Advertisement

A stepwise approach to prescribing novel lipid-lowering medications

  • Hessam Kakavand
    Affiliations
    Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran (Drs Kakavand, Aghakouchakzadeh, Shahi, and Talasaz)
    Search for articles by this author
  • Maryam Aghakouchakzadeh
    Affiliations
    Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran (Drs Kakavand, Aghakouchakzadeh, Shahi, and Talasaz)
    Search for articles by this author
  • Ali Shahi
    Affiliations
    Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran (Drs Kakavand, Aghakouchakzadeh, Shahi, and Talasaz)
    Search for articles by this author
  • Salim S. Virani
    Affiliations
    Health Policy, Quality & Informatics Program, Michael E. DeBakey Veterans Affairs Medical Center Health Services Research and Development Center for Innovations, Houston, Texas, USA (Dr Virani)

    Section of Cardiology, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, USA (Dr Virani)

    Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, Texas, USA (Dr Virani)
    Search for articles by this author
  • Dave L. Dixon
    Affiliations
    Department of Pharmacotherapy and & Outcomes Science, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, United States of America (Drs Dixon, Van Tassell, and Talasaz)

    VCU Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, United States of America
    Search for articles by this author
  • Benjamin W. Van Tassell
    Affiliations
    Department of Pharmacotherapy and & Outcomes Science, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, United States of America (Drs Dixon, Van Tassell, and Talasaz)

    VCU Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, United States of America
    Search for articles by this author
  • Azita H. Talasaz
    Correspondence
    Corresponding author at: VCU School of Pharmacy, 410 North 12th Street, Richmond, VA, United States.
    Affiliations
    Department of Clinical Pharmacy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran (Drs Kakavand, Aghakouchakzadeh, Shahi, and Talasaz)

    Department of Pharmacotherapy and & Outcomes Science, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, United States of America (Drs Dixon, Van Tassell, and Talasaz)
    Search for articles by this author
Published:October 18, 2022DOI:https://doi.org/10.1016/j.jacl.2022.10.003

      Highlights

      • There are many patients who will not reach LDL-C goals with statins.
      • Several novel lipid-lowering agents have come to the market recently.
      • Clinicians need to be familiar with the use of novel LLTs in their practice.
      • Lipids other than LDL-C [HDL-C or Lp(a)] are the pharmacotherapy targets for future.
      Dyslipidemia is a major modifiable risk factor for developing atherosclerotic cardiovascular disease. Despite increasing high intensity statin prescription and adherence to statin therapy, a considerable number of patients will not reach the guideline directed goals due to statin intolerance, lack of adherence or treatment efficacy. Several new lipid lowering medications have received approval by regulatory agencies in the past decade including proprotein convertase subtilisin/kexin type 9 modulators, ATP-citrate lyase inhibitors, angiopoietin-like 3 inhibitors, lomitapide, and icosapent ethyl. Although approved by regulatory agencies, these medications are still under-prescribed worldwide which may be related to cost issues, lack of cardiovascular outcome results, or clinicians not being familiar with their use. In this review, we propose a practical stepwise approach including each class’ efficacy, place in therapy, adverse effects, warnings and precautions, and monitoring parameters. This information can help the clinicians to prescribing these novel lipid lowering medications to achieve treatment goals and reduce the risk of atherosclerotic cardiovascular disease. The aim is to shift the paradigm for high-intensity statins from watch and wait to initial combination therapy for high-risk patients.

