Dr. Sanjay Gupta: Blockbuster weight loss drugs are revealing what we still don’t understand about obesity

Analysis by Dr. Sanjay Gupta, CNN Chief Medical Correspondent

(CNN) — Over the past year, the question has been coming in from everywhere – from my patients and family members, from colleagues and passengers I chatted with on airplanes: Is Ozempic right for me? Or any of the blockbuster weight loss and diabetes drugs that recently caught the world’s attention? While filming my new documentary about the drugs, it became clear that many people have at least considered taking GLP-1 medications, drawn to the possibility of steadier blood sugar, better heart health and especially weight loss.

Even though obesity is now one of the most widespread diseases in the developed world, there is still much debate about how it is diagnosed and what exactly causes it. Some experts question whether it is even a disease at all.

All these topics became the focus of an intense discussion I had in Copenhagen this spring with Dr. Jens Juul Holst, a Danish scientist who helped discover the molecules that are now completely upending the diabetes and weight loss field. By now, you have surely heard of Wegovy, Mounjaro, Zepbound and Ozempic. Some say Holst is a future Nobel Prize winner for this work, while others say he helped further fuel a wildly expensive industry to treat something better addressed with diet and exercise.

Holst is a delightful, energetic, trim and healthy 79-year-old who still rides his bike to work every day. He explained that the original goal of an international team of researchers was to find a molecule that could possibly treat peptic ulcer disease, not diabetes or obesity. Although it wasn’t ultimately beneficial for ulcers, he told me, it was through a series of serendipitous discoveries that they learned that targeting GLP-1 could instead dramatically lower blood sugar and body weight. And importantly for many who had struggled with obesity, these molecules seemed to work when nothing else had. He knew he had helped discover something potentially transformative.

When the first versions of these medications were approved 20 years ago, you might be surprised to learn, there was little fanfare. Hardly anyone heard about them during those early days. Part of the reason was the internal handwringing among pharmaceutical executives not at all confident people would inject themselves to lose weight — and, yes, among scientists like Holst, unclear on what exactly they were treating.

Obesity: A disease in and of itself?

For starters, there is no question that obesity is linked to all sorts of other diseases, such as type 2 diabetes, cancer, heart disease and stroke, to name a few. However, that doesn’t mean the link always exists for everyone or that obesity was by itself the culprit. After all, there are plenty of people who have obesity but don’t have any evidence of heart disease or diabetes. Their blood pressure is normal, and they take no medications. There are no abnormalities in their blood work or impairments in their normal physical function. Their only disease is an elevated BMI — too much weight for their height.

When I asked Karin Conde-Knape, the head of drug development at Novo Nordisk, the maker of Ozempic and Wegovy, about this, she smiled and said, “yes, we call them the ‘happy obese.’” The concern, she added, is that “these patients are on a trajectory toward developing these other diseases.”

Conde-Knape was suggesting that obesity should still be classified as a disease because it will inevitably lead to problems — even if it doesn’t right now. As things stand now, many major medical organizations, including the American Medical Association and the World Health Organization, would agree with her, but it is still a wildly polarizing topic that has become more urgent than ever with the introduction of these drugs.

Flawed history of BMI

A study published in the Lancet this week projects that in 2050, 43.1 million children and adolescents in the United States and 213 million adults will be overweight or obese. And yet, at a time when we can measure particle size of small lipid molecules and genotype tumors, it is remarkable that we still rely on a primitive method known as BMI to diagnose obesity.

BMI, or body mass index, is measured with a formula first used nearly 200 years ago, when mathematicians – not physicians – were trying to determine the ideal weight for humans; more specifically, “the quantifiable characteristics of the normal man.”

Only European men were included in the original measurements – no women, no children. And it wasn’t until more than a hundred years later, in the 1950s, that insurance companies realized more of their claims were coming from people who were obese. Before that, however, there was no recognized correlation between BMI and overall health. BMI doesn’t even distinguish between muscle mass and fat mass. That’s why the fittest, most chiseled and health-conscious person you know might still be considered obese.

Holst, along with others, said a better measure of obesity might be the simple use of a tape measure to check your waist-to-hip ratio, which can assess visceral fat, in addition to body mass index.

The GLP-1 lessons

The debate about whether obesity should be considered a disease, especially as measured by BMI, will probably continue. But there is an area of agreement I found with nearly everyone I spoke to about the topic: Much like depression and addiction are now described as diseases of the brain, scientists are increasingly saying the same about obesity – that, for many people, being obese is not a choice or reflective of a lack of willpower. And, interestingly enough, it may be this new class of medications that really reinforced this point.

Here’s why.

The GLP-1 molecules are described as post-nutrient hormones, meaning substances the human body releases after consuming food. Collectively, they stimulate your pancreas to make more insulin, slow down how quickly food moves into your intestines and activate areas in the brain that make you feel full or satiated.

As a neuroscientist, I found this last point particularly fascinating. It turns out that some people never really feel full, no matter how many calories they have consumed. Instead, they have a constant, maddening food chatter in their brains. Even as they’re eating one meal, they are already thinking about the next one, instead of ever feeling truly satiated. It’s part of the reason they continue to eat far more calories than they require. For them, GLP-1 medications can quite literally quiet those voices in their head.

The joy of food

Holst is also very focused on this particular mechanism of the GLP-1 drugs but worries that it can go too far.

Over a meal of coffee and tasty pastries, he told me that these drugs seem to take away the joy of food for some people. It is perhaps his biggest concern. People stop socializing as much, he told me, knowing they won’t be hungry for dinner. They may also become too skinny too fast and have the associated sagging skin and fatigue. For others, it is the loss of lean muscle mass that accompanies their weight loss and puts them at greater risk for falls. Because the medications work by slowing digestion, terrible constipation becomes a side effect that is too much for some to bear.

Consider this: More than half the people who start these medications end up stopping them within just 12 weeks. For some, the medications are too expensive and can eventually become out of reach financially. Others develop a tolerance to the drugs, and over time, they may stop working as well. But for a lot of people, it is these side effects – including the loss of joy – that drives their dissatisfaction with the meds.

And again, it was that loss of joy that was particularly concerning to Holst. “It is a heavy price to pay,” he told me.

Is Ozempic right for you?

For now, the question keeps coming: Who should consider taking these drugs? Should I try these drugs?

There is little doubt that for most people, regular exercise and eating right is still the best strategy for weight loss and overall health. High-fiber diets, for example tend to release more natural GLP-1. Among people who took GLP-1 medications and stopped, those most likely to keep the weight off had incorporated lifestyle changes in a meaningful way.

Most people do regain weight after stopping the medications, but importantly, not all people and not all the weight. For those able to keep weight off, these medications weren’t a lifelong solution, but rather a burst of motivation to help reverse their obesity trajectory.

Yes, we have a lot of work to do in better defining and assessing obesity. That’s what Holst really wanted me to know after his decades of work on the topic. In the meantime, however, these medications might finally provide a lifeline for those who have truly struggled for too long.

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