GLP-1 agonist weight loss drugs: Leaning the ladder against the wrong wall
GLP-1 agonists like Ozempic are the most successful weight loss drugs ever developed. But what does 'success' actually mean?
In his best-selling book The 7 Habits of Highly Effective People, Stephen Covey cautioned against a common trap: "work[ing] harder and harder at climbing the ladder of success only to discover it’s leaning against the wrong wall." In other words, one should spend some time clarifying what "success" means, before one invests time, money and energy into pursuing it. At this point in my mini-series on GLP-1 agonists such as Ozempic, Wegovy and Saxenda, it's appropriate to ask which wall these drugs are leaning against.
What kind of weight loss?
In Part 1, I discussed the outcomes of clinical trials conducted on these drugs, that were specifically focussed on weight loss. If we measure success in lost kilograms, there's no doubt that GLP-1 agonists are the most successful weight loss drugs ever developed: Trial participants lost on average 12-18 per cent of their starting weight, compared to the meagre 4-5 per cent obtained from previous weight loss drugs such as phentermine/topiramate or bupropion/naltrexone.
But, as an opinion piece published in JAMA Internal Medicine in February 2024 pointed out, anti-obesity medications have gained regulatory approval based solely on weight loss, rather than fat loss, and this is the wrong metric for success :
"Equating weight loss with improved health outcomes is misleading to clinicians and consumers, as fat loss is a much greater factor in health consequences than overall weight loss. It is crucial to note that visceral fat is specifically associated with metabolic complications, such as insulin resistance, type 2 diabetes, heart disease, and certain cancers. If FDA metrics prioritize overall weight loss without differentiating the source of that loss, medications may be deemed effective or superior to others based on weight reduction alone despite not necessarily achieving greater fat loss, which is a more relevant measure of health outcomes...
Overall weight loss, including via AOMs [anti-obesity medications], occurs via both fat and muscle mass loss; the health outcomes of a patient are determined by the proportion of these 2 values. Excessive loss of lean muscle mass can cause sarcopenic obesity, which is associated with functional decline and increased mortality. As such, while visceral fat loss is beneficial, it should be accompanied by preservation of or an increase in muscle mass for ideal health outcomes. More research is needed to clarify the complex relationships between different types of weight loss, body composition, and health outcomes."
Body Composition in Anti-Obesity Medication Trials—Beyond Scales
To underscore the point made by the authors of the JAMA Internal Medicine opinion piece, whenever you lose weight, you will lose both fat and muscle. The simple fact is, it takes more muscle to move a larger, heavier body around. Hence, when you shrink that body, you don't require as much muscle. But rapid weight loss can cause a dramatic loss of muscle mass, especially in older people who have less muscle to start with, due to both age-related decline in lean mass and decreased physical activity levels.
Sarcopenic obesity is the combination of high fat mass, with low muscle mass and either low muscle strength or low physical performance. It is increasingly common in industrialised societies, and it lands people in nursing homes... and in early graves.
Furthermore, muscle mass is one of the principal determinants of basal metabolic rate. So when muscle mass plummets, metabolic rate falls with it, and it becomes harder and harder to prevent weight regain, without restricting calorie intake to a degree that is unsustainable for most people. Could this be yet another reason - on top of the antibody formation and the side-effects discussed in Part 2 - why weight loss plateaued, and even reversed - about a year into the clinical trials of GLP-1 agonists?
To answer this question, we would first need to establish that there are valid grounds for concern that GLP-1 agonists might cause sarcopenic obesity. And to do that, we can turn to the words and deeds of the pharma companies themselves.
According to George Yancopoulos, the Chief Scientific Officer of Regeneron Pharmaceuticals, muscle loss can account for "up to as much as 40% of the weight loss" on GLP-1 agonists. Ouch. But Regeneron doesn't yet have a dog in this fight. What about the companies that do?
Tirzepatide (Mounjaro), the new GLP-1/GIP agonist that - as mentioned in Part 2 - bears a boxed warning for increased risk of thyroid cancer, is made by leading pharmacriminal company Eli Lilly. Eli Lilly has paid out US$2,831,299,676 for 25 separate offences since 2000. In July 2023, Lilly acquired Versanis, a biopharmaceutical company whose lead asset is bimagrumab, a monoclonal antibody that preserves or even increases muscle mass. A clinical trial is currently underway to test "if bimagrumab in addition to semaglutide is able to preserve/increase muscle mass in the presence of weight and/or fat mass loss."
You may recall from Part 1 that semaglutide is made by Novo Nordisk, a competitor to Lilly, and way behind it in the criminality stakes at only US$129,887,792 in penalties since 2000. If Novo Nordisk wishes to market a combination treatment of bimagrumab and semaglutide, it will have to make some kind of deal with Lilly. Or perhaps make them an offer they can't refuse.
