A new generation of "breakthrough" diet pills

The number of obese people worldwide has tripled since 1975; According to the World Health Organization (WHO), in 2016, about 40 percent of adults were considered overweight and 13 percent were obese
.
Being overweight tends to increase the risk of
health problems such as type 2 diabetes, heart disease, and certain cancers.
The World Health Organization recommends a healthier diet and physical activity to reduce obesity, but medications may help
when lifestyle changes aren't enough.
The new drug mimics a hormone called incretin, which lowers blood sugar and suppresses
appetite.
Some of them are already approved for the treatment of type 2 diabetes and are starting to gain approval
for inducing weight loss.

In November 2022, at the Obesity Week conference in San Diego, California, audiences were awaiting the results of
a highly anticipated drug trial.

When Susan Yanovski arrived, the hotel's banquet hall was already packed with scientists
.
Despite arriving 10 minutes early, she had to squeeze into the few empty seats in the back
.
Researchers at the pharmaceutical company Novo Nordisk did not disappoint
.
They describe the details of a survey of promising anti-obesity drugs in adolescents, a group
notoriously resistant to such treatments.
The findings shocked the researchers: Over the course of nearly 16 months, weekly injections and some lifestyle changes, more than a third of the participants lost at least 20 percent
of their body weight.
Previous studies have shown that semaglutide is equally impressive in adults
.

After decades of effort, researchers are finally seeing signs of success: A new generation of anti-obesity drugs that can significantly reduce weight without the serious side effects
that have plagued previous efforts.

The seeds of today's success were planted decades ago, when Jeffrey Friedman was trying to figure out which genetic mutation made the mice in his lab fat
.
In 1994, Friedman, a molecular geneticist at Rockefeller University in New York City, discovered that the defective gene encodes leptin, a hormone produced by fat tissue that causes feelings of
fullness.
Leptin supplementation with leptin in mice deficient reduced their hunger and weight
.

"This really revolutionized the way we think about the biological basis of obesity and appetite regulation," Yanovski said
.

This was followed by research into the root causes of obesity, as well as research into
drug treatments.
But these early drugs only caused mild weight loss as well as serious side effects, especially for the heart
.

Even before the discovery of leptin, researchers had been searching for hormones that regulate blood sugar levels and discovered a hormone
called GLP-1 (glucagon-like peptide 1).
It appears to have the opposite effect on type 2 diabetes — GLP-1 boosts insulin secretion and lowers blood sugar — making it an attractive treatment for obesity, says Jens Juul Holst, a medical physiologist at the University of Copenhagen who discovered and described GLP-1
.

At the beginning of the 21st century, the U.
S.
Food and Drug Administration (FDA) began approving drugs that mimic GLP-1 as a treatment
for type 2 diabetes.
But the scientists noticed that participants in the clinical trial also lost weight
due to GLP-1's effects on receptors in the brain that control appetite and receptors in the gut that slow digestion.
Over time, companies began experimenting with these diabetes drugs to lose weight
.
By the mid-2010s, one of the drugs called liraglutide was able to lose an average of about 8 percent of body weight, 5 percentage points more than people who took a placebo — which was clinically relevant but not surprising
.

Breakthrough drugs explode

At the beginning of 2021, the phase III clinical trial of the same type of new drug, semaglutide, was shocking
.
This molecule is a modified version of liraglutide that acts on the same pathway but remains intact and active in the body for longer
.
He added that it may also have better access to brain regions
that control appetite.

Patients who injected semaglutide weekly lost an average of 14.
9% of their weight after 16 months of treatment; People who took a placebo had an average reduction of 2.
4%.

In 2021, four years after approval for the treatment of diabetes, the FDA approved semaglutide for weight loss
in obese adult patients.

Historically, it has been impossible
to safely reduce body weight by more than 10% through pharmacological methods.
These new treatments also improve cardiovascular health, the opposite of
past approaches.

Now, there may be a better drug on the horizon: Tirzepatide, which combines synthetic mimetics of two hormones, GLP-1 and GIP, and not only targets the GLP-1 receptor, but also mimics another hormone involved in insulin secretion, the glucose-dependent insulin polypeptide (GIP).

After consumption, the intestines naturally release these two hormones, making people feel full.

The treatment, developed by Eli Lilly & Co.
in Indianapolis, Indiana, was approved for type 2 diabetes in 2022, and at the highest dose, the average body weight dropped by 21 percent, compared to just 3 percent
with placebo.

It's unclear why it's better
to mimic two hormones at the same time than just one.
Tirzepatide may be a more potent activator of the GLP-1 receptor, and GIP may help make the side effects of GLP-1 more tolerable, allowing for higher doses
.
It is also possible that GIP itself can lose weight
.
Despite uncertainty, the level of weight loss after taking Tirzepatide is close to what
would normally only be achieved with bariatric surgery.
This method can reduce body weight by 30% or more after six months, and this weight loss effect lasts for a year or two
.

