Understanding Cholesterol-lowering Drugs
Dr. Anne Carol Goldberg
Keeping LDL cholesterol in check is one of several ways to lower your risk of heart disease and stroke. Lifestyle changes, including a healthier diet and physical activity, may lower cholesterol in some people, while for others medication may also be required.
Most heart disease and many strokes are caused by a buildup of fat, cholesterol and other substances called plaque in the inner walls of your arteries. This narrows the arteries and reduces blood flow. If a blood clot forms in one of these narrowed arteries, a heart attack or stroke can result. Your healthcare provider should assess your risk for heart attack or stroke based on your cholesterol levels and other risk factors before prescribing medication.
There are essentially four classes of medications that clinicians use to lower LDL (bad) cholesterol. They each work with a different mechanism and may be combined to reduce LDL cholesterol.
Among various medications used to lower LDL cholesterol, statins are recommended for most patients.
The liver produces cholesterol our bodies need to function properly. It’s when we have too much cholesterol in the blood that problems can arise. Statins are a class of drugs that reduce cholesterol production in the liver. “Statins have the best evidence in terms of reducing cardiovascular event rates,” said endocrinologist Anne Carol Goldberg, M.D., professor of medicine at Washington University School of Medicine in St. Louis.
Statins disrupt the production of cholesterol by blocking a specific enzyme inside cholesterol-producing liver cells. This results in more cholesterol-containing particles being removed from the bloodstream by the liver. Some statins also reduce the inflammatory process caused by elevated cholesterol within blood vessel walls. When the body has a reduced reaction to the invading cholesterol, fewer macrophages are allowed to travel into the artery walls, where they would have formed foam cells and plaque.
Statins have proven to be effective in lowering the risk of heart attack and stroke, typically in the range of 16 percent to 30 percent. “With the higher doses of the stronger ones, you can get the LDL cholesterol reduced by 50 percent or more,” Goldberg said.
Statins are generally well-tolerated, with some people having side effects that can include muscle aches, dizziness, constipation, headache, diarrhea and upset stomach. “Although there’s some increase in risk of diabetes in people who are prone to diabetes, that is really insignificant when you compare it to the benefit in people with a high risk of a heart attack or stroke,” Goldberg said.
This class of LDL-lowering drugs works in the intestines by helping get rid of unneeded cholesterol. The body uses cholesterol to make bile, an acid that helps us digest our food. These medicines bind to bile, rendering the bile useless for digestion. The liver responds by making more bile. The more bile your liver makes, the more cholesterol it uses, reducing the amount of cholesterol left to circulate through your bloodstream.
“They have more side effects than statins, mostly stomach — diarrhea, constipation, gassiness,” Goldberg said. They are added to statin therapy.
These medicines work in a different part of the biology of the cell. PCSK9 is a protein that cells produce that binds to the LDL receptor on the liver. PCSK9 inhibitors are injectable antibodies that target the PCSK9 protein and block it so that more of the receptors on the liver are available to get rid of LDL cholesterol from the blood.
“LDL receptors attach to an LDL particle and bring it into the cell,” Goldberg said. “It comes into a little contained area in the cell. The LDL receptor then comes off of that particle and goes back to the cell’s surface. It’s recycled.”
That’s what normally happens. However, if a person has a lot of PCSK9 molecules, they attach to the LDL receptor and will enter the cell along with the receptor and the particle. “Once inside the cell, the PCSK9 molecules prevent the LDL receptor from detaching from the particle, so it gets broken down like the LDL does,” Goldberg said. “It doesn’t go back to be recycled and work on the cell surface again. PCSK9 inhibitors keep PCSK9 from attaching to the LDL receptors, and that makes the LDL receptors recycle better. They remove more LDL from the blood.”
They’re given by injection every two to four weeks and they lower LDL significantly, by 40 percent to 70 percent. “They’re very, very potent and work in addition to the statins, so you can get really low LDL levels in people who have high levels,” Goldberg said. “They are not a replacement for statins. In fact, they work better if you get the LDL down with statins first.”
This is a relatively new class of medicine and is used for people who start out with very high LDLs, like individuals with familial hypercholesterolemia. They are also approved for people with vascular disease whose LDLs are not low enough. “But it isn’t clear yet exactly at what level they should be started,” Goldberg said. “They’re very expensive, about $14,000 a year.” Recently, moderate discounts have been offered by the manufacturers to better enable access to these therapies.
Selective cholesterol absorption inhibitors
The name describes how this medicine works — it prevents the small intestines from absorbing biliary and dietary cholesterol. Currently, there is only one FDA-approved drug in this class: ezetimibe. “Because cholesterol does not get recycled back to the liver, the liver has to rev up the LDL receptors to take up more cholesterol,” Goldberg said. “Ezetimibe generally reduces LDL by about 20 percent.” It is typically added to statin therapy, though it can be used by itself for those who cannot tolerate high statin doses.
“We use them a lot in people with familial hypercholesterolemia and other people where the LDL is still high despite using statins,” Goldberg said. Side effects are considered negligible.
“As for cost, ezetimibe went off-patent a year or so ago so, it’s coming down. There are some coupon sites where you can get it for about $30 a month,” Goldberg said. (An internet search for “coupon sites for drug discounts” will bring up plenty of options. Learn more about Managing the Costs of Prescription Drugs.)
Niacin and fibrates are sometimes listed as cholesterol lowering, but neither is commonly used for that today. Niacin is a B vitamin that limits the production of blood fats in the liver, but its side effects are unpleasant — itching, flushing; sweating or chills; nausea, diarrhea, belching, gas. Liver function may be closely monitored because niacin can cause toxicity. “Most doctors are not using niacin very much anymore,” Goldberg said.
Fibrates work to lower triglycerides.
Typically, CVD patients are given lifestyle and drug prescriptions. It is crucial that heart patients adhere to whatever your doctor prescribes. Remember, no medication can work as expected if not used as directed. If you have concerns or experience side effects, talk to your healthcare provider immediately.