Whoa-zempic!
The landscape of medical weight loss is poised for a significant transformation with the emergence of a new class of medications that target the hormone amylin, presenting a promising alternative to the currently popular GLP-1 receptor agonists like Ozempic. These new amylin-based drugs, being developed by companies such as AstraZeneca, Eli Lilly, Zealand Pharma, and Novo Nordisk, aim to minimize common side effects, particularly nausea, which affects nearly half of those using existing GLP-1 medications. In clinical trials, an amylin-based drug named cagrilintide has demonstrated impressive results, with participants losing approximately 12% of their body weight over 16 months, while those on the combination drug CagriSema, which targets both amylin and GLP-1, achieved an average weight loss exceeding 20%. This advancement raises critical questions in obesity research about the extent of weight loss these medications should aim for, especially when compared to more invasive options like bariatric surgery, which can result in around 30% weight loss but carries significant risks.
The research into amylin, spearheaded by scientists like Thomas Lutz at the University of Zurich, has evolved since the hormone was first isolated in the 1990s. Initially overlooked in favor of more prominent hormones like GLP-1 and leptin, amylin is now gaining recognition for its role in appetite regulation and weight management. Unlike pramlintide, an earlier amylin analogue that required multiple daily injections and offered modest weight loss, cagrilintide is administered weekly, making it more user-friendly and effective. As pharmaceutical companies explore a variety of hormonal mechanisms to enhance weight loss, the potential for combination therapies is expanding, with experts suggesting that targeting multiple hormones could lead to more effective treatments. However, this raises concerns about the implications of aggressive weight loss strategies, particularly for individuals who may not require significant weight loss to achieve health improvements.
As the medical community grapples with the ethical and health implications of these powerful new drugs, the debate intensifies around the appropriate weight loss goals for patients. While losing just 5% of body weight can improve metabolic health, those with higher obesity levels may need to lose more to address serious health issues. However, the risk of excessive weight loss, especially in those who may not need it, poses a danger of losing muscle mass and bone density, as noted by experts in the field. With the rise of online pharmacies and less stringent medical oversight, there is a growing concern that individuals might misuse these medications to achieve unrealistic body image goals. The medical community must navigate these challenges carefully, ensuring that patients receive safe and effective treatments while also addressing the societal pressures surrounding weight loss. As we look to the future, the next generation of weight-loss medications promises to revolutionize obesity treatment, but it also necessitates a thoughtful approach to their use and the potential consequences of their effectiveness.
Medical weight loss might be on the verge of a further revolution. For starters, people will likely have the option of taking a new class of medications that seem to have fewer bothersome side effects, such as nausea—which affects about half the people on Ozempic and similar drugs.
Those now-familiar medications target a pathway involving the appetite-regulating hormone GLP-1; the new ones target cell receptors for a different hormone, amylin. AstraZeneca, Eli Lilly, Zealand Pharma, and, of course, Novo Nordisk, which makes Ozempic, are all testing amylin-based obesity drugs. And if the increasing number of new weight-loss medications seems hard to choose from, you might not have to pick just one. Some medications in development, such as CagriSema, go one step beyond, combining components that target amylin
and
GLP-1 to make even more powerful drugs.
In a recent trial, individuals with obesity who took an amylin-based drug called cagrilintide lost about 12 percent of their weight over the course of 16 months. Those on semaglutide, the active ingredient in Ozempic, lost about 15 percent. Those taking CagriSema lost, on average,
more than 20 percent
. (By comparison, bariatric surgery, a dramatic procedure that reconfigures the digestive system, can cause a person to lose about 30 percent of their weight—but it comes with the possibility of serious complications such as hernias and life-threatening infections.) These new combination drugs are pressing weight loss far enough past the limits of existing drugs that the field of obesity research is facing an unprecedented question: How far should medical weight loss go?
Thomas Lutz, who is known by his contemporaries as the “amylin guy,” has been conducting amylin research at the University of Zurich since the early 1990s, beginning only a few years after amylin had been
isolated
and
characterized
in pancreatic cells. Some scientists looked at the molecule with suspicion because it had been isolated in deposits within the pancreas of diabetic patients. Lutz and others helped show that it could reduce appetite in animals. But, perhaps partly because of the lingering mystery of why amylin deposits occur in the body, he found that the wider field took quite a while to get interested in his and other amylin researchers’ work. “We were probably considered outsiders by many others in the field,” Lutz told me. Most of his peers were focused on GLP-1, or leptin, or other peptides—molecules made of the same building blocks as proteins, but smaller. “Not many labs really focused on amylin.”