      Graphical abstract

      Keywords

      Abbreviations:

      ACLY (adenosine triphosphate-citrate lyase), ACS (acute coronary syndrome), AF (atrial fibrillation), ANGPTL3 (angiopoietin-like 3), ASCVD (atherosclerotic cardiovascular disease), ASO (antisense oligonucleotide), CI (confidence interval), CV (cardiovascular), DHA (docosahexaenoic acid), EPA (eicosapentaenoic acid), HDL-C (high-density lipoprotein-cholesterol), HoFH (homozygous familial hypercholesterolemia), HR (hazard ratio), IPE (Icosapent Ethyl), IV (intravenous), LDL-C (low-density lipoprotein-cholesterol), LLTs (lipid-lowering therapies), MI (myocardial infarction), mRNA (messenger ribonucleic acid), MTP (microsomal triglyceride transfer protein), O3FA (omega-3 fatty acid), PCSK9 (proprotein convertase subtilisin/kexin type 9), RCT (randomized controlled trial), SC (subcutaneous), siRNA (small interfering ribonucleic acid, TG, triglyceride)
      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 Journal of Clinical Lipidology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Goldstein JL
        • Brown MS.
        A century of cholesterol and coronaries: from plaques to genes to statins.
        Cell. 2015; 161: 161-172
        • Boren J
        • Chapman MJ
        • Krauss RM
        • Packard CJ
        • Bentzon JF
        • Binder CJ
        • et al.
        Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel.
        Eur Heart J. 2020; 41: 2313-2330
        • Zhang L
        • Zhang S
        • Yu Y
        • Jiang H
        • Ge J.
        Efficacy and safety of rosuvastatin vs. atorvastatin in lowering LDL cholesterol.
        Herz. 2020; 45: 594-602
        • Morrone D
        • Weintraub WS
        • Toth PP
        • Hanson ME
        • Lowe RS
        • Lin J
        • et al.
        Lipid-altering efficacy of ezetimibe plus statin and statin monotherapy and identification of factors associated with treatment response: a pooled analysis of over 21,000 subjects from 27 clinical trials.
        Atherosclerosis. 2012; 223: 251-261
        • Yusuf S
        • Bosch J
        • Dagenais G
        • Zhu J
        • Xavier D
        • Liu L
        • et al.
        Cholesterol lowering in intermediate-risk persons without cardiovascular disease.
        N Engl J Med. 2016; 374: 2021-2031
        • Scandinavian Simvastatin Survival Study Group
        Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S).
        Lancet (London, England). 1994; 344: 1383-1389
        • Cannon CP
        • Blazing MA
        • Giugliano RP
        • McCagg A
        • White JA
        • Theroux P
        • et al.
        Ezetimibe added to statin therapy after acute coronary syndromes.
        N Engl J Med. 2015; 372: 2387-2397
        • Ouchi Y
        • Sasaki J
        • Arai H
        • Yokote K
        • Harada K
        • Katayama Y
        • et al.
        Ezetimibe lipid-lowering trial on prevention of atherosclerotic cardiovascular disease in 75 or older (EWTOPIA 75): a randomized, controlled trial.
        Circulation. 2019; 140: 992-1003
        • Trialists CT.
        Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials.
        Lancet North Am Ed. 2010; 376: 1670-1681
        • Mach F
        • Baigent C
        • Catapano AL
        • Koskinas KC
        • Casula M
        • Badimon L
        • et al.
        2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: the task force for the management of dyslipidaemias of the European society of cardiology (ESC) and European atherosclerosis society (EAS).
        Eur Heart J. 2020; 41: 111-188
        • Grundy SM
        • Stone NJ
        • Bailey AL
        • Beam C
        • Birtcher KK
        • Blumenthal RS
        • et al.
        2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American college of cardiology/American heart association task force on clinical practice guidelines.
