The Weight-Loss Revolution People Didn’t Want

The past few years have witnessed a revolution in highly-effective weight-loss treatments, namely Semaglutide and Tirzepatide, which originally were used to treat diabetes but have been rebranded and repurposed to treat obesity under such brand names as Wegovy, Ozempic (originally for diabetes but also prescribed for weight loss), and Zepbound. They are often referred to as “GLP-1 drugs” for their mechanism of action of activating the GLP-1 receptor, triggering fullness and delaying gastric emptying, subsequently leading to weight loss. Given that worldwide over a billion people are overweight or obese, as to be expected there is a lot of enthusiasm and demand for these drugs. Much of the coverage is positive, and many people on social media report success at losing a lot of weight.

But there is a lot of skepticism too, which is understandable. These drugs are not without potentially serious side effects, and huge demand has led to shortages of the compounds for diabetics. The main focus of this post is to address the non-pecuniary objections, although the cost factor cannot be ignored. Expanding Medicaid coverage to include these drugs will impose a burden on taxpayers, as will employer-sponsored coverage on employers. But aside from costs, there are the same tired criticisms about how it’s “taking the easy way out” or concerns about unforeseen health risks. I will address these.

There is also an interesting class dynamic at work. I have observed that the strongest support is from celebrities and wealthy businessmen, such as Elon Musk, an early Ozempic user whose endorsement on Twitter helped propel the drug into the mainstream–or on the other socioeconomic extreme–middle to lower-middle-class people who are able to obtain these drugs despite the high price tag and sing the praises of their newfound weight loss on social media. Yet somewhere in the top 2-5% of the wealth pyramid are among the strongest critics. Sure, some of this may be due to the social bubble I inhabit , but it’s like the opposite of the Covid vaccines, in which opposition was strongest from working-class or religious types, whereas credentialed, upper-income people in that same bubble or strata overwhelmingly supported the vaccines. But with GLP-1 drugs the intellectual-class is much more divided or reticent in support. The typical megachurch congregation is more likely to be on these drugs or express approval of them compared to attendees of a tech conference.

I am at a loss as to why so many well-educated people who subscribe to the credo of “science and progress” in so far as treating conditions as varied as Alzheimer’s disease, ALS, or cancer, that the frontier of human ingenuity insofar as weight loss is concerned must remain stuck in the past. Or much more nuanced skepticism or reservations by journalists, who also fit this profile. Journalist Johann Hari wrote a whole book about the possible risks of these drugs, although also praising them, after a year on Ozempic and losing 20 kilograms. Would he feel equally concerned or conflicted if he took antibiotics and his infection went away? Or from the New York Post: Child Ozempic use soars 600% in three years — but is it safe? Sure, but less safe than weighing 315lbs as a 17-year-old?

Why so much trepidation when being at the frontier of science necessitates taking the unbeaten path? My point is that the skepticism directed at these drugs is undue and even irrational, especially compared to other drugs for much rarer conditions than obesity, which are equally or more expensive and much less effective. It’s as if science “need not apply” in so far as effective weight loss treatments are concerned.

It’s like: “A mouse model shows promise at extending ALS or Alzheimer’s disease survival by 1-3 months if successful on humans. The drug may cost $30k/month, though.” Response: “Amazing! This will change the world and improve human welfare. We need to make this readily available.”

“Hundreds of thousands of people have lost a lot of weight with GLP-1 drugs, with many curing their obesity when other measures failed.” Response: “Although obesity is a crisis, these drugs will have unforeseen consequences, and too expensive.”

“What if the drugs were made generic after the patents expire? And many people have used them, so they appear safe, at least compared to the unknowns of the mouse Alzheimer’s drug, or many other drugs for that matter. And such unknown side effects must still be weighed against the known health consequences of obesity, which can be quite bad.” Response: “Diet and exercise still better.”

This contrived dialogue is not that much of an exaggeration from the objections one typically encounters in discussions of these drugs. It’s not about the risks or the cost, but the fact that many people cannot bring themselves to accepting that these drugs are effective, or for whatever reason are opposed to them.

