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
Open accessAbstract
Background: Randomized trials of therapies that primarily lowered triglycerides have not consistently shown reductions in cardiovascular events. Methods: We performed a systematic review and trial-level meta-regression analysis of 3 classes of lipid-lowering therapies that reduce triglycerides to a greater extent than they do low-density lipoprotein cholesterol (LDL-C): fibrates, niacin, and marine-derived omega-3 fatty acids. Key inclusion criteria were a randomized controlled trial that reported major vascular events. We also incorporated data from a previous meta-regression of 25 statin trials. The main outcome measure was the risk ratio (RR) for major vascular events associated with absolute reductions in lipid parameters. Results: A total of 197 270 participants from 24 trials of nonstatin therapy with 25 218 major vascular events and 177 088 participants from 25 trials of statin therapy with 20 962 major vascular events were included, for a total of 374 358 patients and 46 180 major cardiovascular events. Starting with non–high-density lipoprotein cholesterol, a surrogate for very-low-density lipoproteins and low-density lipoproteins, the RR per 1-mmol/L reduction in non–high-density lipoprotein cholesterol was 0.79 (95% CI, 0.76–0.82; P <0.0001; 0.78 per 40 mg/dL). In a multivariable meta-regression model that included terms for both LDL-C and triglyceride (surrogates for low-density lipoproteins and very-low-density lipoproteins, respectively), the RR was 0.80 (95% CI, 0.76–0.85; P <0.0001) per 1-mmol/L (0.79 per 40 mg/dL) reduction in LDL-C and 0.84 (95% CI, 0.75–0.94; P =0.0026) per 1-mmol/L (0.92 per 40 mg/dL) reduction in triglycerides. REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial) was a significant outlier and strongly influential trial in the meta-regression. When removed, the RRs became 0.79 (95% CI, 0.76–0.83; P <0.0001) per 1-mmol/L (0.78 per 40 mg/dL) reduction in LDL-C and 0.91 (95% CI, 0.81–1.006; P =0.06) per 1-mmol/L (0.96 per 40 mg/dL) reduction in triglycerides. In regard to omega-3 dose, each 1 g/d eicosapentaenoic acid administered was associated with a 7% relative risk reduction in major vascular events (RR, 0.93 [95% CI, 0.91–0.95]; P <0.0001), whereas there was no significant association between the dose of docosahexaenoic acid and the relative risk reduction in major vascular events (RR 0.96 [95% CI, 0.89–1.03]). Conclusions: In randomized controlled trials, triglyceride lowering is associated with a lower risk of major vascular events, even after adjustment for LDL-C lowering, although the effect is less than that for LDL-C and attenuated when REDUCE-IT is excluded. Furthermore, the benefits of marine-derived omega-3 fatty acids, particularly high-dose eicosapentaenoic acid, appear to exceed their lipid-lowering effects.
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19 of 27 cited sources checked · 11 supported · 0 flagged · accuracy not yet measured
- Premisecitation
The association between triglycerides and cardiovascular risk is well established from epidemiological studies, genome-wide analyses, and Mendelian randomization studies.
“The association between triglycerides and cardiovascular (CV) risk is well established from epidemiological studies,1-5 genome-wide analyses,6-8 and Mendelian randomization studies.9,10”
Quote in the paperSubstantial claim7 of 10 sources checked- cites [1] Nordestgaard BG, Benn M, Schnohr P, Tybjaerg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA. 2007; 298: 299– 308. 17635890 source
- cites [2] Sarwar N, Danesh J, Eiriksdottir G, Sigurdsson G, Wareham N, Bingham S, Boekholdt SM, Khaw KT, Gudnason V. Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies. Circulation. 2007; 115: 450– 458. 17190864 source
- cites [3] Miller M, Cannon CP, Murphy SA, Qin J, Ray KK, Braunwald E, Investigators PI-T. Impact of triglyceride levels beyond low-density lipoprotein cholesterol after acute coronary syndrome in the PROVE IT-TIMI 22 trial. J Am Coll Cardiol. 2008; 51: 724– 730. 18279736 source
- cites [4] Triglyceride Coronary Disease Genetics C, Emerging Risk Factors C, Sarwar N, Sandhu MS, Ricketts SL, Butterworth AS, Di Angelantonio E, Boekholdt SM, Ouwehand W, Watkins H, Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies. Lancet. 2010; 375: 1634– 1639. 20452521 PMC2867029 source
- cites [5] Miller M, Stone NJ, Ballantyne C, Bittner V, Criqui MH, Ginsberg HN, Goldberg AC, Howard WJ, Jacobson MS, Kris-Etherton PM, Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2011; 123: 2292– 2333. 21502576 source
- cites [6] Do R, Willer CJ, Schmidt EM, Sengupta S, Gao C, Peloso GM, Gustafsson S, Kanoni S, Ganna A, Chen J, Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat Genet. 2013; 45: 1345– 1352. 24097064 PMC3904346 source
- cites [7] Teslovich TM, Musunuru K, Smith AV, Edmondson AC, Stylianou IM, Koseki M, Pirruccello JP, Ripatti S, Chasman DI, Willer CJ, Biological, clinical and population relevance of 95 loci for blood lipids. Nature. 2010; 466: 707– 713. 20686565 PMC3039276 source
- cites [8] Willer CJ, Schmidt EM, Sengupta S, Peloso GM, Gustafsson S, Kanoni S, Ganna A, Chen J, Buchkovich ML, Mora S, Discovery and refinement of loci associated with lipid levels. Nat Genet. 2013; 45: 1274– 1283. 24097068 PMC3838666 source
- cites [9] Varbo A, Benn M, Tybjaerg-Hansen A, Jorgensen AB, Frikke-Schmidt R, Nordestgaard BG. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol. 2013; 61: 427– 436. 23265341 source
- cites [10] Varbo A, Benn M, Tybjaerg-Hansen A, Nordestgaard BG. Elevated remnant cholesterol causes both low-grade inflammation and ischemic heart disease, whereas elevated low-density lipoprotein cholesterol causes ischemic heart disease without inflammation. Circulation. 2013; 128: 1298– 1309. 23926208 source
The Abstract describes a Mendelian randomization study and reports that triglycerides and remnant cholesterol are highly correlated. The Risk of IHD: Observational and Causal Associations section reports increased ischemic heart disease risk with genetically higher remnant cholesterol. The study tests remnant cholesterol, however, rather than a direct triglyceride–cardiovascular risk association; it therefore supports the Mendelian-randomization portion of the claim only indirectly. (LLM, conf=0.83)
Experimental — accuracy not yet measured
- Premisecitation
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”
Quote in the paperSubstantial claim3 of 3 sources checked- cites [6] Do R, Willer CJ, Schmidt EM, Sengupta S, Gao C, Peloso GM, Gustafsson S, Kanoni S, Ganna A, Chen J, Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat Genet. 2013; 45: 1345– 1352. 24097064 PMC3904346 source
The paper reports associations of both triglycerides and LDL-C with coronary artery disease across lipid-associated SNPs (Abstract; page unavailable). It does not compare their association strengths per mg/dL or assess the broader outcome of major vascular events. The Online Methods specify that lipid effects were measured in standard-deviation units, not mg/dL. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [8] Willer CJ, Schmidt EM, Sengupta S, Peloso GM, Gustafsson S, Kanoni S, Ganna A, Chen J, Buchkovich ML, Mora S, Discovery and refinement of loci associated with lipid levels. Nat Genet. 2013; 45: 1274– 1283. 24097068 PMC3838666 source
In Results, under “Association of individual lipids with coronary artery disease” (page unavailable), the correlation between lipid-locus effects and CAD effects is lower for triglycerides (r=0.46) than for LDL cholesterol (r=0.74). This supports a narrower comparison of genetic associations, not the claimed difference in association per mg/dL with major vascular events; the paper reports CAD rather than that broader outcome. (LLM, conf=0.82)
Experimental — accuracy not yet measured - cites [35] Ference BA, Kastelein JJP, Ray KK, Ginsberg HN, Chapman MJ, Packard CJ, Laufs U, Oliver-Williams C, Wood AM, Butterworth AS, Association of Triglyceride-Lowering LPL Variants and LDL-C-Lowering LDLR Variants With Risk of Coronary Heart Disease. JAMA. 2019; 321: 364– 373. 30694319 PMC6439767 source
- Premisecitation
Recent 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”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [35] Ference BA, Kastelein JJP, Ray KK, Ginsberg HN, Chapman MJ, Packard CJ, Laufs U, Oliver-Williams C, Wood AM, Butterworth AS, Association of Triglyceride-Lowering LPL Variants and LDL-C-Lowering LDLR Variants With Risk of Coronary Heart Disease. JAMA. 2019; 321: 364– 373. 30694319 PMC6439767 source
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 measured
- Premisecitation
Recent data from the CANTOS trial showed that a 1.6-1.7 mg/dL reduction in hs-CRP was associated with a 17% reduction in major vascular events.
