Of all the known diseases, heart attacks are
the leading cause of death worldwide, with strokes coming a close second. Both are considered types of cardiovascular
disease. Due to their prevalence and lethality, treating
and preventing cardiovascular diseases is a huge priority in our healthcare system. If you are at risk of having a heart attack
or stroke, doctors will likely prescribe you a class of drugs called statins, which decreases
LDL cholesterol levels. So what is LDL cholesterol, how do statins
decrease LDL cholesterol, and why does that decrease the risk of cardiovascular disease? Learn more about how statins work, who should
take them, and what the side effects are in this episode of Medicurio. In humans, cholesterol is an essential molecule
used to make steroid hormones, bile acids, and Vitamin D. It is also a vital part of the cell membrane
of each and every cell in the body. Most of the cholesterol in our body is synthesized
in the liver and transported to other parts of the body via blood. However, cholesterol is insoluble in blood
and must be packaged within special particles called low-density lipoprotein particles to
enter the blood. When cholesterol is within these particles,
it is referred to as LDL-cholesterol. There is generally less than 100 mg/dL of
LDL-cholesterol flowing through the blood of a healthy adult. When the blood vessel wall is damaged due
to high blood pressure, increased fats and cholesterol in blood, high blood sugar from
diabetes, or toxins from smoking, a complex inflammatory response occurs in which plaque
begins to form at the site of damage. Plaque is a buildup of LDL cholesterol, other
fats, and dead immune cells, covered by a cap of smooth muscle cells. What makes plaque so dangerous is that the
cap can rupture, revealing the interior of the plaque which can trigger blood clot formation
and blood vessel blockage. A heart attack occurs when blood vessels within
the heart become blocked by this process. Heart tissue supplied by those blood vessels
become deprived of nutrients and oxygen and eventually die. The heart no longer pumps properly, fatally
shutting down the body. The same blockage could happen in the blood
vessels of the brain to cause strokes, leading to brain damage and possibly death. Considering that LDL cholesterol is one of
the main components of plaque, it is not surprising that many studies have linked higher LDL cholesterol
levels to a higher risk of cardiovascular disease. This prompted scientists to look for drugs
that decrease LDL cholesterol levels to prevent cardiovascular disease. In 1971, biochemist Dr. Akira Endo and his
team isolated the first statin, compactin, from the fungus Penicillium. Based on compactin’s early success in lowering
LDL cholesterol, pharmaceutical companies began creating structurally similar molecules
with different potencies and rates of breakdown, giving patients a wide range of statins to
choose from that will best benefit their individual situations. The effectiveness of statins have made them
one of the most highly prescribed and commercially successful drugs in the world, with the most
popular statin, atorvastatin, raking in over $125 billion dollars worldwide since its creation
in 1996. So why are statins so effective at loweromg
LDL cholesterol? To understand how statins work, we first need
to understand how cholesterol is made in the body. The cholesterol synthesis pathway involves
multiple steps. The most important step of the entire pathway
is the formation of mevalonate from a molecule called HMG-CoA. HMG CoA contains Coenzyme A, which is removed
to form mevalonate. This reaction is carried out by an enzyme
called HMG-CoA reductase. It turns out that statins can also bind to
this enzyme because statins and HMG-CoA have similar structures. However, HMG-CoA cannot bind to the enzyme
if a statin is occupying that binding site, meaning that no reaction occurs and no mevalonate
can be formed. This is how statins stop cholesterol synthesis. So how does stopping cholesterol synthesis
using statins affect LDL cholesterol levels in the blood? Without cholesterol synthesis, the liver now
needs to look for other sources of cholesterol to create bile and other important compounds. The only major source of cholesterol left
now is in the blood, packaged as LDL cholesterol. To reabsorb the LDL cholesterol, liver cells
begin to express LDL receptors on their surface, which bind to LDL particles, internalizes
them, and breaks them down to obtain cholesterol. This removes LDL cholesterol from the blood,
resulting in lower LDL cholesterol levels and a lower risk of developing plaque and
cardiovascular disease. So who should take statins and what are some
possible side effects? Statins should be taken by people who are
at a high risk of developing cardiovascular disease. Though guidelines vary between healthcare
systems, generally this includes people who have very high LDL cholesterol levels above
190 mg/dL, are living with diabetes, have a family history of cardiovascular disease,
or have already had a heart attack, angina, or stroke. Essentially, any conditions that may cause
plaque to form. As for side effects of statins, around 5 to
10% of statin users experience clinically significant muscle pain and weakness, which
understandably causes some of them to stop taking their medication. Although stopping stain use may relieve muscle
pain, high-risk patients lose the preventative effects of statins, possibly resulting in
a lethal heart attack or stroke. Instead, patients should discuss their pain
with their doctor and perhaps switch to other cholesterol-lowering drugs or undergo lifestyle
changes, but once again, do not simply stop taking statins without an alternative method
of decreasing LDL cholesterol. Unfortunately, the mechanism of muscle damage
by statins is not well understood. One possible explanation is that molecules
produced in the cholesterol synthesis pathway are also used to synthesize a molecule called
CoQ10. CoQ10 is involved in cellular energy production, particularly at energy-consuming tissues such as muscles. Inhibiting HMG-CoA reductase by statins may
also be causing a decreased synthesis of CoQ10, which might impair energy production in muscle
to cause muscle pain and weakness. Aside from this, statins are a relatively
safe drug to use with proper dosage. There is no question that statins can reduce
LDL cholesterol levels as intended, and has likely prevented countless heart attacks,
strokes, and deaths worldwide. However, the fact that statins are one of
the most prescribed drug classes points to an underlying problem in lifestyle choices
that have made cardiovascular disease so common. As a society, we should move towards becoming
healthy enough to avoid statin use. Thanks for watching, and see you next time
on Medicurio.
