5 Common questions about GLP-1 answered by Dr. Rob Lustig
Dr. Rob Lustig discusses how weight-loss medications like Ozempic work and why they may not be the cure-all they appear to be.
Approximately 12% of Americans have used a GLP-1 agonist drug like Ozempic or Wegovy. These weight-loss medications were traditionally intended to help patients with obesity or Type 2 diabetes. Lately, they’ve increasingly been used by people without such medical histories. Levels advisor Dr. Rob Lustig sat down with Dr. Casey Means to discuss the popularity of GLP-1 agonist medications, how they work, and how they impact overall health. Below is an edited version of their conversation, with five key takeaways.
What are GLP-1 agonist medications, and how were they discovered?
GLP-1 stands for glucagon-like peptide-1. Glucagon is a hormone that raises blood glucose levels. Endocrinologists give glucagon shots to patients with diabetes when their blood sugar levels drop too low. The glucagon helps them get out of a hypoglycemic state.
In the early 1980s, scientists discovered a protein called preproglucagon. The pancreas’ alpha cells “chopped up” the protein into different bits for different purposes, Dr. Lustig explained. These bits appeared to prompt the beta cells to release more insulin.
“They called these pieces glucagon-like peptides because they look like glucagon, but they’re a little bit different,” Dr. Lusting said. “Those then got to the pharmaceutical industry, and people started making the first GLP-1 agonists.”
The first successful GLP-1 agonist medication—exenatide, sold under the brand name Byetta—was derived from Gila monster spit. Byetta was used in diabetes therapy for several years. The pharmaceutical industry caught on, and new drugs followed.
Semaglutide, or Ozempic, arrived, and the data showed it was a better complement to diabetes treatment than Byetta. It even helped with weight loss. Novo Nordisk soon introduced Wegovy, a weight-loss drug approved by the U.S. Food and Drug Administration in 2021.
“Ozempic and Wegovy are the same medicine,” Dr. Lustig said. “They’re both semaglutides. They’re both GLP-1 agonists. They look like glucagon, but they’re not.”
How do GLP-1 agonist medications work?
GLP-1 agonists bind to specific receptors throughout the body, including in the pancreas and the brain stem. When the agonists bind to receptors in the pancreas, they increase the amount of insulin released, helping control blood glucose—hence why semaglutide was used to treat Type 2 diabetes.
The reasons why these medications work for weight loss are still unclear.
“If you are actually increasing insulin release, which these medicines do, then you should be forcing more energy into fat, but yet people are losing weight,” Dr. Lustig said. “How do you rationalize that? We don’t really know.”
What we do know, he added, is that people who take these medicines eat less. They consume fewer calories. When GLP-1 analogs bind to receptors in the brain stem, your brain effectively believes you’ve eaten.
“This is part of the satiety signal, and we’re hijacking it,” Dr. Lustig said. “And because we have these longer-acting medicines than what our own GLP-1 can do, it can last longer. It basically reduces total food intake, and this ultimately results in weight loss.”
Ozempic is FDA-approved for lowering blood sugar levels but has, especially recently, been used off-label for weight loss. Tirzepatide stimulates both GLP-1 and GIP (gastric inhibitory peptide) receptors. This medication is sold under the brand name Mounjaro when used to treat diabetes and under Zepbound when used for weight management and weight-related health problems like heart disease, high blood pressure, or high cholesterol.
GLP-1 agonist receptor medications work differently from medications like phentermine, an appetite suppressant intended for short-term use. Phentermine, sold under brand names like Lomaira and Adipex-P, is believed to work by increasing levels of norepinephrine, dopamine, and serotonin in the brain, reducing hunger. Still, other drugs like orlistat, sold under brands like the over-the-counter Alli, or the prescription medication Xenical, have a different mechanism of action. Orlistat [works by](https://www.mayoclinic.org/healthy-lifestyle/weight-loss/in-depth/alli/art-20047908#:~:text=Orlistat%20(the%20active%20ingredient%20in,blocks%20the%20work%20of%20lipase.) inhibiting lipase, an enzyme that helps break down dietary fat for storage. Rather than being stored, the fat gets excreted through stool.
What are the possible side effects of GLP-1 agonist medications?
Those who lose weight on GLP-1 agonist medications like Ozempic, Wegovy, or Mounjaro are losing both muscle and fat, which, Dr. Lustig stressed, “is by far and away not a good thing.”
“When you lose both muscle and fat, your body composition is changing in a way that is indicative of starvation,” he continued. “Sarcopenia, which is loss of muscle mass, is one of the hallmarks of aging, and one of the hallmarks of early death.”
The other most common side effects of these weight-loss medications include nausea, vomiting, diarrhea, and constipation. Some possible, more severe side effects include pancreatitis and thyroid tumors, among other medical conditions.
Other potential side effects are suicidal thoughts and depression. Dr. Lustig said this may be related to the drugs’ ability to interfere with the reward response: “If you’re a sugar addict, the only thing keeping you from the abyss is your next dose, and you now are not consuming it. Maybe that’s going to be a problem in terms of reward.”
Dr. Lustig acknowledged that older versions of GLP-1 analogs, like Byetta, also had strong links to pancreatic cancer but that the same correlation has not yet shown up with Ozempic and Wegovy. Still, he stressed that these newer drugs haven’t been on the market long enough to know what the consequences of long-term use are.
Do these weight-loss medications improve overall health?
While these drugs may help reduce body weight, a lower body mass index (BMI) doesn’t necessarily equate to better health.
“You’re bypassing the problem. You’re not fixing the problem,” Dr. Lustig said. “The problem is not that you have GLP-1 deficiency. No one has GLP-1 deficiency.”
Losing fat, especially in “metabolically relevant” places like your visceral adipose tissue, which these drugs help achieve, is beneficial to metabolic health. But “this drug’s job is not to improve metabolic health,” Dr. Lustig said. And again, any loss of fat comes with a loss of muscle, which houses most of our mitochondria.
“You are losing muscle in a way that is potentially unhealthy and even downright dangerous long-term,” he added.
Ultimately, these drugs alone won’t improve overall metabolic health. Diet and lifestyle changes still matter.
“Can you stop your overeating and still be metabolically unhealthy? Absolutely. It’s not going to fix that,” Dr. Lustig said. “But if you eat less, that’s at least less burden on your liver and pancreas. Yes, there are improvements in metabolic parameters related to weight loss, but not related to dietary improvement.”
Who might benefit from taking these medications?
Weight-loss medications can complement other interventions—especially those related to nutrition and physical activity—and help “jumpstart” a path toward improved health. Dr. Lustig says he’s all for using drugs like Ozempic and Wegovy to help people feel a sense of agency and success to propel them forward.
“If you can see that changing your diet will be something you can follow through on and Ozempic and Wegovy help get you there—to that point where you change what’s in your pantry and subdue the cravings—that would be a fine way to do it,” he said. “It could be a short-term jumpstart, and then you come off it.”
Dr. Lustig’s ideal scenario would be for patients to have their healthcare providers show them improved nutrition habits, like how to navigate the grocery store, for instance. The GLP-1 agonist medications would be “an adjunct to a more codified lifestyle program.”
Additionally, many people who lose weight on these medications end up gaining it back once they quit. One clinical trial examining the effects of semaglutide withdrawal found that, one year after going off the drug, participants regained two-thirds of the weight they initially lost. Establishing healthy habits and addressing the root of metabolic syndrome is vital for long-term success.
