The DOI matches its Crossref record; 81 of the 81 references it cites were found in a registry or an index; 7 of the 21 sources its claims cite were checked for support.
Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions: A Systematic Review and Meta-analysis
Open accessAbstract
IMPORTANCE: The comparative clinical benefit of nonstatin therapies that reduce low-density lipoprotein cholesterol (LDL-C) remains uncertain. OBJECTIVE: To evaluate the association between lowering LDL-C and relative cardiovascular risk reduction across different statin and nonstatin therapies. DATA SOURCES AND STUDY SELECTION: The MEDLINE and EMBASE databases were searched (1966-July 2016). The key inclusion criteria were that the study was a randomized clinical trial and the reported clinical outcomes included myocardial infarction (MI). Studies were excluded if the duration was less than 6 months or had fewer than 50 clinical events. Studies of 9 different types of LDL-C reduction approaches were included. DATA EXTRACTION AND SYNTHESIS: Two authors independently extracted and entered data into standardized data sheets and data were analyzed using meta-regression. MAIN OUTCOMES AND MEASURES: The relative risk (RR) of major vascular events (a composite of cardiovascular death, acute MI or other acute coronary syndrome, coronary revascularization, or stroke) associated with the absolute reduction in LDL-C level; 5-year rate of major coronary events (coronary death or MI) associated with achieved LDL-C level. RESULTS: A total of 312 175 participants (mean age, 62 years; 24% women; mean baseline LDL-C level of 3.16 mmol/L [122.3 mg/dL]) from 49 trials with 39 645 major vascular events were included. The RR for major vascular events per 1-mmol/L (38.7-mg/dL) reduction in LDL-C level was 0.77 (95% CI, 0.71-0.84; P < .001) for statins and 0.75 (95% CI, 0.66-0.86; P = .002) for established nonstatin interventions that work primarily via upregulation of LDL receptor expression (ie, diet, bile acid sequestrants, ileal bypass, and ezetimibe) (between-group difference, P = .72). For these 5 therapies combined, the RR was 0.77 (95% CI, 0.75-0.79, P < .001) for major vascular events per 1-mmol/L reduction in LDL-C level. For other interventions, the observed RRs vs the expected RRs based on the degree of LDL-C reduction in the trials were 0.94 (95% CI, 0.89-0.99) vs 0.91 (95% CI, 0.90-0.92) for niacin (P = .24); 0.88 (95% CI, 0.83-0.92) vs 0.94 (95% CI, 0.93-0.94) for fibrates (P = .02), which was lower than expected (ie, greater risk reduction); 1.01 (95% CI, 0.94-1.09) vs 0.90 (95% CI, 0.89-0.91) for cholesteryl ester transfer protein inhibitors (P = .002), which was higher than expected (ie, less risk reduction); and 0.49 (95% CI, 0.34-0.71) vs 0.61 (95% CI, 0.58-0.65) for proprotein convertase subtilisin/kexin type 9 inhibitors (P = .25). The achieved absolute LDL-C level was significantly associated with the absolute rate of major coronary events (11 301 events, including coronary death or MI) for primary prevention trials (1.5% lower event rate [95% CI, 0.5%-2.6%] per each 1-mmol/L lower LDL-C level; P = .008) and secondary prevention trials (4.6% lower event rate [95% CI, 2.9%-6.4%] per each 1-mmol/L lower LDL-C level; P < .001). CONCLUSIONS AND RELEVANCE: In this meta-regression analysis, the use of statin and nonstatin therapies that act via upregulation of LDL receptor expression to reduce LDL-C were associated with similar RRs of major vascular events per change in LDL-C. Lower achieved LDL-C levels were associated with lower rates of major coronary events.
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Claims the paper makes
7 of 21 cited sources checked · 1 supported · 0 flagged · accuracy not yet measured
Every source the paper cites for this claim was checked and supports it.
In the paper
“the clinical benefit of the previously recommended use of nonstatin therapies to lower LDL-C is less definitive.7”
§ Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions A Systematic Review and Meta-analysis > Abstract
What the sources say
- Supportedcites [7] 7. Hegele RA, Gidding SS, Ginsberg HN, et al. Nonstatin low-density lipoprotein-lowering therapy and cardiovascular risk reduction. Arterioscler Thromb Vasc Biol. 2015;35(11):2269-2280. source
The Conclusion says statins have the greatest body of randomized-trial evidence for cardiovascular risk reduction. The Abstract describes mixed results for nonstatin therapies and says larger, longer trials were needed for definitive proof of benefit from emerging PCSK9 inhibitors. This supports the comparative claim that the clinical benefit of nonstatin LDL-C-lowering therapies was less definitive, without implying that none had demonstrated benefit. (LLM, conf=0.86)
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“These data suggest that drugs that ultimately reduce LDL-C level predominantly through upregulation of LDL receptor expression should, barring any off-target adverse effects, lead to clinical benefit in proportion to the degree of LDL-C reduction.64”
§ Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions A Systematic Review and Meta-analysis > 77 Full-text articles assessed for eligibility
What the sources say
- Partly supportedcites [64] 64. Cohen JC, Boerwinkle E, Mosley TH Jr, et al. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354(12):1264-1272. sourceExperimental — accuracy not yet measured
The Discussion reports that coronary-event reductions in clinical trials were directly related to the magnitude of LDL-C reduction, and the passage on statin treatment (p. 1272) says statins increase LDL-receptor gene expression. The paper does not establish that this relationship applies to drugs generally when they predominantly act through LDL-receptor upregulation, or assess the off-target-effects condition. (LLM, conf=0.82)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“These results are also supported by genetic association and Mendelian randomization studies demonstrating similarly lower rates of cardiovascular outcomes per unit lower LDL-C in patients with loss-of-function variants in the Niemann-Pick C1-Like1 protein (the target of ezetimibe) and in HMG-CoA reductase (the target of statins).62,63”
§ Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions A Systematic Review and Meta-analysis > 77 Full-text articles assessed for eligibility
What the sources say
- Partly supportedcites [62] 62. Ference BA, Majeed F, Penumetcha R, et al. Effect of naturally random allocation to lower low-density lipoprotein cholesterol on the risk of coronary heart disease mediated by polymorphisms in NPC1L1, HMGCR, or both. J Am Coll Cardiol. 2015;65(15):1552-1561. sourceExperimental — accuracy not yet measured
The Results (External Validation Analyses; page not available) report similar reductions in coronary heart disease risk per 10 mg/dl lower LDL-C mediated by NPC1L1 and HMGCR polymorphisms. But the Methods describe genetic scores based on selected polymorphisms, not loss-of-function variants in both genes. The Discussion mentions rare NPC1L1 loss-of-function mutations as a separate validation finding; it does not establish the claimed comparison for loss-of-function variants in both genes. (LLM, conf=0.88)
- Not matchedcites [63] 63. Grundy SM. Dyslipidaemia in 2015. Nat Rev Cardiol. 2016;13(2):74-75.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Specifically, each 1-mmol/L reduction in LDL-C was associated with an RR of 0.75 (95% CI, 0.66-0.86;P = .002)in major vascular events”
§ Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions A Systematic Review and Meta-analysis > Results
What the sources say
- Not checked — no full text of the sourcecites [49] 49. Dayton S, Pearce ML, Hashimoto S, et al. A controlled clinical trial of a diet high in unsaturated fat in preventing complications of atherosclerosis. Circulation. 1969;39-40(supp 2):1- 63. source
- Not checked — no full text of the sourcecites [50] 50. Dorr AE, Gundersen K, Schneider JC Jr, et al. Colestipol hydrochloride in hypercholesterolemic patients. J Chronic Dis. 1978;31(1):5-14. source
- Partly supportedcites [51] 51. Buchwald H, Varco RL, Matts JP, et al. Effect of partial ileal bypass surgery on mortality and morbidity from coronary heart disease in patients with hypercholesterolemia. N Engl J Med. 1990;323 (14):946-955. sourceExperimental — accuracy not yet measured
Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: Major vascular event components (cardiovascular death, acute MI or other acute coronary syndrome, coronary revascularization, and stroke) have been shown to be reduced by therapies that lower LDL-C.