Lilly has also partnered with BioAge Labs to conduct a clinical trial of BioAge's oral apelin receptor agonist BGE-105 (azelaprag), another muscle regeneration therapy, in combination with its own weight loss drug, tirzepatide.
Roche, sitting pretty at US$432,796,105 in penalties since 2000 (mostly for price fixing and off-label or unapproved promotion of their products), is muscling in - pardon the pun - on the weight loss drug market. In 2023, it gobbled up Carmot Therapeutics, which has an injectable dual GLP-1/GIP receptor agonist and an oral GLP-1 drug in the pipeline. Roche intends to combine these with its own anti-myostatin antibody for muscle preservation.
Meanwhile Regeneron Pharmaceuticals (an absolute novice at pharmacrime, having racked up a measly US$506,035 since 2000, in tax offenses - what are they, Al Capone?) is poised to commence a phase 2 study to test whether adding its muscle-preserving monoclonal antibody trevogrumab to semaglutide, both with and without another of its products, garetosmab, will improve body composition throughout the weight loss process, as well as after people cease taking semaglutide.
Oh yes indeedy - Big pHarma is well aware of the problem of sarcopenic obesity induced by GLP-1 agonists, and is poised to cash in on it.
But what could possibly go wrong with injecting monoclonal antibodies that interfere with muscle proteins? Oh, nothing major - just muscles that are larger, but weaker. So you'll look buff, but you'll still be frail. In fact, in a randomised clinical trial conducted in 180 adults aged 70 years and older, bimagrumab failed to deliver any statistically significant difference in improvement in physical function over placebo. And then there's the abnormal bleeding, diminished bone mass and spontaneous fractures. But don't you worry your pretty little head about those side effects - there are drugs for them, too.
For those of you who are thinking, 'Isn't exercise the best thing for muscle strength?', all I can say is, bless your heart, you dear, sweet, naive little sausage. Don't you know there's a drug in the works for that? I'm not joking:
Too old, sick or fat to get off the couch? Just pop this magic pill - the marketing department will eventually come up with something catchier than "SLU-PP-332" - and you'll reap all the benefits of exercise without breaking a sweat. Honestly.
The other wall
Big pHarma is like a stage illusionist, brandishing a bag of tricks out of which it produces a never-ending stream of simulacra of health: reduced weight with sarcopenic body composition; large but weak muscles; bones that are denser but more fragile; lower glucose levels without a reduction in diabetic complications; and so on and on.
That's because its ladder of success leans against a wall not of health, but of profit. And GLP-1 agonists are profitable beyond the wildest fever dreams of corporate CEOs. As Dr Dariush Mozaffarian highlighted in another JAMA editorial,
"From 2021-2023, the stock price of 2 manufacturers [of GLP-1 agonists], Novo Nordisk and Eli Lilly, more than tripled, with a combined valuation now greater than $1 trillion."
In case you were wondering, only 17 countries in the world have a GDP greater than $1 trillion. Let that sink in.
So Big pHarma is poised to hit the jackpot on GLP-1 agonists. Who will pay for its windfall? Allow Dr Mozaffarian to talk you through it:
"One-half of US adults are interested in taking a prescription weight-loss drug,1 and 93 million meet GLP-1 weight-loss eligibility criteria.2 US list prices are $12 000 to $16 000 per year; even with maximum negotiated discounts, costs will likely exceed $6500 per year. If all eligible US adults received GLP-1 agonists at discounts, the annual cost would be $600 billion—equal to all other US prescription drug spending combined. There are hopes that competition will lower prices, but each GLP-1 agent is protected by approximately 20 patents, many to 2040 or beyond.3 Even if current prices decrease, experience with other major drug classes suggests that newer agents in this class will be introduced, with incremental benefits but continuing high prices and aggressive marketing, making it unlikely that total costs will meaningfully decrease soon...
Weight loss occurs early but then plateaus, with years of continuing treatment required just to maintain initial benefits. This explains why, even with health benefits and discounted prices, these agents are not cost-effective, with incremental costs of $237 000 to $483 000 per quality-adjusted life-year.4 Consequently, even accounting for health benefits, GLP-1 agonists substantially increase costs. In one analysis, total annual health care costs among patients adherent to the drug doubled, from approximately $13 000 per person before starting the drug to $26 000 after.5"
The high price of Big pHarma's profits
Let's make this crystal clear. Obesity is a public health problem, because obese people have a higher risk of a wide range of chronic diseases, and treating these diseases consumes a huge chunk of the health budget. From a public health perspective, the chief criterion for a successful weight loss intervention is reduced health care costs. GLP-1 agonists do exactly the opposite... and that's even before you factor in the additional costs of packaging them up with muscle mass-preserving agents that create the mirage of a healthy body composition, whilst doing nothing to prevent the frailty that leads to functional decline and a one-way ticket to a nursing home.
