Dyslipidemia Part 4 - Laboratory parameters and lipid-lowering agents
May we introduce: the bad cholesterol, LDL, and the good cholesterol, HDL.
Maybe you already know them, for example, from the first episode in this Chalk Talk
series on dyslipidemia.
In particular, elevated LDL and triglyceride levels and low HDL levels are linked with
an increased risk of atherosclerosis and associated cardiovascular diseases.
But what exactly does elevated or lowered mean?
Well, there are always new, inconsistent guidelines and controversial discussions about how to
define these.
In this Chalk Talk episode, we’ll be looking at laboratory parameters of lipid metabolism
in general and the various ways of positively impacting blood lipid levels.
Let's start with laboratory parameters.
Now, here we’re interested in the values relevant to the risk of atherosclerosis.
To better understand these, let’s look at lipoproteins again: HDL cholesterol is associated
with a lower risk of atherosclerosis.
Triglycerides are mainly found in chylomicrons, VLDL, and IDL particles.
Their proportion in LDL and HDL is low.
Both laboratory values, that is, HDL cholesterol and triglycerides, can be determined spectroscopically.
Total cholesterol indicates how much cholesterol all lipoproteins combined carry in the blood.
The LDL value is the most important risk factor for atherosclerosis and, therefore, most relevant
for target values and follow-ups.
The laboratory parameter LDL cholesterol usually includes the values for LDL, as well as for
Lp(a), since Lp(a) belongs to LDL particles due to its density.
Since the direct spectroscopic measurement of LDL cholesterol is relatively expensive,
it’s often calculated using the Friedewald formula.
For this, the values for total and HDL cholesterol, as well as triglycerides, are required.
Non-HDL cholesterol is, understandably, the difference between total and HDL cholesterol.
However, the amount of non-HDL cholesterol can also be inferred indirectly by determining
apolipoprotein B, in short, ApoB, since ApoB is found in all lipoproteins except for HDL.
So, this value is quite interesting because all ApoB-containing lipoproteins are atherogenic.
The amount of lipoprotein(a), whose function isn’t exactly known, is primarily genetically
determined and remains basically constant throughout a lifetime.
It’s been shown to increase the risk of atherosclerotic cardiovascular diseases.
As a laboratory parameter, Lp(a) is only measured once if a genetically caused increase is suspected.
By the way, chylomicrons don’t really affect parameters measured in the fasting state.
They only form shortly after food consumption and are quickly broken down again.
How high should the different blood lipid levels be, and how are they achieved?
As already mentioned, this is subject to discussion among experts.
In general: When setting target blood lipid levels, other cardiovascular risk factors
need to be taken into account.
For individuals with an overall high risk, lower blood lipid levels are recommended than
in individuals with an overall low risk.
So, in practice, the individual cardiovascular risk is always initially assessed so that
the blood lipid levels measured can be interpreted correctly, and appropriate target levels can
be set.
To keep things simple, we’re presenting the reference values for an adult with an
overall low risk.
In this case, total cholesterol levels should be below 200 mg/dL and LDL cholesterol below
100 mg/dL.
For women, the value for HDL cholesterol should be over 50 mg/dL, which is slightly higher
than the value for men with over 40 mg/dL.
ApoB should be under 130 mg/dL, and Lp(a) below 50 mg/dL.
The triglyceride value varies with food intake and should be below 150 mg/dL in a fasting
state, otherwise under 200 mg/dL.
Dyslipidemias can be classified clinically according to various criteria.
Principally, dyslipidemias can be differentiated into hyperlipidemias, that is, metabolic disorders
with elevated blood lipid levels, and hypolipidemias with lowered blood lipid levels.
However, hypolipidemias are generally rare.
Only low HDL levels are relevant to the risk of atherosclerosis.
Therefore, this is the only type of hypolipidemia that we’ll be considering here.
We’ll now present a classification of the most important dyslipidemias based on a constellation
of the different laboratory findings of blood lipid profiles: If only LDL and total cholesterol
levels are elevated and all other laboratory parameters are normal, the dyslipidemia is
classified as familial hypercholesterolemia.
Also, if triglyceride levels are increased and HDL levels decreased, the condition is
termed combined familial hyperlipidemia.
If all values are within the normal range and only HDL levels are decreased, the condition
is called low HDL cholesterol or hyperalphalipoproteinemia.
In hyperlipidemia, triglycerides and total cholesterol levels are increased, whereas
HDL levels are decreased, while LDL cholesterol is within the normal range.
In the case of elevated lipoprotein(a), Lp(a) levels are increased, whereas any combination
is possible for all other measured laboratory values.
So, these are the most important types of dyslipidemia.
Additional information can be found in our AMBOSS article.
Apart from the classification based on the blood lipid profile constellation, dyslipidemias
can also be categorized according to the underlying cause: They can be differentiated into primary,
i.e., genetic, and secondary dyslipidemias.
Primary dyslipidemias are often due to dysfunctional lipid metabolism, e.g., due to a deficient
or defective apolipoprotein.
In contrast, secondary dyslipidemias are complications.
