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
Sorted by citations
Items 701–800 of 1,481
Tokgözoğlu, L. S., & Zamorano, J. L. (2020) · Drugs in Context · doi:10.7573/dic.2020-4-4 · Cited by 11
Ferro, Y., Mazza, E., Salvati, M. A., Santariga, E., Giampà, S., Spagnuolo, R., Doldo, P., Pujia, R., Coppola, A., Gazzaruso, C., et al. (2020) · Endocrinology and Metabolism · doi:10.3803/enm.2020.35.2.298 · Cited by 10
“The incremental decrease in LDL-C by non-pharmacological therapies can translate into reductions in CV event rates [12]; thus, our results are of important clinical significance.”
BackgroundA New Approach to an Old Problem
Cranley, J. J., & MacRae, C. A. (2018) · Circulation Research · doi:10.1161/circresaha.118.310941 · Cited by 9
Ference, B. A. (2019) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.1163 · Cited by 8
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“Large-scale observational [36], interventional [37, 38], and genetic studies [12, 13, 19] support LDL and triglycerides as being causal in the aetiology of CAD.”
Vanhee, C., Jacobs, B., Canfyn, M., Malysheva, S. V., Willocx, M., Masquelier, J., & Hoorde, K. V. (2024) · Foods · doi:10.3390/foods13121919 · Cited by 8
“Alternatively, in recent decades, dietary supplements containing red yeast rice (RYR) have emerged in the USA and Europe and remain very popular nowadays as proclaimed Foods 2024 , 13 , 1919 2 of 20 cholesterol-lowering aids [3,6,7].”
BackgroundIannuzzo, G., Kamboj, G., Barman, P., Dongare, S., & Jawla, S. (2024) · Atherosclerosis Plus · doi:10.1016/j.athplu.2024.10.001 · Cited by 10
High-Density Lipoprotein Particles, Inflammation, and Coronary Heart Disease Risk
Stock, E. O., Asztalos, B. F., Miller, J. M., He, L., Creasy, K. T., Schwemberger, R., Quinn, A. T., Pullinger, C. R., Malloy, M. J., Diffenderfer, M. R., et al. (2025) · Nutrients · doi:10.3390/nu17071182 · Cited by 9
“Clinical trial evidence strongly supports lowering low-density lipoprotein cholesterol (LDL-C) through lifestyle modifications, statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors [11].”
Diretriz Brasileira de Dislipidemias e Prevenção da Aterosclerose – 2025
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“Además, el descenso del cLDL mediado por otros fármacos, como la ezetimiba o los inhi-bidores de la proproteína convertasa subtilisina/kexina tipo 9 (iPCSK9), o incluso por medios no farmacológicos, como la reducción de riesgo por unidad de cLDL reducido 15 .”
Lipid profile screening and ASCVD prevention
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“Reduction in LDL-C is associated with a lower incidence of ischemic cardiovascular events [15], and”
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A population pharmacokinetic model for simvastatin and its metabolites in children and adolescents
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Low-Density Lipoprotein Cholesterol After an Acute Coronary Syndrome: How Low to Go?
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Clinical decision-making: Challenging traditional assumptions
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Campbell, D. J. T., Lee-Krueger, R. C. W., McBrien, K., Anderson, T. J., Quan, H., Leung, A. A. C., Chen, G., Lu, M., Naugler, C. T., & Butalia, S. (2020) · BMJ Open · doi:10.1136/bmjopen-2020-038469 · Cited by 8
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“There is extensive proof for the causative position of LDL-C in CVD development [21,22].”
BackgroundCoremans, C., Delporte, C., COTTON, F. J., van de Borne, P., Boudjeltia, K. Z., & Antwerpen, P. V. (2021) · Molecules · doi:10.3390/molecules26175264 · Cited by 8
“In general, LDL-C, non-HDL-C, and apoB concentrations are highly correlated and provide similar information about ASCVD risk [60].”
BackgroundInfluentialProbiotic Lactobacillus plantarum may reduce cardiovascular risk: An experimental study.