Although Tirzepatide's effects are promising, it has puzzled researchers
.
How GLP-1 can help promote weight loss is obvious, but the role of GIP is surprising
.
In fact, scientists have long believed that GIP actually promotes weight gain: Mice with dysfunctional GIP receptors are resistant to obesity
.
Therefore, to induce weight loss, the researchers believe that the receptor should be turned off
.
But Tirzepatide works the opposite
.
Timo Müller, director of the Helmholtz Munich Institute for Diabetes and Obesity, and his colleagues knew that GIP stimulates insulin secretion depending on blood sugar levels, just like GLP-1, Müller said
.
So they developed molecules
that mimic these two hormones.
After initial studies showed that activating GIP and GLP-1 receptors could lead to weight loss, pharmaceutical companies created their own molecules, achieving the same results, confirming that the approach works
.

Thousand Oaks, Calif.
-based biopharmaceutical company Amgen is developing a drug that activates the GLP-1 receptor while inhibiting the GIP receptor
.
Early clinical trial data showed that this treatment reduced body weight by about
15 percent after 12 weeks.

Other methods include "triple agonists," which mimic the effects of GLP-1, GIP and the third hormone, glucagon, which also stimulates insulin secretion
.
There are other appetite-related gut hormones, such as peptide YY, which have also been studied
.
Some researchers are working on the monoclonal antibody bimagrumab, which can increase muscle mass while reducing fat
.

Different points of view

The ability to reduce weight by adjusting physiology confirms the idea that
obesity is a disease.
In the past, scientists and the public often assumed that those who were obese simply lacked the willpower
to lose weight.
But there is growing evidence that most people's bodies have a natural size
that is difficult to change.

Richard DiMarchi, a chemist at Indiana University Bloomington, said: "The body protects its weight
.
" Some researchers worry that the drugs fuel some society's obsession
with being slim.
Body type does not necessarily mean health
.

Some researchers worry that offering weight loss solutions in slim societies may also inadvertently reinforce the controversial link
between overweight and health.
One study found that nearly 30 percent of people who are considered obese have a healthy
metabolism.
Another study showed that other health problems tend to predict a person's risk of death more than weight, suggesting that factors
other than weight need to be considered when judging health.

Sarah Nutter, a psychologist at the University of Victoria in Canada who specializes in weight stigma and body image, said: "From a weight shame standpoint, I'm really not very excited about something that I think might be harmful
.
" She added: "It is very, very harmful to pathologize a person's health just based on their weight
.
" Nutter worries that people may start these treatments — the side effects of which can be severe — to escape the stigma of weight rather than the real health need
.

Research questions are numerous, including who will respond to treatment and whether people have to take these drugs for life, which are expensive: injections typically cost more than $
1,000 a month.
A group of clinical trial participants who stopped taking Tirzepatide and stopped the study's lifestyle intervention regained about two-thirds
of their weight one year later.

Another unknown is who will react to these drugs and who will not
.
It's too early to tell, but these drugs appear to be less effective at losing weight in people with type 2 diabetes than in people
with non-type 2 diabetes.
Diseases such as fatty liver and the presence of fat around organs (known as visceral fat) can also affect how people respond to
different medications.

Others worry that the drugs solve the problem
too easily.
Leslie Heinberg, a clinical psychologist at the Cleveland Clinic in Ohio who specializes in weight loss behavioral health and body image, says it's a common misconception
about bariatric surgery.
"Some people still cling to those false beliefs and they say, 'Oh, now people can take this drug, it's an easy way to get rid of
obesity,'" she said.
”

Still, obesity researchers are celebrating these advances
.
For the first time, scientists can safely change weight
from drugs.
"This is truly a 'transformative breakthrough.
'
" These drugs are entering the market, but not everyone who needs them is available
.
First, they're expensive — semaglutide's drug, called Wegovy, costs about $1300 a month — and many insurance companies in the U.
S.
refuse to pay for it, largely due to misconceptions about what causes obesity and dismiss the treatment as a "vanity drug.
"

Patty Nece, chairman of the board of directors of the Obesity Action Alliance (OAC), an advocacy group based in Tampa, Florida, said: "Some of these drugs that people talk about are game-changers
.
" But "for individual patients, it will never be a game-changer if they can't afford it or can't get it.
"

Organizations such as OAC are pushing pharmaceutical companies to offer affordable programs
.
For example, Eli Lilly has a Mounjaro "transition program" — a tirzepatide for type 2 diabetes — under which the first three months of medication cost just $
25.
Novo Nordisk has launched a similar project
for Wegovy.

Regardless of the upfront cost, some scientists emphasize that tackling obesity could save the healthcare system a lot of money by reducing a range of
diseases associated with obesity.

Although researchers are still studying the complex combination of causes of obesity — including genetics, environment, and behavior — many support the idea that
biology plays an important role in this.
Healthy eating and exercise will always be part of the treatment, but many people see these medications as a promising add-on
.
Some researchers believe that because these drugs work through biological mechanisms, they will help people understand that a person's weight is often uncontrollable through lifestyle changes
.
"Tirzeepatide makes it very clear that it's not about willpower," Gimeno said
.