"Everybody looks so great... When I look around this room, I can't help but wonder: Is Ozempic right for me?" (Jimmy Kimmel, Academy Awards monologue, 3/12/2023)
The most informative statistics don't always come from studies. On Monday, Vogue Business reported that across 219 fashion shows in New York, London, Milan and Paris this season, 95.6% of looks were sizes 0 to 4. (Only 0.6% percent of looks were plus-size (14+), while 3.8% were mid-size.) Tagwalk, a fashion search engine, reported that since last season, the number of larger models has precipitously declined, confirming fears that the fashion industry has "quietly dumped" these models in favor of their more traditional, cadaverously skinny peers.
Since last year, the return of thinness culture has been frequently noted. I don't do much social media, but those who do report that Kim and Khloe Kardashian are boasting newly slimmed-down frames, low-rise pants are becoming a thing again, and "heroin chic body" has become a popular TikTok search term. And there's Jimmy Kimmel's comment at the Oscars, which is clever but also premised on the toxic, deeply ingrained assumption that weight loss can make you more attractive.
Thin is in again, thanks in part to the popularity of weight-loss drugs such as semaglutide (Ozempic and Wegovy) and terzepatide (Mounjaro). These drugs were developed to treat diabetes, but in 2021, Wegovy was approved by the FDA for treating obesity, and the other two are routinely prescribed off-label for weight loss. Use of these drugs has spiked to the point of creating shortages for diabetes patients.
How did these new weight-loss drugs become so popular? Well, there's a lot of celebrity/influencer/social media buzz – Elon Musk tweeted that Wegovy helped him become "fit, ripped, and healthy" – but it's not just chatter that's driving up demand. The drugs appear to work. Exceptionally well. You can hear about this even from relatively staid sources. For example, here's a typical summation from a Washington Post article published this Monday:
"Research shows that they [semaglutide and terzepatide] cause an average weight loss of 15 to 21 percent."
Those are dramatic statistics. They're not inaccurate. And yet, they're deeply misleading. The point of this newsletter is to show how statistics can be accurate and yet foster profound misunderstandings.
The research evidence
The studies that the Post article cited, published in 2021 and 2022, respectively, are rigorous and quite similar to each other, methodologically speaking. Both were published in the New England Journal of Medicine, one of the most prestigious medical journals. The 2021 study focused on semaglutide (sold as Ozempic, Wegovy, or Rybelsus) while the 2022 study focused on terzepatide (sold as Mounjaro).
In each study, over a thousand overweight adults were randomly assigned to receive weekly injections of either a weight-loss drug (semaglutide or terzepatide) or a placebo for a period of just over one year. Participants didn't know which type of injection they were receiving. Average weight loss among those who received a drug was about 15% (semaglutide) and 22% (terzepatide). In each study, roughly 85% of participants in the drug groups lost at least 5% of their body weight. Impressive, right?
Yes and no.
Limitations of the evidence
1. In each study, the drug was accompanied by a "lifestyle intervention" that lasted for the duration of the study. Here's how one research team described it:
"Lifestyle intervention included regular lifestyle counseling sessions, delivered by a dietitian or a qualified health care professional, to help the participants adhere to healthful, balanced meals, with a deficit of 500 calories per day, and at least 150 minutes of physical activity per week."
So, it's not either drug per se that caused weight loss. It was the drug plus a lifestyle intervention that promotes healthy eating and exercise. This "intervention" was far from trivial, as it consisted of individualized counseling for the duration of the study.
This doesn't mean the drugs don't work. It just suggests that they're not intrinsically beneficial. In other words, they might be like anabolic steroids. If you take steroids, you don't automatically develop greater muscle mass. You cannot obtain even the slightest benefits by mere steroid use. Rather, steroids enhance the muscular growth that stems from activities such as weight training. Just as steroids are genuinely effective, but only if accompanied by training, so the weight-loss drugs may be genuinely effective, but only if accompanied by interventions that change eating behavior and activity levels.
2. The duration of the studies was just over one year.
The semaglutide study lasted 68 weeks; the terzepatide study lasted 72. Methodologically speaking, this is good but not quite good enough. Numerous studies show that after longer periods of time, some dieters gain back the weight they've lost. Here's how one prominent researcher summarized her own comprehensive literature review:
"Although dieters in the studies had lost weight in the first nine to 12 months, over the next two to five years, they had gained back all but an average of 2.1 of those pounds. Participants in the non-dieting waitlist control groups gained weight during those same years, but an average of just 1.2 pounds."
In other words, once you get another year beyond the duration of the two studies I described, the net average weight loss is about 2.1 pounds. If you weighed 210 pounds, for instance, that would be a 1 percent loss.
This doesn't mean that the new weight loss drugs (plus lifestyle intervention) wouldn't continue to have benefits two to five years later. It just means that we don't know. At minimum, people would have to keep taking the drugs (and maintaining a healthy lifestyle).
3. The drugs didn't benefit everyone.
In the 2021 study, about 18% of the glutamide group did not complete the study, owing to failure to adhere to treatment or adverse side effects. In the 2022 study, about 20% of the terzepatide group did not complete the study for similar reasons.
In other words, whatever benefits might accrue from drugs plus lifestyle intervention, and however long those benefits might last, about one fifth of individuals may not make it through the first year of treatment. That proportion would almost surely increase as time goes on.