Neverovskyi, A., Chernyavskyi, V. V., Shypulin, V. P., Hvozdetska, L., Tishchenko, V. V., Nechypurenko, T., & Mikhn`ova, N. (2021) · PubMed Central · doi:10.22122/arya.v17i0.2156 · Cited by 9
Pitavastatin: Coronary Atherosclerotic Plaques Changes and Cardiovascular Prevention
Fıcı, F., Faikoğlu, G., Tarım, B. A., Robles, N. R., Tsioufis, K., Grassi, G. M., & Güngör, B. (2022) · High Blood Pressure & Cardiovascular Prevention · doi:10.1007/s40292-021-00496-0 · Cited by 9
What is the Optimal Low-Density Lipoprotein Cholesterol?
Gagel, A., Zghyer, F., Samuel, C., & Martin, S. S. (2022) · Medical Clinics of North America · doi:10.1016/j.mcna.2021.11.005 · Cited by 8
Masana, L., Ibarretxe, D., Andreychuk, N., Royuela, M., Rodríguez-Borjabad, C., & Plana, N. (2022) · European Atherosclerosis Journal · doi:10.56095/eaj.v1i1.10 · Cited by 10
Bellino, M., Galasso, G., Silverio, A., Tedeschi, M., Formisano, C., Romei, S., Esposito, L., Cancro, F. P., Vassallo, M. G., Accarino, G., et al. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12082922 · Cited by 10
“6 mmol/L), already on maximally tolerated statin dose and ezetimibe, and not reaching the desired therapeutic target [69,70].”
BackgroundMessas, N., Dubé, M., & Tardif, J. (2017) · Current Atherosclerosis Reports · doi:10.1007/s11883-017-0679-5 · Cited by 8
Hajati, F., Atlantis, E. E., Bell, K., & Girosi, F. (2018) · BMJ Open · doi:10.1136/bmjopen-2017-019041 · Cited by 9
“Conversely, randomised controlled trials show that larger reductions in low-density lipoprotein cholesterol (LDL-C) have larger reductions in CVD risk; each 1 mmol/L reduction in LDL-C with statins reduces the relative risk of CVD over 4–5 years by an additional 20%.(5) 6 Evidence on the safety and effectiveness of st…”
BackgroundPCSK9 Inhibitors: From Nature’s Lessons to Clinical Utility
Raal, F. J., CHILTON, R. J., Ranjith, N., Rambiritch, V., Leisegang, R. F., Ebrahim, I. O., van Tonder, A., Shunmoogam, N., Bouharati, C., Musa, M. G., et al. (2020) · Endocrine Metabolic & Immune Disorders - Drug Targets · doi:10.2174/1871530320666200213114138 · Cited by 8
Guevara, M. E., & Ng, B. (2020) · European Journal of Rheumatology · doi:10.5152/eurjrheum.2020.20193 · Cited by 8
“For LDL, there has been a well-documented linear association between decrease in LDL levels and decrease in the rate of CVD (30).”
BackgroundBarrios, V., Escobar, C., Arrarte, V., García, E., Fernández, M. R., Rincon, L. M., & Roldán, C. (2020) · Clínica e Investigación en Arteriosclerosis (English Edition) · doi:10.1016/j.artere.2020.11.001 · Cited by 8
Ooi, B. N. S., Raechell, R., Ying, A. F., Koh, Y. Z., Jin, Y., Yee, S. W. L., Lee, J. H. S., Chong, S. S., Tan, J. W. C., Liu, J., et al. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.605764 · Cited by 8
“High blood cholesterol levels increase the risk of cardiovascular disease, making lipid-lowering medications such as statins important for the therapeutic management of this risk factor (SEARCH Collaborative Group et al., 2010; Cholesterol Treatment Trialists et al., 2012; Silverman et al., 2016).”
