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Current Pharmaceutical Design

Editor-in-Chief

ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Review Article

PCSK9 Inhibitors for the Management of Dyslipidemia in People with Type 2 Diabetes: How Low is Too Low?

Author(s): Ioannis Felekos, Grigoris V. Karamasis and Antonis N. Pavlidis*

Volume 27 , Issue 8 , 2021

Published on: 17 June, 2020

Page: [1008 - 1014] Pages: 7

DOI: 10.2174/1381612826666200617170252

Price: $65

Abstract

Diabetic patients are considered to be at high risk for the development of atherosclerotic disease. Management of hypercholesterolemia is of paramount importance to optimize cardiovascular outcomes in this subset of patients and statins are regarded as the mainstay of treatment. However, the recent advent of PCSK-9 inhibitors has provided a useful alternative in the management of dyslipidemia, especially when statins cannot be tolerated or when hypolipidemic targets cannot be achieved. In this review, we discuss current trends in their use, and we focus on their role in the management of diabetic dyslipidemia.

Keywords: PCSK9 inhibitors, dyslipidemia, diabetes, hypercholesterolemia, atherosclerotic disease, hypolipidemic.

[1]
American Diabetes Association. Standards of medical care in diabetes-2017. Diabetes Care 2017; 40(Suppl. 1): S1-S135.
[2]
Mach F, Baigent C, Catapano AL, et al. ESC Scientific Document Group. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2020; 41(1): 111-88.
[http://dx.doi.org/10.1093/eurheartj/ehz455] [PMID: 31504418]
[3]
Sillars A, Sattar N. Management of Lipid Abnormalities in Patients with Diabetes. Curr Cardiol Rep 2019; 21(11): 147.
[http://dx.doi.org/10.1007/s11886-019-1246-1] [PMID: 31758270]
[4]
Handelsman Y, Lepor NE. PCSK9 Inhibitors in Lipid Management of Patients With Diabetes Mellitus and High Cardiovascular Risk: A Review. J Am Heart Assoc 2018; 7(13): e008953.
[http://dx.doi.org/10.1161/JAHA.118.008953] [PMID: 29934421]
[5]
Cannon CP, Blazing MA, Giugliano RP, et al. IMPROVE-IT Investigators. IMPROVE-IT Investigators. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015; 372(25): 2387-97.
[http://dx.doi.org/10.1056/NEJMoa1410489] [PMID: 26039521]
[6]
Vergès B. Pathophysiology of diabetic dyslipidaemia: where are we? Diabetologia 2015; 58(5): 886-99.
[http://dx.doi.org/10.1007/s00125-015-3525-8] [PMID: 25725623]
[7]
Lorenzo C, Hartnett S, Hanley AJ, et al. Impaired fasting glucose and impaired glucose tolerance have distinct lipoprotein and apolipoprotein changes: the insulin resistance atherosclerosis study. J Clin Endocrinol Metab 2013; 98(4): 1622-30.
[http://dx.doi.org/10.1210/jc.2012-3185] [PMID: 23450048]
[8]
Jialal I, Singh G. Management of diabetic dyslipidemia: An update. World J Diabetes 2019; 10(5): 280-90.
[http://dx.doi.org/10.4239/wjd.v10.i5.280] [PMID: 31139315]
[9]
Borén J, Watts GF, Adiels M, et al. Kinetic and related determinants of plasma triglyceride concentration in abdominal obesity: multicenter tracer kinetic study. Arterioscler Thromb Vasc Biol 2015; 35(10): 2218-24.
[http://dx.doi.org/10.1161/ATVBAHA.115.305614] [PMID: 26315407]
[10]
Mark L, Vallejo-Vaz AJ, Reiber I, Paragh G, Kondapally Seshasai SR, Ray KK. Non-HDL cholesterol goal attainment and its relationship with triglyceride concentrations among diabetic subjects with cardiovascular disease: A nationwide survey of 2674 individuals in Hungary. Atherosclerosis 2015; 241(1): 62-8.
[http://dx.doi.org/10.1016/j.atherosclerosis.2015.04.810] [PMID: 25966441]
[11]
Jialal I, Vikram N. Nutrition therapy for diabetes: Implications for decreasing cardiovascular complications. J Diabetes Complications 2017; 31(10): 1477-80.