“Recent data from the CANTOS trial showed that a 1.6-1.7 mg/dL reduction in hs-CRP was associated with a 17% reduction in major vascular events.50”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [50] Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Fonseca F, Nicolau J, Koenig W, Anker SD, Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med. 2017; 377: 1119– 1131. 28845751 source
The Results report a 17% lower risk for the key secondary cardiovascular end point with 150-mg canakinumab versus placebo (hazard ratio 0.83). They also report a greater reduction in hs-CRP, but express it as 37 percentage points, not a 1.6–1.7 mg/dL reduction. The paper does not establish the claimed association between that specific hs-CRP reduction and the event reduction. (LLM, conf=0.90)
Experimental — accuracy not yet measured
- Findingown data
In omega-3 fatty acid trials, the RR (95% CI) per 1 mmol/L reduction in non-HDL-C for major vascular events was 0.51 (0.40-0.64).
“Examining individual classes, the RR (95%CI) per 1 mmol/L reduction in non-HDL-C was 0.80 (0.77-0.82) (0.79 per 40 mg/dl) for statins, 0.79 (0.71-0.88) (0.78 per 40 mg/dl) for fibrates, 0.84 (0.75-0.95) (0.83 per 40 mg/dl) for niacin, and 0.51 (0.40-0.64) (0.50 per 40 mg/dl) for omega-3 fatty acid trials (Supplemental Figure 2).”
Quote in the paperSubstantial claim
- Findingown data
In a meta-regression by EPA dose, each 1 gram/day of EPA administered was associated with a 7% relative lower risk in major vascular events (RR 0.93 [0.91-0.95], p<0.0001).
“In a meta-regression by EPA dose, for each 1 gram/day of EPA administered there was a 7% relative lower risk in major vascular events (RR 0.93 [0.91-0.95], p<0.0001, Figure 3a).”
Quote in the paperSubstantial claim - Findingown data
In niacin trials, the RR (95% CI) per 1 mmol/L reduction in non-HDL-C for major vascular events was 0.84 (0.75-0.95).
“Examining individual classes, the RR (95%CI) per 1 mmol/L reduction in non-HDL-C was 0.80 (0.77-0.82) (0.79 per 40 mg/dl) for statins, 0.79 (0.71-0.88) (0.78 per 40 mg/dl) for fibrates, 0.84 (0.75-0.95) (0.83 per 40 mg/dl) for niacin, and 0.51 (0.40-0.64) (0.50 per 40 mg/dl) for omega-3 fatty acid trials (Supplemental Figure 2).”
Quote in the paperNot a substantial claim - Findingown data
When REDUCE-IT was removed, the risk ratio for major vascular events was 0.79 (95% CI 0.76-0.83, P<0.0001) per 1 mmol/L (0.78 per 40 mg/dl) reduction in LDL-C.
“When removed, the RRs became 0.79 (0.76-0.83, P<0.0001) per 1 mmol/L (0.78 per 40 mg/dl) reduction in LDL-C”
Quote in the paperSubstantial claim- The authors state this as an assumption: As the dose of a drug goes to zero, the lipid effect goes to zero and the treatment effect goes to zero (the origin).
- Rests on an assumption: Non-HDL-C is a surrogate for VLDL and LDL, and LDL-C and triglyceride are surrogates for LDL and VLDL.
- Findingown data
In a multivariable meta-regression model including terms for both LDL-C and triglyceride, the risk ratio for major vascular events was 0.80 (95% CI 0.76-0.85, P<0.0001) per 1 mmol/L (0.79 per 40 mg/dl) reduction in LDL-C.
“In a multivariable meta-regression model that included terms for both LDL-C and triglyceride (surrogates for LDL and VLDL), the RR (95%CI) was 0.80 (0.76-0.85, P<0.0001) per 1 mmol/L (0.79 per 40 mg/dl) reduction in LDL-C”
Quote in the paperSubstantial claim- The authors state this as an assumption: As the dose of a drug goes to zero, the lipid effect goes to zero and the treatment effect goes to zero (the origin).
- Rests on an assumption: Non-HDL-C is a surrogate for VLDL and LDL, and LDL-C and triglyceride are surrogates for LDL and VLDL.
- Findingown data
In 44 trials with necessary lipid data, the RR (95% CI) per 1 mmol/L reduction in LDL-C for major vascular events was 0.80 (0.76-0.85, P<0.0001).
“When pooling 44 trials with necessary lipid data (nine fibrate, three niacin, eight omega-3 fatty acid, and 25 statin trials), the RR (95%CI) was 0.80 (0.76-0.85, P<0.0001) per 1 mmol/L (0.79 per 40 mg/dl) reduction in LDL-C and 0.84 (0.75-0.94, P=0.0026) per 1 mmol/L (0.92 per 40 mg/dl) reduction in triglycerides (Figure 2a, 2b).”
Quote in the paperSubstantial claim - Findingown data
With REDUCE-IT removed, the RR (95% CI) per 1 mmol/L reduction in LDL-C became 0.79 (0.76-0.83, P<0.0001).
