TY - JOUR
T1 - Changes in plasma lipids predict pravastatin efficacy in secondary prevention
AU - Jayawardana, Kaushala S.
AU - Mundra, Piyushkumar A.
AU - Giles, Corey
AU - Barlow, Christopher K.
AU - Nestel, Paul J.
AU - Barnes, Elizabeth H.
AU - Kirby, Adrienne
AU - Thompson, Peter
AU - Sullivan, David R.
AU - Alshehry, Zahir H.
AU - Mellett, Natalie A.
AU - Huynh, Kevin
AU - McConville, Malcolm J.
AU - Zoungas, Sophia
AU - Hillis, Graham S.
AU - Chalmers, John
AU - Woodward, Mark
AU - Marschner, Ian C.
AU - Wong, Gerard
AU - Kingwell, Bronwyn A.
AU - Simes, John
AU - Tonkin, Andrew M.
AU - Meikle, Peter J.
AU - behalf of the LIPID Study Investigators
PY - 2019/7/11
Y1 - 2019/7/11
N2 - BACKGROUND. Statins have pleiotropic effects on lipid metabolism. The relationship between these effects and future cardiovascular events is unknown. We characterized the changes in lipids upon pravastatin treatment and defined the relationship with risk reduction for future cardiovascular events. METHODS. Plasma lipids (n = 342) were measured in baseline and 1-year follow-up samples from a Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) study subcohort (n = 4991). The associations of changes in lipids with treatment and cardiovascular outcomes were investigated using linear and Cox regression. The effect of treatment on future cardiovascular outcomes was examined by the relative risk reduction (RRR). RESULTS. Pravastatin treatment was associated with changes in 206 lipids. Species containing arachidonic acid were positively associated while phosphatidylinositol species were negatively associated with pravastatin treatment. The RRR from pravastatin treatment for cardiovascular events decreased from 23.5% to 16.6% after adjustment for clinical risk factors and change in LDL-cholesterol (LDL-C) and to 3.0% after further adjustment for the change in the lipid ratio PI(36:2)/ PC(38:4). Change in PI(36:2)/PC(38:4) mediated 58% of the treatment effect. Stratification of patients into quartiles of change in PI(36:2)/PC(38:4) indicated no benefit of pravastatin in the fourth quartile. CONCLUSION. The change in PI(36:2)/PC(38:4) predicted benefit from pravastatin, independent of change in LDL-C, demonstrating its potential as a biomarker for monitoring the clinical benefit of statin treatment in secondary prevention. TRIAL REGISTRATION. Australian New Zealand Clinical Trials Registry identifier ACTRN12616000535471. FUNDING. Bristol-Myers Squibb; NHMRC grants 211086, 358395, and 1029754; NHMRC program grant 1149987; NHMRC fellowship 108026; and the Operational Infrastructure Support Program of the Victorian government of Australia.
AB - BACKGROUND. Statins have pleiotropic effects on lipid metabolism. The relationship between these effects and future cardiovascular events is unknown. We characterized the changes in lipids upon pravastatin treatment and defined the relationship with risk reduction for future cardiovascular events. METHODS. Plasma lipids (n = 342) were measured in baseline and 1-year follow-up samples from a Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) study subcohort (n = 4991). The associations of changes in lipids with treatment and cardiovascular outcomes were investigated using linear and Cox regression. The effect of treatment on future cardiovascular outcomes was examined by the relative risk reduction (RRR). RESULTS. Pravastatin treatment was associated with changes in 206 lipids. Species containing arachidonic acid were positively associated while phosphatidylinositol species were negatively associated with pravastatin treatment. The RRR from pravastatin treatment for cardiovascular events decreased from 23.5% to 16.6% after adjustment for clinical risk factors and change in LDL-cholesterol (LDL-C) and to 3.0% after further adjustment for the change in the lipid ratio PI(36:2)/ PC(38:4). Change in PI(36:2)/PC(38:4) mediated 58% of the treatment effect. Stratification of patients into quartiles of change in PI(36:2)/PC(38:4) indicated no benefit of pravastatin in the fourth quartile. CONCLUSION. The change in PI(36:2)/PC(38:4) predicted benefit from pravastatin, independent of change in LDL-C, demonstrating its potential as a biomarker for monitoring the clinical benefit of statin treatment in secondary prevention. TRIAL REGISTRATION. Australian New Zealand Clinical Trials Registry identifier ACTRN12616000535471. FUNDING. Bristol-Myers Squibb; NHMRC grants 211086, 358395, and 1029754; NHMRC program grant 1149987; NHMRC fellowship 108026; and the Operational Infrastructure Support Program of the Victorian government of Australia.
KW - secondary prevention
KW - pravastatin efficacy
KW - plasma lipids
KW - Statins
KW - pleiotropic effects
KW - lipid metabolism
UR - http://www.scopus.com/inward/record.url?scp=85070659111&partnerID=8YFLogxK
UR - http://purl.org/au-research/grants/NHMRC/211086
UR - http://purl.org/au-research/grants/NHMRC/358395
UR - http://purl.org/au-research/grants/NHMRC/1149987
UR - http://purl.org/au-research/grants/NHMRC/108026
UR - http://purl.org/au-research/grants/NHMRC/1029754
U2 - 10.1172/jci.insight.128438
DO - 10.1172/jci.insight.128438
M3 - Article
C2 - 31292301
AN - SCOPUS:85070659111
SN - 2379-3708
VL - 4
JO - JCI insight
JF - JCI insight
IS - 13
M1 - e128438
ER -