In his sledgehammer-to-the-skull exposé, Deadly Medicines And Organised Crime: How Big Pharma has corrupted healthcare, Danish medical researcher Dr Peter Gøtzsche states, in typically blunt fashion,
"The main reason we take so many drugs is that drug companies don’t sell drugs, they sell lies about drugs. Blatant lies that — in all the cases I have studied — have continued after the statements were proven wrong."
Deadly Medicines And Organised Crime: How Big Pharma has corrupted healthcare
And no matter how many blatant lies these serially criminal companies tell, and how many times they are caught out lying - and fined unfathomable sums of money for it - it seems there is always a willing audience for the lies.
People struggling with diabetes want to believe they can pop pills that will magically get their blood glucose back under control. People battling obesity want to believe they can take drugs that melt fat off their bodies while making their muscles grow. And doctors whose waiting rooms are clogged with obese and diabetic patients want to believe that Big pHarma's latest shiny new objects really are the solution to these diseases of modernity.
Here's what one such doctor, Daniel Frank, MD, had to say in response to Dariush Mozaffarian's critique of GLP-1 agonists:
"These are the most life changing agents for obesity ever in the history of medicine and represent one of the greatest advances for managing chronic disease that we've seen, an advance on par with biologics for rheumatology, statins for cardiology, and artificial joints for orthopedics."
<sarcasm> Now that's a high bar. </sarcasm>
Frank goes on:
"The proper metric here is not cost per year of additional life, but the quality of the life the patient is actually living right now. Of course the health care system cannot pay for this [sic] drugs as currently priced. People who can afford these drugs and want to take them should pay for them and be on them. There are 15 million households in the US with incomes over $200K. Therefore, there are millions of people who can afford these drugs and derive this benefit. It is a revenue stream to the pharmaceutical companies we should all want to see after 50+ years of failed drug development for obesity. This revenue and profit is exactly the incentive needed to bring more competition to this marketplace."
Translation: It's only right that wealthy people who got obese by overeating the slop produced by Big Food, should fatten the wallets of Big pHarma so they can afford to develop more drugs. Making Big pHarma more profitable will be good for all of us. Obviously.
Want more words of wisdom from Dr Frank? Of course you do:
"Medicine has produced considerable iatrogenic injury to obese patients by repeatedly flogging them with diet and exercise admonitions when it should be pretty obvious by now that homo sapiens cannot self-regulate body weight or food intake in the present environment. Setting patients up for failure by pushing diet only further damages mental health and further lowers quality of life for an obese patient."
Stop fat-shaming obese patients by encouraging them to improve their eating habits and increase their activity level! It's harmful to them!!!!! Don't you know it's impossible, impossible I tell you, to control what, or how much, you put in your mouth?
And finally, according to Dr Frank:
"No one really understands why we have seen such a sharp increase in obesity since the 1970s and no population-wide solution exists. Until that puzzle is solved, the new GLP-1 agents represent our first and best approach to managing obesity."
Yep, those skyrocketing rates of obesity are a complete mystery, aren't they? Oh, wait... back in 2009, Australian researcher Boyd Swinburn calculated the difference between calorie needs and actual calorie intake in US children and adults, in the 1970s vs the 2000s.
The title of his article, 'Increased food energy supply is more than sufficient to explain the US epidemic of obesity', gives the punchline away. People gain weight because they eat too many calories. Doesn't matter whether it's too many calories from sugar, or "seed oils", or sirloin steak. There's no “puzzle” to be “solved”. If you eat more calories than you burn off, you'll get too fat. Full stop, end of story.
However, Dr Frank is not completely wrong. It is true that we don't have a "population-wide solution" for the chronic overconsumption of calories that has caused the obesity epidemic. The problem, as I explained in Ultra-processed foods: Cheap, tasty, convenient, and deadly, is that the ultra-processed food that dominates the modern food environment, drives overconsumption of calories.
And, hidden in the giant steaming pile of GLP-1 agonist bullcrap deposited by Big pHarma, there are a few nuggets of truth. GLP-1 is, as mentioned in Part 1, a gut hormone that occupies a crucial niche in the complex web of biochemical reactions which regulates appetite. GLP-1 lets us know when we've taken in enough calories, by making us feel full. And it discourages further eating until the calories we've just taken in, have been used up. Research is now shedding light on which foods induce more GLP-1 secretion, allowing us to regulate our food intake without feeling hungry all the time. I'll be delving into this research in the final (at least for now) part of this mini-series. See you then!
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“bless your heart, you dear, sweet, naive little sausage.” Keep these gems coming.
after NOVO's huge crash in stock markets today I had to go back to your excellent podcasts regarding this topic. People wondering why it's stock price has gone down so much because of a mere miss of weight loss target.