“With REDUCE-IT removed, the RRs became 0.79 (0.76-0.83, P<0.0001) per 1 mmol/L (0.78 per 40 mg/dl) reduction in LDL-C and 0.91 (0.81-1.006, P=0.06) per 1 mmol/L (0.96 per 40 mg/dl) reduction in triglycerides (Figure 2a, 2b).”
Quote in the paperSubstantial claim - Findingown data
The risk ratio for major vascular events per 1 mmol/L reduction in non-HDL-C was 0.79 (95% CI 0.76-0.82, P<0.0001) (0.78 per 40 mg/dl).
“Starting with non-HDL-C, a surrogate for VLDL and LDL, the RR (95%CI) per 1 mmol/L reduction in non-HDL-C was 0.79 (0.76-0.82, P<0.0001) (0.78 per 40 mg/dl).”
Quote in the paperSubstantial claim- The authors state this as an assumption: As the dose of a drug goes to zero, the lipid effect goes to zero and the treatment effect goes to zero (the origin).
- Rests on an assumption: Non-HDL-C is a surrogate for VLDL and LDL, and LDL-C and triglyceride are surrogates for LDL and VLDL.
- Findingown data
The RRs for fibrate, niacin, and statin trials were similar (p≥0.39 for differences between classes).
“The RRs for fibrate, niacin, and statin trials were similar (p≥0.39, for differences between classes), and when pooling these three classes the RR was 0.80 (0.78-0.82) (0.79 per 40 mg/dl).”
Quote in the paperSubstantial claim - Findingown data
When pooling fibrate, niacin, and statin trials, the RR (95% CI) per 1 mmol/L reduction in non-HDL-C for major vascular events was 0.80 (0.78-0.82).
“The RRs for fibrate, niacin, and statin trials were similar (p≥0.39, for differences between classes), and when pooling these three classes the RR was 0.80 (0.78-0.82) (0.79 per 40 mg/dl).”
Quote in the paperSubstantial claim - Findingown data
Data from 25 statin trials included an additional 177,088 patients and 20,962 major vascular events, for a grand total of 374,358 patients and 46,180 major vascular events.
“In addition to these trials, we also had data from 25 statin trials (Supplemental Table 5) which included an additional 177,088 patients and 20,962 major vascular events, for a grand total of 374,358 patients and 46,180 major vascular events (Table).”
- Also stated in: § Results · plain
“A total of 197,270 participants from 24 trials of non-statin therapy with 25,218 major vascular events and 177,088 participants from 25 trials of statin therapy with 20,962 major vascular events were included, for a total of 374,358 patients and 46,180 major CV events.”
Quote in the paperSubstantial claim - Also stated in: § Results · plain
- Findingown data
Pooling 37 trials together, the RR (95% CI) per 1 mmol/L reduction in non-HDL-C for major vascular events was 0.79 (0.76-0.82, P<0.0001).
“Pooling the 37 trials together, the RR was 0.79 (0.76-0.82, P<0.0001) (0.78 per 40 mg/dl) (Figure 1).”
Quote in the paperSubstantial claim - Findingown data
In 44 trials with necessary lipid data, the RR (95% CI) per 1 mmol/L reduction in triglycerides for major vascular events was 0.84 (0.75-0.94, P=0.0026).
“When pooling 44 trials with necessary lipid data (nine fibrate, three niacin, eight omega-3 fatty acid, and 25 statin trials), the RR (95%CI) was 0.80 (0.76-0.85, P<0.0001) per 1 mmol/L (0.79 per 40 mg/dl) reduction in LDL-C and 0.84 (0.75-0.94, P=0.0026) per 1 mmol/L (0.92 per 40 mg/dl) reduction in triglycerides (Figure 2a, 2b).”
Quote in the paperSubstantial claim - Findingown data
In 19 statin trials with non-HDL-C data, the RR (95% CI) per 1 mmol/L reduction in non-HDL-C for major vascular events was 0.80 (0.77-0.82, P<0.0001).
“The relationship was similar in 19 statin trials with non-HDL-C data, with a RR (95% CI) of 0.80 (0.77-0.82, P<0.0001) (0.79 per 40 mg/dl).”
- Also stated in: § Non-HDL-C Lowering and Major Vascular Events · plain
“Examining individual classes, the RR (95%CI) per 1 mmol/L reduction in non-HDL-C was 0.80 (0.77-0.82) (0.79 per 40 mg/dl) for statins, 0.79 (0.71-0.88) (0.78 per 40 mg/dl) for fibrates, 0.84 (0.75-0.95) (0.83 per 40 mg/dl) for niacin, and 0.51 (0.40-0.64) (0.50 per 40 mg/dl) for omega-3 fatty acid trials (Supplemental Figure 2).”
Quote in the paperSubstantial claim - Also stated in: § Non-HDL-C Lowering and Major Vascular Events · plain
- Findingown data
With REDUCE-IT removed, the overall meta-regression RR became 0.80 (95% CI 0.78-0.82, P<0.0001).
“With REDUCE-IT removed, the RR for omega-3 fatty acids became similar to the other classes (RR 0.76, 95% CI 0.27-2.16) (0.75 per 40 mg/dl) and the overall meta-regression RR became 0.80 (95% CI 0.78-0.82, P<0.0001) (0.79 per 40 mg/dl).”
Quote in the paperNot a substantial claim - Findingown data
In fibrate trials, the RR (95% CI) per 1 mmol/L reduction in non-HDL-C for major vascular events was 0.79 (0.71-0.88).
“Examining individual classes, the RR (95%CI) per 1 mmol/L reduction in non-HDL-C was 0.80 (0.77-0.82) (0.79 per 40 mg/dl) for statins, 0.79 (0.71-0.88) (0.78 per 40 mg/dl) for fibrates, 0.84 (0.75-0.95) (0.83 per 40 mg/dl) for niacin, and 0.51 (0.40-0.64) (0.50 per 40 mg/dl) for omega-3 fatty acid trials (Supplemental Figure 2).”
Quote in the paperSubstantial claim - Findingown data
When REDUCE-IT was removed, the risk ratio for major vascular events was 0.91 (95% CI 0.81-1.006, P=0.06) per 1 mmol/L (0.96 per 40 mg/dL) reduction in triglycerides.
“and 0.91 (0.81-1.006, P=0.06) per 1 mmol/L (0.96 per 40 mg/dL) reduction in triglycerides.”
Quote in the paperSubstantial claim- The authors state this as an assumption: As the dose of a drug goes to zero, the lipid effect goes to zero and the treatment effect goes to zero (the origin).
- Rests on an assumption: Non-HDL-C is a surrogate for VLDL and LDL, and LDL-C and triglyceride are surrogates for LDL and VLDL.
- Findingown data
In 18 non-statin trials with non-HDL-C data, the RR (95% CI) per 1 mmol/L reduction in non-HDL-C for major vascular events was 0.77 (0.69-0.86, P=0.0001).
“When pooling 18 non-statin trials with non-HDL-C data (eight fibrate, three niacin, and eight omega-3 fatty acid trials), the RR (95% CI) per 1 mmol/L reduction in non-HDL-C was 0.77 (0.69-0.86, P=0.0001) (0.76 per 40 mg/dl).”
