A study led by researchers from the Ecole Polytechnique Fédérale de Lausanne (EPFL) in Switzerland, revealed a new liver- and gut-targeted oral drug that can safely lower triglycerides and other blood lipids.
Researchers of the study, published last Friday in Nature Medicine, said the innovative drug could represent a breakthrough in treating metabolic diseases related to high triglycerides in the body.
The study said that when we eat, our bodies convert extra calories, especially from carbs, sugar, fats, and alcohol, into molecules called “triglycerides.”
Triglycerides are a form of fat or “lipid,” which the body stores away into its fat cells as an energy fuel for energy between meals.
But, excess amounts of fat in the body can be dangerous, causing a condition known as “hypertriglyceridemia” (“excess triglycerides in the blood”), which significantly increases the risk of heart disease, stroke, and pancreatitis.
This is why we are universally advised to make healthy lifestyle choices in diet, exercise, while particularly bad cases require medication.
The study also found that keeping blood fats in check depends on a careful balance.
It said the liver and intestine release fat particles into the bloodstream, while enzymes work to break them down and clear them away.
When fat production outpaces clearance, triglycerides build up, setting the stage for metabolic diseases like dyslipidemia, acute pancreatitis, and metabolic dysfunction-associated steatotic liver disease (MASLD).
One of the master switches in this system is a protein called Liver X Receptor, or LXR, which controls several genes that are involved in making and handling fats.
When LXR is active, triglycerides and cholesterol tend to rise.
Therefore, dialing it down through medication seems promising, but as LXR is also involved in protective cholesterol pathways elsewhere in the body, blocking it everywhere could do more harm than good.
Now, scientists have addressed this problem with an orally administered compound that can repress the activity of LXR specifically in the liver and gut to lower triglycerides without disrupting the body’s protective cholesterol pathways.
The compound, TLC‑2716, is what is known as an “inverse agonist” for the LXR. Unlike a “blocker” (“antagonist”) that merely stops a receptor from being activated, an “inverse agonist” makes the receptor signal the opposite effect to what it would normally do.
Clinical Trial
The lab findings set the stage for a randomized, placebo-controlled Phase 1 study in healthy adults. Participants received TLC‑2716 for 14 days given as a single dose per day and the trial focused first on safety and tolerability, and the authors report that the drug met these primary endpoints.
But even this short trial had clear effects: participants who received higher doses of TLC‑2716 showed notable drops in triglycerides as well as remnant cholesterol.
At the highest doses of TLC‑2716 (12mg), triglycerides fell by up to 38.5%, while postprandial (“after eating”) remnant cholesterol dropped by as much as 61%.
This happened despite participants starting with relatively normal lipid levels and without the use of other lipid-lowering drugs, the study showed.
Also, the treatment sped up triglyceride clearance by reducing the activity of two proteins that normally slow it down, ApoC3 and ANGPTL3.
At the same time, the study did not detect reductions in blood-cell expression of ABCA1 and ABCG1, genes used here as markers linked to reverse cholesterol transport.
Researchers said larger trials will be needed, but, for now, the concept has its first human proof of principle.
