We Are Witnessing the End of Obesity

Table of Contents

• Why the Line Went Up
• The Diets
• No End in Sight
• Something Remarkable Happened
• Are These Solutions Working?
• Benefits Beyond Weight Loss
• Retatrutide, the Liver and the Heart Rate
• Stopping, Costs and the New Pills
• A Warning About Retatrutide Bought Online
• Side Effects
• The Fourth Solution: Amylin
• My Verdict
• References

Why the Line Went Up

Scientists found a big clue to why obesity rates started climbing around 1980 [1], from an elegant experiment done in 2018.

Twenty adults moved into a research ward at the NIH for a month. For two weeks they ate ultra-processed food. For the other two weeks, unprocessed food.

Crucially, the ultra-processed and unprocessed meals matched for calories, sugar, salt, fat and fibre.

And, the participants could eat as much as they liked.

See at the time, scientists had long suspected that it was something about ultra-processed foods that contributed to weight gain. But this was the first controlled experiment done to explore that idea, especially with the calories, sugar, salt, fat and fibre being the same [2].

Here's what they found.

On the ultra-processed food, people ate about five hundred extra calories a day. They gained nearly a kilogram in two weeks. On the unprocessed food, they lost nearly a kilogram [3].

Remember, both diets had the exact same amount of calories, sugar, salt, fat and fibre. The only difference was the processing.

And here's the fascinating part. They didn't feel any hungrier or any less full on either diet. They didn't even rate the processed food as tastier. They just ate it faster, and each bite packed in more calories [3].

A follow-up trial this year explored this in more detail. Turns out, most of the extra eating came from how many calories each bite carried, and how hard the food was to stop eating. Processing on its own added very little [4].

But big food companies had already figured this out.

To maximize their profits, they want us to eat as much as possible. The more food they sell, the better it is for their bottom line.

So they designed foods that were specifically designed to be hyper-palatable by adding extra fat, sugar, salt and refined carbohydrates into our foods.

By one count, 62 percent of the foods in the American food database fit that description [5]. Designed to give us dopamine hits, and to make us overeat.

Combine that with fancy packaging and advertising, and it's no wonder that calories consumed started rising in the early 1980s and by 2010 there were about 450 more calories consumed per day per person [6]. One model found that much extra food was more than enough to explain the weight the country gained [7].

And the food companies did very well. From 1980 to the end of 2009, while the obesity line climbed, shares in Coca-Cola rose about 40-fold. McDonald's, about 60-fold. The stock market as a whole rose about ten-fold [8].

Companies were cashing in on making us fat.

So our food environment was poisoning us.

And many of us moved into desk jobs. We were more stressed than ever, not finding the time to look after our health and exercise.

And it wasn't like we didn't try to fight back. Diet after diet was sold to us as our saviour from this toxic food environment that was thrust upon us by big food companies.

The Diets

For example, in 2003, 63 adults with obesity were randomised to an Atkins-style low-carb diet or a standard low-fat one. At three months and six months, low-carb was ahead. At twelve months it was 4.4 percent of body weight against 2.5, a gap that could have been chance. And the authors wrote that many people struggled to stick to either diet, and many dropped out [9].

I'm not blaming anyone. When we are working long hours to provide for our families and that's the priority, health takes a back seat and the path of least resistance is to get consumed by our toxic food environment.

Many trials like this were done, trying to find the best diet. Was it keto? Low-fat? Paleo?

Or was it carbs driving up our insulin, and insulin driving the weight gain? That idea is called the carbohydrate-insulin model.

Pool the trials of low-carb against other diets, and low-carb leads by about a kilogram at six months, and by less than a kilogram at one to two years [10]. In one two-year trial, paleo followed the same curve [11]. And when 811 people were given one of four very different diets for two years, every group ended about three kilograms down. None beat the others [12]. And none could resist the effects of the big food companies.

But maybe a more intensive intervention is needed? More coaching? Less insulin? Or a test to match each person to the right diet?

Here's the trial that tested all of those ideas.

609 adults. One year. A healthy low-fat diet against a healthy low-carb diet, with plenty of coaching on both. And at the start, everyone had a genetic test and an insulin test, to see whether people who make more insulin do better cutting carbs. The result? 5.3 kilograms against 6. No real difference. And neither test predicted who did better on which diet [13].

