In addition to statins, there are several other medications that reduce cholesterol and
can be used either alone or in combination with statins. As with statin therapy, any
decision about a non-statin drug calls for a discussion between patient and doctor to
assess individual risk factors, the benefits and risks of treatment, patient preferences,
and cost if a PCSK9 (proprotein convertase subtilisin–kexin type 9) inhibitor is
The 2018 ACC/AHA guidelines do not recommend routine use of non-statin drugs
for people at borderline or intermediate cardiovascular risk since any additional
benefit is likely to be marginal. If further lowering of LDL-C is warranted for them,
increasing statin dosage is the preferred option.
The 2018 ACC/AHA guidelines advise that those with CVD or are at very high risk,
to use additional non-statin LDL-C lowering medication. Some individuals at high
CVD risk can’t tolerate high-dose statins, and for others, high-dose statins don’t
lower LDL the recommended 50%. If their LDL cholesterol remains ≥70 mg/dl,
the guidelines advise consideration of the addition of ezetimibe to statin therapy.
Ezetimibe (Zetia), is one of a class of lipid-lowering compounds that selectively
inhibits the intestinal absorption of cholesterol. It can lower LDL-C an additional
20%. Like statins, ezetimibe is now available as an inexpensive generic.
Vytorin contains a combination of ezetimibe and simvastatin (a statin). The Improved
Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT)
reported that adding ezetimibe to effective statin therapy in stable patients who experienced
an acute coronary syndrome reduced LDL-C from 70 mg/dl to 54 mg/dl
and reduced risk of atherosclerotic cardiovascular disease outcome at seven years
from 34.7% to 32.7%.
Another approach to inhibiting the intestinal absorption of cholesterol is through the
use of bile acid sequestrants. They are absorptive resins usually taken as a powder
or pill in combination with a statin or niacin. Typically, they lower LDL-C by 10%
If the addition of ezetimibe to a statin doesn’t reduce LDL enough, and LDL-C remains
≥70 mg/dl, the ACC/AHA guidelines suggest that a PCSK9 inhibitor would
be a “reasonable” adjunct. In 2003 it was discovered that gain-of-function mutations
in the gene encoding PCSK9 caused familial hypercholesterolemia. The subsequent
discovery that loss-of-function mutations in PCSK9 cause lower LDL-C
led to the development of monoclonal antibodies that inhibit PCSK9 action and
lower LDL-C and HDL-C.
Two of the monoclonal antibodies in this relatively new
treatment category, evolocumab (Repatha) and alirocumab (Praluent), have been
extensively tested. In 2015, the FDA approved their use by patients as an adjunct
to diet and maximally tolerated statin therapy for the treatment of adults with familial
hypercholesterolemia or clinical atherosclerotic cardiovascular disease, who
require additional lowering of LDL-C.
A trial of evolocumab, injected subcutaneously every two weeks or monthly as an
adjunct to standard lipid-lowering therapy, caused an additional 61% reduction in
LDL-C levels. A similar trial of alirocumab also lowered LDL-C by 61%. A
more recent trial among high-risk patients who were followed for an average of 2.2
years found an average decline in LDL-C of 59%, a decline in HDL-C of 51% and
a decline in triglycerides of 16%. The main study endpoints, cardiovascular death,
myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization,
occurred in 9.8% of evolocumab-treated patients as compared with 11.3% of patients who received a placebo; this corresponded to a 15% risk reduction.
PCSK9 inhibition confers additional cardiovascular benefit beyond that achieved
by usual lipid-lowering treatments, but the gain among the high-risk patients in the
clinical trials is modest, and the cost is steep. Initially provided at about $14,000
per year, to treat 20 million Americans would add up to $280 billion a year and,
“…the cost of this single drug would match the entire cost for all other prescription
pharmaceuticals for all diseases in the United States combined.” Recent price
cuts of about 50% to these drugs may help them to have a role in treating some patients
who do not respond well to other therapies, including those with statin intolerance. Even with 2018 reductions in price, these are expensive drugs, and PCSK9 inhibitors have been approved only for people who have CVD or very high LDL-C.
In February 2020, the FDA approved a new drug, Nexletol (bempedoic acid), an
oral, once-daily, non-statin for LDL-C lowering. Nexletol is indicated as an adjunct
to diet and maximally tolerated statin therapy for the treatment of adults with
familial hypercholesterolemia or established atherosclerotic cardiovascular disease
(ASCVD) who require additional lowering of LDL-C. In studies, Nexletol provided
an average of 18% LDL-C lowering when used with moderate or high-intensity
statins. The effect of Nexletol on the biomarkers of cardiovascular disease suggests
benefits, but this has not yet been demonstrated by clinical trials.
This blog presents opinions and ideas and is intended to provide helpful general information. I am not engaged in rendering advice or services to the individual reader. The ideas, procedures and suggestions in that are presented are not in any way a substitute for the advice and care of the reader’s own physician or other medical professional based on the reader’s own individual conditions, symptoms or concerns. If the reader needs personal medical, health, dietary, exercise or other assistance or advice the reader should consult a physician and/or other qualified health professionals. The author specifically disclaims all responsibility for any injury, damage or loss that the reader may incur as a direct or indirect consequence of following any directions or suggestions given in this blog or participating in any programs described in this blog or in the book, The Building Blocks of Health––How to Optimize Your Health with a Lifestyle Checklist (available in print or downloaded at Amazon, Apple, Barnes and Noble and elsewhere). Copyright 2021 by J. Joseph Speidel