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A century ago, August Krogh, a Danish physiologist who had just won the Nobel Prize, embarked on a U.S. lecture tour. Krogh studied the intricate network of blood vessels that nourish our muscles, but he was increasingly interested in diabetes—a condition that his wife, the physician Marie Krogh, not only treated but also suffered from. Marie asked her husband to stop in Toronto, where a surgeon and a medical student had experimented with “pancreatic extract,” which appeared to shift sugar from the bloodstream into muscles and other organs. Krogh returned to Denmark with permission to sell the stuff. He and some colleagues started Nordisk Insulinlaboratorium, and in the spring of 1923 they injected their first patients with an early miracle drug: insulin.
The next year, two Nordisk employees, brothers named Thorvald and Harald Pedersen, left the company. Krogh apparently asked Harald, “What are you going to do?”
“We want to make insulin,” Harald responded.
“Well, you’ll never manage that,” Krogh said.
Krogh was wrong. The Pedersens founded Novo Terapeutisk Laboratorium, and for decades, the two rival companies produced much of the world’s insulin. In the early days, they operated hospitals mostly for people with Type 1 diabetes, a previously fatal autoimmune condition in which the body produces little or no insulin. In the second half of the twentieth century, however, their market grew: obesity and an associated condition, Type 2 diabetes, were becoming more common. Novo and Nordisk, which merged in 1989, explored other potential diabetes remedies, including a naturally occurring hormone, GLP-1, that appeared to exert exquisite control over blood sugar. It would eventually form the basis for one of the world’s most profitable drugs.
Krogh once argued that, for many biological problems, “there will be some animal of choice, or a few such animals, on which it can be most conveniently studied”—an insight known as Krogh’s principle. Originally, GLP-1 wasn’t considered a useful medicine because it dissolved too quickly in the body. But in the nineteen-nineties, as though in homage to Krogh, an endocrinologist at the Department of Veterans Affairs discovered that the venom of Gila monsters, a type of lizard native to North America, carried a peptide similar to GLP-1 that lasted for hours. He licensed his finding to researchers who developed a twice-daily injection that imitated the lizard peptide. Meanwhile, scientists at Novo Nordisk developed their own GLP-1 analogue and, in 2010, released a once-daily injection called liraglutide, or Victoza, for Type 2 diabetes. The GLP-1 drugs had another effect, too: people taking them lost a little weight.
If the story ended there, so-called GLP-1 agonists—also known as incretin mimetics, because they mimic natural gut hormones—would not be very well known. But Novo Nordisk wanted a medication that people didn’t have to inject every day, so it developed a once-weekly formulation. For reasons that remain a mystery, semaglutide, which is sold under the brand names Ozempic and Wegovy, caused profound reductions in weight. A two-hundred-pound woman might easily lose thirty pounds on the medication. People who had struggled to lose weight since childhood suddenly could.
Last year, the news spilled from scientific journals onto social media, generating hope for patients, excitement among doctors, and a windfall for Novo Nordisk. It is now the most valuable listed company in Europe, worth nearly half a trillion dollars, and Novo Nordisk is responsible for essentially all of Denmark’s recent economic growth. Meanwhile, there are scores of similar drugs in development, including pills, which patients prefer to injections. In June, a clinical trial sponsored by Eli Lilly found that a pill with the melodious name orforglipron caused weight reductions on par with Ozempic’s. Soon, millions of people could wake up, brush their teeth, and swallow their orforglipron along with their multivitamins or baby aspirin.
The science of GLP-1 agonists has often zigged, and now it might zag. GLP-1 produces all sorts of cascading effects; the human body has receptors for it not only in the gut but also in the liver, muscles, and brain. Studies keep turning up surprises: some of the medications appear to reduce the incidence of heart attacks and strokes, slow the progression of kidney disease, and shrink dangerous fat deposits in the liver. People who take them have reported diminished cravings for alcohol and tobacco; some have reported feeling less compelled to gamble, compulsively pick at their skin, and engage in other addictive behaviors. “It’s an unprecedented situation,” Christian Hendershot, a University of North Carolina clinical psychologist who is studying semaglutide’s effect on alcohol use, told me. “The anecdotal reports of people saying these drugs are helping them cut back on drinking or smoking have come much faster than our clinical studies can confirm.” Lizard venom helped to turn an obscure hormone into potent diabetes medications, and then into the most promising weight-loss treatments in history. We’re still discovering how much they’ll change our lives.
