Toda we will cover the topic of dyslipidaemias.

You will the find the file on the Moodle platform, I have organised the file in this
way, first we will talk about drugs and classes of drugs, I ask for your attention
for approximately half an hour. Then we discuss the risk benefit of statins
because it is a very important topic for pharmacoepidemiology, a large number of
people are treated, there is a significant cost for the national health system and
as we will see considering the NNT and NNH will give you an idea of the net
benefit of the general population. So, first part pharmacology, second part
pharmacoepidemiology.
Slide 3
Lets starts with very simple concepts, dyslipidaemia, hyperlipidaemia are
modifiable risk factors, and as you can see this is the NEJM 1995, death rate for
ischaemic heart disease goes up and serum cholesterol goes up. So, there is a
good reason to keep cholesterol under control.
Slide 4
Just a brief reminder, cholesterol is mainly transported by LDL and HDL mainly.
The VLDL, LDL is the atherogenic transport from the live to the arterial wall and
HDL is the so cold antiatherogenic transport, HDL is the so-called good
cholesterol. LDL is the bad cholesterol, the one that we want to decrease, HDL is
the one if possible, we aim at increasing. The thing is the there are many ways to
reduce LDL cholesterol, the way to increase HDL cholesterol have not been so
successful so far as we shall see the drugs that have substantially failed.
Slide 5
So this is a summary of drugs effects on plasma lipids. Only some of this drugs
are included in the top 100 drug list specifically statins, that is why I
concentrated most of this lesson in statins but of course giving you a wider view
of the class, I will also mention Resins, in particular Colerestiramine, fibrates and
nicotinic acid. All these drugs are approved for use, they are on the market and
we should mention them and it’s a good idea to have a broader view of the top.
(From the graph) You see the drug have different effects on the cholesterol and
triglycerides. Statins acts mostly on cholesterol; fibrates in particular mostly act
on triglycerides. So, it possible, theoretically to make this statement at the
beginning, to combine statins with fibrates because they have complement
action, the thing is that both statins and fibrates can damage the skeletal muscle,
they can induce myopathy. So, in selected circumstances, it is possible to
associate statins and fibrates, but you have to be very careful about potential
side effects, specifically myopathy. I also highted here the effects that fibrates
have on HDL cholesterol, this is a second effect on HDL cholesterol. This is a
secondary effect of fibrates and we mention this here because apart from
fibrates, the other drugs that have been developed to increase specifically HDL,
were actually used in experimental studies and clinical studies but they were not
marketed because they were unsuccessful because of side effects.

Slide 6
Lets start with a brief review of statins, (these are structures of statins) of course
I don’t care about the chemistry but I show you these structures of you see the
closed ring, the lactone ring, which has a very good resemblance with mevalonic
acid,
Slide 7,
The key point to remember is that all statins have a mechanism of action, were
they are able to block the endogenous, the liver synthesis of cholesterol. This is
their main mechanism of action. And as a consequence of this blockage of
cholesterol synthesis in the liver (continues below)
Slide 8
this is what happens without a drug (on the left) and with a statin (on the right) in
the liver. You see that in the liver, there is synthesis of cholesterol from acetate,
and HMG- coA reductase is the key enzyme, the rate limiting enzyme of this
cascade. Of course, cholesterol has an inhibitory effect on LDL uptake from the
liver cells. When you give a statin, the statin blocks this enzyme, there is much
less cholesterol, much less inhibition and as you can see, a lot more LDL is taken
up from the outside. And so, that why, LDL and cholesterol is reduced by statins.
This is he primary mechanism of action, enzyme inhibition, so remember for
instance, beta blockers act on a receptor, statins act on an enzyme, so they take
some time to act. Have you an idea of how long it takes for statins to act. Is it 2
days, 3 weeks, 2 months, what is your opinion? 3 weeks is a good guess because
when you start a statin, when you prescribe a statin you usually check, the blood
plasma cholesterol levels after a month. That’s a good time to check for
effectiveness. Remember it acts on an enzyme, so the effect is not immediate.
Slide 9
The effect of statins is that they have some other additional effects, these are
complimentary effects of statins that are believed to facilitate plaque
stabilization. I would say tht these are secondary effects, there is good evidence,
experimental evidence in experimental models that suggest that statins can also
good SMC function in the vessels, they can inhibit macrophage activation but
these are of course all secondary effects, they are of course beneficial but I
wouldn’t insist on them because the main mechanism is the one that I just
illustrated here (slide 8)
Slide 10
The other point is the different potency of statins. For perhaps at the 3 rd year, I
don’t want to bother you with selection of the best statin depending on the
condition of the patient but upon looking at this graph, which is the most potent
statin according to this graph? Rosuvastatin is the most potent.
So, when you fail to reach your target with for instance Simvastatin or
pravastatin, you can consider, the high potency statins. This is all about
pharmacodynamics.
Slide 11,
Now a brief mention about the pharmacokinetics. As we discussed in the general
pharmacology lessons, statins are usually absorbed by the intestines, they reach
the liver and they are metabolized by these enzymes (see slide) in the liver but
also in the gut. Most of the statins undergo major metabolisms by these
enzymes, especially CYP3A4 both in the liver and in the gut. And there are
transporters in controlling the uptake of statins in the liver.