In trying to explain this skepticism, GLP-1 drugs are like the modern-equivalent of oral contraceptives in that the social ramifications seem to overshadow the medical ones. It’s not just about losing weight, but also implicitly a statement about the people who use these drugs and society. It has been ingrained in culture and personal experience that weight loss is supposed to be a struggle. The possibility that it doesn’t have to be this way, naturally invites skepticism or suspicion that it must come at the cost of moral or ethical purity, like Faust who traded his soul to the devil. Or like having one’s wish granted, but it comes with some major unforeseen consequence (e.g. wishing to be the most famous person on earth, but then everyone else dies.) Framing obesity as a disease–a medical condition rather than a personal failing–reframes weight loss as a treatment outcome, not a reward for willpower. The idea that weight loss must be “earned through suffering” is as outdated as blaming illness on evil spirits.

Consider the indefatigable enthusiasm for everything Alzheimer’s disease related, either breathless media coverage about treatments that may add only months of life expectancy (or not work at all), or the latest theory of the cause of Alzheimer’s, which will be replaced by a new theory in a few months with equally credulous coverage (is it due to gum disease, diabetes, inflammation, or is the amyloid plaque theory, a favorite during the 90s, now wrong?). The latest Alzheimer’s drug, Lecanemab, has about the same annual cost as Wegovy, at around $26,000 per year, so it’s not like it’s that much cheaper. Worse, the track record for Alzheimer’s drugs is much more spotty, and treatments only slow the rate of cognitive decline a bit and does not prolong survival or prevent the inevitable development of dementia. From a report, “In those analyses, participants treated with lecanemab took 25.5 months to reach the same degree of worsening on a common dementia test as the placebo group did at 18 months — a time saving of 7.5 months.” So half a year. A previous Alzheimer’s drug, Aducanumab, did not even work yet was still approved, whereas Wegovy clearly does, but we cannot be too hasty with the new weight-loss drugs, huh? That would be reckless and dangerous.

In fairness, there was a lot of controversy about the FDA approval of Aducanumab, and rightfully so. The drug did not work. But GLP-1 drugs work on at least 70-80% of people who take them at producing clinically meaningful weight loss (at least 10%). Regarding cost, true, people with Alzheimer’s disease are at the end stage of life and have a much shorter life expectancy compared to the the typical person on Wegovy. So GLP-1 drugs end up being a lot more expensive over a lifetime, but this seems to be a red herring. The objections persist even when people choose to pay out of pocket, or if hypothetically such drugs were made generically available at low cost, or if an economic argument can be made that GLP-1 drugs have a positive ROI by improving productivity and by reducing healthcare spending due to reducing obesity-related complications. The goalposts are always moved to something else.

Someone who takes antibiotics isn’t admonished for taking the easy way out. Nor are they admonished for using Narcan for drug addiction. Telling someone with a cognitive disability to ‘think harder’ or someone with cystic fibrosis to ‘breathe harder’ is understood to be mean and ineffective. So why is obesity different? Why have so many people found success with GLP-1 drugs when dieting failed? Even Oprah, despite having access to the best personal trainers and chefs money could buy, still was unable to keep the weight off, until secretly taking one of these drugs. And then the weight just melted off. So much weight, that amid public speculation she was forced to admit the truth, which saw Weight Watchers stock lose half its value after she stepped down from the board. Why is the expectation that drug addicts get costly support networks and rehab, but treating obesity always circles back to ‘eat less and move more’, which to a drug addict would be as helpful as instructing to ‘put the needle down’ or telling a schizophrenic to ‘stop hearing voices’ . Imagine treating drug addicts or the mentally ill with the same unimaginativeness used in treating obese people and being shocked that it doesn’t work. When drug users relapse or an anti-depressant stops working, a new treatment protocol is tried. Things like electroconvulsive therapy. But when most or all of the weight is regained, as is usually the case, it’s the dieter’s fault for not having enough willpower, never the diet. The possibility that the paradigm of weight loss needs to be reevaluated is seldom entertained or dismissed. Sure, some people do lose weight with dieting and keep it off, just as some people are cured of depression using cognitive behavioral therapy, but the expectation is depressed people have way more choices of treatment, including powerful drugs, in addition to experimental treatments. Those who object to antidepressants tend to be shunned or ridiculed, like famously Tom Cruise a few decades back.

