Should everyone be on Semaglutide?
In some of the wealthier parts of the world, it seems like everyone’s on it, and if they’re not it’s because they can’t get hold of it as its maker, the Danish company Novo Nordisk, can’t manufacture it fast enough.
It’s turned Novo Nordisk into Europe’s most valuable company by market capitalization, and worth more than the country’s economy. The company’s share price has more than doubled over the past year and quadrupled over the past five. It’s now the world’s second most valuable pharmaceutical company, ahead of Johnson & Johnson and Merck.
Not since Viagra has the brand name of a prescription pharmaceutical product dominated the conversation so much in popular culture. But Ozempic and Wegovy, the brand names of Novo’s jackpot product, semaglutide, are potentially for everyone in the developed world, not just for men with erectile dysfunction. They’re the first thing people want to talk about at the best parties and behind the cameras at fashion shows, and there are articles about them in newspapers and all the glossy magazines.
First things first. What is it?
It’s been hailed as the answer to the world’s obesity crisis, but let’s take a closer look at that claim and see if it’s accurate. First, what is semaglutide? It’s one of the first of a new class of drugs called glucagon-like peptide-1 receptor (GLP-1) agonists. Activation of these receptors in the pancreas stimulates the production and release of insulin. They’re normally activated by GLP-1 itself, which is one of a group of special peptide hormones called incretins that are released by the small intestine.
Let’s have a quick physiology recap. It’s important to understand some of these terms, because we’re going to be hearing a lot more about substances like this in years to come, and they all stem ultimately from our DNA.
Peptides are short chains of amino acids, typically up to fifty. Longer chains of amino acids are called polypeptides, and proteins are constructed of a number of polypeptide chains bound together by peptide bonds.
Hormones are substances that are made in one part of the body and have an effect on another, which might be just millimetres away as in parts of the brain, or in a distant part of the body as in some of the sex hormones.
How does it work?
Incretins are an example of gut-derived peptide hormones. They’re synthesised and rapidly released by the cells lining the small intestine in response to the intestine recognising food. There are two main human incretins – glucose-dependent insulinotropic polypeptide (also known as gastric inhibitory peptide, GIP) and glucagon-like peptide-1 (GLP-1), and they’re released into the veins that carry blood from the intestine back towards the heart, and then they’re carried to the pancreas, where they stimulate pancreatic beta cells to manufacture and release insulin, and the reduce the release of glucagon.
Just as a reminder, insulin reduces the level of glucose in your blood, while glucagon increases it, and when the intestine and pancreas are functioning normally the release of both is adjusted automatically by peptide hormones such as GIP and GLP. Obesity is one of a range of health problems that can result from metabolic disorders that upset this delicate balance. For example, people with obesity are typically resistant to insulin, a mechanism that is thought to be caused by the effects of some of the breakdown products of lipids, such as diacylglycerol (DAG), lysophosphatidic acid (LPA), ceramides, and acylcarnitines. If cells become resistant to insulin, blood glucose levels rise, eventually resulting in Type 2 Diabetes and secondary problems such as cardiovascular diseases.
Semaglutide mimics GLP-1 and stimulates GLP-1 receptors. The physiological term for a substance that stimulates receptors is that it acts as an agonist, and the converse, if it suppresses them, it’s known as an antagonist. And for the sake of completion, there are two forms of GLP, GLP-1 and GLP-2. They have similar effects on gastric emptying and gut motility, but it’s only GLP-1 that has an effect on insulin secretion.
How does it reduce weight?
By mimicking GLP-1 and stimulating GLP-1 receptors, it promotes the release of insulin, which reduces the sensation of hunger, reduces glucagon release, and it also delays gastric emptying, so your stomach stays full for longer. It tightens the pylorus, the muscle connecting the stomach to the first part of the small bowel, and reduces motility throughout the small intestine, so any food eaten stays in the bowel for longer, contributing to the reduction in the desire to eat. Much of its effect on intestinal motility is thought to be mediated by inhibition of the vagus nerve.
The combined effect of these actions is to make you feel full for longer, so you simply don’t want to eat as much or as often. And hey presto, several months later, up to a third of people who’ve been taking it have lost up to 20% of their body weight. That’s both good and bad, as we’ll see shortly.
A short side step to mTOR
The mammalian target of rapamycin (mTOR) is a protein encoded by the mTOR gene. It’s central to a crucial eponymous pathway that regulates the synthesis of proteins, including muscle, cell autophagy (the recycling of dead cells), apoptosis (cell death) and the synthesis of cellular organelles such as mitochondria.
When the mTOR pathway is activated, more mTOR protein is synthesised, which in turn leads to effects such as muscle growth. We know that the mTOR pathway is activated by insulin, which is not surprising as insulin is a key hormone is muscle and fat synthesis. But activation of the mTOR pathway is also known to promote cellular proliferation, which in turn can contribute to the initiation of tumours and the growth of tumours that are already present.
Activation of the mTOR pathway has also been shown in a number of studies across different organisms, but not humans, to be associated with shorter life expectancy. Conversely, blockage or inhibition of the pathway has been shown, also not in humans, to be associated with a reduction in the signs and diseases of aging and a longer life expectancy.