A study published this year went further. Researchers made people lose the same amount, about 10 percent, on keto, Mediterranean, or very low-fat food. Keto cleared more fat from the liver. But the keto group also ate more protein. And the weight loss itself was the same, by design [14].

Notice the pattern. Some diets pull ahead at six months. By one to two years, they even out.

I bring these studies up, because there isn't a magic 'best diet' that's going to solve the rising obesity levels.

What we do find from this data is that some people respond really well to one diet, and others to a different diet.

Within each diet, some people lost 30 kilograms and some gained 10 [13]. If you're one of the people a diet worked for, you didn't imagine it. But the spread was just as wide on both diets, and nobody has found a reliable way to predict who suits which one [15][16].

This is why you'll see glowing testimonials about a particular diet. Those people were hyper-responders to that diet which is great for them, but it doesn't mean that the diet will work for everyone. Diet gurus capitalize on these testimonials though to sell expensive courses.

Instead, for most people, the body fights the weight loss.

Fat cells don't disappear when you lose weight. They shrink. Shrunken fat cells make less of a hormone called leptin, and the brain reads that as starvation. So hunger goes up [17].

The body runs colder to burn less calories.

Involuntary movements are less, again so that the body can preserve its calories because it thinks that it's starving.

So even when a diet works, for most people the weight creeps back over the years [18][19][20].

About half of American adults say they tried to lose weight in the past year, and the obesity line kept climbing [21]. Big food companies kept winning.

No End in Sight

It seemed like there was no end in sight.

Something Remarkable Happened

Then the answer arrived from the strangest possible direction, and we now have 4 solutions. Two approved and one nearly there, and a fourth still in trials.

In 1980, a gastroenterologist named Jean-Pierre Raufman started testing animal venoms at the NIH, to see what they did to the pancreas. He later called it a "fishing expedition". The venom that caused the biggest reaction came from a Gila monster [22].

The Gila monster eats about four or five times a year, taking as much as a third of its own body weight in a single meal. But researchers have long noted that its blood sugar stays remarkably steady between those meals [23].

At a veterans' hospital in the Bronx, a doctor named John Eng took a closer look. In 1992 he found a new compound in the venom. He called it exendin-4. It worked like a human gut hormone called GLP-1, the signal that tells the pancreas to release insulin after a meal. But our own GLP-1 is broken down fast. The lizard's version lasted far longer [24][25].

Almost nobody cared. So Eng put up a poster at a diabetes conference. A scientist from a small company called Amylin stopped to read it. In 2005 the first GLP-1 drug was approved, for diabetes [25][26].

The drugs that followed were built on our own GLP-1. Liraglutide in 2010. Semaglutide in 2017. Each one stronger and longer-lasting. And at a higher dose, tested for obesity instead of diabetes, semaglutide took off about 15 percent of body weight. It was approved for obesity in June 2021 [27][28].

GLP-1 is the first solution.

Tirzepatide is the second. It pairs GLP-1 with a second gut hormone called GIP. 21 percent weight loss. Approved for obesity in November 2023 [29][28].

The third is retatrutide. It adds another hormone, glucagon. It isn't approved yet. It's still in trials.

This part is important for selecting which option to use.

Glucagon is insulin's opposite. When your blood sugar drops, glucagon tells your liver to release sugar. It was first found in the 1920s as an impurity in early insulin, one that pushed blood sugar up. So for decades, research on it was mostly about blocking it [30][31].

The theory is that glucagon turns up the body's energy burn, its metabolism, and tells the liver to burn its fat.

On the 29th of September 2026, retatrutide's main phase 3 trial was published. 2,339 people over 80 weeks, the top dose took off 28 percent of body weight if everyone had stayed on it. Counting everyone who started, 25. More than a third of the people on the top dose lost at least 30 percent. Those results are now published in the New England Journal of Medicine [32].

Are These Solutions Working?

So are these solutions working? Bearing in mind that it's only semaglutide and tirzepatide that have done the heavy lifting so far. Let alone retatrutide or the 4th solution that we're going to talk about shortly.

In medical records, where people are weighed in the clinic, obesity went from 42.3 percent in 2021 to 40.7 percent early this year [33][34][35][36]. And the share of Americans taking one of these drugs for weight loss has gone from 3 percent to 11 percent since 2024 [37].