        J Am Coll Cardiol. 2019; 73: e285-e350
        • Cannon CP
        • De Lemos JA
        • Rosenson RS
        • Ballantyne CM
        • Liu Y
        • Gao Q
        • et al.
        Use of lipid-lowering therapies over 2 years in GOULD, a registry of patients with atherosclerotic cardiovascular disease in the US.
        JAMA Cardiol. 2021; 6: 1060-1068
        • Ray KK
        • Haq I
        • Bilitou A
        • Aguiar C
        • Arca M
        • Connolly DL
        • et al.
        Evaluation of contemporary treatment of high-and very high-risk patients for the prevention of cardiovascular events in Europe–Methodology and rationale for the multinational observational SANTORINI study.
        Atherosclerosis Plus. 2021; 43: 24-30
        • Bytyçi I
        • Penson PE
        • Mikhailidis DP
        • Wong ND
        • Hernandez AV
        • Sahebkar A
        • et al.
        Prevalence of statin intolerance: a meta-analysis.
        Eur Heart J. 2022; ([updated Feb 16. 2022/02/17:[ehac015]. Available from)
        • Lloyd-Jones DM
        • Morris PB
        • Ballantyne CM
        • Birtcher KK
        • Covington AM
        • DePalma SM
        • et al.
        ACC expert consensus decision pathway on the role of nonstatin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk.
        J Am Coll Cardiol. 2022; (0(0))
        • Geng Q
        • Li X
        • Sun Q
        • Wang Z.
        Efficacy and safety of PCSK9 inhibition in cardiovascular disease: a meta-analysis of 45 randomized controlled trials.
        Cardiol J. 2021;
        • Cao Y-X
        • Liu H-H
        • Li S
        • Li J-J.
        A meta-analysis of the effect of PCSK9-monoclonal antibodies on circulating lipoprotein (a)levels.
        Am J Cardiovasc Drugs. 2019; 19: 87-97
        • Nicholls SJ
        • Puri R
        • Anderson T
        • Ballantyne CM
        • Cho L
        • Kastelein JJ
        • et al.
        Effect of evolocumab on progression of coronary disease in statin-treated patients: the GLAGOV randomized clinical trial.
        JAMA. 2016; 316: 2373-2384
        • Sabatine MS
        • Giugliano RP
        • Keech AC
        • Honarpour N
        • Wiviott SD
        • Murphy SA
        • et al.
        Evolocumab and clinical outcomes in patients with cardiovascular disease.
        N Engl J Med. 2017; 376: 1713-1722
        • Casula M
        • Olmastroni E
        • Boccalari MT
        • Tragni E
        • Pirillo A
        • Catapano AL.
        Cardiovascular events with PCSK9 inhibitors: an updated meta-analysis of randomised controlled trials.
        Pharmacol Res. 2019; 143: 143-150
        • Ray KK
        • Wright RS
        • Kallend D
        • Koenig W
        • Leiter LA
        • Raal FJ
        • et al.
        Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol.
        N Engl J Med. 2020; 382: 1507-1519
        • Talasaz AH
        • Ho AC
        • Bhatty F
        • Koenig RA
        • Dixon DL
        • Baker WL
        • et al.
        Meta-analysis of clinical outcomes of PCSK9 modulators in patients with established ASCVD.
        Pharmacotherapy. 2021; 41: 1009-1023
        • Strilchuk L
        • Fogacci F
        • Cicero AF.
        Safety and tolerability of injectable lipid-lowering drugs: an update of clinical data.
        Expert Opin Drug Saf. 2019; 18: 611-621
        • Schwartz GG
        • Steg PG
        • Szarek M
        • Bhatt DL
        • Bittner VA
        • Diaz R
        • et al.
        Alirocumab and cardiovascular outcomes after acute coronary syndrome.
        N Engl J Med. 2018; 379: 2097-2107
        • Giugliano RP
        • Mach F
        • Zavitz K
        • Kurtz C
        • Im K
        • Kanevsky E
        • et al.
        Cognitive function in a randomized trial of evolocumab.
        N Engl J Med. 2017; 377: 633-643
        • Ray KK
        • Colhoun HM
        • Szarek M
        • Baccara-Dinet M
