Losing weight, and keeping it off, is no easy feat!
Only about 20% of adults who manage to lose a significant amount of weight are actually able to keep it off long term.
In fact, a meta-analysis of long-term weight loss studies found that people regained more than half of the weight they lost within two years and more than 80% within five years.
Despite these challenges, 45 million Americans go on a diet every year.
The weight loss market is fueled by both aesthetics and the belief that “thin equals healthy”—a mantra that’s deeply tied to our reliance on the body mass index (or BMI) as the ultimate indicator of health.
There’s just one problem: it’s a flawed metric.
BMI, which divides weight in kilograms by height in meters squared, was invented in the mid-1800s by a Belgian statistician who was obsessed with studying what he thought of as the ideal manby taking measurements from various populations.
An important to note ,though, is that these populations were still all white males.
It also doesn’t account for muscle mass vs. fat when considering weight, making it an inaccurate measure for athletes.
And some might argue that the cut off numbers for each category are a bit arbitrary.
A BMI of 25 or over is considered “overweight” and a BMI of 30 or higher is “obese.” But that wasn’t always so. The cut off for “overweight” used to be 27.8 or higher.
One day in 1998, the NIH lowered the threshold of what counts as “overweight” to 25, which instantly moved 29 million Americans out of the “normal” range.
These days, according to the CDC, 42.5% of adults over 20 years old have obesity, and another 31.1% are considered overweight based on their BMI.
But one study found that 29% of people who were considered “medically obese” were actually perfectly healthy by all metabolic standards, and 30% of people in the normal range were actually metabolically unhealthy.
I think the real issue is that even the original inventor of the ratio which would turn into BMI never intended for it to be used as a measure of build or amount of fat. He simply used it to collect data about averages within a population.
Despite all of this we still use BMI as the most common measure of “health,” even though we know that other measurements (like someone’s waist to hip ratio, or the amount of exercise they get per week) are better indicators.
This focus on BMI re-emphasizes the perceived importance of losing weight as a part of being healthy, regardless of whether that’s actually necessary for everyone.
The size of the weight loss market has recently ballooned thanks to a new tool in the battle against metabolism: GLP-1 agonists.
Short for glucagon-like peptide-1, GLP-1 agonists are a class of medications that mimic the actions of a naturally occurring hormone our bodies produce in our intestines.
That hormone stimulates insulin release and suppresses glucagon production, two things that the body needs to reduce your blood sugar.
When it comes to weight loss, this class of medication works in very interesting ways.
Given as a weekly, self-administered injection, the drugs interact with signals in the brain that control appetite and hormones in the gut that influence the rate of digestion.
They slow what’s known as “gastric emptying.” This is the process by which the contents of your stomach are emptied into your intestines to be absorbed into your bloodstream.
By slowing this process down, people feel full longer, which can reduce the amount of food they eat.
GLP-1 aganosts also seem to quiet cravings. There are hormones that are released by your gut that tell your brain that you’re full, and it seems like these medications have processes that release more of those hormones, so you’re not even thinking about eating more food.
This is a key reason why people tend to regain weight after diets: the signals that tell your brain “I’m full” are quieter without the GLP-1 agonists.
Not only that, the hormones that send a signal that says “I am hungry please feed me!” increase when you’re in a calorie deficit because your body wants more energy.
So while we know that the key to losing weight is to eat fewer calories than you burn or burn more than you eat, these medications seem to be able to effectively accomplish that by reducing the amount of food people eat without making them think about all the food they’re not eating but wish they were.
It’s very effective. In clinical trials, people who took Semaglutide (which goes by the name brand Wegovy) lost an average of 15% of their body weight after 16 months of weekly injections.
Wegovy and Ozempic are identical drugs, but they have different names because the FDA has approved them for different uses.
Ozempic is for type 2 diabetes management, while Wegvoy is for weight management.
A newer compound called tirzepatide (known as Munjaro for diabetes management and Zepbound for weight management) uses both a GLP-1 agonist and another compound that mimics glucose-dependent insulinotropic polypeptide.
This compound saw a 21% reduction in body weight in clinical trial users.
It’s not completely clear why this combo works better than just a GLP-1 agonist. Maybe it gives a little boost to the GLP-1 receivers, or maybe it does something to reduce the side effects so a higher dose is better tolerated.
Weight loss isn’t the only dramatic change we’re seeing from these drugs.
A lot of people are skeptical of “miracle” weight loss drugs because of the collective social memory of 1950s housewives essentially taking speed to stay trim or the use of the diet drug fen-phen in the 1990s, which was discontinued when it was found to cause heart damage.
But something about this new class of medications is different.