BackgroundCainzos‐Achirica, M., Quispe, R., Mszar, R., Dudum, R., Rifai, M. A., Erbel, R. M., Stang, A., Jöckel, K., Lehmann, N., Schramm, S. H., et al. (2022) · Journal of the American Heart Association · doi:10.1161/jaha.122.025737 · Cited by 8
“…recommendations are based on the benefits that are expected to be achieved through LDL-C reduction, regardless of the specific drug used for this purpose, and extrapolate the benefits observed in primary prevention with statins 28 to other LDL-C– lowering options, such as ezetimibe and PCSK9i.”
The Lower the ApoB, the Better: Now, How Does ApoB Fit in the Upcoming Era of Targeted Therapeutics?
Elshazly, M. B., & Quispe, R. (2022) · Circulation · doi:10.1161/circulationaha.122.061188 · Cited by 8
Li, Y., Zhai, Y., Hu, S., Liu, J., Zhang, W., Yue, J., & Wang, Z. (2025) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2025.1516326 · Cited by 7
Nogo-B inhibition facilitates cholesterol metabolism to reduce hypercholesterolemia
Xue, C., Zeng, P., Gong, K., Li, Q., Feng, Z., Wang, M., Chen, S., Yang, Y., Li, J., Zhang, S., et al. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114691 · Cited by 8
O'Toole, T., Shah, N. P., Giamberardino, S. N., Kwee, L. C., Voora, D., McGarrah, R. W., Ferencik, M., Lu, M. T., Kraus, W. E., Foldyna, B., et al. (2024) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2024.09.006 · Cited by 7
Ahn, W., Burnett, F. N., Wojnar‐Lason, K., Doja, J., Sreekumar, A., Ghoshal, P., Singla, B., Gonsalvez, G. B., Harris, R. A., Wang, X., et al. (2024) · Redox Biology · doi:10.1016/j.redox.2024.103423 · Cited by 8
Li, S., Liu, H., & Li, J. (2024) · Drugs · doi:10.1007/s40265-024-02113-5 · Cited by 8
Kenkre, J. S., Mazaheri, T., Neely, R. D. G., Soran, H., Datta, D. B. N., Penson, P. E., Downie, P., Yates, A. M., Hayden, K., Patel, M., et al. (2025) · Annals of Clinical Biochemistry International Journal of Laboratory Medicine · doi:10.1177/00045632251315303 · Cited by 8
A New Insight on Atherosclerosis Mechanism and Lipid-Lowering Drugs
Li, P., & Jiang, W. (2025) · Reviews in Cardiovascular Medicine · doi:10.31083/rcm25321 · Cited by 8
“Elevated levels of LDL-C are an independent risk factor for atherosclerosis, and lowering LDL-C levels is a crucial strategy for primary and secondary prevention of atherosclerotic CVDs [92].”
Campuzano, R., Mostaza, J. M., Barrios, V., Cabello, I. E., Gómez-Cerezo, J. F., Pallarés‐Carratalá, V., Martínez‐López, I., Castellanos, M., Hernández-Subirá, I., Talamante, N. M., et al. (2025) · Journal of Clinical Medicine · doi:10.3390/jcm14072340 · Cited by 8
Integrating New Technologies in Lipidology: A Comprehensive Review
Escobar, C., García, J. S., Torremocha, A., Lorenzo, C. C., Lara-García, A., Muñoz, L. C., González, R. M., García, J. V., & Banach, M. (2025) · Journal of Clinical Medicine · doi:10.3390/jcm14144984 · Cited by 10
“Despite all of them having demonstrated in clinical trials to significantly reduce the risk of cardiovascular outcomes in patients with dyslipidemia, the fact is that LDLc control rates remain far from optimal [26–28].”
Intensive Lipid-Lowering Therapy Following Acute Coronary Syndrome: The Earlier the Better
Pradhan, A. K., Sharma, P., Prajapathi, S., Aracri, M., Iellamo, F., & Perrone, M. A. (2025) · Journal of Cardiovascular Development and Disease · doi:10.3390/jcdd12080300 · Cited by 8
The effects of opium uses on syntax score of angiography patients with coronary artery disease (CAD)
Moezi, S. A., Azdaki, N., Kazemi, T., et al. (2021) · Toxin Reviews · doi:10.1080/15569543.2021.2000434 · Cited by 7
“The meta-regression analysis of clinical trials showed that 1-mmol/L reduction in LDL-C level was associated with reduction in major vascular events (Silverman et al. 2016).”
