Obesity is a chronic health condition affecting nearly a third of Australians. As a risk factor for illness and death it’s second only to smoking. Holding excess weight has been linked to 30 diseases including type 2 diabetes, kidney, liver and heart problems, sleep apnoea, dementia, and cancer. Overall, the Australian government estimates that obesity contributes to 10% of annual deaths.
However, losing even 5% of body weight can significantly mitigate the risk of developing serious health complications and increase quality of life. This is where medications for obesity can come into play.
Trick or treatment
Treatments for obesity have focused on lifestyle interventions like eating different foods or increasing physical activity. However, maintaining weight loss is difficult for most people due to complex interactions between biology, behaviour and environment.
Biologically, losing weight prompts changes in several areas of the brain that control eating, alters hormones involved in feeling hungry and feeling full, and reduces overall energy expenditure disproportionate to the weight actually lost. These physiological changes seem to promote subsequent weight gain, leading scientists to theorise that bodies strive to maintain a certain set weight.
In terms of behaviour, challenges exist in the psychological connection of food as a reward, exercise as a punishment, and societal stigma. Many obese people have faced prejudice and discrimination in healthcare settings. These factors mean that people are disheartened at the thought of addressing their obesity, reluctant to seek out treatment, and have low expectations of care.
Environmentally, losing weight can be difficult in a world where the tastiest and most convenient foods are energy-dense, stress is constant, sleep is inadequate, and there is little time or opportunity for recreational exercise.
Due to these factors, most people who lose weight through diet and exercise alone will regain it over time.
As such, there’s a role for medication in treating obesity.
In a narrative review for The Medical Journal of Australia, Associate Professor and Endocrine Society of Australia member Priya Sumithran and her PhD student Rosalind Walmsley discuss current and future pharmacological treatments for obesity in Australia.
Medications for obesity
Existing medications
Orlistat
OrlistatOrlistat (sold as Xenical) prevents the digestion of fat by making gastric and pancreatic lipases inactive. This means that up to 35% of the fat from food just goes straight through. Unsurprisingly, its side effects include needing to rush to the loo, and minor incontinence. Unlike other drugs on this list, Orlistat is available from pharmacies without a prescription, but it’s recommended to take a multivitamin alongside Orlistat to make up for the reduced absorption of fat-soluble vitamins. In trials, patients taking this drug reported a weight loss of 4-10kg over 12 months.
Phentermine
Phentermine, sold under a number of names, reduces hunger and reward-related eating by increasing the amount of neurotransmitters in the brain. While it’s been in use for over 60 years, it’s only recommended as a short-term intervention as it loses its effects over time and can be addictive. In trials, patients taking Phentermine lost an average of 12.2kg in 36 weeks.
Naltrexone–bupropion
Bupropion is an antidepressant, and Naltrexone stimulates neurons in the hypothalamus. Combined, they affect the hunger and reward systems in the brain. Care has to be taken when prescribing Naltrexone-bupropion as it can easily interact with other drugs and cause serious complications. Its side effects include nausea and constipation. Clinical trials have reported an average weight loss of 5–6 kg over 12 months.
Glucagon-like peptide 1 receptor agonists
Liraglutide (sold as Saxenda), Semaglutide (sold as Ozempic) and Tirzepatide (sold as Mounjaro)
were originally developed as treatments for Type 2 Diabetes, but have been prescribed off-label to treat obesity. Liraglutide and Semaglutide mimic the GLP-1 hormone, which is created by the digestive system when a person starts eating. GLP-1 tells the stomach to slow down digestion and the pancreas to produce more insulin and less glucagon. It usually breaks down a few minutes after delivering its messages, but Liraglutide and Semaglutide stick around for a week, meaning people feel satiated for much longer.
Tirzepatide works similarly, but also mimics another hormone, GIP, which has a similar function. This means it uses two mechanisms rather than one, and so does it work more effectively.
These drugs are extremely expensive in Australia, but popular due to their efficacy. While Liraglutide resulted in weight loss of 6-8kg over 12 months, Semaglutide resulted in a loss of 15-18kg and Mounjaro 15-20kg.
Their off-label use for obesity has meant that shortages have affected people prescribed the drugs for diabetes and other conditions.
Topiramate
Topiramate was originally developed for epilepsy and migraines. It is not known how Topiramate causes weight loss. Its side effects can include paraesthesia (strange feelings in the skin), change in the sense of taste, sleepiness, memory, attention and concentration difficulties, and mood disturbances. Trials have found that Topiramate produced a weight loss of 5.3kg in 16 weeks.
New medications
Cagrilintide
Cagrilintide mimics the hormone amylin, which is secreted alongside insulin by the pancreas. Amylin tells the stomach to slow down digestion, and calms down the reward pathway in the mid- and hind-brain to produce a feeling of satiation and reduce the rewarding feeling of food.
Cagrilintide is currently in Phase 2 trials. This means its safety to humans has been established, and it has been given to a small number of patients to determine its efficacy in treating their condition. Results from this small trial have indicated weight loss of up to 11 kg over 26 weeks. A combination of Cagrilintide and Semaglutide is also being looked into as a possibility.
Setmelanotide
Setmelanotide has been developed for certain genetic disorders that result in obesity. These disorders are characterised by extreme hunger at an early age, leading to childhood overweight and obesity. Setmelanotide is approved for use in the United States and Europe for patients over the age of 6 who have been diagnosed with POMC deficiency, PCSK1 deficiency or LEPR deficiency and is undergoing trials for Bardet–Biedl syndrome, Alström syndrome and Prader–Willi syndrome.
Bimagrumab
Bimagrumab is a drug for treating muscle loss and weakness, but has recently entered drug trials for the treatment of obesity. It is an antibody that attaches and binds to the Activin Type II Receptor (ActRII). This prevents ligards binding to ActRII, which would usually negatively regulate muscle growth and promote brown fat activity. While it’s unknown exactly how Bimagrumab works, early results show that participants in a small Phase 2 trial lost 20.5% of their fat mass and gained 3.6% in lean mass.
Other gut hormone-based agents
Several other medications are being developed that affect multiple digestive hormones at once. These drugs aims to mimic the way complementary hormones are released when eating, as well as having two- and three-fold effects on appetite, satiation and blood sugar.
Not the be-all and end-all
With all this said, the average weight loss reported for these medication is just that – an average. Individual responses vary widely, so what may induce 10kg of weight loss in one person may only stimulate 1kg in another.
Medications also differ in their physiological effects and impact on related health complications. For example, Orlistat has a positive impact on cholesterol and fatty liver disease, while Naltrexone–Bupropion does nothing to improve blood pressure, and Liraglutide, Semaglutide and Tirzepatide are good for regulating blood sugar. Few studies have directly compared outcomes of different obesity medications, so the choice of medication is currently down to patient preference of side-effects, consideration of concurrent medications, mode of administration, and cost.
All the medications listed above work better and improve quality of life to a greater degree if used in conjunction with lifestyle interventions. As the drugs stop working when people stop taking them, they should either be taken long-term (although there is currently limited data on long-term safety and outcomes) or be used as one part of a long-term management plan.