[http://dx.doi.org/10.1016/j.jdiacomp.2017.07.008] [PMID: 28830659]
[12]
Hyde PN, Sapper TN, Crabtee CD, et al. Dietary carbohydrate restriction improves metabolic syndrome independent of weight loss. JCI Insight 2019; 4(12): e128308.
[13]
Wilding JPH. The importance of weight management in type 2 diabetes mellitus. Int J Clin Pract 2014; 68(6): 682-91.
[http://dx.doi.org/10.1111/ijcp.12384] [PMID: 24548654]
[14]
Wing RR, Lang W, Wadden TA, et al. Look AHEAD Research Group. Benefits of modest weight loss in improving cardiovascular risk factors in overweight and obese individuals with type 2 diabetes. Diabetes Care 2011; 34(7): 1481-6.
[http://dx.doi.org/10.2337/dc10-2415] [PMID: 21593294]
[15]
Scicchitano P, Cameli M. Nutraceuticals and dyslipidaemia: Beyond the common therapeutics. J Funct Foods 2014; 6: 11-32.
[http://dx.doi.org/10.1016/j.jff.2013.12.006]
[16]
Stone NJ, Robinson JG, Lichtenstein AH, et al. American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014; 63(25 Pt B): 2889-934.
[http://dx.doi.org/10.1016/j.jacc.2013.11.002] [PMID: 24239923]
[17]
Devaraj S, Rogers J, Jialal I. Statins and biomarkers of inflammation. Curr Atheroscler Rep 2007; 9(1): 33-41.
[http://dx.doi.org/10.1007/BF02693938] [PMID: 17169243]
[18]
Collins R, Armitage J, Parish S, Sleigh P, Peto R. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003; 361(9374): 2005-16.
[http://dx.doi.org/10.1016/S0140-6736(03)13636-7] [PMID: 12814710]
[19]
Neil HA, DeMicco DA, Luo D, et al. CARDS Study Investigators. Analysis of efficacy and safety in patients aged 65-75 years at randomization: Collaborative Atorvastatin Diabetes Study (CARDS). Diabetes Care 2006; 29(11): 2378-84.
[http://dx.doi.org/10.2337/dc06-0872] [PMID: 17065671]
[20]
Kearney PM, Blackwell L, Collins R, et al. Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet 2008; 371(9607): 117-25.
[http://dx.doi.org/10.1016/S0140-6736(08)60104-X] [PMID: 18191683]
[21]
Ridker PM, Danielson E, Fonseca FA, et al. JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359(21): 2195-207.
[http://dx.doi.org/10.1056/NEJMoa0807646] [PMID: 18997196]
[22]
Aiman U, Najmi A, Khan RA. Statin induced diabetes and its clinical implications. J Pharmacol Pharmacother 2014; 5(3): 181-5.
[http://dx.doi.org/10.4103/0976-500X.136097] [PMID: 25210397]
[23]
Freeman DJ, Norrie J, Sattar N, et al. Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study. Circulation 2001; 103(3): 357-62.
[http://dx.doi.org/10.1161/01.CIR.103.3.357] [PMID: 11157685]
[24]
Rajpathak SN, Kumbhani DJ, Crandall J, Barzilai N, Alderman M, Ridker PM. Statin therapy and risk of developing type 2 diabetes: a meta-analysis. Diabetes Care 2009; 32(10): 1924-9.
[http://dx.doi.org/10.2337/dc09-0738] [PMID: 19794004]
[25]
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): 735-42.
[http://dx.doi.org/10.1016/S0140-6736(09)61965-6] [PMID: 20167359]
[26]
Huang CH, Huang YY, Hsu BR. Pitavastatin improves glycated hemoglobin in patients with poorly controlled type 2 diabetes. J Diabetes Investig 2016; 7(5): 769-76.
[http://dx.doi.org/10.1111/jdi.12483] [PMID: 27181110]
[27]
Keech A, Simes RJ, Barter P, et al. FIELD study investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005; 366(9500): 1849-61.
[http://dx.doi.org/10.1016/S0140-6736(05)67667-2] [PMID: 16310551]
[28]
Ginsberg HN, Elam MB, Lovato LC, et al. ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010; 362(17): 1563-74.
[http://dx.doi.org/10.1056/NEJMoa1001282] [PMID: 20228404]
[29]
Landray MJ, Haynes R, Hopewell JC, et al. HPS2-THRIVE Collaborative Group. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med 2014; 371(3): 203-12.