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“This concept is further supported by human genetic analyses of variants that have been associated with low LDL-C, increased LDL receptors, and decreased coronary heart disease.58,62,63,65”
§ Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions A Systematic Review and Meta-analysis > 77 Full-text articles assessed for eligibility
What the sources say
- Not matchedcites [58] 58. Landray MJ, Haynes R, Hopewell JC, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014;371(3):203- 212.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Partly supportedcites [62] 62. Ference BA, Majeed F, Penumetcha R, et al. Effect of naturally random allocation to lower low-density lipoprotein cholesterol on the risk of coronary heart disease mediated by polymorphisms in NPC1L1, HMGCR, or both. J Am Coll Cardiol. 2015;65(15):1552-1561. sourceExperimental — accuracy not yet measured
The Results (External Validation Analyses; page not provided) associate LDL-C-lowering polymorphisms with lower coronary heart disease risk and describe the hepatic LDL-C receptor as a common final pathway. The paper discusses receptor up-regulation by ezetimibe and statins, but does not establish that the studied variants themselves are associated with increased LDL receptors. (LLM, conf=0.84)
- Not matchedcites [63] 63. Grundy SM. Dyslipidaemia in 2015. Nat Rev Cardiol. 2016;13(2):74-75.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Could not verifycites [65] 65. Goff DC Jr, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk. Circulation. 2014;129(25)(suppl 2):S49-S73. sourceExperimental — accuracy not yet measured
Section 6.2, Critical Question 2 (page not supplied), discusses cumulative exposure to cardiovascular risk factors, but not genetic variants associated with low LDL-C, increased LDL receptors, and reduced coronary heart disease. Searches for those terms in our copy found no passage addressing the claimed genetic analyses. (LLM, conf=0.76)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Not matched
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The observed RR of major vascular events for each of the 5 different established interventions that ultimately act predominantly through upregulation of LDL receptor expression (ie, statins, diet, bile acid sequestrants, ileal bypass, and ezetimibe) was within 0.02 (ie, 2%) of the predicted value from the regression line”
§ Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions A Systematic Review and Meta-analysis > Results
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: Major vascular event components (cardiovascular death, acute MI or other acute coronary syndrome, coronary revascularization, and stroke) have been shown to be reduced by therapies that lower LDL-C.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Combining the data from all 33 of the aforementioned trials generated the meta-regression line (predicted RR of major vascular events for various levels of LDL-C reduction) in Figure 3, in which each 1-mmol/L reduction in LDL-C was associated with an RR of 0.77 (95% CI, 0.75-0.79) in major vascular events.”
§ Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions A Systematic Review and Meta-analysis > Results
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: Major vascular event components (cardiovascular death, acute MI or other acute coronary syndrome, coronary revascularization, and stroke) have been shown to be reduced by therapies that lower LDL-C.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“For the 25 statin trials, each 1-mmol/L (38.7-mg/dL) reduction in LDL-C level was associated with an RR of 0.77 (95% CI, 0.71-0.84;P < .001)for major vascular events (Figure 2A).”
§ Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions A Systematic Review and Meta-analysis > Results
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: Major vascular event components (cardiovascular death, acute MI or other acute coronary syndrome, coronary revascularization, and stroke) have been shown to be reduced by therapies that lower LDL-C.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“(P = .72for between-group difference with statin therapy)”
§ Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions A Systematic Review and Meta-analysis > Results
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: Major vascular event components (cardiovascular death, acute MI or other acute coronary syndrome, coronary revascularization, and stroke) have been shown to be reduced by therapies that lower LDL-C.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“There were 15 trials of interventions that do not reduce LDL-C levels primarily through upregulation of LDL receptor expression (9 trials with fibrates, 3 trials with niacin [1 of which was a multigroup trial that also studied fibrates], and 3 trials with CETP inhibitors).”
§ Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions A Systematic Review and Meta-analysis > Results
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
- Probably not a substantial claim. 16
- It may state two separate claims as one. 16
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“a timeframe during which a clinical benefit of lipid-lowering therapy would not be expected to emerge 10”
§ Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions A Systematic Review and Meta-analysis > Methods
What the sources say
- Partly supportedcites [10] 10. Bulbulia R, Bowman L, Wallendszus K, et al. Effects on 11-year mortality and morbidity of lowering LDL cholesterol with simvastatin for about 5 years in 20,536 high-risk individuals. Lancet. 2011;378(9808):2013-2020. sourceExperimental — accuracy not yet measured
The Results report no statistically significant reduction in major vascular events during the first year of simvastatin treatment, with significant reductions in subsequent years. The Discussion nevertheless notes fewer events in the first year. Neither passage establishes that clinical benefit would not be expected within six months, so the specific timeframe is unsupported. (LLM, conf=0.79)
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
- Partly supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In terms of the other interventions, the observed RR of 0.94 (95% CI, 0.89-0.99)for major vascular events for niacin was greater (ie, less risk reduction) than the expected RR from meta-regression of 0.91 (95% CI, 0.90-0.92;P = .24),but with 95% CIs that encompass the regression line and z score testing showing no significant difference (P = .24).”
§ Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions A Systematic Review and Meta-analysis > Results
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The observed RR of 0.88 (95% CI, 0.83-0.92)for fibrates was lower (ie, greater risk reduction) than the expected RR of 0.94 (95% CI, 0.93-0.94)(P = .02).”
§ Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions A Systematic Review and Meta-analysis > Results
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“resulting in approximately 1.3 million person-years of follow-up.”
§ Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions A Systematic Review and Meta-analysis > Results
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The mean follow-up was 4.3 years”
§ Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions A Systematic Review and Meta-analysis > Results
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, the observed RR reduction in major vascular events was 4% (95% CI, -3% to 10%) in HPS2-Thrive, 11% (95% CI, 1% to 20%) in FIELD, and 8% (95% CI, -8% to 21%) in ACCORD, which were similar to the RR reductions predicted from the meta-regression (7%, 9%, and 0%, respectively).”
§ Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions A Systematic Review and Meta-analysis > 77 Full-text articles assessed for eligibility
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“0.88 (95% CI, 0.83-0.92)vs 0.94 (95% CI, 0.93-0.94)for fibrates (P = .02),which was lower than expected (ie, greater risk reduction)”
§ Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions A Systematic Review and Meta-analysis > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“There were 2 trials with PCSK9 inhibitors.”
§ Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions A Systematic Review and Meta-analysis > Results
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The absolute reduction in LDL-C accounted for 98% of the between-study variability (R 2 value) in the reduction of major vascular events, whereas the percentage reduction in LDL-C only accounted for 79%.”
§ Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions A Systematic Review and Meta-analysis > Results
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“A total of 240 citations were identified and reviewed for eligibility (Figure 1)”
§ Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions A Systematic Review and Meta-analysis > Results
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“When recalculating the regression slope using non-HDL-C, the RR per 1-mmol/L reduction in non-HDL-C was 0.80 (95% CI, 0.77-0.82),which was similar to the RR with LDL-C reduction.”
§ Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions A Systematic Review and Meta-analysis > Results
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In this systematic review and meta-regression analysis of 49 trials involving 9 different interventions to lower LDL-C that included more than 300 000 patients and approximately 40 000 major vascular events, there was a similar association”
- Also stated in: § 77 Full-text articles assessed for eligibility · plain
“between absolute reductions in LDL-C and lower RRs for major vascular events across therapies that ultimately work predominantly through upregulation of LDL receptor expression, such that each 1-mmol/L (38.7-mg/dL) reduction in LDL-C was associated with an RR of 0.77 (ie, 23% relative reduction) in the risk of major vascular events.”
§ Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions A Systematic Review and Meta-analysis > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: The therapies classified as acting predominantly via upregulation of LDL receptor expression indeed act predominantly through that mechanism.
- Also stated in: § 77 Full-text articles assessed for eligibility · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“There were 25 statin trials.”
§ Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions A Systematic Review and Meta-analysis > Results
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The observed RR of 1.01 (95% CI, 0.94-1.09)associated with CETP inhibitors was significantly greater than the expected RR of 0.90 (95% CI, 0.89-0.91;P = .002)(ie, less risk reduction) with no appreciable clinical benefit in a meta-analysis of the compounds studied to date.”
§ Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions A Systematic Review and Meta-analysis > Results
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“49 trials, spanning 9 different treatment modalities were included in the meta-regression analysis”
§ Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions A Systematic Review and Meta-analysis > Results
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the RR reduction for major vascular events was 6.4% (95% CI, 1%-11%), with an absolute risk reduction of 2% over 7 years.”
§ Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions A Systematic Review and Meta-analysis > 77 Full-text articles assessed for eligibility
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The estimated RR of 0.49 (95% CI, 0.34-0.71)associated with PCSK9 inhibitors was numerically lower, but not significantly different, than the expected RR of 0.61 (95% CI, 0.58-0.65),with wide 95% CIs that included the regression line (P = .25).”
§ Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions A Systematic Review and Meta-analysis > Results
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“1.01 (95% CI, 0.94-1.09)vs 0.90 (95% CI, 0.89-0.91)for cholesteryl ester transfer protein inhibitors (P = .002),which was higher than expected (ie, less risk reduction)”
§ Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions A Systematic Review and Meta-analysis > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, the data in the present meta-regression analysis raise the possibility that other interventions, especially those that ultimately act predominantly through upregulation of LDL receptor expression, may provide additional options and may potentially be associated with the same relative clinical benefit per each 1-mmol/L reduction in LDL-C.”
§ Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions A Systematic Review and Meta-analysis > 77 Full-text articles assessed for eligibility
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: The therapies classified as acting predominantly via upregulation of LDL receptor expression indeed act predominantly through that mechanism.
In the paper
“A systematic review and trial-level meta-regression analysis of randomized clinical trials that evaluated the effect of therapy to lower LDL-C on cardiovascular outcomes was performed and the results are reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines.9”
§ Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions A Systematic Review and Meta-analysis > Methods
What the sources say
- Not matchedcites [9] 9. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses. Ann Intern Med. 2009;151(4):264-269, W64.
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
- Not matched
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All disagreements were discussed and resolved by consensus.”
§ Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions A Systematic Review and Meta-analysis > Methods
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“In the earlier trials that did not report LDL-C levels, LDL-C values at baseline and while in the study were estimated from total cholesterol levels (the Supplement provides additional details).”
§ Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions A Systematic Review and Meta-analysis > Methods
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Based purely on LDL-C lowering and given the number of events accrued, the statistical power for their primary end points was only approximately 51% for HPS2-Thrive, 19% for FIELD, and 3% for ACCORD.”
§ Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions A Systematic Review and Meta-analysis > 77 Full-text articles assessed for eligibility
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Two authors independently extracted and entered data into standardized data sheets and data were analyzed using meta-regression.”
§ Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions A Systematic Review and Meta-analysis > Abstract
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“and background therapy has changed, which may account for some of the difference in absolute event rates between trials.”
§ Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions A Systematic Review and Meta-analysis > 77 Full-text articles assessed for eligibility
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Fourth, the studies included in the analysis were conducted over a span of 51 years”
§ Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions A Systematic Review and Meta-analysis > 77 Full-text articles assessed for eligibility
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Third, the data for statins are more extensive than the data for other interventions, with more than 20 000 events from statin trials vs several thousand events each for ezetimibe, niacin, fibrates, and CETP inhibitor trials; several hundred events each for diet, bile acid sequestrants, and ileal bypass trials; and only 2 trials with 111 events during a mean follow-up of 1.2 years for the PCSK9”
§ Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions A Systematic Review and Meta-analysis > 77 Full-text articles assessed for eligibility
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Sixth, hazard ratios were not available in all trials and risk ratios were used when they were not.”
§ Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions A Systematic Review and Meta-analysis > 77 Full-text articles assessed for eligibility
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“First, the meta-analysis was not performed on patient-level data.”
§ Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions A Systematic Review and Meta-analysis > 77 Full-text articles assessed for eligibility
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“by definition the analyses were at the trial level, examining the association between LDL-C reduction and the RR of major vascular events within a trial.”
§ Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions A Systematic Review and Meta-analysis > 77 Full-text articles assessed for eligibility
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
The paper relies on this without support.
The comparative clinical benefit of nonstatin therapies that reduce LDL-C remains uncertain.
“The comparative clinical benefit of nonstatin therapies that reduce low-density lipoprotein cholesterol (LDL-C) remains uncertain.”
The paper relies on this without support.
Major vascular event components (cardiovascular death, acute MI or other acute coronary syndrome, coronary revascularization, and stroke) have been shown to be reduced by therapies that lower LDL-C.
“because all these events have been shown to be reduced by therapies to lower LDL-C.”
The paper relies on this without support.
Fibrates substantially reduce levels of very low-density lipoprotein, an atherogenic particle that contains both cholesterol and triglycerides.
“Fibrates also substantially reduce levels of very low-density lipoprotein, an atherogenic particle that contains both cholesterol and triglycerides.”
The paper relies on this without support.
The therapies classified as acting predominantly via upregulation of LDL receptor expression indeed act predominantly through that mechanism.
“among the trials of statins and established nonstatin therapies that ultimately act predominantly via upregulation of LDL receptor expression”
The paper relies on this without support.
The absolute risk reduction observed in a given trial depends in part on the patient population, the end point, and the duration of follow-up.
“Second, the absolute risk reduction observed in a given trial will depend in part on the patient population, the end point, and the duration of follow-up”
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Studies have shown that dyslipidemia, particularly elevated low-density lipoprotein cholesterol (LDL-C), is an independent risk factor for CHD (3–5).”
From Remnant cholesterol, lipid ratios, and the severity of coronary artery lesions: a retrospective cohort study in patients with coronary heart disease (2025) · cites this paper as [3]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The major limitation of this trial was a relatively short duration of follow-up as compared with that in other lipid-lowering trials, in which follow-up periods have averaged approximately 5 years.28”
From Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease (2017) · cites this paper as [28]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“elevated low-density lipoprotein cholesterol (LDL-C) maintains its position as the most significant risk factor associated with adverse cardiovascular results.”
From Inclisiran SiRNA therapy for durable LDL-C reduction: a systematic review and meta-analysis highlighting a breakthrough in long-term cardiovascular risk management (2026) · cites this paper as [3]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“LDLR plays a crucial role in the uptake of LDL-C from the circulation by hepatocytes 1,2,7 .”
From Dietary cholesterol activates a Ral-dependent pathway driving LDLR turnover (2026) · cites this paper as [7]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The regulation of LDLR trafficking and turnover is essential for maintaining cholesterol homeostasis and remains a major focus of therapeutic strategies for CVD 1,2,7 .”
From Dietary cholesterol activates a Ral-dependent pathway driving LDLR turnover (2026) · cites this paper as [7]
Experimental — accuracy not yet measured
The cited source says what the claim attributes to it.
In the citing paper
“Lipid-lowering therapy has transformed the landscape of cardiovascular disease (CVD) prevention, with low density lipoprotein cholesterol (LDL-C) firmly established as a central driver of atherosclerotic CVD (ASCVD) risk [1].”
From Targeting Triglycerides in Cardiovascular Disease Prevention: Evidence, Mechanisms, and Emerging Therapies (2026) · cites this paper as [1]
The cited source says what the claim attributes to it.
In the citing paper
“Like LDLC, non-HDLC is treatable with existing lipid-lowering agents and there is a direct, consistent relationship between the magnitude of non-HDLC lowering and cardiovascular risk reduction observed in meta-analyses and trials with statins and other lipid-lowering agents [56,57].”
From Quantifying atherogenic lipoproteins for lipid-lowering strategies: Consensus-based recommendations from EAS and EFLM (2020) · cites this paper as [57]
The cited source says what the claim attributes to it.
In the citing paper
“These observations are in accord with meta-analyses of data from clinical trials of different lipid-lowering interventions, which show consistent clinical benefits per unit reduction in LDL cholesterol.28”
From Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease (2017) · cites this paper as [28]
The cited source says what the claim attributes to it.
In the citing paper
“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”
From Association of Triglyceride-Lowering LPL Variants and LDL-C–Lowering LDLR Variants With Risk of Coronary Heart Disease (2019) · cites this paper as [4]
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Evidence suggests that atherosclerotic plaques are unlikely to further develop if LDL is at or below 70 mg/dL or 1.8 mmol/L [43].”
From The Effect of Exercise Training on Blood Lipids: A Systematic Review and Meta-analysis (2025) · cites this paper as [43]
Experimental — accuracy not yet measuredIn the citing paper
“Numerous epidemiological studies, Mendelian randomization studies, and RCTs have consistently demonstrated a log-linear relationship between the absolute changes in plasma LDL-C and the risk of ASCVD [34,45-50].”
From 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk (2019) · cites this paper as [49]
In the citing paper
“In contrast, Mendelian randomization studies do not provide compelling evidence that HDL-C is causally associated with the risk of ASCVD [49,61,62].”
From 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk (2019) · cites this paper as [49]
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.
IMPROVE-IT citation points to a different trial
MinorThe text cites reference 53 for IMPROVE-IT, but reference 53 in the provided list is the Lipid Research Clinics Coronary Primary Prevention Trial, not IMPROVE-IT.
“Ezetimibe was studied in the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) trial 53”
“53. The Lipid Research Clinics Coronary Primary Prevention Trial results, 1: reduction in incidence of coronary heart disease.”
