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Cardiac glycosides found in the leaves of the foxglove plant potentially could reduce LDL cholesterol differently than statins. Stephen Duncan, Ph.D., Chair of the Department of Regenerative Medicine, says the glycosides were identified through a stem cell screen for compounds that could be used off-label for the treatment of high cholesterol. “The nice thing about finding new uses for drugs already on the market is that they can be used relatively quickly in patients, because most of the needed safety trials have already been completed.”
Not everyone with high LDL cholesterol responds to statins. Statins increase levels of a cell surface receptor that removes LDL cholesterol from the bloodstream. However, statins do not work in patients with familial hypercholesterolemia (FH) who have a rare mutation in that receptor. It is an inherited disorder that leads to aggressive and premature cardiovascular disease. FH patients have very high cholesterol and can die of cardiovascular disease by their forties. The existing drugs for FH can cause fatty liver disease, and the best treatment is a liver transplant.
Duncan and his graduate student Max Cayo, who is finishing his medical degree at the Medical College of Wisconsin, developed a drug screen to identify an alternative to statins. Apolipoprotein B (apoB) is a molecule that liver cells use to make LDL. Drugs that decreased apoB could potentially lower cholesterol independently of the LDL receptor in FH patients and also in patients with other forms of high cholesterol.
FH was a perfect model for testing alternatives to statins. Yet the rarity of FH meant these liver cells were scarce. Duncan’s group made induced pluripotent stem cells out of skin fibroblasts taken from a single patient with FH. A sample of converted skin cells from a single patient with FH provided a renewable source of liver-like cells that retained the mutation.
The group tested these liver-like cells with the SPECTRUM library, a collection of 2,300 pharmaceuticals, many of which had reached clinical trials. Surprisingly, all nine cardiac glycosides in the collection, some widely prescribed for heart failure, reduced apoB in the liver-like cells from the patient with FH.
Next, the team combed through the medical records of more than 5,000 patients who also had LDL cholesterol records. Similar drops in LDL levels were observed in patients prescribed cardiac glycosides for heart failure.
This study provides the first evidence that cardiac glycosides could potentially reduce LDL cholesterol independently of the LDL receptor by reducing apoB.