        • Bhatt DL
        • Bittner VA
        • et al.
        Effects of alirocumab on cardiovascular and metabolic outcomes after acute coronary syndrome in patients with or without diabetes: a prespecified analysis of the ODYSSEY OUTCOMES randomised controlled trial.
        Lancet Diabetes Endocrinol. 2019; 7: 618-628
        • Kelly MS
        • Sulaica EM
        • Beavers CJ.
        Role of bempedoic acid in dyslipidemia management.
        J Cardiovasc Pharmacol. 2020; 76: 376-388
        • Ray KK
        • Bays HE
        • Catapano AL
        • Lalwani ND
        • Bloedon LT
        • Sterling LR
        • et al.
        Safety and efficacy of bempedoic acid to reduce LDL cholesterol.
        N Engl J Med. 2019; 380: 1022-1032
        • Goldberg AC
        • Leiter LA
        • Stroes ES
        • Baum SJ
        • Hanselman JC
        • Bloedon LT
        • et al.
        Effect of bempedoic acid vs placebo added to maximally tolerated statins on low-density lipoprotein cholesterol in patients at high risk for cardiovascular disease: the CLEAR wisdom randomized clinical trial.
        JAMA. 2019; 322: 1780-1788
        • Laufs U
        • Banach M
        • Mancini GJ
        • Gaudet D
        • Bloedon LT
        • Sterling LR
        • et al.
        Efficacy and safety of bempedoic acid in patients with hypercholesterolemia and statin intolerance.
        J Am Heart Assoc. 2019; 8e011662
        • Ballantyne CM
        • Banach M
        • Mancini GJ
        • Lepor NE
        • Hanselman JC
        • Zhao X
        • et al.
        Efficacy and safety of bempedoic acid added to ezetimibe in statin-intolerant patients with hypercholesterolemia: a randomized, placebo-controlled study.
        Atherosclerosis. 2018; 277: 195-203
        • Dai L
        • Zuo Y
        • You Q
        • Zeng H
        • Cao S.
        Efficacy and safety of bempedoic acid in patients with hypercholesterolemia: a systematic review and meta-analysis of randomized controlled trials.
        Eur J Preventive Cardiol. 2021; 28: 825-833
        • Ballantyne CM
        • Laufs U
        • Ray KK
        • Leiter LA
        • Bays HE
        • Goldberg AC
        • et al.
        Bempedoic acid plus ezetimibe fixed-dose combination in patients with hypercholesterolemia and high CVD risk treated with maximally tolerated statin therapy.
        Eur J Preventive Cardiol. 2020; 27: 593-603
        • Markham A.
        Bempedoic acid: first approval.
        Drugs. 2020; 80: 747-753
        • Bays HE
        • Banach M
        • Catapano AL
        • Duell PB
        • Gotto Jr, AM
        • Laufs U
        • et al.
        Bempedoic acid safety analysis: pooled data from four phase 3 clinical trials.
        Journal of clinical lipidology. 2020; 14: 649-659
        • Dewey FE
        • Gusarova V
        • Dunbar RL
        • O'Dushlaine C
        • Schurmann C
        • Gottesman O
        • et al.
        Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease.
        N Engl J Med. 2017; 377: 211-221
        • Raal FJ
        • Rosenson RS
        • Reeskamp LF
        • Hovingh GK
        • Kastelein JJ
        • Rubba P
        • et al.
        Evinacumab for homozygous familial hypercholesterolemia.
        N Engl J Med. 2020; 383: 711-720
        • Rosenson RS
        • Burgess LJ
        • Ebenbichler CF
        • Baum SJ
        • Stroes ESG
        • Ali S
        • et al.
        Evinacumab in patients with refractory hypercholesterolemia.
        N Engl J Med. 2020; 383: 2307-2319
        • Ahmad Z
        • Banerjee P
        • Hamon S
        • Chan KC
        • Bouzelmat A
        • Sasiela WJ
        • et al.
        Inhibition of angiopoietin-like protein 3 with a monoclonal antibody reduces triglycerides in hypertriglyceridemia.
        Circulation. 2019; 140: 470-486
        • Cuchel M
        • Bloedon LT
        • Szapary PO