Citations
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Cited by
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Items 201–300 of 1,481
Khan, T. J., Kuerban, A., Razvi, S. S., Mehanna, M. G., Khan, K. A., Almulaiky, Y. Q., & Faidallah, H. M. (2018) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2018.07.134 · Cited by 52
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Fuenzalida, B., Sobrevia, B., Cantin, C., Carvajal, L., Salsoso, R., Gutiérrez, J., Contreras‐Duarte, S., Sobrevía, L., & Leiva, A. (2018) · Scientific Reports · doi:10.1038/s41598-018-25985-6 · Cited by 51
Cholesterol-Lowering Agents: Statins—For Everyone?
Hadjiphilippou, S., & Ray, K. K. (2019) · Circulation Research · doi:10.1161/circresaha.118.313245 · Cited by 49
Low LDL cholesterol by PCSK9 variation reduces cardiovascular mortality
Benn, M., Tybjærg-Hansen, A., & Nordestgaard, B. G. (2019) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2019.03.517 · Cited by 51
2019 ESC/EAS Guidelines for management of dyslipidaemia: strengths and limitations
Zeitouni, M., Sabouret, P. F., Kernéis, M., Silvain, J., Collet, J., Bruckert, É., & Montalescot, G. (2020) · European Heart Journal - Cardiovascular Pharmacotherapy · doi:10.1093/ehjcvp/pvaa077 · Cited by 56
Soltani, S., Saraf‐Bank, S., Basirat, R., Salehi‐Abargouei, A., Mohammadifard, N., Sadeghi, M., Khosravi, A., Fadhil, I., Puska, P., & Sarrafzadegan, N. (2021) · Public Health · doi:10.1016/j.puhe.2021.09.006 · Cited by 50
Advances in statin adverse reactions and the potential mechanisms: A systematic review
Zeng, W., Deng, H., Luo, Y., Zhong, S., Huang, M., & Tomlinson, B. (2024) · Journal of Advanced Research · doi:10.1016/j.jare.2024.12.020 · Cited by 58
“Clinical studies and meta -analysis have confirmed that statins could reduce cardiovascular events by about 20 % for every 1 mmol/L (38.7 mg/dL) reduction in low-density lipoprotein (LDL) cholesterol [2,3].”
InfluentialHypertriglyceridemia-Associated Pancreatitis: New Concepts and Potential Mechanisms
Hansen, S. E. J., Varbo, A., Nordestgaard, B. G., & Langsted, A. (2023) · Clinical Chemistry · doi:10.1093/clinchem/hvad094 · Cited by 51
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“In addition, RCTs of medications which lower cholesterol demonstrate marked reductions in ASCVD with no evidence of a J-shaped curve.(42) Elevated plasma levels of triglycerides are associated with higher rate of ASCVD.”
BackgroundThe Immunomodulatory Effects of Statins on Macrophages
Sheridan, A., Wheeler-Jones, C. P. D., & Gage, M. C. (2022) · Immuno · doi:10.3390/immuno2020021 · Cited by 48
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Drapkina, O. M., Karamnova, N. S., Васильевна, К. А., Gornyi, B., Дадаева, В. А., Drozdova, L. Y., Yeganyan, R. A., Олеговна, Е. С., Izmailova, O. V., Lavrenova, Е. A., et al. (2021) · CARDIOVASCULAR THERAPY AND PREVENTION · doi:10.15829/1728-8800-2021-2952 · Cited by 62
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“, statins, and proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors [2], both of which up-regulate hepatic LDL receptor expression, and for drugs acting on other pathways, such as ezetimibe [3], which inhibits intestinal absorption of cholesterol [4].”
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High cholesterol absorption: A risk factor of atherosclerotic cardiovascular diseases?
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JCS 2023 Guideline on the Primary Prevention of Coronary Artery Disease
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“However, bile acid sequestrant efficacy was lower compared to statins [40].”
BackgroundSilbernagel, G., Scharnagl, H., Kleber, M. E., Delgado, G., Stojaković, T., Laaksonen, R., Erdmann, J., Rankinen, T., Bouchard, C., Landmesser, U., et al. (2018) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2018.12.024 · Cited by 43
“Interventional studies on lipids have primarily focused on low density lipoprotein (LDL) cholesterol (5, 6), which per the classical definition of LDL by the Friedewald equation and β quantification is inclusive of intermediate-density lipoprotein (IDL) (7).”
BackgroundFamilial Hypercholesterolaemia in 2020: A Leading Tier 1 Genomic Application
Pang, J., SULLIVAN, D. R., Brett, T., Kostner, K., Hare, D. L., & Watts, G. F. (2019) · Heart Lung and Circulation · doi:10.1016/j.hlc.2019.12.002 · Cited by 48
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Lipid lowering drugs and inflammatory changes: an impact on cardiovascular outcomes?
Ruscica, M., Ferri, N., Macchi, C., Corsini, A., & Sirtori, C. R. (2018) · Annals of Medicine · doi:10.1080/07853890.2018.1498118 · Cited by 43
“reductions) were associated with a reduced incidence of major CV events (8).”
BackgroundBrunaldi, V., Farias, G. F., de Rezende, D. T., Cairo-Nunes, G., Riccioppo, D., de Moura, D. T. H., Santo, M. A., & de Moura, E. G. H. (2020) · Gastrointestinal Endoscopy · doi:10.1016/j.gie.2020.03.3757 · Cited by 43
Development of the novel ACLY inhibitor 326E as a promising treatment for hypercholesterolemia
Xie, Z., Zhang, M., Song, Q., Cheng, L., Zhang, X., Song, G., Sun, X., Gu, M., Zhou, C., Zhang, Y., et al. (2022) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2022.06.011 · Cited by 45
De Filippo, O., D’Ascenzo, F., Iannaccone, M., Bertaina, M., Leone, A., Borzillo, I., Ravetti, E., Solano, A., Pagliassotto, I., Nebiolo, M., et al. (2023) · Cardiovascular Diabetology · doi:10.1186/s12933-023-02022-z · Cited by 43
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Barrios, V., Pintó, X., Escobar, C., Varona, J. F., & Gámez, J. M. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12093187 · Cited by 42
“This observation may be related, at least in part, to the fact that the benefit may not depend on specific LLT, but on the effectiveness of the drug in reducing LDL-C [40].”