Obesity has existed in some form since antiquity. So-called Venus figurines, which date back tens of thousands of years, portray women with wide hips and bellies that, in times of food scarcity, might have signified wealth and well-being. But, over time, obesity has assumed harshly negative connotations. When Alexander Hamilton was Treasury Secretary, his sister-in-law, in England, fretted in a letter that “our dear Hamilton writes too much and takes no exercise and grows too fat.” Just before assuming the Presidency, William Howard Taft, perhaps the first American politician to be defined by his weight, enlisted the services of a British weight-loss physician. “No real gentleman,” Taft wrote, “weighs more than 300 pounds.” His weight yo-yoed for the rest of his life, and a generation of cartoonists ruthlessly caricatured him. According to one study, between 1922 and 1999, a period when many Americans gained weight, the average weight of a beauty-pageant winner declined by twelve per cent. An unrealistic and often harmful ideal of beauty was taking hold, even as sedentary jobs, targeted advertising, and ultra-processed foods made it less attainable. Corporations were hiring food scientists to test combinations of sugar, salt, and fat that hijacked the brain’s reward circuitry. “We’ve built a consumer society that extracts profit from consumers by exploiting our inability to control our cravings,” Scott Galloway, an N.Y.U. marketing professor and podcaster, told me. “The industrial food complex offers us what we’re evolutionarily unable to resist.”
It is hard to overstate how little progress the United States has made on this issue. Weight is not always a health problem: people with larger bodies can be metabolically healthy, just as people with normal B.M.I.s can develop diabetes and heart disease. But, over the years, obesity has been medicalized because of its links to diabetes, hypertension, and heartburn; arthritis, strokes, and heart disease; cirrhosis, sleep apnea, and kidney failure; depression, infertility, and cancer. Even so, the share of the population that is overweight has increased virtually every year since the nineteen-seventies. In the years after the National Institutes of Health essentially declared war on obesity, in 1998, rates of severe obesity doubled, and deaths from obesity-related heart disease tripled.
These poor results are not for lack of trying: when prescriptions of “diet and exercise” proved insufficient, there were the fen-phen debacle of the nineties, the Atkins craze of the early two-thousands, and the soda taxes of the twenty-tens. Advocates have argued for more walkable neighborhoods, changes to food subsidies, and the removal of junk foods from vending machines in schools; researchers developed protocols that produced small reductions in weight, only to see patients quickly gain it back. Today, nearly three-quarters of the U.S. population is considered overweight, and more than forty per cent is considered obese. Globally, twice as many people are overweight today as there were humans on the planet a century ago. Too often, obesity has been blamed on bad choices. In truth, it is a condition that, perhaps more than any other, has been manufactured by modernity.
As a doctor, I regularly treat patients for whom obesity has worsened an illness or complicated a treatment. Often, the impact is obvious: severe sleep apnea makes an older woman’s pneumonia worse; a man who doesn’t drink suffers from cirrhosis, because fat has infiltrated and inflamed his liver; an adolescent who has been mercilessly bullied for her weight arrives in an emergency department with suicidal thoughts. At other times, the medical system itself can make it harder for patients. Years ago, when I was still in medical training, I was surprised when a surgeon refused to operate on a patient of mine who was overweight. Obesity, I learned, is linked to complications like wound infections, blood clots, kidney problems, and difficulty weaning off a ventilator. But my patient had a medical condition that made it difficult for him to exercise, and his job as a taxi-driver made it virtually impossible. Asking him to lose fifty pounds before a surgery that we all knew he needed seemed cruel and futile.
For patients like these, the new medications could be transformative. Doctors who once had little to offer could soon have many effective treatments to choose from. Ozempic and its sister drug, Wegovy, mimic the effects of GLP-1 to lower blood sugar, suppress appetite, and produce a faster sense of fullness. In clinical trials, people who’ve taken the medications have lost, on average, fifteen per cent of their weight. A newer drug, Mounjaro, also mimics a second hormone, producing even greater reductions in weight; in Phase II trials of retatrutide, a “triple-agonist” that mimics three hormones, people taking the highest dosage lost nearly a quarter of their body weight—a decline approaching that of a much more invasive intervention, gastric-bypass surgery. These drugs tend to make food less appealing, leading to fundamental and durable health benefits, at least while patients take them.
Over the past year, demand for Ozempic, Wegovy, and Mounjaro has greatly outstripped supply, creating persistent shortages for patients who need them. (Technically, Ozempic and Mounjaro are approved for diabetes, while Wegovy and Zepbound are approved for obesity. In practice, all have been used for weight loss, and “Ozempic”—which was the first to market—has become a kind of shorthand for the class.) Suspected fake Ozempic pens have spread across Europe and caused several people in Austria to be hospitalized; in the U.S., some have turned to off-brand compounding pharmacies for their supply. Unfortunately, unreasonable beauty standards are driving some of the demand, showing us just how far we are from having truly healthy relationships with our bodies. People have used the drugs to get into wedding shape, and have taken out credit cards or second jobs to pay for them; wealthy Americans look around at thin neighbors and ask, “Who’s on Vitamin O?” This spring, speaking to a crowd of annoyingly attractive actors at the Academy Awards, Jimmy Kimmel mused, “When I look around at this room, I can’t help but wonder: Is Ozempic right for me?”
Galloway, the marketing professor, is convinced that new weight-loss drugs will reshape American society almost as profoundly as processed foods once did, leading to better health, elevated moods, more sex, deeper creativity, and even a reorientation of the capitalist drives that manufactured our obesity epidemic. In a sense, the enormous collateral damage of one industry, Big Food, is helping to supercharge another industry, Big Pharma. In recent months, shares of beer, snacking, and fast-food companies have fallen, in anticipation of the changing consumption habits of tens of millions of Americans. (Investors seem to hold special concern for the prospects of Krispy Kreme.) Some think that lighter passengers could save airlines millions on fuel costs, and medical-device manufacturers are scrambling to assure investors that people will still need glucose monitors and knee prosthetics. Obesity is a problem that our high-tech society invented; now we’re finding out whether technology can also be the solution.
