GLP-1 & Weight Loss
This is the start of a new era of effective treatments for obesity - Dr. Robert F. Kushner
image by: Calibrate
After learning that the venom of a Gila monster lizard contained hormones that can regulate blood sugar, Daniel Drucker started wondering why. And could the venom somehow help treat diabetes?
Drucker is a scientist and endocrinologist at the University of Toronto who has dedicated his career to understanding the universe of hormones in the body, which do everything from regulating appetite to helping with digestion. His curiosity about the Gila monster led to a call with a zoo in Utah. In 1995, Drucker had a lizard shipped from Utah to his lab and began experiments on the deadly venom.
Ten years later, a synthetic version of a hormone in the venom became the first medicine of its kind approved to treat type 2 diabetes. Known as a GLP-1 (for glucagon-like peptide-1) receptor agonist, the medicine set off a cascade of additional venom-inspired discoveries.
After doctors noticed mice and humans on the drug for diabetes appeared to lose weight, they began to consider its use in obesity science. In June 2021, another effective treatment, this one for obesity, got Food and Drug Administration approval. Called semaglutide and marketed as Wegovy, it also takes its structure from the lizard’s venom.
If this origin story sounds outlandish, consider the history of obesity treatments. Over the years, people have turned to extreme and unlikely interventions to try to lose weight, from jaw wiring, laxatives, and vagotomies to lap band operations and fen-phen, a “miracle” diet drug that was ultimately recalled.
The new treatment — a once-weekly injectable from Novo Nordisk, a Danish pharmaceutical company that has hired many leading diabetes and obesity scientists as consultants — is poised to safely help many people with health-threatening obesity, physicians and researchers say. It may even illuminate some of the mysteries around how appetite works in the first place.
“It’s phenomenal,” says Michael Krashes, a diabetes and obesity investigator at the National Institutes of Health. Semaglutide is “a big step forward — we finally have something that’s reliable and able to produce sustained effects over time,” adds Ivan de Araujo, a neuroscientist who studies brain-gut interactions at Mount Sinai’s Icahn School of Medicine. Neither scientist is affiliated with Novo Nordisk.
Doctors who treat obesity patients told Vox they wished they had a treatment option like semaglutide years ago, and patients described the drug as life-altering.
Yet many people with obesity may not seek out semaglutide, and doctors may not prescribe it to them — not only because of the dangerous history of weight loss medications, but also because of a persistent bias and stigma around a disease that now afflicts nearly half of Americans. Obesity is still widely viewed as a personal responsibility problem, despite scientific evidence to the contrary. And history has shown that the most effective medical interventions, such as bariatric surgery — currently the gold standard for treating obesity — often go unused in favor of dieting and exercise, which for many don’t work.
There’s also a practical challenge: Health insurers don’t typically cover obesity medications, says Scott Kahan, an obesity doctor and professor at Johns Hopkins Bloomberg School of Public Health and the George Washington University School of Medicine. “Medicare explicitly excludes weight medications,” Kahan, who consults with Novo Nordisk, says. “And most insurers follow what Medicare does.”
The new drug certainly won’t be a cure-all for obesity, Krashes adds. “You are not taking a 280-pound person and making them 130,” he points out, though reductions that are enough to improve health outcomes are typical. Drucker, who began consulting with Novo Nordisk and other drug companies after his reptilian discovery, agrees that it’s a starting point for obesity: “It will only scratch the surface of the problem in the population that needs to be healthier.”
But semaglutide is the most powerful obesity drug ever approved, he adds. “Drugs that will produce 15 percent body weight loss — we did not have that before in the medical therapy of obesity.” With additional, potentially more effective GLP-1 receptor agonists coming online in the future, we’re at the beginning of a promising new chapter of obesity therapeutics. A look at the fascinating science of how the medication works could also go a long way to changing how Americans think about this disease.
“We have to thank the lizard for that,” Drucker says.
What semaglutide reveals about weight problems
To understand how semaglutide causes some people to eat less, it’s helpful to understand what hormones do. They’re the body’s traveling messengers: Manufactured in one area, they move to another to deliver messages through receptors — molecules that bind to specific hormones — in distant organs and cells.
The gut makes dozens of hormones, and many of them travel to the brain receptors that either curb appetite or stimulate it, Drucker explains. GLP-1 is one such gut hormone. It’s unleashed in the gut in response to food and stimulates the pancreas to make more insulin after a meal, which lowers blood sugar. (GLP-1 is also made in the brain stem, where it may modify appetite.)
“It sends a signal to our brain that says, ‘You know, we’ve had enough to eat,’” says Drucker.
Enter semaglutide, one of a class of medicines — the GLP-1-receptor agonists — that imitate GLP-1, helping the body lower glucose (in the case of people with diabetes) and, researchers suspect, curb appetite (in the case of people living with obesity who may also have diabetes).