BackgroundKoren, M. J., Descamps, O., Hata, Y., Hengeveld, E. M., Hovingh, G. K., Ikonomidis, I., Radu Juul Jensen, M. D., Langbakke, I. H., Martens, F. M. A. C., Søndergaard, A. L., et al. (2024) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(23)00325-x · Cited by 43
Burger, P. M., Dorresteijn, J. A. N., Koudstaal, S., Holtrop, J., Kastelein, J. J. P., Jukema, J. W., Ridker, P. M., Mosterd, A., & Visseren, F. L. J. (2024) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2024.118540 · Cited by 52
“The reduction in CVD risk observed with lipid-lowering therapy has been shown to be proportional to the absolute reduction in LDL-C [1,2].”
InfluentialBhindi, R., Guan, M., Zhao, Y., Humphries, K. H., & Mancini, G. B. J. (2019) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2019.03.005 · Cited by 42
Nanna, M. G., Návar, A. M., WOJDYLA, D. M., & Peterson, E. D. (2019) · Journal of the American Geriatrics Society · doi:10.1111/jgs.16123 · Cited by 42
Steinke, I., Ghanei, N., Govindarajulu, M., Yoo, S., Zhong, J., & Amin, R. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.567899 · Cited by 44
Natural compounds as anti-atherogenic agents: Clinical evidence for improved cardiovascular outcomes
Penson, P. E., & Banach, M. (2020) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2020.11.015 · Cited by 42
“[28] Silverman, MG, Ference, BA, Im, K, et al.”
Global prevalence of dyslipidaemia in adult populations: a systematic review protocol
Mohamed-Yassin, M.-S., Baharudin, N., Abdul-Razak, S., Ramli, A. S., & Lai, N. M. (2021) · BMJ Open · doi:10.1136/bmjopen-2021-049662 · Cited by 44
Low-Density Lipoprotein Cholesterol-Lowering Drugs: A Narrative Review
Ferri, N., Ruscica, M., Fazio, S., & Corsini, A. (2024) · Journal of Clinical Medicine · doi:10.3390/jcm13040943 · Cited by 44
“Considering that the achieved cardiovascular benefit is independent of the mechanism by which LDL-C is lowered [4], it is important to shift the treatment paradigm for very high-risk patients from “an intensive statin therapy” approach to an “intensive lipid-lowering therapy” approach [5].”
Dietary Cholesterol in the Elderly Chinese Population: An Analysis of CNHS 2010–2012
Pang, S., Jia, S., Man, Q., Song, S., Li, Y., Song, P., Zhao, W., & Zhang, J. (2017) · Nutrients · doi:10.3390/nu9090934 · Cited by 41
“There is therefore a need to know the national status of dietary cholesterol intake, its food sources, and its association with risk factors for CVD in the elderly Chinese population.”
BackgroundInfluentialThe roles of FGF21 in atherosclerosis pathogenesis
Shanehbandpour-Tabari, F., Karimian, A., Parsian, H., Rameshknia, V., Mahmoodpoor, A., Majidinia, M., Maniati, M., & Yousefi, B. (2019) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-019-09488-x · Cited by 41
Casula, M., Olmastroni, E., Boccalari, M. T., Tragni, E., Pirillo, A., & Catapano, A. L. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2019.03.021 · Cited by 44
The Potential Role of Biomarkers Associated with ASCVD Risk: Risk-Enhancing Biomarkers
Choi, S. (2019) · Journal of Lipid and Atherosclerosis · doi:10.12997/jla.2019.8.2.173 · Cited by 41
Yousufuddin, M., Takahashi, P. Y., Major, B. T., Ahmmad, E. M., Alzu’bi, H., Peters, J., Doyle, T., Jensen, K. L., Al-Ward, R., Sharma, U., et al. (2019) · BMJ Open · doi:10.1136/bmjopen-2018-028638 · Cited by 41
Colesterol LDL y aterosclerosis: evidencias
Guijarro, C., & Cosı́n-Sales, J. (2021) · Clínica e Investigación en Arteriosclerosis · doi:10.1016/j.arteri.2020.12.004 · Cited by 41
Webberley, T. S., Masetti, G., Bevan, R. J., Kerry-Smith, J., Jack, A. A., Michael, D. R., Thomas, S., Glymenaki, M., Li, J., McDonald, J. A. K., et al. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.843105 · Cited by 46
“Obesity and high cholesterol increase the risk of development of AD (Anstey et al., 2011; Saiz-Vazquez et al., 2020) and metabolic disease states such as cardiovascular disease (Silverman et al., 2016).”
BackgroundApoB in clinical care: Pro and Con
Sniderman, A. D., & Robinson, J. G. (2018) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2018.11.001 · Cited by 40
Day, E. A., Ford, R. J., Lu, J. H., Lu, R., Lundenberg, L., Desjardins, E. M., Green, A. E., Lally, J., Schertzer, J. D., & Steinberg, G. R. (2020) · Biochemical Journal · doi:10.1042/bcj20200278 · Cited by 41
Desai, T., Roberts, M. G., & Bottoms, L. M. (2020) · European Journal of Nutrition · doi:10.1007/s00394-020-02355-5 · Cited by 40
Jones, L. K., McMinn, M., Kann, D., Lesko, M. G., Sturm, A. C., Walters, N., Chen, N., Fry, K., Brownson, R. C., Gidding, S. S., et al. (2021) · Implementation Science Communications · doi:10.1186/s43058-021-00135-8 · Cited by 41
The Potential Role of Creatine in Vascular Health
Clarke, H. E., Hickner, R. C., & Ormsbee, M. J. (2021) · Nutrients · doi:10.3390/nu13030857 · Cited by 44
“Not to forget as well, creatine demonstrated the potential to lower both LDL-C and total cholesterol, both of which positively impact vascular health and reduce CVD risk [82].”
BackgroundOuchi, G., Komiya, I., Taira, S., Wakugami, T., & Ohya, Y. (2022) · Lipids in Health and Disease · doi:10.1186/s12944-021-01612-8 · Cited by 40
“This is supported by a recent meta-analysis including 14 statin trials, 7 fibrate trials, and 6 nicotinic acid trials [28].”
ResultChin, Y. H., Lim, O. Z.-H., Lin, C., Chan, Y. Y., Kong, G., Ng, C. H., Chong, B., Syn, N. L. X., Chan, K. E., Muthiah, M. D., et al. (2022) · European Heart Journal - Quality of Care and Clinical Outcomes · doi:10.1093/ehjqcco/qcac060 · Cited by 40
PCSK9 Inhibition and Risk of Diabetes: Should We Worry?
