ASCVD

atherosclerotic cardiovascular disease

CAC

coronary artery calcium

LDL-C

low-density lipoprotein cholesterol

mAb

monoclonal antibody

PCSK9

proprotein convertase subtilisin/kexin type 9

Cardiovascular disease is the leading cause of death in women in the United States and world-wide. Reducing patients’ lifetime exposure to low-density lipoprotein cholesterol (LDL-C) lowers their risk of atherosclerotic cardiovascular disease (ASCVD), as multiple clinical trials and meta-analyses have shown.1  Every 1.0-mmol/L (38.7-mg/dL) reduction in LDL-C is associated with a 23% relative risk reduction in major ASCVD events.2  Abundant clinical trial evidence has led to statins becoming the cornerstone of LDL-C–lowering therapy.3  Although many patients achieve target LDL-C levels with statins, some patients have a suboptimal response stemming from treatment intolerance, genetic differences, treatment nonadherence, or therapeutic inertia. Since the 2013 cholesterol guidelines were published,4  major advances in nonstatin therapies, including the development and approval of additional agents, have enabled greater LDL-C reduction and expanded treatment options. Clinical trials of more recent nonstatin therapies, including IMPROVE-IT,5  FOURIER,6  ODYSSEY OUTCOMES,7  and CLEAR Outcomes,8  have provided support for the additional benefits nonstatin therapies and LDL-C reduction provide.9 

Nonstatin therapies currently available for reducing LDL-C levels include ezetimibe, bempedoic acid, bile acid– binding resins, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and evinacumab (Table I). Ezetimibe as monotherapy can reduce LDL-C by 18%, and ezetimibe with statins as combination therapy reduces LDL-C by 50% to 70%. Bempedoic acid as monotherapy provides 24% LDL-C reduction. Bile acid–binding resins used in addition to statins provide a 15% to 27% reduction, although there are no outcome data for this combination. Evolocumab and alirocumab (PCSK9 monoclonal antibodies [mAbs]) are highly effective in reducing LDL-C, doing so by about 60%. Inclisiran, a small interfering RNA against PCSK9, provides 48% to 52% LDL-C reduction when combined with a statin. Evinacumab, a mAb infusion targeting ANGPTL3, is used in patients with homozygous familial hypercholesterolemia, for whom it provides 49% LDL-C reduction.

TABLE I.

Nonstatin Therapy Options: LDL-C–Lowering Efficacy

Nonstatin Therapy Options: LDL-C–Lowering Efficacy
Nonstatin Therapy Options: LDL-C–Lowering Efficacy

In high-risk patients, the goal is an LDL-C level below 1.4 mmol/L (55 mg/dL); levels above that warrant the consideration of additional lipid-lowering therapy. These recommendations are based on FOURIER and ODYSSEY OUTCOMES, 2 trials that demonstrated the cardiovascular outcomes benefits of reducing LDL-C levels. Since the 2018 cholesterol guidelines were released,10  PCSK9 inhibitors have become more affordable and therefore are increasingly incorporated into clinical practice, which helps patients achieve these target LDL-C levels. In high-risk patients with clinical ASCVD who require greater LDL-C reduction than a single additional therapy can be expected to achieve, it may be reasonable to consider the simultaneous addition of 2 agents to reduce the patient's risk of recurrent events more rapidly. In such cases, combination therapy with high-intensity or maximally tolerated statin therapy and ezetimibe or maximally tolerated statin therapy with or without ezetimibe and PCSK9 mAbs can be used.4,9 

Subclinical atherosclerosis assessment can be incorporated into practice for risk assessment and treatment. The coronary artery calcium (CAC) score has been widely incorporated into practice to guide lipid-lowering therapy because it is a powerful prognostic indicator of future events. For individuals with a CAC score (also called the Agatston score) of 0 in the absence of diabetes, an LDL-C level of 4.9 mmol/L (190 mg/dL) or higher, a family history of premature coronary heart disease, or active cigarette smoking, it is reasonable to defer statin therapy and reassess CAC in 3 to 5 years while focusing on lifestyle modifications. For individuals with a CAC score of 1 to 99 who are in less than the 75th percentile for their age and sex, moderate-intensity statin therapy is reasonable. In the Multi-Ethnic Study of Atherosclerosis, individuals with a CAC score higher than 100 or who were in at least the 75th percentile had a 10-year incidence rate of hard ASCVD events of more than 7.5%, a data point that supports the initiation of moderate- or high-intensity statin therapy. Titration to high-intensity statin therapy may be considered if the patient achieves less than 30% LDL-C reduction or their LDL-C remains at 2.6 mmol/L (100 mg/dL) or higher. Patients with CAC scores of at least 1,000 who are not on statin therapy have high annual clinical ASCVD event rates (3.3 per 100 person-years). If the patient is already on statin/ezetimibe therapy, addition of a PCSK9 mAb may be considered for LDL-C reduction.

Achieving optimal LDL-C levels is challenging in patients with statin intolerance, a condition that occurs more often in women.10  Since the 2022 Expert Consensus Decision Pathway on nonstatin therapy recommendations was published, CLEAR Outcomes, which enrolled approximately 50% female participants, showed that bempedoic acid effectively reduced LDL-C levels compared with placebo and that it reduced major adverse cardiovascular events.8  The ongoing ORION-4 trial is examining the effects of inclisiran on cardiovascular events in patients with ASCVD. Agents in development and currently undergoing clinical trials include an oral PCSK9 inhibitor and lipoprotein(a)-targeting therapies.

