Enlicitide: What to know about the new cholesterol-lowering pill
September 28, 2026
In 2015, a new class of cholesterol-lowering injectable drugs called PCSK9-inhibitors was approved by the Food and Drug Administration (FDA) as a result of clinical research led by UT Southwestern.
A decade later, we’re carrying on the tradition. Our clinical trial findings, published in The New England Journal of Medicine, contributed to FDA approval of enlicitide, the first PCSK9-inhibitor available in pill form. Enlicitide offers a new treatment option for patients who prefer not to take injections.
I was the lead author of the manuscript for this phase three double-blind, randomized, placebo-controlled CORALreef Lipids clinical trial, which investigated whether enlicitide was effective in reducing low-density lipoprotein (LDL) or “bad” cholesterol long term. Our data showed that after 24 weeks, enlicitide lowered LDL cholesterol by more than 57%, compared with just a 3% decrease with a placebo.
High LDL cholesterol is one of the main causes of heart attack and stroke because it contributes to plaque buildup in the arteries, known as atherosclerosis. LDL levels can rise without causing noticeable symptoms until tragedy strikes, making proactive management with lifestyle changes and medication very important.
But taking injections can be cumbersome for some, and high price points, insurance coverage challenges, and limited awareness of PCSK9-inhibitors have hampered their use.
Our research shows that, when taken alongside statins or other cholesterol medications, enlicitide can substantially lower LDL cholesterol without requiring injections, opening the door for more patients to achieve better cholesterol management.
Although enlicitide is very potent at lowering LDL cholesterol, it has not yet been proven to lower heart attacks and strokes. Those studies are ongoing.
How does enlicitide work?
Both the injectable and once-daily pill forms of PCSK9-inhibitors block proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein involved in regulating LDL cholesterol. The result is less LDL cholesterol circulating in the bloodstream, reducing the risk of a heart attack or stroke.
The drugs were designed to work alongside statins, which are the gold standard in reducing high cholesterol. They also lowered cholesterol in people not on statins or on less than the highest dose of statins. In the clinical trial, about 97% of participants were taking statins, and about one-quarter were also taking another cholesterol medicine.
Participants took either 20mg of daily enlicitide or a placebo for 52 weeks. At 24 weeks, the average LDL cholesterol level of patients in the enlicitide group fell from 95 mg/dL to about 39 mg/dL. About two-thirds of them reached an LDL cholesterol level below 55 mg/dL, which is the new target in those with known heart disease, according to the 2026 cholesterol guidelines.
How is enlicitide different from statins?
LDL receptors on liver cells remove LDL cholesterol from the bloodstream. The PCSK9 protein binds to these receptors and causes some to break down, leaving fewer receptors to clear LDL cholesterol. Enlicitide binds to the PCSK9 protein and prevents it from attaching to LDL receptors. This allows more receptors to remain available and remove LDL cholesterol from the blood.
Statins and enlicitide, sold under the brand name Lipfendra, affect different parts of the same process. This is why adding enlicitide to a statin can produce such a large additional reduction in LDL cholesterol.
For some patients, taking a statin may be enough to manage LDL cholesterol. Decades of clinical trials show that statins are highly effective for reducing the risk of heart attack and stroke. Statins are inexpensive, widely available, and among the most extensively studied medicines we prescribe.
However, many patients will need more than one medication to effectively reduce LDL cholesterol and its harmful cardiovascular effects.
How can high LDL cholesterol harm your health?
High LDL cholesterol usually causes no symptoms in its early stages. You cannot see or feel it accumulating in your arteries as plaque buildup (atherosclerosis), which narrows the space where blood can flow. This can eventually lead to a heart attack or stroke.
Eating foods that are high in saturated fat or trans fat increases the risk of high cholesterol, as does getting limited exercise, having obesity, smoking, and drinking excess alcohol. Many people have high cholesterol from genetic causes as well, and even with the best lifestyle they still need medicine to lower it. High cholesterol is common in people who have metabolic conditions such as diabetes or kidney, thyroid, or liver disease.
About 1 in 250-400 people in the U.S. have a genetic condition that causes extremely high cholesterol called familial hypercholesterolemia.
Getting regular blood tests is the only way to know your levels and whether treatment is working.
What should my LDL cholesterol level be?
In March 2026, 11 medical associations jointly published new guidelines for managing cholesterol in the Journal of the American College of Cardiology and Circulation. I contributed to these guidelines along with UT Southwestern cardiologists Parag Joshi, M.D., and Anand Rohatgi, M.D.
The 2026 cholesterol management guidelines are based on advances in cardiovascular risk prediction, lipid testing, and treatment options. They spell out the ideal LDL level for you based on your cardiovascular risk factors. In general, we aim for these levels:
- Below 100 mg/dL for adults at borderline or intermediate risk
- Below 70 mg/dL for people at high risk
- Below 55 mg/dL for people with atherosclerotic cardiovascular disease (ASCVD) who are at very high risk of another cardiovascular event
Who can benefit from taking enlicitide?
The FDA has approved enlicitide for adults with high LDL cholesterol, including those with familial hypercholesterolemia. Enlicitide may benefit you if you:
- Have high LDL cholesterol despite taking a statin
- Have ASCVD or a high risk of heart attack or stroke
- Have familial hypercholesterolemia and need multiple medications to control cholesterol
- Cannot tolerate statins despite trying different statins or adjusting the dose under a doctor’s supervision
- Need PCSK9 treatment and prefer a daily pill to an injection
Patients who are pregnant or planning to become pregnant should discuss treatment options with their doctor. The prescribing information recommends discontinuing enlicitide during pregnancy unless the expected benefit outweighs the potential risk to the fetus.
Cholesterol and heart disease risks
Amit Khera, M.D., a cardiologist at UT Southwestern, explains how cholesterol contributes to plaque buildup in the arteries. Learn what steps you can take to protect your heart, including lifestyle changes, screening, and treatment options.
Decades of leadership in heart disease prevention
Enlicitide may be new, but it builds on our history of extensive cardiovascular research at UT Southwestern. Michael Brown, M.D., and Joseph Goldstein, M.D., discovered the LDL receptor and explained its role in cholesterol regulation. Their work, which received the 1985 Nobel Prize in Physiology or Medicine, helped lay the scientific foundation for statins.
Years later, Helen Hobbs, M.D., and Jonathan Cohen, Ph.D., used data from the groundbreaking Dallas Heart Study to identify people with genetic changes that caused them to produce less functional PCSK9. These findings helped establish PCSK9 as an effective treatment target, leading first to the development of injectable PCSK9-inhibitors and now to enlicitide.
If you currently take a statin or another cholesterol medication, do not stop it or change the dose without talking with your doctor. Your current routine may be the best treatment option for your needs.
But if your LDL cholesterol level remains above your target range despite treatment, talk with a doctor about whether enlicitide may be appropriate for you. We can help you find a treatment plan that you can follow consistently to protect your heart health for the long term.
To talk with an expert about cholesterol management, make an appointment by calling 214-645-8000 or request an appointment online.
