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Statins & more

Overview of common lipid-lowering drugs used in secondary prevention to reach LDL treatment goals



Updated by Konstantin A. Krychtiuk, 20 August 2021

In patients who have suffered an AMI, an LDL-C reduction of at least 50% from baseline together with an LDL-C goal of <55 mg/dL (<1.4 mmol/L) are recommended (both goals need to be achieved). [1][2] High-intensity statins such as atorvastatin 40-80 mg or rosuvastatin 20-40 mg usually result in an LDL-C reduction of around 50%. If target levels cannot be reached with maximally dosed high-intensity statins, ezetimibe should be added; for further reduction of LDL-C levels, a PCSK9-inhibitor is recommended. (Table 1)

Main recommendation

Table 1. Lipid-Lowering treatment in Secondary Prevention – Key messages

Treatment Goals: LDL<55 mg/dL (<1.4 mmol/L) AND at least a 50% reduction from baseline values.

Available Drugs Dosage Expected LDL-C reduction Comment
Atorvastatin 40 mg, 80 mg once daily ≥ 50%  
Rosuvastatin 20mg, 40 mg once daily ≥ 50%  
Ezetemibe 10 mg once daily 15-20% as add-on refer to specialist
Evolocumab 140 mg s.c. every other week; 420 mg s.c. monthly 50-60% as add-on  refer to specialist
Alirocumab 75 mg, or 150 mg s.c., every other week 50-60% as add-on  refer to specialist
Inclisiran 284 mg s.c., on day 1, day 90 and every 6 months 40-50% as add-on No CV outcome trials available yet
Bempedoic acid 180 mg once daily 23% as monotherapy
35% in combination with ezetimibe
No CV outcome trials available yet

 

Optimal lipid management for patients after an acute myocardial infarction (AMI) is of paramount importance. Prompt initiation of high-intensity statin therapy is strongly recommended for every patient after an AMI – regardless of baseline LDL-cholesterol levels, – within 1-4 days of the index event[1]. The type and dose chosen should achieve LDL-C values of <55mg/dL (<1.4 mmol/L) AND a reduction of at least 50%. This includes atorvastatin 40-80mg and rosuvastatin 20-40mg (see Table 1) [2].

LDL-C levels should be re-checked after 6-8 weeks. If patients fail to reach target levels, ezetimibe 10mg once daily should be added and is associated with improved outcomes. In patients with high LDL-C unlikely to reach goal with a statin alone, an statin-ezetimibe combination treatment should be considered upfront during index hospitalization. [3]

Patients with an established ASCVD and especially those in the early phase after an AMI who present with persistently elevated levels of LDL-C despite treatment at the the maximum tolerated statin dose combined with ezetemibe or patients with true statin intolerance, should receive treatment with a PCSK-9 inhibitor to further improve outcome. [2] Such patients should in addition be referred to a lipid specialist for screening for familial hypercholesterolemia.

Patients that experience a second vascular event within two years while taking maximum-tolerated statin therapy, an LDL-C goal of < 40mg/dL may be considered.

Further information

Statins

By inhibiting the HMG-CoA-reductase activity in hepatocytes, statins reduce hepatic cholesterol synthesis, leading to lower intracellular cholesterol levels. This in turn, causes LDL-receptor upregulation on the hepatocyte surface, which results in increased uptake thereby further decreases the LDL-C levels in the circulation. The degree of this action is dependent on the dose and type of statin used (see Table 1).

As it is one of the most intensively investigated drugs in cardiovascular medicine, the underlying evidence can only be partially discussed here. The Cholesterol Treatment Trialists (CTT) data including >170,000 participants from 26 randomized controlled trials (RCTs) suggest that a 40 mg/dL reduction in LDL-C results in a 10% reduction of all-cause and a 20% drop of CAD mortality as well as a 23% reduction in major coronary events [4]. These benefits were consistent in all subgroups and even more significant after a longer period of treatment.

In secondary prevention, particularly after an AMI, the beneficial effects of statins are particularly significant involving other (pleiotropic) statin effects including potentially anti-inflammatory or plaque-stabilizing effects [5].

Adverse Effects of Statins

Muscle symptoms ranging from myalgia without any rise in creatine kinase levels to rhabdomyolysis, are the most commonly described adverse effects and the principal reason for statin discontinuation with potential detrimental effect on the patient. The reported frequency varies considerably, with evidence suggesting a 5% occurrence rate [6]. It is not recommended to routinely check creatine kinase levels after a statin therapy is started. Diagnosis should be based on clinical observation: whether symptoms disappear after discontinuation and re-appear after re-challenge with at least three statin types and various dosages. In secondary prevention especially, it is of utmost importance to secure the diagnosis of statin-associated muscle symptoms (SAMS) with a structured work-up and treat the few truly affected patients on the maximum tolerated statin dose combined with non-statin lipid-lowering therapies to attain the recommended LDL-C targets. Further information can be found in the Consensus Statement of the European Atherosclerosis Society [7]. A systematic review found that the incidence of drug-induced hepatotoxicity in patients taking statins is unknown [8], but it is recommended to have the liver enzymes (alanine transaminase - ALT) checked every 8–12 weeks after a statin treatment is started or the dose has been increased.

Ezetemibe

As a cholesterol absorption inhibitor, Ezetemibe inhibits intestinal cholesterol uptake and thereby reduces cholesterol transport to the liver. This causes the LDL-receptor upregulation which in turn, lowers the circulating LDL-C levels. Monotherapy with Ezetemibe results in lower LDL-levels, around 15-22%, while adding statin therapy causes a further 15-20% drop. In IMPROVE-IT, Ezetemibe was added to 40 mg Simvastatin in more than 18,000 patients after ACS, this led to an additional LDL-reduction, which resulted in another slight yet statistically significant reduction in cardiovascular events [9].

Bempedoic acid

Bempedoic acid is a novel, oral small molecule inhibiting cholesterol synthesis within the liver by blocking adenosine triphosphate citrate lyase, an enzyme upstream of HMG-CoA reductase. In contrast to statins, inhibition of cholesterol biosynthesis is liver-specific which results in reduced side effects, in particular a reduction of muscle symptoms as compared to statins. It was recently approved in the US and Europe. Addition of bempedoic acid (180mg once daily) to maximally tolerated statin therapy reduced LDL-C levels by 16.5 and 17.2%, while administration as a combination therapy with ezetimibe was associated with a 36.2% reduction. A phase III cardiovascular outcome trial (CLEAR-Outcomes) in statin-intolerant patients is currently being undertaken (NCT02993406; clinicaltrials.gov).

PCSK-9 Inhibitors

After LDL-uptake, PCSK-9 binds to the now intracellular LDL-receptors causing lysosomal degradation. Inhibiting this protein reduces LDL-receptor degradation, thereby causing an increased LDL-receptor expression on the hepatocyte which decreases the circulating LDL-levels. PCSK-9 inhibitors are injected subcutaneously every other week or every month. The efficacy in reducing LDL-C is very high with reported reductions of 50-60% independently of any background therapy. Two phase III randomized controlled cardiovascular outcome trials evaluating the two available PCKS-9 antibody treatments suggested a reduction of cardiovascular events upon treatment with PCSK9-inhibitors. [11] [12]

Therefore, a PCSK9 inhibitor should be prescribed for patients who have suffered an AMI with persistent high LDL-C despite treatment at the maximum tolerated statin dose, in combination with ezetimibe, or for patients with confirmed statin intolerance.

Inclisiran

Inclisiran is a small, interfering RNA agent (siRNA) and reduces hepatic PCSK-9 synthesis. It is injected subcutaneously on day 1, day 90 and and every 6 months thereafter. In the ORION study program, this therapeutic regime resulted in an approximately 40-50% reduction in circulating LDL-C levels. [13] As of now, no data from outcome trials are available, a phase III cardiovascular outcome trial is currently being conducted (ORION-4; NCT03705234; clinicaltrials.gov).

References


[1]. Jean-Philippe Collet, Holger Thiele, Emanuele Barbato, Olivier Barthélémy, Johann Bauersachs, Deepak L Bhatt, Paul Dendale, Maria Dorobantu, Thor Edvardsen, Thierry Folliguet, Chris P Gale, Martine Gilard, Alexander Jobs, Peter Jüni, Ekaterini Lambrinou, Basil S Lewis, Julinda Mehilli, Emanuele Meliga, Béla Merkely, Christian Mueller, Marco Roffi, Frans H Rutten, Dirk Sibbing, George C M Siontis, ESC Scientific Document Group 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation; Eur Heart J. 2021 Apr 7;42(14):1289-1367 DOI: 10.1093/eurheartj/ehaa575