Slide 12
To make things as simple as possible, I would just say most statins especially
Lovastatin, Atorvastatin and simvastatin are largely metabolized by CYP3A4, the
only statin that is not significantly metabolised by the liver and this can be useful
in specific patients is pravastatin. So major liver metabolism for all statins except
pravastatin. The other thing that most of these statins are given once daily
because as we said the effect is not immediate, it may take some time, the effect
is not strictly related to the plasma levels, and that is why they are given with or
without depending on the compound and that is why its important to take a look
at the SPC for directions on how best the drugs should be taken, in the evening,
at bed time, anytime or with or without food. But most importantly drug
metabolism by the liver.
Slide 13
Another point that I wanted to make, is the basics of the pharmacokinetics and
pharmacodynamics of statins, is the drugs that can influence the so-called good
cholesterol, HDL. As we said, these class of drugs that was developed in the past
15-20 years was actually very unsuccessful. None of these drugs actually entered
market. They were actually withdrawn before ending the clinical trials.
Slide 14 - 15
What have we learned in this lesson? That these drugs were very good at
increasing HDL cholesterol. But they caused a change in systolic blood pressure.
You see torcetrapib which was a drug very good at increasing HDL cholesterol, so
theoretically a patient treated with a statin decreasing LDL cholesterol and with
torcetrapib, a drug increasing HDL cholesterol would achieve better effect. The
thing is that, for a reason that implies secretion of aldosterone, I don’t want to
get into details, this drug can cause hypertension. So, it is not a good idea to
combine these classes of drug because of this secondary effect. So, this type of
drug is a good example of a drug that is effective on a secondary end point,
increase HDL cholesterol but it fails on another point decreasing cardiovascular
events. Torcetrapib failed because it had no effect on the on the heart clinical
endpoints, we require from these agents but was good on the secondary,
surrogate marker markers we consider efficacy.
Slide 16
The only class of drugs that has some effect on HDL cholesterol is fibrates. This
drug is not included in the Top 100 drug list but we mention them because these
fibrates can be used in patients with hypertriglyceridemia. But they enhance the
fatty acid oxidation in the liver and the muscle. And so, they reduce the rate of
lipid genesis in the liver and in consequence they reduce the VDL. As you see (on
the slide) they reduce VLDL and so indirectly increase HDL.
Slide 17
This is a closer detail of how the fibrates act, they act on a system called
peroxisome proliferator activator alpha but this is a molecular detail and I would
not insist on it apart from the fact that it can be associated with statins and this
case it must be very carefully monitored.
Slide 18
Another drug, I only mention this is because it’s a drug on a market. Ezetimibe
has a very simple mode of action, it reduced cholesterol absorption from the
intestine, so it acts on the absorption site.
Slide 19
Finally, another drug, Colestyramine, if you remember the resins. Resins is a very
big molecule, that is given orally up to 24 grams a day. Colestyramine is a resin
that binds bile acids. By binding the bile acids, there is less enterohepatic
circulation of bile acids and this of course causes cholesterol depletion.
Slide 20
This is in more detail pharmacodynamics of Colestyramine, with the drug and
without the drug. You see that the effect is very similar to that we see of statin, a
reduction of LDL cholesterol. And as a matter of fact, Colestyramine can be
associated with statins when statins do not reach the target.
Slide 21
To conclude the drugs that are available on the market, in particular these new
drugs are only prescribed by the specialist. These are monoclonal antibodies that
can be used when you do not reach that target with statins and the other drugs I
have mentioned. While as the drugs I have mentioned so far are given orally,
these are injected, these are monoclonal antibodies, these are very toxic drugs.
These are names I have just mentioned just to give you a name (alirocumab,
evolocumab). There important thing with these drugs that have been just
approved in the past 5 years. It is the PSC-k9 targeted monoclonal antibodies.
How do they work?
Slide 22
They work by decreasing the degradation of LDL receptors on liver cells. The
monoclonal antibodies bind psck9. Psck9 is the mediator of LDL receptor
turnover. So, when you give these antibodies you decrease the turnover of LDL
receptors. That’s the very elegant mechanism that explains the action of this
drug.
Slide 23
Finally, they are other drug under development, like antisense oligo nucleotides,
but actually these are drugs for the future used by specialists so I would not insist
on them for 3rd year, your purposes.