I should specify – not “yet” in humans. There haven’t been any studies demonstrating shorter human lifespan through activation or inhibition of the mTOR pathway, which isn’t surprising really. In fact, it’s difficult to envisage how any such studies could be undertaken at all, and even if they were it would take many decades to demonstrate any result either way.
So all studies looking at the effect on lifespan and healthspan with respect to activation or inhibition of the mTOR pathway have been done in cellular and animal models with shorter life expectancies. They also tend to have different diseases associated with aging but these topics are covered in more depth in another article.
What are the effects of semaglutide on the mTOR pathway?
Semaglutide promotes insulin secretion via activation of GLP-1 receptors, and one of the primary consequences of insulin release is the synthesis of more muscle and fat, so it would be reasonable to expect it to activate mTOR, but it actually suppresses it. This effect is likely to be the result of its effect on gastric and intestinal motility rather than its effect on insulin pathways.
In moderation, suppression of the mTOR pathway is thought to have beneficial effects on lifespan in some animal models. But it’s all about moderation and balance. Too much inhibition of mTOR can result in compromise of the body’s immune system and hinder its ability to react to a range of threats, both from without such as infectious organisms, and within such as tumours and autoimmune conditions. So it’s a complex situation in a rapidly changing field and we don’t have many answers yet. But we do have some, and we’re getting new answers every month.
Beneficial effects of semaglutide on cardiac function
We know that semaglutide has largely beneficial effects on cardiac function. A study released in August 2023 showed a 20% reduction in major adverse cardiovascular events (MACE) in patients with overweight (the terminology has to be adjusted because that just isn’t good grammar) or obesity who had been having once weekly injections of semaglutide 2.4 mg. This study, known by its acronym SELECT, enrolled 17,604 adults aged 45 years or older with overweight or obesity and established cardiovascular disease (CVD) but with no prior history of diabetes. It showed a reduction of 20% in the treated group compared to the placebo group in MACE, defined as cardiac death, non-fatal myocardial infarction and stroke.
Another study, also released in August 2023, showed that the same 2.4 mg weekly dose of semaglutide (the Wegovy dose, rather than the lower Ozempic dose), improved symptoms of heart failure, such as walking distance, improved quality of life, reduced hospitalisations, and reduced body weight in obese patients who had a median body weight at the start of the study of 105.1 kg (231 lbs).
Effects of semaglutide on body composition
So it’s looking very good for semaglutide from the perspective of both weight loss and reduction in cardiovascular disease impact, but it’s swings and roundabouts. Sure, patients taking semaglutide, especially in the higher Wegovy doses can lose a lot of weight, but much of this weight loss comes from losing muscle.
In some of our earlier Longevity IQ clients who we put onto semaglutide to lose weight, we found in their three monthly DEXA body composition scans – which we do in all our clients on programs lasting three months or longer – that they lost a lot of weight, but much of this weight loss came from a reduction in muscle mass. They lost more muscle by mass than fat, so while they lost weight and had to buy smaller clothes sizes, their percentage body fat rose, so they became fatter. And others have also reported this.
We have subsequently implemented mechanisms in our clients to attenuate and in most cases reverse this loss in muscle mass, but unless you take specific steps to preserve or ideally increase muscle mass, people taking semaglutide will weigh less but they will be flabbier, have loose skin, and will often look older, which is the opposite of what most of them want.
Is semaglutide suitable for everyone?
There aren’t any doubts that it has beneficial effects on reducing weight in patients with overweight and obesity, as well as those with type 2 diabetes or cardiovascular disease. And there are also beneficial effects on liver disease that we cover in other articles. But it’s not that simple, as we have just seen with its effect on muscle mass. There is also evidence that it can reduce bone density, and the combination of reduced muscle mass and bone density in older people predisposes them to falls, fractures, hospitalisations and potentially a reduction in life expectancy.
As it suppresses the mTOR pathway it may be reasonable to theorize that it might reduce tumour genesis or proliferation, but it might conversely impair the body’s immune system so much that it’s unable to identify and eliminate potential cancerous cells before it’s too late.
It’s also expensive
It’s one of the biggest blockbuster drugs ever. Wegovy costs around USD 1,500 a month in the United States. While it’s a fraction of this elsewhere in the world, it’s typically several hundred dollars a month wherever it’s available. It’s unaffordable for health systems and insurers, and the health economic case taking into consideration the reduction in morbidity from obesity, cardiovascular, liver and other diseases, has not yet been made.
This is a rapidly developing field. More research is being published every month showing its benefits, and we can expect to see more about its risks and potential drawbacks. But perhaps more importantly, semaglutide is just the first of many drugs with similar actions to hit the market, and we can expect the conversation about weight loss drugs like it to become louder for years to come.
“But will it help me live longer?”
Our current position is that we administer it to people on our programs if they are overweight or obese, but we monitor everyone much more closely than conventional health systems can, and we take a range of specific precautions including but not limited to intensive muscle building and cardio training programs to mitigate the loss of skeletal muscle and the reduction in bone density.
You may know that longevity itself isn’t enough for us. We want all our clients to be happy, feel stronger and healthier, and to be able to enjoy their lives more than they felt they could before they came to see us. Losing weight, or more specifically losing fat, is an important component of that for many of them, and semaglutide is something we consider for all our clients.