24 Comments

Agree that it's still a new drug and there will be unknown unknowns. Personally, I see myself being less enthusiastic with the incretin hormones e.g. loss of lean body mass. I am concerned seeing otherwise young and "healthy" people jump to glp1s, essentially committing to years/decades to long term usage. Side effects are a certainty with risk that increases with duration of exposure. On the flip side, I'm concerned about its use in the geriatric population also whose lean mass and strength is important, and using GLP1s may be counter productive. There is no free lunch.

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I'd love to see Sensible Medicine engage more sensibly on the topic of obesity. The "click" you mention..... isn't it something like 5% of all dieters maintain their weight loss long term? That's a pretty small number of people. And most people who lose weight gain it back plus more. So, to the extent obesity is a problem it seems like a more reasonable treatment goal is weight maintenance rather than weight loss. Then you have to look at the pipeline from dieting to eating disorders, and weigh the real harms of eating disorders. Please please please bring Ragen Chastain (she writes Substack "Weight and Healthcare") to one of your panels for a discussion.

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The “long term use” of any therapy will run into some of the same limitations you noted here: specifically, what happens after you exceed the follow up duration from the landmark trials? I suspect this concern will apply to nearly any medicine for any chronic condition. Statins, ACE inhibitors, beta blockers…DOACs….heck even ASA for secondary prevention…. Do you really know that the benefit persists even decades after initiation? No….and you can’t know, since it hasn’t been studied.

What does seem clear is that GLP-1 analogues do NOT have any legacy effect. But that’s not a knock against them…most drugs only work when you are actively taking them.

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"What I mean is that patients that I have seen who have lost weight and maintained it with lifestyle change have something click." - This might be well worth understanding. The drugs have really altered some balance, perhaps forever.

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Apr 3, 2023Liked by John Mandrola

This topic of GLP-1 Receptor Agonist also deserves its own Sensible Medicine podcast for the rampant obesity and diabetes epidemic we see in first world countries.

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Why not take a further step back and ask yourself, the fact that people would rather take a pill than do basic activities, how fucking profoundly sick are we?

Coffin's already sealed, my friend. Doctors like you need to call it, and you probably won't because you're so entrenched.

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1. Why do you assume it's not a durable effect? The trials of discontinuation that I'm familiar with were blinded, i.e. the patients didn't ever attempt to transition to "maintenance". I've had luck with many patients when they know they are going off the drug.

2. I take anti-hypertensives and they normalize my blood pressure. Should I be disappointed that there was no "click"? (I plan to take indefinitely).

3. Why is obesity somehow due to poor will power, but hypertension isn't? I suppose we're going back to treating alcohol use disorder as a defect of character, like obesity. Why can't we add diabetes and hypertension to the list?

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Apr 3, 2023·edited Apr 3, 2023

1. Why assume anything? Just state the facts.

2. It depends on why you are taking anti-hypertensives. Why am I explaining this to a doctor? Isn't this basic causal logic? You're not going to get a "click" if your belief system entails you relegating your disease to "genetics" (whatever that means) and we know hypertension is multi-causal.

3. This is an ignorant argument and is a non-starter. Again these are all different diseases and you're assuming a uniformity that is simply not there in the facts. Volition is not well understood in medicine but certainly people can and do make major behavioral changes to affect the impact of their actions on their health and doctors work actively against this fact, apparently, in order to market drugs. There's plenty of research on its effectiveness as well, it's simply not pushed by doctors like you who want to push the victim narrative. Seriously dude, grow up. There is a reason people trust doctors less and less.

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I spend my day "pushing" people to take their health seriously and to exhaust non-drug therapies. "Doctors like me" understand well the "multi-causal" nature of the things we treat. My experience with GLP-1 drugs is that they work quite poorly without serious effort from the patient.

The fact is, though, even with intense (very expensive -- in the neighborhood of these drugs) non-drug therapy for obesity, success rates are dismally low. The fact that some have succeeded when 94% haven't isn't an argument that the 94% could if they only tried harder.

And "the facts" don't support a lack of durability -- no strategies for transition to other drug or non-drug therapies have been tested, as far as I know. A blinded placebo washout is not how one would study this.

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thanks for the nice response

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Clearly an effective class of drug. What’s interesting is the hesitancy and often outright refusal of doctors to prescribe it. Exchange the diagnosis obesity for hypertension and it would be malpractice to withhold these medications. We have so many assumptions about people who are obese-undisciplined, uneducated, self indulgent etc.

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Isn't it true for the VAST VAST VAST majority? I'm not exactly thin, but I'm not morbidly obese. When the scales creep up, I control it with more walking or less eating. It's a simple input/output engine. Sure, the impossible portions served at restaurants don't help, but no one points a gun to anyone's head to finish it. The fact that we think EVERYTHING should be treated with a pill is how we got to be the most medicated citizens but not the the healthiest. So yes, empirical evidence from other countries tell us we don't need this type of a drug. What we need is more education that leads to discipline.

