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Vol. 69. Issue 3.
Pages 342-343 (March 2016)
Vol. 69. Issue 3.
Pages 342-343 (March 2016)
Scientific letter
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Maximum Low-density Lipoprotein Cholesterol Lowering Capacity Achievable With Drug Combinations. When 50 Plus 20 Equals 60
Máxima reducción de colesterol unido a lipoproteínas de baja densidad alcanzable con combinaciones farmacológicas. Cuando 50 más 20 suma 60
Lluis Masana?
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Corresponding author:
, Daiana Ibarretxe, Nuria Plana
Unidad de Medicina Vascular y Metabolismo, Hospital Universitario Sant Joan, Universidad Rovira I Virgili, Instituto Investigación Sanitaria Pere Virgili (IISPV), CIBERDEM, Reus, Tarragona, Spain
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Table. Theoretical Low-density Lipoprotein Reduction in Percentage Induced by Drugs in Monotherapy or in Combination
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To the Editor,

The results from the IMPROVE-IT trial and data from Mendelian randomization studies reinforce the causal role of low-density lipoprotein (LDL) cholesterol in atheromatous cardiovascular disease.1,2 The “lower is best” concept has robust evidence-based support, and high-intensity cholesterol-lowering strategies ought to be implemented instead of high-intensity statin therapy.3

A clinically relevant question is “What is the maximum LDL-lowering capacity that will be achieved by combination therapy after the introduction of the new proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors?”

Statins have accumulated the most scientific evidence in cardiovascular prevention. Their average cholesterol-lowering effect ranges from 30% to 50%. By adding ezetimibe, their LDL-lowering capacity increased by 20% (22% in the IMPROVE-IT trial).1 New PCSK9 inhibitors add an LDL reduction capacity of approximately 60%.4,5 It must be taken into account that these reduction percentages are average values that may vary due to individual response. In addition, these percentages are achieved from the starting LDL values. Therefore, when calculating the overall impact of drug combinations, the effect of previous drugs must be taken into account. The absolute effect of adding drugs is lower than the addition of their relative effects.

For example, in a patient with LDL levels of 200mg/dL, a high potency statin will decrease LDL cholesterol by 50% to 100mg/dL. By adding ezetimibe, we expect a 20% incremental LDL reduction; therefore, LDL concentrations of 100mg/dL will decrease to 80mg/dL (20% less). Thus, this patient will have a final reduction of 120mg/dL, which is a 60% reduction from the starting point (200mg/dL). Therefore, by adding a drug that reduces LDL by 50% and another that reduces it by 20%, we will have a final absolute reduction of 60% instead of 70%. The same principle can be applied to PCSK9 inhibitors. In this patient, we can expect an incremental LDL reduction of 60%, so the LDL cholesterol level of 80mg/dL will decrease to 32mg/dL. This is exactly an 84% reduction, 24% more from the baseline value. This is indeed the maximum LDL-lowering capacity according to available drugs.

The efficacy of different drug combinations can be calculated by the formula in the Figure.


Formula to calculate the percentage of low-density lipoprotein lowering efficacy of drug combinations.


Several points should be stressed. The maximum LDL-lowering capacity obtained with a statin plus ezetimibe was 60%. The maximum LDL-lowering capacity when combining the more potent statin plus a PCSK9 inhibitor was 80%. The maximum LDL-lowering capacity using the 3 drugs in combination was 84% (Table).


Theoretical Low-density Lipoprotein Reduction in Percentage Induced by Drugs in Monotherapy or in Combination

Drugs in monotherapy or in combination  Theoretical LDL cholesterol reduction, % 
Low intensity statin  30 
Moderate intensity statin  40 
High intensity statin  50 
Ezetimibe  20 
PCSK9 inhibitor  60 
Low intensity statin+ezetimibe  44 
Moderate intensity statin+ezetimibe  52 
High intensity statin+ezetimibe  60 
Low intensity statin+PCSK9 inhibitor  72 
Moderate intensity statin+PCSK9 inhibitor  76 
High intensity statin+PCSK9 inhibitor  80 
Low intensity statin+ezetimibe+PCSK9 inhibitor  78 
Moderate intensity statin+ezetimibe+PCSK9 inhibitor  80 
High intensity statin+ezetimibe+PCSK9 inhibitor  84 

Low, moderate and high intensity statins are defined according to Stone et al.6

LDL, low-density lipoprotein.

This theoretical exercise has implications for clinical decision-making and should also be taken into account in clinical guidelines.

For example, when statins are used as monotherapy (a maximum LDL lowering effect of 50%), only patients with LDL levels below 140mg/dL will reach secondary prevention targets (LDL<70mg/dL). With a statin plus ezetimibe (maximum LDL lowering capacity of 60%), only patients with LDL below 175mg/dL will reach secondary prevention targets.

With triple therapy (LDL lowering capacity of 84%), almost anyone with LDL levels up to 437mg/dL could achieve secondary prevention LDL targets.

It seems reasonable to adapt clinical guidelines and recommendations to clinical feasibility.


L. Masana receives lecture or advisory fees from Amgen, Sanofi, MSD, Kowa, Recordati, Esteve, Danone, Chiesi; Praxis. N. Plana receives lecture fees from MSD Esteve, and D. Ibarretxe receives lecture fees from MSD.

C.P. Cannon, M.A. Blazing, R.P. Giugliano, A. McCagg, J.A. White, P. Theroux, IMPROVE-IT Investigators, et al.
Ezetimibe added to statin therapy after acute coronary syndromes.
N Engl J Med., 372 (2015), pp. 2387-2397
B.A. Ference, F. Majeed, R. Penumetcha, J.M. Flack, R.D. Brook.
Effect of naturally random allocation to lower low-density lipoprotein cholesterol on the risk of coronary heart disease mediated by polymorphisms in NPC1L1, HMGCR, or both: a 2×2 factorial mendelian randomization study.
J Am Coll Cardiol., 65 (2015), pp. 1552-1561
L. Masana, J. Pedro-Botet, F. Civeira.
IMPROVE-IT clinical implications. Should the “high-intensity cholesterol-lowering therapy” strategy replace the “high-intensity statin therapy”?.
Atherosclerosis., 240 (2015), pp. 161-162
J.G. Robinson, M. Farnier, M. Krempf, J. Bergeron, G. Luc, M. Averna, et al.
ODYSSEY LONG TERM Investigators. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events.
N Engl J Med., 372 (2015), pp. 1489-1499
M.S. Sabatine, R.P. Giugliano, S.D. Wiviott, F.J. Raal, D.J. Blom, J. Robinson, et al.
Open-label Study of Long-term Evaluation against LDL Cholesterol (OSLER) Investigators. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events.
N Engl J Med., 372 (2015), pp. 1500-1509
N.J. Stone, J.G. Robinson, A.H. Lichtenstein, C.N. Bairey Merz, C.B. Blum, R.H. Eckel, et al.
2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
Circulation., 129 (2014), pp. S1-S45
Copyright © 2015. Sociedad Española de Cardiología
Revista Española de Cardiología (English Edition)

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