Last month, claims that a new drug could revolutionize anti-obesity medication hit the headlines. The drug’s makers, Eli Lilly, reported that people with obesity lost an average of 14.5 kilograms (52 pounds) – up to 22.5 percent of their body weight – in a large phase 3 clinical trial. Considering other weight loss drugs generally yield around a 5-10 percent weight loss, the claim is pretty impressive. The results have not yet been published or peer-reviewed, so must be viewed with caution, but medical experts seem suitably excited.
The drug’s effect “appears to be significantly better than any other anti-obesity medication that is currently available in the US,” Dr Lee Kaplan, an obesity expert at the Massachusetts General Hospital told The New York Times.
Tirzepatide, as it is called, might be the weight loss drug on everybody’s lips right now, but how exactly does it work? How does any weight loss drug work for that matter?
Weight loss drugs are, as you might suspect, drugs designed to help people lose weight. They are not, however, a quick fix to lose a few pounds. Instead, they are prescribed by medical professionals to help people with health problems related to being overweight or having obesity.
Weight loss drugs may be prescribed to adults with a Body Mass Index (BMI) over 30, or at least 27, but with related health concerns, such as high blood pressure or type 2 diabetes. They are generally more effective when combined with lifestyle changes, and so are often recommended alongside adopting healthier eating and exercise habits.
Obesity is a chronic disease that affects more than four in 10 American adults. Worldwide, its prevalence has nearly tripled since the 1970s: As of 2016, more than 650 million adults were obese. People with the condition are at greater risk of debilitating and sometimes life-threatening diseases including heart disease, stroke, and some types of cancer. It is also incredibly financially costly – people with obesity face medical bills $1,429 higher than those at a healthy weight.
It is, unfortunately, difficult to treat – lifestyle changes, drugs, and bariatric surgery can all help, but their success varies between treatments and individuals – hence the need for a wide range of therapeutic options to be researched and made available to help those living with obesity and weight-related conditions.
There are currently five anti-obesity weight loss medications approved by the US Food and Drug Administration (FDA) for long-term use (over 12 weeks): liraglutide, semaglutide, orlistat, naltrexone-bupropion, and phentermine-topiramate.
Unsurprisingly, different drugs work in different ways. For example, some curb appetite, while others increase feelings of fullness or make it harder for the body to absorb fat.
“There are five types [of weight loss drug],” Joseph Proietto, Professor Emeritus at the University of Melbourne and a specialist in Diabetes and Obesity, told IFLScience. “Gut Hormones; Phentermine; Topiramate; Orlistat; Bupropion/naltrexone.”
Liraglutide, semaglutide, and tirzepatide all belong to a class of drug called incretins. These are metabolic hormones that are released into the bloodstream within minutes of eating and have essential physiological roles, including the regulation of insulin and blood glucose levels.
All three of these drugs “are analogues of gut hormones that inhibit our hunger after a meal by binding to their receptors in the brain,” Proietto told IFLScience.
Specifically, they mimic the natural incretin hormone GLP-1 – while tirzepatide also mimics another hormone, GIP – to slow stomach emptying, regulate insulin, and decrease appetite.
Liraglutide was initially approved by the FDA in 2010 as a treatment for type 2 diabetes and is administered by daily injection. As a weight loss drug, it was approved in 2015.
Mimicking the hormone GLP-1, liraglutide binds to receptors in the central nervous system to quell feelings of hunger. For example, the drug has been found to interact with the hypothalamus – an area of the brain associated with appetite and food reward – as well as with a group of neurons in the brainstem, responsible for balancing food intake and energy expenditure.
To slow gastric emptying and reduce food intake, liraglutide also acts on the stomach, relaxing the central parts of the stomach, while contracting the parts further from the center.
As another GLP-1 agonist, semaglutide acts in the same way to induce weight loss. It was approved in the US just last year, making it the most recent addition to the FDA’s list. It has since been approved in the UK, as well, and, Proietto says, will be making its way to Australia soon.
Though yet to be approved, tirzepatide – the latest offering from Eli Lilly – also uses the same weight loss mechanisms. But, it has the added benefits of the hormone GIP, which has previously been found to reduce food intake and increase energy expenditure.
Phentermine is an anorectic that decreases appetite. In the US, it is approved as a short-term weight loss drug and is prescribed for long-term use alongside topiramate – an anticonvulsant used to treat seizures or migraines, which also has an effect on hunger.
The combination was approved by the FDA for weight loss in 2012 and while studies elucidating its mechanism have not been completed in humans, animal studies have given us some clues as to how it might work.
