Friera, L., Mendiguren, J. M., Andrés, V., Bueno, H., Sanz, J., Martínez de Vega, V., Abu-Assi, E., et al. (2021) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2021.04.059 · Cited by 254 · see citing works
Palaniappan, L. P., Allen, N. B., Almarzooq, Z., Anderson, C. A. M., Arora, P. K., Avery, C. L., Baker-Smith, C. M., Bansal, N., Currie, M. E., Earlie, R. S., et al. (2026) · Circulation · doi:10.1161/cir.0000000000001412 · Cited by 312 · see citing works
2026 ACC/AHA/AACVPR/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Dyslipidemia
Blumenthal, R. S., Morris, P. B., Gaudino, M., Johnson, H. M., Anderson, T. S., Bittner, V. A., Blankstein, R., Brewer, L. C., Cho, L., de Ferranti, S. D., et al. (2026) · JACC · doi:10.1016/j.jacc.2025.11.016 · Cited by 304 · see citing works
Causes and consequences of hypertriglyceridemia
Packard, C. J., Boren, J., & Taskinen, M.-R. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.00252 · Cited by 239 · see citing works
“In this context, it is important to note the findings of a recent study in which genetic variants that lower plasma triglyceride were associated with reduced ASCVD risk only when there was a commensurate decrease in apo B (18).”
BackgroundSelf-citationNordestgaard, B. G., Langlois, M. R., Langsted, A., Chapman, M. J., Aakre, K. M., Baum, H., Borén, J., Bruckert, E., Catapano, A., Cobbaert, C., et al. (2020) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2019.12.005 · Cited by 240 · see citing works
“Furthermore, Mendelian randomization studies demonstrated that the reduction in cardiovascular risk associated with genetic variation in clearance and processing of apoB-containing lipoproteins, including LDL particles as well as TG-rich VLDL particles and their remnants, was correlated with the change of concentratio…”
BackgroundSelf-citationCoronary heart disease risk: Low-density lipoprotein and beyond
Shaya, G. E., Leucker, T. M., Jones, S. R., Martin, S. S., & Toth, P. P. (2021) · Trends in Cardiovascular Medicine · doi:10.1016/j.tcm.2021.04.002 · Cited by 243 · see citing works
2023 Chinese guideline for lipid management
Li, J., Zhao, S., Zhao, D. H., Lü, G., Peng, D., Liu, J., Chen, Z., Guo, Y., Wu, N., Yan, S.-K., et al. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1190934 · Cited by 227 · see citing works
Ference, B. A., Bhatt, D. L., Catapano, A. L., Packard, C. J., Graham, I. M., Kaptoge, S. K., Ference, T. B., Guo, Q., Laufs, U., Ruff, C. T., et al. (2019) · JAMA · doi:10.1001/jama.2019.14120 · Cited by 222 · see citing works
Self-citationCardiovascular disease in diabetes, beyond glucose
Eckel, R. H., Bornfeldt, K., & Goldberg, I. J. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.07.001 · Cited by 224 · see citing works
Zodasiran, an RNAi Therapeutic Targeting ANGPTL3, for Mixed Hyperlipidemia
Rosenson, R. S., Gaudet, D., Hegele, R. A., Ballantyne, C. M., Nicholls, S. J., Lucas, K. J., San Martin, J., Zhou, R., Muhsin, M., Chang, T., et al. (2024) · New England Journal of Medicine · doi:10.1056/nejmoa2404147 · Cited by 213 · see citing works
Self-citationWelsh, C., Celis-Morales, C. A., Brown, R., Mackay, D. F., Lewsey, J., Mark, P. B., Gray, S. R., Ferguson, L. D., Anderson, J. J., Lyall, D. M., et al. (2019) · Circulation · doi:10.1161/circulationaha.119.041149 · Cited by 191 · see citing works
Olezarsen for Hypertriglyceridemia in Patients at High Cardiovascular Risk
Bergmark, B. A., Marston, N. A., Prohaska, T. A., Alexander, V. J., Zimerman, A., Moura, F. A., Murphy, S. A., Goodrich, E. L., Zhang, S., Gaudet, D., et al. (2024) · New England Journal of Medicine · doi:10.1056/nejmoa2402309 · Cited by 198 · see citing works
Self-citationThe Roles of ApoC-III on the Metabolism of Triglyceride-Rich Lipoproteins in Humans
Borén, J., Packard, C. J., & Taskinen, M.-R. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.00474 · Cited by 196 · see citing works
“showing that reductions in triglyceride levels do not reduce CVD risk unless there was an accompanying reduction in circulating apoB levels, and that the reduction in risk was proportional to the decrement in apoB (105).”
