You’re on Ozempic? How Quaint
In recent years, the landscape of obesity treatment has dramatically evolved, with groundbreaking advancements in pharmacological options that promise to redefine how we approach weight management. Following the approval of tirzepatide, marketed as Mounjaro, a new wave of next-generation obesity drugs is on the horizon, poised to offer even more effective solutions. These innovative medications target various hormones and pathways in the body, enabling potential weight loss of nearly 25% on average, and they are designed to cater to the diverse metabolic profiles of patients. As Angela Fitch, chief medical officer at Knownwell, aptly states, “We don’t have a disease of obesity. We have a disease of obesities.” This sentiment underscores the complexity of obesity, suggesting that a tailored approach to treatment may soon be the norm, allowing healthcare providers to match specific medications to individual patient needs.
Currently, available drugs like semaglutide (Ozempic, Wegovy) and tirzepatide (Mounjaro) have shown varying degrees of efficacy, with some patients experiencing significant weight loss while others struggle with minimal results or adverse side effects. For instance, clinical trials indicate that while semaglutide can lead to an average weight loss of around 10%, a third of participants may lose less than 5%, and some may even gain weight. This inconsistency highlights the necessity for a more personalized treatment approach, as one medication may not suit every individual. The next generation of obesity drugs is exploring combinations of hormones to enhance efficacy and reduce side effects. For example, tirzepatide, which targets both GLP-1 and GIP hormones, has shown promising results, with an average weight loss of about 20%. However, researchers are also investigating other combinations, such as GLP-1 plus amylin or glucagon, and even triple-action drugs like retatrutide, which have demonstrated remarkable weight loss potential in early trials.
As the obesity drug market expands, patients may soon have access to a broader array of treatment options tailored to their unique metabolic conditions. This paradigm shift could lead to a trial-and-error approach in finding the most effective medication, with experts envisioning a future where blood tests could predict individual responses to specific drugs. Moreover, the focus on weight loss is evolving; not all patients will seek maximum weight reduction, and some may prioritize convenience or muscle preservation, particularly older adults. Drug manufacturers are responding to these diverse needs by developing formulations such as daily pills or monthly injections. In just a decade, the obesity treatment landscape has transitioned from limited options to a burgeoning field of targeted therapies, suggesting that the future of obesity management will be more personalized and effective than ever before.
“
Ozempic is about to be old news
,” my colleague Yasmin Tayag wrote in 2023, just before an even more powerful obesity drug, tirzepatide, then best known as Mounjaro, was approved. Well, two years later, Mounjaro is becoming old news, too. A whole slew of next-generation obesity drugs are on the horizon, some already advanced enough in clinical trials to be looking as good as—if not better than—those already on the market. The novel medications continue to push the upward limits of weight loss, now to
almost 25 percent
of body weight on average, but they also differ in their modes of action. They target different cells and different parts of cells in the brain and body.
Obesity, after all, is not monolithic. “We don’t have a disease of obesity. We have a disease of obesities,” Angela Fitch, chief medical officer at Knownwell, a national obesity-care clinic, and a former president of the Obesity Medicine Association, told me. With the coming explosion of obesity drugs, doctors could soon match each patient’s condition to their optimal medication: A 25-year-old with fatty-liver disease may need a different drug than a 75-year-old with low muscle mass. About 100 million adults live with obesity in just the U.S., a market massive enough for multiple mediations to find a niche. “One size will not fit all, and one size will not be best for all,” Richard DiMarchi, a chemist at Indiana University who has worked on obesity drugs at both Eli Lilly and Novo Nordisk, told me.
The most obvious way obesity drugs are not one-size-fits-all is that those on the market
do not actually work for all
. Although patients on semaglutide, the drug in Ozempic and Wegovy, lost on average
10 percent of their body weight
, a third lost less than 5 percent in one clinical trial. Some even
gain
weight taking the drug
. And others suffer such terrible side effects, including constant nausea and vomiting, that they cannot take it at all.
