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Dual Therapy for Dyslipidemia: When Two May Be Better Than One

      Outside of our Special Topic updates, it is rare that Clinical Therapeutics publishes more than one article addressing an evolving therapeutic or modified therapeutic strategy in a single issue. However, this month we present to our audience 4 unsolicited, international research articles exploring adjunct therapies for the treatment of dyslipidemia across our global community.Over the past few years, randomized controlled clinical trials have suggested that a dual therapy approach for the treatment of hypercholesterolemia proves more effective at reducing cholesterol levels in high-risk individuals than monotherapy with first-line statins.
      • Ling H
      • Burns TL
      • Hilleman DE.
      Novel strategies for managing dyslipidemia: treatment beyond statins.
      ,
      • Sabatine MS
      • Giugliano RP
      • Keech AC
      • et al.
      Evolocumab and clinical outcomes in patients with cardiovascular disease.
      In 2017, Sabatine et al
      • Sabatine MS
      • Giugliano RP
      • Keech AC
      • et al.
      Evolocumab and clinical outcomes in patients with cardiovascular disease.
      published on the efficacy of evolocumab, a monoclonal antibody that inhibits proprotein convertase subtilisin–kexin type 9 (PCSK9). PCSK9 promotes lysosomal degradation of hepatic LDL receptors. As a result, LDL uptake is reduced, and LDL-C concentrations become elevated.
      • Bergeron N
      • Phan BA
      • Ding Y
      • et al.
      Proprotein convertase subtilisin/kexin type 9 inhibition: a new therapeutic mechanism for reducing cardiovascular disease risk.
      By combining a PCSK9 inhibitor
      (ie, evolocumab) with a statin, patients significantly reduce their LDL levels and overall cardiovascular mortality compared with statins alone.
      • Sabatine MS
      • Giugliano RP
      • Keech AC
      • et al.
      Evolocumab and clinical outcomes in patients with cardiovascular disease.
      In this issue of Clinical Therapeutics, Iqbal et al
      • Iqbal S
      • Sabbour HM
      • Siddiqui MS
      • et al.
      The first report of a real-world experience with a PCSK-9 inhibitor in a large familial hyperlipidemia and very-high risk Middle Eastern population.
      explore the safety and efficacy of evolocumab in high-risk Middle Eastern and North African populations. The authors report that in those individuals prescribed evolocumab, there was a reduction in LDL, triglyceride, and cholesterol ratios with few adverse events. This study supports the use of evolocumab in this predominantly Arabic cohort and provides the first safety data supporting the use of the drug in those individuals who cannot tolerate a statin or who require an adjunct therapy due to their high-risk profile.
      Additional therapies to combat dyslipidemia include ezetimibe, a drug that both inhibits absorption of cholesterol in the small intestine and decreases the amount of cholesterol available to liver cells.
      • Ouchi Y
      • Sasaki J
      • Arai H
      • et al.
      Ezetimibe Lipid-Lowering Trial on Prevention of Atherosclerotic Cardiovascular Disease in 75 or Older (EWTOPIA 75): a randomized, controlled trial.
      This month, we present 3 original articles highlighting the benefits of combining ezetimibe with a statin for reducing LDL levels in high-risk patients.
      • Han SJ
      • Soon JH
      • Cho J-M
      • et al.
      A multi-center, randomized, double-blinded active-controlled factorial design phase III clinical trial to evaluate the efficacy and safety of combination therapy of pitavastatin and ezetimibe versus monotherapy of pitavastatin in patients with primary hypercholesterolemia.
      • Qian J
      • Li Z
      • Zhang X
      • et al.
      Efficacy and safety of ezetimibe and atorvastatin fixed-dose combination versus atorvastatin monotherapy in Chinese patients with hypercholesterolemia—results from phase 3, randomized, active-controlled study.
      • Chou M-T
      • McGirr A
      • Jong G-P
      • et al.
      Effect of 1PC111, a fixed-dose combination of pitavastatin and ezetimibe versus pitavastatin or ezetimibe monotherapy on lipid profiles in patient with hypercholesterolemia or mixed dyslipidemia: a randomized, double-blind, multicenter, phase III study.
      All authors conclude that ezetimibe, in combination with a statin, proves superior to either drug as a monotherapy for the treatment of hypercholesterolemia.
      While the field of cardiology continues to make therapeutic advancements to reduce morbidity and mortality, studying these emerging therapies to ensure safety and efficacy across diverse patient populations is imperative. Clinical Therapeutics is proud to play an important role in critically reviewing trials conducted across the globe that aim to verify the results seen in trials largely based in the United States. The international studies highlighted in this issue involve subjects from Taiwan, South Korea, China, and the United Arab Emirates. Each study validates and reminds us of the benefit or potential benefit of dual therapy to treat dyslipidemia across diverse populations. For certain conditions that carry a high risk of morbidity worldwide, two drugs and multiple studies across ethnicities may indeed be better than one.

      References

        • Ling H
        • Burns TL
        • Hilleman DE.
        Novel strategies for managing dyslipidemia: treatment beyond statins.
        Postgrad Med. 2012; 124 (NovPMID: 23322138): 43-54https://doi.org/10.3810/pgm.2012.11.2612
        • Sabatine MS
        • Giugliano RP
        • Keech AC
        • et al.
        Evolocumab and clinical outcomes in patients with cardiovascular disease.
        N Engl J Med. 2017 May 4; 376: 1713-1722
        • Bergeron N
        • Phan BA
        • Ding Y
        • et al.
        Proprotein convertase subtilisin/kexin type 9 inhibition: a new therapeutic mechanism for reducing cardiovascular disease risk.
        Circulation. 2015 Oct 27; 132: 1648-1666
        • Iqbal S
        • Sabbour HM
        • Siddiqui MS
        • et al.
        The first report of a real-world experience with a PCSK-9 inhibitor in a large familial hyperlipidemia and very-high risk Middle Eastern population.
        Clin Ther. 2022; 44: 1297-1309
        • Ouchi Y
        • Sasaki J
        • Arai H
        • et al.
        Ezetimibe Lipid-Lowering Trial on Prevention of Atherosclerotic Cardiovascular Disease in 75 or Older (EWTOPIA 75): a randomized, controlled trial.
        Circulation. 2019 Sep 17; 140: 992-1003
        • Han SJ
        • Soon JH
        • Cho J-M
        • et al.
        A multi-center, randomized, double-blinded active-controlled factorial design phase III clinical trial to evaluate the efficacy and safety of combination therapy of pitavastatin and ezetimibe versus monotherapy of pitavastatin in patients with primary hypercholesterolemia.
        Clin Ther. 2022; 44: 1310-1325
        • Qian J
        • Li Z
        • Zhang X
        • et al.
        Efficacy and safety of ezetimibe and atorvastatin fixed-dose combination versus atorvastatin monotherapy in Chinese patients with hypercholesterolemia—results from phase 3, randomized, active-controlled study.
        Clin Ther. 2022; 44: 1282-1296
        • Chou M-T
        • McGirr A
        • Jong G-P
        • et al.
        Effect of 1PC111, a fixed-dose combination of pitavastatin and ezetimibe versus pitavastatin or ezetimibe monotherapy on lipid profiles in patient with hypercholesterolemia or mixed dyslipidemia: a randomized, double-blind, multicenter, phase III study.
        Clin Ther. 2022; : 1272-1281