Lipid-lowering therapies: Better together

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