Vnitr Lek 2018, 64(12):1186-1189

PCSK9 inhibitors and diabetes mellitus

Branislav Vohnout1,2,3,*, Jana Lisičanová3, Andrea Havranová4
1 Ústav výživy, FO a ZOŠ a Koordinačné centrum pre familiárne hyperlipoproteinémie, Slovenská zdravotnícka univerzita v Bratislave, Slovenská republika
2 Ústav epidemiológie LF UK v Bratislave, Slovenská republika
3 Diabetologická ambulancia Diabeda s.r.o., Bratislava, Slovenská republika
4 Ústav klinického a translačného výskumu, Biomedicínske centrum Slovenskej akadémie vied, Bratislava, Slovenská republika

Proproteinconvertase subtilisin kexin 9 (PCSK9) is a key regulator of low-density lipoprotein receptor (LDLR) expression. Anti-PCSK9 monoclonal antibody (MAb) therapy reduces LDL-cholesterol (LDL-C) by ~60 % and reduces also the risk of major adverse cardiovascular events. Mendelian randomisation studies showed that patients carrying loss-of-function PCSK9 genetic variants display lower LDL-C and have an increased risk of developing type 2 diabetes (T2DM). Randomized controlled trials with anti-PCSK9 MAbs however showed no effect on the risk. A possible explanation of the discrepancy is that the deficiency of locally but not circulating PCSK9 is responsible for increased LDLR expression in pancreatic islets, which results in cholesterol accumulation and B-cell dysfunction. Thus PCSK9 lowering therapy with MAb targeting mainly circulating PCSK9 might have a limited impact on LDLR expression in pancreatic cells and on the risk of T2DM. Long-term clinical trials are however needed to confirm it.

Keywords: diabetes mellitus; LDL receptor; PCSK9

Received: November 9, 2018; Accepted: November 15, 2018; Published: December 1, 2018  Show citation

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Vohnout B, Lisičanová J, Havranová A. PCSK9 inhibitors and diabetes mellitus. Vnitr Lek. 2018;64(12):1186-1189.
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    References