Quote in the paperSubstantial claim - Findingown data
With REDUCE-IT removed, the RR for omega-3 fatty acids became similar to the other classes (RR 0.76, 95% CI 0.27-2.16).
“With REDUCE-IT removed, the RR for omega-3 fatty acids became similar to the other classes (RR 0.76, 95% CI 0.27-2.16) (0.75 per 40 mg/dl) and the overall meta-regression RR became 0.80 (95% CI 0.78-0.82, P<0.0001) (0.79 per 40 mg/dl).”
Quote in the paperSubstantial claim - Findingown data
Each 1 gram/day of EPA administered was associated with a 7% relative risk reduction in major vascular events (RR 0.93 [95% CI 0.91-0.95], P<0.0001).
“In regard to omega-3 dose, each 1 gram/day of EPA administered was associated with a 7% relative risk reduction in major vascular events (RR 0.93 [0.91-0.95], P<0.0001)”
Quote in the paperSubstantial claim - Findingown data
With REDUCE-IT removed, the RR (95% CI) per 1 mmol/L reduction in triglycerides became 0.91 (0.81-1.006, P=0.06).
“With REDUCE-IT removed, the RRs became 0.79 (0.76-0.83, P<0.0001) per 1 mmol/L (0.78 per 40 mg/dl) reduction in LDL-C and 0.91 (0.81-1.006, P=0.06) per 1 mmol/L (0.96 per 40 mg/dl) reduction in triglycerides (Figure 2a, 2b).”
Quote in the paperSubstantial claim - Findingown data
There was no significant reduction in major vascular events with DHA (RR 0.96 [95% CI 0.89-1.03]).
“whereas there was no significant reduction in major vascular events with DHA (RR 0.96 [0.89-1.03]).”
Quote in the paperSubstantial claim - Findingown data
In a meta-regression by DHA dose, 1 gram/day was associated with a non-significant 4% lower risk in major cardiovascular events (RR 0.96 [0.89-1.03], p=0.27).
“In contrast, in a meta-regression by DHA dose, 1 gram/day was associated with a non-significant 4% lower risk in major cardiovascular events (RR 0.96 [0.89-1.03], p=0.27, Figure 3b).”
Quote in the paperSubstantial claim - Findingown data
Of the significant outliers, only REDUCE-IT had moderate influence on the meta-regression line (D=0.35).
“Of these significant outliers, only REDUCE-IT had moderate influence on the meta-regression line (D = 0.35, if D >0.45 relatively influential) (Supplement Figure 4).”
Quote in the paperNot a substantial claim - Findingown data
In the same multivariable meta-regression model, the risk ratio for major vascular events was 0.84 (95% CI 0.75-0.94, P=0.0026) per 1 mmol/L (0.92 per 40 mg/dl) reduction in triglycerides.
“and 0.84 (0.75-0.94, P=0.0026) per 1 mmol/L (0.92 per 40 mg/dl) reduction in triglycerides.”
Quote in the paperSubstantial claim- The authors state this as an assumption: As the dose of a drug goes to zero, the lipid effect goes to zero and the treatment effect goes to zero (the origin).
- Rests on an assumption: Non-HDL-C is a surrogate for VLDL and LDL, and LDL-C and triglyceride are surrogates for LDL and VLDL.
- Findingown data
The observed clinical benefit of 25% relative risk reduction in REDUCE-IT was well beyond the approximately 9% risk reduction expected based on the 0.41 mmol/L of non-HDL-C lowering.
“The observed clinical benefit of 25% relative risk reduction was well beyond the approximately 9% risk reduction expected based on the 0.41 mmol/L of non-HDL-C lowering, and raises the question as to what might be driving the difference between expected and observed risk reductions.”
Quote in the paperSubstantial claim - Findingown data
There was a high correlation between the change in non-HDL-C and the change in triglycerides (r=0.90, P<0.0001) in non-statin trials.
“Indeed, there was a high correlation between the change in non-HDL-C and the change in triglycerides (r=0.90, P<0.0001) in non-statin trials, supporting the decision not to include them in the same model.”
Quote in the paperSubstantial claim - Premisecitation
Randomized controlled trials of therapies that primarily lower triglycerides have not consistently shown reductions in major vascular events.
“Randomized trials of therapies that primarily lowered triglycerides have not consistently shown reductions in cardiovascular events.”
- Also stated in: § Background · plain
“However, randomized controlled clinical trials of therapies that primarily lower triglyceride levels have not consistently shown a reduction in major vascular events.11-34”
Quote in the paperSubstantial claim0 of 1 sources checked- cites 11-34
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Also stated in: § Background · plain
- Interpretationreasoning
Prior trials of drugs that primarily lower triglyceride may have been underpowered with regard to degree of triglyceride or non-HDL-C lowering to show a statistically significant benefit on their own.
“Thus, prior trials of drugs that primarily lower triglyceride may have been underpowered with regard to degree of triglyceride or non-HDL-C lowering to show a statistically significant benefit on their own.”
Quote in the paperSubstantial claim - Interpretationown data
Nearly all non-statin trials focusing on triglyceride lowering have been underpowered with respect to degree of non-HDL-C lowering to detect a clinical difference in major vascular events.
“Third, nearly all non-statin trials focusing on triglyceride lowering have been underpowered with respect to degree of non-HDL-C lowering to detect a clinical difference in major vascular events.”
- Also stated in: § Discussion · plain
“Given the modest reductions in non-HDL-C seen in non-statin trials (fibrates, niacin, omega-3 fatty acids), virtually all were underpowered to detect a statistical difference in clinical outcomes.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · plain
- Study design and conductown data
There was no evidence for publication bias.
“There was no evidence for publication bias (Supplemental Table 6 and Supplemental Figure 3).”
Quote in the paperNot a substantial claim - Interpretationreasoning
Obtaining CV benefit with a purely VLDL or triglyceride-lowering drug will be more difficult to achieve.
“Therefore, obtaining CV benefit with a purely VLDL or triglyceride-lowering drug will be more difficult to achieve.”
Quote in the paperSubstantial claim - Interpretationcitation
Interventions that lower VLDL (and therefore TG) but not LDL-C should still have cardiovascular benefit.
“As a result, interventions that lower VLDL (and therefore TG) but not LDL-C should still have cardiovascular benefit.”
Quote in the paperSubstantial claim - Interpretationown data
A reduction in non-HDL-C is strongly associated with lower risk of major vascular events regardless of the lipid-lowering drug class.
“First, a reduction in non-HDL-C, a measure of atherogenic LDL and VLDL particles, is strongly associated with lower risk of major vascular events regardless of the lipid-lowering drug class.”
Quote in the paperSubstantial claim - Interpretationown data
The benefits of marine-derived omega-3 fatty acids, particularly high-dose EPA, appear to exceed their lipid-lowering effects.
“Furthermore, the benefits of marine-derived omega-3 fatty acids, particularly high-dose EPA, appear to exceed their lipid-lowering effects.”
