Revolutionary weight-loss drugs like Wegovy come with a catch

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Anti-obesity drugs cause people to lose more than just fat.

More than 73% of American adults are overweight, according to the CDC. This puts them at increased risk of death and many serious health issues, but losing weight and keeping it off through diet changes and exercise — the standard approach — is notoriously difficult.

That made the FDA’s 2021 approval of Novo Nordisk’s semaglutide (Wegovy) as an obesity treatment seem like something of a miracle.

The drug is in a class known as GLP-1 agonists, which were created to treat type 2 diabetes. Because they reduce appetite and trigger the release of insulin, they also have a proven ability to help people shed pounds, reduce blood pressure and cholesterol, and even reduce the risk of death. 

The problem is that all pounds are not created equal. 

Generally speaking, weight loss only occurs when your body needs more calories than you are eating. To make up the difference, your body taps into the energy stored in your fat cells. This causes the fat cells to shrink, and you lose weight.

Your body doesn’t just pull energy from fat, though — it also pulls it from “lean mass,” such as muscle tissue. All ways of losing weight, including dieting, typically involve losing muscle mass as well as body fat. But if you lose too much muscle, you can experience fatigue and a slower metabolism.

In older people, who are already experiencing normal muscle loss due to aging, losing too much muscle mass could potentially reduce mobility and increase the risk of falls.

“Just because we’re losing weight doesn’t always mean we’re getting healthier,” Michelle Hauser, obesity medicine director of the Stanford Lifestyle and Weight Management Center, told the New York Times.

In studies, 20-40% of the weight lost by people taking GLP-1 agonists is muscle mass.

Strength training and eating a high-protein diet can combat muscle loss if you’re losing weight using traditional methods — in those instances, a person can expect the weight they lose to be about 25% lean mass and 75% fat mass.

People just taking GLP-1 agonists may simply be eating less, though, and in studies, 20-40% of the weight they’re losing is muscle mass. This is inspiring drug developers to hunt for another kind of miracle cure: a medication that can prevent muscle loss while you lose weight. 

Especially for older adults — who have the most to gain from a drug that lowers the risk of heart disease but also need to preserve muscle strength — combining a muscle-preserving drug with GLP-1 agonists could be a big deal. 

Here are four of the most promising candidates:

The anti-aging med

The drug: BioAge Labs’ azelaprag is a drug that mimics the activity of apelin, a natural hormone secreted during exercise that helps regulate metabolism and promotes muscle regeneration.

The details: BioAge began developing azelaprag as an anti-aging medication, because the expression of apelin tends to decrease as we get older — one possible reason we lose muscle as we age. In a trial of 21 healthy seniors confined to bed rest for 10 days, it was well-tolerated and demonstrated an ability to reduce muscle atrophy compared to a placebo.

In studies on obese mice, combining azelaprag with Eli Lilly’s weight-loss drug, tirzepatide, actually resulted in more weight loss than tirzepatide alone. It also improved muscle function and body composition.

In October 2023, BioAge announced plans to collaborate with Eli Lilly on a phase 2 trial of azelaprag and tirzepatide in people with obesity. In February 2024, it closed a $170 million fundraising round to help support the trial, which is expected to kick off in mid-2024.

The advantage: Azelaprag is administered orally, so taking it alongside a GLP-1 agonist wouldn’t be much of a burden for patients.

The limitation: Though the bed rest trial and animal experiment results are promising, we won’t actually know whether azelaprag can prevent muscle loss due to medication (and not inactivity) until we start seeing the results of this new trial.

What they’re saying: “Our oral drug azelaprag, combined with an incretin drug, has the potential to improve weight loss quantity and quality. Tackling obesity can help cut the population burden of age-related disease.” – BioAge Lab’s CEO Kristen Fortney

Eli Lilly’s other bet

The drug: Versanis Bio’s bimagrumab is a monoclonal antibody, which is a kind of lab-made protein that seeks out and binds to specific receptors. Bimagrumab binds to “activin type II receptors,” which both encourages fat loss and prevents metabolic activity that typically leads to muscle loss.

The details: As of June 2023, bimagrumab had been administered to more than 1,000 people. In one phase 2 trial of people with obesity, some of whom also had type 2 diabetes, participants lost 20.5% of their fat mass while increasing their lean muscle mass by 3.6% over 48 weeks of treatment.

In animal experiments, administering bimagrumab along with a GLP-1 agonist preserved muscle mass while increasing the amount of fat lost. In January 2023, Versanis launched a phase 2b human trial of bimagrumab as an obesity treatment, either alone or co-administered with semaglutide, Novo Nordisk’s GLP-1 agonist. The first results are expected in mid-2024.

In July 2023, Eli Lilly acquired Versanis. If the phase 2b trial goes well, it’s possible the company could trial the combination of bimagrumab and tirzepatide — or another one of the GLP-1 agonists in its pipeline.

