Issue 05
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The future of weight loss

14th September 2021
23 Mins

We have eradicated smallpox, cured many bacterial diseases, and invented a vaccine for Covid-19 within the year. But for a very long time we haven’t had a single good treatment for obesity.

Heart attacks can be prevented with cholesterol and blood pressure drugs, bacterial infections can be eliminated with antibiotics, and even HIV is now treatable with antiviral drugs. But obesity remains a remarkably stubborn condition.

Losing weight is hard, with or without the help of a doctor. Two-thirds of American adults with obesity try to lose weight each year using every diet imaginable, yet the adult obesity rate remains at 43%. Even intensive diet and lifestyle interventions have historically struggled to exceed a sustained 5% loss of body weight, and most weight loss drugs are no more effective. Compounding the problem, primary care doctors often can’t deliver the best diet and lifestyle tools that are available. “I spent my career trying to get primary care providers to deliver effective weight loss interventions in their office,” says Donna Ryan, professor emerita at the Pennington Biomedical Institute and president of the World Obesity Federation. “It’s hopeless.”

Doctors understand the profound impact obesity has on their patients, and the remarkable benefits of even modest weight loss, but have historically been unable to do much about it.

That is changing.

“Our recent experience treating patients with obesity,” says David Macklin, MD, “is similar to the experience physicians have when they provide blood pressure drugs to patients with high blood pressure or asthma medications to patients with asthma. We finally have a drug that effectively treats the condition.” Macklin, an 18-year veteran of obesity medicine and coauthor of the Canadian Adult Obesity Clinical Practice Guidelines, is referring to his two years of experience treating over a thousand people with obesity using the relatively new drug semaglutide.

In his hands, semaglutide causes an average of 18–20% loss of body weight when paired with diet and lifestyle advice. In other words, a person who walks into his office weighing 250 pounds and chooses semaglutide can expect to shed about 48 pounds.

Semaglutide is just the leading edge of a wave of new obesity therapies in development that reflect our deepening understanding of the human body and that promise to fundamentally change the lives of people with obesity.

Outcompeting the surgeons

Macklin’s account may sound like a tall tale, but it’s supported by rigorous randomized controlled trials. The STEP-1 and STEP-4 trials, published this year, report that semaglutide paired with diet and exercise advice caused an average of 15% and 18% loss of body weight respectively, over 68 weeks in people with obesity or overweight.

At lower doses, semaglutide has been in use for type 2 diabetes since the US Food and Drug Administration (FDA) approved it in 2017 and the European Medicines Agency (EMA) and Health Canada approved it in 2018. This is how doctors like Macklin have been able to unofficially use it “off label” to treat obesity. The FDA was impressed enough by the safety and effectiveness of semaglutide that it approved a higher dose of the drug for the treatment of obesity on June 4 of this year under the brand name Wegovy, which requires one injection per week. If you live in the US, it’s currently headed to a pharmacy near you.

There is one, and only one, highly effective weight loss method that predates semaglutide: bariatric surgery. For the low, low price of $20,000, a person can have part of his digestive tract permanently excluded from food contact, altering gut-brain communication and durably reducing body weight by about a quarter for the most common surgery types. Bariatric surgery provides all the health benefits one might expect from the massive loss of body fat it causes. Yet it isn’t a scalable solution to the obesity epidemic, and many people don’t want to undergo a treatment that’s so invasive.

Semaglutide, and the drugs that will follow it, may soon replace most bariatric surgeries. “Slowly, slowly, slowly, we outcompete the surgeons,” predicts Macklin, who is already referring many fewer patients for surgery. “They know we’re coming.”

Semaglutide may sound too much like a free lunch, and it is indeed far from free in a financial sense. Ryan estimates that Wegovy will cost about $1,300 per month in the US, although it will probably cost about a quarter of that in other countries. In the US, many people won’t have immediate access to it due to insurance coverage and other limitations, and it remains to be seen how accessible it will be in other countries.

Compounding this problem is the fact that US insurance companies usually require doctors to submit burdensome “prior authorization” paperwork to justify the prescription of weight loss drugs. “The result is that most doctors don’t fool with it,” explains Ryan. “It tends to be the obesity medicine specialists,” which most people with obesity never see.

