If one of the world's most serious weekly opinion magazines, 'The Economist', announces something on its cover then know that something is happening that will either cost big money or deliver equally big or even bigger. In the issue of 4 March 2023, the cover opened with... a mustard hot dog that, instead of a sausage, had a plastic pen like the one for subcutaneous injections. On this pen was the mysterious name 'Ozempic' and the succinct title: 'Eat, inject, repeat'. The editor-in-chief, Zanny Minton Beddoes, ensured in the first sentence of her editorial that the cover finally gave the good news, as for the past few months it had been rather the war in Ukraine, Turkey's slide into authoritarianism, the destruction of globalisation, uncontainable inflation, etc., that had been emanating from it.

What is the good news? There are many indications that a new group of weight-loss drugs has entered the market with a bang. This is serious business and a potentially gigantic market.

The media is shaken by story after story about the deaths of adolescents with giant obesity, the type of a 15-year-old with a body weight of almost 150 kg, to say nothing of the television documentary series like 'My 600 lb life', which has been broadcast for many years. According to the WHO, the number of obese children and adolescents worldwide rose from 11 million in 1975 to 124 million in 2016, with an additional 213 million overweight. If current trends continue, by 2025 there will also be approx. 70 million children under the age of five with excess body weight. Against this backdrop, Poland does not look too bad so far, but it is quickly climbing up in these sad rankings, especially concerning children. Three in five adult Poles are already overweight. One in four is obese. The National Health Fund (NFZ) estimates that in six years' time one in three of us will be obese, when today about 10 per cent of young children (1-3 years old), 30 per cent of early school-age children and almost 22 per cent of adolescents up to the age of 15 are obese or overweight.

SIGN UP TO OUR PAGE The problem no longer affects the societies of so-called highly industrialised countries because junk food and fast food are the cheapest and globally available food alternatives. For previously regularly starving populations with organisms as energy-efficient as possible, this change is literally the nail in the coffin (because obesity is a risk factor for dangerous diseases ranging from cancer to diabetes to heart attack). Unfortunately, the civilisational progress of the so-called Third or Second World countries manifests itself in widespread access to a greasy burger with fries and a sweetened fizzy drink, rather than improved medical infrastructure and access to it for the poorest sections of society. And it is they who are feeding themselves and their children this junk food.

All these people, and not just Hollywood celebrities with a tendency to be overweight, will need a cheap and effective anti-obesity drug that, in addition, works miraculously, i.e. requires neither dietary sacrifices nor additional physical activity during treatment. A billion people are therefore counting on such a miracle today.

It comes as no surprise that in a serious magazine, which is the indispensable reading of 'fat' investors around the world, we can read that 'Hollywood is moved' and 'influencers on TikTok talk about nothing else and are delighted'. When you add that Elon Musk himself claims that "it works and he knows it from his own experience" and, after all, he doesn't have to make a living as a product presenter in telesales, something must be up. And this does not at all apply to consumer enclaves like Hollywood.

How does the miracle drug work?

So it remains to be seen how it works and whether it will help us lose weight. Pharmaceutical giants are continually inventing new ways of combating excessive weight, including Novo Nordisk, which has already registered such a product, and Eli Lilly, which is completing the process of marketing an "even better" product, although from the same family of so-called GLP-1 receptor agonists. One of these compounds - semaglutide, under the aforementioned brand name Ozempic - is already unavailable in Polish pharmacies, although it is only available by prescription and is most commonly used in combination therapy with other type 2 diabetes drugs.[1]. As you can see, the voice of TikTok's delighted influencers has also reached under our roofs.

Anyone who has ever slimmed down in their life - especially from serious obesity, i.e. a dozen or so unnecessary kilograms - knows that it is a difficult, arduous and long-lasting process. And after a few years of finishing a diet, the effect often disappears, as there is a yo-yo effect, i.e. a return to an even greater body weight than before the weight loss. There are, therefore, too many life, psychological and social factors and conditions to believe in miracle diets, let alone miracle cures.

So far, we have assisted this difficult process with so-so results (rather cosmetic) with L-carnitine, chromium, taurine, coenzyme Q10, fibre and/or chitin or other indigestible stomach 'fillers', green tea and green coffee, and nettle or knotweed, an ingredient in most 'weight loss teas'. Of course, there were also methods based on regular use of laxatives, unfortunately dehydrating, so when this goes on for a long time, it can get us into a hospital bed. Like the tapeworm swallowing, which was supposed to help combat excess weight, but of course only made us seriously ill.

The feeling of hunger and satiety is regulated on many levels, linked together in a complex network, from the cellular level to the central nervous system. And even on the psychological level, because we can eat for hunger, appetite, for company, to drown out problems or to cope with anxiety, which makes us as addicted to food, especially sweet and fatty foods, as we are to alcohol or drugs. In addition to the two well-known hormones that ensure proper blood glucose levels, i.e. insulin and glucagon, and leptin, discovered a quarter of a century ago and which we have probably heard of, there are a whole host of compounds and peptides in our body that are active in the question of 'to burn or not to burn'. In turn, each of these has its own receptor somewhere on our cells and has an effect on the whole body.

