Weekend Reads | The Science Behind Ozempic, Wegovy, and Other GLP-1 Agonists

by Kevin Schofield

This weekend's read is a Substack post by Dr. Scott Alexander on the latest "wonder drugs," Ozempic and Wegovy. Both started as treatments for diabetes, but in the last year have gained fame as weight-loss drugs. More recently, research has emerged suggesting that they might be useful treatments, or preventative medications, for a wide variety of other ailments: stroke, heart disease, kidney disease, Parkinson's, and Alzheimer's, as well as a number of different kinds of addictions (both substance and behavioral).

It sounds like someone is selling snake oil off the back of their wagon. And yes, as Alexander points out, a decade from now the list of diseases that Ozempic and Wegovy are good for treating will certainly have narrowed significantly. But at the same time, in this instance, there is real evidence that the uses are broad, something that is very unusual — almost unheard of — in health care. So Alexander digs into the biochemistry of why, this time, it might live up to the hype.

Ozempic and Wegovy are in a class of medicines called "GLP-1 agonists," a term that requires some unpacking. GLP-1 is a hormone, a molecule used by our internal organs to communicate with each other. In this case, the GLP-1 hormone is created naturally by our intestine when it senses the presence of food, chiefly as a signal to the pancreas. The pancreas is responsible for maintaining the right level of glucose in our blood, by releasing two other chemicals: insulin to remove glucose or glucagon to add more. When GLP-1 attaches to receptors on pancreas cells, the pancreas knows that digested food is about to be turned into a fresh supply of glucose, so it ramps up the insulin and tamps down the glucagon.

People with diabetes have trouble regulating their own insulin levels, often because their body doesn't properly generate GLP-1 when needed. Unfortunately, the GLP-1 hormone that is naturally generated by our bodies only lasts for about two minutes, so we can't simply take it from one person and inject it into another. Instead, researchers invented new molecules called "GLP-1 agonists" that mimic GLP-1 well enough to activate the same receptors in the pancreas but last much longer — up to a month. By reactivating our body's ability to control insulin and glucagon levels, these drugs are effective treatments for some forms of diabetes.

Where this story gets interesting is the discovery that there are several other types of cells, spread throughout our body, that also have GLP-1 receptors — so when the intestine starts sending out GLP-1, they get triggered too. Some of them are in the part of our brain that recognizes when we are satiated, i.e. when we've had enough to eat. In retrospect, that shouldn't be surprising at all; if there is food in our digestive system, we should stop eating. But that is at the heart of why these drugs are now being used for weight loss: They tell our brains that we don't need to eat.

It turns out that there are also cells with GLP-1 receptors in the "reward center" of our brain: the part tied to cravings and addictions. It also shouldn't be surprising to learn that the brain's reward center talks with our gut, since we all have food cravings and a tie to the digestive system is an effective way for our body to prioritize getting food (including specific kinds of food) when it feels like it's missing some important nutrients. Or the opposite: The body can use GLP-1 as a signal for the brain to stop craving more food when it has had enough. But that is the same reward center that is implicated in a wide swath of other addictions, both to substances such as alcohol, opioids, and stimulants, as well as behaviors like porn and gambling addictions. And that is possibly why GLP-1 agonists might be useful to treat addiction. Researchers are still early in their investigation of this link, but some are very excited by the possibilities of new treatments.

And this brings us even farther afield, to Parkinson's and Alzheimer's diseases and other forms of dementia. Alexander explains that this is not well understood yet, but we do know that one of the traits these diseases share is they involve damage to cells. For example, it's well known that diabetes increases the risk for Parkinson's and Alzheimer's, most likely because high glucose levels in the blood can damage cells in our body. But Alexander also notes that GLP-1 agonists seem to help with these diseases even for people who don't have diabetes, so something else must be going on as well. He suggests that the most likely connection is that GLP-1 agonists help to reduce inflammation. Inflammation is part of our immune system's response to foreign invaders, creating an environment that is slightly toxic to our own cells but highly toxic to invaders. But long-term chronic inflammation can cause enough damage to our body to lead to Parkinson's, Alzheimer's, other forms of dementia, and other "auto-immune" diseases such as MS. Sadly, the modern Western diet, high in fat and sugar, can often lead to chronic inflammation, and eventually contribute to these diseases. But to the extent that Ozempic, Wegovy, and other GLP-1 agonists keep inflammation at bay, they might turn out to be effective preventative measures — or treatments.

It's important to remember that a lot of this is still speculative, and some of it will ultimately turn out not to be true. And we've been down this path before with treatments that doctors believe might have broad health effects: the hormones in birth control pills (researchers are still trying to fully understand their effects), aspirin, serotonin, testosterone, and other treatments that mimic naturally occurring substances in our bodies. But it's also true that GLP-1 agonists won't be the last one of these that we discover either; there's plenty we still don't know about the cross-talk between parts of the human body and where a change in one part will percolate out to many others.

Read the full Substack post "Why Does Ozempic Cure All Diseases?" online.

📸 Featured Image: Ozempic semaglutide injection pens and box, Nov. 16, 2023. (Photo: Marc Bruxelle/Shutterstock.com)