Lipid-lowering drugs are used to treat elevated levels of circulating cholesterol and triglycerides,
with the goal of preventing cardiovascular events such as heart attack or stroke.
These lipids can come from diet, from stores in adipose tissue, or can be synthesized endogenously.
Cholesterol and triglycerides are transported in blood plasma within large particles known
as lipoproteins, composed of lipids and proteins.
There are four major lipoprotein particles: chylomicrons, very low-density lipoprotein
(VLDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL).
They differ in lipid content, hence density, and have different sets of proteins, and different
functions.
HDL acts to remove excess cholesterol from the circulation to the liver, and is therefore
beneficial for blood vessel health, unlike the other 3.
The liver secretes cholesterol in bile, part of which is eliminated from the body in feces;
the rest is recycled back to the liver.
Lipid-lowering therapy aims to reduce the circulating levels of chylomicrons, VLDL,
and LDL, but increase the level of HDL.
Mechanisms of existing drugs include: inhibition of cholesterol or lipoprotein production;
inhibition of intestinal cholesterol absorption; inhibition of bile reabsorption to promote
cholesterol removal; and promotion of lipoprotein degradation.
Statins are typically the first-line therapy, they inhibit endogenous production of cholesterol.
Statins are competitive inhibitors of HMG-CoA reductase - the enzyme that controls the rate-limiting
step in cholesterol synthesis.
As intracellular cholesterol decreases, the cells import more cholesterol from blood plasma
to fulfill their needs, effectively lowering plasma LDL levels.
Statins are best taken before bedtime, because cholesterol synthesis typically occurs during
fasting at night.
Common side effects include muscle pain and muscle injury which may increase with vigorous
exercise.
Other adverse effects include new development of diabetes and liver damage.
Another class of drugs are inhibitors of bile reuptake.
Normally, about 95% of bile acids delivered to the duodenum are reabsorbed back into the
blood.
The 5% that is excreted in feces is compensated for by newly synthesized bile in the liver.
Bile-binding resins adhere to negatively charged bile acids in small intestine, preventing
them from being reabsorbed, thus promoting their excretion.
As more bile is excreted in feces, the liver produces more new bile from cholesterol, effectively
removing more cholesterol from the blood.
These resins are best taken with meals.
Common side effects include nausea, bloating, and stomach cramping.
In addition, absorption of fat-soluble vitamins may be reduced; production of liver enzymes
may also increase.
Ezetimibe inhibits the absorption of dietary and biliary cholesterol from the small intestine
without affecting bile.
It is taken with meals.
Ezetimibe can cause fatigue, diarrhea, headache, runny nose, sore throat, body aches, and some
other more serious but less common side effects.
Fibrates are agonists for PPAR-alpha.
PPARs are transcription factors that mediate the effect of dietary fatty acids on lipoprotein
metabolism.
Activation of PPAR-alpha has several effects: it promotes degradation of triglyceride-rich
particles by lipoprotein lipase, it reduces production of VLDL, and increases production
of HDL by upregulating apolipoprotein A1 - the major protein component of HDL.
Fibrates are usually taken before meals.
Common side effects include indigestion, abdominal pain, fatigue, dizziness, leg cramp, and increased
serum creatinine.
PCSK9 inhibitors are monoclonal antibodies that bind to and inhibit PCSK9.
PCSK9 is an enzyme that promotes degradation of LDL receptors which are required for cellular
uptake of LDL from the blood.
Inhibition of PCSK9 increases LDL receptors, removing more LDL from blood plasma.
These drugs are administered by subcutaneous injections.
They can cause local injection site reactions such as erythema, pain, and bruising.
Niacin lowers plasma VLDL, LDL and triglyceride levels, and raises HDL significantly.
Proposed mechanisms include: decreased triglyceride synthesis, decreased degradation of apolipoprotein
A1, and increased activation of another PPAR, PPAR-gamma.
This drug is taken with meals.
Niacin is often poorly tolerated, with many side effects ranging from unpleasant to severe.