Carugo, S., Sirtori, C. R., Corsini, A., Tokgözoğlu, L. S., & Ruscica, M. (2022) · Current Atherosclerosis Reports · doi:10.1007/s11883-022-01074-y · Cited by 40
Cholesterol-Lowering Nutraceuticals Affecting Vascular Function and Cardiovascular Disease Risk
Bianconi, V., Mannarino, M. R., Sahebkar, A., Cosentino, T., & Pirro, M. (2018) · Current Cardiology Reports · doi:10.1007/s11886-018-0994-7 · Cited by 40
Li, Y.-H., Lee, C., Huang, W.-C., Wang, Y.-C., Su, C.-H., Sung, P., Chien, S.-C., & Hwang, J. (2020) · PubMed Central · doi:10.6515/acs.202007_36(4).20200619a · Cited by 39
Barańska, A., Błaszczuk, A., Kanadys, W. M., Baczewska, B., Jędrych, M., Wawryk‐Gawda, E., & Polz‐Dacewicz, M. (2021) · Nutrients · doi:10.3390/nu13082531 · Cited by 42
“Several meta-analyses have shown that reduction of serum LDLC by about 5–6% and a 3% increase in HDL-C are associated with improved cardiovascular outcomes [11,12].”
BackgroundNovel and Emerging LDL-C Lowering Strategies: A New Era of Dyslipidemia Management
Agnello, F., Ingala, S., Laterra, G., Scalia, L., & Barbanti, M. (2024) · Journal of Clinical Medicine · doi:10.3390/jcm13051251 · Cited by 39
Role of Berry Bioactive Compounds on Lipids and Lipoproteins in Diabetes and Metabolic Syndrome
Basu, A. (2019) · Nutrients · doi:10.3390/nu11091983 · Cited by 38
“In a meta-regression analysis of 49 clinical trials with 312,175 participants, each 1 mmol/L reduction in LDL-C level was associated with a 23% risk reduction of major vascular events for statins, and a 25% risk reduction for non-statin interventions, including dietary approaches to lower LDL-C [3] Studies have furthe…”
MethodInfluentialFralick, M., Colacci, M., Odutayo, A., Siemieniuk, R. A. C., & Glynn, R. J. (2020) · Journal of Diabetes and its Complications · doi:10.1016/j.jdiacomp.2020.107704 · Cited by 38
Kauppinen, K. J., Aho, I., & Sutinen, J. (2022) · AIDS · doi:10.1097/qad.0000000000003245 · Cited by 39
“dietary measures or lipid lowering medication) a similar cardiovascular risk reduction is observed [20].”
BackgroundLi, L., Ouyang, F., He, J., Qiu, D., Luo, D., & Xiao, S. (2022) · Frontiers in Public Health · doi:10.3389/fpubh.2022.878126 · Cited by 38
Zuurbier, L. C., Defesche, J. C., & Wiegman, A. (2021) · Genes · doi:10.3390/genes12081168 · Cited by 38
Gupta, M., Mancini, G. B. J., Wani, R. J., Ahooja, V., Bergeron, J., Manjoo, P., Pandey, A. S., Reiner, M. T., Beltran, J., Oliveira, T., et al. (2022) · CJC Open · doi:10.1016/j.cjco.2022.03.003 · Cited by 39
Chinese expert consensus on blood lipid management in patients with diabetes (2024 edition)
Xiao, Y., Yu, B., Chen, C., Wang, S., Hu, D., Wu, C., Luo, Y., Xie, L., Li, C., Peng, D., et al. (2024) · Journal of Translational Internal Medicine · doi:10.2478/jtim-2024-0014 · Cited by 37
Xue, H., & Pan, W. (2020) · PLoS Genetics · doi:10.1371/journal.pgen.1009105 · Cited by 37
“In contrast, after accounting for possible horizontal pleiotropy, our proposed methods CD-Egger and CD-GLS would both conclude the causal direction from LDL to CAD, in agreement with the previous MR analysis and RCT results reported in the literature [19, 13, 12, 44].”
ResultSchaefer, E. J., Ikezaki, H., Diffenderfer, M. R., Lim, E., Liu, C., Hoogeveen, R. C., Guan, W., Tsai, M. Y., & Ballantyne, C. M. (2023) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2023.01.015 · Cited by 37
Thau, H., Neuber, S., Emmert, M. Y., & Nazari‐Shafti, T. Z. (2024) · Cardiology and Therapy · doi:10.1007/s40119-024-00353-w · Cited by 42
“After a meta-analysis demonstrated a 23% relative risk reduction of major cardiovascular events for every 38.7 mg/dL reduction in LDL-C [101], therapeutic lowering of LDL-C levels became a cornerstone for secondary CVD prevention [102].”
