Article Type : Short commentary
Authors : Bando H
Keywords : Inclisrian statin dyslipidemia; LDL-C; Atherosclerotic cardiovascular disease (ASCVD)
Up-to-date pharmacological topics for inclisiran and statin
for dyslipidemia are described. The efficacy of inclisiran has been reported
for reduction of LDL-C values. Inclisiran has been involved in gene silencing,
which brings selective inhibition of a protein by targeting its mRNA. For RCTs
of inclisiran, ORION 10/11 studies were conducted, where inclisiran and control
groups were followed 1.5 years. LDL-C reduced in 53.8%/49.2%. RCTs of 19
meta-analyses showed whether statins will prolong life and its degree. As a
result, statin can delay onset of events compared to placebo for cardiovascular
death 9.3 days, myocardial infarction 18 days, and stroke 6.1 days.
In actual clinical
practice, metabolic syndrome is increasing worldwide. The underlying problem
would be the presence of dyslipidemia. Concerning dyslipidemia, current topics
can include inclisiran and other agents [1,2]. This paper introduces the latest
reports and developments on dyslipidemia. As a new agent for dyslipidemia, the
efficacy of inclisiran has been reported. It is used for patients associated
with high LDL-C. For large studies, the ORION-10 and the ORION-11 tests were
conducted. The former was intended for patients with atherosclerotic
cardiovascular disease (ASCVD). The latter is intended for patients with ASCVD
or at risk comparable to ASCVD. Both protocols were RCTs comparing two groups
of inclisiran (284 mg) and placebo for 1.5 years. Regarding the protocols,
inclisiran was given by subcutaneous injection on the 1st and 90th days, and
every 6 months thereafter. For the evaluation, the changed ratio in LDL-C was
measured as the primary outcome. As a result, the LDL-C after 1.5 years was found
to decrease by 53.8% in the former and 49.2% in the latter. All data were
significantly different from placebo (p <0.001). In the light of adverse
effects, some pain and swelling at the injection site were more common in the
inclisiran group [2].
Inclisiran has been
involved in gene silencing, which brings selective inhibition of a protein by
targeting its mRNA [1]. As to the safety of inclisiran, pre-specified analysis
of ORION-1 was conducted, especially from hematological parameters [3].
Inclisiran is a siRNAs (small interfering RNA molecules) directed against
PCSK9. It is indeed that its benefit is with large efficacy for lowering LDL-C,
but weak point is expensive. Then, its use has been often discontinued, that
may leave the patients keeping higher cardiovascular risk [4]. Inclisiran is an
interfering RNA targeting PCSK9 (proprotein convertase subtilisin-kexin type
9). As to inclisiran, pharmacodynamic property was investigated for subjects
with renal impairment and normal function [5]. As a result, both groups showed
similar data, indicating no necessity of dose adjustments for renal function.
Inclisiran has an unknown effect on cardiovascular prognosis at this stage [2].
Therefore, we look forward to the accumulation of evidence in the future.
Conventionally, n-3
unsaturated fatty acids have been reported to have benefits for the
cardiovascular system. Several systematic review meta-analyses in n-3 USFA have
been reported. A recent review included a double-blind RCT 17 study (n=83,617)
with a follow-up period of ?1 year. When the dose of n-3 unsaturated fatty
acids became higher, the benefits became greater. In other words, the risk
reduction of cardiovascular disease was not revealed at 1 g or less per day.
Second, at 2 g daily, the rate of cardiac death was significantly reduced, with
a relative risk (RR) 0.55. Furthermore, when 3 g or more was administered
daily, a significant reduction in risk was observed. Regarding the detailed RR,
the remarkable effects were shown: cardiac death 0.82, sudden death 0.70, and
stroke 0.74 [6].
For elderly people with
frailty, a systematic review was conducted on the cardiovascular prognosis of
statins. Of these, 6 cohort studies were included and RCTs meeting the
acceptance criteria were not included. In addition, the results for
cardiovascular events and the effects on primary prevention were not included.
This included a study of the secondary prophylaxis population, which showed a
reduced risk of death as HR 0.28 [7].
There is an ASPREE
(Aspirin in Reducing Events in the Elderly) study that investigated the
efficacy of statins in healthy elderly people. The results of this secondary
analysis have recently been reported. ASPREE has been an RCT that examines the
effect of aspirin on healthy life expectancy. The subjects were 19,114 aged 65
and over, of which 18,096 aged 70 and over (median 74.2 years, 56.0% female)
were extracted in the secondary analysis. Among them, two groups were compared,
between who were taking statins at the beginning of the study and those who
were not. The investigated factors were survival condition without disability
(combined outcomes of total mortality, dementia, and persistent physical
dysfunction). Follow-up of 4.7 years in median found no significant difference
between statin use and unimpaired survival as Hazard ratio (HR) 0.92. Thus,
secondary analysis of RCTs showed little benefit of statins on healthy life
expectancy [8]. Judging from this, the effects of statins on the general
elderly will not necessarily be significant. There is a cohort study
investigating statin treatment in the elderly for primary prevention of
cardiovascular disease. Among them, the subjects were 326 thousand US veterans
aged 75 and over. The average age was 81.1 years, 97% male and 91% Caucasian,
with an average follow-up of 6.8 years. As a result, cardiovascular deaths per
1000 man-years were 22.6 for statin users and 25.7 for non-users. Corrected by
propensity score matching, HR was 0.75 total mortality, 0.80 cardiovascular
mortality, and 0.92 arteriosclerotic cardiovascular event. All of them were
found to be significantly lower in statin users [9]. The results of RCTs
analyzed the extent to which statins could prolong life, associated with the
publication of 19 meta-analysis. The degree of delayed onset of events compared
to placebo showed cardiovascular death 9.3 days, non-cardiovascular death 1.5
days, myocardial infarction 18 days, and for stroke 6.1 days [10].
Various factors were
investigated that affect cardiac statins for medication adherence. A review was
conducted in a systematic review associated with the summary reported. From
detail examination of nine reviews, factors with positive effects on medication
adherence were found to be high social/economic status, high education level,
and age of middle-aged people. On the other hand, there were many factors
related to the decrease in medication adherence. They include older, younger,
female subjects, lower economic and social levels, higher out-of-pocket costs,
new statin users as medication history, dosage/dose complexity, and experience
of reverse effects. Psychologically, distrust of medical care and lack of
realization of clinical effects were included, and lifestyle habits included
daily drinking and smoking [11].
Conflicts of
Interest
The author declares that
they have no conflicts of interest.
Funding
The author does not have
any funding concerning our medical research.