Revista Española de Cardiología (English Edition) Revista Española de Cardiología (English Edition)
Rev Esp Cardiol. 2016;69:342-3 - Vol. 69 Num.03 DOI: 10.1016/j.rec.2015.11.014

Maximum Low-density Lipoprotein Cholesterol Lowering Capacity Achievable With Drug Combinations. When 50 Plus 20 Equals 60

Lluis Masana a,, Daiana Ibarretxe a, Nuria Plana a

a Unidad de Medicina Vascular y Metabolismo, Hospital Universitario Sant Joan, Universidad Rovira I Virgili, Instituto Investigación Sanitaria Pere Virgili (IISPV), CIBERDEM, Reus, Tarragona, Spain

Article

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 200 mg/dL, a high potency statin will decrease LDL cholesterol by 50% to 100 mg/dL. By adding ezetimibe, we expect a 20% incremental LDL reduction; therefore, LDL concentrations of 100 mg/dL will decrease to 80 mg/dL (20% less). Thus, this patient will have a final reduction of 120 mg/dL, which is a 60% reduction from the starting point (200 mg/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 80 mg/dL will decrease to 32 mg/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.

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 140 mg/dL will reach secondary prevention targets (LDL < 70 mg/dL). With a statin plus ezetimibe (maximum LDL lowering capacity of 60%), only patients with LDL below 175 mg/dL will reach secondary prevention targets.

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

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

CONFLICTS OF INTEREST

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.

Corresponding author: luis.masana@urv.cat

Bibliography

1. Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, et al, IMPROVE-IT Investigators. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387-97.
2. Ference BA, Majeed F, Penumetcha R, Flack JM, Brook RD. 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. 2015;65:1552-61.
3. Masana L, Pedro-Botet J, Civeira F. IMPROVE-IT clinical implications. Should the “high-intensity cholesterol-lowering therapy”strategy replace the “high-intensity statin therapy”?. Atherosclerosis. 2015;240:161-2.
4. Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, et al. ODYSSEY LONG TERM Investigators. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1489-99.
5. Sabatine MS, Giugliano RP, Wiviott SD, Raal FJ, Blom DJ, Robinson J, 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. 2015;372:1500-9.
6. Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, 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. 2014;129(25 Suppl 2):S1-S45.

1885-5857/© 2016 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved

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