MethodMeng, Q., Yang, J., Wang, F., Cheng, L., Sang, G., Liu, H., Shen, D., Zhang, J., Jiang, S., Yusufu, A., et al. (2023) · Diabetes Metabolic Syndrome and Obesity · doi:10.2147/dmso.s404683 · Cited by 8
Mohamed, A. A. M., & Ray, K. K. (2023) · Current Opinion in Cardiology · doi:10.1097/hco.0000000000001074 · Cited by 7
“This indicates that the reduction measure in LDL-C establishes benefits rather than the mechanism by which this is achieved [14,36].”
BackgroundTandirerung, F. J. (2023) · Cardiovascular Drugs and Therapy · doi:10.1007/s10557-023-07505-5 · Cited by 7
“Hence, despite evidence suggesting that LDL-C reduction and cardiovascular risk tend to be linear [58], it is still unknown whether the documented cardiovascular risk reduction following PCSK9i treatment will actually be similar or different between genotypes.”
Salamah, H. M., Marey, A., Elsayed, E., Hasan, M. T., Mahmoud, A., Abualkhair, K. A., Abo‐elnour, D. E., Abdelhaleem, I. A., & Abd‐ElGawad, M. (2023) · Scientific Reports · doi:10.1038/s41598-023-46274-x · Cited by 9
“Elevated TG and LDL levels have been linked to the progression of atherosclerosis and other cardiovascular complications, emphasizing the significance of addressing lipid abnormalities in diabetes management 35,36 .”
BackgroundMarcos‐Garcés, V., Merenciano-Gonzalez, H., Mas, M. L. M., Palau, P., Alberola, J. I. C., Perez, N., López, L., Argente, M. C. E., Reig, M. V., Alcover, R. M., et al. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm13010127 · Cited by 8
“Available evidence suggests that each reduction of 38 mg/dL (1 mmol/L) in LDL-C levels can achieve a reduction of 22–25% in major adverse cardiovascular events [28,29].”
BackgroundChong, S., Mu, G., Cen, X., Xiang, Q., & Cui, Y. (2024) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2024.5381 · Cited by 8
“…with alirocumab (62). compared to other LdL‑c‑lowering drugs, where a reduc‑ tion of 1 mmol/l is associated with a relative risk (RR) of 0.77 [95% confidence interval (CI), 0.75‑0.79] for major vascular events, the estimated RR for PcSK9 inhibitors is lower at 0.49 (95% CI, 0.34‑0.71) ( 63).”
BackgroundInfluentialTang, M., Yang, S., Zou, J., Li, M., Sun, Y., Wang, M., Li, W., He, J., Chen, Y., & Tang, Z. (2024) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2024.1336264 · Cited by 8
Statin alternatives for the treatment of hypercholesterolemia - a safety evaluation
Zeng, W., & Tomlinson, B. (2024) · Expert Opinion on Drug Safety · doi:10.1080/14740338.2024.2424411 · Cited by 7
Rabaeus, M., Nguyen, P., & de Lorgeril, M. (2017) · Journal of Controversies in Biomedical Research · doi:10.15586/jcbmr.2017.18 · Cited by 7
“One notes that most of the authors have significant links with the statin industry, which might have contributed to the surprising selection of the trials included in the meta-analyses (12, 13).”
BackgroundSchade, D. S., Helitzer, D., & Eaton, P. (2017) · World Journal of Cardiovascular Diseases · doi:10.4236/wjcd.2017.79025 · Cited by 7
“This approach is the least invasive or lifestyle altering when medications (primarily statins and lifestyle interventions) have been used as the intervention arm, but surgical ileal bypass, diet trials, and bile acid sequestrants also have been employed as LDL cholesterol lowering procedures [9].”
