This is the second in a three-part series on the obesity crisis. Part one tackles a complicated question – why does the obesity rate keep rising despite our efforts to stop it? -- and can be found here. Part three shows how doctors and patients can make treatment better and can be found here.
July 5, 2023 -- In the mid-1980s, Louis Aronne strolled into a lab at Rockefeller University where a colleague was breeding mice. “I will never forget what he showed me,” said Aronne, now the director of obesity research and treatment at Weill Cornell Medicine in New York City. “He had a cage with 10 mice, one severely obese and the others normal weight. He took blood from one of the thin mice and gave it to the fat mouse.”
When Aronne returned 3 days later, that obese mouse had turned thin.
It was proof of something Aronne already suspected: Obesity had biological causes and wasn’t just a failure of willpower.
Years later, in 1994, that research led to the discovery of leptin, a hormone released from fat cells that’s involved in the regulation of body weight. It was a watershed moment in obesity research.
Since then, Aronne and others have worked to build the clinical field of obesity medicine, attempting to shift the public and medical view of obesity from a purely behavioral issue to a disease worthy of medical treatment.
All the while, the U.S. obesity rate soared.
Now, another watershed moment: We finally have highly effective obesity drugs. The hype is real, and so are the weight loss results.
“I’ve been saying for 30 years that when we find treatments that really work, people aren’t going to believe the results,” Aronne says. “It took longer than I expected, but it’s gratifying now to see.”
All this excitement raises a crucial question: Will the new drugs finally end the obesity crisis? Experts have their doubts.
The Big Question
The emerging class of obesity medications known as GLP-1 agonists is indeed a game changer. The weight loss drug semaglutide (Ozempic, Wegovy) showed groundbreaking results, and studies suggest a parade of even more impressive drugs are on the way.
Yes, the drugs offer new hope to millions with obesity complications. But to truly turn the tide on our 42% obesity rate, much more work remains to be done, researchers said, including answering a big question:
How do these weight loss drugs work?
“We have new blockbuster drugs, and we don’t even know why they reduce body weight,” says Samuel Klein, MD, professor of medicine and nutritional science at Washington University School of Medicine in St. Louis. “It was by accident that this was discovered.”
Oops, We Created a Weight Loss Drug
Developed to treat diabetes, the GLP-1 drugs’ weight loss effects were a surprise. Now that those effects are confirmed, pharmaceutical companies and researchers are racing to figure out how these drugs work.
In the 1960s, scientists discovered the incretin effect – when you eat glucose (sugar), your body makes more insulin than it does if glucose is given intravenously. Glucose passes through the GI tract and the gut releases hormones that stimulate insulin secretion. It’s “essentially a feed-forward signal to your pancreas to tell it, 'By the way, you need to be ready because there’s a bunch of glucose coming,'” said Randy Seeley, MD, director of the Michigan Nutrition Obesity Research Center, funded by the National Institutes of Health.
One of these hormones -- or “incretins” -- is GLP-1. In experiments, people with type 2 diabetes who were hooked up to GLP-1 saw their blood sugar go down.
“That led to the idea that if we could take this native hormone and make it last longer, we’d have a therapy for type 2 diabetes,” said Seeley. Thanks to a GLP-1-like compound in the saliva of the Gila monster, that idea became reality in the 2000s.
Along the way, a surprising side finding came to light: In early trials, diabetes patients on these drugs dropped weight.
Both Ozempic and Wegovy -- brand names for semaglutide -- are once-weekly injections (pill forms to treat obesity are on the way), but the latter is a higher dose.
“That dose results in about 40% of patients in the clinical trials achieving a 20% weight loss. We’ve just had nothing like that in terms of efficacy before,” said Seeley, who has worked with some of the drug companies (including Novo Nordisk, the maker of Ozempic and Wegovy, and Eli Lilly, maker of Mounjaro) that market the GLP-1s.
By contrast, semaglutide’s once-a-day predecessor liraglutide (Saxenda, also made by Novo Nordisk) can lead to about 10% weight loss.
“And one of the ironies is, we don’t really know why,” Seeley says. “We don’t know why semaglutide is a better molecule for weight loss than liraglutide.”
Initially, scientists believed that the drugs, in addition to telling the pancreas to secrete more insulin, were also signaling the brain that you’re full. “Turns out that’s not really the way it works,” Seeley says. “GLP-1 made from your gut probably doesn’t get into your brain very much. But you make GLP-1 in your brain as well.”
For weight loss, it’s the brain’s GLP-1 system, not the gut’s, that the drugs are thought to hijack. But exactly which parts of the brain they affect and how is unknown. “That’s something lots of people are working on, including our own lab,” Seeley said. (Another surprise: The drugs may have potential as an anti-addiction treatment.)