And look at this. This is great news for us, and terrible news for the food companies. Six months after someone starts one of these drugs, their household spends about 11 percent less on chips and savoury snacks, about 8 percent less on sweet baked goods, and about 7 percent less on cookies and soft drinks. Spending on yogurt and fresh produce goes up a little [38].

But beware, these big food companies in their investor conference calls have said that they are designing foods that resist the GLP-1 effect. Which as a primary care doctor, I find difficult not to get irritated about.

None of this factors in the fourth molecule that I'm going to discuss shortly.

Benefits Beyond Weight Loss

First though, I want to emphasize that these medications have benefits over and above their weight loss effect. This is very important to recognise.

In two trials of 469 people with obesity and moderate-to-severe sleep apnoea, tirzepatide cut the breathing pauses by 25 to 29 an hour, against about 5 on placebo. In December 2024 it became the first drug approved for sleep apnoea [39][40].

This is to say that we absolutely need to still improve sleep quality, and these medications can help.

Next is joints. 407 people with knee arthritis and obesity, semaglutide, 68 weeks: pain scores fell 42 points out of 100, against 28 on placebo [41].

Part of that is simple physics. Every kilogram you lose takes about four kilograms of load off your knee, with every step you take [42].

But a team in China wondered if there was more to it. So they tested it in mice with arthritis. One group got semaglutide. Another group was fed just enough less to lose exactly the same weight, with no drug.

Same weight loss. Different knees. The dieting mice kept losing cartilage. Only the semaglutide mice kept theirs [43].

Di Chen, one of the study authors, put it like this: "This controlled experiment demonstrates that semaglutide's protective effect on cartilage in osteoarthritis is independent of weight loss." [44]

So if it's not weight loss, what's happening?

Here's the simplest way to think about it. Your cartilage cells need energy to maintain and repair the tissue around them. In arthritis, those cells get stuck running on an inefficient fuel source. Think of a factory running on a sputtering generator. There's barely enough energy to keep the lights on, and nowhere near enough to rebuild anything. Semaglutide seems to flip a switch inside those cells, moving them onto a cleaner, more efficient energy source. Enough energy to start repairing [43].

But mouse cartilage isn't human cartilage. Does it actually work in people?

So the scientists ran a pilot clinical study. 20 patients aged 50 to 75, all with obesity and knee osteoarthritis. Half received standard treatment, hyaluronic acid injections. The other half received hyaluronic acid plus weekly semaglutide [43].

After 24 weeks, they put them in MRI scanners. The semaglutide group showed an average 17% increase in cartilage thickness, suggesting regeneration. The control group: less than 1%. The thickened cartilage was visible in weight-bearing areas of the knee, the areas that take the most punishment [43].

Patients also experienced reduced pain and improved joint function. The tissue that every orthopaedic textbook calls irreplaceable appeared to be growing back [43].

The study results open the possibility of a radical new approach to osteoarthritis. We already know we can reduce pain through weight loss. It now appears we may also be able to actually regenerate cartilage.

By looking after our joints, and reducing pain, people can do more exercise. None of this is a replacement for sleep or exercise.

Next is the heart, then finally the liver.

I covered the heart part in my recent video on heart attacks. In 17,604 people who already had heart disease, semaglutide cut major heart events by about a fifth over three years [45]. And blood pressure falls with the weight, about a point off the top number for every kilogram lost [46].

Retatrutide, the Liver and the Heart Rate

Now, the liver. And here's a crucial point about selecting retatrutide vs tirzepatide.

These medications work wonderfully to reduce liver fat, but because retatrutide has a glucagon agonist, it speeds up the process of the liver burning through its fat stores. And as we saw before, it offers greater weight loss compared to tirzepatide.

There's a problem though. Because of the glucagon agonist, which speeds up metabolism, it also raises the heart rate. That's probably not ideal in the long run.

Retatrutide has its own particular side effects too. In the main trial, one in eight people on the top dose had an odd, heightened feeling in their skin. One in nine stopped the drug because of side effects, against one in twenty on placebo. And its heart-outcome trial won't report until about 2029 [47][48].

Interestingly though, by the end of the trial, only about half the people assigned the top dose were still on that top dose. More than one in five had stepped down to a lower dose, most often because they, or their doctor, felt they were losing too much weight [32].

That's how powerful these medications are now. People lose too much weight.

The trial's own authors now suggest that, once it's approved, doctors should aim for the lowest dose that gets each person to a target weight, not the highest dose they can tolerate [32].

