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Cited by 1,483Lipoproteins and Cardiovascular HealthAcute Myocardial Infarction ResearchDiabetes, Cardiovascular Risks, and Lipoproteins

Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions: A Systematic Review and Meta-analysis

Open access
Silverman, Michael G., Ference, Brian A., Im, Kyungah, Wiviott, Stephen D., Giugliano, Robert P., Grundy, Scott M., Braunwald, Eugene, Sabatine, Marc S.·2016·JAMA
DOI 10.1001/jama.2016.13985
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Abstract

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.

Integrity signals

Registry

Crossref · 10.1001/jama.2016.13985

Cites

82 of 82 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

7 of 21 cited sources checked · 1 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    The clinical benefit of the previously recommended use of nonstatin therapies to lower LDL-C is less definitive.

    “the clinical benefit of the previously recommended use of nonstatin therapies to lower LDL-C is less definitive.7”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [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
  • Interpretationcitation

    Drugs that reduce LDL-C predominantly through upregulation of LDL receptor expression should, barring off-target adverse effects, lead to clinical benefit in proportion to the degree of LDL-C reduction.

    “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”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [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. source

      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)

      Experimental — accuracy not yet measured
  • Premisecitation

    Genetic association and Mendelian randomization studies demonstrate similarly lower rates of cardiovascular outcomes per unit lower LDL-C in patients with loss-of-function variants in NPC1L1 and HMG-CoA reductase.

    “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”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [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. source

      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)

      Experimental — accuracy not yet measured
    • cites [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.

  • Findingown data

    In the 8 trials of established nonstatin therapies that ultimately act predominantly via upregulation of LDL receptor expression, each 1-mmol/L reduction in LDL-C was associated with an RR of 0.75 (95% CI, 0.66-0.86; P = .002) for major vascular events.

    “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”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [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
    • cites [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
    • cites [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. source

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

      Experimental — accuracy not yet measured
    • 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.
  • Premisecitation

    Human genetic analyses of variants associated with low LDL-C, increased LDL receptors, and decreased coronary heart disease support the concept.

    “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”
    Quote in the paperSubstantial claim2 of 4 sources checked
    • cites [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.

    • cites [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. source

      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)

      Experimental — accuracy not yet measured
    • cites [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.

    • cites [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. source

      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)

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 16
  • May combine two claims. 16

  • Classified as probably not a substantial claim.

    Premisecitation

    A clinical benefit of lipid-lowering therapy would not be expected to emerge within a timeframe of less than 6 months.

    “a timeframe during which a clinical benefit of lipid-lowering therapy would not be expected to emerge 10”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [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. source

      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)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    For niacin, the observed RR of major vascular events was 0.94 (95% CI, 0.89-0.99), which was not significantly different from the expected RR of 0.91 (95% CI, 0.90-0.92) from meta-regression (P = .24).

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    For fibrates, the observed RR of major vascular events was 0.88 (95% CI, 0.83-0.92), which was lower than the expected RR of 0.94 (95% CI, 0.93-0.94) from meta-regression (P = .02).

    “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).”
    Quote in the paperSubstantial claim

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

    Findingown data

    The total follow-up was approximately 1.3 million person-years.

    “resulting in approximately 1.3 million person-years of follow-up.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The mean follow-up was 4.3 years.

    “The mean follow-up was 4.3 years”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    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, similar to the RR reductions predicted from the meta-regression (7%, 9%, and 0%, respectively).

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    For fibrates, the observed RR for major vascular events was 0.88 (95% CI, 0.83-0.92) vs expected 0.94 (95% CI, 0.93-0.94) based on degree of LDL-C reduction, with P=.02, which was lower than expected (greater risk reduction).

    “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)”
    Quote in the paperSubstantial claim

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

    Findingown data

    There were 2 trials with PCSK9 inhibitors.

    “There were 2 trials with PCSK9 inhibitors.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The absolute reduction in LDL-C accounted for 98% of the between-study variability in the reduction of major vascular events, whereas the percentage reduction in LDL-C accounted for 79%.

    “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%.”
    Quote in the paperSubstantial claim

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

    Findingown data

    A total of 240 citations were identified and reviewed for eligibility.

    “A total of 240 citations were identified and reviewed for eligibility (Figure 1)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    When the regression slope was recalculated using non-HDL-C, the RR per 1-mmol/L reduction in non-HDL-C was 0.80 (95% CI, 0.77-0.82), similar to the RR with LDL-C reduction.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In this systematic review and meta-regression of 49 trials involving 9 interventions to lower LDL-C, more than 300,000 patients, and approximately 40,000 major vascular events, there was a similar association between absolute reductions in LDL-C and lower RRs for major vascular events across therapies that work predominantly through upregulation of LDL receptor expression, such that each 1-mmol/L,

    “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.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The therapies classified as acting predominantly via upregulation of LDL receptor expression indeed act predominantly through that mechanism.

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

    Findingown data

    There were 25 statin trials.

    “There were 25 statin trials.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    For CETP inhibitors, the observed RR of major vascular events was 1.01 (95% CI, 0.94-1.09), significantly greater than the expected RR of 0.90 (95% CI, 0.89-0.91; P = .002), with no appreciable clinical benefit in a meta-analysis of the compounds studied to date.

    “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.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Findingown data

    49 trials spanning 9 different treatment modalities were included in the meta-regression analysis.

    “49 trials, spanning 9 different treatment modalities were included in the meta-regression analysis”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The RR reduction for major vascular events was 6.4% (95% CI, 1%-11%), with an absolute risk reduction of 2% over 7 years.

    “the RR reduction for major vascular events was 6.4% (95% CI, 1%-11%), with an absolute risk reduction of 2% over 7 years.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    For PCSK9 inhibitors, the estimated RR of major vascular events was 0.49 (95% CI, 0.34-0.71), numerically lower but not significantly different from the expected RR of 0.61 (95% CI, 0.58-0.65), with wide 95% CIs that included the regression line (P = .25).

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    For cholesteryl ester transfer protein inhibitors, the observed RR for major vascular events was 1.01 (95% CI, 0.94-1.09) vs expected 0.90 (95% CI, 0.89-0.91) based on degree of LDL-C reduction, with P=.002, which was higher than expected (less 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)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The data raise the possibility that other interventions, especially those acting predominantly through upregulation of LDL receptor expression, may provide additional options and may be associated with the same relative clinical benefit per 1-mmol/L reduction in LDL-C.

    “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.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The therapies classified as acting predominantly via upregulation of LDL receptor expression indeed act predominantly through that mechanism.

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

    Study design and conductcitation

    The systematic review and meta-regression were performed and reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines.

    “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”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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.

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

    Study design and conductnone given

    All disagreements were discussed and resolved by consensus.

    “All disagreements were discussed and resolved by consensus.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    In earlier trials that did not report LDL-C levels, LDL-C values at baseline and during the study were estimated from total cholesterol levels.

    “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).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductreasoning

    Based purely on LDL-C lowering and given the number of events accrued, the statistical power for the primary end points was approximately 51% for HPS2-Thrive, 19% for FIELD, and 3% for ACCORD.

    “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.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Two authors independently extracted and entered data into standardized data sheets.

    “Two authors independently extracted and entered data into standardized data sheets and data were analyzed using meta-regression.”
    Quote in the paperNot a substantial claim

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

    Study design and conductreasoning

    Background therapy has changed over the 51-year span, which may account for some of the difference in absolute event rates between trials.

    “and background therapy has changed, which may account for some of the difference in absolute event rates between trials.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The studies included in the analysis were conducted over a span of 51 years.

    “Fourth, the studies included in the analysis were conducted over a span of 51 years”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    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 inhibitor

    “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”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Hazard ratios were not available in all trials, and risk ratios were used when they were not.

    “Sixth, hazard ratios were not available in all trials and risk ratios were used when they were not.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The meta-analysis was not performed on patient-level data.

    “First, the meta-analysis was not performed on patient-level data.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    The analyses were at the trial level, examining the association between LDL-C reduction and the RR of major vascular events within a trial.

    “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.”
    Quote in the paperSubstantial claim
30 of 30

  • 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”
5 of 5

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?

  • Elevated LDL-C is an independent risk factor for CHD.

    “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]

    The Abstract (page unavailable) calls LDL-C a well-established cardiovascular risk factor, and the Results (page unavailable) report an association between achieved LDL-C and major coronary events. The paper does not establish that this association is independent of other CHD risk factors, so the qualifier “independent” is not fully supported. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • A major limitation of FOURIER was a relatively short duration of follow-up as compared with other lipid-lowering trials, in which follow-up periods have averaged approximately 5 years.

    “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]

    The Results report a mean follow-up of 4.3 years across 49 lipid-lowering trials, supporting the comparison to approximately five years. The paper does not assess FOURIER or identify its follow-up duration as a limitation, so it supports only the comparison, not the claim about FOURIER. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Elevated LDL-C is the most significant risk factor associated with adverse cardiovascular results.

    “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]

    The paper describes LDL-C as a well-established cardiovascular risk factor (opening background passage; page not provided), and the Results link lower LDL-C levels with fewer major coronary events. It does not compare LDL-C with other risk factors or establish that it is the most significant one. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • LDLR plays a crucial role in the uptake of LDL-C from the circulation by hepatocytes.

    “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]

    The Methods section states that PCSK9 inhibitors increase LDL-C clearance through the LDL receptor and links other LDL-lowering therapies to increased receptor expression. It does not specify uptake from the circulation by hepatocytes, so that cellular detail is not established by this paper’s text. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • The regulation of LDLR trafficking and turnover is essential for maintaining cholesterol homeostasis and remains a major focus of therapeutic strategies for CVD.

    “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]

    The Methods and Conclusions (pages unavailable) describe therapies that increase LDL receptor expression or LDL-C clearance and associate LDL-C reduction with fewer cardiovascular events. They do not address LDLR trafficking or turnover specifically, or establish that their regulation is essential for cholesterol homeostasis. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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

    Minor

    The 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.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 13

  1. [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.
  2. [8]8. US Food and Drug Administration. Withdrawal of approval of indications related to the coadministration with statins in applications for niacin extended-release tablets and fenofibric acid delayed-release capsules. Fed Regist. 2016;81(74): 22612-22613.
  3. [22]22. GISSI Prevenzione Investigators. Results of the low-dose (20 mg) pravastatin GISSI Prevenzione trial in 4271 patients with recent myocardial infarction. Ital Heart J. 2000;1(12):810-820.
  4. [25]25. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease. Lancet. 1994;344(8934):1383-1389.
  5. [33]33. Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER). Lancet. 2002;360(9346): 1623-1630.
  6. [34]34. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care. JAMA. 2002;288(23):2998-3007.
  7. [37]37. Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS). Lancet. 2004;364(9435):685-696.
  8. [41]41. Pedersen TR, Faergeman O, Kastelein JJ, et al. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction. JAMA. 2005;294(19):2437-2445.
  9. [44]44. Nakamura H, Arakawa K, Itakura H, et al. Primary prevention of cardiovascular disease with pravastatin in Japan (MEGA Study). Lancet. 2006; 368(9542):1155-1163.
  10. [46]46. Armitage J, Bowman L, Wallendszus K, et al. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction. Lancet. 2010;376(9753): 1658-1669.
  11. [50]50. Dorr AE, Gundersen K, Schneider JC Jr, et al. Colestipol hydrochloride in hypercholesterolemic patients. J Chronic Dis. 1978;31(1):5-14.
  12. [53]53. The Lipid Research Clinics Coronary Primary Prevention Trial results, 1: reduction in incidence of coronary heart disease. JAMA. 1984;251(3):351-364.
  13. [63]63. Grundy SM. Dyslipidaemia in 2015. Nat Rev Cardiol. 2016;13(2):74-75.

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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.
ORCID
Venue
JAMA
Publisher
American Medical Association (AMA)
Published
2016-09-27
Volume
316
Issue
12
Pages
1289
ISSN
  • 0002-9955 (ISSN-L)
  • 0098-7484
DOI
10.1001/jama.2016.13985
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 · 2015: 1
FWCI
23.09
Type
journal article
Language
en
Open access
Locations
  • JAMA (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Heart, Lung, and Blood Institute (T32HL007604)
Topics
  • Health Sciences › Medicine › Surgery › 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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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

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Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-19.

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