The Ozempic revolution could still disappoint us. For one thing, the medications don’t work for everybody. “Everyone wants to be that person they see on TikTok or Instagram who lost fifty pounds,” Fatima Cody Stanford, an obesity-medicine physician at Massachusetts General Hospital, told me. “The reality is that there are high-responders and low-responders, and people need to be prepared that they could fall anywhere along the spectrum.” Stanford wants pharmaceutical companies to study the role of genomics in the effects of GLP-1 drugs: “Why is Jane Doe losing tons of weight while John Doe, poor guy, hardly loses any weight at all?”
Ozempic and Wegovy can cause nausea, constipation, diarrhea, and other gastrointestinal symptoms. A man in his early fifties told me that he has persistently experienced these side effects since starting Ozempic six months ago. He said he lives with the trade-off in hopes of avoiding obesity in old age, when it’s most harmful. “I’ve come to accept that the side effects are kind of how the drugs work,” he said. “It’s the price you pay for gaining the ability to not overeat.” Still, one analysis found that, although most people tolerate the drugs in clinical trials, roughly two-thirds of real-world patients discontinue them within a year. One major downside of the drugs is that if you stop taking them you tend to regain the weight.
Weight loss can come with its own risks for older adults. People can lose fat on the medications, but also bone density and muscle mass, which in turn has been linked to an increased risk of falls and other problems in older individuals. (Several pharmaceutical companies are studying weight-loss drugs that could reduce these potential risks.) “I try not to call these drugs game-changing or earth-shattering or whatever,” Stanford said. “They are another tool in our tool kit. Yes, that tool kit is growing more effective—maybe a lot more effective—but these drugs have some issues, and they should be understood as one part of the over-all solution.”
The cost of the medications presents a further challenge, especially in the U.S., where a thirty-day supply of Ozempic is priced at close to a thousand dollars. (It costs a hundred and forty-seven dollars in Canada, and just ninety-three in the United Kingdom.) Even Americans with health coverage may find that insurers don’t want to pay for decades of drugs, and Medicare, which covers sixty-five million Americans, is currently prohibited from paying for weight-loss medications. (If advocates succeed in changing that, Medicare could face a colossal budgetary problem: if everyone diagnosed with obesity used the drugs, coverage could cost more than the program’s current spending on all other drugs combined.) Meanwhile, Medicaid’s tight budgets could make low-income Americans, who have the highest rates of obesity, the least likely to benefit from the new medications.
Even as new competitors enter the market, reducing prices, “the huge numbers of people who could benefit from these medications, multiplied by the indefinite period of time they need to take them, makes this a very big and very long-term spending problem,” Stacie Dusetzina, a drug-policy expert at Vanderbilt, told me. She pointed out that Sovaldi, an antiviral that can help cure hepatitis C, débuted in 2013 at a cost of nearly ninety thousand dollars; although versions of the drug are now sold for less than half that price, only a third of eligible American adults have been treated. “The fact that we missed so badly with hep C doesn’t inspire a lot of confidence when it comes to drugs,” Dusetzina said. There are some three million Americans with hepatitis C; there are more than a hundred million with obesity.
Early in my medical training, I thought that I might devote my career to fighting obesity. I interned at a tobacco-control organization, hoping to apply the lessons of one public-health campaign to another. I shadowed an obesity-medicine doctor, took classes on food marketing and food addiction, and researched the causes of childhood adiposity. Over time, though, I became disillusioned. Whereas the harms of smoking can be traced to tobacco and the companies that peddle it, obesity is tangled up in our food, jobs, culture, education, and neighborhoods. Year after year, in visit after visit, I couldn’t help feeling that I was failing my patients. As I sat in the clinic, asking them to try “diet and exercise” or intermittent fasting—these appeals have limited effectiveness, according to numerous studies—my recommendations started to feel hollow. I was reading them a script, knowing how the story would end.
Lately, I’ve been thinking back to the moment in late 2020 when COVID treatments and vaccines started to change the course of the pandemic. For months, doctors could do hardly anything as patients suffered and died. Then, suddenly, we could do a lot. Steroids helped patients survive, antiviral medications seemed to reduce symptoms, and soon we had not one but several powerful vaccines. For me as a doctor, the arrival of these medications this past year has felt like a similar kind of tipping point—the moment when a leading threat to human health may finally have started to recede. We may look back on these drugs as some of the greatest advances in the annals of chronic disease. They are not a cure for obesity, or the stigma associated with it; some people will struggle with side effects, and others will struggle to pay for them. But, for many millions of people, our post-Ozempic world will be better than the one we lived in before. For the first time in years, I’m reading from a new script. This one has a more hopeful ending. ♦
Sourse: newyorker.com