MethodIndividual trends in LDL-C control in patients with previous myocardial infarction
Ródenas‐Alesina, E., Escalona, R., Pariggiano, I., Oristrell, G., Miranda, B., Belahnech, Y., Soriano-Colomé, T., Rello, P., Gordon, B., Barrabés, J. A., et al. (2019) · REC CardioClinics · doi:10.1016/j.rccl.2019.10.001 · Cited by 7
Hu, X., Yang, X., Li, X., Luo, D., Zhou, Y., & Dong, H. (2020) · Lipids in Health and Disease · doi:10.1186/s12944-020-01272-0 · Cited by 7
Vaccaro, O., Vitale, M., Costanzo, S., Masulli, M., Riccardi, G., Curtis, A. D., Donati, M. B., Rivellese, A. A., de Gaetano, G., & Iacoviello, L. (2020) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2020.108370 · Cited by 7
Watts, G. F., SULLIVAN, D. R., Hare, D. L., Kostner, K., Horton, A., Bell, D. A., Brett, T., Trent, R. J., Poplawski, N. K., Martin, A. C., et al. (2021) · American Journal of Preventive Cardiology · doi:10.1016/j.ajpc.2021.100151 · Cited by 7
Barrios, V., Escobar, C., Anguita, M. P., Esteban, V. I. A., Ruíz, R. C., Cosı́n-Sales, J., Cabello, M. I. E., Martínez, J. M. G., Guijarro, C., Mostaza, J. M., et al. (2021) · REC CardioClinics · doi:10.1016/j.rccl.2021.05.002 · Cited by 7
Mensink, F. B., Los, J., ten Cate, T. J. F., Oemrawsingh, R. M., Brouwer, M. A., Messaoudi, S. E., van Royen, N., Cornel, J. H., Riksen, N. P., & van Geuns, R. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2022.1061346 · Cited by 7
Iso, H., Noguchi, M., Yokoyama, T., Yoshida, T., Saito, I., Shintani, A., Sairenchi, T., Nishizawa, H., Imano, H., Kitamura, A., et al. (2023) · Journal of Atherosclerosis and Thrombosis · doi:10.5551/jat.64100 · Cited by 7
Ups and downs in PCSK9 inhibition in the cardiovascular arena: a review
McClintick, D. J., & Giugliano, R. P. (2023) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000897 · Cited by 7
“inhibitors (PCSK9i) [3,4], and most recently with bempedoic acid [5], has been proven to reduce cardiovascular events in patients with atherosclerotic cardiovascular disease (ASCVD) with elevated LDL-C [6].”
BackgroundSelf-citationPearson, T. A. (2016) · Medical Care · doi:10.1097/mlr.0000000000000682 · Cited by 7
“All approaches to modify LDL-C levels were recently reviewed for their effect on cardiovascular outcomes.(11) One strong conclusion is that the reduction in LDL-C is related to reduction in CVD clinical outcomes regardless of whether any of several classes of drugs, surgical procedures, or dietary changes were used.”
MethodFjukstad, K. K., Engum, A., Lydersen, S., Dieset, I., Steen, N. E., Andreassen, O. A., & Spigset, O. (2017) · European Psychiatry · doi:10.1016/j.eurpsy.2017.04.001 · Cited by 6
“30 nmol/l and hypothesize that this causes a corresponding effect (although in the opposite direction) than taking a statin [56], the relative risk increase of a major cardiovascular event could be estimated to a mere 5–10% (i.”