Aside from its slimming effect on the wallet, semaglutide often causes other unpleasant side effects like nausea, heartburn, diarrhea, constipation, fatigue, and headache, but they are usually mild and transient if the dose is started low and escalated gradually. “In my clinical experience,” states Macklin, “discontinuation of semaglutide because of side effects is generally nil.” Trials also report that few people stop taking the drug due to side effects.

Some animal studies have also suggested that similar drugs increase the risk of cancer of the thyroid and pancreas. Yet Daniel Drucker, professor of medicine at the University of Toronto and one of the grandfathers of this drug class, emphasizes that these concerns have not been borne out in numerous large drug trials or medical records representing millions of patient-years of treatment. “There’s no signal,” he says, “that’s pretty compelling now after 15–16 years.”

Equally compelling are the trials reporting that semaglutide and related drugs improve metabolic health, reduce cardiovascular disease risk, and reduce deaths from all causes. The PIONEER-6 and SUSTAIN-6 trials showed that semaglutide reduces major cardiovascular events by 21–24% in people with type 2 diabetes and high cardiovascular risk respectively, which is comparable to commonly used cholesterol-lowering drugs. Larger and longer trials are currently underway.

When researchers pool the data from completed trials, they find that semaglutide and related drugs reduce the overall risk of dying by about 12% in people with type 2 diabetes. This tells us that even if semaglutide causes some kind of deadly side effect that hasn’t been identified yet, it’s likely to be more than offset by the drug’s benefits.

This robust safety data is important because, historically, the deadly side effects of weight loss drugs have often flown under the radar until it’s too late.

From high explosives to reverse marijuana

The history of medicine is littered with failed weight loss pills. One of the first popular weight loss drugs was 2,4-dinitrophenol, a high explosive used in munitions in World War I. When ingested, it has effects that are equally incendiary: it causes the little power plants in our cells to waste calories as heat, which increases metabolic rate by 30–50% at a commonly prescribed dose. The largest study of the drug, published in 1935 by an enthusiastic team of doctors in the prestigious Journal of the American Medical Association, reported that it caused an average of 17 pounds of weight loss over three months. However, 2,4-dinitrophenol is hard to dose correctly and happens to occasionally cook people from the inside out when they take too much, among other serious side effects. Its use in humans was banned in the US in 1938 under the Food, Drug, and Cosmetic Act, although a few people still use it illegally.

A more recent but equally bitter failure is that of rimonabant, which acts on the brain in a manner opposite to marijuana. You can think of it as “reverse marijuana,” and its effects on appetite as the “reverse munchies”: a reduction in hunger and the seductiveness of calorie-rich foods. Large trials in Europe and North America published in 2005 and 2006 reported that rimonabant caused a 6% loss of body weight over one to two years in people with obesity or overweight when combined with a low-calorie diet and exercise. “Rimonabant was generally well tolerated,” reported the European trial, “with mild and transient side effects.” In 2006, the drug was approved for weight loss in Europe under the brand name Acomplia.

But the problems caused by rimonabant had been underestimated in these trials, possibly because they rigorously excluded people at high risk of depression and/or psychiatric disease. As the evidence broadened over the next two years, the EMA came to the disturbing conclusion that rimonabant doubled the risk of psychiatric disorders in people using it for weight loss. In October of 2008, the agency recommended that sales of the drug be suspended in the European Union, and it was never approved by the FDA. The largest rimonabant trial ever conducted, a herculean effort spanning 974 hospitals in 42 countries, was halted prematurely one month later. Before the trial’s end, four people in the rimonabant group had committed suicide.

Breaking the magical barrier

Mads Tang-Christensen is head of obesity research at Novo Nordisk, the Danish company that developed semaglutide. He attended the 2010 Obesity Society meeting in San Diego after the demise of rimonabant and another weight loss drug called sibutramine, and by his account, “everyone was depressed.” Doctors were left with few effective options for treating obesity, and pharmaceutical companies had lost their appetite for developing anti-obesity drugs. Except Novo Nordisk.

