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Tag: muscle cells

  • Ozempic Makes You Lose More Than Fat

    Ozempic Makes You Lose More Than Fat

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    The newest and much-hyped obesity drugs are, at their core, powerful appetite suppressants. When you eat fewer calories than you burn, the body starts scavenging itself, breaking down fat, of course, but also muscle. About a quarter to a third of the weight shed is lean body mass, and most of that is muscle.

    Muscle loss is not inherently bad. As people lose fat, they need less muscle to support the weight of their body. And the muscle that goes first tends to be low quality and streaked with fat. Doctors grow concerned when people start to feel weak in everyday life—while picking up the grandkids, for example, or shoveling the driveway. Taken further, the progressive loss of muscle can make patients, especially elderly ones who already have less muscle to spare, frail and vulnerable to falls. People trying to slim down from an already healthy weight, who have less fat to spare, may also be prone to losing muscle. “You have to pull calories from somewhere,” says Robert Kushner, an obesity-medicine doctor at Northwestern University, who was also an investigator in a key trial for one of these drugs.

    Kushner worries about patients who start with low muscle mass and go on to become super responders to the drugs, losing significantly more than the average 15 to 20 percent of their body weight. The more these patients lose, the more likely their body is breaking down muscle. “I watch them very carefully,” he told me. The impacts of losing muscle may go beyond losing just strength. Muscle cells are major consumers of energy; they influence insulin sensitivity and absorb some 80 percent of the glucose flooding into blood after a meal. Extreme loss might alter these metabolic functions of muscle too.

    Exactly how all of this will affect people on Wegovy and Zepbound, which are still relatively novel obesity drugs, is too early to say. (You may have heard these same two drugs referred to as Ozempic and Mounjaro, respectively, which are their names when sold for diabetes.) These drugs cause a proportion of muscle loss higher than diet and exercise alone, though roughly on par with bariatric surgery. Lifestyle changes can blunt the loss, but pharmaceutical companies are on the hunt for new drug combinations that could build muscle while burning fat.

    The arrival of powerful weight-loss drugs has moved the field beyond simple weight loss, Melanie Haines, an endocrinologist at Massachusetts General Hospital, told me. That challenge is largely solved. Instead of fixating on the number of pounds lost, researchers, doctors, and ultimately patients can focus on where those pounds are coming from.

    Doctors currently offer two pieces of standard and unsurprising advice to protect people taking obesity drugs against muscle loss: Eat a high-protein diet, and do resistance training. These recommendations are perfectly logical, but their effectiveness against these drugs specifically is unclear, John Jakicic, a professor of physical activity and weight management at the University of Kansas Medical Center, told me. He is now surveying patients to understand their real-world behavior on these drugs.

    Fatigue, for example, is a common side effect. “When you’re tired, and you’re fatigued, do you really feel like exercising?” he said. Haines wonders the same about eating enough protein. The drugs are so good at suppressing appetite, she said, that some people might not be able to stomach enough food to get adequate protein. (Food companies have started pitching high-protein snacks and shakes to people on obesity drugs.)

    Read: The Ozempic plateau

    If patients stop taking Wegovy and Zepbound—and about half of patients do stop within a year, at least in real-world studies of people taking this class of drugs for diabetes—the weight regained comes back as fat more than muscle, says Tom Yates, a physical-activity professor at the University of Leicester. Muscle mass tends not to entirely recover. It’s “almost as if you’re better off staying where you are than going through cycles of weight loss,” he told me.

    Yet, he pointed out, the U.K. recommends Wegovy for a maximum of two years. In the U.S., patients who can’t afford the steep out-of-pocket price have been forced to stop when insurance companies abruptly cut off coverage or a manufacturer’s discount coupon expires. These policies are likely to trigger cycles of weight loss and gain that lead, ultimately, to net muscle loss.

    Meanwhile, drug companies are already thinking about the next generation of weight-loss therapies. “Wouldn’t it be great to have another mechanism that’s moving away from just appetite regulation?” Haines said. Companies are testing ways to preserve—perhaps even enhance—muscle during weight loss by combining Wegovy or Zepbound with a second muscle-boosting drug. Such a combination could, in theory, allow patients to lose fat and gain muscle at the same time.