BackgroundRossignol, M., Labrecque, M., Cauchon, M., Breton, M.-C., & Poirier, P. (2017) · Family Practice · doi:10.1093/fampra/cmx124 · Cited by 9
Pharmacoepidemiology of statins
Bezin, J., & Moore, N. D. (2019) · Therapies · doi:10.1016/j.therap.2019.01.004 · Cited by 7
Baum, S. J., Wade, R. L., Xiang, P., Arellano, J., Olmos, C. C., Nunna, S., Chen, C., Carter, C. M., & Desai, N. R. (2019) · Therapeutics and Clinical Risk Management · doi:10.2147/tcrm.s216606 · Cited by 7
Barrios, V., Escobar, C., Arrarte, V., García, E., Fernández, M. R., Rincon, L. M., & Roldán, C. (2020) · Clínica e Investigación en Arteriosclerosis · doi:10.1016/j.arteri.2020.05.002 · Cited by 7
Gonzalez‐Cordón, A., Assoumou, L., Camafort, M., Doménech, M., Guaraldi, G., Domingo, P., Rusconi, S., Raffi, F., Katlama, C., Masia, M., et al. (2020) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dkaa292 · Cited by 7
Vázquez-Manjarrez, N., Guevara‐Cruz, M., Flores‐López, A., Pichardo‐Ontiveros, E., Tovar, A. R., & Torres, N. (2021) · Clinical Nutrition · doi:10.1016/j.clnu.2021.02.048 · Cited by 7
New players in the treatment of hypercholesterolaemia: focus on bempedoic acid and inclisiran
Ruscica, M., Sirtori, C. R., Ferri, N., & Corsini, A. (2021) · European Heart Journal Supplements · doi:10.1093/eurheartj/suab090 · Cited by 7
“This link is valid across different statin and non-statin trials with the relative risk reduction in major ASCVD events being similar for different lipid-lowering drug classes (statins, bile acid sequestrants, ezetimibe, fibrates, and PCSK9 inhibitors).(2) However, considering that many patients do not achieve optimal…”
BackgroundVani, A. K., & Underberg, J. A. (2018) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.1133 · Cited by 7
Unraveling the Risk of Peripheral Artery Disease
Joshi, P. H., & Martin, S. S. (2018) · Circulation · doi:10.1161/circulationaha.118.036347 · Cited by 7
First-in-human gene editing for lipid lowering: the initial results
Tual‐Chalot, S., & Stellos, K. (2024) · Cardiovascular Research · doi:10.1093/cvr/cvae037 · Cited by 6
Muck, M. A., Fischer, M., Hamerle, M., Strack, C., Holzhaeuer, M., Pfeffer, D., Hubauer, U., Maier, L. S., & Baessler, A. (2024) · Biology of Sex Differences · doi:10.1186/s13293-024-00642-y · Cited by 7
Pu, J., Gao, M., Yu, P., et al. (2024) · Diabetology & Metabolic Syndrome · doi:10.1186/s13098-024-01514-6 · Cited by 6
Association of Metabolomics With Incidence of Age-Related Macular Degeneration: The UK Biobank Study
Yu, J. Q., Zhang, Y., Ho, M., Zhang, X. J., Kam, K. W., Young, A. L., Pang, C. P., Tham, C. C. Y., Yam, J. C. S., & Chen, L. J. (2024) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.65.14.43 · Cited by 6
“Fourth, opposite roles of HDL, VLDL, and LDL were found between AMD and CVD.”
InfluentialYamashita, S., Fujita, H., Yokota, D., Isogai, Y., & Kitamoto, R. (2025) · Journal of Atherosclerosis and Thrombosis · doi:10.5551/jat.65336 · Cited by 6
“Many global trials have shown that lowering lipid levels, specifically low-density lipoprotein cholesterol (LDL-C), can reduce cardiovascular risk 10) .”
Shaw, A., Teng, R., Fasina, T., Gonzales, A.-S., Wong, A., Schweitzer, D. R., & Akefe, I. O. (2025) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2025.111299 · Cited by 6
“Elevated cholesterol levels and in particular low-density lipoprotein cholesterol (LDL-C) have been shown to be associated with atherosclerosis and cardiovascular disease (Silverman et al., 2016).”