Quote in the paperSubstantial claim - Study design and conductreasoning
There were differences in patient populations, baseline lipid levels, treatment doses or formulations, and co-therapies across the included trials.
“Given the large number of trials, there were differences in patient populations, baseline lipid levels, treatment doses or formulations, and co-therapies (e.g., statins).”
Quote in the paperSubstantial claim - Study design and conductnone given
Very few of the included trials had a substantial proportion of patients with very high triglyceride levels (>400 mg/dl).
“It should also be noted that very few of these trials included a substantial proportion of patients with very high triglyceride levels (ie, >400 mg/dl), a group in whom triglyceride lowering would be expected to associate with the largest clinical benefit.”
Quote in the paperSubstantial claim - Interpretationown data
The benefits of marine-derived omega-3 fatty acids, particularly high dose EPA, appear to exceed their lipid-lowering effects.
“Furthermore, the benefits of marine-derived omega-3 fatty acids, particularly high dose EPA, appear to exceed their lipid-lowering effects.”
Quote in the paperSubstantial claim - Interpretationown data
Fibrates should offer clinical benefit proportional to the degree of non-HDL-C lowering.
“While niacin has notable side effects,23 our data suggest fibrates should offer clinical benefit proportional to the degree of non-HDL-C lowering (being mindful of side effects including an increased risk of myopathy when combined with a statin).”
Quote in the paperSubstantial claim
- May combine two claims. 29
- Classified as probably not a substantial claim. 15
- The quote only partly states this claim. 1
May combine two claims.
Interpretationown dataTriglyceride-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”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [35] Ference BA, Kastelein JJP, Ray KK, Ginsberg HN, Chapman MJ, Packard CJ, Laufs U, Oliver-Williams C, Wood AM, Butterworth AS, Association of Triglyceride-Lowering LPL Variants and LDL-C-Lowering LDLR Variants With Risk of Coronary Heart Disease. JAMA. 2019; 321: 364– 373. 30694319 PMC6439767 source
Classified as probably not a substantial claim.
PremisecitationLower 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”
Quote in the paperSubstantial claim3 of 3 sources checked- cites [6] Do R, Willer CJ, Schmidt EM, Sengupta S, Gao C, Peloso GM, Gustafsson S, Kanoni S, Ganna A, Chen J, Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat Genet. 2013; 45: 1345– 1352. 24097064 PMC3904346 source
The paper reports that variants associated with lower triglycerides and lower LDL cholesterol tend to be associated with lower coronary artery disease risk (results passage, page unavailable). It does not report the claimed condition of lower apolipoprotein B levels; LDL cholesterol is not the same measurement. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [8] Willer CJ, Schmidt EM, Sengupta S, Peloso GM, Gustafsson S, Kanoni S, Ganna A, Chen J, Buchkovich ML, Mora S, Discovery and refinement of loci associated with lipid levels. Nat Genet. 2013; 45: 1274– 1283. 24097068 PMC3838666 source
The Results section (‘Association of individual lipids with coronary artery disease’; page not provided) reports that triglyceride-related genetic effects correlate with CAD risk, supporting the lower-triglyceride portion of the claim. It does not establish that the association depends on accompanying lower apolipoprotein B levels; the paper’s APOB mention concerns a protein-interaction network, not measured apolipoprotein B levels. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [35] Ference BA, Kastelein JJP, Ray KK, Ginsberg HN, Chapman MJ, Packard CJ, Laufs U, Oliver-Williams C, Wood AM, Butterworth AS, Association of Triglyceride-Lowering LPL Variants and LDL-C-Lowering LDLR Variants With Risk of Coronary Heart Disease. JAMA. 2019; 321: 364– 373. 30694319 PMC6439767 source
Classified as probably not a substantial claim. May combine two claims.
PremisecitationTriglycerides 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”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [35] Ference BA, Kastelein JJP, Ray KK, Ginsberg HN, Chapman MJ, Packard CJ, Laufs U, Oliver-Williams C, Wood AM, Butterworth AS, Association of Triglyceride-Lowering LPL Variants and LDL-C-Lowering LDLR Variants With Risk of Coronary Heart Disease. JAMA. 2019; 321: 364– 373. 30694319 PMC6439767 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationProposed non-lipid lowering mechanisms for icosapent ethyl include anti-inflammatory, anti-arrhythmic, and anti-platelet properties.
“Proposed non-lipid lowering mechanisms for icosapent ethyl include anti-inflammatory, anti-arrhythmic, and anti-platelet properties.49”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [49] Preston Mason R New Insights into Mechanisms of Action for Omega-3 Fatty Acids in Atherothrombotic Cardiovascular Disease. Curr Atheroscler Rep. 2019; 21: 2. 30637567 PMC6330561 source
The paper identifies icosapent ethyl as a purified EPA preparation. In “Omega-3 Fatty Acids and Atherothrombotic Disease” (page unavailable), it reports reduced inflammatory markers with prescription EPA; Table 2 in “Distinct Roles of EPA and DHA in Cellular Function and Atherosclerosis” (page unavailable) lists reduced platelet activation. It does not propose an anti-arrhythmic mechanism: its REDUCE-IT discussion instead reports a higher rate of hospitalization for atrial fibrillation or flutter with EPA. (LLM, conf=0.87)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationThe 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.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [35] Ference BA, Kastelein JJP, Ray KK, Ginsberg HN, Chapman MJ, Packard CJ, Laufs U, Oliver-Williams C, Wood AM, Butterworth AS, Association of Triglyceride-Lowering LPL Variants and LDL-C-Lowering LDLR Variants With Risk of Coronary Heart Disease. JAMA. 2019; 321: 364– 373. 30694319 PMC6439767 source
May combine two claims. The quote only partly states this claim.
Findingown dataThe 24 non-statin trials included 197,270 patients with an average age of 63 years and a mean baseline triglyceride level of 163 mg/dL (median 151, IQR 143-165 mg/dL).
“These trials included a total of 197,270 patients with an average age of 63 years old and a mean baseline triglyceride level of 163 mg/dL (median 151, IQR 143-165 mg/dL).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThree non-statin trials were outliers and significantly deviated from the regression line: VA-HIT (p=0.02), JELIS (p=0.0495), and REDUCE-IT (p=0.0002).
“Three non-statin trials were outliers and significantly deviated from the regression line: a fibrate trial, VA-HIT (p=0.02), and two omega-3 fatty acid trials, JELIS (p=0.0495) and REDUCE-IT (p=0.0002).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe average median trial follow-up was 4.8 years, during which there were 25,218 major cardiovascular events.
“The average median trial follow-up was 4.8 years during which there were 25,218 major CV events (Table).”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Findingown dataA total of 24 triglyceride-lowering trials were included in the meta-regression analyses.
“Of these, 24 triglyceride lowering trials were included in the meta-regression analyses.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataBased on the observed meta-regression relationship and actual non-HDL-C lowering in non-statin trials, the power to detect a significant clinical benefit was ≤20% in 14 trials, 21-50% in two trials, 51-79% in two trials, and ≥80% in only one trial.
