Peter Attia MDPros and cons of GLP-1 weight loss drugs and metformin as a geroprotective agent [AMA 45 sneak peek]
CHAPTERS
- 0:02 – 1:59
Book launch countdown and the episode's two topics
The hosts open by noting the book launch is about two weeks away. They then say the episode will cover two subjects, GLP-1 agonists and metformin, both touched on in the past but with new data and many listener questions.
- •The book launch is about two weeks away at the time of release
- •A dedicated book podcast is planned
- •The episode covers GLP-1 agonists and metformin
- •Both topics were covered before and have new studies and questions
- 1:59 – 4:33
Why GLP-1 drugs went from under the radar to the most talked-about drugs
Peter recounts how he and Bob discussed GLP-1 agonists in AMA 29 long before the public attention. He says semaglutide and its relatives are now the most talked-about drugs, and that he has a much stronger point of view after more clinical experience.
- •An internal journal club on the topic took place in spring 2020
- •Patients were on semaglutide by fall 2020
- •Peter gets pinged daily about these drugs
- •He has a stronger point of view than he did almost three years ago
- •Metformin will be covered as a geroprotective agent, not for diabetics
- 4:33 – 9:05
How GLP-1 and GIP work: type 2 diabetes and appetite effects
Peter explains that GLP-1 and GIP are gut hormones that stimulate insulin release and inhibit glucagon, which lowers blood glucose in type 2 diabetes. He notes weight loss was an observed effect and that the exact reason is unclear, though it appears to be a central reduction in appetite.
- •GLP-1 and GIP are released from the gut and affect insulin
- •Type 2 diabetes is described as extreme insulin resistance
- •The drugs stimulate insulin release and inhibit glucagon release
- •Weight loss appears to be a central effect on appetite, with an unclear mechanism
- 9:05 – 11:11
Other diabetes drug classes: metformin and SGLT2 inhibitors
Using a figure of anti-diabetic drugs, Peter describes where metformin, SGLT2 inhibitors, sulfonylureas and incretin therapies act. Metformin mainly reduces hepatic glucose output, and SGLT2 inhibitors such as canagliflozin make you excrete glucose. He says metformin will be discussed for geroprotective effects.
- •Peter would argue the goal should be increasing insulin sensitivity rather than just lowering glucose
- •Metformin primarily reduces hepatic glucose output
- •SGLT2 inhibitors impair glucose reabsorption in the kidneys
- •Canagliflozin was discussed previously for longevity benefits
- •Metformin will be framed through its geroprotective effects
- 11:11 – 12:21
Who is asking: weight loss interest among people without diabetes
The host points out that most people asking about GLP-1 drugs don't have diabetes. Peter agrees, saying some genuinely need to lose weight while others who aren't overweight want to lose 10 pounds for a vacation.
- •Virtually none of those contacting Peter have type 2 diabetes
- •Some have a large share of body weight as fat and genuinely need to lose weight
- •Peter finds it disturbing that people who aren't overweight want the drug for cosmetic reasons
- 12:21 – 14:33
Defining "geroprotective"
Peter defines geroprotective as describing drugs that act broadly across hallmarks of aging, even if exact mechanisms are unknown. He contrasts lipid-lowering drugs, which target one specific element, with rapamycin, SGLT2 inhibitors and potentially metformin. The host also recommends the Richard Miller episode.
- •Geroprotective drugs act across various hallmarks of aging
- •Lipid-lowering drugs improve longevity but target lipoproteins specifically
- •Rapamycin, SGLT2 inhibitors and potentially metformin are given as examples
- •The Richard Miller episode (number 148) is recommended
- 14:33 – 19:10
Semaglutide: Ozempic, Wegovy, dosing and approvals
Peter explains that semaglutide is a pure GLP-1 agonist, roughly half as potent as native GLP-1, deliberately designed for a longer half-life so it can be dosed weekly. Ozempic and Wegovy are the same drug with different branding and dosing, and he walks through their approvals.
- •Semaglutide is a pure GLP-1 agonist, about half as potent as native GLP-1
- •Longer half-life allows weekly injection
- •Ozempic comes in 0.5, 1 and 2 mg auto-injector pens and was approved in late 2017
- •Wegovy is the same drug dosed up to 2.4 mg weekly for obesity
- •Wegovy was recently approved for kids age 12 and up
- 19:10 – 22:55
Tirzepatide: a GIP and GLP-1 co-agonist (Mounjaro)
Peter describes tirzepatide as a co-agonist with about a quarter of native GLP-1 potency but GIP activity virtually identical to native GIP. He covers Mounjaro's dosing, its type 2 diabetes approval, and a New England Journal of Medicine study suggesting better weight loss than semaglutide, with off-label use for obesity in the meantime.
- •Tirzepatide acts on both GIP and GLP-1
- •About a quarter as potent as native GLP-1 but equivalent to native GIP
- •Mounjaro pens range from 2.5 mg up to 15 mg
- •Not yet FDA approved for obesity, so use is off-label and typically paid out of pocket
- •A NEJM study showed it was better than semaglutide for weight loss
- 22:55 – 27:08
Oral options and comparing effectiveness, then sneak peek wrap-up
A host asks whether these drugs could ever be taken as pills, and Peter says an oral semaglutide exists for type 2 diabetes and is also expensive. The host then raises how semaglutide and tirzepatide compare on weight loss and HbA1c, and the sneak peek ends with a membership message.
- •An oral semaglutide exists for type 2 diabetes
- •It may suit people who dislike needles or refrigeration
- •The host asks how the two drugs compare on weight loss and HbA1c
- •The full AMA is available to members
