#246 – AMA #45: Pros and cons of GLP-1 weight loss drugs and metformin as a geroprotective agent

"The thing that concerns me the most with these drugs. . .is this drive towards sarcopenia.” —Peter Attia

Read Time 33 minutes

In this “Ask Me Anything” (AMA) episode, Peter focuses the discussion on two topics getting a lot of attention recently. He first dives deep into GLP-1 agonists, most notably semaglutide and tirzepatide, which originally came to market as diabetes drugs but are now being studied and prescribed for weight loss. He walks through the data and compares the effectiveness of the two drugs, the side effects, and perhaps more importantly, his reservations around wide use of these drugs and who he would consider to be a candidate for them. Next, Peter discusses how metformin, another drug originally brought to market for diabetes management, gained popularity as a potential longevity drug even for non-diabetics. Peter gives his take on this possibility and reviews data from a more recent study investigating the question of whether metformin should be used for general “geroprotection.”

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We discuss:

  • The hype around semaglutide, tirzepatide, and other GLP-1 agonists for weight loss [2:30];
  • Overview of GLP-1 agonists and why these drugs are getting so much attention [6:15];
  • Defining the term “geroprotective” [11:30];
  • Semaglutide: background, brand names, indications, and more [15:15];
  • Tirzepatide: background, brand names, indications, and more [19:15];
  • How semaglutide and tirzepatide compare in their efficacy in terms of weight loss and other metabolic health metrics [23:45];
  • Data showing sustained weight loss and improved metabolic metrics with after more than a year of using semaglutide and tirzepatide [29:00];
  • What happens to body weight when a patient discontinues the medication? [34:45];
  • Noteworthy side effects of GLP-1 agonists and similar classes of drugs [40:45];
  • Increased resting heart rate and other concerning trends in patients using GLP-1 agonists [45:15];
  • Changes in body composition (body fat and lean muscle) in patients on GLP-1 agonists [50:45];
  • Possible reasons for the loss of lean muscle mass and tips for protecting lean mass [59:00];
  • GLP-1 agonists and thyroid cancer [1:01:30];
  • Who might be a candidate for GLP-1 agonists? [1:03:45];
  • The large financial cost of this class of drugs [1:08:30];
  • Metformin as a geroprotective drug: origin of the idea that metformin could be a longevity agent even for non-diabetic patients [1:11:30];
  • A 2022 study on metformin sheds more light on the question of whether metformin should be used for “geroprotection” in non-diabetics [1:21:00];
  • Peter’s current approach with metformin for his patients [1:25:15]; and
  • More.


The hype around semaglutide, tirzepatide, and other GLP-1 agonists for weight loss [2:30]


Today’s discussion

  • Two different subject both of which have been covered before but new data and insights have come to light

Topic 1: GLP-1 agonists

  • GLP-1 agonists were covered in AMA #29
  • When that episode came out, these “weight loss” drugs weren’t yet being covered as much as they are now
  • In some way, they were “too far ahead of the curve” when having that discussion
  • The first real discussion about semaglutide and other similar drugs amongst Peter and the team was in the spring of 2020
  • By the fall of 2020, they were putting patients on one of the drugs (semaglutide)
  • A year later after that, they did AMA #29 on that subject but it was still very under the radar
  • And today, semaglutide (and similar drugs like tirzepatide) might be the single most talked about drug
    • Semaglutide is branded as Ozempic and Wegovy
    • Tirzepatide is branded as Mounjaro
  • Peter has a much stronger view about these drugs than he did a couple years ago and he will share that today

Topic #2: Metformin

  • They will be looking at some new data on metformin 
  • Peter will provide his updated view on metformin as a potential geroprotective agent more so for those who are in the camp of taking it as a longevity agent (rather than a diabetic patient)


Overview of GLP-1 agonists and why these drugs are getting so much attention [6:15]

Listen to AMA #29 and if anyone wants to get deep into the science of these drugs


Overview of the GLP-1 drugs and why people are so excited about them

  • We’re really going to be talking about two hormones today, GLP-1, or glucagon-like peptide 1, and GIP, glucose-dependent insulinotropic polypeptide
    • Both of these are hormones that are released from the gut
    • One is released from one part of the gut, one is released from the other
    • But the net-net is their effect on insulin
  • You got to understand that these drugs really started as drugs to take care of patients with type 2 diabetes

What is type 2 diabetes?

  • It’s a disorder of carbohydrate metabolism
  • Blood glucose gets too high and that is the defining feature of it
  • Now, you could argue that might not be the right defining feature and maybe we should be defining it earlier on, but it’s basically a very extreme state of insulin resistance
  • In a person who is developing type 2 diabetes, their cells, most notably their muscle cells, but also other cells in the body such as the liver, are becoming resistant to the effects of insulin
  • And as such, their blood glucose levels are rising
  • The reason for that, of course, is that the muscle is the most important storage depot for glucose and so if the muscles are resistant to the effect of insulin, glucose will accumulate in the bloodstream.

So what are we to do about this? 

Figure 1. Source: Wikipedia DPP-4 inhibitors

  • There are lots of things to do about it
  • But what this figure shows is that an important strategic plan is using things that either stimulate insulin to be released and/or inhibit glucagon release
  • Both of those things will have the same net increase, which is to lower blood glucose, because if you stimulate insulin release, you’re going to put more insulin into circulation

{end of show notes preview}

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  1. This is particularly of interest to anesthesiologists and surgeons. The GLP-1 agonists cause gastroparesis and a hazard in the operating room. The NPO guidelines that we love to use are no longer relevant in patients taking high dose semaglutide. These patients should be considered “full stomach”. In my anesthesia practice, I try to discontinue semaglutide at least 1 week prior to surgery to lessen the gastrointestinal emptying effects. One of my colleagues will perform an ultrasound guided examination of their stomach contents prior to induction. I am not aware of other anesthesiology practices that are targeting semaglutide in this way but I have many colleagues reporting pulmonary aspirations on induction due to the suspected semaglutide effects. I think there will be a string of bad outcomes that will change practice habits. In the meantime, there should be a discussion in the surgical and anesthesiology community sharing the safety concerns that this medication class has in the operating room.

  2. Some GLP-1 Medications come with the Dreaded FDA Black Box warning. As a patient we are not given the Absolute Risk % of Cancer from the medication.

    Future topic ?

  3. Very interesting discussion. I would note from the side effects I have experienced on Mounjaro, insomnia and interestingly, a drop in alcohol consumption. I am sure I have lost muscle mass but I never did a Dexa.

  4. Great talk, thanks.
    In regards to US medical care, my two cents is 1. We don’t provide “health care”, but instead “medical problem care”. We don’t make people healthy or address diet and exercise much at all.
    2. We are no longer doctors taking care of patients. We are providers giving customers what they want. Customer satisfaction is all that matters. If they want Ozempic, they get it.

  5. Of course Ha1C and weight will come up if SAD +SALifestyle is still in place. The burden of SAD+SAL is nasty. Justa take a detailed look along the whole 5 year study from Virta Health. (They don’t even publish results beyond 2 years!)

    I bet $100 that Big Pharma won’t publish results beyond the 2year mark.

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