To understand the story on the latest cover of 'The Economist', you need to look at just one such peptide, completely natural and produced in our gut by certain cells (known as endocrine cells), and called GLP-1. Here I will remind you what glucagon is: it is a hormone made by the alpha cells of the pancreas that makes glucose stored in the liver in the form of a polysaccharide - glycogen - get back into the bloodstream from the liver. This is because, for example, we are running fast and have not eaten for a long time, so we urgently need sugar shot in our cells. Glucagon therefore acts opposite to insulin. Now: in order for the short hormone protein glucagon to be formed at all, the relevant enzymes have to cut up its precursor - the much longer protoglucagon. And this happens in the pancreas. The gene encoding protoglucagon is also active in the intestines, but the protein formed there is processed differently - this is where GLP-1, or glucagon-like peptide number 1, is formed.

While GLP-1 receptors are found in many organs of our body (it generally has a protective and building role there), therapeutically its action on the pancreas has proved to be of most interest. It stimulates the production and release of insulin and inhibits the production and release of glucagon. And this means that it lowers blood sugar levels after a meal. That is, it could work wonders in type 2 diabetes sufferers. Unfortunately, GLP-1 is very impermanent in the body.

A market worth $150 billion

It is therefore necessary to invent more durable analogues of it, capable of being agonists - that is, substances that bind to GLP-1 receptors and cause the expected response in cells. Analogues that will not be abolished by our internal mechanisms that extinguish true GLP-1. And there must be no inhibition of the production of this peptide due to some cross-reactivity with its analogues. GLP-1 - in addition to the aforementioned enhancement of post-meal insulin release and inhibition of glucagon secretion - also delays gastric emptying, reduces appetite (by inhibiting the appetite centre in the hypothalamus) and counteracts hepatic steatosis.

Such analogues have been successfully invented by pharmaceutical chemists and tested on animals. In the tests, they generally proved safe, except for the fact that the rodents were more likely to get cancer of the thyroid - a hormone gland insanely involved in our proper metabolism, whose underactivity is associated with certain forms of obesity. These substances are therefore not recommended for people with pancreatitis and if there has been a family history of thyroid tumours. Clinical trials of GLP-1 analogues in type 2 diabetes secured the registration of several specifics more than a decade ago ('for use in adults with type 2 diabetes in combination with metformin or a sulphonylurea derivative in whom existing glycaemic control is inadequate').

Today, however, it appears that manufacturers and the market are interested in using these analogues more as weight-loss drugs, on a mass scale. There is already a registered drug that has a higher dose of one of the GLP-1 analogues, liraglutide (Saxenda), approved for the treatment of obesity in people who do not have diabetes and dispensed in Poland only on a full-pay medical prescription.

As 'The Economist' reminds us in its pages, so far the history of such specifics has been rather sad. In the first wave, in which and Greta Garbo lost a dozen unnecessary pounds in Hollywood in the 1930s, 100,000 Americans used dinitrophenol. It proved to cause cataracts and, more rarely, death - so it was banned in the 1970s, which, unfortunately, does not prevent people from continuing to be lured by this drug in online "pharmacies". Then came amphetamines, but it is now clear that they are addictive. Two other weight-loss drugs popular in the USA, rimonabant and sibutramine, have been withdrawn from sale for safety reasons. Must it be different for GLP-1 receptor agonists? For now, the side effects listed are, sometimes disappearing with prolonged dosing, nausea, vomiting and diarrhoea. "A bit too little to back off", many of us would probably say.

For now, these drugs are expensive and their long-term effects are not well understood (apart from the aforementioned mouse study). Despite their uninviting form of application - because they have to be injected daily or weekly - they are becoming fashionable. And because they are of the dream-fulfilling drug genre, like Viagra, they will be popular and overused. Because they provide weight loss of 10-20 per cent of body weight, without more or less draconian diets or physical activity (which their leaflets obviously encourage).

As 'The Economist' notes, analysts estimate that the market for 'GLP-1 drugs' could reach $150 billion by 2031, not much different from today's cancer drug market. And that they could become as widely used as beta-blockers or statins. Obesity, on the other hand, is a disease, a chronic, difficult-to-treat, life-threatening disease, and the associated diabetes has taken on the characteristics of a global epidemic - as the only non-communicable disease on this list. It therefore deserves effective and widely available, at least partially reimbursed drugs.

By 2035, half the people on the planet are expected to be overweight or obese. Will a miracle pen filled with GLP-1 agonists change this situation without causing us more problems? Today it is already clear that time will soon begin to show this.

– Magladena Kawalec-Segond
-Translated by Tomasz Krzyżanowski

TVP WEEKLY. Editorial team and jornalists

[1] Here it is important to mention that there is no longer any type 2 diabetes, but only 4 different conditions with a similar clinical picture but different aetiology and potential treatment. These are namely: severe insulin deficiency diabetes (called SIDD), severe insulin resistant diabetes (SIRD), mild obesity-related diabetes (MOD) and mild age-related diabetes (MARD).
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Sources:
https://www.economist.com/leaders/2023/03/02/new-drugs-could-spell-an-end-to-the-worlds-obesity-epidemic
https://www.economist.com/the-economist-explains/2023/03/03/how-the-new-generation-of-weight-loss-drugs-work
GLP-1 agonists for practitioners - Via Medica Journals, A. Ratajczak, M. Szulinska, P. Bogdanski, Forum of Metabolic Disorders 2014, vol. 5, no. 4, 165-171