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I am really sympathetic to this way of thinking, but it assumes that your issue and the weight problems of the severely obese are the same thing.

After years of working with them, and particularly on this new class of drugs, I'm convinced that they are not.

The intensity of the neurological drive to eat is not the same from one individual to the next. When the severely obese take these medicines, the overwhelming description they give is "I feel normal now." That is, they can still have indiscretions like all of us, but they finally feel as if "I control it with more walking and less eating" works for them on this drug. It's not as though they have no other "effort," or something like that.

These tools are like any other -- high use for some things, low use for others, and mis-use in other cases.

But "traditional exercise and diet" recommendations -- even with intense follow up, counseling, and support -- generally only get about 5% of people to lose medically-significant weight and maintain it.

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But then why is this a UNIQUELY USA problem? The VAST majority of Koreans are not fat. Japanese, Singaporeans, and Taiwanese are not fat. Europeans tend to be much skinnier than Americans. So it's not a medical issue, it's a cultural issue. You can argue that they are the same, but you can't "catch fatness" but you can be influenced by culture. That's the point I was making. It's the lack of education that leads to lack of discipline. I had to LAUGH when the Whitehouse rep on 60 min said that "when you see overweight parents, the kids tend to be overweight...so it's genetics" I believe she was a medical doctor. I was aghast. I think any sane person would conclude that parents who eat poorly (health-wise) will lead to children who would do the same. That's the Occam's Razor but of course she pivoted to "it's not your fault, it's your genetics"

Do some people benefit from biome/DNA/something that helps them to be skinnier? Of course. I have a brother who can eat anything and not get fat. It's much harder for me. But I also know that every slice of pizza that I stuff into my mouth is the problem. Not my genetics.

Everyone who doesn't have a true metabolic issue will lose weight if we send them through Ranger School in the Army. Hell even Army basic would be sufficient. So clearly, it's not a medical issue. It's the inability to self regulate. But I'm sure the drug will be a hit given that so many people want to identify as a victim in one way or another.

PS: The average weight loss at Ranger School is 20-30 lbs (it's a 2 month long course). Why? Because it's incredibly physical and rigorous and you don't get to eat much.

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I share your frustration. The wake up call for me is looking at the increasing obesity rates over time in one country (e.g., Australia). So in the 1970s everyone became lazy and lost willpower? No. Most people were always lazy and with low willpower. But their environment didn't permit this so they were not obese. People who are normal weight today are the exception. Why aren't their habits being studied more? It's not genetics as they haven't changed since 1970. But I think you're right that the culture of acceptance has exacerbated the problem. In other cultures there is less acceptance of excesses of eating and drinking. Social approval drivers are powerful. I'm not convinced that pretending obesity isn't a problem and that obese people are helpless to change is any more beneficial than it would be for alcoholism. It is an input/output issue. But the reasons people pursue unhealthy behaviours (over eating, inactivity, smoking, drug taking, drinking, sun beds) are complex. It's more likely to be something behavioural science can solve in conjunction with price signals.

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I think there's something to be said about larger portions becoming a thing and more people living a sedentary sub-urban life. When you CELEBRATE morbid obesity as a "normal" thing, we've lost the battle. As Bill Maher once said "have you ever seen a fat 90 year old?"

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Certainly impressive results. Long term studies will take decades; why the reluctance to treat patients long term with GLP-1 analogues ? No such reluctance to use long term anti hypertensives, insulin, antidepressants, etc. Seems still a stigma of obesity treatment. As if the “click” refers to an individual having the moral strength to change their eating habits rather than a physiologic event.

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The “click” point doesn’t make any sense to me. Almost everything stops working if you stop taking/doing it.

For those that lose weight with diet/exercise... what happens when you revert back to your previous habits? You gain it all back.

Most medical treatments are not antibiotics and appendectomies. No one makes the same arguments about anticoagulation for atrial fibrillation or diabetes medications.

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Cost. Over $1,000 per month for most. And they won’t be off patent for many years.

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Well, too many mom and pop compounding pharmacies are selling this skinny shot for a fraction of cost.

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This is not something a mom and pop pharmacy could make. Or are you arguing they sell it for less than the suggested price?

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Yes, lots of sterile compounding pharmacies do with a prescription. They work. "Less than suggested price" is an understatement. It's way cheaper.

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Compounding pharmacies using recombinant DNA technology is news to me, but if you say so.....

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Novo Nordisk has issued cease-and-desist letters to some for infringes on its intellectual property. This didn't stop them from doing it.

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