BackgroundInfluentialRecent perspectives on the role of nutraceuticals as cholesterol-lowering agents
Ward, N. C., Sahebkar, A., Banach, M., & Watts, G. F. (2017) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000455 · Cited by 36
Evaluation of the Pleiotropic Effects of Statins
Labos, C., Brophy, J. M., Smith, G. D., Sniderman, A. D., & Thanassoulis, G. (2017) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.117.310052 · Cited by 36
Biomarkers and Clinical Cardiovascular Outcomes With Ezetimibe in the IMPROVE-IT Trial
Qamar, A., Giugliano, R. P., Bohula, E. A., Park, J., Jarolı́m, P., Murphy, S. A., Blazing, M. A., Califf, R. M., Cannon, C. P., D, E. B. M., et al. (2019) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2019.06.038 · Cited by 36
Self-citationSmall Dense Low-Density Lipoprotein Cholesterol and Carotid Intimal Medial Thickness Progression
Ikezaki, H., Furusyo, N., Yokota, Y., Ai, M., Asztalos, B. F., Murata, M., Hayashi, J., & Schaefer, E. J. (2020) · Journal of Atherosclerosis and Thrombosis · doi:10.5551/jat.54130 · Cited by 36
Luca, L. D., Arca, M., Temporelli, P. L., Meessen, J. M. T. A., Riccio, C., Bonomo, P., Colavita, A. R., Gabrielli, D., Gulizia, M. M., & Colivicchi, F. (2020) · International Journal of Cardiology · doi:10.1016/j.ijcard.2020.05.055 · Cited by 36
Lowering low-density lipoprotein cholesterol: from mechanisms to therapies
Luo, J., Wang, J.-K., & Song, B. (2022) · Life Metabolism · doi:10.1093/lifemeta/loac004 · Cited by 37
Zhang, H., Qi, Z., Dong, F., et al. (2023) · Lipids in Health and Disease · doi:10.1186/s12944-023-01843-x · Cited by 35
“Abbreviations CVAI Chinese Visceral Adiposity Index CHARLS China Health and Retirement Longitudinal Study Q4 Quartile group DALY Disability-Adjusted Life Year GBD Global burden of disease WC Waist circumference WHR Waist-to-hip ratio BMI Body mass index HDL-C High-density lipoprotein cholesterol TG Triglycerides VAI V…”
BackgroundInfluentialPCSK9 in cholesterol metabolism: from bench to bedside
Reiss, A. B., Shah, N. B., Muhieddine, D., Zhen, J., Yudkevich, J., Kasselman, L. J., & DeLeon, J. R. (2018) · Clinical Science · doi:10.1042/cs20180190 · Cited by 35
Lipoprotein Subfractions and Glucose Homeostasis in Prediabetes and Diabetes in Taiwan
Hsu, H., Hsu, P.-W., Cheng, M., Ito, Y., Kanda, E., Schaefer, E. J., & Ai, M. (2019) · Journal of Atherosclerosis and Thrombosis · doi:10.5551/jat.48330 · Cited by 35
Suzuki, K., Oikawa, T., Nochioka, K., Miura, M., Kasahara, S., Sato, M., Aoyanagi, H., Shiroto, T., Takahashi, J. A., Miyata, S., et al. (2019) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.119.312336 · Cited by 35
“ing from the previous reports in the general population where most of the participants did not receive statin treatments.(18,34,35)”
ResultKöenig, W., Conde, L. G., Landmesser, U., Leiter, L. A., Ray, K. K., Schwartz, G. G., Wright, R. S., Han, J., & Raal, F. J. (2022) · Cardiovascular Drugs and Therapy · doi:10.1007/s10557-022-07413-0 · Cited by 37
Fixed Combination for the Treatment of Dyslipidaemia
Ferri, N., Ruscica, M., Santos, R. D., & Corsini, A. (2023) · Current Atherosclerosis Reports · doi:10.1007/s11883-023-01142-x · Cited by 38
Bohula, E. A., Marston, N., Ruzza, A., Murphy, S. A., Ferrari, G. M. D., Díaz, R., Leiter, L. A., Elliott‐Davey, M., Wang, H., Bhatia, A. K., et al. (2023) · American Heart Journal · doi:10.1016/j.ahj.2023.12.004 · Cited by 36
Self-citationCardiovascular Risk Estimation and Stratification Among Individuals with Hypercholesterolemia
Bosco, G., Mszar, R., Piro, S., Sabouret, P. F., & Gallo, A. (2024) · Current Atherosclerosis Reports · doi:10.1007/s11883-024-01225-3 · Cited by 39
“Similarly, both the relative and absolute reductions in cardiovascular risk correlate with the magnitude of LDLc reduction [11].”
Recent advances in synthetic pharmacotherapies for dyslipidaemias
Sirtori, C. R., Yamashita, S., Greco, M. F., Corsini, A., Watts, G. F., & Ruscica, M. (2019) · European Journal of Preventive Cardiology · doi:10.1177/2047487319845314 · Cited by 34
Association of Dietary Phytosterols with Cardiovascular Disease Biomarkers in Humans
Kaur, R., & Myrie, S. B. (2020) · Lipids · doi:10.1002/lipd.12262 · Cited by 37
Ismail, M. A., Norhayati, M. N., & Mohamad, N. (2021) · PeerJ · doi:10.7717/peerj.11173 · Cited by 34
Significance of blood lipid parameters as effective markers for arteriogenic erectile dysfunction
Li, M., Ma, Z., Zhang, X., Guo, L., & Yuan, M. (2020) · Andrology · doi:10.1111/andr.12776 · Cited by 32
Novel Lipid-Lowering Therapies to Reduce Cardiovascular Risk
Wilkins, J. T., & Lloyd‐Jones, D. M. (2021) · JAMA · doi:10.1001/jama.2021.2244 · Cited by 33
Lipids and Lipoproteins in Health and Disease: Focus on Targeting Atherosclerosis
Lee, C., Liao, C., Meng, S., Wu, W., Chiang, J., & Wu, M. (2021) · Biomedicines · doi:10.3390/biomedicines9080985 · Cited by 39
“Previous studies on fibrates, niacin, and cholesteryl ester transfer protein inhibitors did not demonstrate a robust or convincing reduction in the risk of ASCVD in an optimal cholesterol-lowering population [82,83].”
ResultCicero, A. F. G., Fogacci, F., Zambon, A., Toth, P. P., & Borghi, C. (2022) · American Heart Journal Plus: Cardiology Research and Practice · doi:10.1016/j.ahjo.2022.100127 · Cited by 34
“Robust and growing evidence highlights that this linear association is observed regardless of the LDL-C lowering approach adopted, i.e., lipid lowering diet, ezetimibe, bile acid binding resins, PCSK9 inhibitors, etc. [43].”
Background
Metadata
- Authors
- Silverman, M. G., Ference, B. A., Im, K., Wiviott, S. D., Giugliano, R. P., Grundy, S. M., Braunwald, E., & Sabatine, M. S.
- Affiliations
- Brigham and Women's Hospital (US)
- Wayne State University (US)
- The University of Texas Southwestern Medical Center (US)
- TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
- Corresponding author
- Sabatine, Marc S.
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2016-09-27
- Volume
- 316
- Issue
- 12
- Pages
- 1289
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- OpenAlex
- W2465758073
- Cited by
- 1,483
- References
- 79
- Citations by year
- 2026: 111 · 2025: 163 · 2024: 182 · 2023: 202 · 2022: 152 · 2021: 151 · 2020: 170 · 2019: 152 · 2018: 115 · 2017: 70 · 2016: 13
- FWCI
- 23.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (T32HL007604)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Acute Myocardial Infarction Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- LDL cholesterol lowering, cardiovascular risk reduction, statins, non-statin lipid-lowering therapy, LDL receptor upregulation, ezetimibe, bile acid sequestrants, ileal bypass, dietary intervention, myocardial infarction, major vascular events, coronary revascularization, stroke, cardiovascular mortality, acute coronary syndrome, LDL cholesterol targets
- MeSH terms
- Hypolipidemic Agents, Cardiovascular Diseases, Female, Humans, Cholesterol, LDL, Male, Middle Aged, Myocardial Infarction, Niacin, Receptors, LDL, Up-Regulation, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Stroke, Risk Reduction Behavior
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