To understand how semaglutide was developed, we have to rewind to 1983. Researchers at the Chiron Corporation identified a gene fragment in hamsters they thought might encode a previously unknown hormone. They dubbed this mysterious molecule “glucagon-like peptide-1” (GLP-1). Joel Habener, a diabetes researcher at Harvard, assigned his trainee Daniel Drucker the project of figuring out what GLP-1 did. Drucker exposed a variety of cell types to GLP-1, and noted that, in cells from the pancreas, it stimulated the secretion of insulin. Almost simultaneously at the University of Copenhagen across the Atlantic, Jens Holst and colleagues observed the same effect. Later that year, Steven Bloom at the Royal Postgraduate Medical School in London reported that GLP-1 increases insulin secretion in humans too.

We now know that the intestine secretes GLP-1 when we eat, which prods the pancreas to secrete enough insulin to help metabolize our food. An interesting feature of this effect is that it requires extra blood sugar, like the spike that happens after a meal. If GLP-1 could be developed as a drug, the thinking went, it might be able to help people with type 2 diabetes make more insulin specifically around meals, which is when blood sugar rises and they need insulin the most. Habener patented GLP-1 as a treatment for diabetes.

Yet GLP-1 had serious problems. The first was that it was degraded in the blood by an enzyme within a few minutes. This meant that it wasn’t useful as a drug in its native form because it would have to be injected far too often. This problem was solved by using another version of the hormone identified in the saliva of the gila monster lizard, called exendin-4, which was resistant to the offending enzyme and lasted for hours in circulation.

The second problem was that, at clinically useful doses, GLP-1 made people feel quite sick. That was solved by starting with a low dose and gradually ramping it up as people got used to it. The first GLP-1–based drug, a synthetic version of exendin-4, was approved by the FDA as a treatment for diabetes in 2005, and marketed by AstraZeneca as Byetta and Bydureon.

The promising effects of GLP-1 weren’t limited to insulin. Bloom demonstrated in 1996 that injecting GLP-1 into the brains of rats “powerfully inhibits feeding,” and in 1998 Holst confirmed that infusing the hormone into the general circulation also reduces food intake in humans.

According to Tang-Christensen, this was around the time that Novo Nordisk got interested in GLP-1. Chemist Lotte Bjerre Knudsen and others developed a new version of the hormone that had several modifications that extended its half-life even further and increased its effectiveness. The result was liraglutide, first approved for the treatment of type 2 diabetes by the EMA in 2009 and the FDA in 2010 and initially marketed as Victoza.

As it turned out, liraglutide didn’t just improve blood sugar control—it also caused weight loss. The weight loss observed in diabetes trials was only a few pounds, but later trials with higher doses in people with obesity reported sustained losses of about 7% of body weight when paired with diet and exercise advice. Nearly all of the weight lost was fat. In 2014, the FDA approved liraglutide under the brand name Saxenda for the treatment of obesity, and the EMA followed suit in 2015.

While liraglutide offered proof-of-concept that GLP-1-based drugs could safely cause meaningful weight loss, it was no revolution in the treatment of obesity. “The magical barrier was 10–15%,” recalls Tang-Christensen; “that was the holy grail.”

Researchers at Novo Nordisk were already working on the next generation of GLP-1–based drugs. By subtly tweaking the structure of the molecule and testing various versions in animals, a team led by Jesper Lau and Thomas Kruse identified one that was as effective as liraglutide, but with a much longer half-life: semaglutide. Rather than needing an injection every day, patients would only need one injection per week.

However, when semaglutide entered human trials, the team got quite a surprise: it caused more than twice as much weight loss as liraglutide, making it by far the most effective anti-obesity drug ever to gain regulatory approval. “All of a sudden,” recalls Tang-Christensen, “the magical barrier was gone.”

Turning down the thermostat

Initially, the weight-reducing effect of semaglutide and related drugs was thought to be straightforward: they delay stomach emptying, making people feel more full after meals. Yet work published in 2012 by Tang-Christensen and Knudsen demonstrated that the effect on stomach emptying dissipated quickly in rats, while the reduction in body weight persisted. This was later confirmed in humans, establishing that delayed stomach emptying could not be responsible for the sustained impact of semaglutide on body weight.

Two years later, the same group published a study reporting that not only does liraglutide get into the brain when injected into the general circulation, but the regions it accesses are the very same that regulate food intake and body weight: the brainstem and the hypothalamus.

