The Gene That Explains the Surprising Side Effects of Statins


Statins, one of the most studied drugs in the world, adopted by tens of millions of Americans alone, they have had negative effects for a long time. Most patients—about 5 percent in clinical trials, and up to 30 percent in observational studies—experience muscle pain, especially in the upper arms and legs. A very small minority, less than 1 percent, develop muscle weakness or myopathy so severe that it is difficult for them to “climb the stairs, get up off the couch, get up from the toilet,” says Robert Rosenson, a cardiologist at Mount Sinai. He has caused patients to fall into the street because they could not lift their leg over the curb.

But why should anticholesterol drugs weaken the muscles of the arms and legs? Recently, two groups of scientists did not find the answer. They did not want to study statins. They weren’t studying cholesterol at all. They were looking for genes that cause a very serious disease called limb girdle muscular dystrophy. After all these groups investigated the disease through a few families in the US and a Bedouin family in IsraelTheir suspicions in particular came down to mutations in the gene encoding the most interesting enzyme.

The enzyme is known as HMG-CoA reductase, and to doctors, it is unknown. In fact, it is the enzyme that statins inhibit to prevent the production of cholesterol. And so, a answers to two mysteries it suddenly became known at the same time: Disruption of this protein causes muscle weakness from leg girdle and muscular dystrophy with statins.

This connection between a rare disease and a common medicine surprised researchers. Joel Morales-Rosado, a medical expert who worked on one of these studies as a postdoctoral researcher at the Mayo Clinic said: “It seemed too good to be true. “One of the first things you learn in medical school is the connection between statins and myopathy. Now the answer to the cause—along with a possible treatment—has emerged from the DNA of only a handful of patients with a seemingly unrelated disease.

The first patient the Mayo team studied had been showing symptoms of girdle muscular dystrophy since childhood, and her symptoms worsened over time until she was unable to walk or breathe easily. (The disease can also affect the large muscles of her pelvis.) Now in her 30s, she wanted to know the cause of her condition before having children and the possibility of passing it on to them. His two brothers also had the disease. So the team looked at the genes that all three brothers had mutated in both copies, in which they mutated the HMG-CoA reductase gene.

Six more patients from four other families confirmed the connection. They also all had the same gene mutation, and they were all diagnosed with muscular dystrophy. (Interestingly, for reasons we do not understand, they all have normal or low cholesterol.)

Unbeknownst to the Mayo group, a group of researchers halfway around the world was already studying a large Bedouin family with a history of muscular dystrophy. This family also carried mutations in the HMG-CoA reductase gene. The patients began to experience minor symptoms in their 30s, such as muscle spasms, which worsened over time. The oldest members of the family, in their late 40s or 50s, had lost the use of their arms and legs. A bedridden woman had to breathe constantly through her windpipe. One had died in their mid-50s, Ohad Birk, a geneticist and physician at Ben-Gurion University of the Negev, Israel, told me. When his team noticed that the family had a mutation in HMG-CoA reductase, they also immediately recognized the potential connection with statins.

The two studies in the US and Israel “strongly show” that statins cause muscle damage through the same HMG-CoA reductase pathway, says Andrew Mammen, a neurologist at the National Institutes of Health who was not involved in any of the research. He told me that the activity of the enzyme was suspected, but “never proven, especially in humans.” (Questions remain, however. For example, the enzyme is found in tissues all over the body, so why do these effects appear in muscle in particular?) Rosenson, at Mount Sinai, wondered if this genetic variation could explain why. statins do not affect everyone equally. Perhaps patients with serious muscle problems already have low levels of the enzyme, which is difficult unless they start taking statins, which reduce their effectiveness. This research could improve the lives of some patients who have been severely affected by statins.

That’s because Birk’s team in Israel didn’t stop at identifying the changes. For twenty years, he and his friends have been studying hereditary diseases in this Bedouin community in the Negev and making genetic tests so that parents can avoid passing it on to their children. (Cousin marriages are traditional there, and when two parents are related, they are more likely to carry and pass on the same mutation to a child.) With limb girdle muscular dystrophy, his team went one step further than usual: They found a cure. treatment.

The drug, called mevalonolactone, allows muscle cells to function properly even without the enzyme HMG-CoA reductase. Birk’s team first tested it in mice given high doses of statins to weaken their legs; those who were also given mevalonolactone continued to crawl and hang from the wire upside down. They didn’t seem to be sick at all. When the experimental drug was administered to a Bedouin woman who was bedridden and had weakened muscles in her legs and feet, she regained control of her arms and legs. Eventually he was able to raise his hand, sit on his own, lift his knees, and even feed his grandson by himself. It was a big change. Birk told me that he had heard of many patients with muscle wasting problems around the world who could benefit from this treatment.

Mammen and others think the drug may also help a small group of patients who take statins. However, many patients—those with mild or moderate pain that goes away after switching statins or reducing their dose—may not need this new treatment. It may also block the overall absorption of statins: Mevalonolactone eventually turns into cholesterol in the body, so “you’re giving yourself the building blocks to make more cholesterol,” Mammen said. But for some people, numbering in the thousands, severe muscle weakness does not go away even after they stop taking statins. These patients have it developed antibodies to HMG-CoA reductasewhich Mammen suspects continues to bind and inhibit the enzyme.

Mammen is eager to get these patients to try mevalonolactone, and has contacted Birk, who unfortunately does not have enough of the drug to distribute. In fact, he doesn’t even have enough to do for the rest of the family in Israel who are clamoring to do so. “We are not a factory. “We are a research lab,” Birk told me. Mevalonolactone is available as a research drug, but it is not pure and safe for people to drink. Birk’s graduate student Yuval Yogev had to create the drug himself using genetically modified bacteria to produce mevalonolactone, which he purified with difficulty. and this standard is a big undertaking, even for commercial labs. Birk is looking for a pharmaceutical company that can produce the drug on a large scale – for both patients with rigid-limb muscular dystrophy and those with more severe forms of statin-related muscle damage .

Back in 1980, the first person to receive experimental dose of statins His muscles became so weak that he could not walk. (He was given a very high dose.) Forty years later, muscle pain and weakness are still the most common reasons patients give up this powerful drug. This latest breakthrough is pointing researchers toward a better understanding of how statins damage muscle, although they still can’t fix everyone.


Source link

Leave a Reply

Your email address will not be published. Required fields are marked *