[http://dx.doi.org/10.1056/NEJMoa1300955] [PMID: 25014686]
[30]
Jialal I, Abby SL, Misir S, Nagendran S. Concomitant reduction in low-density lipoprotein cholesterol and glycated hemoglobin with colesevelam hydrochloride in patients with type 2 diabetes: a pooled analysis. Metab Syndr Relat Disord 2009; 7(3): 255-8.
[http://dx.doi.org/10.1089/met.2009.0007] [PMID: 19344229]
[31]
Seidah NG, Benjannet S, Wickham L, et al. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc Natl Acad Sci USA 2003; 100(3): 928-33.
[http://dx.doi.org/10.1073/pnas.0335507100] [PMID: 12552133]
[32]
Bhatt DL, Steg PG, Miller M, et al. REDUCE-IT Investigators. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med 2019; 380(1): 11-22.
[http://dx.doi.org/10.1056/NEJMoa1812792] [PMID: 30415628]
[33]
Burke AC, Dron JS, Hegele RA, Huff MW. PCSK9: Regulation and target for drug development for dyslipidemia. Annu Rev Pharmacol Toxicol 2017; 57: 223-44.
[http://dx.doi.org/10.1146/annurev-pharmtox-010716-104944] [PMID: 27575716]
[34]
Oikawa S, Yokoyama M, Origasa H, et al. JELIS Investigators, Japan. Suppressive effect of EPA on the incidence of coronary events in hypercholesterolemia with impaired glucose metabolism: Sub-analysis of the Japan EPA Lipid Intervention Study (JELIS). Atherosclerosis 2009; 206(2): 535-9.
[http://dx.doi.org/10.1016/j.atherosclerosis.2009.03.029] [PMID: 19447387]
[35]
Rana K, Reid J, Rosenwasser JN, et al. A spotlight on alirocumab in high cardiovascular risk patients with type 2 diabetes and mixed dyslipidemia: a review on the emerging data. Diabetes Metab Syndr Obes 2019; 12: 1897-911.
[http://dx.doi.org/10.2147/DMSO.S167375] [PMID: 31571964]
[36]
Ray KK, Landmesser U, Leiter LA, et al. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N Engl J Med 2017; 376(15): 1430-40.
[http://dx.doi.org/10.1056/NEJMoa1615758] [PMID: 28306389]
[37]
Fitzgerald K, White S, Borodovsky A, et al. A Highly Durable RNAi Therapeutic Inhibitor of PCSK9. N Engl J Med 2017; 376(1): 41-51.
[http://dx.doi.org/10.1056/NEJMoa1609243] [PMID: 27959715]
[38]
Grundy M, Stone NJ, Bailey LA, et al. AHA/ACC/AACVPR/AAPA/ ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: executive summary. J Am Coll Cardiol 2018.
[http://dx.doi.org/10.1016/j.jacc.2018.11.002] [PMID: 30423391]
[39]
Ginsberg HN, Rader DJ, Raal FJ, et al. Efficacy and safety of alirocumab in patients with heterozygous familial hypercholesterolemia and LDL-C of 160mg/dl or higher. Cardiovasc Drugs Ther 2016; 30(5): 473-83.
[http://dx.doi.org/10.1007/s10557-016-6685-y] [PMID: 27618825]
[40]
Giugliano RP, Mach F, Zavitz K, et al. EBBINGHAUS Investigators. Cognitive Function in a Randomized Trial of Evolocumab. N Engl J Med 2017; 377(7): 633-43.
[http://dx.doi.org/10.1056/NEJMoa1701131] [PMID: 28813214]
[41]
Farnier M, Hovingh GK, Langslet G, et al. Long-term safety and efficacy of alirocumab in patients with heterozygous familial hypercholesterolemia: An open-label extension of the ODYSSEY program. Atherosclerosis 2018; 278: 307-14.
[http://dx.doi.org/10.1016/j.atherosclerosis.2018.08.036] [PMID: 30293878]
[42]
Ganda OP, Plutzky J, Sanganalmath SK, et al. Efficacy and safety of alirocumab among individuals with diabetes mellitus and atherosclerotic cardiovascular disease in the ODYSSEY phase 3 trials. Diabetes Obes Metab 2018; 20(10): 2389-98.
[http://dx.doi.org/10.1111/dom.13384]
[43]
Ginsberg HN, Farnier M, Robinson JG, et al. Efficacy and safety of alirocumab: pooled analyses of 1048 individuals with diabetes mellitus from five placebo-controlled Phase 3 studies of at least 52 weeks duration. Circulation 2015; 132: A17070.
[44]
