Ozempic Dreams

Reflections on Obesity, Dieting, and the New New Thing

© photo by Bertie

A Little History

The Gila monster has a face that only a mother can love. 

The largest lizard native to the United States, it lives in the American southwest and Mexico.  Its little eyes lay flush against beaded, scaly skin. Its body coloring is a patchwork of orange and black. Its hands, feet, and the front of its head look as if they had been dipped into a pot of ink. It snorts and hisses as it waddles around, flicking out its thick, long, gray, forked tongue. Its razor-sharp teeth deliver a nasty, venomous bite (common in snakes but rare in lizards).

But, as for humans, so for reptiles: beauty is in the eye of the beholder. 

Gila monsters spend 95% of their time underground, emerging to eat only four or five times a year. This amazing fact makes them beautiful to students of metabolism.

In 1995, Dr. Daniel Drucker, an endocrinologist at the University of Toronto, heard about the Gila Monster and asked himself some questions: How does the Gila Monster regulate energy over such a long period of time without food? How can it maintain stable blood glucose during prolonged fasts? Is there something it can teach us about metabolic diseases like diabetes?

Indeed there was.

Gila Monster venom contains a novel molecule called Exendin-4, which is an incretin, a hormone produced in the gut that regulates pancreatic activity such as insulin release. This makes it intriguing as a potential therapy for diabetes. Humans produce an incretin called GLP-1 (Glucagon-like peptide), which has similar effects but is rapidly metabolized, limiting its use as a therapeutic agent.

Fast forward ten years to 2005. Dr. Drucker’s research has paid off, resulting in a synthetic, long-lasting, injectable GLP1 receptor agonist based on Exendin-4. Named Exenatide (now marketed as Byetta), the FDA approved it as a new treatment for diabetes.

What does all this have to do with obesity?

Well, doctors soon noticed an interesting side effect of Exenatide in their diabetic patients: weight loss. This was counterintuitive. GLP1 receptor agonists are insulinogenic, which means they stimulate the pancreas to release insulin, which drives sugar out of the blood and into the cells, where it belongs. But that should increase body weight, not decrease it. Indeed, Type-2 diabetics usually gain weight when they start taking insulin.

It turns out that GLP1 receptor agonists do indeed cause weight loss, through a poorly understood combination of acting on the brain to decrease hunger and acting on the gut to decrease motility. This combination of factors makes the patient feel full, reducing calorie intake enough to produce a 15% loss in body weight. 

That’s comparable to bariatric surgery.

You can only imagine how quickly drug companies jumped on that finding. Soon enough the race was on, and a whole new class of weight-loss drugs came tumbling out of the pipeline. We now have Wegovy, Byetta (the OG), Ozempic, Mounjaro, Victoza, Saxenda, and others - all competing in the quest for the holy grail of a safe and effective medication for obesity (so far only Wegovy is FDA approved for this indication).

It’s like a non-feeding frenzy.

Over the past year, the use of GLP1 receptor agonists has exploded. They are the new new thing, the flavor of the month. Everyone and their sister, from Kim Kardashian to the mom at drop off, either admits or adamantly denies using them to finally fit into that dress or lose those last, stubborn, fifteen pounds.

No one believes the deniers.

I have one good friend whose own experience has turned him into such a zealot that it has become a part-time job convincing our other friends that no, they do not belong on Ozempic, despite his exhortations.

Partly as a result of this craze, the supply has dried up. Wegovy has been unobtainable for months, even for diabetics, with Ozempic and the others also in short supply. And they are expensive, running up to $1800 a month if not covered by insurance - which they usually are not.

Are they being properly used, or abused? A beneficial therapy or a risky, privileged indulgence? A shiny new path or just another lazy shortcut? What should we think?

A Little Analogy

As a way of parsing the controversy surrounding these medications, I think it helps to view them as analogous to antidepressants, like Prozac, Lexapro, or Wellbutrin. This comparison may not seem obvious at first, so bear with me.

Depression has long carried the stigma of moral weakness. So too with obesity.

Depression is often thought of as fixable with a change of attitude and behavior. So too with obesity.