        • Kolansky DM
        • Wolfe ML
        • Sarkis A
        • et al.
        Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia.
        N Engl J Med. 2007; 356: 148-156
        • Liu X
        • Men P
        • Wang Y
        • Zhai S
        • Zhao Z
        • Liu G.
        Efficacy and safety of lomitapide in hypercholesterolemia.
        Am J Cardiovasc Drugs. 2017; 17: 299-309
        • Manson JE
        • Cook NR
        • Lee I-M
        • Christen W
        • Bassuk SS
        • Mora S
        • et al.
        Marine n− 3 fatty acids and prevention of cardiovascular disease and cancer.
        N Engl J Med. 2019; 380: 23-32
        • Group ASC.
        Effects of n− 3 fatty acid supplements in diabetes mellitus.
        N Engl J Med. 2018; 379: 1540-1550
        • Bhatt DL
        • Steg PG
        • Miller M
        • Brinton EA
        • Jacobson TA
        • Ketchum SB
        • et al.
        Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia.
        N Engl J Med. 2019; 380: 11-22
        • Yokoyama M
        • Origasa H
        • Matsuzaki M
        • Matsuzawa Y
        • Saito Y
        • Ishikawa Y
        • et al.
        Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis.
        Lancet North Am Ed. 2007; 369: 1090-1098
        • Nicholls SJ
        • Lincoff AM
        • Garcia M
        • Bash D
        • Ballantyne CM
        • Barter PJ
        • et al.
        Effect of high-dose omega-3 fatty acids vs corn oil on major adverse cardiovascular events in patients at high cardiovascular risk: the STRENGTH randomized clinical trial.
        JAMA. 2020; 324: 2268-2280
        • Kalstad AA
        • Myhre PL
        • Laake K
        • Tveit SH
        • Schmidt EB
        • Smith P
        • et al.
        Effects of n-3 fatty acid supplements in elderly patients after myocardial infarction: a randomized, controlled trial.
        Circulation. 2021; 143: 528-539
        • Budoff MJ
        • Bhatt DL
        • Kinninger A
        • Lakshmanan S
        • Muhlestein JB
        • Le VT
        • et al.
        Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: final results of the EVAPORATE trial.
        Eur Heart J. 2020; 41: 3925-3932
        • Lombardi M
        • Carbone S
        • Del Buono MG
        • Chiabrando JG
        • Vescovo GM
        • Camilli M
        • et al.
        Omega-3 fatty acids supplementation and risk of atrial fibrillation: an updated meta-analysis of randomized controlled trials.
        Eur Heart J Cardiovascular Pharmacotherapy. 2021; 7: e69-e70
        • Solnica B
        • Sygitowicz G
        • Sitkiewicz D
        • Cybulska B
        • Jóźwiak J
        • Odrowąż-Sypniewska G
        • et al.
        2020 Guidelines of the Polish Society of Laboratory Diagnostics (PSLD) and the Polish Lipid Association (PoLA) on laboratory diagnostics of lipid metabolism disorders. Archives of medical science. 16. AMS, 2020: 237-252
        • Yao X
        • Shah ND
        • Gersh BJ
        • Lopez-Jimenez F
        • Noseworthy PA.
        Assessment of trends in statin therapy for secondary prevention of atherosclerotic cardiovascular disease in US adults from 2007 to 2016.
        JAMA Network Open. 2020; 3 (e2025505-e)
        • Banach M
        • Penson PE.
        Statins and LDL-C in secondary prevention—So much progress, so far to go.
        JAMA Network Open. 2020; 3 (e2025675-e)
        • Ray KK
        • Reeskamp LF
        • Laufs U
        • Banach M
        • Mach F
        • Tokgözoğlu LS
        • et al.
        Combination lipid-lowering therapy as first-line strategy in very high-risk patients.
        Eur Heart J. 2021;
        • Wang H-X
        • Xiong M-H
        • Wang Y-C
        • Zhu J
        • Wang J
        N-acetylgalactosamine functionalized mixed micellar nanoparticles for targeted delivery of siRNA to liver.
        J Controlled Release. 2013; 166: 106-114