#246 - AMA #45: Pros and cons of GLP-1 weight loss drugs and metformin as a geroprotective agent
Host Peter Attia and Nick Stenson preview an AMA episode discussing GLP-1 agonists (semaglutide, tirzepatide) for weight loss, highlighting Attia's reservations, and exploring metformin's potential as a geroprotective agent for non-diabetics.
Deep Dive Analysis
9 Topic Outline
Introduction to AMA #45: GLP-1 Agonists and Metformin
The Hype Around GLP-1 Agonists for Weight Loss
Overview of GLP-1 and GIP Hormones and Their Effects
Mechanism of Action for GLP-1 and GIP Agonists in Type 2 Diabetes
Defining 'Geroprotective' Drugs
Semaglutide (Ozempic, Wegovy): Background and Dosing
Tirzepatide (Mounjaro): Background and Co-Agonist Mechanism
Oral Semaglutide: An Alternative Delivery Method
Comparing Effectiveness of Semaglutide and Tirzepatide
5 Key Concepts
GLP-1 (Glucagon-Like Peptide 1)
GLP-1 is a hormone released from the gut that stimulates insulin release and inhibits glucagon release. These actions collectively lead to a reduction in blood glucose levels, making it relevant for type 2 diabetes treatment.
GIP (Glucose-Dependent Insulinotropic Polypeptide)
GIP is another hormone released from the gut that, similar to GLP-1, stimulates insulin release and inhibits glucagon release. Its combined action with GLP-1 contributes to lowering blood glucose.
Geroprotective
This term describes drugs whose exact mechanisms of aging might not be fully known but appear to act broadly across various hallmarks of aging. These drugs aim to improve lifespan and healthspan beyond just treating a single disease.
Semaglutide
A pure GLP-1 agonist designed to replicate the effects of native GLP-1 but with a much longer half-life, allowing for weekly injections. It is used for type 2 diabetes (Ozempic) and obesity (Wegovy).
Tirzepatide
A co-agonist drug that acts on both GIP and GLP-1 receptors. It is a potent GIP agonist and a weaker GLP-1 agonist compared to native GLP-1, branded as Mounjaro for type 2 diabetes.
5 Questions Answered
GLP-1 agonists are drugs that mimic gut hormones (GLP-1 and sometimes GIP) which stimulate insulin release and inhibit glucagon, originally used for type 2 diabetes. They gained popularity for weight loss because they significantly reduce appetite, leading to less food intake and weight reduction.
Geroprotective refers to drugs that appear to broadly impact various hallmarks of aging, aiming to improve overall lifespan and healthspan rather than just targeting a single disease.
Semaglutide is a pure GLP-1 agonist, while tirzepatide is a co-agonist, acting on both GIP and GLP-1 receptors. Tirzepatide is a potent GIP agonist and a weaker GLP-1 agonist compared to native GLP-1, whereas semaglutide is a slightly weaker pure GLP-1 agonist.
While GLP-1 agonists like semaglutide (Ozempic) and tirzepatide (Mounjaro) were initially approved for type 2 diabetes, a higher dose of semaglutide (Wegovy) is approved for obesity without diabetes, and tirzepatide is also being used off-label for weight loss.
Yes, there is an oral version of semaglutide available, primarily indicated for type 2 diabetes. The injectable versions are often preferred due to factors like potency, half-life, and the need for refrigeration for injectables.
11 Actionable Insights
1. Seek Professional Medical Advice
This podcast is for general informational purposes only and not a substitute for professional medical advice; always seek assistance from healthcare professionals for any medical conditions.
2. Prioritize Insulin Sensitivity
When addressing type 2 diabetes, the primary goal should be to increase insulin sensitivity, as this will ultimately result in a reduction in blood glucose levels.
3. Evaluate GLP1 Use Critically
Critically evaluate the use of GLP1 agonists for weight loss, especially if not genuinely overweight, as many individuals seek them for minor cosmetic weight loss rather than medical necessity.
4. Explore Gyroprotective Drugs
Consider exploring “gyroprotective” drugs such as rapamycin, SGLT2 inhibitors, or metformin, as they appear to act broadly across various hallmarks of aging to improve overall lifespan and healthspan.
5. Lower Blood Glucose Strategy
An important strategic plan to lower blood glucose involves using things that either stimulate insulin release or inhibit glucagon release, as both actions reduce blood glucose levels.
6. Listen to Richard Miller (148)
To understand the science, testing, and considerations for “gyroprotective” drugs, listen to podcast episode 148 featuring Richard Miller for amazing insights.
7. Consider Oral Semaglutide
If you prefer not to inject or face refrigeration challenges, consider oral semaglutide as an alternative to injectable GLP1 agonists, though it is also very expensive.
8. Understand GLP1 Agonists
If you are thinking about taking, currently taking, or curious about GLP1 agonists like semaglutide (Ozempic, Wegovy) or terzepatide, listen to this episode for deep insights and reservations.
9. Explore Metformin’s Benefits
If you have an interest in metformin, particularly its potential “gyroprotective” effects beyond diabetes, this episode delves deeper into the relevant studies.
10. Watch Podcast Video
Subscribers can watch the full video of this podcast on the show notes page, while non-subscribers can find a sneak peek on the YouTube page.
11. Leave a Podcast Review
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3 Key Quotes
Today I would say this is the single most talked about drug period. There cannot be a drug that is getting more attention right now than semaglutide and its ilk.
Peter Attia
We don't have a really clear explanation for why virtually everybody who's had any clinical experience with these and who has looked at the literature agrees that it's clearly a central effect meaning there is something about these hormones that is changing our appetite namely of course reducing our appetite and so when you take these hormones your appetite goes down you eat less you lose weight.
Peter Attia
Perhaps more disturbing to me is the people who are reaching out to me who are frankly not overweight remotely but are saying like I really want to lose 10 pounds to look good on my vacation and I should be taking this right.
Peter Attia