Williams, M. S., Levine, G. N., Kalra, D. K., Agarwala, A., Baptiste, D., Cigarroa, J. E., Diekemper, R. L., Foster, M., Gulati, M., Henry, T. D., et al. (2025) · Circulation Cardiovascular Quality and Outcomes · doi:10.1161/hcq.0000000000000140 · Cited by 8
Fujimoto, D., Fuster, V., & Jang, I. (2025) · Nature Cardiovascular Research · doi:10.1038/s44161-025-00664-8 · Cited by 6
Saito, Y., Tateishi, K., Kato, K., Kitahara, H., & Kobayashi, Y. (2025) · Internal Medicine · doi:10.2169/internalmedicine.5950-25 · Cited by 8
“In settings of both primary and secondary prevention, achieved LDL-C levels are linearly associated with the (29).”
Emara, A., Gadelmawla, A. F., Awashra, A., Rifai, M. K., Elgendy, M. S., Diaa, A., Emara, M. R., Odat, R. M., Assaassa, A., & Shubietah, A. R. M. (2025) · Diabetes Obesity and Metabolism · doi:10.1111/dom.70316 · Cited by 6
Association of Ratio of Apolipoprotein B to Apolipoprotein A1 With Survival in Peritoneal Dialysis
Yu, J., Xia, X., Huang, N., Qiu, Y., Yang, X., Mao, H., Chen, W., & Huang, F. (2022) · Frontiers in Nutrition · doi:10.3389/fnut.2022.801979 · Cited by 7
Dhameliya, H. A., Solanki, J. D., Patel, D. T., George, L.-B., Thakkar, V. R., & Subramanian, R. B. (2022) · Applied Biochemistry and Biotechnology · doi:10.1007/s12010-022-04307-7 · Cited by 6
“Clearance of LDL-cholesterol via upregulation of LDL-receptor expression is associated with reduced CVD risk [22].”
BackgroundCalabrò, P., Spaccarotella, C., Cesaro, A., Andò, G., Piccolo, R., Rosa, S. D., Zimarino, M., Mancone, M., Gragnano, F., Moscarella, E., et al. (2023) · Journal of Cardiovascular Medicine · doi:10.2459/jcm.0000000000001440 · Cited by 6
Restoration of normal blood flow in atherosclerotic arteries promotes plaque stabilization
Schake, M. A., McCue, I. S., Curtis, E. T., Ripperda, T. J., Harvey, S., Hackfort, B. T., Fitzwater, A., Chatzizisis, Y. S., Kievit, F. M., & Pedrigi, R. M. (2023) · iScience · doi:10.1016/j.isci.2023.106760 · Cited by 6
“It is remarkable that the degree of plaque stabilization in mice treated with restored normal blood flow was comparable to those treated with atorvastatin, given the well-documented efficacy of the latter as a firstline therapeutic for atherosclerosis in patients that reduces the 10-year incidence of heart attack by 2…”
ResultEchevarría, A. B., García-Díaz, J. D. D., Caixàs, A., Plana, N., Corral, M. Á. R., Bridges, I. M., Dhalwani, N. N., Menchen, S. G., & Ray, K. K. (2023) · Clínica e Investigación en Arteriosclerosis · doi:10.1016/j.arteri.2023.04.004 · Cited by 6
Ebenbichler, C. F., Drexel, H., Hanusch, U., Toplak, H., Dhalwani, N. N., Bridges, I. M., Hoelzl, R., Hemetsberger, M., & Ray, K. K. (2023) · Wiener klinische Wochenschrift · doi:10.1007/s00508-023-02245-w · Cited by 6
Is there a role for earlier use of combination therapy?
Revankar, S., Park, J. K., Satish, P., & Agarwala, A. (2024) · American Journal of Preventive Cardiology · doi:10.1016/j.ajpc.2024.100639 · Cited by 6
Li, J., Yang, L., Song, J., Yan, B., Morris, A. J., Moseley, H., Flight, R. M., Wang, C., Liu, J., Weiss, H. L., et al. (2024) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2024.117479 · Cited by 7
Individualized Dose-Response to Statins Associated With Cardiovascular Disease Outcomes
Aggarwal, S. K., Jiang, L., Liu, G., Grabowska, M. E., Ong, H. H., Wilke, R. A., Feng, Q., & Wei, W. (2024) · JACC Advances · doi:10.1016/j.jacadv.2024.100894 · Cited by 6
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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