    1. Ference BA, Ginsberg HN, Graham I et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2017; 38(32): 2459-2472. Dostupné z DOI: <http://dx.doi.org/10.1093/eurheartj/ehx144>. Go to original source... Go to PubMed...
    2. Vohnout B, Havranová A. LDL-cholesterol - hlavný rizikový faktor aterosklerózy. AtheroRev 2016; 1(2)2: 88-92. Go to original source...
    3. Baigent C, Blackwell L, Emberson J et al. Cholesterol Treatment Trialists' (CTT) Collaboration, 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(9753): 1670-1681. Dostupné z DOI: <http://dx.doi.org/10.1016/S0140-6736(10)61350-5>. Go to original source... Go to PubMed...
    4. Cannon CP, Blazing MA, Giugliano RP et al. IMPROVE-IT Investigators. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med 2015; 372(25): 2387-2397. Dostupné z DOI: <http://dx.doi.org/10.1056/NEJMoa1410489>. Go to original source... Go to PubMed...
    5. Lagace TA. PCSK9 and LDLR degradation: regulatory mechanisms in circulation and in cells. Curr Opin Lipidol 2014; 25(5): 387-393. Dostupné z DOI: <http://dx.doi.org/10.1097/MOL.0000000000000114>. Go to original source... Go to PubMed...
    6. 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. <http://dx.doi.org/10.1056/NEJMoa054013>. Go to original source... Go to PubMed...
    7. Abifadel M, Varret M, Rabès JP et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 2003; 34(2): 154-156. Dostupné z DOI: <http://dx.doi.org/10.1038/ng1161>. Go to original source... Go to PubMed...
    8. Schwartz GG, Steg PG, Szarek M et al. [ODYSSEY OUTCOMES Committees and Investigators]. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. N Engl J Med 2018. Dostupné z DOI: <http://dx.doi.org/10.1056/NEJMoa1801174>. Go to original source... Go to PubMed...
    9. Sabatine MS, Giugliano RP, Keech AC et al. [FOURIER Steering Committee and Investigators]. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med 2017; 376(18): 1713-1722. Dostupné z DOI: <http://dx.doi.org/10.1056/NEJMoa1615664>. Go to original source... Go to PubMed...
    10. Ridker PM, Revkin J, Amarenco P et al. [SPIRE Cardiovascular Outcome Investigators]. Cardiovascular Efficacy and Safety of Bococizumab in High-Risk Patients. N Engl J Med 2017; 376(16): 1527-1539. Dostupné z DOI: <http://dx.doi.org/10.1056/NEJMoa1701488>. Go to original source... Go to PubMed...
    11. Sattar N, Preiss D, Murray HM et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 2010; 375(9716): 735-742. Dostupné z DOI: <http://dx.doi.org/10.1016/S0140-6736(09)61965-6>. Go to original source... Go to PubMed...
    12. Preiss D, Seshasai SR, Welsh P et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA 2011; 305(24): 2556-2564. Dostupné z DOI: <http://dx.doi.org/10.1001/jama.2011.860>. Go to original source... Go to PubMed...
    13. Swerdlow DI, Preiss D, Kuchenbaecker KB et al. HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. Lancet 2015; 385(9965): 351-361. Dostupné z DOI: <http://dx.doi.org/10.1016/S0140-6736(14)61183-1>. Go to original source... Go to PubMed...
    14. White J, Swerdlow DI, Preiss D et al. Association of Lipid Fractions With Risks for Coronary Artery Disease and Diabetes. JAMA Cardiol 2016; 1(6): 692-699. Dostupné z DOI: <http://dx.doi.org/10.1001/jamacardio.2016.1884>. Go to original source... Go to PubMed...
    15. Fall T, Xie W, Poon W et al. Using Genetic Variants to Assess the Relationship Between Circulating Lipids and Type 2 Diabetes. Diabetes 2015; 64(7): 2676-2684. Dostupné z DOI: <http://dx.doi.org/10.2337/db14-1710>. Go to original source... Go to PubMed...
    16. Ference BA, Robinson JG, Brook RD et al. Variation in PCSK9 and HMGCR and Risk of Cardiovascular Disease and Diabetes. N Engl J Med 2016; 375(22): 2144-2153. Dostupné z DOI: <http://dx.doi.org/10.1056/NEJMoa1604304>. Go to original source... Go to PubMed...
    17. Besseling J, Kastelein JJ, Defesche JC et al. Association between familial hypercholesterolemia and prevalence of type 2 diabetes mellitus. JAMA 2015; 313(10): 1029-1036. Dostupné z DOI: <http://dx.doi.org/10.1001/jama.2015.1206>. Go to original source... Go to PubMed...
    18. Filippatos TD, Panagiotopoulou T, Tzavella E et al. Hypolipidemic Drugs and Diabetes Mellitus-Mechanisms and Data From Genetic Trials. J Cardiovasc Pharmacol Ther 2018; 23(3): 187-191. Dostupné z DOI: <http://dx.doi.org/10.1177/1074248418757011>. Go to original source... Go to PubMed...
    19. Schmidt AF, Swerdlow DI, Holmes MV et al. PCSK9 genetic variants and risk of type 2 diabetes: A mendelian randomisation study. Lancet Diabetes Endocrinol 2017; 5(2): 97-105. Dostupné z DOI: <http://dx.doi.org/10.1016/S2213-8587(16)30396-5>. Go to original source... Go to PubMed...
    20. Lotta LA, Sharp SJ, Burgess S et al. Association between low-density lipoprotein cholesterollowering genetic variants and risk of type 2 diabetes: A meta-analysis. JAMA 2016; 316(13): 1383-1391. Dostupné z DOI: <http://dx.doi.org/10.1001/jama.2016.14568>. Go to original source... Go to PubMed...
    21. Karatasakis A, Danek BA, Karacsonyi J et al. Effect of PCSK9 Inhibitors on Clinical Outcomes in Patients With Hypercholesterolemia: A Meta-Analysis of 35 Randomized Controlled Trials. J Am Heart Assoc 2017; 6(12). pii: e006910. Dostupné z DOI: <http://dx.doi.org/10.1161/JAHA.117.006910>. Go to original source... Go to PubMed...
    22. Colhoun HM, Ginsberg HN, Robinson JG et al. No effect of PCSK9 inhibitor alirocumab on the incidence of diabetes in a pooled analysis from 10 ODYSSEY Phase 3 studies. Eur Heart J 2016; 37(39): 2981-2989. Dostupné z DOI: <http://dx.doi.org/10.1093/eurheartj/ehw292>. Go to original source... Go to PubMed...
    23. de Carvalho LSF, Campos AM, Sposito AC. Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors and Incident Type 2 Diabetes: A Systematic Review and Meta-analysis With Over 96,000 Patient-Years. Diabetes Care 2018; 41(2): 364-367. Dostupné z DOI: <http://dx.doi.org/10.2337/dc17-1464>. Go to original source... Go to PubMed...
    24. Leiter LA, Müller-Wieland D, Baccara-Dinet MT et al. Efficacy and safety of alirocumab in people with prediabetes vs those with normoglycaemia at baseline: a pooled analysis of 10 phase III ODYSSEY clinical trials. Diabet Med 2018; 35(1): 121-130. Dostupné z DOI: <http://dx.doi.org/10.1111/dme.13450>. Go to original source... Go to PubMed...
    25. Norata GD, Tavori H, Pirillo A et al. Biology of proprotein convertase subtilisin kexin 9: beyond low-density lipoprotein cholesterol lowering. Cardiovasc Res 2016; 112(1): 429-442. Dostupné z DOI: <http://dx.doi.org/10.1093/cvr/cvw194>. Go to original source... Go to PubMed...
    26. Hao M, Head WS, Gunawardana SC et al. Direct effect of cholesterol on insulin secretion: a novel mechanism for pancreatic beta-cell dysfunction. Diabetes 2007; 56(9): 2328-2338. Dostupné z DOI: <http://dx.doi.org/10.2337/db07-0056>. Go to original source... Go to PubMed...
    27. Cnop M, Hannaert J, Grupping A et al. Low density lipoprotein can cause death of islet beta-cells by its cellular uptake and oxidative modification. Endocrinology 2002; 143(9): 3449-3453. Dostupné z DOI: <http://dx.doi.org/10.1210/en.2002-220273>. Go to original source... Go to PubMed...
    28. Paul R, Choudhury A, Choudhury S et al. Cholesterol in pancreatic beta-cell death and dysfunction: underlying mechanisms and pathological implications. Pancreas 2016; 45(3): 317-324. Dostupné z DOI: <http://dx.doi.org/10.1097/MPA.0000000000000486>. Go to original source... Go to PubMed...
    29. Da Dalt L, Ruscica M, Bonacina F et al. PCSK9 deficiency reduces insulin secretion and promotes glucose intolerance: the role of the low-density lipoprotein receptor. Eur Heart J 2018. Dostupné z DOI: <http://dx.doi.org/10.1093/eurheartj/ehy357>. Go to original source...

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