Lipid-lowering therapies: Better together
2021; Elsevier BV; Volume: 320; Linguagem: Inglês
10.1016/j.atherosclerosis.2021.01.009
ISSN1879-1484
AutoresMaciej Banach, Peter E. Penson,
Tópico(s)Diabetes, Cardiovascular Risks, and Lipoproteins
ResumoExposure to low-density lipoprotein cholesterol (LDL-C) causes atherosclerotic cardiovascular disease (ASCVD) [[1]Ference B.A. Ginsberg H.N. 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: 2459-2472Crossref PubMed Scopus (983) Google Scholar], and the importance of the mantra “lower is better for longer” [[2]Penson P.E. Pirro M. Banach M. LDL-C Lower is better for longer-even at low risk.BMC Med. 2020; 18: 320Crossref PubMed Scopus (20) Google Scholar,[3]Cybulska B. Kłosiewicz-Latoszek L. Penson P.E. et al.How much should LDL cholesterol be lowered in secondary prevention? Clinical efficacy and safety in the era of PCSK9 inhibitors.Prog. Cardiovasc. Dis. 2020; https://doi.org/10.1016/j.pcad.2020.12.008Crossref Scopus (6) Google Scholar] cannot be understated. However, “lower” (specifically guideline-directed treatment targets), can be hard to achieve in clinical practice owing to possible adverse effects, poor compliance and adherence, and the ceiling effects of individual pharmaceutical agents at maximally tolerated doses [[4]Ray K.K. Molemans B. Schoonen W.M. et al.EU-wide cross-sectional observational study of lipid-modifying therapy use in secondary and primary care: the DA VINCI study.Eur. J. Prev. Cardiol. 2020; https://doi.org/10.1093/eurjpc/zwaa047Crossref Google Scholar]. If we additionally add the rules of “the earlier the better” and the “the longer the better”, achieving effective lipid lowering therapy can be very difficult indeed. A rational approach is therefore to use available lipid-lowering therapies (LLTs) in combination [2Penson P.E. Pirro M. Banach M. LDL-C Lower is better for longer-even at low risk.BMC Med. 2020; 18: 320Crossref PubMed Scopus (20) Google Scholar, 3Cybulska B. Kłosiewicz-Latoszek L. Penson P.E. et al.How much should LDL cholesterol be lowered in secondary prevention? Clinical efficacy and safety in the era of PCSK9 inhibitors.Prog. Cardiovasc. Dis. 2020; https://doi.org/10.1016/j.pcad.2020.12.008Crossref Scopus (6) Google Scholar, 4Ray K.K. Molemans B. Schoonen W.M. et al.EU-wide cross-sectional observational study of lipid-modifying therapy use in secondary and primary care: the DA VINCI study.Eur. J. Prev. Cardiol. 2020; https://doi.org/10.1093/eurjpc/zwaa047Crossref Google Scholar, 5Banach M. Penson P.E. Statins and LDL-C in secondary prevention-so much progress, so far to go.JAMA Netw. Open. 2020; 3e2025675Crossref PubMed Scopus (12) Google Scholar]. However, whilst abundant evidence exists for the LDL-C reduction efficacy of individual lipid-lowering agents, there is less support from the literature as to how multiple drugs should be used together, especially with respect to new lipid lowering drugs such as bempedoic acid. A rigorous study conducted by Rubino and colleagues, and published in this issue of Atherosclerosis, addresses this important knowledge gap [[6]Rubino J. MacDougall D.E. Sterling L.R. et al.Combination of Bempedoic Acid, Ezetimibe, and Atorvastatin in Patients with Hypercholesterolemia: a Randomized Clinical Trial. Atherosclerosis, 2020https://doi.org/10.1016/j.atherosclerosis.2020.12.023Abstract Full Text Full Text PDF Scopus (4) Google Scholar]. In their phase 2, randomized, double-blind, placebo-controlled study, Rubino et al. took participants with hypercholesterolemia, but no history of cardiovascular events, who underwent washout of any lipid-lowering therapy before randomization to triple therapy (bempedoic acid 180 mg, ezetimibe 10 mg, and moderate intensity atorvastatin 20) or placebo. After six weeks treatment, LDL-C was reduced by 63.6% in the treatment group, compared with 3.1% in the placebo group, a statistically significant between-group difference of −60.5% (95% confidence interval (CI) −68.0 to −53.0%). The inflammatory marker high-sensitivity C-reactive protein (hsCRP) was significantly reduced by treatment difference, −41.9% (95% CI, −60.0 to −21.4%). Significant changes were also observed for non-HDL-C, total cholesterol, apolipoprotein B (apoB) and triglycerides, but not high-density lipoprotein cholesterol (HDL-C). The substantial reduction in hsCRP noted in this study is