Food for thought – PharmaTimes

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Weight loss drugs are the word on the street and it’s getting serious

With all the noise surrounding ‘miracle’ weight loss drugs recently, it is easy to lose sight of their clinical implications – for good and ill.

First, the good. Without question, GLP-1 receptor agonists (GLP-1 R+) have had a significant clinical impact, improving glycemic control, promoting weight loss, and reducing cardiovascular risks in patients with type 2 diabetes and obesity.

Best known under brand names Ozempic and Wegovy, these are essentially the same, containing the active agent semaglutide, a GLP-1 stimulator which increases insulin secretion and suppresses glucagon secretion.

Ozempic is not licenced for weight loss alone (it is a type 2 diabetes treatment), but for canny patients willing to pay, there are plenty of ways to obtain a prescription.

The GLP-1 R+ market is significant, and growing, with conservative estimates putting it into double digit billions of dollars and predicted sustainable growth approaching double digit CAGR, driven substantially by an increasing penetration in diabetes and obesity patient populations.

There’s clearly big money to be made in weight loss. Novo Nordisk, manufacturer of Wegovy and Ozempic, now has a higher market capitalisation than the yearly GDP of its home country, Denmark.

The drug company’s impact on the Danish economy is so large that the country has been able to keep interest rates lower than EU states, and pharmaceutical companies accounted for almost all the export trade growth in the country between 2021 and 2023.

Like many of the best drugs, GLP-1 R+ hijacks regulatory mechanisms already present in the body.

GLP-1 is a naturally occurring hormone that travels around the body to let a host of tissues know that you’ve just eaten a meal and it is time to deal with an imminent load of sugars and fats. It works as follows.

  • It increases insulin production and reduces that of its opposing hormone – glucagon. The effect of this change in ratio is get glucose out of your blood stream and to stop pumping it in from the liver.
  • Hidden away deep in the brain is the arcuate nucleus (ARC) which is part of a neural network controlling your appetite. GLP-1 acts here to give you the sensation of being full after a meal, so you don’t go all Henry VIII at the all-you-can-eat Chinese buffet.
  • The ARC is also a central coordinator for other hormonal and neural cascades regulating the hedonistic pleasure of gluttony and post-prandial somnolence. It’s effects, in part, are mediated by cocaine- and amphetamine-regulated transcript (CART), which is why Ozempic users can look like they are using other drugs.

Weight in vain

Tricking the body into thinking a big meal has been consumed has proven effective in undermining energy homeostasis.

Ordinarily, the body has a target weight and tissue composition, and consumption and expenditure of energy is matched to maintain this.

When all these mechanisms of energy balance were evolving, they were highly effective because acquiring food had an energy cost. It was very difficult to chronically overdose on calories.

Today it is easy to fall into a positive feedback look where excess energy consumption means you are less able to exercise because of accumulated body fat.

The energy cost of ‘Deliveroo’ et al. is minimal, while the calorific content of take away food is usually remarkably high.

The short-term benefit is clear. But what of the longer-term effects of these miracle drugs on bodies not necessarily adapted to the rapid switch between perceived famine and feast?

Here, the picture may be less rosy, and prolonged GLP-1 R+ use may reveal some problematic biochemical hangovers.

One of the biggest risks to emerge could be the impact GLP-1 R+ has on over reward mechanisms in the brain. Down-regulating pathways which make a person feel happy is a dangerous endeavour.

The European Medical Agency’s safety committee, PARC, is currently monitoring the incidence of psychiatric side effects in this drug category, following evidence of increased depression, self-harm and even suicide in patients.

Other longer term side effects are, yet, unknown, though there have been some reports of gastrointestinal side effects.

And what happens when you come off these comparatively expensive drugs? If you need the drugs to keep weight off, you may need them for life.

Come off them, and weight gain will be rapid. A GLP-1 R+ prescription should not be seen as an alternative to healthy eating and regular exercise.

As the current cohort of patients are testing the long-term effects of these drugs, it is hard to be certain of the future. Should, as provisionally seems to be the case, GLP-1 R+ revolutionise the treatment of extreme obesity, there will be knock-on effects for bariatric care.

Treatments for sleep apnoea, bariatric adaptations and even conventional weight loss services may fall in demand. Conversely, we would anticipate an increase in plastic surgery demand to address excess skin and underlying collagen.

If we are entering an age of effort-free weight management then many of our assumptions around the drivers of healthcare demand will have to be revisited.

Michelle Tempest is Senior Partner at Candesic and Dr Joe Taylor is Special Adviser at Candesic

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