Health, weight & metabolism

Over the last few years, GLP-1 receptor agonist drugs (often just called GLP-1s) have changed the game for anyone living with obesity. Used together with diet and exercise, they can lead to an average weight loss as high as 22%. That makes them almost as effective as bariatric surgery – and vastly more effective than diet and exercise alone.

And they’re also a cultural phenomenon, with much ink spilled over their rights and wrongs. “They’re everywhere in the public sphere, and there are a lot of cynical takes around them,” says Professor Zane Andrews, Professor of Physiology at the Monash Biomedicine Discovery Institute.

But he’s clear: these drugs are critical for those that need them.

“Obesity affects almost every single organ and tissue in the body. If you can reduce your body weight by five to 10%, that can have a massive impact on your health.”

- Professor Zane Andrews - Deputy Head, Metabolism, Diabetes & Obesity Program, Monash Biomedicine Discovery Institute

And plenty of people fall into that category. We usually say someone is overweight when their BMI is over 25, and obese when their BMI tips over 30. According to this metric, rates of obesity have risen dramatically over the past few decades. In Australia, the proportion of adults living with obesity has climbed from around 13% in 1990 to 32% in 2022.

Obesity is a disease

To understand why these medicines are so revolutionary, we need to delve into the nature of obesity itself.

We all know that carrying a lot of extra weight is detrimental, ramping up the risk of heart disease, type 2 diabetes, liver disease, sleep apnoea and stroke. But it’s only recently that obesity has been considered a disease rather than a personal failing.

“We should be thinking of this as a disease in the same way as heart disease, and we shouldn’t be stigmatising those who have excess weight,” notes Andrews.

Some people with a high BMI can store their fat well, without any real metabolic consequences. But others are not so lucky.  When a person’s fat cells can no longer store the fat appropriately, it starts leaking out of the cells and floats around the body, where it can wreak havoc.

It’s genetics that define the tipping point here. “In twin studies, they have found that up to 80% of the variation in body weight can be explained by genetic factors,” he says. “As the saying goes, your genes load the gun and your environment pulls the trigger.”

The brain-gut connection

Perhaps surprisingly, most of the genetic variations associated with obesity are specific to the brain. “That tells us that obesity is largely a brain disease,” says Andrews. “The brain and the gut have co-evolved, and we have so much connection between the two.”

In simple terms, the brain works like a thermostat to control our energy balance. When we’re hungry, the body tells the brain to find some food. When we’re satiated, the body tells the brain to stop eating. It’s a constant dialogue, underpinned by our neural nerves and metabolic hormones.

These signals feed back to a region of the brain called the hypothalamus, which contains specialised populations of neurons that detect when you’re hungry and when you’re full. The hunger neurons (known as AgRP) increase fat storage and glucose production, decrease energy expenditure, and motivate you to seek food. The satiety neurons (known as POMC) decrease glucose production, increase fat burning, and suppress food-seeking behaviours.

For obese people, problems in the signalling system can push the thermostat out of balance. Some grow resistant to leptin, a metabolic hormone that tells the brain you have enough energy. Some see reductions in dopamine, a reward-seeking hormone that is released in response to food. That means they need to overeat just to restore a normal dopamine balance in the brain.

If this sounds maladaptive, just consider how rare obesity would have been in our ancestral past. “From an evolutionary point of view, our primary concern has always been to get calories into our body and to keep them there,” says Professor Andrews. “In many ways, being able to store more fat indicates that you’re an evolutionary success story.”

Enter GLP-1s

GLP-1s work by fixing the thermostat. These drugs (including Wegovy, Zepbound and Saxenda) mimic the GLP-1 hormone – a part of our brain-body messaging system that promotes satiety, curbs appetite and dampens our reward system around food. But unlike the GLP-1 hormone in our body, which enters the blood only for a few minutes, these imitators have a very long half-life and only need to be injected once a week.

The GLP-1 hormone was first isolated in 1985. But it wasn’t until the mid-90s that drug development could really get underway. The turning point came when scientists discovered a very similar molecule with a much longer half-life, extracted from the venom of a lizard that only needs to eat a few times a year. They were able to use this molecule to learn how GLP-1 works, and engineer it for greater efficacy. “Of course, the rest is history,” says Andrews.

Some GLP-1 drugs imitate other hormones, too. Mounjaro mimics the GIP hormone as well as GLP-1, while retatrutide – which is currently in development – mimics GLP-1, GIP and glucagon. In trials, it led to an average of 25% weight loss, with all the health benefits to match.

GLP-1 drugs reduce rates of type 2 diabetes, they burn liver fat, they reduce heart disease and chronic kidney disease. They also reduce craving for smoking, reduce alcohol intake, and might even help with obsessive compulsive disorder.

- Professor Zane Andrews

Not for everyone

But despite the laundry list of benefits, Andrews warns that we shouldn’t treat these medicines as miracle drugs. They aren’t suitable for everyone with obesity – you shouldn’t take them when trying to get pregnant, for instance – and side effects can include gastrointestinal disturbances, loss of lean mass, and (rarely) pancreatitis

You also need to stay on the drugs long-term to preserve their beneficial effects. “When people go off these drugs, invariably the weight comes back,” says Andrews. “There are a number of drug companies and even academic researchers trying to work out how you can titrate yourself off the drug but maintain the weight loss.”

There are also issues around access and affordability, as well as some residual stigma and a real risk of abuse. Then there’s the fact they simply don’t work for everybody: around 10-15% of people have a genetic variation associated with the GLP-1 receptor that dampens down their response.

Despite these challenges, the GLP-1 space is growing fast, with many new drugs (including pill forms) in development. For Andrews, the message is nuanced: these drugs are revolutionary for those that need them, but we do need to exert a measure of caution. Ultimately, more research is needed.

“It’s fundamental research that has led to the discovery of GLP-1s to treat obesity,” he says. “So we need to support research today in order to come up with new therapies for tomorrow.”