“Bimagrumab addresses a critical unmet need.”

Mark Pruzanski

The advantage: While people on GLP-1 agonists tend to gain back any weight lost if they stop taking the meds, that might not be the case for bimagrumab — 12 weeks after their last dose, the people in the 1,000-person phase 2 trial had yet to regain any weight.

The limitation: Monoclonal antibodies are expensive to produce, and while bimagrumab only needs to be taken once every four weeks, it needs to be administered intravenously, which has to happen in a medical facility. Most GLP-1 agonists come in injector pens that can be used by patients at home. 

What they’re saying: “While the new generation of incretin therapies have been revolutionary for patients living with obesity, bimagrumab addresses a critical unmet need as a therapeutic that targets fat loss while building muscle mass.” – Versanis CEO Mark Pruzanski

The solo act

The drug: Altimmune’s pemvidutide is a combination GLP-1 agonist and glucagon agonist. While the GLP-1 agonist suppresses appetite, the glucagon agonist increases energy expenditure. Together, they are meant to mimic the effects of diet and exercise.

The details: In March 2024, Altimmune announced the results of MOMENTUM, a phase 2 trial in which people received weekly injections of pemvidutide as an obesity treatment. 

After 48 weeks, participants lost an average of 15.6% of their weight, and about 75% of the lost weight was fat — a favorable ratio comparable to what’s seen in people who manage to lose weight through improved diet and exercise.

The company plans to present a more detailed analysis of the MOMENTUM trial data at a TBD scientific conference.

The advantage: A single medication that helps people lose weight while also mostly preserving their muscle mass could be preferred over two separate drugs.

The limitation: During the MOMENTUM trial, participants also exercised more, so isolating the drug’s impact is difficult.

What they’re saying: “There is a growing appreciation that the quality of weight loss is as important as the quantity of weight loss … we believe that pemvidutide, if approved, could stand out as an attractive option for weight loss and weight maintenance.” – Altimmune’s CMO Scott Harris

The team effort

The drugs: Regeneron’s trevogrumab and garetosmab are monoclonal antibodies. While trevogrumab binds to and inhibits myostatin, a protein that limits skeletal muscle growth, garetosmab neutralizes a protein called activin A, which is linked to muscle atrophy. 

The details: Trevogrumab was developed to treat muscle loss linked to immobility or aging, while garetosmab was created as a treatment for a rare disease where muscle tissue is replaced by bone (called “fibrodysplasia ossificans progressiva”).

In February 2024, Regeneron announced plans to launch a phase 2 trial in mid-2024 that will test combining semaglutide for obesity with either trevogrumab or trevogrumab and garetosmab.

The hope is that the meds will not only prevent excess muscle loss, but potentially help people keep weight off even after they stop taking the GLP-1 agonist.

“Inhibiting new pathways on top of GLP-1 receptor agonism has the potential to achieve … improved quality of a weight loss.”

George Yancopoulos

The advantage: Because Regeneron is targeting two different pathways linked to muscle preservation, its approach could be more impactful than those that target just one. 

The limitation: More meds means more opportunities for side effects, and because trevogrumab and garetosmab are monoclonal antibodies, they could be costly and complicated to administer. As is the case with azelaprag, we currently have no idea how these medications will perform in people taking weight-loss drugs, either.

What they’re saying: “We believe that inhibiting new pathways on top of GLP-1 receptor agonism has the potential to achieve comparable overall reductions in body weight, but with improved quality of a weight loss, resulting in more fat loss while preserving or actually increasing muscle mass.” – Regeneron’s CSO George Yancopoulos

The big picture

If any of these medications (or combinations of medications) can actually enable people to lose weight while preserving muscle mass, the impact on public health could be huge — but it’ll likely be years before they reach the market.

In the meantime, people taking GLP-1 agonists for weight loss may need to lean on old fashioned methods for retaining muscle — exercise and a healthy diet — and there are groups trying to make this easier.

Fitness company Equinox has launched the GLP-1 protocol, a coaching program specifically designed to help people on the meds retain and even build muscle. Country club operator Life Time, meanwhile, has launched a new membership program that can help people get prescribed the meds and then build workout routines to accompany them.

Healthcare company Abbott has unveiled a line of high-protein shakes designed to help prevent muscle loss in people taking GLP-1 agonists, and food delivery service Daily Harvest now has a GLP-1 Companion Food collection tailored to people on the meds.

Even if we get to the point that medications alone can help people with obesity lose weight while preserving muscle, being in the “normal” weight range with a good muscle-to-fat ratio doesn’t guarantee good health — as much as we might wish it weren’t true, a better diet and more exercise might still be necessary.

“The fundamentals of obesity management will always be changes to diet and exercise,” said Vijaya Surampudi, assistant director of the UCLA Weight Management Program. “But having anti-obesity medications is another tool in the toolbox.” 

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