One study found that its use actually reduced the risk of death from heart attacks.
And it’s starting to look like the little voice that plays in our brain over and over again saying “feed me” might not be the only voice that’s quieted.
Early research is showing GLP-1s could help curb addiction to opioids or alcohol, and randomized control trials are under way.
Of course, nothing is without risk, so it feels like a good time to segue into the side effects of these medications.
Unsurprisingly, things that mess with your guts can...mess with your guts.
Nausea is the most common side effect of GLP-1 agonists. One study found that 25% of participants who got the med had nausea around week 20, but that amount went down over time, though it was steady at around 15% of people for the duration.
Diarrhea and constipation were also common at the start of these medications.
There are also some more serious, but less common adverse events of concern.
A small increase in the risk of pancreatitis has been linked to the medication, but it seems like that is more dependent on individual health histories, as for some people being on these medications actually lowers their risk.
Some people experience gastroparesis, or a paralyzing of the stomach which prevents stomach contents from moving into the intestines for digestion and absorption. It can cause vomiting, nausea and painful bloating that makes people afraid to eat.
It's a condition that’s been in the news lately because of a number of lawsuits.
And it does appear there is an increased risk of developing gastroparesis from GLP-1 agonists, though it’s relatively small: less than 1% according to current studies. Still, if a lot of people are taking the medication that 1% will equal a big number.
Muscle mass loss is a side effect, but not at a rate any higher than what we see when people lose the same amount of weight with just diet and exercise.
A review of muscle loss studies found that, of the weight lost, 20-50% was from lean body mass (muscle), which is the same as what you’d see with diet-based weight loss or bariatric surgery.
Your muscles are important. They store your excess sugars and vitamins, and keep your bones together. So, any weight loss plan that’s going to decrease muscle mass should include resistance training as a part of it to keep you balanced and healthy.
So, is it worth it? No medical intervention is 100% risk free. The thing that matters is the risk vs. benefit for each person.
Prior to the approval of these medications, bariatric surgery was the closest option people had with similar efficacy.
Bariatric surgery refers to a number of different surgeries performed on the stomach for weight loss.
But abdominal surgery is expensive, requires recovery time in addition to lifestyle changes, and simply isn’t accessible for all people.
From 2022-2023 (the first big boom time for GLP-1 drugs), one study estimated that bariatric surgeries decreased by 25% as a direct result of the medication’s availability.
While name-brand GLP-1 meds aren’t cheap, a loophole for affordable versions has developed into a highly lucrative market: compounded drugs.
These days we see pharmacies mostly as the place we wait to text us when our drugs have been delivered and are available for pickup. But they used to actually be the place that drugs were mixed and bottled and given to patients based on their needs.
And that sort of thing still happens today at places called “compounding pharmacies.”
They typically exist to make medications for people who have special needs. For example, turning what’s usually a pill into a liquid, adding a flavor, or removing an ingredient someone is allergic to.
They also have permission to make medications when supply chain issues mean that drugs have to be added to the FDA’s official drug shortage list. Like when, say, a drug becomes extremely popular.
This is why you may have seen ads for online services that claim to offer semaglutide or tirzepatide: both drugs have been in short supply for a while.
In October, the FDA removed injectable tirzepatide from the drug shortage list, which should have made it illegal for compounding pharmacies to continue to make it. But the agency quickly backtracked, saying that compounding could continue due to the high cost of the drugs.
The cost of a drug has never been a permissible reason for compounding, and allowing it now is a decision that’s ruffling some feathers in the pharmaceutical world.
Obviously, companies like Eli Lilly and Novo Nordisk, who created these products, want to keep their monopoly on sales while their patents are in place.
That’s the whole reason drug patents exist - so that companies can recoup the cost of research and development before the patent expires and cheaper, generic versions are available.
The bigger issue is that compounded drugs aren’t FDA approved.
Which makes sense when you think about the original intention of allowing compounding: It would be incredibly burdensome for a small, bespoke pharmacy to meet the regulation requirement of a huge producer.
But the issue is that these pharmacies aren’t so small anymore and are producing these medications at high volumes to feed the demand, with no guarantee they are safe or even effective.
There are also what’s known as “outsourcing” pharmacies, which have quality control standards set by the FDA to avoid contamination, but that’s not all compounding pharmacies.
And we’re starting to see the ill effects of that.
The FDA has received so many reports of adverse events happening after the use of compounded GLP-1 agonists, some requiring hospitalization, that they issued a drug safety alert specifically for concerns about compounds of these medications.
And poison control centers have seen a 1,500% increase in calls regarding injectable semaglutide from people accidentally overdosing.
