Cholesterol drug find could offer alternative to statins - 'new treatment option'

Cholesterol drug find could offer alternative to statins - 'new treatment option' Scientists say a breakthrough could offer hope for patients A potential alternative to statins could help manage dangerously high cholesterol levels, according to scientists. Researchers have uncovered how elevated cholesterol dismantles the liver's natural defences - and how a new medication might counteract this process. Heart disease linked to cholesterol continues to be the world's leading cause of death. While doctors now have more treatment options than ever before, including statins, many patients still struggle to reach safe cholesterol levels, or find themselves unable to tolerate the side effects associated with existing medications. In the UK, doctors usually prescribe Atorvastatin (Lipitor) and Simvastatin (Zocor). These can help control high cholesterol and prevent heart disease. Atorvastatin is normally the first choice for stronger treatment. There are, however, other options, such as Fluvastatin, Rosuvastatin and Pravastatin. Atorvastatin (Lipitor) and other statins can cause muscle pain, tenderness, or weakness in some patients. Yet actual muscle damage is not seen often, and a large number of patients have no side effects. Now American scientists have revealed a previously hidden biological mechanism that explains why diets high in cholesterol gradually undermine our body's capacity to eliminate harmful low-density lipoprotein (LDL) - or bad cholesterol - from the bloodstream. The research team from University of California San Diego School of Medicine have also pinpointed a drug candidate that has already been proven safe in humans and could potentially address this issue. Study senior author Professor Alan Saltiel said: "We've known for a long time that a high-cholesterol diet reduces the liver's ability to clear cholesterol from the blood, but we didn't fully understand why. This new discovery explains a critical piece of that puzzle." He explained that the liver serves as the primary organ responsible for extracting cholesterol from the blood so it can be processed and utilised elsewhere in the body. Prof Saltiel said: "This is done through LDL receptors, which sit on the surface of liver cells and act like docking stations, grabbing LDL cholesterol from the bloodstream and pulling it inside the cell for processing. "The more LDL receptors on liver cells, the more cholesterol gets cleared from the blood - which is why most cholesterol-lowering drugs, such as statins or PCSK9 inhibitors, work by preserving or increasing the number of these receptors." The groundbreaking study, published in the journal Nature, was carried out using a combination of mice and human cells. It uncovered a previously unidentified mechanism that silently works against the body's cholesterol removal process, gradually diminishing the number of LDL receptors and contributing to raised blood cholesterol levels. Researchers discovered that the process is triggered when a protein known as Ral — which Prof Saltiel has previously examined in fat cells — is activated by high levels of dietary cholesterol. The greater the activation of Ral, the fewer LDL receptors remain available to flush cholesterol from the bloodstream. Prof Saltiel explained that the depletion process ultimately hinges on an enzyme called cathepsin A, or CTSA. 'New opportunity' The team found that blocking CTSA using a small molecule inhibitor was sufficient to stabilise LDL receptors and "dramatically lower" circulating LDL cholesterol in mice. Prof Saltiel said: "There's still a real need for new cholesterol-lowering options, since some people can't get to safe levels even with the drugs we have now. "This new pathway we discovered is completely separate from anything that existing drugs target, so it gives us a new opportunity to fill that gap." Following the breakthrough, Prof Saltiel noted that it typically requires considerable further research to develop drugs that can target it. In this instance, however, a CTSA inhibitor has already progressed through the early stages of drug development, originally intended as a treatment for heart failure. Although it was ultimately shelved for strategic reasons, the drug had previously advanced to a Phase 1 clinical trial, where it was successfully assessed for safety. Prof Saltiel believes the new discovery indicates that the investigational drug is now ready to be tested in a Phase 2 trial targeting high cholesterol. He added: "Luckily, there's an experimental drug sitting on the shelf that's already been shown to be safe in humans. "We hope to test whether this might be effective by conducting a clinical trial - which could potentially bring a new treatment option to patients much sooner than would have been expected."