New weapons are badly needed in the fight against obesity, but developing drugs with lasting results and fewer side effects isn’t easy. By Nicky Pellegrino
Increasingly, obesity is being viewed as a complex disease rather than a lifestyle problem. The pandemic has accelerated this shift in attitude. The very overweight, and those suffering from associated conditions such as Type 2 diabetes and hypertension, have been hardest hit by Covid-19.
The World Obesity Federation predicts one billion people globally will be living with the disease by 2030. To treat it, a new generation of diet drugs is being developed, with the aim of greater weight loss and fewer side effects.
The history of diet drugs so far has been fairly inglorious. Medications have been introduced and then withdrawn as they were found to cause side effects as diverse as heart damage, cancer and suicidal thoughts.
In New Zealand, four weight-loss medicines are available currently, although none are subsidised. Xenical prevents some of the fat from food being absorbed by the body, and the others work in various ways to suppress appetite. All carry potential side effects – mostly gastro-intestinal problems – and result in a relatively modest weight loss.
Developing better therapies is especially challenging because they need to fight against a survival mechanism. There are multiple pathways in the body that control hunger and satiety. If you lose one, then another can come into play, says Patrick Sexton, of Australia's Monash Institute of Pharmaceutical Science. An effective treatment therefore needs to be safe, well tolerated and also target more than one pathway.
Another issue is that early drug trials tend to be done using rats, and they differ from humans in ways that may be significant.
"It is likely that the wiring is different in their brains and, also, rodents don't vomit," says Sexton. "They can feel unwell but they don't have the same responses you get in people. So, it may be that in rodents you can continue using one of the pathways that is less effective in people."
Sexton's work involves uncovering the secrets of cell receptors, and he has been helping to fill gaps in the knowledge about the way promising new obesity medications work. He has been looking at a class of drugs known as DACRAs (dual amylin and calcitonin receptor agonists), which recently have caused excitement due to encouraging results in trials of the drug cagrilintide.
Using cutting-edge technology, Sexton has found out exactly how this drug interacts with receptors. "We now have an atomic level of detail about the specific interactions."
Cagrilintide, which is being developed by drug company Novo Nordisk, is a long-acting version of amylin, a pancreatic hormone that induces satiety and reduces appetite. Injected weekly, the drug also slows gastric emptying. It has been particularly successful when combined with a drug previously used to treat diabetes, semaglutide, which works via a different pathway.
"If you've got two mechanisms occurring simultaneously, then your body can't compensate as well and so you have the potential for a stronger effect," says Sexton.
Researchers are hopeful these new drugs will provide a less invasive alternative to surgical weight loss, but they do carry some unpleasant potential side effects, including nausea, vomiting and gastrointestinal problems.
The other downside is that patients may need to take the medications for years, and possibly for life, to avoid regaining weight they lose.
"The reality is, like most things with obesity, once you stop the treatment, most people over time will move back to being overweight again, so it is likely they will need to be on it for an extended period," says Sexton.
He hopes it will be possible to develop oral versions of the new drugs, which patients tend to prefer to injectables.
Last year, under the brand name Wegovy, semaglutide was cleared by the US Food and Drug Administration for the treatment of adults with a BMI of 30 and over, and those with a BMI of 27 who also have weight-related medical problems.
It is intended to be used alongside a low-calorie diet and increased physical activity, with the aim that patients lose 15 per cent of their original weight or more.
This is the first prescription slimming medication to get FDA approval in seven years, and there are reports it is flying off the shelves, with the manufacturer struggling to meet demand. However, due to its high cost and a lack of long-term data, it is not expected to be widely available in New Zealand for some time.