    Years ago, scientists first became interested in potential muscle-enhancing drugs that mimic mutations found in certain breeds of almost comically ripped dogs and cattle. At the time, they hoped to treat muscle-wasting diseases. The drugs never quite worked for that purpose, but the trial for one such drug, an antibody called bimagrumab, found that patients also lost fat in addition to gaining lean mass. A start-up acquired the drug and began testing it for weight loss in combination with semaglutide, the active ingredient in Wegovy, or Ozempic. And last year, Eli Lilly, the maker of Zepbound, snapped up that company for up to $1.9 billion—in hopes of making its own combination therapy.

    Read: Are you sure you want an Ozempic pill?

    Pairing bimagrumab with an existing obesity drug could potentially maximize the weight loss from both. Losing weight tends to get harder over time; as you lose muscle, your body burns fewer calories. A drug that minimizes that muscle loss—or even flips it into muscle gain—could help patients boost the amount of energy their body expends, while Wegovy or Zepbound suppresses calories consumed. The mechanisms of how this might actually work in the body still need to be understood, though. Previous studies of bimagrumab found that patients grew more muscle, but they didn’t necessarily become faster or stronger. Haines, who is planning a small study of her own with bimagrumab, is most interested in how the combination affects not the structural but the metabolic functions of muscle.

    Bimagrumab is the furthest along of several drugs that tinker with the same pathway for muscle growth. The biotech company Regeneron recently published promising data on two of its muscle-enhancing antibodies paired with semaglutide in primates; a trial in humans is due to begin later this year. The start-up Scholar Rock is testing another antibody called apitegromab. Other companies are interested in combining the obesity drugs with different potential muscle boosters that work by mimicking certain hormones such as apelin or testosterone. If they succeed, the next generation of drugs could help sculpt a more muscular body, not just a smaller one. Eating less can only do so much to better your health.

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    Sarah Zhang

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  • America’s Most Popular Drug Has a Puzzling Side Effect. We Finally Know Why.

    America’s Most Popular Drug Has a Puzzling Side Effect. We Finally Know Why.

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    Statins, one of the most extensively studied drugs on the planet, taken by tens of millions of Americans alone, have long had a perplexing side effect. Many patients—some 5 percent in clinical trials, and up to 30 percent in observational studies—experience sore and achy muscles, especially in the upper arms and legs. A much smaller proportion, less than 1 percent, develop muscle weakness or myopathy severe enough that they find it hard to “climb stairs, get up from a sofa, get up from the toilet,” says Robert Rosenson, a cardiologist at Mount Sinai. He’s had patients fall on the street because they couldn’t lift their leg over a curb.

    But why should an anticholesterol drug weaken muscles in the arms and legs? Recently, two groups of scientists stumbled upon an answer. They didn’t set out to study statins. They weren’t studying cholesterol at all. They were hunting for genes behind a rare disease called limb girdle muscle dystrophy, in which muscles of the upper arms and legs—sound familiar?—become weak and waste away. After both teams tracked the disease through a handful of families in the U.S. and a Bedouin family in Israel, their suspicions separately landed on mutations in a gene encoding a particularly intriguing enzyme.

    The enzyme is known as HMG-CoA reductase, and to doctors, it is not obscure. It is, in fact, the very enzyme that statins block in the process of halting cholesterol production. And so, the answers to two mysteries suddenly became clear at once: Dysfunction in this enzyme causes muscle weakness from both limb girdle muscular dystrophy and statins.

    This connection between a rare disease and a common drug stunned the researchers. “It seemed too good to be true,” says Joel Morales-Rosado, a pathologist who worked on one of the studies as a postdoctoral researcher at the Mayo Clinic. “One of the first things you learn in medical school is association between statins and myopathy.” Now the answer as to why— along with a potential treatment for it—has emerged from the DNA of just a few patients living with a seemingly unrelated genetic disease.

    The first patient the Mayo team studied had been showing signs of limb girdle muscular dystrophy since he was a child, and his symptoms worsened over time until he lost the ability to walk or breathe with ease. (The disease can also affect large muscles in the torso.) Now in his 30s, he wanted to know the genetic cause of his disease before having children and potentially passing it on to them. His two brothers had the disease as well. So the team looked for genes in which all three brothers had mutations in both copies, which is how they zeroed in on the gene for HMG-CoA reductase.