The Ice Bucket Challenge was a global internet phenomenon in 2014 as millions of people doused themselves in ice water–hence the name–to raise awareness for ALS research. Media coverage and social commentary was almost always positive. Unlike weight-loss drug related news coverage, there was no concern about ALS patients having it too easy, lacking willpower, or concerns over unforeseen side effects or risks of new and effective ALS drugs. Same for coverage of Alzheimer’s disease or Cystic Fibrosis treatment. Why is one condition more deserving of help or public outpouring of compassion than another, especially when obesity affects so many more people and causes more overall deaths? ALS affects just 30,000 people annually in U.S., with only 5,000 new cases every year. By comparison a third of Americans are obese, so at least 100 million people. Medical science should be about improving people’s lives. The millions of people who lost weight with these drugs can attest that their lives have been improved. This should be celebrated. And given the sometimes bad side effects for these weight-loss drugs like diarrhea and cramping, including possibly more serious ones, it’s not at all like ‘taking the easy way out’, unless by ‘easy’ that means effective, which is something that I am sure people desire in medical intervention.

A case can be made that Alzheimer’s and ALS are scarier than obesity, and are certainly more serious on an individual case basis. Dementia has been described as a fate worse than death. ALS causes severe disability and early death, typically within a couple years of the diagnosis being established. But the stats on obesity and weight loss are abysmal too, with most dieters eventually regaining what little weight is lost. Not to mention, the collective loss of quality of life and shortened life expectancy, multiplied by millions of overweight or obese people, which adds up to the loss of billions of quality-adjusted life years (QALY). Despite the so-called “replication crisis,” the low success rate of dieting is one of the most well-reproduced findings of human science. From nih.gov, “According to a meta-analysis of 29 long-term weight loss studies, more than half of the lost weight was regained within two years, and by five years more than 80% of lost weight was regained.” According to a comprehensive meta study, obese subjects over a 52-week period on a ‘low calorie diet’ lose only around 1.7 to 8.1 kg from peak to trough, which is slowly regained. It’s believed that metabolic adaptation results in much less weight loss than predicted, even controlling for reduced bodyweight, which can explain the low success rates for diets, in addition to compliance problems, which is a fancy way of saying that voluntarily withholding food is hard:

The magnitude of LCD-induced negative energy balance used to predict treatment-related weight loss assumes that a 1-kg reduction in body weight requires an energy deficit of 7700 kcal (16). Ingesting 500 kcal/d less than required for weight maintenance results in an energy deficit of 3500 kcal/wk, which should produce a weight loss of ≈0.5 kg/wk. However, the observed rate and amount of weight loss are typically far less than this prediction. For example, the rate of subjects’ weight loss was <25% of the predicted value in some of the studies presented in Table 1.

Even as little as a 5kg long-term weight loss is sometimes touted as a ‘success’ for dieting, but daily fluctuations such as water can account for most of this.

In contrast, the most powerful GLP-1 drug, Mounjaro, a diabetes drug rebranded as Zepbound for weight loss, the typical weight loss is 15-25% of initial bodyweight. A prototype drug, Retatrutide, involving a triple-mechanism of action produces an average of 25% weight loss, which is comparable to gastric bypass surgery. In fact, many people who underwent bypass or lap band surgery have turned to GLP-1 drugs for additional weight loss, or when bypass stops working, as is common after many years as the stomach expands and old eating habits return. GLP-1 drugs are more potent in that they fix the underlying overeating problem at the brain-gut level, whereas gastric bypass is only a superficial solution that makes overeating physically impossible but does nothing to stop the underlying food addiction. People on GLP-1 drugs don’t just eat less, some lose interest in food altogether. Users report that other addictions may also be attenuated, such as drinking, smoking, or even gambling.