The compound has been used as a drug in the past, Lutz said, albeit in less potent incarnations. Pramlintide, an analogue of amylin, was approved by the FDA for treating diabetes in 2005. The formulation degrades rapidly enough that it has to be injected before every major meal, though; cagrilintide sticks around longer and is injected only
once a week
. Pramlintide also doesn’t have as big an effect on weight loss compared with the more recent array of amylin drugs. In one trial, twice as many people receiving it lost at least 5 percent of their body weight after four months, relative to those receiving the placebo. But that’s a modest effect.
Amylin is just one of a bevy of hormones involved in metabolism that pharmaceutical companies are thinking of using as components in future weight-loss therapies. “Companies are kind of going down the list,” looking at peptides that are secreted after meals and might have commercial potential, Kevin Hall, a metabolism scientist and co-author of the new book
Food Intelligence
, told me. There are drugs in the works that join the action of GLP-1 with that of GIP, a hormone released from the upper intestine, despite uncertainty about how GIP influences appetite. Some companies are looking at drugs based on the hormone glucagon. Others are investigating peptide YY, a gut hormone that signals to the brain that a meal has been consumed.
Because the body tends to adapt to drugs that depend on just one hormonal mechanism, combination medications that target multiple hormones should yield more effective treatments, Beverly Tchang, an endocrinologist at Weill Cornell Medicine who’s on the governing board of the Obesity Society, told me. As the available combinations increase and the weight-loss effects presumably nudge up as well, the question becomes: How much weight loss should these medications aim to produce? “The fact that we have to ask that question is crazy,” Tchang said. “Five years ago, we couldn’t ask that question, because we weren’t hitting these thresholds.”
For many individuals with obesity who lose about 5 percent of their weight, their blood levels of certain fat molecules start to improve. At about 10 percent weight loss, their risk of
heart attack and stroke
typically goes down. When weight loss reaches more than 15 percent, some people start to see the resolution of health problems that often go hand in hand with obesity. “It’s not that their high blood pressure is only getting better,” Tchang said. “It’s going away.”
But not everyone sees their risk factors go away when they lose 15 or 20 percent of their weight, which is one reason doctors see a market for more potent drugs. Many people who are morbidly obese need to shed a higher percentage of weight to achieve certain health goals, which is why some undergo bariatric surgery, even with all of its associated risks. Of course, people who are less obese might not benefit from losing a lot of weight. “Not all of our patients need 20 percent, 25 percent, 30 percent weight loss,” Timothy Garvey, an endocrinologist and professor at the University of Alabama at Birmingham who has led trials of amylin drugs, told me. “In fact, it’s unhealthy for many people, and it’s way beyond what we need to improve health.”
Doctors often consider body mass index (the imperfect but broadly used measure based on someone’s weight and height) to judge if someone is over- or underweight: A BMI of less than 18.5 is considered underweight. If someone’s weight loss causes their BMI to fall below that in a clinical trial, the person generally has to leave the experiment. But social pressures to lose weight can be tremendous, and GLP-1 drugs are already available at online pharmacies, where physician oversight is less rigorous. Some doctors worry that if more potent combination drugs come along—at the same time that generic GLP-1 drugs are available—people might take their weight loss too far.
Since GLP-1 drugs have been widely available, people have used them not just to tend to their health but also to modify their appearance. Christoffer Clemmensen, an obesity researcher at the University of Copenhagen, drew a parallel between the excessive use of weight-loss medications and inappropriate uses of anabolic steroids to bulk up muscles. Without support from a doctor or other medical professionals, people using these drugs, or even more effective ones, could lose significant muscle mass, Michael Lyon, the medical director of the Obesity Medicine and Diabetes Institute in a suburb of Vancouver, British Columbia, told me. In some rare cases, people’s weight loss on GLP-1 drugs doesn’t level off. “They just keep losing and keep losing,” Garvey said. “You are losing bone; you’re losing muscle.” Already, people who want to lose weight have some of the most powerful tools ever available. In the next year, they’ll likely have even more options.