Depression is often attributed to social factors. So too with obesity.

And just as our understanding of the etiology and treatment of depression has evolved, so has our understanding of obesity evolved in a parallel fashion. 

We now see affective disorders like anxiety and depression as resulting from a complex interplay between environment and biology. 

Family dynamics and social stressors certainly play a role. No one would deny that domestic abuse, loneliness, alienation from work, the breakdown of communal structures - the list goes on and on - all contribute to anxiety and depression. But neither would anyone argue against the idea that brain chemistry is also involved, particularly serotonergic pathways that are interestingly shared by the gut.

Similarly, our current understanding of the roots of obesity is also multifactorial. 

Society certainly plays a role. We move less and eat more. And what we eat - thanks in large part to the pervasive influence of the food-industrial complex that continually tempts us with treats laden with fat, sugar, and salt - has become more addictive and calorie-dense.

But genes and biology are now understood to play a crucial, if not primary, role. Doubters have only to look at the best way we have for untangling the influence of nature and nurture: twin studies. 

If you take twins that were separated at birth and raised in completely different environments, they nevertheless tend to end up with similar BMIs. In fact, twin studies suggest that the heritability of obesity ranges from 70-80%, a number that is only exceeded by height, and far greater than most diseases that are generally accepted to be “genetic” (like Type-1 diabetes).

Modern genetics has supported this understanding. Genome studies done in the last decade have found more than fifty genes linked to obesity - most with small effects that amplify each other and accumulate over time.

Back to depression. Consistent with our understanding of its multifactorial roots, depression is likewise treated with a multifactorial approach. Studies have shown that medication and therapy are equally effective in the treatment of depression and that they work better in combination than alone.

Is there any reason why treating obesity shouldn’t involve a similar approach? 

Sure some people can lose weight with behavior change alone and keep it off, but they are few and far between. The more extreme the diet (keto is one of many examples), the less sustainable it is. And the more sustainable the diet (choosing a salad for lunch without tracking calories, for example), the less effective it is. 

The body has more patience than you have willpower. It has all the time in the world and knows exactly how much it wants to weigh. As soon as your determination flags - and it will just ask Oprah, hardly a weak-willed person - the scale will start creeping back up to that setpoint.

Of course, if you’ve ever tried to lose weight, then I doubt I am saying anything you don’t already know. 

And please don’t think I’m hating on diet and exercise. The opposite is true: I harp on them ad nauseam - ask any of my patients. But studies show that 80-95% of people eventually regain the weight they worked so hard to lose, which unfortunately matches my clinical experience. 

The hard truth is that weight loss is a paradox: incredibly simple and incredibly complex. 

Simple, because it’s purely a matter of energy balance - calories in vs. calories out. Every weight loss method that has ever been invented - from diet to exercise to medications to surgery - has to follow this law: If you run an energy deficit you will lose weight; if you don’t you won’t; period. 

Some laws are made to be broken, but not the laws of physics.

Complex, because the variables that interact to determine energy balance - hormonal, physiologic, genetic, neurological, psychological, cultural, familial, environmental, societal - in short nature plus nurture - are impossible to disentangle and control. Move one variable one way, and other variables will promptly compensate by moving the opposite way.

A Little Wrinkle

So yes, it’s hard. But there is another problem with trying to run an energy deficit in order to lose weight: eating disorders. 

It turns out that you can take a completely average person - male or female - with no prior history of disordered eating whatsoever, and induce an eating disorder purely by restricting caloric intake.

In one classic study done during WWII, researchers trying to understand the effects of wartime starvation and refeeding had 36 young, healthy men restrict calories over a six-month period. They developed all of the abnormal behaviors associated with anorexia, bulimia, and binge-eating disorder. Granted, the weight loss, in that case, was 25% of body weight, which is very extreme, but research since then has shown similar results with weight loss of as little as 5% or less.

But who needs studies? It should be obvious to anyone living in the real world that restrictive diets are associated with eating disorders. If you have any doubt, ask people who need to maintain an abnormally low BMI: light-weight athletes, gymnasts, dancers, figure skaters, actors, models…. The rate of eating disorders in these cohorts is astronomical.