So here's how I think retatrutide will fit in, once approved.

I think retatrutide will be used to help people reach a healthy weight, and burn through their liver fat.

Then, once someone is a healthy weight and their fatty liver has gone, I think they'll move to tirzepatide to keep it off. That way they're not on glucagon for years before we have its long-term heart data.

Stopping, Costs and the New Pills

Which brings me to an important point, then we'll talk about the 4th solution to the rising obesity levels.

If people stop these medicines, their appetite comes back, and so does the weight. In the semaglutide trial, people taken off the drug regained two-thirds of what they'd lost within a year [49].

So what I suggest to my patients in the clinic once they've reached their target weight, is to stay on tirzepatide and use the click counting method.

I'm going to get in trouble for talking about the click counting method, but if it saves you money then I don't care.

The maximum dose of tirzepatide is 15 milligrams. If you buy the 15 milligram pen, you can 'click' the dose so that you only take part of it. For most people, a 5 milligram dose might be enough to stay where they are. So in a 15 milligram pen, if you click 20 times, you'll have a 5 milligram dose.

That's a lot cheaper, compared to buying the 5 mg pen.

Speaking of costs, in the US these drugs used to list at a thousand dollars a month or more. After a deal with the government in November 2025, self-pay prices now start at about $150 a month for the lowest-dose pill, and around $350 for the injections [50]. Outside the United States, generic semaglutide is arriving. Canada approved its first generics this spring, and one maker says it will sell at about a third of the brand price [51][52].

And in April 2026 a daily tablet, orforglipron, was approved [53]. The pills are weaker, about 11 to 14 percent [54][55]. But in a trial where people who'd lost weight on the injections switched to the tablet, they kept about three-quarters of their loss, against half or less on a dummy pill. The authors call it a "globally scalable" option [56].

A Warning About Retatrutide Bought Online

One warning. Retatrutide is only legally available inside Lilly's trials. Many of you have told me you're buying it online and choosing your own dose. In the trials, the dose was started low, raised slowly, and monitored, and even then one in nine stopped because of side effects. Lilly's own trial protocol warns that people in retatrutide trials have developed starvation ketoacidosis, a dangerous build-up of acid in the blood, likely from eating too little. A vial from a website comes with no monitoring, and nobody checks what's in it [47][32].

Side Effects

In terms of side effects, the common ones are in the gut. Nausea, vomiting, and either constipation or diarrhoea. For most people, their body gets used to the medications and the side effects go away. So in the clinic, we start on low doses, have close follow-up, and slowly build up the dose. If there are issues, then we have the tools to deal with the side effects [27][57].

Large, real-world studies have been largely reassuring on pancreatitis and thyroid cancer [58][59][60].

I've done a separate video about a very rare stroke of the optic nerve, called NAION [57].

In my view, the most important side effect of any weight loss strategy is muscle loss. Muscle loss is the same on these medications compared to other weight loss strategies such as dieting or bariatric surgery.

That's why the American Diabetes Association advises enough protein and muscle-strengthening exercise [61].

The Fourth Solution: Amylin

Here's the fourth solution to rising obesity rates, still in trials: amylin.

Your pancreas releases it alongside insulin, and it acts on its own receptors in the brain to signal that the meal is over.

Some options in development are blanket amylin drugs: cagrilintide hits the amylin receptors and the related calcitonin receptor too. Eloralintide prefers one of the amylin receptors over the calcitonin receptor about twelve to one. In theory, the more targeted drug should cause fewer side effects, and fewer side effects would mean more people stay on it.

When eloralintide was added to tirzepatide, so a triple hormone therapy, people with type 2 diabetes lost up to 23 percent over 48 weeks if they stayed on it, against 15 percent on tirzepatide alone [62].

The main issue though with amylin agonists is the nausea.

I think, if the side effects can be tamed, tirzepatide plus an amylin drug, with no glucagon, could become another long-term option. And further out, you could even see eloralintide added to retatrutide, four hormones in one treatment.

My Verdict

So, my verdict. Obesity as a condition medicine couldn't treat is over. The number itself has only just stopped climbing, and these medications are gaining momentum.

That's great for you and me. It's terrible for food companies and diet gurus selling expensive courses.

None of this is a replacement for a great diet, regular exercise, and high quality sleep.

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