Advertisement

Lipoprotein(a) and coronary atheroma progression rates during long-term high-intensity statin therapy: Insights from SATURN

      Highlights

      • In patients treated with 24-months of maximally intensive statin therapy, Lp(a) levels did not associate with coronary atheroma progression-regression.
      • The majority of patients displayed net coronary atheroma volume regression, including patients with Lp(a) levels ≤ 50 mg/dL (median 11 mg/dL) and >50 mg/dL (median 83 mg/dL).
      • No relationship between changes in plaque volume were evident with Lp(a) across all levels of LDL-C and CRP.
      • Significant associations with MACE were noted in those patients with higher Lp(a) levels and lower CRP, who demonstrated lower MACE compared with those with higher CRP.

      Abstract

      Background & aims

      Lipoprotein(a) [Lp(a)] is a low-density lipoprotein (LDL)-like particle that associates with major adverse cardiovascular events (MACE). We examined relationships between Lp(a) measurements and changes in coronary atheroma volume following long-term maximally-intensive statin therapy in coronary artery disease patients.

      Methods

      Study of coronary atheroma by intravascular ultrasound: Effect of Rosuvastatin Versus Atorvastatin (SATURN) used serial intravascular ultrasound measures of coronary atheroma volume in patients treated with rosuvastatin 40 mg or atorvastatin 80 mg for 24 months. Baseline and follow-up Lp(a) levels were measured in 915 of the 1039 SATURN participants, and were correlated with changes in percent atheroma volume (ΔPAV).

      Results

      Mean age was 57.7 ± 8.6 years, 74% were men, 96% were Caucasian, with statin use prior to study enrolment occurring in 59.3% of participants. Baseline [median (IQR)] LDL-cholesterol (LDL-C) and measured Lp(a) levels (mg/dL) were 114 (99, 137) and 17.4 (7.6, 52.9) respectively; follow-up measures were 60 (47, 77), and 16.5 (6.7, 57.7) (change from baseline: p < 0.001, p = 0.31 respectively). At baseline, there were 676 patients with Lp(a) levels <50 mg/dL [median Lp(a) of 10.9 mg/dL], and 239 patients with Lp(a) levels ≥ 50 mg/dL [median Lp(a) of 83.2 mg/dL]. Quartiles of baseline and follow-up Lp(a) did not associate with ΔPAV. Irrespective of the achieved LDL-C (<vs. ≥70 mg/dL), neither baseline nor on-treatment (<vs. ≥median) Lp(a) levels significantly associated with ΔPAV. No significant differences were observed in ΔPAV in Lp(a) risers versus non-risers, nor in those patients with baseline or on-treatment Lp(a) levels < vs. > 50 mg/dL.

      Conclusions

      In coronary artery disease patients prescribed long-term maximally intensive statin therapy with low on-treatment LDL-C levels, measured Lp(a) levels (predominantly below the 50 mg/dL threshold) do not associate with coronary atheroma progression. Alternative biomarkers may thus associate with residual cardiovascular risk in such patients.

      Keywords

      Abbreviations:

      SATURN (Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin Versus Atorvastatin), LDL-C (low-density lipoprotein cholesterol), HDL-C (high-density lipoprotein cholesterol), TG (triglyceride), CRP (C-reactive protein), Lp(a) (lipoprotein(a)), PAV (percent atheroma volume), MACE (major adverse cardiovascular events)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Emerging Risk Factors C.
        • Erqou S.
        • Kaptoge S.
        • et al.
        Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality.
        JAMA. 2009; 302: 412-423
        • Kamstrup P.R.
        • Tybjærg-Hansen A.
        • Steffensen R.
        • et al.
        GEnetically elevated lipoprotein(a) and increased risk of myocardial infarction.
        JAMA. 2009; 301: 2331-2339
        • Kamstrup P.R.
        • Tybjærg-Hansen A.
        • Nordestgaard B.G.
        Extreme lipoprotein(a) levels and improved cardiovascular risk prediction.
        J. Am. Coll. Cardiol. 2013; 61: 1146-1156
        • Clarke R.
        • Peden J.F.
        • Hopewell J.C.
        • et al.
        Genetic variants associated with Lp(a) lipoprotein level and coronary disease.
        N. Engl. J. Med. 2009; 361: 2518-2528
        • Baigent C.
        • Blackwell L.
        • Emberson J.
        • et al.
        Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.
        Lancet. 2010; 376: 1670-1681
        • Cholesterol Treatment Trialists C.
        • Mihaylova B.
        • Emberson J.
        • et al.
        The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials.
        Lancet. 2012; 380: 581-590
        • Hopkins P.N.
        • Hunt S.C.
        • Schreiner P.J.
        • et al.
        Lipoprotein(a) interactions with lipid and non-lipid risk factors in patients with early onset coronary artery disease: results from the NHLBI family heart study.
        Atherosclerosis. 1998; 141: 333-345
        • Kronenberg F.
        • Kronenberg M.F.
        • Kiechl S.
        • et al.
        Role of lipoprotein(a) and apolipoprotein(a) phenotype in atherogenesis: prospective results from the Bruneck study.
        Circulation. 1999; 100: 1154-1160
        • von Eckardstein A.
        • Schulte H.
        • Cullen P.
        • et al.
        Lipoprotein(a) further increases the risk of coronary events in men with high global cardiovascular risk.
        J. Am. Coll. Cardiol. 2001; 37: 434-439
        • Luc G.
        • Bard J.M.
        • Arveiler D.
        • et al.
        Lipoprotein (a) as a predictor of coronary heart disease: the PRIME Study.
        Atherosclerosis. 2002; 163: 377-384
        • Suk Danik J.
        • Rifai N.
        • Buring J.E.
        • et al.
        Lipoprotein(a), measured with an assay independent of apolipoprotein(a) isoform size, and risk of future cardiovascular events among initially healthy women.
        JAMA. 2006; 296: 1363-1370
        • O'Donoghue M.L.
        • Morrow D.A.
        • Tsimikas S.
        • et al.
        Lipoprotein(a) for risk assessment in patients with established coronary artery disease.
        J. Am. Coll. Cardiol. 2014; 63: 520-527
        • Afshar M.
        • Pilote L.
        • Dufresne L.
        • et al.
        Lipoprotein(a) interactions with low-density lipoprotein cholesterol and other cardiovascular risk factors in premature acute coronary syndrome (ACS).
        J. Am. Heart Assoc. 2016; : 5
        • Nicholls S.J.
        • Borgman M.
        • Nissen S.E.
        • et al.
        Impact of statins on progression of atherosclerosis: rationale and design of SATURN (study of coronary atheroma by InTravascular ultrasound: effect of rosuvastatin versus AtorvastatiN).
        Curr. Med. Res. Opin. 2011; 27: 1119-1129
        • Nicholls S.J.
        • Ballantyne C.M.
        • Barter P.J.
        • et al.
        Effect of two intensive statin regimens on progression of coronary disease.
        N. Engl. J. Med. 2011; 365: 2078-2087
        • Nicholls S.J.
        • Hsu A.
        • Wolski K.
        • et al.
        Intravascular ultrasound-derived measures of coronary atherosclerotic plaque burden and clinical outcome.
        J. Am. Coll. Cardiol. 2010; 55: 2399-2407
        • Marcovina S.M.
        • Albers J.J.
        • Scanu A.M.
        • et al.
        Use of a reference material proposed by the International Federation of Clinical Chemistry and Laboratory Medicine to evaluate analytical methods for the determination of plasma lipoprotein(a).
        Clin. Chem. 2000; 46: 1956-1967
        • Nordestgaard B.G.
        • Chapman M.J.
        • Ray K.
        • et al.