BackgroundSelf-citationHolmes, M. V., Richardson, T. G., Ference, B. A., Davies, N. M., & Davey Smith, G. (2021) · Nature Reviews Cardiology · doi:10.1038/s41569-020-00493-1 · Cited by 184 · see citing works
Self-citationBjörnson, E., Adiels, M., Taskinen, M.-R., Burgess, S., Rawshani, A., Borén, J., & Packard, C. J. (2023) · European Heart Journal · doi:10.1093/eurheartj/ehad337 · Cited by 183 · see citing works
“The clusters could now be used to ascertain if the per-particle atherogenicity of TRL/remnants differed from that of LDL.”
InfluentialSelf-citationThe LDL cumulative exposure hypothesis: evidence and practical applications
Ference, B. A., D, E. B. M., & Catapano, A. L. (2024) · Nature Reviews Cardiology · doi:10.1038/s41569-024-01039-5 · Cited by 191 · see citing works
“…reduction in cardiovascular risk for the same reduction in LDL-C levels is nearly identical for all genetic variants that lower LDL levels (or the levels of APOB-containing lipoproteins in general), including variants in genes encoding the targets of various lipid-lowering therapies 18,71–73 .”
InfluentialSelf-citationBalling, M., Afzal, S., Varbo, A., Langsted, A., Davey Smith, G., & Nordestgaard, B. G. (2020) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2020.09.610 · Cited by 175 · see citing works
Newman, C. B., Blaha, M. J., Boord, J. B., Cariou, B., Chait, A., Fein, H. G., Ginsberg, H. N., Goldberg, I. J., Murad, M. H., Subramanian, S., et al. (2020) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaa674 · Cited by 180 · see citing works
Self-citationThe first MASH drug therapy on the horizon: Current perspectives of resmetirom
Petta, S., Targher, G., Romeo, S., Pajvani, U. B., Zheng, M., Aghemo, A., & Valenti, L. (2024) · Liver international (Print) · doi:10.1111/liv.15930 · Cited by 174 · see citing works
“39 Based on Mendelian randomization studies, 40 it could be estimated, as shown in Table 2 , that the observed resmetirom-induced improvement in circulating lipids would reduce major adverse cardiovascular events by 16–21%, respectively.”
BackgroundPlasma lipids and risk of aortic valve stenosis: a Mendelian randomization study
Nazarzadeh, M., Pinho-Gomes, A.-C., Bidel, Z., Dehghan, A., Canoy, D., Hassaine, A., Ayala Solares, J. R., Salimi-Khorshidi, G., Smith, G. D., Otto, C. M., et al. (2020) · European Heart Journal · doi:10.1093/eurheartj/ehaa070 · Cited by 163 · see citing works
Gaggini, M., Gorini, F., & Vassalle, C. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms24010075 · Cited by 183 · see citing works
Nicholls, S., Lincoff, A. M., Bays, H. E., Cho, L., Grobbee, D. E., Kastelein, J. J., Libby, P., Moriarty, P. M., Plutzky, J., Ray, K. K., et al. (2021) · American Heart Journal · doi:10.1016/j.ahj.2020.10.060 · Cited by 136 · see citing works
Self-citationAverna, M. R., Banach, M., Bruckert, É., Drexel, H., Farnier, M., Gaiță, D. I., Magni, P., März, W., Masana, L., Silva, A. M. E., et al. (2021) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2021.03.039 · Cited by 142 · see citing works
Self-citationLi, Z., Zhang, B., Liu, Q., Tao, Z., Ding, L., Guo, B., Zhang, E., Zhang, H., Meng, Z., Guo, S., et al. (2023) · EBioMedicine · doi:10.1016/j.ebiom.2023.104543 · Cited by 137 · see citing works
REDUCE-IT USA: Results From the 3146 Patients Randomized in the United States
Bhatt, D. L., Miller, M., Brinton, E. A., Jacobson, T. A., Steg, P. G., Ketchum, S. B., Doyle, R. T., Juliano, R. A., Jiao, L., Granowitz, C., et al. (2020) · Circulation · doi:10.1161/circulationaha.119.044440 · Cited by 136 · see citing works
Self-citationWilson, P. W. F., Jacobson, T. A., Martin, S. S., Jackson, E. J., Le, N., Davidson, M. H., Vesper, H. W., Frikke‐Schmidt, R., Ballantyne, C. M., & Remaley, A. T. (2021) · Journal of clinical lipidology · doi:10.1016/j.jacl.2021.09.046 · Cited by 134 · see citing works
PCSK9 inhibition and inflammation: A narrative review
Ruscica, M., Tokgözoğlu, L. S., Corsini, A., & Sirtori, C. R. (2019) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2019.07.015 · Cited by 130 · see citing works
“In addition to the well established role of LDL-C [35], the contribution of triglycerides (TG) to a raised CV risk has become clear both after long-term prospective studies [36] and a recent mendelian randomization analysis [37].”