“Based on the observed meta-regression relationship between non-HDL-C lowering and reduction in major vascular events and the actual non-HDL-C lowering in non-statin trials, the power to detect a significant clinical benefit given the number of events in each of the non-statin trials was quite limited, being ≤20% in 14 trials, 21-50% in two trials, 51-79% in two trials and ≥80% in only one trial (S”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe RR for omega-3 fatty acid trials differed significantly from the RRs seen in fibrate (p=0.008), niacin (p=0.004), and statin (p=0.005) trials.
“In contrast, the RR for omega-3 fatty acid trials differed significantly from the RRs seen in fibrate (p=0.008), niacin (p=0.004), and statin (p=0.005) trials.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataREDUCE-IT was a significant outlier and strongly influential trial in the meta-regression.
“REDUCE-IT was a significant outlier and strongly influential trial in the meta-regression.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataREDUCE-IT was a significant outlier (P=0.007) and had strong influence on the meta-regression (D=2.27).
“Once again, REDUCE-IT was a significant outlier (P=0.007) and had strong influence on the meta-regression (D = 2.27, if D >1.39 relatively influential) (Supplement Figure 5).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingown dataModels with terms for intercept showed that the intercept terms were close to the origin and not significant.
“As a check, models with terms for intercept were also created, and showed that the intercept terms were close to the origin and not significant.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe 4 grams/day EPA dose in REDUCE-IT gave the trial high leverage but was not influential on the regression line (D=0.27).
“The significantly higher dose of 4 grams/day of EPA in REDUCE-IT gave the trial high leverage, but was not influential on the regression line (D = 0.27, if D >0.45 relatively influential).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingown dataThe included trials comprised nine fibrate trials, three niacin trials, and 13 omega-3 fatty acid trials, with one trial having both fibrate and niacin experimental arms.
“There were nine fibrate trials (Supplemental Table 2), three niacin trials (Supplemental Table 3) and 13 omega-3 fatty acids trials (Supplemental Table 4) (one trial had both fibrate and niacin experimental arms).”
Quote in the paperNot a substantial claimMay combine two claims.
FindingreasoningJELIS and DOIT were the only other two trials to test >1 gram/day of EPA and both had CV risk reduction beyond what was expected based on non-HDL-C lowering.
“JELIS and DOIT were the only other two trials to test >1 gram/day of EPA and both had CV risk reduction beyond what was expected based on non-HDL-C lowering, supporting the potential pleiotropic benefits of higher-dose EPA.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductcitationPublication bias was assessed by funnel plots and Egger's regression test.
“Publication bias was also assessed by funnel plots and Egger’s regression test.48”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [48] Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997; 315: 629– 634. 9310563 PMC2127453 source
May combine two claims.
PremisecitationMost fibrate trials, both statin-era niacin trials, and all but two omega-3 trials have failed to show a statistically significant reduction in major vascular events.
“Most of the fibrate trials, both of the statin-era niacin trials, and all but two of the omega-3 trials have failed to show a statistically significant reduction in major vascular events.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites 11-34
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductcitationAll results are reported in accordance with Preferred Reporting Items for Systematic reviews and Meta-Analysis guidelines.
“All results are reported in accordance with Preferred Reporting Items for Systematic reviews and Meta-Analysis guidelines.41”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [41] Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009; 151: 264– 269, W264. 19622511 source
May combine two claims.
InterpretationreasoningDeveloping drugs that achieve large reductions in VLDL and triglycerides and/or targeting patients with high baseline levels of VLDL or triglycerides would likely increase the probability of showing a meaningful clinical benefit.
“Specifically, developing drugs that achieve large reductions in VLDL and triglycerides and/or targeting patients with high baseline levels of VLDL or triglycerides would likely increase the probability of showing a meaningful clinical benefit.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataIn randomized controlled trials, triglyceride lowering is associated with lower risk of major vascular events, even after adjusting for LDL-C lowering, although the effect is attenuated when REDUCE-IT is excluded.
“In randomized controlled trials, triglyceride lowering is associated with lower risk of major vascular events, even after adjusting for LDL-C lowering, although the effect is attenuated when REDUCE-IT is excluded.”
Quote in the paperSubstantial claim- The authors state this as an assumption: As the dose of a drug goes to zero, the lipid effect goes to zero and the treatment effect goes to zero (the origin).
- Rests on an assumption: Non-HDL-C is a surrogate for VLDL and LDL, and LDL-C and triglyceride are surrogates for LDL and VLDL.
May combine two claims.
InterpretationreasoningA decrease in 40 mg/dl of LDL-C should translate into approximately 20% lower CV risk, but a similar 40 mg/dL reduction in triglycerides is associated with only around 4-5% lower CV risk.
“Specifically, a decrease in 40 mg/dl of LDL-C should translate into an approximately 20% lower CV risk, but a similar 40 mg/dL reduction in triglycerides is associated with only around 4-5% lower CV risk.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Interpretationnone givenREDUCE-IT may have been an outlier because of the type of omega-3 fatty acid and/or the dose that was used.
“Fifth, REDUCE-IT may have been an outlier because of the type of omega-3 fatty acid and/or the dose that was used.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataTriglyceride lowering is associated with lower risk of cardiovascular events, but to a lesser extent per absolute amount of reduction than with LDL-C.
“Second, triglyceride lowering (a surrogate of triglyceride-rich VLDL) is associated with lower risk of cardiovascular events, but to a lesser extent per absolute amount of reduction than with LDL-C (a surrogate for cholesterol-rich LDL).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataEach trial was reviewed independently by 2 authors, and disagreements were resolved by consensus.
“Each trial was reviewed independently by 2 of the authors (N.A.M. and M.S.S.).”
- Also stated in: § Methods · plain
“All disagreements were discussed and resolved by consensus.”
Quote in the paperNot a substantial claim- Also stated in: § Methods · plain
May combine two claims.
Interpretationown dataREDUCE-IT was the most significant outlier and influencer of the meta-regression, and removing it attenuated the effect estimate for triglyceride lowering with an upper bound of the 95% CIs that just crosses 1.0.
“Fourth, REDUCE-IT was the most significant outlier and influencer of the meta-regression, and removing it attenuated the effect estimate for triglyceride lowering with an upper bound of the 95% CIs that just crosses 1.0.”
Quote in the paperSubstantial claimMay combine two claims.
Study design and conductown dataSensitivity analyses including terms for duration of follow up and proportion of background statin use showed no significant interactions (p=0.53 and p=0.55).
“Sensitivity analyses including terms for duration of follow up and proportion of background statin use (in trials of non-statin therapy) were performed but showed no significant interactions (p values for interaction of 0.53 and 0.55, respectively).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductcitationRisk-of-bias assessments were performed for each trial using the Cochrane Collaboration tool.
“Risk-of-bias assessments were performed for each trial using the Cochrane’s Collaboration tool.53”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [53]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Study design and conductown dataNo significant bias was detected across trials, although JELIS was the only trial with an open-label design.
