The United States and much of the industrialized world has an obesity problem. The environment is obesogenic. The food is delicious and engineered by PhDs to target and titillate our brain reward systems. The portions are enormous. Half of our waking hours are devoted to sitting slumped over in a chair staring into an electronic device—for work and for pleasure. We eat carbs we don’t need, use seed oils in quantities our bodies haven’t adapted to handling, and largely avoid the most important food our ancestors evolved consuming: animal protein. The cheapest food is the worst and the healthiest is the most expensive.
It’s a big mess, and many people resist the dietary and lifestyle changes required to fix the issue. It’s no wonder many people have been hoping for a pill or medication that fixes the obesity problem.
Over the last few years, scientists appear to have found a class of medications that can help: GLP-1 agonists like semaglutide (sold as Ozempic® and Wegovy®) and liraglutide (aka Victoza® and Saxenda®). Hollywood celebrities and fashion models are taking these drugs in vast quantities. Silicon Valley tech circles are taking them—Elon Musk, most famously, is on semaglutide. In short, almost everyone with the money and access and weight to lose is using semaglutide and related drugs to stay thin. I know several docs who prescribe it for overweight patients.
Originally designed as diabetes drugs, these agents mimic the effects of glucagon-like peptide-1, an incretin hormone the body releases when you eat food. GLP-1 has two primary effects:
It stimulates the release of insulin and inhibits the release of glucagon.
It slows down gastric motility and the passage of food through the gut, keeping you full for longer.
GLP-1 is a hormone that “signals” fullness. There are all sorts of positive downstream effects as well:
Lower glucose production
More glucose uptake by muscles
Increased insulin sensitivity
Lower blood pressure
Improved endothelial function
The new weight loss drugs bind to the receptors that normally interact with GLP-1 and elicit the same effect as the hormone itself.
Do the obesity drugs work for losing weight?
Yes. They work. Out of all the weight loss drugs the industry has pushed and tested and tried, the GLP-1 agonists actually help people lose weight.
A recent paper tested semaglutide for two years in obese people.1 The average starting body weight was 106 kilos, or 233 pounds. Average starting BMI was 38. Most were women. One group got the drug, the other got placebo. Both groups were counseled to follow a “behavioral intervention,” which probably means exercise and other typical things.
By 104 weeks, the semaglutide group had lost an average of 15.2 percent of their bodyweight. The placebo group had lost an average of 2.6 percent.
Now, this didn’t make them thin. At the end, most were still overweight or obese. 15 percent of 233 pounds is about 35 pounds. That’s a great improvement, but it’s not enough to get you to a normal body weight. Furthermore, there was a major plateau of weight loss in the semaglutide group around 68 weeks. They didn’t really lose any more weight after that (as a group), and they even started to slightly gain by the end of the study. It was a very minor uptick, but an uptick nonetheless.
Semaglutide wasn’t enough for them. They were still mostly overweight, and the weight wasn’t continuing to come off—and it may have been starting to come back on.
But these drugs aren’t just about weight loss. There are other beneficial effects, too:
So these obesity drugs also improve other health markers. That’s great and suggests that the effects while you’re taking the drug are mostly positive.
I see some potential downsides, however.
Potential Downsides of GLP-1 Agonists
You probably have to take it for life. A recent paper followed a group of people who had taken semaglutide for over a year and lost a lot of body weight in the process.7 Half of them continued taking the med and the other half got placebo injections. This went on for 48 weeks. Those who were still on the sauce kept most of the weight off. Those who went off the drug quickly regained most of the weight and lost almost all of the other health benefits (blood sugar, blood lipids, blood pressure, etc.).
It’s expensive. At least as of now, the monthly cost of a GLP-1 agonist subscription is $1500. Insurance may cover much of that, but you have to be severely overweight or wait til these drugs are prescribed for mild overweight—but even then, assuming you have insurance, someone’s paying.
Liraglutide has been shown to increase adipogenesis, the creation of new fat cells, at least in mice.8 Even as the rodents lost weight, they increased the number of fat cells in their body. This is a process that normally occurs in childhood. It’s one reason why childhood obesity is so hard to overcome and so often leads to adult obesity. You have a ton of “extra” fat cells from when you were obese as a kid, so filling them up becomes easier and easier. If liraglutide or semaglutide also increase the creation of new fat cells, what happens when you stop taking it? What happens in five or ten years? Do those “empty” fat cells quickly fill up? It’s an interesting question we simply don’t know the answer to. Yet.
GLP-1 agonists increase resting heart rate, with the longer-lasting versions like injectable semaglutide (the most common used for weight loss) leading to sustained and long-lasting rises in resting heart rate.9 Whether this portends an increase in health issues down the road remains to be seen, but it’s generally accepted that a higher resting heart rate is a bad thing.
GLP-1 agonists cause nausea and diarrhea. They’re actually the most common side effects people complain about, and they may even contribute to the disinterest in food people report. It’s hard to be hungry when you feel like throwing up.
GLP-1 agonists cause loss of lean mass.10 This isn’t unique to GLP-1 agonist-related weight loss; it’s typical whenever you lose weight, but anecdotally, it doesn’t seem to happen when people lose weight following a Primal way of eating and exercising. This could potentially be avoided by simply emphasizing protein and making sure to lift heavy things rather than relying on the semaglutide to do all the work.
The benefits level off after about 68 weeks. They might continue if you bump up the dose, but that will also increase the chance of side effects like nausea, diarrhea, and any issues related to increased adipogenesis.
We don’t know what we don’t know. These are fairly new drugs and we don’t have any good long term (10 to 20 years) data.
My Final Take on GLP-1 Agonists
It’s not going to fix obesity. All the studies find that it helps users shed significant body weight but that there’s a lull in the loss. It’s not enough. It’s doesn’t get you past obesity and overweight into true leanness. To do that, you also have to address other aspects of your diet and lifestyle to really make the changes stick and extend them into perpetuity.
I do think it can help people stick to a better diet. While the fanfare focuses on the fact that you can “eat whatever you want” and still lose weight, it’s also been shown to reduce cravings for junk food and starches.11 A smart use of this drug would be to pair it with a healthy low-carb diet based on whole food that emphasizes animal protein. Whole food so you’re getting the micronutrients you need and protein so you’re getting adequate protein to stave off muscle loss.
Ultimately, most people reading this don’t need semaglutide injections. You’re already willing to do the work and make permanent changes to your diet, lifestyle, and exercise habits that set you up for long term success. But millions of people aren’t. While I have some major reservations about the long term effects of these drugs—after all, I strongly suspect there’s no free lunch when it comes to stuff like this—they may be beneficial on net to people who’d otherwise never consider changing their diet and lifestyle.
Mark Sisson is the founder of Mark’s Daily Apple, godfather to the Primal food and lifestyle movement, and the New York Times bestselling author of The Keto Reset Diet. His latest book is Keto for Life, where he discusses how he combines the keto diet with a Primal lifestyle for optimal health and longevity. Mark is the author of numerous other books as well, including The Primal Blueprint, which was credited with turbocharging the growth of the primal/paleo movement back in 2009. After spending three decades researching and educating folks on why food is the key component to achieving and maintaining optimal wellness, Mark launched Primal Kitchen, a real-food company that creates Primal/paleo, keto, and Whole30-friendly kitchen staples.