They can be triggered by poor nutrition, alcohol consumption, smoking or underlying conditions,
such as type 2 diabetes mellitus, but also by drugs, such as contraceptives, immunosuppressants,
or thiazide diuretics.
Pregnancy can also lead to secondary dyslipidemia, but it usually resolves after birth.
So, what needs to be done if blood lipid levels are elevated?
Even if it’s not always the most popular measure, the first thing in an attempt to
reduce lipid levels is changing your lifestyle.
Depending on your previous lifestyle, a reduction in LDL levels of up to 40% can be achieved.
This includes a healthy diet that is low in saturated and trans fats, salt, and alcohol.
Body weight should be reduced to a BMI to approximately between 20 and 25 kg/m2, and
physical activity should be incorporated wherever possible into the daily routine.
Smoking should be stopped or at least reduced.
If these measures don’t result in the desired blood lipid levels or if there’s an overall
high risk, lipid-lowering agents are used supplementarily.
In genetically elevated lipoprotein(a) levels or, in exceptional cases when drug therapeutics
fail, a technical procedure can also be used, lipoprotein apheresis.
In this extracorporeal procedure, a machine is used to remove LDL, VLDL, and Lp(a) particles
from the blood.
In this Chalk Talk episode, we’d like to focus on the different lipid-lowering agents:
First-line lipid-lowering agents are statins because they’re generally well tolerated
and can reduce total and LDL cholesterol levels by as much as 60%.
Statins block the body's cholesterol synthesis by inhibiting HMG-CoA reductase.
With this, they inhibit the key enzyme in cholesterol synthesis that converts HMG-CoA
to mevalonate.
As a result, cholesterol levels in the blood decrease and cells compensatorily express
more LDL receptors, therefore absorbing more LDL into the cells; LDL levels continue to
decline.
Also, the amount of other ApoB-containing lipoproteins in the blood decreases.
Subsequently, HDL cholesterol levels increase, whereas triglyceride levels decrease.
Statins also have pleiotropic effects.
These are effects, which the active ingredient exhibits in other target structures in the
body in addition to the known primary effect.
Pleiotropic effects of statins include increased nitric oxide formation, reduced LDL oxidation,
and decreased inflammatory and thrombogenic processes.
These effects cause endothelial and plaque stabilization in atherosclerosis, therefore
contributing an important additional protective benefit.
Second-line lipid-lowering agents include cholesterol absorption inhibitors that reduce
cholesterol absorption from food.
One example is ezetimibe.
It inhibits the NPC1L1 transporter in the enterocyte membrane, which is responsible
for cholesterol absorption.
Consequently, LDL levels decrease.
Cholesterol absorption inhibitors can be used in combination with statins if the latter
insufficiently reduce LDL levels.
In such cases, both endogenous cholesterol production and intake from food is inhibited
effectively.
Another means of reducing cholesterol is to use bile acid resins, such as anion exchange
resins, that increases cholesterol consumption in the body.
This is how they work: The bile acids bound by the active ingredient in the intestinal
lumen are no longer absorbed but excreted.
The enterohepatic circulation is interrupted, and the body consumes more cholesterol through
bile acid resynthesis.
Blood cholesterol levels therefore decrease.
Also, bile acid resins can be used in combination with statins.
However, caution should be exercised in patients with high triglyceride levels, as bile acid
binders can increase these blood levels.
Fibrates intervene in lipid metabolism by increasing the activity of lipoprotein lipase.
Here’s a brief reminder: In the first part of this Chalk Talk series, we introduced lipoprotein
lipase as the enzyme that cleaves triglycerides in chylomicrons and lipoproteins to release
fatty acids.
Therefore, fibrates lower the concentration of triglycerides and are mainly used in hypertriglyceridemia.
Fibrates don’t exert consistent effects on cholesterol levels but are generally low.
Their benefit in cardiovascular risk reduction hasn’t yet been proven.
Fibrates and statins are only combined in exceptional cases because this increases the
risk of myopathy.
A relatively new lipid-lowering agent on the market is PCSK9 inhibitors.
They were developed mainly for high-risk patients who don’t achieve optimal LDL cholesterol
levels through statins or patients that don't tolerate statins well.
However, this monoclonal antibody therapy is expensive due to production costs.
They selectively inhibit the enzyme PCSK9 and, therefore, lysosomal degradation of LDL
receptors.
This increases LDL uptake into the cells and significantly reduces LDL cholesterol in the
blood.
The sole administration of PCSK9 inhibitors can reduce LDL cholesterol by as much as 60%,
and in combination with statins and cholesterol absorption inhibitors by as much as 85%.
Finally, we’d like to point out the lipid-lowering effect of niacin or vitamin B3, which is one
of the oldest and inexpensive hyperlipidemic agents still used in the US.
Niacin inhibits lipolysis and, therefore, particularly decreases the level of triglycerides
in blood.
To a lesser extent, it also lowers LDL levels.
Okay.
So, that wraps it up for laboratory parameters and therapeutic options of dyslipidemia.
If you like, you can now test your knowledge with a quiz on the next slide.