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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 31, No 5, September/October 2020
250
AFRICA
The most current South African dyslipidaemia guidelines
recommend ezetimibe as a second-line treatment in combination
with a statin when the LDL-C target is not achieved with the
highest tolerated statin dose, when there is intolerance to statins
or when there is a contra-indication to a statin.
18
However, the
guidelines in place at the time of the study was conducted did
not strongly endorse ezetimibe, as no cardiovascular outcome
evidence was available for ezetimibe at the time the guidelines
were compiled.
19
Lack of cardiovascular outcome data may have
dissuaded some practitioners from prescribing ezetimibe.
Although one would expect a greater proportion of study
participants receiving ezetimibe, especially when added to the
highest possible statin dose, to reach LDL-C target, this was
not the case. This finding is not unexpected as the authors
frequently observe in clinical practice that clinicians are more
likely to prescribe ezetimibe to patients who were far from
their LDL-C goal. We have also noted that many funders in
South Africa will not reimburse ezetimibe if patients are close
to target. The use of ezetimibe may well increase as single-
pill combination tablets of ezetimibe with a potent statin
(atorvastatin or rosuvastatin) become available in South Africa,
and especially if these combination tablets are less costly than
prescribing two individual medications.
In our modelling analysis, we evaluated the impact of four
different treatment strategies in bringing patients to goal.
Because doubling the dose of a statin on average only decreases
LDL-C level by a further 6%, the statin maximisation strategy
was able to bring only 18% of those not at goal to goal. Adding
ezetimibe following statin maximisation would allow 34% of
patients previously not at goal to achieve goal. Because PCSK9
inhibitors reduce LDL-C level on average by about 60% when
added to statin therapy, the addition of a PCSK9 inhibitor to
a statin would allow over 90% of patients to reach goal. Most
patients receiving a PCSK9 inhibitor would be able to reach goal
without a statin dose increase or the addition of ezetimibe.
A simulation of various lipid-lowering strategies in American
patients with atherosclerotic cardiovascular disease using
data from a large administrative database showed that statin
intensification would bring about 67.3% of patients to an
LDL-C target of 1.8 mmol/l, while approximately 14% of
patients would require a PCSK9 inhibitor.
20
In our cohort, many
more patients would require PCSK9 inhibitors to reach target as
we selected a population that was already receiving the maximal
tolerated statin dose and specifically included patients with FH.
As PCSK9 inhibitors are costly monoclonal antibodies, access to
these drugs will be limited once they are commercially available
in South Africa.
The 2018 update of the South African dyslipidaemia
guidelines recommends considering PCSK9 inhibitor therapy
in three groups of patients: first, in patients with atherosclerotic
cardiovascular disease (coronary artery disease, symptomatic
peripheral artery disease, ischaemic stroke) at very high risk
who have substantially elevated LDL-C levels despite maximally
tolerated statin with or without ezetimibe therapy;
18
second, in
patients with FH without clinically diagnosed atherosclerotic
cardiovascular disease, at high or very high cardiovascular risk,
and with substantially elevated LDL-C levels despite maximally
tolerated statin plus ezetimibe therapy;
18
last, in patients with
atherosclerotic cardiovascular disease and at very high risk
who do not tolerate appropriate doses of at least three statins
and who have elevated LDL-C levels despite alternative lipid-
lowering therapies, such as ezetimibe.
18
Initial priority will need
to be given to those patients with the highest baseline risk and
LDL-C level in whom the number needed to treat will be the
lowest.
Limitations
Potential study sites were conveniently sampled and patients
attending these sites may not be fully representative of the
spectrum of South African patients with dyslipidaemia. Only
one study site was in the public sector and this site was based
at a tertiary-level teaching hospital. Public sector patients are
therefore not adequately represented in this study.
We were not able to objectively assess adherence to lipid-
lowering therapy and incomplete adherence may well have been
a contributing factor in some patients not at goal. We were
unable to describe the specific statin dose for 23 patients because
the information was not collected in the case report forms. This
was an error that we detected after completion of the study and
logistical issues precluded us from obtaining missing information
from sites. In our opinion it is improbable that this would make
a material difference to the results, discussion and conclusion of
this study.
For our modelling analysis, we made several assumptions,
including that patients will adhere to the prescribed therapy
perfectly and that it will be possible to up-titrate all patients to
the maximum statin dose. Because responses to lipid-lowering
therapies may be variable, some patients may show larger or
smaller decreases in LDL-C level at the various stages of our
titration algorithm, but in a large population we would expect
the average response to be close to previously published values.
Incomplete adherence would reduce the number of patients
reaching target at the various steps of our titration algorithm, as
would an inability to titrate all patients to the maximum statin
dose.
Conclusion
The majority of study participants were not at LDL-C goal
despite maximum-tolerated statin with or without ezetimibe
therapy, highlighting the importance of further treatment
intensification in this high-risk population. Currently PCSK9
inhibitors, in combination with statin, is the most effective
therapeutic strategy to reach LDL-C goals, but because of the
anticipated high cost of the drug, access will be limited in South
Africa. Despite the under-usage of ezetimibe in this study, the
addition of ezetimibe to existing maximum-tolerated statin
would result in a larger proportion of the study population
reaching target LDL-C goals, therefore contributing to a greater
reduction in atherosclerotic cardiovascular disease.
We thank the patients and investigators for their contributions.
PN, AvT and MGM are employees of Sanofi. PN, AvT and MGM do
not own stocks in Sanofi or Regeneron. Sanofi manufactures and markets
lipid-lowering therapies. Sanofi and Regeneron manufacture and market a
PCSK9 inhibitor.
Prof Dirk Jacobus Blom has received honoraria for lectures, advisory
board payments from Sanofi and Amgen and institutional payment for clini-
cal trials from Sanofi and Amgen. Prof Frederick Johan Raal has received