Evidence map›Statins × lipids›PMID 19075102›Full record

Trial reportCirculation2009

Evidence for statin pleiotropy in humans: differential effects of statins and ezetimibe on rho-associated coiled-coil containing protein kinase activity, endothelial function, and inflammation.

Ping-Yen Liu, Yen-Wen Liu, Li-Jen Lin, Jyh-Hong Chen, James K Liao

Open access · bronzeAbstract readRandomized Controlled Trial
PubMed Full text at PMC Publisher
In one paragraph

Trial report in Circulation, 2009. The graph read 1 number from its abstract, feeding 1 cell of the map: it favours the comparator in 1. Cited by 90 papers, 4 of them syntheses that pooled it.

1number the graph read from it
1cell of the map it votes in
90citing papers in PubMed, 4 pooled it
20.5field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

← favours the treatmentfavours the comparator →
38.00 · no effect
Low-density lipoprotein cholesterolsimvastatin 40 mg/d vs placebo tabletsfavours the comparator · dyslipidemiafeeds one cell of the map
RR 38.0P<0.01
Compared with the placebo group, both treatment regimens decreased low-density lipoprotein cholesterol by 38% and C-reactive protein by 38% to 40% after 28 days (P<0.01 for both compared with placebo).
FeedsStatins×lipids

clause the extractor read what became the number

2 · Its place on the map

Where it lands on the map

Rows are treatments, columns are outcomes. The coloured squares are the cells this paper feeds, coloured by the vote it casts there. Click one to jump to what this paper adds to it.

supports the treatmentfavours the comparatorno clear differenceread, but no usable result
3 · What it changes

What it adds to each cell

For every cell the paper feeds: the belief in the claim with and without this paper, and this paper's estimate drawn against every other readable study in the cell. The ringed dot is this paper.

Statins×lipids

ContradictsOpen on the map →What to test next →

38 readable studies in this cell: 27 favour the treatment, 5 find no difference, 6 favour the comparator.

Belief with this paper
0.50contested · 21 families support, 7 contradict · against placebo
Without it
0.78This paper moves it by −0.28. It would be replicated.
← favours the treatmentfavours the comparator →
0 · no effect
This paper · 2009
RR 38.0
NCT002899002,340 enrolled · 2006
Δ -13.2-16.8 to -9.60
Effect of evolocumab or ezetimibe added to moderate- or high-intensity…PMID 24825642 · 2,067 enrolled · 2013
reduced -66.0-73.0 to -58.0
NCT02546323543 enrolled · 2015
Δ -35.5-40.2 to -30.7
NCT01678820299 enrolled · 2012
Δ 0.50-4.80 to 5.80
NCT01218204287 enrolled · 2010
Δ 5.47-15.7 to 26.7
Lipid-Lowering Effect and Safety of Ezetimibe and Atorvastatin 5 mg in…PMID 40357888 · 252 enrolled · 2022
Δ -47.6
NCT0093525931 enrolled · 2009
Δ -51.7
Effect of Patient Financial Incentives on Statin Adherence and Lipid C…PMID 33034639 · 2020
reductions -33.6-38.8 to -28.4
Icosabutate, a Structurally Engineered Fatty Acid, Improves the Cardio…PMID 27160246 · 2016
Δ -7.40
Efficacy and safety of fluvastatin in patients with non-insulin-depend…PMID 8198023 · 1994
decrease -24.3
Rosuvastatin in older patients with systolic heart failure.PMID 17984166 · 2007
Δ 45.0
L-Carnitine/Simvastatin Reduces Lipoprotein (a) Levels Compared with S…PMID 27914033 · 2017
Δ -19.4
4 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

5 · Its place in the literature

Who cites it

90 citing papers in PubMed, 4 syntheses or guidelines pooled it, 223 citations in OpenAlex.