“I watch rats eat for a living,” quips Randy Seeley, director of the Michigan Nutrition Obesity Research Center. Seeley, whose work is partially funded by Novo Nordisk, has dedicated his career to understanding the mechanisms by which bariatric surgery and weight loss drugs make us slimmer. He and other researchers have used mouse experiments to determine how drugs like semaglutide work, by “knocking out” the receptor for GLP-1 in different parts of the mouse brain. This research has demonstrated that the effect is entirely mediated by the brain, and specifically a region of the brain called the brainstem, and probably also another region called the hypothalamus.

As a result of its actions in the brain, semaglutide clearly reduces food intake in people with obesity. “They’re three quarters of the way through their meal and they say ‘I’m good,’” Macklin notes of the typical patient. Yet these drugs are more than just appetite suppressants, and understanding their true nature sheds light on the true nature of obesity itself.

Not only are people who take semaglutide less hungry, they’re less easily seduced by tempting, calorie-rich foods. Research from two independent groups suggests that semaglutide causes food cravings to fade quite substantially. You might be tempted to attribute this to the reduction in hunger, which after all is “the best sauce.” That’s probably part of the story, but not all of it. In Macklin’s patients, semaglutide reduces the drive to engage in a wide spectrum of dopamine-fueled behaviors, including drinking alcohol and shopping. “People say they’re on Amazon way less,” observes Macklin.

The animal research backs this up, reporting that semaglutide and similar drugs reduce alcohol intake in alcoholic monkeys and the use of a variety of dopamine-spiking addictive drugs in rodents. So one reason why semaglutide is so effective may be that it curbs food intake from two angles: our brain’s perceived need for calories (hunger), and our tendency to be seduced by food even when we aren’t hungry (reward). “They are no longer subject to the prime symptom of obesity,” observes Macklin of his patients, “which is this motivational drive to eat, triggered by external cues around them, modulated by stress and fatigue.”

Seeley believes semaglutide and similar drugs act in another important way: they directly or indirectly affect the brain circuits (mostly in the hypothalamus) that regulate the size of the body’s fat stores, making the body “want” to be leaner.

To understand this possibility, we must first understand something fundamental about obesity. Body fatness isn’t just the haphazard result of however much we decide to eat and how often we go for a jog—it’s actively regulated by the brain, with strong genetic influences. And the brain’s “setpoint” for body fatness is higher in people with obesity.

As an analogy, imagine someone turning up the temperature on the thermostat in your house by 10 degrees, against your will. You try to cool the house down by opening the windows, but the thermostat reacts by turning on the furnace. Even with the windows open, you’re still hotter than you’d rather be. This is what it’s like to struggle against a regulated system.

Similarly, one of the primary barriers to weight loss is the fact that the human brain, including those of people with obesity, “defends” our current waistline. This process is every bit as nonconscious as the way the brain regulates body temperature, but the output is all too familiar to most people who have tried to slim down: as soon as the pounds come off, their hunger goes up, metabolic rate goes down, and calorie-rich foods become more appealing. Most of the lost weight usually returns. This deeply wired “starvation response” is an unfortunate relic of our hunter-gatherer days, when weight loss was a potentially mortal threat.

Seeley’s observations in rodent models of obesity suggest that both semaglutide and bariatric surgery lower the body fat setpoint. “The important point for everyone to understand is that what these drugs do, and what the surgeries do, is not really primarily affect food intake,” explains Seeley. “They change the setpoint.” You can think of this like turning down the temperature on the thermostat in your overheated house: the house returns to a comfortable temperature, and you no longer have to struggle against the furnace to keep it there.

Leaving behind the dark ages

To the uninitiated, the work of a modern neuroscientist may sound like far-fetched science fiction. For example, Michael Krashes, senior investigator at the National Institutes of Health in Bethesda, Maryland, studies the brain circuits that generate the motivation to eat. He and his team use a combination of genetically engineered mice, harmless genetically engineered viruses that deliver light-sensitive genes from algae, and fiber-optic-guided lasers to precisely control the activity of specific populations of neurons in the brain. This technique is called optogenetics, and it’s part of a palette of high-tech methods that have revolutionized neuroscience in recent years.

When Krashes and others in his field apply this method to the right neurons, they can make well-fed animals start gorging, literally with the flip of a switch. By activating or silencing other populations of neurons, they can suppress eating and cause rapid weight loss. Using these methods and others, Krashes and his field are dissecting the brain circuits that govern food intake and body fatness down to the cellular and molecular level.