Although GLP-1 drugs are understood to affect the endocrine system, there may also be a mental component, too, in changing how the mind perceives hunger to desire less food. GLP-1 drugs work in part by fixing this faulty wiring, so there is less ‘food noise‘ and hunger. According to people on GLP-1-drugs, it just ‘works’ and the weight effortlessly comes off, unlike dieting advice, in which it’s always the fault of the recipient for not following the precise instructions or for not being among the lucky few for whom said advice is applicable to. “This is what it feels like to be normal” is the typical response to not being bombarded by constant thoughts of food or hunger. Users describe eating normal-sized quantities of food and then feeling full for hours, not eating until physically impossible or feeling hungry shortly after.

Elon Musk uses Ozempic, and his posts praising or endorsing the drug are also among his most highly ‘ratioed’ and criticized, including by his biggest fans such as ‘Zuby’:

Diet and exercise >

— ZUBY: (@ZubyMusic) April 18, 2024

Could he lose weight if he ate less? Sure. But maybe like Oprah he already tried that and it didn’t work as well as he had hoped. Or he has multiple companies to run, so something like Ozempic makes it easier instead of having to obsess about food or always feeling hungry. Nobody would second-guess a cancer patient for opting for chemotherapy, but a drug that can potentially cure obesity when optimistically the long-term success rate of dieting is around 5-20% (depending on the consulted source), a third that of average survival rate of cancer? As Zuby suggests, diet and exercise works for some, but the data as explicated above is pretty abysmal. By comparison, hundreds of thousands of people have had success on these GLP-1 drugs. I would say in terms of meeting the burden of proof or criteria of what constitutes effective treatment, the GLP-1 drugs are the clear winner.

If you can make willpower work, great. Keep at it. But these are the data laid bare. Same for the failure of any particular diet to work especially well for a general population; all diets tend to work equally well, that being poorly. The adage “the best diet is one you can stick to” is circular, as it presupposes that such a diet exists for everyone when the evidence is pretty lacking. The minimum bar for science is to be able to draw conclusions at some threshold of statistical significance, which dieting advice often fails at. No one can decide if ‘fats are good’ or not, if sugar or fats are the real culprit, or how much protein is optimal. In the end, it likely does not matter. Same for ‘meal timing’ which also seems to make no difference. Or from from The Atlantic, “The Fad Diet to End All Fad Diets: There isn’t much evidence that intermittent fasting leads to lasting weight loss.” To say “isn’t much evidence” is being generous; it’s more like “none.” Nutrition is perhaps the only “science” where it’s possible to become a leading expert even though the field has accumulated decades of research with surprisingly little to show for it in terms of actionable advice (e.g. weight loss).

Keeping weight off requires life-long diligence. Willpower is finite, but it’s not like dieting gets easier with time. Due to the practical constraints of tracking people for long periods, most studies of dieting only track participants for a year or two, but longer studies show there is no point or threshold where weight does not return–even 4-10 years later people are still regaining weight. Eventually, life gets in the way, such as work or family-related stress, and the weight comes back with a vengeance when old eating habits return. Research from “The Biggest Loser” contestants shows that the body resists weight loss efforts years after the initial weight is lost, perhaps indefinitely, with possible metabolic damage too (although this is disputed). There is no evidence to suggest after some amount of time has passed that the body ever stops trying to put the weight back on. According to Kevin D. Hall, a National Institutes of Health researcher, “…for every 2.2 pounds of weight participants lost, their appetite increased by 83 calories daily.”

Typically, it’s the Left that complains about drug prices and gouging, but interestingly regarding GLP-1 drugs, it’s now the Right doing the complaining. A common argument is that Novo Nordisk and Eli Lilly are profiting from bad eating habits. If people only ate healthier then these drugs would not be needed. Debating this stuff is funny because you see people rediscovering what has already been tried for a hundred years and shown to not work, yet think they stumbled on some new insight or epiphany. “Just eat healthy!” Who knew? Thanks.