Despite all available therapies, many patients do not achieve optimal LDL-C levels because of changes in guidelines, competing comorbidities and polypharmacy, statin intolerance, cost issues, and treatment nonadherence. Combination therapy with nonstatin agents, medication titration to achieve LDL-C goals, and the close monitoring of LDL-C levels will help provide greater LDL-C reduction and a greater reduction in clinical events.

Open Access: © 2023 The Author(s). Published by The Texas Heart Institute®. This is an Open Access article under the terms of the Creative Commons Attribution-NonCommercial License (CC BY-NC, https://creativecommons.org/licenses/by-nc/4.0/), which permits use and distribution in any medium, provided the original work is properly cited, and the use is noncommercial.

Author Contributions: Mini G. Varughese wrote the original draft of the manuscript. Christie M. Ballantyne was involved in the review, editing, and supervision of the manuscript and its resources.

Conflict of Interest Disclosure: Mini G. Varughese, MD, has no financial relationships to report. Christie M. Ballantyne, MD, has the following financial relationships to report: grant/research support from Abbott Diagnostics; Akcea Therapeutics, Inc; American Diabetes Association; American Heart Association; Amgen, Inc; Arrowhead Pharmaceuticals, Inc; Esperion Therapeutics, Inc; Ionis Pharmaceuticals; Merck & Co, Inc; the National Institutes of Health; NewAmsterdam Pharma; Novartis; Novo Nordisk; Regeneron Pharmaceuticals, Inc; and Roche Diagnostics (all paid to the institution, not the individual) and has received consulting fees from 89bio, Inc; Abbott Diagnostics; Alnylam Pharmaceuticals; Althera Pharmaceuticals; Amarin Corporation plc; Amgen, Inc; Arrowhead Pharmaceuticals, Inc; AstraZeneca; Denka Seiken Co, Ltd; Esperion Therapeutics, Inc; Genentech, Inc; Gilead Sciences, Inc; Illumina, Inc; Ionis Pharmaceuticals; Matinas BioPharma Holdings, Inc; Merck & Co, Inc; NewAmsterdam Pharma; Novartis; Novo Nordisk; Pfizer, Inc; Regeneron Pharmaceuticals, Inc; and Roche Diagnostics.

Funding/Support: None.

Section Editor: Stephanie Coulter, MD.

Meeting Presentation: Presented at the 12th Annual Women's Heart & Vascular Symposium; May 6, 2023; virtual.

1.
Gencer
B
,
Marston
NA
,
Im
K
, et al
Efficacy and safety of lowering LDL cholesterol in older patients: a systematic review and meta-analysis of randomised controlled trials
.
Lancet
.
2020
;
396
(
10263
):
1637
-
1643
.
doi:
2.
Ference
BA
,
Ginsberg
HN
,
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
(
32
):
2459
-
2472
.
doi:
3.
Stone
NJ
,
Robinson
JG
,
Lichtenstein
AH
, et al;
American College of Cardiology/American Heart Association Task Force on Practical Guidelines
.
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
.
J Am Coll Cardiol
.
2014
;
63
(
25 pt B
):
2889
-
2934
.
doi:
4.
Grundy
SM
,
Stone
NJ
,
Bailey
AL
, et al
2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines
.
J Am Coll Cardiol
.
2019
;
73
(
24
):
3168
-
3209
.
doi:
5.
Cannon
CP
,
Blazing
MA
,
Giugliano
RP
, et al;
IMPROVE-IT Investigators
.
Ezetimibe added to statin therapy after acute coronary syndromes
.
N Engl J Med
.
2015
;
372
(
25
):
2387
-
2397
.
doi:
6.
Sabatine
MS
,
Giugliano
RP
,
Keech
AC
, et al;
FOURIER Steering Committee and Investigators
.
Evolocumab and clinical outcomes in patients with cardiovascular disease
.
N Engl J Med
.
2017
;
376
(
18
):
1713
-
1722
.
doi:
7.
Schwartz
GG
,
Steg
PG
,
Szarek
M
, et al;
ODYSSEY OUTCOMES Committees and Investigators
.
Alirocumab and cardiovascular outcomes after acute coronary syndrome
.
N Engl J Med
.
2018
;
379
(
22
):
2097
-
2107
.
doi:
8.
Nissen
SE
,
Lincoff
AM
,
Brennan
D
, et al;
CLEAR Outcomes Investigators
.
Bempedoic acid and cardiovascular outcomes in statin-intolerant patients
.
N Engl J Med
.
2023
;
388
(
15
):
1353
-
1564
.
doi:
9.
Lloyd-Jones
DM
,
Morris
PB
,
Ballantyne
CM
, et al;
Writing Committee
.
2022 ACC Expert Consensus Decision Pathway on the role of nonstatin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report of the American College of Cardiology Solution Set Oversight Committee
.
J Am Coll Cardiol
.
2022
;
80
(
14
):
1366
-
1418
.
doi:
10.
Goldstein
KM
,
Zullig
LL
,
Bastian
LA
,
Bosworth
HB
.
Statin adherence: does gender matter?
Curr Atheroscler Rep
.
2016
;
18
(
11
):
63
.
doi: