Dr. Baum (00:00):
Hello. My name is Seth Baum. I'm a preventive cardiologist and a clinical lipidologist, and I'm here today to do a brief recap
of a great symposium that we had done previously with Drs. Pam Taub, Pam Morris, and Jamie Underberg. It was a great session,
part of the second annual going back to the heart of cardiology. And it was specifically about adjunctive lipid modifying
therapy explored.
Dr. Baum (00:29):
We started our discussion with an overarching view of the burden of cardiovascular disease and what LDL does in the context
of cardiovascular disease. And this is foundational, frankly, for our approach, and I think we should emphasize now, even
in this brief recap.
Dr. Baum (00:48):
First, it's important to know that cardiovascular disease remains the leading cause of death in the United States. It has
been the leading cause of death for decades. It continues to be the leading cause of death. We thought we were making headway,
but in fact the tides have turned, and now we're going in the wrong direction.
Dr. Baum (01:04):
We also know that LDL causes cardiovascular disease. We used to call this the LDL hypothesis. We now call it the LDL fact.
We've done enough studies on multiple levels to be able to understand that LDL in fact does cause atherosclerosis, LDL does
cause heart attack, stroke, and cardiovascular death.
Dr. Baum (01:26):
Fortunately, we also know that lowering LDL reduces the cardiovascular risk I just cited. If we lower LDL, we've learned that
for every 38 and a half milligrams per deciliter, that we lower LDL cholesterol, we reduce cardiovascular risk by 21%. And
this is a linear relationship.
Dr. Baum (01:48):
What about our therapeutics? Well, we have therapeutics. We have a tremendous number of therapeutics in our lipid lowering
therapy armamentarium. They are available to us, yet most patients continue to have high risk levels of LDL, even the very
high risk patients. Why is that? It's because we're not using the therapeutics as we should be using them.
Dr. Baum (02:10):
We then showed that deaths attributable to cardiovascular disease between 1910 and 2015 rose, and then started declining in
the 1970 to 2015 time. But as I stated earlier, these deaths are now rising again, so we're in a bit of trouble with regard
to that.
Dr. Baum (02:32):
With regard to the breakdown of deaths attributable to cardiovascular disease, coronary heart disease remains the leader at
44%, and stroke is 17%.
Dr. Baum (02:43):
We then spoke about FH, and we spoke about ASCVD, and we differentiated them a bit. FH, a very important disease, genetic
disorder. And it is far more common than we used to think. As many as one in 200 or 250 people has familial hypercholesterolemia.
In 2013 though, we found through Nordestgaard's paper that fewer than 1% of these patients in the US had been identified.
Fewer than 1% of this very high risk patient population. Now that has improved over the years because of the ICD-10 codes,
but it is still very, very low.
Dr. Baum (03:24):
With regard simply to ASCVD, not considering FH, in the United States someone suffers an MI or a stroke every 40 seconds.
That is quite frequent. Almost 20% of these patients who have had an MI will have another cardiovascular event within a year.
What that highlights is the very, very important year that follows the acute coronary syndrome, with regard to the fact that
it's a time of urgency, we need to approach these patients urgently, and carefully, and aggressively lower their LDL to reduce
the risk of another event.
Dr. Baum (03:59):
[inaudible 00:03:59] demonstrated that among the nine modifiable risk factors in MI in 52 countries, lipids is overwhelmingly
the most important one. So from a population attributable risk standpoint, if we lower lipids, and that means lower LDL, we
get the most bang for our buck, we decrease cardiovascular event rates the most.
Dr. Baum (04:20):
We looked at registry data to discern lipid lowering therapy information. And we started with FH, and then moved on to ASCVD.
When we look at FH, we review the CASCADE FH Registry network. Now CASCADE FH was started by the FH Foundation about eight
or nine years ago. They're now 40 sites in the nation. And we've gleaned quite a lot from the papers that have been published
as output from all of the research done in this really wonderful registry network.
Dr. Baum (04:55):
We saw that even though the AAP/ACC/AHA have guidelines stipulating that high risk children should have lipids checked at
two years, all children at nine to 11 years, and everyone at 17 to 21 years, this is not in fact happening. And as a consequence,
in the FH patient, remember this a very high risk patient with a very high LDL level, the statins were not initiated till
age 44 on average, and the FH diagnosis was not made until age 48. What this does is it diminishes an opportunity for us to
intervene and to decrease the extraordinarily high risk for atherosclerotic cardiovascular events that these patients have.
In fact, FH patients have a higher risk for coronary artery disease at any age. Whether it's less than 18 or greater than
65, it's always higher. Their burden of LDL is extraordinary, and even starts in utero. They are consistently and constantly
bathed in high LDL, and it is our obligation to identify them first, and then to treat them appropriately.
Dr. Baum (06:08):
We then moved onto ASCVD and looked at some registry data, turning first to the NCDR PINNACLE Registry, and this demonstrated
that among all groups of patients, from the lowest risk to the very highest risk, we under treat them with lipid lowering
therapy. And if we look at the one million plus patients with confirmed ASCVD, this very high risk patient population, nearly
30% were not on any lipid lowering therapy.
Dr. Baum (06:37):
The GOULD Registry looked at LDL treatment patterns over time in about 5,000 patients at 119 US centers between 2016 and 2018.
There were three cohorts. One was those taking PCSK9 inhibitors, and the two others not taking PCSK9 inhibitors had baseline
LDLs 70 to 99, or greater than 100. These patients were then looked at over time, and remarkably that even in the face of
ASCVD, only 17% had lipid lowering therapy intensification after two years. Remember, these are pretty good sites. These are
sites that were chosen for the GOULD Registry, and yet very few of these patients had lipid lowering therapy intensification
after two years. As a consequence, two thirds of the patients had an LDL over 70. Remember that our current guidelines, which
I'll get to in a second, stipulate that LDL in this very high risk patient population should be under 70. Thus, we clearly
need to do more here.
Dr. Baum (07:36):
We then looked at insurance data to inform us about statin adherence. And we found that even in patients who had had a prior
MI, 57% are not fully adherent to therapy after six months, only six months after an MI. Remember that one year post MI is
a 20% incidence of another cardiovascular event. There's an urgency in that year to lower LDL, and yet 57% of these patients
are not fully adherent six months after an MI.
Dr. Baum (08:07):
We saw also when we look at proportion of days covered that the lower or the fewer number of days that patients were covered
by the payers for their medicine, the higher the risk of an event. And that obviously stands to reason, if they're not taking
their medicine and their LDL is not treated, they're going to have more events. So adherence is very important. Getting access
to the medicine is very important.
Dr. Baum (08:34):
We looked at several aspects of promoting adherence to lipid lowering therapy. How can we do that? Use reminder systems, intensify
patient care by engaging others, pharmacists, nurse, team-based interventions, the root of the medicine, simplifying the drug
regimen. All these efforts can pay off.
Dr. Baum (08:51):
We looked at a study done by Myers et al, and I was fortunate enough to be part of this study. It was very interesting, informative,
and frankly, disturbing. And it was published in Cardiovascular Quality and Outcomes. The title was Effective Access to Prescribed
PCSK9 Inhibitors on Cardiovascular Outcomes. And what we concluded was that individuals who were either rejected or abandoned,
meaning they got the prescription but it was too expensive for them to continue, in both of those cohorts, they had an increased
risk of cardiovascular events compared with those in the paid cohort. Rejection, abandonment disparities related to PCSK9
inhibitor prescriptions were definitely related to higher cardiovascular outcome rates. In other words, if you don't get the
medicine, if you don't take the medicine, there's a greater chance you're going to have a heart attack, stroke, or cardiovascular
death.
Dr. Baum (09:42):
So why do we focus so much on LDL? How can we best achieve our LDL reduction goals? Well, you've seen while we focus on it
so much, but we then looked briefly at the cholesterol treatment trial as collaboration, again to reinforce that there's this
linear relationship between LDL and cardiovascular events, such that for every 38 and a half milligrams per deciliter we lower
LDL, we reduce risk by 21 or 22%.
Dr. Baum (10:09):
But although statins are the foundation of our lipid lowering therapy, they are not always the answer. Some people can't tolerate
them. Some people don't have as much of a benefit from them, from a lipid lowering therapy standpoint. Still, remember they
are the foundation.
Dr. Baum (10:31):
We then went on to look at lipid lowering therapy or cholesterol guidelines. And we looked at and compared the US Multi-Society
guidelines and the European cholesterol guidelines. They were separated by only about nine months, AHA, CC and Multi-Society
guidelines being published in 2018, European guidelines in 2019. Both were revised to reflect newer evidence in lipid management
for ASCVD risk reduction. Both emphasized LDL cholesterol as the primary target of therapy, with the concept of LDL lower
is better. So the lower LDL is better concept though, is really more heavily emphasized in Europe in a number of ways. We
here in the US do understand that, and do state that. It's perhaps more aggressive in the European guidelines. Both guidelines
recommend assessment of risk in both primary and secondary prevention, but there are some substantive differences.
Dr. Baum (11:30):
There still is a commonality here though, which is we treat according to risk. And we see that the absolute number of events
avoided are impacted by baseline risk. The higher the risk, the more events we can avoid, both vascular deaths and major vascular
events.
Dr. Baum (11:51):
We looked at risk assessment in primary prevention using different scoring systems. Here in the US, the pooled cohort equation,
and in Europe, the score systems. They're both tenure systems. They both have their flaws, their benefits too, or their advantages.
But because of their inadequacies, in a sense, risk enhancers or risk modifiers should be considered for further refinement
or reclassification. And we looked at... In the US, we have ASCVD risk enhancers like metabolic syndrome, chronic kidney disease,
persistently elevated triglycerides, CRP, Lp(a), et cetera. In Europe, there are risk modifiers, such as social deprivation,
physical inactivity, major psychiatric disorders. And then also chronic kidney disease, non-alcohol fatty liver disease, Lp(a),
et cetera. There are a number of them. The key point here though, is we need to know them, we need to think about them, we
need to use them, because this should not be a simplistic calculus. We need to look at each individual patient as a unique
individual, and really be able to assess risk, and therefore provide the best therapy available for that particular patient.