“No significant bias was detected across trials although it was notable that JELIS was the only trial with an open-label design.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Interpretationnone givenIn patients with very high triglyceride levels (>400 mg/dl), triglyceride lowering would be expected to associate with the largest clinical benefit.
“It should also be noted that very few of these trials included a substantial proportion of patients with very high triglyceride levels (ie, >400 mg/dl), a group in whom triglyceride lowering would be expected to associate with the largest clinical benefit.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningIt is possible the magnitude of clinical benefit observed in REDUCE-IT could reflect a combination of both lower triglycerides and lower hs-CRP in the EPA arm vs. the comparator arm of mineral oil, but even those two factors together seem insufficient.
“Thus, it is possible the magnitude of clinical benefit observed in REDUCE-IT could reflect a combination of both lower triglycerides and lower hs-CRP in the EPA arm vs. the comparator arm of mineral oil, but even those two factors together seem insufficient.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
Study design and conductreasoningThe meta-analysis was not performed on patient-level data.
“The meta-analysis was not performed on patient-level data.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataIn randomized controlled trials, triglyceride lowering is associated with lower risk of major vascular events, even after adjusting for LDL-C lowering, but that relationship was attenuated when REDUCE-IT is excluded.
“In randomized controlled trials, triglyceride lowering is associated with lower risk of major vascular events, even after adjusting for LDL-C lowering, but that relationship was attenuated when REDUCE-IT is excluded.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductown dataThere was visual evidence of publication bias (less small negative trials than expected) but this was not statistically significant.
“There was visual evidence of publication bias (less small negative trials than expected) but this was not statistically significant.”
Quote in the paperNot a substantial claimMay combine two claims.
Study design and conductnone givenFew omega-3 trials used high doses, giving REDUCE-IT greater influence on the meta-regression line.
“Finally, few omega-3 trials used high doses, giving REDUCE-IT greater influence on the meta-regression line.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim. May combine two claims.
Study design and conductnone givenAll lipid measurements were not available in every trial and almost no trials had data on apoB.
“All lipid measurements were not available in every trial and almost no trials had data on apoB.”
Quote in the paperSubstantial claim
The authors state this as an assumption.
As the dose of a drug goes to zero, the lipid effect goes to zero and the treatment effect goes to zero (the origin).
“In each analysis the intercept was set at 0 to reflect the clinical assumption that as the dose of a drug goes to zero, the lipid effect goes to zero and the treatment effect goes to zero (ie, the origin).”
The paper relies on this without support.
Non-HDL-C is a surrogate for VLDL and LDL, and LDL-C and triglyceride are surrogates for LDL and VLDL.
“Starting with non-HDL-C, a surrogate for VLDL and LDL”
“In a multivariable meta-regression model that included terms for both LDL-C and triglyceride (surrogates for LDL and VLDL)”
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?
Older people gain significant benefits from lipid lowering for primary prevention, and these benefits are even more impactful in people with diabetes.
“Increasing evidence now shows that older persons gain significant benefits from lipid lowering for primary prevention, and these benefits are even more impactful in persons with DM.”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [361]
The Conclusions (page unavailable) associate triglyceride lowering with fewer major vascular events in randomized trials, supporting a general cardiovascular benefit. The Results give an average participant age of 63, but the paper does not establish a significant primary-prevention benefit specifically for older people or show that benefits are greater in people with diabetes. (LLM, conf=0.83)
Experimental — accuracy not yet measuredNeither linear assumption-driven meta-regressions nor stratified dose analyses have conclusively estimated the dose-response relationship between ω3 PUFA intake and relative risk reduction, raising the possibility of a nonlinear dose-response curve.
“Neither linear assumption‐driven meta‐regressions 38 , 39 , 40 , 41 , 42 nor stratified dose analyses 42 , 43 have conclusively estimated the dose–response relationship between ω3 PUFA intake and relative risk reduction, raising the possibility of a nonlinear dose–response curve. 30”
From Association Between Omega-3 Fatty Acid Intake and Dyslipidemia: A Continuous Dose-Response Meta-Analysis of Randomized Controlled Trials (2023) · cites this paper as [38]
Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredHypertriglyceridemia is common and is associated with an increased risk of atherosclerosis.
“H ypertriglyceridemia is common and is associated with an increased risk of atherosclerosis, 1-4”
From Targeting <i>APOC3</i> with Olezarsen in Moderate Hypertriglyceridemia (2025) · cites this paper as [1]
The Background states that triglyceride levels are associated with cardiovascular risk, supporting the risk portion of the claim. It does not establish that hypertriglyceridemia is common, and it cautions that triglycerides themselves may not be atherogenic, instead marking atherogenic VLDL particles (Background; page unavailable). (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe association between triglyceride-lowering and omega-3 PUFA intake could causally lead to reduction of cardiovascular risks in patients with high triglyceride.
“The association between triglyceride‐lowering and ω3 PUFA intake could causally lead to the reduction of cardiovascular risks in patients with high triglyceride, as previously reported in trials 18 , 19 and meta‐analyses. 38”
From Association Between Omega-3 Fatty Acid Intake and Dyslipidemia: A Continuous Dose-Response Meta-Analysis of Randomized Controlled Trials (2023) · cites this paper as [38]
The Discussion > Conclusions (page unavailable) reports that triglyceride lowering is associated with fewer major vascular events and that marine-derived omega-3 fatty acids, particularly high-dose EPA, appear to have benefits beyond lipid lowering. It also says the association weakens when REDUCE-IT is excluded. The source does not establish that triglyceride lowering through omega-3 intake causally reduces cardiovascular risk specifically in patients with high triglycerides. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe mechanisms for end point prevention appear to be attributed to the pleiotropic effects in addition to serum lipid regulation.
“The mechanisms for end point prevention appear to be attributed to the pleiotropic effects in addition to serum lipid regulation. 38 , 148”
From Association Between Omega-3 Fatty Acid Intake and Dyslipidemia: A Continuous Dose-Response Meta-Analysis of Randomized Controlled Trials (2023) · cites this paper as [38]
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 [1]
Reductions in plasma triglyceride are associated with reduction in the risk of atherosclerotic cardiovascular disease events after adjustment for statin-induced LDL-C lowering.
“There is also evidence that reductions in plasma TG are associated with reduction in the risk of ASCVD events after adjustment for statin-induced LDL-C lowering.39–42”
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.
DHA trials include a zero-DHA dose
MinorThe reported range for the 11 trials with DHA starts at 0 mg. A trial receiving 0 mg of DHA cannot be one of the trials with DHA.
“In the 11 trials with DHA, the mean dose was 411 mg (median 380 mg) with a range of 0 mg to 950 mg.”
“Among the 13 omega-3 fatty acids trials, all but two used a combination of EPA + DHA.”
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Targeting RNA With Antisense Oligonucleotides and Small Interfering RNA in Dyslipidemias
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Triglycerides and cardiovascular disease
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“Our findings move in line with the current literature supporting the concept that triglycerides in the range of low normality are recommended [19, 21].”
