David Kessler, MD ’79, recalls the moment he realized that GLP-1 drugs like Ozempic and Zepbound could be game changers for public health.
It was 2023, and Kessler was at the dinner table with a plate of ricotta-stuffed chicken breast in front of him. In the past, he would have dug into the meal eagerly. But Kessler had recently begun taking a GLP-1 agonist: an anti-obesity medication that suppresses food cravings by mimicking the effects of a gut hormone called glucagon-like peptide-1. “I could hardly eat a bite,” he writes in his new book Diet, Drugs, and Dopamine: The New Science of Achieving a Healthy Weight. “I almost had to fake eating altogether.”
Like many Americans, Kessler had long struggled to control what he describes as “the food noise of daily existence”: the cravings for fat, sugar, and salt, driven by biological instinct, that provoke overeating in a world of foods designed to be addictive. But Kessler also has a unique vantage point. He’s a physician with a nuanced understanding of how ultraprocessed foods hijack the brain’s reward system and of how accumulating fat in the abdomen can contribute to chronic disease. He’s also the former commissioner of the Food and Drug Administration who, in the 1990s, led the agency’s fight against Big Tobacco.
Kessler’s new book weaves insights from these experiences with the latest research to explore obesity, food addiction, and the potential of GLP-1 medications to improve health. He spoke with Harvard Medicine Associate Editor Molly McDonough about how the medical community can balance the enormous promise of these drugs with their possible risks and long-term unknowns. This interview has been edited for length and clarity.
Do you think the prevailing narrative around GLP-1 drugs gets the messaging right?
I think that this should not be about weight. It’s not about how big or small you are. The most important thing about the GLP-1 drugs is that they change the landscape of how we look at obesity.
I think cardiologists, nephrologists, endocrinologists, diabetologists, obesity medicine physicians, some neurologists, and even some oncologists are waking up to the fact that many people have an underlying metabolic disorder. It’s a disorder in which adipose cells — fat cells, especially visceral fat in our abdominal cavity that gets into the liver, pancreas, and heart — accumulate and are causal in a range of cardiac, renal, and metabolic issues. By reducing this visceral adiposity, there’s evidence that GLP-1 drugs cause marked improvements across all those organs.
In some ways, this changes medicine. Much of medicine deals with the end-organ damage of disease processes that begin decades earlier. But there is an extraordinary opportunity, now that we understand this metabolic adipose disease, to profoundly affect chronic disease.
Should this changing perspective on obesity also include a shift in the way that medical professionals think about overeating?
These drugs underscore that overeating has never been about lack of discipline or willpower, a bias that has prevailed even within the medical profession. You have a food industry making these ultraprocessed, or “ultraformulated” foods, as I call them, which stimulate appetite and the reward circuits of the brain. In essence, these foods are addictive. The GLP-1 drugs help tamp down that addiction.
The drugs work through biology. They work through effects on the gastrointestinal and central nervous system circuits, the circuits that drive overeating. They markedly affect appetite. They are highly effective and powerful. They’re only one tool, but they put to rest the question about willpower.
If they’re just one tool, what are the other tools that medical providers should encourage patients to use?
The premise of the pharmaceutical industry is that people will be on these drugs for life, but that’s not the reality for most people. The data show that the average person only takes these drugs for eight to nine months. So we need to be able to understand how we use these drugs in the real world. Otherwise we’re going to turn around in three to five years and find that the majority of people who were on these drugs went off them and gained back the weight after spending thousands of dollars.
In the end, people have to change their relationship with food. If these drugs are going to be used successfully over the long term, they need to be used along with nutrition therapy, behavioral therapy, and physical activity. That’s because this metabolic adipose disease is a lifelong progressive chronic condition that’s going to need chronic care and a range of tools to be able to treat it effectively.
You’ve written about how taking these medications changed your own relationship with food. How did your firsthand experience challenge or deepen your understanding of how GLP-1 medications work?
There’s a lot of science in this book, and I probably talked to and cited hundreds of experts. But there’s no doubt that experiencing these drugs firsthand changed my relationship to food.
With eating, there’s a sense of satisfaction, there’s a sense of fullness and then there’s Thanksgiving fullness, then there’s being pushed to the edge of nausea — or over the edge. It’s important to note that everybody experiences this differently. But these drugs pushed me to the edge of nausea. I got more careful about what I wanted to eat and just didn’t want food sitting in my stomach.
Pharmaceutical companies promoting GLP-1 drugs claim that gastrointestinal effects are mild to moderate, downplaying the effects of gastric slowing. But I think the reality is these drugs delay gastric emptying, and they do that in part through their effects on the hindbrain and the GI tract. When you have food stay in your stomach longer, you learn to condition yourself; you don’t want to put any more food in your stomach, and you learn to eat less. That counterbalances the reward circuits and addictive circuits that are at play with all these ultraformulated foods.
So that’s why, as you argue, those feelings of bloating, nausea, and food aversion are not just side effects: They’re fundamental mechanisms of how the drugs work. How can physicians support patients in managing the discomfort?
I think we have to admit that the average primary care physician has not been trained to treat this condition, nor have we found the models to optimize care here. When these drugs work well, it requires titration of dose. You’re trying to get to the right dose so that people get pushed to that edge of nausea, but you don’t push them over the edge. They reduce their appetite; they condition themselves to want to eat less. But that takes time and needs a team approach.
If you look at the people taking these drugs, many are eating less than a thousand calories a day. Now, this can be done safely without hospitalization, but it needs a team approach. It needs dietitians, it needs people who have expertise in managing chronic metabolic disease of visceral adiposity.
Is there also an important role here for researchers to figure out those models for optimizing care? What questions should they be asking?
We don’t know enough about how to use these drugs in the real world. I mean, if the FDA approves these drugs for long-term use but people only stay on them for eight or nine months, is that enough? What other changes do you need to make while you are on these drugs in terms of diet and exercise? If you go off these drugs, can you go back on these drugs? Do you develop tolerance? What are the doses? Will it continue to be effective using drugs that way? We need to figure all of this out. If we don’t, the vast majority of people are going to gain back their weight.
If we can reduce visceral adiposity, we can have as great an impact on saving lives as we did when we took on the tobacco industry. The fight against tobacco, certainly in our lifetime, has been the great public health success. Obesity has been the great public health failure. But it’s so important that we do more research to answer these questions, because the public health potential with GLP-1 agonists is enormous.
Molly McDonough is the associate editor of Harvard Medicine.