Advertisement

Plasma PCSK9 is increased by Fenofibrate and Atorvastatin in a non-additive fashion in diabetic patients

      Abstract

      Objective

      Proprotein convertase subtilisin kexin/type 9 (PCSK9) is an inhibitor of the low density (LDL) lipoprotein receptor. Plasma PCSK9 is increased by Fenofibrate and statins. Here, we determined how standard dose of statin and combined therapy with Fenofibrate modulate PCSK9.

      Methods

      Randomized, open-label cross-over study investigating the effect of Fenofibrate (160 mg), Atorvastatin (10 mg), and combination of both in patients with type 2 diabetes mellitus and atherogenic dyslipidemia. After the single administration of Atorvastatin and Fenofibrate for 6 weeks, patients received both for another 6 weeks. PCSK9, lipids and lipoproteins levels were determined at day 1, weeks 6, 9 and 12.

      Results

      Upon 6 weeks of treatment, Atorvastatin decreased LDL-cholesterol by 30% (p < 0.001) and Fenofibrate decreased triglyceride level by 31% (p < 0.01) and increased HDL-cholesterol by 13% (p < 0.05). Combination did not show further benefit. Atorvastatin increased PCSK9 by 24% at day 1 and by 14% at week 6 (p ≤ 0.01). Fenofibrate increased PCSK9 by 26% at week 6 (p ≤ 0.01), but had no effect at day 1. Three weeks of combination therapy increased PCSK9 by 42%, 6 weeks by 19% (p ≤ 0.01). PCSK9 changes were not different between treatments over 6-week periods.

      Conclusion

      Fenofibrate and Atorvastatin increased circulating PCSK9 in diabetic patients, with no additive effect after 6 weeks of combined therapy.