The precise way the drug works on obesity is still unknown, in part because scientists don’t understand exactly how appetite works. But researchers generally agree that the drug harnesses the brain’s GLP-1 receptors to curb food intake. When researchers delete the GLP-1 receptors from the brains of mice, the drug loses its appetite-suppressing effects, says Krashes.
Obesity is “primarily an issue of our brain biology, and the way it’s processing info about the environment we live in,” says Randy Seeley, a University of Michigan researcher focused on obesity treatments, who also consults with Novo Nordisk.
With semaglutide, the idea is that “we’re changing your brain chemistry for your brain to believe you should be at a lower weight,” Seeley added.
This brain-based pharmacological approach is likely to be more successful than diet and exercise alone, Seeley says, because “the most important underlying part of somebody’s weight has to do with how their brain operates,” not a lack of willpower.
Not quite a “game changer”
Some people with a higher body mass index are perfectly healthy and don’t require any treatment. Semaglutide was only indicated by the FDA for patients who classify as clinically obese — with a body mass index of 30 or greater — or those who are overweight and have at least one weight-related health problem.
For the many people who have used it, it has proved safe and effective, according to the FDA. In weight loss clinical trials, semaglutide helped people lose about 15 percent of their body weight on average — significantly more than the currently available obesity drugs and more than enough to improve health outcomes.
The drug’s most common side effects — nausea, diarrhea, constipation, and vomiting — were mostly short-lived. De Araujo is finding that adverse reactions might be caused by how the drug differs from the naturally occurring peptide hormone: The hormone acts mostly locally and degrades quickly, while the medicine works mainly on the brain and is designed to stick around in the body. “That’s where the nausea, vomiting probably derive from,” De Araujo argues.
Patients who have tried semaglutide told Vox that it helped them manage their weight and relationship to food, and that their side effects were manageable and quickly resolved.
Jim Eggeman, a 911 operator in Ohio, said that before taking semaglutide, “I could sit down and eat a large pizza, and now it’s one to two pieces at the most.” He started on the drug for diabetes after a heart attack in December 2019 and lost 35 pounds, bringing his weight to 220.
Paula Morris-Kaufman, of Cheshire, UK, used the drug to address weight gain following cancer treatments. It helped her bring her weight back to a normal range, she says, and curb her habit of compulsive eating. “If you give me a plate of food, I just eat a small portion of it — and feel full really quickly.”
It’s possible that some of the benefits of treatment come in part from lifestyle changes, which were encouraged by the clinical trials. In many cases, patients on semaglutide also switched to a healthier diet when they started on the drug and added exercise to their routines. But study participants taking the drug still lost significantly more weight than those under the same conditions who received a placebo.
The need for additional interventions — like diet and exercise — is one reason why Kahan stops short of calling this drug a game changer. “It’s an incremental improvement” over existing drugs, he says, and it’s still out of reach for many of the individuals who could benefit from it. “The ‘game changer’ description is not appropriate, because many people don’t have access to these medicines.”
A mindset shift
Only about 1 percent of eligible patients were using FDA-approved medications for obesity in 2019, a study showed. The same is true for bariatric surgery, currently the most effective intervention for obesity, which can also drive type 2 diabetes into remission.
“If someone walks into your office with heart disease and you as a physician don’t try to treat it, that’s malpractice,” Seeley says. “If somebody comes in with a BMI over 30 and you don’t treat it, that’s Tuesday.” He thinks some of the hesitancy for treating patients with obesity medications comes from the history of dangerous weight loss drugs.
Ingrained biases about obesity have also made it harder for patients to get access, Kahan says. “Obesity tends to be categorized as a cosmetic issue in health insurance policies,” he says. “In order to get coverage, employers have to explicitly decide to buy a rider and sign a contract to add weight management services and products to their insurance plans.” He’d like to see obesity treatments covered by insurers in the same way diabetes and hypertension drugs are.
That will require a shift in mindset, Drucker says. “We would never blame other individuals for developing high blood pressure or cardiovascular disease or cancer,” he says. It’s widely known that those conditions are driven by complex biological determinants, including genes, as well as environmental factors. “Obesity is no different.”
When Drucker started in endocrinology in the 1980s, he didn’t have many tools to help patients. With the addition of semaglutide, there are multiple surgical options and drugs for obesity and diabetes. The challenge now is helping those who would benefit gain access.
“I would be delighted if no one needed GLP-1 for diabetes and obesity,” Drucker says. That might be possible in a food landscape that didn’t nudge people toward the overeating and poor diet that leads to these chronic conditions. But for now, “we have new options that are safe, appear to reduce complications, and are very effective. ... We shouldn’t just throw up our hands and say there’s nothing we can do.”
Source: Julia Belluz, How a lizard’s venom inspired the promising weight loss drug Wegovy, Vox, July 5, 2021.