        Lipoprotein(a) as a cardiovascular risk factor: current status.
        Eur. Heart J. 2010; 31: 2844-2853
        • Libby P.
        The forgotten majority: unfinished business in cardiovascular risk reduction.
        J. Am. Coll. Cardiol. 2005; 46: 1225-1228
        • Khera A.V.
        • Everett B.M.
        • Caulfield M.P.
        • et al.
        Lipoprotein(a) concentrations, rosuvastatin therapy, and residual vascular risk: an analysis from the JUPITER trial (justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin).
        Circulation. 2014; 129: 635-642
        • Ridker P.M.
        • Danielson E.
        • Fonseca F.A.
        • et al.
        Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein.
        N. Engl. J. Med. 2008; 359: 2195-2207
        • Baldassarre D.
        • Tremoli E.
        • Franceschini G.
        • et al.
        Plasma lipoprotein(a) is an independent factor associated with carotid wall thickening in severely but not moderately hypercholesterolemic patients.
        Stroke. 1996; 27: 1044-1049
        • Nicholls S.J.
        • Tang W.H.
        • Scoffone H.
        • et al.
        Lipoprotein(a) levels and long-term cardiovascular risk in the contemporary era of statin therapy.
        J. Lipid Res. 2010; 51: 3055-3061
        • Maher V.M.
        • Brown B.G.
        • Marcovina S.M.
        • et al.
        Effects of lowering elevated LDL cholesterol on the cardiovascular risk of lipoprotein(a).
        JAMA. 1995; 274: 1771-1774
        • Gaw A.
        • Brown E.A.
        • Docherty G.
        • et al.
        Is lipoprotein(a)-cholesterol a better predictor of vascular disease events than total lipoprotein(a) mass? A nested case control study from the West of Scotland Coronary Prevention Study.
        Atherosclerosis. 2000; 148: 95-100
        • Schreiner P.J.
        • Morrisett J.D.
        • Sharrett A.R.
        • et al.
        Lipoprotein[a] as a risk factor for preclinical atherosclerosis.
        Arterioscler. Thromb. 1993; 13: 826-833
        • Hartmann M.
        • von Birgelen C.
        • Mintz G.S.
        • et al.
        Relation between lipoprotein(a) and fibrinogen and serial intravascular ultrasound plaque progression in left main coronary arteries.
        J. Am. Coll. Cardiol. 2006; 48: 446-452
        • Hikita H.
        • Shigeta T.
        • Kojima K.
        • et al.
        Lipoprotein(a) is an important factor to determine coronary artery plaque morphology in patients with acute myocardial infarction.
        Coron. Artery Dis. 2013; 24: 381-385
        • Niccoli G.
        • Cin D.
        • Scalone G.
        • et al.
        Lipoprotein (a) is related to coronary atherosclerotic burden and a vulnerable plaque phenotype in angiographically obstructive coronary artery disease.
        Atherosclerosis. 2016; 246: 214-220
        • Bos S.
        • Duvekot M.H.
        • Touw-Blommesteijn A.C.
        • et al.
        Lipoprotein (a) levels are not associated with carotid plaques and carotid intima media thickness in statin-treated patients with familial hypercholesterolemia.
        Atherosclerosis. 2015; 242: 226-229
        • Hervio L.
        • Chapman M.J.
        • Thillet J.
        • et al.
        Does apolipoprotein(a) heterogeneity influence lipoprotein(a) effects on fibrinolysis?.
        Blood. 1993; 82: 392-397
        • Feric N.T.
        • Boffa M.B.
        • Johnston S.M.
        • et al.
        Apolipoprotein(a) inhibits the conversion of Glu-plasminogen to Lys-plasminogen: a novel mechanism for lipoprotein(a)-mediated inhibition of plasminogen activation.
        J. Thromb. Haemostasis. 2008; 6: 2113-2120
        • Puri R.
        • Libby P.
        • Nissen S.E.
        • et al.
        Long-term effects of maximally intensive statin therapy on changes in coronary atheroma composition: insights from SATURN.
        Eur. eart J. Cardiovasc. Imaging. 2014; 15: 380-388
        • Puri R.
        • Nicholls S.J.
        • Shao M.
        • et al.
        Impact of statins on serial coronary calcification during atheroma progression and regression.
        J. Am. Coll. Cardiol. 2015; 65: 1273-1282
        • Tsimikas S.
        The re-emergence of lipoprotein(a) in a broader clinical arena.
        Prog. Cardiovasc. Dis. 2016; 59: 135-144
        • Guan W.
        • Cao J.
        • Steffen B.T.
        • et al.
        Race is a key variable in assigning lipoprotein(a) cutoff values for coronary heart disease risk assessment: the Multi-Ethnic Study of Atherosclerosis.
        Arterioscler. Thromb. Vasc. Biol. 2015; 35: 996-1001