The diabetes medication tirzepatide (Mounjaro), expected to be approved for weight loss as early as this year, is also a weekly injection, but it has a unique feature: It starts a response not just for GLP-1 but also for another incretin called GIP. Turns out, two is better than one: Trial participants on tirzepatide lost up to 22.5% of their body weight.
More of these hybrid drugs are on the way, Seeley said. In mid-stage clinical trials, the drug retatrutide, which targets three hormones, led to 24% weight loss. “The idea is the more bullets we can load into the gun, the more we can push the biology into a place where it’s easier to lose weight.”
Shifting From Prevention to Damage Control
Less invasive and more scalable than surgery (only 1% of the eligible population gets bariatric surgery), the drugs offer doctors a safe, effective way to treat many patients with obesity. That’s cause for excitement, but concerns remain because they are expensive, costing about $800 to $1,300 per month out of pocket. Many health insurers, including Medicare, do not cover them for weight loss.
“You have this significant advance in obesity treatment, but very few will be able to access it,” said Gary Foster, PhD, adjunct professor of psychology in psychiatry at the University of Pennsylvania and chief scientific officer at WW (formerly Weight Watchers).
There is a push, including a proposed bill, to get Medicare to cover obesity medication. But given the expense of the drugs, the health economics do not support that move, according to an editorial in the New England Journal of Medicine. If Medicare were to cover obesity meds, the budget impact would likely be huge, potentially driving up premiums. If other payers followed suit, the impact could be felt across the U.S. health care system.
Other drawbacks include side effects – including nausea, diarrhea, stomach pain, and vomiting – that can be so bad that some patients can’t tolerate them.
And critically, the drugs do not deal with the root cause of the problem, said Robert Lustig, MD, an endocrinologist and pediatrician at the University of California, San Francisco, who has suggested that excess insulin is driving obesity. “No one has the disease that these drugs are treating. No one has GLP-1 deficiency. They’re bypassing the problem. They’re band-aiding the problem.”
Because the drugs work by mimicking starvation – they appear to curb hunger, so you eat less – people on them lose not just fat but also healthy lean mass, Lustig said.
Concerns about pancreatitis did not really bear out in post-marketing reports. (The drugs are still not recommended in people with pancreatitis, or a history of a type of thyroid cancer or a type of tumor called multiple endocrine neoplasia.) But predicting longer-term outcomes can be hard, notes Lustig.
Then there are philosophical questions, said James Hill, PhD, director of the Nutrition Obesity Research Center at the University of Alabama at Birmingham.. “If you’re continuing to not exercise and eat not healthy foods and take a medication, is that success? Have we won when people are at a lower weight but not doing a healthy behavior?”
‘We Can’t Treat Our Way Out of This’
The fact is, ending the obesity epidemic is a tall order, even for drugs as impressive as these.
“We can’t treat our way out of this,” said Jamy Ard, MD, co-director of Wake Forest Baptist Health Weight Management Center in Winston-Salem, NC. “The treatments we have now are great, and there will be more coming. But we do need to figure out the prevention side of things.”
Seeley agrees but adds we can’t diet-and-exercise our way out either.
“There’s no switch to be flipped,” Seeley says. “If you told me we shouldn’t spend all this money on these drugs, we should spend it on prevention – great! What would we do?”
And prevention efforts won’t help the millions already living with health problems from obesity, Aronne said.
“Getting people to stop smoking prevents lung cancer. But stopping smoking doesn’t treat lung cancer,” Aronne said. “Once the physical changes occur in the lung that cause a tumor to grow, it’s too late. You have to think of obesity the same way.”
Seeley points out that “fearmongering” around the drugs highlights our lingering bias that obesity is a lifestyle issue that should not be medically treated.
“People say, ‘When you stop taking it, you’re going to gain the weight back,’” Seeley said. “There’s truth to that, but when you stop taking your hypertension medication, your blood pressure goes up. We don’t think of that as a [reason] for why you shouldn’t take your blood pressure medication. But that gets trumpeted into all these conversations about whether people [with obesity] should be treated at all.”
Like obesity, blood pressure was once thought to be a behavioral problem too, Aronne said. But blood pressure meds prevent heart attacks and strokes. And it's likely obesity meds will do the same.
One 55-year-old patient on the road to kidney failure lost weight on obesity medications, including semaglutide, Aronne said. Now, 6 years later, his kidney function is back to normal. “Normally, we think of kidney disease as irreversible,” Aronne said.
In that respect, these drugs should save money in the long run by virtue of heading off those health care costs, said Seeley, who imagines a future where obesity is not gone but better managed, like high blood pressure is now.
In the end, the drugs are another step toward what Aronne and many others have always pushed for: Treating obesity as a disease.
How doctors and patients can do everything better -- read part three here.