[2]. 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); François Mach, Colin Baigent, Alberico L Catapano, Konstantinos C Koskinas, Manuela Casula, Lina Badimon, M John Chapman, Guy G De Backer, Victoria Delgado, Brian A Ference, Ian M Graham, Alison Halliday, Ulf Landmesser, Borislava Mihaylova, Terje R Pedersen, Gabriele Riccardi, Dimitrios J Richter, Marc S Sabatine, Marja-Riitta Taskinen, Lale Tokgozoglu, Olov Wiklund, ESC Scientific Document Group; Eur Heart J. 2020 Jan 1;41(1):111-188. doi: 10.1093/eurheartj/ehz455

[3]. Practical guidance for combination lipid-modifying therapy in high- and very-high-risk patients: A statement from a European Atherosclerosis Society Task Force; Maurizio Averna, Maciej Banach, Eric Bruckert, Heinz Drexel, Michel Farnier, Dan Gaita, Paolo Magni, Winfried März, Luis Masana, Alberto Mello E Silva, Zeljko Reiner, Emilio Ros, Michal Vrablik, Alberto Zambon, Jose L Zamorano, Jane K Stock, Lale S Tokgözo─člu, Alberico L Catapano; Atherosclerosis. 2021 May;325:99-109 doi: 10.1016/j.atherosclerosis.2021.03.039

[4]. Cholesterol Treatment Trialists C, Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, Peto R, Barnes EH, Keech A, Simes J, Collins R. Efficacy and safety of more intensive lowering of ldl cholesterol: A meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376:1670-1681

[5]. Davignon J. Beneficial cardiovascular pleiotropic effects of statins. Circulation. 2004;109:III39-43

[6]. Parker BA, Capizzi JA, Grimaldi AS, Clarkson PM, Cole SM, Keadle J, Chipkin S, Pescatello LS, Simpson K, White CM, Thompson PD. Effect of statins on skeletal muscle function. Circulation. 2013;127:96-103

[7]. Stroes ES, Thompson PD, Corsini A, Vladutiu GD, Raal FJ, Ray KK, Roden M, Stein E, Tokgozoglu L, Nordestgaard BG, Bruckert E, De Backer G, Krauss RM, Laufs U, Santos RD, Hegele RA, Hovingh GK, Leiter LA, Mach F, Marz W, Newman CB, Wiklund O, Jacobson TA, Catapano AL, Chapman MJ, Ginsberg HN, European Atherosclerosis Society Consensus P. Statin-associated muscle symptoms: Impact on statin therapy-european atherosclerosis society consensus panel statement on assessment, aetiology and management. European heart journal. 2015;36:1012-1022

[8]. Law M, Rudnicka AR. Statin safety: A systematic review. The American journal of cardiology. 2006;97:52C-60C

[9]. Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, Darius H, Lewis BS, Ophuis TO, Jukema JW, De Ferrari GM, Ruzyllo W, De Lucca P, Im K, Bohula EA, Reist C, Wiviott SD, Tershakovec AM, Musliner TA, Braunwald E, Califf RM, Investigators I-I. Ezetimibe added to statin therapy after acute coronary syndromes. The New England journal of medicine. 2015;372:2387-2397

[10]. Markham, A. (2020) Bempedoic Acid: First Approval. Drugs 80, 747-753

[11]. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease.
Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, Kuder JF, Wang H, Liu T, Wasserman SM, Sever PS, Pedersen TR; FOURIER Steering Committee and Investigators.N Engl J Med. 2017 May 4;376(18):1713-1722. doi: 10.1056/NEJMoa1615664.

[12]. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome.
Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner VA, Diaz R, Edelberg JM, Goodman SG, Hanotin C, Harrington RA, Jukema JW, Lecorps G, Mahaffey KW, Moryusef A, Pordy R, Quintero K, Roe MT, Sasiela WJ, Tamby JF, Tricoci P, White HD, Zeiher AM; ODYSSEY OUTCOMES Committees and Investigators.N Engl J Med. 2018 Nov 29;379(22):2097-2107. doi: 10.1056/NEJMoa1801174.

[13]. Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol.
Ray KK, Wright RS, Kallend D, Koenig W, Leiter LA, Raal FJ, Bisch JA, Richardson T, Jaros M, Wijngaard PLJ, Kastelein JJP; ORION-10 and ORION-11 Investigators.N Engl J Med. 2020 Apr 16;382(16):1507-1519. doi: 10.1056/NEJMoa1912387.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

The ESC Prevention of Cardiovascular Disease programme is supported by AMGEN, AstraZeneca, Ferrer, and Sanofi and Regeneron in the form of educational grants.

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