The only real point of studies is to put to rest any debate over correlation versus causation. In other words, it’s not just that people with eating disorders are attracted to restrictive diets, it’s that restrictive diets directly cause eating disorders.

Call it the dieter’s catch-22: to lose weight you need to run a calorie deficit, which leads to disordered eating, which sabotages the process, or worse. That’s one way to understand the common phenomenon of yo-yo dieting, where weight cycles up and down like a roller coaster.

What to do? We seem to have painted ourselves into a corner. The only solution to the paradox is paradoxical itself: restriction without restricting. 

If it were possible to sustainably change our eating habits and reduce caloric intake enough to lose weight without the associated psychological consequences, that would be ideal. 

Indeed, some people can do this naturally; others are able to learn how; but most of us simply cannot. I know that many of you will vehemently disagree with me on this - proponents of “intuitive eating,” for example, who believe that anyone can get to a normal weight if they would only just listen to their body - but sorry, it’s true. What may work for the small minority will not work for the large majority. I offer the trillion-dollar diet industry into evidence as exhibit A.

That's where medication comes in.

If GLP-1 receptor agonists work in part by blunting appetite and decreasing GI motility, maybe they can likewise bypass the psychological side effects of calorie restriction. You can eat what you want, you just want less.

In other words, restriction without restricting.

Circling back to the depression analogy, just as medication is rightly seen as an adjunct to therapy, helping to remove obstacles to change that are erected by the nature of the mood disorder, so too medication should be seen as an adjunct to diet, helping to remove the obstacles to change erected by the nature of the metabolic disorder.

And just as it’s considered cruel and ignorant to withhold medication from a depressed patient on the grounds that they should just pull themselves up by their bootstraps, it’s likewise cruel and ignorant to withhold medication from an obese patient on the grounds that they just need to eat less and move more.

As with depression, so with obesity: lifestyle change should be seen as necessary but not always sufficient, with the option of medication as a useful adjunct.

A Little UX

What has been my experience prescribing GLP1 receptor agonists over the past few months? Overall positive. 

I think of using these medications in three groups of patients.

First, diabetics, for whom GLP1 receptor agonists are well established as one of many options to help the patient control blood sugar and lower their A1C. No controversy there.

Second, obese patients, with or without comorbidities, as an adjunct to diet and exercise. Not a ton of controversy there, either.

Third, healthy, overweight patients, who have been unsuccessful with behavior change alone, especially if their attempts at weight loss have led to disordered thoughts or behavior. More controversy there.

Won’t patients gain back the weight as soon as they stop taking the medication? Yes, they will, as with any other weight loss strategy, unless they also change their behavior, at least to some degree. 

Remember that you have to run a greater energy deficit to lose weight than to maintain weight. So once they reach their target weight, the patient should eventually require a lower dose or be able to stop taking medication altogether. 

The goal would be to lose weight with the help of medication and maintain it with lifestyle changes. As with antidepressants, some patients may be able to stop medication without a relapse, while others may need to take it long-term. 

The main pitfalls include cost, access, side effects, and complications.

Eventually, these medications will have to be covered by insurance. Until then, there is no getting around the fact that unless you have diabetes, only the rich can afford them (of course, the price may seem less exorbitant once you factor in alternative costs - programs like Jenny Craig and even apps like Noom can cost hundreds of dollars a month if you sign up for all the bells and whistles…).

Side effects mostly include nausea, heartburn, and abdominal discomfort associated with decreased gastric motility, which can be prohibitive for some patients. They can also make you lose your taste for alcohol, which can be disconcerting but is usually not such a bad thing.

Complications remain to be seen. That’s a wild card. GLP1 receptor agonists are relatively new, and the emergence of events too rare to show up in earlier trials is always a possibility - remember Phen Phen. 

But if that doesn’t happen, we may finally have a medication that will do for obesity what Prozac did for depression. In which case I have this little piece of advice, inspired by the great Willie Nelson: Mammas Don’t Let Your Babies Grow Up to Be Bariatric Surgeons.