Slide 24
So, we have just briefly reviewed all classes of drugs, lets now just focus on the
risk benefit of assessment of statins.

Slide 25
We have already seen the meaning of NNT and NNH. The was once a study, a
study published on pravastatin which was tested again placebo and this was the
purpose of the trial, I uploaded in the supplementary this full study so that if you
wish you can calculate absolute risk reduction, NNH and NNT. The NNT from that
study in that case was 45, that means that you had one less cardiovascular event
in the group treated in the group treated with pravastatin compared to placebo.
Of course when you consider the number of 45, it means that 1 of these 45
patients get the benefit, the other 44 get no benefit but they are also exposed to
2 very important things; they are exposed to side effects so you must consider
the side effects that these patients must face but also cost.
Slide 26
Soo lets start to consider the potential of the side effects. The dimension of the
benefits you see is around 10, 20, 45, 50 depending on the baseline risk of the
patient, you must consider the side effects. What are the side effects of statins?
Slide 27
Well, they can damage liver cells and cause elevation of transaminases. In some
cases, the effect is only a minor case and it reverses. Sometimes it is more
important and requires withdrawal of the treatment. The other point is that
statins have the potential to damage the skeletal muscle and so that’s why in the
worst scenario, it is not only myositis but also rhabdomyolysis. Which means
skeletal muscle is damaged to the extent that the myoglobin within the muscle is
released into the plasma and can travel to the kidney and damage the
glomerulus. So, you have an important kidney damage that leads to sever renal
insufficiency. So the 3 important things to remember are potential for liver
damage, potential for skeletal muscle damage and also the other point that you
would notice if you looked at the tp 100 drug book, these drugs should be used
during pregnancy.