Limitations of media coverage
Let's revisit what the Washington Post had to say about the two studies:
"Research shows that they [semaglutide and terzepatide] cause an average weight loss of 15 to 21 percent."
Now you can see how misleading this statement is. The drugs didn't "cause" the weight loss – it's was the drugs plus a lifestyle intervention – and it's not clear whether the weight loss would persist beyond the two year mark, when some dieters have regained most or all of the weight they initially lost.
Elsewhere the Post has used similar language to describe these studies ("the medications induce loss of 15 to 22 percent of body weight on average"), as have other news outlets, and, apparently, lots of social media sources. This is irresponsible, because it implies that by simply taking the pills, the weight falls off.
Confluent interests
I have no reason to question the integrity of the academic researchers who conducted the studies or the doctor who wrote the Washington Post article. But it's worth noting, in passing, that these individuals are all incentivized to claim that the drugs are effective and safe. The 2021 study was designed, overseen, and financially supported by Novo Nordisk, the maker of semaglutide. The 2022 study was designed, overseen, and financially supported by Eli Lily, the maker of terzepatide. The author of the Washington Post article is a doctor who acknowledges consulting for both companies.
Further cause for concern
Both studies were conducted by multi-site research teams and published in the New England Journal of Medicine, and the FDA approved semaglutide as an anti-obesity medication in 2021 based largely on Norvo Nordisk's data. In short, the research could be said to have some inherent credibility. But medications are more widely trusted among experts when independent research attests to their effectiveness and safety.
In fact, experts have been airing concerns about the use of these drugs, both authorized and off-label, to treat weight problems. One concern is simply the paucity of data on their use. Both studies I described focused on people with relatively severe weight problems (average BMIs in the upper 30s). The effectiveness of these drugs for people with weight issues of lesser severity is unknown. Meanwhile safety issues have been identified, including side effects ranging from nausea to dehydration to disrupted bowel movements. (In the two studies discussed here, adverse effects were significantly greater among the drug groups than those who received a placebo, although it's debatable how much those effects should be a cause for concern.)
The drug companies would probably respond that because we know how the drugs work (by mimicking hormonal changes that enhance blood sugar regulation and make you feel fuller longer), we can predict that they'd work just as well with mildly overweight people as they do with people who experience obesity. Perhaps so. But we also know that amphetamines produce weight loss, and we know why they do so. Keep taking amphetamines, and you're very likely to keep the weight off. But you'll develop health problems as well. So, I would say there are unresolved concerns about the safety of the new weight-loss drugs along with questions about their effectiveness.
Conclusion
As you've probably noticed, I have no quarrel with the statistics underlying the recent studies on semaglutide and terzepatide. Methodologically speaking, they're great studies. But they only show what they show. There's no evidence that the drugs are effective without intensive lifestyle interventions. There's no evidence that their benefits extend much beyond a year. There's no evidence that they benefit people with minor weight issues. They clearly don't benefit everyone, and some people experience severe side effects. But sure, in ideal circumstances, the drugs, in combination with intensive lifestyle interventions, clearly benefit people with obesity in the short run.
The best-case scenario seems to be that if you take semaglutide or terzepatide once a week, and you maintain a healthy lifestyle, you'll lose weight and keep the weight off. But a lot of other conditions will have to be met. You'll need to be able to afford the drug (roughly a thousand dollars per month without insurance). You may need to take it for the rest of your life, while maintaining that healthy lifestyle. Hopefully the drug will continue to be effective after a year, assuming it worked for you in the first place without adverse side effects…
The harms created by thinness culture, particularly for women, have been widely documented and so I won't repeat them here. Suffice to say that "heroin chic body" is not a desirable ideal. Meanwhile, both research and theory suggest that if you're seeking better health and a longer life span, physical activity may be more influential than weight loss. Not that losing weight is irrelevant to the management of obesity, but simply that, as described in a 2021 review of literature, "weight-neutral" strategies may be the healthiest approach. One conclusion of this review is that for some outcomes, weight loss without increased fitness is not beneficial, yet people benefit from increased fitness without losing weight. In other words, if you want to be healthier, forget what the scale or the mirror are telling you, and focus on increasing activity and exercise levels. (And, perhaps also do what you can to pursue better food choices, more sleep, and less stress.)
Final comment: A place for anecdote
Researchers will tell you that the worst thing you can do when discussing topics like this is to start trotting out anecdotes. In a sense, I agree. Statistical evidence can tell us what's generally true, as opposed to what's true of that one unusual friend of yours who smoked and drank and weighed 300 pounds but lived to be 98. And yet, in the end, a person is not a statistic. What's best for most people may not be best for you. In this case, both research and anecdotal observations suggest that if you lead a reasonably active and healthy lifestyle, you may not need to worry about your weight. And so, I close with an anecdote about a pair of obese individuals who are very near and dear to me…
My two rabbits, to be frank, are real porkers. They have ordinary-sized heads and enormous butts – they look like furry light bulbs. And yet they're both 8 years old, they've never been ill, and, when startled, they can still propel those butts more than a foot up into the air. The secret? They're uncaged and they move around a lot. This is purely anecdotal of course. But in the end anecdotes count too.
Obsessed with your obese rabbits!!!