Dr. Baum (13:01):
Therapeutic recommendations. Statin therapy, again, is foundational for both. In the US, we use what's called a threshold.
Let's say for the very high risk patient, the threshold is 70, where if a LDL is 70 or greater, it triggers a signal saying,
"Eh, we need to do more." In Europe, there's really an absolute number that we're directed to get our LDLs under. And then
those numbers are actually more aggressive, 55 in the very high risk patient. The highest risk patient, less than 40. Those
are people who've had more than one event within a couple of years.
Dr. Baum (13:37):
Both systems recommend lifestyle modifications as a foundation, a high intensity statin, or modern intensity statin based
on risk. And we also have to recognize that other agents such as the ezetimibe or PCSK9 inhibitors are stipulated.
Dr. Baum (13:54):
I think it's also important to note that what we're doing here in both guidelines is lowering LDL. That is the target. So
when there are other therapeutics that have been approved that are available to lower LDL, we should use them as well. Bempedoic
acid, for example, is one of those therapeutics.
Dr. Baum (14:11):
We then went on to look a little more specifically at the very high risk definition in the US and how we would get to these
other non-statin therapeutics. We also discussed this from a European standpoint. Again, both really getting to the same place,
get the LDL down.
Dr. Baum (14:31):
When we summarized the guideline comparisons, we recognized that the recommendation were based on similar concepts and principles,
and in fact, were in broad agreement with one another. There were differences though in classification of risk groups, thresholds
versus goals or targets, et cetera. But again, the bottom line is get the LDL down, use every therapeutic that is necessary,
in a strategic fashion, in order to achieve your goal or get beyond a particular threshold.
Dr. Baum (15:02):
Dr. Taub then went on to discuss new lipid lowering therapies in their place, in our management of these patients. She discussed
the PCSK9 inhibitors, bempedoic acid, and inclisiran, and reviewed the mechanism of action of non-statin agents, looking at
HMG coenzyme A reductase inhibitors, the statins, and then went on to talk about ATP citrate lyase, for example, in bempedoic
acid, Niemann-Pick C1-Like 1 transporter in the use of, or with ezetimibe, and then the PCSK9 inhibitors. There are two PCSK9
inhibitors on the market, evolocumab and alirocumab. And she went through the indications for these agents. I think it's important
to note that the indication is simply for LDL cholesterol reduction in patients who require for the reduction of LDL. We don't
use these meds as first line therapy though for cost reasons, really. And we use statins instead because of their history,
their studies, and the cost. But we should know that these meds are available. But they're also indicated in heterozygous
familial hypercholesterolemia, in homozygous familial hypercholesterolemia, and to lower the risk of a major cardiovascular
event, such as MI, stroke, or coronary revas.
Dr. Baum (16:21):
When Dr. Taub discussed bempedoic acid and the [inaudible 00:16:25] action, she highlighted the fact that bempedoic acid targets
ATP citrate lyase, which is an enzyme upstream of HMG coenzyme A reductase, the enzyme that the statin utilizes or blocks.
And she emphasized also that the isoenzyme, ACS VL1, which converts bempedoic acid into its active drug, is not present in
skeletal muscle. It is in liver. So this drug, bempedoic acid, is activated in skeletal muscle. It's not there to cause skeletal
muscle problems.
Dr. Baum (16:58):
She did a very nice overview of the phase three trials, the CLEAR trials, CLEAR Harmony, CLEAR Wisdom, CLEAR Tranquility,
CLEAR Serenity, all these different trials that looked at HtFH, that looked at ASCVD, that looked at patients with statin
intolerance, and demonstrated a robust reduction in LDL cholesterol, especially when bempedoic acid plus ezetimibe was utilized.
She highlighted the fact that the CLEAR-outcomes trial is ongoing. This is a cardiovascular outcomes trial in patients either
with or at high risk for cardiovascular disease who are statin intolerant. It's an ongoing trial with nearly 13,000 patients
enrolled, and we all are chomping at the bit, can't wait to see the results of this study.
Dr. Baum (17:46):
Finally, she spoke briefly about inclisiran, which although it has not yet been FDA approved, we are hopeful that it will
be FDA approved in the near future, mean reduction LDL 50 to maybe even up to 60%. And it is a small interfering RNA for PCSK9,
nice safety profile, as I mentioned, good efficacy, probably most importantly, twice a year dosing. So if and when this drug
is approved, it really will introduce a genuine paradigm shift in how we approach lipid lowering therapy, and in cardiovascular
disease prevention, frankly.
Dr. Baum (18:23):
We finally ended with couple of cases that were beautiful cases. One on ASCVD by Dr. Pam Morris, and one on heterozygous FH
by Dr. Jamie Underberg, an expert in FH. They were great cases. And that was our program. So I hope you enjoyed this recap.
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