Slide 28
This gives you the dimension of all the slide effects of statins, You see that is
quite frequent to observe pain in the muscles, it much less frequent to observe
the worst case scenario which rhabdomyolysis and again this liver damage with
elevation of transaminases.
Slide 29
If you translate trials into numbers, and myopathy or rhabdomyolysis the NNH,
the number need to harm i.e. number needed to observe one event of
rhabdomyolysis or CPK elevation more than 10 times of the upper limit in normal
is 3400 and the NNT to prevent one event in this study was 27. So, you see in
this study, we have a wide difference between this severe muscle damage and in
the NNT we observe in patients treated to prevent cardiovascular events.
Slide 30
The other issue to take care of when you prescribe statins, is the potential for
drug interactions. I do not want to go into details because these (first column of
the table) are some drugs you can prescribe with statins, these are metabolic
pathways (middle column), and (on the far right of the table) these are some
examples that could potentially interfere with statins. To see more of these
drugs, you see these drugs are inhibitors of CYP3A4, of course if you inhibit these
enzymes you will increase the effect of statins with potentially huge side effects.
Again this (CYP2C9) is another enzyme responsible for the metabolism of statins
and there is potential of interaction here (see table in slide).
Slide 31
Let’s have a look at the dimension of the interaction. It is quite significant.
Rifampin is known a drug that is a very potent inducer of CYP3A4. With no drug
you see a higher concentration of Simvastatin, with the drug you see a very low
concentration of simvastatin, concentrations at which the drug will no be
effective.
On the other hand, if you give an inhibitor, Verapamil is a calcium channel
blocker, you see an increase in statin concentration compared to no drug. There
is potential of toxicity and the toxicity will be evident for instance in the liver but
could also appear in the muscle damage.
Slide 32-33
Another example, there was a safety newsletter from the FDA, in this case,
amiodarone, an antiarrhythmic agent which has an important interaction and is
also on the Top 100 drug list. And the potential for amiodarone is that since it
interferes with the metabolism of statins, it is much more likely that you have
muscle toxicity or liver toxicity when the 2 drugs are associated.
Slide 34
So, in summary what are the clinical benefits and the potential adverse effects of
the use of statins. This is a nice scheme taken from nature reviews if you are
interested the full paper is available in the supplementary material. But to make
things as short as possible you see statins are very effective at reducing
cardiovascular events, they also can reduce the risk of stroke but you can see
they can damage the liver, muscle and they can also increase the incidence of
new onset diabetes myelitis. So these are the adverse effects to be taken into
account.
Slide 35
Again, the number needed to treat for a given population of patients depends on
the baseline risk as the YouTube video mentioned, sometimes there are some
tricks in interpreting the NNT, for instance if the baseline risk is mainly low the
NNT of statins, in this is case it was the WOSCOPS trial, the NNT in low risk
patients was 66, in high risk patients the NNT is 17, so I is no the same things to
decide whether low risk patients should or should no be treated. What are the 2
dimensions that should be evaluated before making a decision? Side effects and
cost
Slide 36
So, lets try to answer this question. This is a paper published in 2017 in the
lancet. To makes things very short and simple, if you use statins in secondary
prevention the NNT can be as low as 10. It means you save a patient from one
Cardiovascular event, every 10 patients that you treat.
And in primary prevention, the figures are quite different, can you calculate the
NNT when the absolute risk reduction is 1%? 100.
So you see that if in primary prevention, which means that prevention of
cardiovascular events in patients who have not experienced any cardiovascular
events before, this is primary prevention, if the absolute risk reduction is 1%, the
NNT is 100. And what about the risk, you see that the risk for myopathy is low
because the NNH is 2000 but you see that the risk of diabetes has an NNH
between 100 and 200 so in primary prevention you treat a population where the
NNT is 100, this is very very close to the NNH and so it might not be a good idea
if the absolute risk reduction of 1%. Whereas in those circumstances where the
risk reduction is 5%, the NNT is 20, you see that it can be reasonable.
Slide 37
So, to conclude, this hour of teaching, I would just like to mention to extra things.
This one is in Italian (I don’t care about the details). What does NOTA13 mean?
(as you remember, we mentioned NOTA Aifa in the fundamentals course. Aifa is
the Italian Medicines Agency.) It means that when it comes to deciding whether
or not the national health service should pay for the statins prescribed by a
physician, there are categories of dldjljsl (no idea what he says)
And of course for those patients at high risk with a gain so important. Statins can
be charged to the national health service. In those conditions where the risk is
low or very low, there is actually no need for statins because you must consider
the risk and so considering the risks and the cost, it is not a good idea to use
statins and that is why in that case the statins are not charged to the health
service. This is the official position of the Italian Medical Agency and so this is a
regulatory document and it is important because when physicians prescribe
these medicines, they must take this into account.
Slide 38
The other document, which is an expensive document which I uploaded in case
you are interested. This is a document produced by the European Society of
Cardiology and it is the last version published in summer of 2019. And here you
see that depending on the risk levels, the green levels are areas where you give
lifestyles advice and no drug, yellow areas where the drugs could potentially
useful and the red areas where the drugs are actually needed. Of course it not
necessary for you at this stage to study every detail of this complex diagrams,
the important things for your 3rd year exam is that you must know statins, you
must know the dimensions of risk benefit evaluation and you must know that
they are guidelines. For example, the regulatory document (slide 37) that is
compulsory for all physicians in Italy and the scientific advice (ESC). However, I
must say that these ESC are much more general when it comes to deciding when
treating a patient
Slide 39
Finally, I just want to mention this Jupiter trial, which is a paradigm trial. You see
in this case statin, rosuvastatin was given to prevent vascular events in men and
women who have an elevated CRP. These patients are healthy individuals without
hypercholesterolaemia but with elevated CRP. As you may know CRP is an
inflammation protein and it is associated with cardiovascular risk. In this trial, one
half was the placebo half and the other half the rosuvastatin half. What did the
study conclude?
Slide 40
Please remember that in these Jupiter trial, these subjects had no
hypercholesterolaemia and just an elevated CRP. In this Jupiter trial, the risk of
hard cardiac events was reduced by 1.8% in the placebo arm and 0.8 % in the
rosuvastatin arm. So, the absolute risk reduction was 0.9%, which means that the
NNT was 112. If you consider that the risk for diabetes in the same population
was increased from 2.4 to 3%, the NNH was 167, so they are not so different. So,
should we treat all patients with CRP elevation with statins to reduce
cardiovascular event, what is your answer? The same question was posed to
American doctors in polling promoted by NEJM. Answer is no.
52% of American physicians answered that is was not a good idea to prescribe
statins with these “patients”. So, it is important that when you prescribe statins
that you consider the pharmacoepidemiology of the population and also the cost.

I would say this is it for dyslipidaemia drugs