BackgroundResultThe Cardio-Kidney Patient: Epidemiology, Clinical Characteristics and Therapy
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Targeting <i>APOC3</i> with Olezarsen in Moderate Hypertriglyceridemia
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Self-citationGlobal Trends in the Epidemiology and Management of Dyslipidemia
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“Fibrates are recommended to lower triglyceride levels [21,23–25,27–30,34], but there are still no trials to show the cardiovascular benefit of fibrates except for meta-analysis of high triglyceride and low HDL-C groups [36], and recently the Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Pa…”
BackgroundCooreman, M. P., Butler, J., Giugliano, R. P., Zannad, F. M., Dzen, L., Huot-Marchand, P., Baudin, M., Beard, D. R., Junien, J., Broqua, P., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-47919-9 · Cited by 70 · see citing works
“Improving proatherogenic lipid levels, including TG and APO-B, may reduce CV events 32 , and the recognition of APO-C3 as an independent risk factor for atherosclerosis has led to renewed interest in APO-C3 as ther-apeutictarget.”
Self-citationNew Therapies for Lowering Triglyceride-Rich Lipoproteins
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Revisiting secondary prevention in coronary heart disease
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New Trends in Dyslipidemia Treatment
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JCS 2023 Guideline on the Primary Prevention of Coronary Artery Disease
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The Roles of Carotenoid Consumption and Bioavailability in Cardiovascular Health
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“Also, when all randomized trials with some triglyceride reduction using fibrates, niacin, omega-3 fatty acids, and statins were meta-analyzed, baseline median plasma triglyceride was only 1.7 mmol/L (151 mg/dL) while mean LDL cholesterol was 3.3 mmol/L (127 mg/dL) 41 .”
InfluentialEPA’s pleiotropic mechanisms of action: a narrative review
Nelson, J. R., Budoff, M. J., Wani, O. R., Le, V. T., Patel, D. K., Nelson, A., & Nemiroff, R. L. (2021) · Postgraduate Medicine · doi:10.1080/00325481.2021.1921491 · Cited by 44 · see citing works
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“The REDUCE-IT trial showed that treatment with icosapent ethyl significantly reduced CVD events without any change in non–HDL-C in patients with CVD risk and increased baseline TGs but well-controlled LDL-C [30, 34].”
BackgroundMethodDing, L., Fu, B., Zhang, H., Dai, C., Zhang, A., Yu, F., Mi, L., Hua, W., & Tang, M. (2024) · BMC Geriatrics · doi:10.1186/s12877-024-04992-5 · Cited by 40 · see citing works
“Marston et al. conducted meta-analysis of randomized controlled trials, and supported that lowering TG was associated lower risk of major vascular events [43].”
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Hypertriglyceridaemia: an update
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“23 116 Its use is now not recommended in many guidelines.”
BackgroundThe critical issue linking lipids and inflammation: Clinical utility of stopping oxidative stress
Bale, B. F., Doneen, A. L., Leimgruber, P. P., & Vigerust, D. J. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2022.1042729 · Cited by 38 · see citing works
Advances in Dyslipidaemia Treatments: Focusing on ApoC3 and ANGPTL3 Inhibitors
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Omega-3 Fatty Acids in Arterial Hypertension: Is There Any Good News?
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“3 fatty acids (Marston et al., 2019) which may reflect an improvement in the risk of atherosclerosis.”
BackgroundInfluentialTargeting hypertriglyceridemia to mitigate cardiovascular risk: A review
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Multitrait GWAS to connect disease variants and biological mechanisms
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“The role of TGs in CAD has also been confirmed by epidemiological studies[52], genome-wide association studies[5], Mendelian randomization studies[53] and randomized controlled trials aiming the lower of TGs[54].”
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“175 mg/dL); furthermore, 1:500 has TG. 10 mmol/L (.”
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“The majority of studies showed a reduction on TG and total cholesterol levels that is known to lower the risk of vascular events [89,90].”
BackgroundLipids and Cardiovascular Risk with CKD
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“In a 2019 meta-analysis of 49 randomized controlled clinical trials of lipid-lowering agents which spanned over 43 years, a total of 374,358 patients from 24 trials of nonstatin therapies and 25 trials of statin therapies with a total of 46,180 major cardiovascular events were analyzed (7).”
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“Prior studies indicate that a 40 mg/dL reduction in LDL cholesterol and triglycerides translates into a 20% and 4–5% decrease in risk for developing cardiovascular disease, respectively, independent of baseline risk (79).”
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“Recently, a systematic review and metaregression analysis of randomized controlled trials also showed a significant association between TG-lowering and CV risk reduction, even after adjusting for LDL-C lowering, although the effect attenuated when REDUCEIT was excluded from the analysis [49].”
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“All factors were adjusted for age, sex, drinking, smoking, education, marital status, total cholesterol, triglycerides, creatinine, blood urea nitrogen, C-reactive protein, uric acid, hypertension, and kidney disease. atherosclerosis progression (57).”
Extensive Evidence Supports the Martin–Hopkins Equation as the LDL-C Calculation of Choice
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“In a recent meta-analysis of 13 trials of omega-3 fatty acids (11 trials of DHA + EPA and 2 trials of EPA monotherapy), including some of the more recent trials reviewed below, the median dose of omega-3 fatty acids was 1000 mg (median EPA, 500 mg; median DHA, 380 mg) [19].”
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A Tale of Two New Targets for Hypertriglyceridaemia: Which Choice of Therapy?
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Updates on dyslipidemia in patients with diabetes
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Birth Weight and Early Postnatal Outcomes: Association with the Cord Blood Lipidome
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- Authors
- Marston, N. A., Giugliano, R. P., Im, K., Silverman, M. G., O’Donoghue, M. L., Wiviott, S. D., Ference, B. A., & Sabatine, M. S.
- Affiliations
- Brigham and Women's Hospital (US)
- Harvard University (US)
- University of Cambridge (GB)
- ORCID
- Venue
- Circulation
- Published
- 2019-10-15
- Volume
- 140
- Issue
- 16
- Pages
- 1308-1317
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- PMC
- PMC6791781
- OpenAlex
- W2973983647
- Cited by
- 301
- References
- 55
- Citations by year
- 2026: 19 · 2025: 58 · 2024: 51 · 2023: 45 · 2022: 42 · 2021: 51 · 2020: 32 · 2019: 3
- FWCI
- 30.54
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (L30 HL143770, K08HL153950, F32HL144029)
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- triglyceride lowering, cardiovascular risk reduction, lipid-lowering therapy, fibrates, nicotinic acid, omega-3 fatty acids, non-HDL cholesterol, LDL cholesterol, major vascular events, REDUCE-IT trial, icosapent ethyl, statins, surrogate endpoints, meta-regression, cardiovascular disease prevention, hypertriglyceridemia, VLDL
- MeSH terms
- Cardiovascular Diseases, Humans, Cholesterol, LDL, Niacin, Risk, Triglycerides, Fatty Acids, Omega-3, Randomized Controlled Trials as Topic, Hydroxymethylglutaryl-CoA Reductase Inhibitors
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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.
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