From 1944-1945 Dr. Ancel Keys subjected 36 conscientious objectors to a diet of 1,570 calories/day to test the effects of starvation in the context of war. The participants were closely supervised, with calorie counts fastidiously tracked and all the food supplied by Keys himself, which made cheating nearly impossible. After many months, the participants lost up to a third of their initial body weight. The final phase of the study allowed the participants to eat however much they wanted, again under Keys’ supervision. The weight was rapidly regained, and then some (it took an additional 2 years for the excess weight to be lost). Keys was trying to replicate the austere conditions of wartime, so this meant bland food that was low in protein and high in carbohydrate, such as potatoes, bread, and vegetables. Keys abhorred junk food (or what was the ’40s equivalent of junk food), so it’s not like he was feeding his subjects cakes and other sweets. Yet his participants still regained all the weight they had lost. Some individuals consumed up to ten-thousand calories in a single day when unrestricted. This shows the problem has not so much to do with the type of food, but that dieters tend to eventually overeat regardless of what diet or macro composition is tried. The body, sensing a deficit, fights to restore the lost weight. This explains why all diets fail or are equally unsuccessful. All diets emphasize healthy food, not junk food, yet still fail. GLP-1 drugs work in that they prevent this binging. It’s not physically possible to consume even close to 10k calories in a day on something like Wegovy.

Keys’ diet was carb-heavy, so this invites the question if a protein-heavy diet would have worked better. Unlikely. If this were true, then carnivore or ketogenic diets would be much more effective compared to others in terms of studies or self-reported weight loss, but the data does not bear it out. On the Reddit diet subs I visit, it’s not like the carnivore or keto folks are seeing markedly better results compared to other dieters. The main commonality across all these communities is that weight loss is hard no matter what diet is tried, and that no specific diet works particularly well in the aggregate. Another objection is that Keys’ subjects lost weight too fast and that a gradual approach would have been better, but again, the data shows that crash dieting is not worse than slow, steady dieting in terms of long-term weight loss.

The above suggests the best approach to solving obesity is preventing it in the first place. Once someone becomes obese, the mind-gut connection is rewired in such a way that the body seeks to stay obese for a long time, perhaps forever. Many obese adults started as healthy-weight during adolescence but ‘blew up’ in midlife, typically after college, suggesting some sort of phase shift that causes sudden fat storage, which then becomes hard to undo. Perhaps starting low-dose GLP-1 drugs at the outset of creeping weight gain, before one actually becomes obese, can be one way of nipping obesity in the bud, much like how screening can remove growths before they become cancerous.

If one of the biggest points of criticism is the cost, shouldn’t we be happy then that it’s effective? Why would we want to waste money on treatments that don’t work well? In trying to answer why ‘effective and easy’ is good in the context of other drugs, but less so in the context of weight loss medications, it’s always been an unwritten rule that medical intervention should not make people ‘better than average’. This is why there is so much controversy over embryo screening, as some fear it may lead to eugenics. Or opposition to performance-enhancing drugs on the grounds of being unfair (which never made sense to me, given if all competitors are taking them or are allowed to, it’s no longer a fairness issue). Weight-loss drugs fall into this latter category of not only improving health by mitigating weight-related health complications, but also making people ‘better’ overall on a more superficial level. This is not the case with drugs that treat overactive bladder, for example, as restoring bodily functions does not raise one’s social status in the same way weight loss, which is a visible improvement, does. It’s not like Alzheimer’s drugs make people smarter than average, as was the plotline of Flowers for Algernon. Same for insulin or anti-depressants, in which weight gain is a common side effect and hence a lowering of one’s status. [Antidepressants often cause weight gain, which ironically compounds the depression.] Consider that there is nothing controversial about CPAP machines, but taking a drug that can prevent or attenuate obesity–and thus also fix sleep apnea–is somehow an unearned or undeserved short cut. Treating obesity-related consequences in isolation is not controversial, but a drug that summarily fixes obesity and thus many of the consequences downstream from obesity, is. This seems wholly illogical.