Phentermine mimics amines – derivatives of ammonia – and stimulates the release of adrenaline and noradrenaline in the central nervous system. Phentermine also, but to a lesser extent, enhances serotonin and dopamine release. By increasing levels of neurotransmitters in the brain, phentermine can reduce feelings of hunger. Based on animal studies, it is thought that phentermine acts on the hypothalamus and nucleus accumbens, both of which are associated with appetite and food reward.
Topiramate, meanwhile, remains a bit of an enigma. It affects neuronal activity via a number of mechanisms, which may be able to explain its weight loss effects.
“Topiramate acts by increasing GABA activity in the brain,” Proietto told IFLScience. Although, he adds, “how this inhibits hunger is not known.”
It also inhibits the activity of glutamate – an amino acid – potentially having an impact on energy intake. Some animal studies have suggested it could boost metabolism, as well.
Orlistat is another type of weight loss drug, known as a lipase inhibitor. Approved as a prescription medication in 1999, it is something of a dinosaur among the FDA-approved long-term weight loss drugs, but that’s not to say it isn’t still a valid treatment option for obesity. In 2007, it became the first FDA-approved over-the-counter weight loss pill.
“Orlistat is an inhibitor of lipase [the enzyme that breaks down fat] so it slows digestion of fat in the gut, reducing energy entry into the body,” Proietto said.
On orlistat, around a third of total fat consumed is not absorbed, and therefore cannot contribute to weight gain. The undigested fat then leaves the body – as undigested things always do – in your poop.
Orlistat doesn’t prevent the body from absorbing calories from sugar and other foods though, so is generally prescribed alongside caloric restriction.
Naltrexone-bupropion, FDA-approved in 2014, is another combination of drugs. Naltrexone is an opiate agonist used to treat drug and alcohol dependence, while bupropion is an antidepressant. Together, they act to reduce appetite and control food cravings.
The individual drugs each have their own weight loss effects, but combined have a synergistic effect, providing better weight loss outcomes than each drug alone.
Naltrexone binds to and blocks opiate receptors, including a particular receptor that is implicated in eating behavior. In doing so, studies have found that it blocks endorphin release. Eating food is linked to the release of endorphins, which is what makes it a generally enjoyable experience. By blocking these endorphins, naltrexone can reduce the cravings associated with food and has led to lower food consumption in rodents.
Its inhibition of endorphins can also reduce appetite. “Bupropion/Naltrexone acts by increasing the activity of the melanocortin system in the hypothalamus,” Proietto told IFLScience.
When we’re full, cells in the hypothalamus (pro-opiomelanocortin (POMC) cells) secrete a hormone that instructs us to stop eating. This hormone is released alongside an endorphin, which negates the stop-eating effect, allowing us to regulate our appetite. By blocking the action of the endorphin, naltrexone disinhibits the stop-eating hormone, meaning appetite will continue to be suppressed.
Bupropion has also been found to stimulate POMC cells. It is related to amphetamines, which are known to reduce appetite. Exactly how is not perfectly clear, but it has been suggested that it could be linked to food reward.
The drug prevents the reuptake of the neurotransmitters dopamine and noradrenaline in the brain, which increases their levels in synapses. Dopamine is one of the main agents of food reward and plays an important role in controlling food intake. By enhancing the concentration of dopamine outside of cells, which is seen in the brains of animals after feeding, bupropion could provide a feeling of reward without any food having to be consumed, thus suppressing hunger and leading to weight loss.
As for how all these weight loss drugs size up against each other, there is a clear hierarchy, according to Proietto: “The most potent (per molecule) is Semaglutide, followed by liraglutide and tirzepatide, phentermine, Bupropion/naltrexone, Topiramate, Orlistat in that order.”
As the global obesity epidemic escalates, there is an increased reliance on existing weight loss drugs. Researchers are constantly seeking new medications to relieve the burden placed on the handful already approved and improve the lives of the millions of people across the globe who are living with obesity.
“Because everybody has their own unique response to these drugs, both in terms of side effects and efficacy, it is important to have more to try to cover more patients,” Proietto told IFLScience.
To achieve this, future strategies may look to alternative mechanisms. Regulating several gut hormones at once, for example, is something that Proietto recommends to reduce side effects: “[Companies] should copy nature and instead of using large doses, such as for liraglutide and semaglutide, they should combine hormones.”
Or perhaps future medications will target specific genes known to cause obesity. They might even consider manipulating the gut microbiome to control weight loss and gain.
For now, tirzepatide is on the horizon and, Proietto believes, “a combination of GLP-1 and Amylin [a peptide hormone] is undergoing trials.” Watch this space.
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