Ozempic functions by mimicking a single hormone called GLP-1; the drug’s mode of action is relatively simple but limited. To improve upon Ozempic, drugmakers have started targeting GLP-1 in combination with other hormones linked to hunger and satiety. The second drug currently on the market, the tirzepatide found in Mounjaro and Zepbound, resembles GLP-1 in addition to another hormone called GIP, hitting receptors for both in the brain. The GIP component may serve a double function, promoting additional satiety while suppressing some of the nausea caused by GLP-1. However tirzepatide truly works—and experts caution that no one knows—it prompts, on average,
about 20 percent weight loss
. It’s only the first of the “GLP-1 plus” drugs to market.
Other GLP-1-plus drugs in development include GLP-1 plus amylin, GLP-1 plus glucagon, and GLP-1 plus anti-GIP, which surprisingly could work as well as Mounjaro’s combination of GLP-1 plus GIP. (“If you aren’t confused,” Randy Seeley, an obesity researcher at the University of Michigan, told me, “you aren’t paying attention.”) In fact, all of these combinations seem to work—at least based on preliminary data from clinical trials—even as a precise understanding of the science lags. Some of the hormone mimics, such as for
amylin
, might also
work alone
. And others could be remixed into combinations of more than two. The drug retatrutide, which is in trials, is a triple hitter that targets GLP-1 plus glucagon plus GIP receptors, all at once. In an
early Phase 2 trial
, patients lost on average 24 percent of their weight, the highest of any obesity drug so far. The best responders lost
upwards of 40 percent
.
Even more intriguing than the top-line weight-loss numbers are metabolic changes unique to particular drugs. Glucagon, for example, ramps up liver metabolism; drugs based on this hormone could help break down fat accumulated in the livers of patients who also have fatty-liver disease. (The FDA is expediting review of one such drug, survodutide, for
liver-disease
patients.) Meanwhile, GLP-1-based drugs appear to protect against cardiovascular disease, even
independent of weight loss
. Patients prone to heart disease might fare best on medication that includes a GLP-1 component. When it comes to obesity, Seeley said, “your flavor of metabolic disease will be different than the next person’s.” Obesity drugs of the future may finally reflect that diversity, too.
An extensive menu of obesity drugs that work via distinct biological mechanisms means that patients will have more options to try. If they aren’t losing weight on drug A, they can move on to drug B or C. Experts don’t yet understand why the drugs work differently in different people, but hormone receptors in our brains likely vary in subtle yet important ways. The new drugs not only hit distinct combinations of hormone receptors; they also each tickle those receptors in a unique way.
In the near future, doctors and patients will probably have to trial-and-error their way to what works best. Further down the line, experts tell me, they hope to have a test, such as a blood test, that can forecast how patients will fare. Doctors could tell patients that they’ve got five different drugs at the ready, “and if I do this one test on you, I do this one test on you, I can predict which one of these drugs is the best for you,” Jonathan Campbell, an obesity researcher at Duke University, told me.
Maximum weight loss might not always be the goal for everyone though. The 40 percent that some people lose on retatrutide would be far too much for a patient barely over the BMI cutoff for obesity. Patients who don’t need to optimize weight loss may choose to prioritize convenience instead, which drugmakers are also happy to oblige. Most obesity drugs on the market are formulated as weekly injections. But Eli Lilly is developing a daily pill called orforglipron, and Amgen is testing a monthly injection called MariTide. And some patients, especially those who are elderly with already low muscle mass, might need
extra help preserving their strength
. The powerful appetite suppression that induces fat loss can induce muscle loss too. A number of drugmakers are now trialing obesity drugs in combination with
various
muscle
–
preserving drugs
.
A mere decade ago, obesity drugs powerful enough for people to routinely drop double-digit percentages of their body weight were unheard-of. Today, there are two, and they feel ubiquitous. In yet another 10 years, this toolbox of just two obesity drugs will likely appear tiny and outdated. The next phase of the obesity-drug revolution is coming, with more drugs to choose from.