Toth PP, Descamps O, Genest J, et al. PROFICIO Investigators. Proficio Investigators. Pooled safety analysis of evolocumab in over 6000 patients from double-blind and open-label extension studies. Circulation 2017; 135(19): 1819-31.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.116.025233] [PMID: 28249876]
[45]
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): 2981-9.
[http://dx.doi.org/10.1093/eurheartj/ehw292] [PMID: 27460890]
[46]
Ray KK, Leiter LA, Müller-Wieland D, et al. Alirocumab vs usual lipid-lowering care as add-on to statin therapy in individuals with type 2 diabetes and mixed dyslipidaemia: The ODYSSEY DM-DYSLIPIDEMIA randomized trial. Diabetes Obes Metab 2018; 20(6): 1479-89.
[http://dx.doi.org/10.1111/dom.13257] [PMID: 29436756]
[47]
Leiter LA, Cariou B, Müller-Wieland D, et al. Efficacy and safety of alirocumab in insulin-treated individuals with type 1 or type 2 diabetes and high cardiovascular risk: The ODYSSEY DM-INSULIN randomized trial. Diabetes Obes Metab 2017; 19(12): 1781-92.
[http://dx.doi.org/10.1111/dom.13114] [PMID: 28905478]
[48]
Zhang XL, Zhu QQ, Zhu L, et al. Safety and efficacy of anti-PCSK9 antibodies: a meta-analysis of 25 randomized, controlled trials. BMC Med 2015; 13: 123.
[http://dx.doi.org/10.1186/s12916-015-0358-8] [PMID: 26099511]
[49]
Sattar N, Preiss D, Robinson JG, et al. Lipid-lowering efficacy of the PCSK9 inhibitor evolocumab (AMG 145) in patients with type 2 diabetes: a meta-analysis of individual patient data. Lancet Diabetes Endocrinol 2016; 4(5): 403-10.
[http://dx.doi.org/10.1016/S2213-8587(16)00003-6] [PMID: 26868195]
[50]
Sabatine MS, Leiter LA, Wiviott SD, et al. Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial. Lancet Diabetes Endocrinol 2017; 5(12): 941-50.
[http://dx.doi.org/10.1016/S2213-8587(17)30313-3] [PMID: 28927706]
[51]
Kausik K. Efficacy and safety of alirocumab among patients with and without diabetes: prespecified analysis of a randomised placebo-controlled trial. Lancet Diabetes Endocrinol 2019; 7(8): 618-28.
[http://dx.doi.org/10.1016/S2213-8587(19)30158-5] [PMID: 31272931]
[52]
Leiter LA, Teoh H, Kallend D, et al. Inclisiran Lowers LDL-C and PCSK9 Irrespective of Diabetes Status: The ORION-1 Randomized Clinical Trial. Diabetes Care 2019; 42(1): 173-6.
[http://dx.doi.org/10.2337/dc18-1491] [PMID: 30487231]
[53]
Preiss D, Mafham M. PCSK9 inhibition: the dawn of a new age in cholesterol lowering? Diabetologia 2017; 60(3): 381-9.
[http://dx.doi.org/10.1007/s00125-016-4178-y] [PMID: 28025677]
[54]
Nicholls SJ, Puri R, Anderson T, et al. Effect of evolocumab on progression of coronary disease in statin-treated patients: the GLAGOV randomized trial. JAMA 2016; 316(22): 2373-84.
[http://dx.doi.org/10.1001/jama.2016.16951] [PMID: 27846344]
[55]
Schwartz GG, Bessac L, Berdan LG, et al. Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY outcomes trial. Am Heart J 2014; 168(5): 682-9.
[http://dx.doi.org/10.1016/j.ahj.2014.07.028] [PMID: 25440796]
[56]
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): 1713-22.
[http://dx.doi.org/10.1056/NEJMoa1615664] [PMID: 28304224]
[57]
Schmidt AF, Swerdlow DI, Holmes MV, et al. LifeLines Cohort study group; UCLEB consortium. PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study. Lancet Diabetes Endocrinol 2017; 5(2): 97-105.
[http://dx.doi.org/10.1016/S2213-8587(16)30396-5] [PMID: 27908689]
[58]
Steg PG, Szarek M, Bhatt DL, et al. Effect of alirocumab on mortality after acute coronary syn- dromes: an analysis of the ODYSSEY OUTCOMES randomized clinical trial. Circulation 2019; 140: 103-12.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.118.038840] [PMID: 31117810]

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