interesting, and potentially very promising with respect to the efficacy of this combination therapy in ASCVD, in light of recent evidence from randomized-controlled trials [[7]Ridker P.M. Everett B.M. Thuren T. et al.Antiinflammatory therapy with canakinumab for atherosclerotic disease.N. Engl. J. Med. 2017; 377: 1119-1131Crossref PubMed Scopus (3239) Google Scholar] and observational studies [[8]Penson P.E. Long D.L. Howard G. et al.Associations between very low concentrations of low density lipoprotein cholesterol, high sensitivity C-reactive protein, and health outcomes in the Reasons for Geographical and Racial Differences in Stroke (REGARDS) study.Eur. Heart J. 2018; 39: 3641-3653Crossref PubMed Scopus (41) Google Scholar] relating to the causative role of inflammation in ASCVD residual risk. Statins, the mainstay of lipid-lowering therapy since the 1990s, reduce hepatic production of cholesterol, and are effective at reducing ASCVD events, and are generally well-tolerated [[9]Collins R. Reith C. Emberson J. et al.Interpretation of the evidence for the efficacy and safety of statin therapy.Lancet. 2016; 388: 2532-2561Abstract Full Text Full Text PDF PubMed Scopus (880) Google Scholar], but might be associated with adverse effects such as muscle symptoms – which in extreme cases (usually less than 5%) can lead to complete statin intolerance and in the consequence statin discontinuation [[10]Banach M. Rizzo M. Toth P.P. et al.Statin intolerance - an attempt at a unified definition. Position paper from an International Lipid Expert Panel.Arch. Med. Sci. 2015; 11: 1-23Crossref PubMed Scopus (259) Google Scholar]. However, muscle symptoms are often misattributed to statins [[11]Penson P.E. Mancini G.B.J. Toth P.P. et al.Introducing the 'Drucebo' effect in statin therapy: a systematic review of studies comparing reported rates of statin-associated muscle symptoms, under blinded and open-label conditions.J. Cachexia Sarcopenia Muscle. 2018; 9: 1023-1033Crossref PubMed Scopus (38) Google Scholar] and with careful management, including switching between statins and dose reduction, applying alternate-day statin therapy or combination therapy [[12]Penson P. Toth P. Mikhailidis D. et al.Step by step diagnosis and management of statin intolerance: position paper from an international lipid expert panel.Eur. Heart J. 2019; 40: P705Crossref PubMed Google Scholar], approximately 95% of seemingly intolerant patients can manage some degree of statin therapy [[13]Banach M. Mikhailidis D.P. Statin intolerance: some practical hints.Cardiol. Clin. 2018; 36: 225-231Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar]. Statins reduce ASCVD events by about one-quarter for each mmol/L reduction in LDL cholesterol. High intensity therapy with atorvastatin 40–80 mg or rosuvastatin 20–40 mg daily can achieve a ≥50% reduction in LDL-C [[14]Cannon C.P. Blazing M.A. Giugliano R.P. et al.Ezetimibe added to statin therapy after acute coronary syndromes.N. Engl. J. Med. 2015; 372: 2387-2397Crossref PubMed Scopus (2302) Google Scholar]. The IMPROVE-IT trial demonstrated that adding ezetimibe (an inhibitor of intestinal cholesterol absorption) to statin therapy resulted in further reduction in a composite cardiovascular endpoint: hazard ratio (HR) 0.936 (95% CI 0.89 to 0.99). More recently, inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) have demonstrated remarkable reductions in LDL-C, and associated reductions in ASCVD events [[15]Banach M. Penson P.E. What have we learned about lipids and cardiovascular risk from PCSK9 inhibitor outcome trials: ODYSSEY and FOURIER?.Cardiovasc. Res. 2019; 115: e26-e31Crossref PubMed Scopus (29) Google Scholar], however, these monoclonal antibodies must be administered by injection, and the high cost restricts access to them for most patients, and in most countries they are reimbursed within the drug programs only for very high-risk and extremely high risk patients with familial hypercholesterolemia (FH) and/or acute coronary syndrome (ACS). The approach to lipid-reduction with bempedoic acid, presented already in many available phase 2, and 3 trials, as well as pooled data analyses [[16]Banach M. Duell P.B. Gotto Jr., A.M. et al.Association of bempedoic acid administration with atherogenic lipid levels in phase 3 randomized clinical trials of patients with hypercholesterolemia.JAMA Cardiol. 