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What’s the deali-O with new weight loss drugs? Part 1

Stanford Medicine researchers weigh in on the promise and peril of increasingly popular diabetes drugs being used for weight loss.

I confess it took me a while to catch up with the buzz about Ozempic. The diabetes drug has been on everyone's lips -- or, more accurately for an injectable drug, getting under everyone's skin -- even before Jimmy Kimmel addressed the (suddenly svelte) elephant in the room at the Academy Awards when he quipped, "When I look around the room, I can't help but wonder ... is Ozempic right for me?"

It's easy to see why.

Ozempic -- one of the brand names of a drug called semaglutide -- doesn't just help people with Type 2 diabetes manage their blood sugar levels. It also causes them to shed up to 15% of their body weight within a few months -- a seeming miracle for people struggling with severe, intractable obesity. The rapid, reliable weight loss is enticing to people without diabetes who just want to lose a few pounds. But is that a good idea? How does it work? Is it ethical for doctors to prescribe a diabetes drug for garden-variety weight loss? What are the downsides? Stanford Medicine diabetes, weight loss and obesity experts say the answer isn't straightforward.

How do diabetes drugs like Ozempic work?

It's a chicken and egg (and lizard!) story. Or, more accurately, a snack and digestion story. Since the 1950s, surgeons have been perfecting ways to reduce the absorption of calories from food to treat people with intractable obesity. Some procedures reroute the path that food takes through the digestive system; others severely restrict the volume of the stomach, decreasing the amount of food that can be comfortably eaten. Some do both.

Often, the results of these procedures, broadly called bariatric surgery, are remarkable. People lose as much as 30% of their body weight in the weeks and months after surgery, and other health problems associated with obesity (high blood pressure, elevated cholesterol and sleep apnea) also frequently resolve.

But as surgeons honed their technique, they noticed other, dramatic changes in their patients' health.

"Within days, before any weight was lost, 80% of people with Type 2 diabetes who had these surgical interventions stop being diabetic -- they no longer get those dangerous swings in blood sugar levels after eating," said Dan Azagury, MD, associate professor of surgery and medical director of the Stanford Lifestyle and Weight Management Clinic. "Clearly, something else was going on." 

That something else turned out to be a hormone produced in the gut called GLP-1, for glucagon-like peptide 1. Levels of GLP-1 (and another similar hormone, GIP) increase significantly after surgery, with decided metabolic effects.

Scientists identified GLP-1 in pigs and humans in the 1980s when studies showed the hormone stimulated the secretion of insulin after eating. Insulin helps cells remove and store a sugar called glucose from the blood. Soon after, scientists discovered that GLP-1 also reduces the secretion of another hormone called glucagon, a kind of anti-insulin that increases blood sugar levels in response to exercise, fasting or protein-heavy meals.

Fine-tuning sugar levels in Type 2 diabetes patients

The push and pull of insulin and glucagon help the body fine-tune blood sugar levels in healthy people, but those with Type 2 diabetes either don't make enough insulin or don't respond to it appropriately (a condition called insulin resistance). The resulting sustained high blood sugar levels damage tissues and lead to life-threatening complications.

While diabetes researchers were perking up their ears at the discovery of GLP-1 and its effects on insulin in humans, researchers studying the venom of the Gila monster, the only venomous lizard in North America, were unknowingly on a parallel path (stay with me here). The Gila monster -- scientific name Heloderma suspectum -- eats massive but infrequent meals, leading to large spikes in blood sugar after feeding. The researchers found that the lizards make a hormone called exendin-4 that can control these spikes. Upon closer inspection, the researchers found that exendin-4 is structurally similar to human GLP-1.

Pharmaceutical companies and drug developers took note and began to design drugs that mimic the activity of GLP-1 -- a category of molecules called GLP-1 receptor agonists. Enter Ozempic. The drug, which was approved as a Type 2 diabetes treatment by the Food and Drug Administration in 2017, lowers blood sugar by stimulating insulin secretion in response to elevated blood sugar levels. But there was another side effect.

"GLP-1 receptor agonists act on appetite centers in the brain and slow the transit of food through the gut, which leads to a feeling of fullness sooner after eating," said Sun Kim, MD, associate professor of endocrinology and member of the Stanford Diabetes Research Center. "People taking GLP-1 receptor agonists find it easier to eat less."

"When we began using these drugs as diabetes drugs, we noticed that some people lost significant amounts of weight," Azagury said. "We've come full circle -- the diabetes drugs we discovered through weight loss surgery can help people with obesity. And the results are amazing. This is the first family of drugs that is really effective. If you give it to patients, you know the vast majority will respond in a significant way."

But questions remain: Is semaglutide really the golden ticket to weight loss? Are there ethical considerations? Are there side effects? Is it safe? Stay tuned for answers to these questions in What's the deali-O: Part 2.

Photo by VadimGuzhva

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