      Keywords

      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

        • Grundy S.M.
        • Cleeman J.I.
        • Merz C.N.
        • et al.
        Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines.
        Circulation. 2004; 110: 227-239
        • Davidson M.H.
        • Maki K.C.
        • Pearson T.A.
        • et al.
        Results of the National Cholesterol Education (NCEP) Program Evaluation ProjecT Utilizing Novel E-Technology (NEPTUNE) II survey and implications for treatment under the recent NCEP Writing Group recommendations.
        Am J Cardiol. 2005; 96: 556-563
        • Rosenson R.S.
        Fenofibrate: treatment of hyperlipidemia and beyond.
        Expert Rev Cardiovasc Ther. 2008; 6: 1319-1330
        • Tikkanen M.J.
        • Holme I.
        • Cater N.B.
        • et al.
        Comparison of efficacy and safety of atorvastatin (80 mg) to simvastatin (20 to 40 mg) in patients aged <65 versus >or = 65 years with coronary heart disease (from the Incremental DEcrease through Aggressive Lipid Lowering [IDEAL] study).
        Am J Cardiol. 2009; 103: 577-582
        • Abifadel M.
        • Varret M.
        • Rabes J.P.
        • et al.
        Mutations in PCSK9 cause autosomal dominant hypercholesterolemia.
        Nat Genet. 2003; 34: 154-156
        • Costet P.
        • Krempf M.
        • Cariou B.
        PCSK9 and LDL cholesterol: unravelling the target to design the bullet.
        Trends Biochem Sci. 2008; 33: 426-434
        • Zhang D.W.
        • Lagace T.A.
        • Garuti R.
        • et al.
        Binding of PCSK9 to EGF-A repeat of LDL receptor decreases receptor recycling and increases degradation.
        J Biol Chem. 2007; 282: 18602-18612
        • Cohen J.C.
        • Boerwinkle E.
        • Mosley Jr., T.H.
        • Hobbs H.H.
        Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.
        N Engl J Med. 2006; 354: 1264-1272
        • Cariou B.
        • Ouguerram K.
        • Zair Y.
        • et al.
        PCSK9 dominant negative mutant results in increased LDL catabolic rate and familial hypobetalipoproteinemia.
        Arterioscler Thromb Vasc Biol. 2009; 29: 2191-2197
        • Costet P.
        • Cariou B.
        • Lambert G.
        • et al.
        Hepatic PCSK9 expression is regulated by nutritional status via insulin and sterol regulatory-element binding protein 1c.
        J Biol Chem. 2006; 281: 6211-6218
        • Dubuc G.
        • Chamberland A.
        • Wassef H.
        • et al.
        Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia.
        Arterioscler Thromb Vasc Biol. 2004; 24: 1454-1459
        • Jeong H.J.
        • Lee H.S.
        • Kim K.S.
        • Kim Y.K.
        • Yoon D.
        • Park S.W.
        Sterol-dependent regulation of proprotein convertase subtilisin/kexin type 9 expression by sterol regulatory element-binding protein-2.
        J Lipid Res. 2007; 49: 399-409
        • Careskey H.E.
        • Davis R.A.
        • Alborn W.E.
        • Troutt J.S.
        • Cao G.
        • Konrad R.J.
        Atorvastatin increases human serum levels of proprotein convertase subtilisin/kexin type 9.
        J Lipid Res. 2008; 49: 394-398
        • Dubuc G.
        • Tremblay M.
        • Pare G.
        • et al.
        A new method for measurement of total plasma PCSK9: clinical applications.
        J Lipid Res. 2010; 51: 140-149
        • Lakoski S.G.
        • Lagace T.A.
        • Cohen J.C.
        • Horton J.D.
        • Hobbs H.H.
        Genetic and metabolic determinants of plasma PCSK9 levels.
        J Clin Endocrinol Metab. 2009; 94: 2537-2543
        • Berge K.E.
        • Ose L.
        • Leren T.P.
        Missense mutations in the PCSK9 gene are associated with hypocholesterolemia and possibly increased response to statin therapy.
        Arterioscler Thromb Vasc Biol. 2006; 26: 1094-1100
        • Rashid S.
        • Curtis D.E.
        • Garuti R.
        • et al.
        Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9.
        Proc Natl Acad Sci USA. 2005; 102: 5374-5379
        • Zaid A.
        • Roubtsova A.
        • Essalmani R.
        • et al.
        Proprotein convertase subtilisin/kexin type 9 (PCSK9): hepatocyte-specific low-density lipoprotein receptor degradation and critical role in mouse liver regeneration.
        Hepatology. 2008; 48: 646-654
        • Kourimate S.
        • Le M.C.
        • Langhi C.
        • et al.
        Dual mechanisms for the fibrate-mediated repression of proprotein convertase subtilisin/kexin type 9.
        J Biol Chem. 2008; 283: 9666-9673
        • Lambert G.
        • Jarnoux A.L.
        • Pineau T.
        • et al.
        Fasting induces hyperlipidemia in mice overexpressing PCSK9: lack of modulation of VLDL hepatic output by the LDLr.
        Endocrinology. 2006; 147: 4985-4995
        • Troutt J.S.
        • Alborn W.E.
        • Cao G.
        • Konrad R.J.
        Fenofibrate treatment increases human serum proprotein convertase subtilisin kexin type 9 (PCSK9) levels.
        J Lipid Res. 2009; 51: 345-351
        • Mayne J.
        • Dewpura T.
        • Raymond A.
        • et al.
        Plasma PCSK9 levels are significantly modified by statins and fibrates in humans.
        Lipids Health Dis. 2008; 7: 22
        • Lambert G.
        • Ancellin N.
        • Charlton F.
        • et al.
        Plasma PCSK9 concentrations correlate with LDL and total cholesterol in diabetic patients and are decreased by Fenofibrate treatment.
        Clin Chem. 2008; 54: 1038-1045
        • Kourimate S.
        • Chetiveaux M.
        • Jarnoux A.L.
        • Lalanne F.
        • Costet P.
        Cellular and secreted pro-protein convertase subtilisin/kexin type 9 catalytic activity in hepatocytes.
        Atherosclerosis. 2009; 206: 134-140
        • Li H.
        • Dong B.
        • Park S.W.
        • Lee H.S.
        • Chen W.
        • Liu J.
        Hepatocyte nuclear factor 1alpha plays a critical role in PCSK9 gene transcription and regulation by the natural hypocholesterolemic compound berberine.
        J Biol Chem. 2009; 284: 28885-28895
        • Dong B.
        • Wu M.
        • Li H.
        • et al.
        Strong induction of PCSK9 gene expression through HNF1{alpha} and SREBP2: mechanism for the resistance to LDL-cholesterol lowering effect of statins in dyslipidemic hamsters.
        J. Lipid Res. 2010;
        • Palmer C.N.
        • Hsu M.H.
        • Griffin K.J.
        • Raucy J.L.
        • Johnson E.F.
        Peroxisome proliferator activated receptor-alpha expression in human liver.
        Mol Pharmacol. 1998; 53: 14-22
        • Chan J.C.
        • Piper D.E.
        • Cao Q.
        • et al.
        A proprotein convertase subtilisin/kexin type 9 neutralizing antibody reduces serum cholesterol in mice and nonhuman primates.
        Proc Natl Acad Sci USA. 2009; 106: 9820-9825
      1. Effects of combination lipid therapy in type 2 diabetes mellitus.
        N. Engl. J. Med. 2010;