2020; https://doi.org/10.1001/jamacardio.2020.2314Crossref Scopus (27) Google Scholar], and now employed by Rubino et al. is very attractive. The use of a submaximal statin dose is likely to reduce the frequency of treatment-limiting side effects, whilst the addition of two other agents ensures that lipid-lowering is not compromised. The achieved reduction of LDL-C by ≥ 60% ensures goal attainment for most of patients, even those at very high CVD risk. The inclusion of bempedoic acid in the regimen is both interesting and logical. Bempedoic acid is a prodrug, which is activated when combined with coenzyme A by an enzyme which is located only in the liver. The active conjugate inhibits adenosine triphosphate (ATP) citrate lyase (ACL), which lies upstream of the target of statins in the mevalonate pathway of cholesterol production. The liver-specific activation of this agent reduces the potential for muscle-symptoms, and means it is especially suitable for individuals with any degree of dose-limiting statin intolerance and it is not surprising that in the main cardiovascular outcomes trial – CLEAR Outcomes only patients with statin intolerance are included (the study actually randomized 14,014 patients to treatment with bempedoic acid 180 mg daily or matching placebo and will continue until 1620 patients experience a primary endpoint, and minimum treatment duration of 36 months and a projected median treatment exposure of 42 months) [[17]Penson P. McGowan M. Banach M. Evaluating bempedoic acid for the treatment of hyperlipidaemia.Expet Opin. Invest. Drugs. 2017; 26: 251-259Crossref PubMed Scopus (29) Google Scholar]. Furthermore, whilst statin therapy might be associated with an increased risk of new onset diabetes mellitus (NODM) (especially at high doses), a recent meta-analysis has demonstrated that bempedoic acid reduces the risk of NODM [[18]Cicero A.F.G. Fogacci F. Hernandez A.V. et al.Efficacy and safety of bempedoic acid for the treatment of hypercholesterolemia: a systematic review and meta-analysis.PLoS Med. 2020; 17e1003121Crossref PubMed Scopus (16) Google Scholar]. Thus, combining drugs at reduced doses has substantial potential to reduce and mitigate adverse effects, compared to high-dose monotherapy, and in the consequence might result in not only goal achievement but its maintenance for a long time. The data collected by Rubino and colleagues are highly relevant to clinical practice and add further support to recent guideline recommendations regarding the use of bempedoic acid in combination with other LLTs. The recent recommendations on the lipid disorders management in Poland (to the best of our knowledge for the first time) recommend that bempedoic acid may be combined with statins and ezetimibe in patients with ASCVD or familial hypercholesterolaemia who fail to achieve treatment targets (IIb B). When statins are not tolerated at any dose, bempedoic acid and ezetimibe dual therapy can be employed (IIb B) [[19]Banach M. Jozwiak J. Dudek D. PTL/KLRwP/PTK/PTDL/PTD/PTNT 2021 Recommendations on the lipid disorders management in Poland.Arch. Med. Sci. 2021; 17 (In Press)PubMed Google Scholar]. Assuming the relatively low price of bempedoic acid and especially its combination with ezetimibe (based on the available data from US it might be between 7 and 10$ a pill), this lipid lowering therapy might be potentially highly beneficial for many patients at high CVD risk over LDL-C target on statins. Clinical trials should ideally ask questions which directly inform clinical practice. The choice of placebo as a comparator in the study by Rubio et al. might seem odd in this respect – as the likely alternative to their treatment regimen in practice would be high-dose statin monotherapy, rather than no treatment. Indeed, it would be interesting and important to know how the treatment responses in this population under trial conditions would have compared to more conventional treatment regimens. However, viewed from another perspective, the use of a ‘washout’ period in which no lipid-lowering therapy was administered, and the choice of placebo comparator are prescient approaches to trial design. Current guidelines generally advocate initiating LLT with a single drug, with additional agents added later if targets are not met [[20]Mach F. Baigent C. Catapano A.L. et al.ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk.Eur. Heart J. 2019; 41 (2020): 111-188Crossref Scopus (1514) Google Scholar]. However, this approach does not take account of the fact that the proportional lipid reduction achievable with current treatments is predictable [[20]Mach F. Baigent C. Catapano A.L. et al.ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk.Eur. Heart J. 2019; 41 (2020): 111-188Crossref Scopus (1514) Google Scholar], and in many cases with very high baseline LDL-C, monotherapy is initiated regardless of the fact that it is extremely unlikely to reach their treatment target without additional agents. There is therefore an argument, to initiate therapy (especially for those at very and extremely high CV risk) with multiple agents at once (as in this study), an approach which is already used in the management of hypertension [[21]Williams B. Mancia G. Spiering W. et al.ESC/ESH Guidelines for the management of arterial hypertension.Eur. Heart J. 2018; 39 (2018): 3021-3104Crossref PubMed Scopus (2940) Google Scholar]. Similarly in the case of statin intolerance, it may be preferable to start treatment immediately with available non-statin agents, rather than waiting months until the maximally tolerated dose of statin can be titrated, increasing the risk of LDL-C visit-to-visit variability and increased CVD event risk [[5]Banach M. Penson P.E. Statins and LDL-C in secondary prevention-so much progress, so far to go.JAMA Netw. Open. 2020; 3e2025675Crossref PubMed Scopus (12) Google Scholar]. Enthusiasm for these exciting results should be tempered by the fact that the study was of short duration, and therefore used lipid levels as endpoints rather than cardiovascular events. However, considering the well-established relationship between LDL-C, inflammatory markers and cardiovascular disease, and the proven efficacy of each of the three LLTs in mono or dual-therapy, it would be surprising if the favourable changes in lipid profile observed in this study (if sustained over a longer period) did not translate to clinical benefit. When considering the results of a trial such as this, it is important to consider how easily the intervention can realistically be implemented in clinical practice, and whether the treatment benefit would likely be so large outside of the setting of a clinical trial in which patient support and monitoring is likely to lead to greater compliance with treatment regimens than is common in the ‘real world’. In the case of the LLT regimen used in this study, the possibility exists to combine the three orally available small-molecule lipid lowering drugs into a single dosage form (a combination of bempedoic acid and ezetimibe already exists), and thereby improve compliance, using a ‘polypill’ approach [[22]Franczyk B. Gluba-Brzozka A. Jurkiewicz L. et al.Embracing the polypill as a cardiovascular therapeutic: is this the best strategy?.Expet Opin. Pharmacother. 2018; 19: 1857-1865Crossref PubMed Scopus (9) Google Scholar]. Rubino and colleagues should be congratulated for their excellent work, which does appear to demonstrate that ezetimibe, bempedoic acid and atorvastatin are ‘better together’. Should (as is likely) their approach be sustainable in the long term, and translate to improved outcomes, they will have contributed an important solution to the large unmet need of unmet lipid targets. PEP owns four shares in AstraZeneca PLC and has received honoraria and/or travel reimbursement for events sponsored by AKCEA , Amgen , AMRYT , Link Medical , Mylan , Napp , Sanofi ; MB - speakers bureau: Amgen , Daichii Sankyo , Herbapol , Kogen , KRKA , Mylan , Novartis , Novo-Nordisk , Polpharma , Sanofi , Servier , Teva , Zentiva ; consultant to Amgen , Daichii Sankyo , Esperion , Freia Pharmaceuticals , Mylan , Polfarmex , Sanofi / Regeneron , Teva ; Grants from Amgen , Mylan , Sanofi , and Valeant . Combination of bempedoic acid, ezetimibe, and atorvastatin in patients with hypercholesterolemia: A randomized clinical trialAtherosclerosisVol. 320PreviewMany patients with hypercholesterolemia fail to achieve sufficient low-density lipoprotein cholesterol (LDL-C) lowering despite use of guideline-recommended lipid-lowering therapies. This study evaluated LDL-C lowering with the combination of bempedoic acid, ezetimibe, and atorvastatin. Full-Text PDF
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