Being thin conveys socially-desirable traits like self-control and discipline, compared to sloth, impulsivity, and gluttony by being fat. But now there are a class of drugs that makes the social signal accessible to the masses, which subsequently dilutes its exclusivity. If there were a safe and effective pill that could give anyone six-pack abs, those who earned their abs the hard way may feel peeved that this uncommon signifier of fitness is suddenly more accessible and hence no longer as special. As a caveat though, individual weight loss is still highly variable and up to a quarter of people on GLP-1 drugs lose only a little to no weight, and patients may still be overweight even after losing a lot of weight, so thinness is not assured.

Regarding safety, yes, there was the whole Fen-Phen mess, but why do weight-loss drugs deserve this extra scrutiny even though there have been many notable recalls for a wide range of drug types, not just weight-loss drugs? If we want to go down this route, then let’s limit our options to penicillin, aspirin, and Tylenol, as those have a sufficiently long track record, I suppose (even though acetaminophen, the active ingredient of Tylenol, kills far more people every year than fen-phen ever did, but let’s ignore that inconvenient fact). Acetaminophen is responsible for “56,000 emergency department visits, 2,600 hospitalizations, and 500 deaths per year in the United States,” yet considered by many to be perfectly safe.

Moreover, concerns over GLP-1 drugs being new or unproven (even though they are neither) does not explain the enthusiasm for other new and largely unproven drugs. An obvious example are the Covid vaccines, which saw widespread use after rapid development and appear to be safe despite being new. Same for the revolutionary 2019 cystic fibrosis drug, Trikafta, which significantly prolongs survival in 90% of people with the otherwise lethal genetic disorder (and extremely expensive, too, at a list price of $300k/year for a year’s worth of supply). No one was saying, “Yes, although Trikafta works, no, let’s wait 10 more years until we have more data, as there may be possible unforeseen consequences, even though head and shoulders this is the best drug that exists on the market for treating cystic fibrosis.” Second, such unknowns need to weighed against the known consequences of obesity, which are expensive to treat and degrade quality of life. As mentioned in the intro paragraph, GLP-1 weight-loss drugs can be thought of as repurposed diabetes drugs, but with a longer-lasting active ingredient. The first GLP-1 receptor agonist, Byetta, received FDA approval in 2005, and Liraglutide, a second agonist, was approved in 2009. Related drugs include Victoza, Saxenda, and Trulicity, which are used to treat diabetes and preceded Wegovy/Ozempic by many years. So there is an almost two-decade track record of this family of drugs being safe and well-tolerated by patients.

It’s nice knowing effective and safe weight-loss drugs exist, with even better drugs on the horizon that can handle possible side effects such as muscle loss, which is an ongoing concern. Same for research on preventing or slowing weight regain after someone discontinues a GLP-1 drug. But limiting our options because a treatment offends some arbitrary notion of morality is not only unfair to individuals, it makes society worse off by forcing us to spend billions of dollars treating obesity-related complications that might otherwise be prevented. Science cannot be completely divorced from ethical concerns, but this is not a debate about eugenics or whether embryos are people. It is simply about making fat people not fat–as was commonplace in the 1970s, before obesity rates exploded for reasons that remain poorly understood.

To butcher that famous Donald Rumsfeld quote, we live in the society we have, not the society we want. In today’s society, people become obese really easily despite exercising more than ever, a plethora of dieting and fitness apps and content, and possibly eating fewer calories compared to generations ago. Why so many people are suddenly storing so much fat, who knows (maybe it’s pesticides, antibiotics, seed oils, falling core body temperatures, or microplastics as proposed mechanisms), but we’re stuck with this problem–hence we need better solutions even if they are imperfect–compared to what we’ve always done in the pre-Wegovy era, which is clearly not working. When it comes to solving obesity, I say let’s bring on the science, like we do and is expected for other medical conditions. Enough with the willpower. I’m ready and I’m here for it.