    Six more patients from four other families confirmed the link. They too all had mutations in the same gene, and they too were all diagnosed with some degree of limb girdle muscular dystrophy. (Interestingly, for reasons we don’t entirely understand, they all have normal or low cholesterol.)

    Unbeknownst to the Mayo team, a group of researchers halfway around the world was already studying a large Bedouin family with a history of limb girdle muscular dystrophy. This family also carried mutations in the gene encoding HMG-CoA reductase. Those afflicted began experiencing minor symptoms in their 30s, such as muscle cramps, that worsened over time. The oldest family members, in their late 40s or 50s, had lost all movement in their arms and legs. One bedridden woman had to be ventilated full-time through a hole in her windpipe. Another had died in their mid-50s, Ohad Birk, a geneticist and doctor at Ben-Gurion University of the Negev, in Israel, told me. When his team saw that this family had the mutations in HMG-CoA reductase, they too immediately recognized the potential link to statins.

    This pair of studies in the U.S. and Israel “really strongly suggests” that statins cause muscle damage via the same HMG-CoA reductase pathway, says Andrew Mammen, a neurologist at the National Institutes of Health who was not involved in either study. The enzyme’s role had been suspected, he told me, but “it had never been proven, especially in humans.” (Questions still remain, however. The enzyme, for example, is found in tissues throughout the body, so why do these common side effects show up in muscles specifically?) Rosenson, at Mount Sinai, wondered if variations in this gene could explain why statins don’t affect everyone the same. Perhaps patients who suffer particularly severe muscle side effects already have less functional versions of the enzyme, which becomes problematic only when they start taking statins, which reduce its function even further. This research might end up concretely improving the life of at least some of the patients most severely affected by statins.

    That’s because Birk’s team in Israel did not stop at simply identifying the mutation. For two decades, he and his colleagues have been studying genetic disorders in this Bedouin community in the Negev and developing genetic tests so parents can avoid passing them 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 drug to treat it.

    This drug, called mevalonolactone, allows muscle cells to function more normally even without the HMG-CoA reductase enzyme. Birk’s team first tested it in mice given doses of statins high enough to weaken their limbs; those also given mevalonolactone continued to crawl and even hang upside down on a wire just fine. They seemed to suffer no ill effects. When that experimental drug was given to the Bedouin woman bedridden with limb girdle muscular dystrophy, she also started regaining control of her arms and legs. She could eventually lift her arm, sit up by herself, raise her knees, and even feed her grandchild on her own. It was a dramatic improvement. Birk told me he has since heard about dozens of patients with limb girdle muscular dystrophy around the world who may benefit from this experimental drug.

    Mammen and others think the drug could help a small subset of patients who take statins as well. However, the majority of patients—those with relatively minor pains or weaknesses that go away after they switch statins or have their dosage reduced—probably don’t need this new treatment. It probably even undermines the whole point of taking statins: Mevalonolactone eventually gets turned into cholesterol in the body, so “you’re basically supplying the building blocks for making 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 developed antibodies to HMG-CoA reductase, which Mammen suspects continue to bind and disable the enzyme.

    Mammen is eager for these patients to try mevalonolactone, and he’s been in touch with Birk, who unfortunately doesn’t have enough of the drug to share. In fact, he doesn’t even have enough to treat all of the other family members in Israel who are clamoring for it. “We’re not a factory. We’re a research lab,” Birk told me. Mevalonolactone is available as a research chemical, but that’s not pure and safe enough for human consumption. Birk’s graduate student Yuval Yogev had to manufacture the drug himself by genetically engineering bacteria to make mevalonolactone, which he then painstakingly purified. Making a drug to this standard is a huge amount of work, even for commercial labs. Birk is looking for a pharmaceutical company that could manufacture the drug at scale—for both patients with limb girdle muscular dystrophy and those with the most severe forms of statin-associated muscle damage.

    Back in 1980, the very first person to receive an experimental dose of statins suffered muscle weakness so severe, she could not walk. (She had been given an extremely high dose.) Forty years later, muscle pain and weakness are still common reasons patients quit these very effective drugs. This recent breakthrough is finally pointing researchers toward a better understanding of statins’ toll on muscles, even if they still can’t fix it for everyone.

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    Sarah Zhang

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