  1. Pooled it
  2. Pooled it
  3. Pooled it
  4. Pooled it
  5. Statin initiation and early stroke recurrence in the Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke Trial (POINT) trial population.Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association · 2025
    Trial
  6. Trial
  7. Trial
  8. Exogenous nitric oxide inhibits Rho-associated kinase activity in patients with angina pectoris: a randomized controlled trial.Hypertension research : official journal of the Japanese Society of Hypertension · 2015
    Trial
  9. Trial
  10. Trial
  11. Trial
  12. Differences in synthesis and absorption of cholesterol of two effective lipid-lowering therapies.Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologica · 2012 · on this map
    Trial
  13. Trial
  14. Trial
  15. Review
  16. Review
  17. Review
  18. Review
  19. Review
  20. Review

30 more citing papers are in PubMed but not listed here.

6 · The record

Corrections and comments

7 · Who and what money

Authors and funding

5 authors at 1 institution in 1 country.

Ping-Yen LiuCardiovascular Division, Brigham and Women's Hospital, Cambridge, MA 02139, USA.
Yen-Wen Liu
Li-Jen Lin
Jyh-Hong Chen
James K Liao
National Cheng Kung University Hospital · TW

Funding

LIPOPROTEINS EFFECTS ON G PROTEIN FUNCTIONR01HL052233 · BRIGHAM AND WOMEN'S HOSPITAL · 1995 to 2004
$1.7M
INTERDEPARTMENTAL STROKE PROGRAMP01NS010828 · MASSACHUSETTS GENERAL HOSPITAL · 1989 to 1990
–
NHLBI NIH HHS HL052233NHLBI NIH HHS R01 HL052233NHLBI NIH HHS R01 HL080187NINDS NIH HHS P01 NS010828
8 · The paper itself

Abstract

The marked sentences are the ones the graph read a number from.

backgroundBy inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase, statins not only reduce cholesterol biosynthesis but also decrease the formation of isoprenoids, which are important for mediating signaling through the Rho-associated coiled-coil containing protein kinase (ROCK) pathway. Increased ROCK activity has been implicated in endothelial dysfunction and vascular inflammation. We hypothesize that ezetimibe, which inhibits intestinal cholesterol absorption, may not exert similar cholesterol-independent or pleiotropic effects of statins and, when used with a lower dose of statin, have less effect on ROCK activity than a higher dose of statin. METHODS AND

resultsIn a prospective, randomized, observer-blinded study, we treated 60 dyslipidemic subjects without cardiovascular disease with simvastatin 40 mg/d, simvastatin/ezetimibe 10/10 mg/d, or placebo tablets for 28 days (n=20 in each arm). We evaluated baseline demographics and lipid levels, ROCK activity, C-reactive protein, and flow-mediated dilation before and after treatment. Compared with the placebo group, both treatment regimens decreased low-density lipoprotein cholesterol by 38% and C-reactive protein by 38% to 40% after 28 days (P<0.01 for both compared with placebo). Although the low-density lipoprotein cholesterol and C-reactive protein reductions were comparable with either lipid-lowering regimen, only simvastatin 40 mg reduced ROCK activity and improved flow-mediated dilation (P<0.01 for both compared with baseline). Reduction in ROCK activity with simvastatin 40 mg remained significant even after controlling for changes in low-density lipoprotein cholesterol (P=0.01) and correlated with improvement in flow-mediated dilation (R(2)=-0.78, P<0.01). No correlation was found between changes in flow-mediated dilation and changes in low-density lipoprotein cholesterol or C-reactive protein.

conclusionsThese results indicate that high-dose statin monotherapy exerts greater effects on ROCK activity and endothelial function, but not on C-reactive protein, than low-dose statin plus ezetimibe. These findings provide additional evidence of statin benefits beyond cholesterol lowering.

Indexed as

AdultAgedAged, 80 and overAnticholesteremic AgentsAzetidinesCholesterol, HDLCholesterol, LDLC-Reactive ProteinDrug Therapy, CombinationEndothelium, VascularEnzyme ActivationEzetimibeFemaleHumansHyperlipidemiasLeukocytesAnticholesteremic AgentsAzetidinesCholesterol, HDLCholesterol, LDLC-Reactive ProteinEzetimiberho-Associated KinasesSimvastatinTriglycerides

Identifiers

PMID19075102
PMCPMC2745913
OpenAlexW2084242433

What Socratic holds

Texttitle and abstract
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.