BackgroundFeeney, E. L., Lamichhane, P., & Sheehan, J. J. (2021) · International Journal of Dairy Technology · doi:10.1111/1471-0307.12755 · Cited by 132 · see citing works
“…relatively high levels of saturated fatty acids (SFAs), which are commonly perceived as negatively impacting the healthfulness of the diet, and have been associated with increased blood LDL-cholesterol levels, often considered a marker for cardiovascular disease (CVD) risk (Ference et al. 2019).”
BackgroundMeta-analysis investigating the role of interleukin-6 mediated inflammation in type 2 diabetes
Bowker, N., Shah, R. L., Sharp, S. J., Luan, J., Stewart, I. D., Wheeler, E., Ferreira, M. A. R., Baras, A., Wareham, N. J., Langenberg, C., et al. (2020) · EBioMedicine · doi:10.1016/j.ebiom.2020.103062 · Cited by 126 · see citing works
“Statistical approaches have been proposed to model these differences and formulate approximate projections of a range of possible effects of drug treatment on the basis of the magnitude of genetic associations [56,57].”
BackgroundRole of Omega-3 Fatty Acids in Cardiovascular Disease: the Debate Continues
Sherratt, S. C. R., Libby, P., Budoff, M. J., Bhatt, D. L., & Mason, R. P. (2022) · Current Atherosclerosis Reports · doi:10.1007/s11883-022-01075-x · Cited by 132 · see citing works
Self-citationMach, F., Baigent, C., Catapano, A. L., Koskinas, K. C., Casula, M., Badimon, L., Chapman, M. J., De Backer, G. G., Delgado, V., Ference, B. A., et al. (2020) · European Heart Journal · doi:10.1093/eurheartj/ehz455 · Cited by 8,961 · see citing works
Self-citationMakover, M. E., Shapiro, M. D., & Toth, P. P. (2022) · American Journal of Preventive Cardiology · doi:10.1016/j.ajpc.2022.100371 · Cited by 133 · see citing works
Therapeutic potential of popular fermented dairy products and its benefits on human health
Saleem, G., Gu, R., Qu, H., Khaskheli, G. B., Rajput, I. R., Qasim, M., & Chen, X. (2024) · Frontiers in Nutrition · doi:10.3389/fnut.2024.1328620 · Cited by 134 · see citing works
Writing Committee Members, Blumenthal, R. S., Morris, P. B., Gaudino, M., Johnson, H. M., Anderson, T. S., Bittner, V. A., Blankstein, R., Brewer, L. C., Cho, L., et al. (2026) · Circulation · doi:10.1161/cir.0000000000001423 · Cited by 122 · see citing works
Animal Models of Atherosclerosis–Supportive Notes and Tricks of the Trade
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Mendelian Randomization as a Tool for Cardiovascular Research
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“26,52”
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- Authors
- Ference, B. A., Kastelein, J. J. P., Ray, K. K., Ginsberg, H. N., Chapman, M. J., Packard, C. J., Laufs, U., Oliver-Williams, C., Wood, A. M., Butterworth, A. S., Di Angelantonio, E., Danesh, J., Nicholls, S. J., Bhatt, D. L., Sabatine, M. S., & Catapano, A. L.
- Affiliations
- University of Cambridge (GB)
- Amsterdam UMC Location University of Amsterdam (NL)
- Imperial College London (GB)
- Columbia University (US)
- Inserm (FR)
- University of Glasgow (GB)
- Leipzig University (DE)
- MRC/BHF Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
- Monash University (AU)
- Brigham and Women's Hospital (US)
- University of Milan (IT)
- Corresponding author
- Ference, Brian A.
- ORCID
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2019-01-29
- Volume
- 321
- Issue
- 4
- Pages
- 364
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- PMC
- PMC6439767
- OpenAlex
- W2911290113
- Semantic Scholar
- 79708784ea168e7e24e1ab47deffcd9005c32cfd
- Cited by
- 724
- References
- 39
- Citations by year
- 2026: 51 · 2025: 74 · 2024: 113 · 2023: 89 · 2022: 68 · 2021: 111 · 2020: 100 · 2019: 71
- FWCI
- 55.19
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- other-oa
- Locations
- JAMA (publishedVersion, other-oa)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- Bristol Research (University of Bristol) (acceptedVersion, other-oa)
- Europe PMC (PubMed Central) (submittedVersion)
- PubMed Central (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Keywords
- lipoprotein lipase, LDL receptor, apolipoprotein B, triglycerides, LDL cholesterol, coronary artery disease, cardiovascular risk, genetic score
- MeSH terms
- Loss of Function Mutation, Apolipoproteins B, Coronary Disease, Female, Humans, Lipoprotein Lipase
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 2026-10-19.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-19.
Cited sources are checked by gpt-6-sol.
Statistics and arithmetic are recomputed, not judged.
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