The brain circuits that govern these functions appear quite similar in humans and mice, so in principle these same methods could work in humans to directly control eating drive and body fat regulation at their source. “I promise you,” says Krashes, “if we could activate some of these neurons in people, they would have the same effects.” Perhaps in the distant future, when we’ve overcome substantial technical hurdles. But for now, this research is expanding the frontier of knowledge from which to build the next generation of obesity therapies.

This expanding frontier of knowledge is what led to the development of semaglutide, and it’s already pushing beyond it. What will the next generation of weight loss therapies look like? In the near future, it will probably continue to revolve around brain-acting hormones like GLP-1. “The gut-brain axis has been the source of most of our innovations,” relates Seeley, “and will continue to be.”

These advances are already coming. In May, Novo Nordisk published a trial combining semaglutide with another drug called cagrilintide for weight loss in people with obesity. Cagrilintide is based on the protein amylin, a hormone that’s released by the pancreas when we eat and that reduces food intake via the brain. Adding cagrilintide nearly doubled the weight loss caused by semaglutide alone, with an apparently similar safety profile. This was only a 20-week safety trial, but it seems likely that longer trials will reveal weight losses of more than 20%, which would place it in the range of bariatric surgery.

“When I joined Novo Nordisk in 2010, I thought that if I get to double digits, maybe 20% by my retirement, then I will have been successful,” states Tang-Christensen. “But now we’re already there, and I’m not going to retire any time soon.” Given the number and promise of the drugs currently being tested, some of them will surely make it to the pharmacy, even if this particular combination does not.

Novo Nordisk isn’t the only pharmaceutical company pursuing the strategy of targeting more than one brain-acting hormone system at once. The remarkable effectiveness of this strategy in animal models of obesity has contributed to renewed interest in weight loss drugs across the industry. A recent trial conducted by Eli Lilly suggests that its new diabetes drug tirzepatide, which combines activity of the hormones GLP-1 and gastric inhibitory polypeptide (GIP), may cause more weight loss than semaglutide. Like GLP-1, GIP stimulates insulin secretion around meals, making it an attractive target for treating diabetes. Tirzepatide has performed well in clinical trials and appears poised to gain FDA approval for treating type 2 diabetes.

The next generation of weight loss drugs may also cause effects on body composition that are more sophisticated than a simple loss of weight. Another drug-in-testing with a strange name and interesting mechanism is bimagrumab, developed by Novartis, which inhibits a pathway that naturally constrains muscle growth. The result in a recent clinical trial in people with type 2 diabetes was a loss of one-fifth of their fat mass and a 4% gain in lean mass, which is the opposite of what usually happens to lean mass in weight loss trials. This was coupled with a significant improvement in blood sugar control. The drugs of the future may make us leaner, healthier, and more muscular.

For those who prefer to avoid drugs and surgery, Donna Ryan thinks commercial weight loss programs are the future because they offer intensive behavior change interventions that are more effective than what most doctors can provide. “We need to be investing in those and letting the doctors do what they do best: knowledgeable prescribing, not lifestyle intervention,” says Ryan. The options for evidence-based weight loss and diabetes management programs are expanding—they include WW International (formerly Weight Watchers), NutriSystem, Real Appeal, Omada, Wondr Health, and Virta Health—and insurance policies are increasingly covering them.

Drugs like semaglutide only reduce body weight for as long as people remain on them; cessation leads to an insidious regain of weight. Although this is the same situation as medications for other chronic diseases, like drugs for high blood pressure, cholesterol, and blood sugar, it’s still a substantial downside.

Some in the pharmaceutical industry are already thinking about the ultimate weight loss therapy: drugs that durably reset the body fat setpoint itself. A drug that durably resets the setpoint to a lower level wouldn’t require ongoing treatment to maintain results: it would effectively be a cure for obesity, like penicillin is a cure for bacterial infections. For now, the feasibility of such a cure remains unknown and it will probably require expanding our foundation of scientific understanding. But it would be “the ultimate dream,” says Tang-Christensen, and Drucker agrees.

Semaglutide may not be the ultimate dream, but it is an auspicious new reality for people with obesity. This drug and those that follow promise to leave behind, as Macklin calls it, “the dark ages of obesity medicine.”

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