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Peter Attia MDMetabolic health & pharmacologic interventions: SGLT-2 inhibitors, metformin (AMA 53 sneak peek)
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CHAPTERS
- 0:02 – 3:06
Toothpicks and the Plan for the AMA
The host and Peter Attia open with banter about toothpicks. The host then lays out the AMA: a follow-up to AMA 51 on metabolic disease, covering pharmacologic options (SGLT2 inhibitors, metformin, GLP-1) and then statins and insulin resistance.
- •Banter about Peter's toothpick habit
- •Follow-up to AMA 51 on metabolic disease, one of the four horsemen
- •Part one covers SGLT2 inhibitors, metformin, GLP-1 and others
- •Possible geroprotective benefits will be discussed
- •Part two covers statins and insulin resistance
- 3:06 – 9:15
How SGLT2 Inhibitors Work in the Kidney
Peter explains the SGLT2 acronym and uses the nephron and a dresser-cleaning analogy to describe how the kidney filters everything and then reabsorbs what it needs. Blocking SGLT2 keeps glucose and sodium in the urine, which lowers blood glucose in type 2 diabetes.
- •SGLT2 stands for sodium glucose co-transporter protein two
- •The kidney filters everything out and pulls back what it wants to keep
- •SGLT2 pulls sodium and glucose back into the cell together
- •Blocking it makes people excrete more glucose and sodium
- •Compared with metformin (glucose lowering) and GLP-1 (insulin sensitizing, eating less)
- 9:15 – 15:04
From Phlorizin in Apples to Modern Gliflozins
Peter describes how SGLT2 inhibitors derive from phlorizin, a compound found in apples that caused glucose in the urine. He compares it with modern drugs and with other naturally derived drugs such as metformin, statins and rapamycin, and jokes about Osler tasting urine.
- •Phlorizin was isolated in the 17th century from apples
- •It induced glucose in urine in non-diabetic people, pointing to the pathway
- •Four SGLT2 inhibitors exist, all ending in "-flozin"
- •Structural differences affect dosing and potency
- •Metformin, statins and rapamycin are also naturally derived
- 15:04 – 19:13
Comparing Canagliflozin and the Other SGLT2 Inhibitors
Peter goes through canagliflozin, the one with the most data, including its dose-dependent A1c reductions alone and with metformin. He compares it with metformin on A1c and weight loss, notes blood pressure effects, and names the other three approved drugs.
- •Canagliflozin was approved in 2013 and lowers A1c by about 0.7 to 1% in absolute terms
- •With metformin the average A1c reduction was 1.8%
- •Metformin monotherapy gives up to 1.3% reduction and probably slightly more weight loss
- •Blood pressure drops, possibly from sodium loss
- •Dapagliflozin, empagliflozin and ertugliflozin were approved between 2013/2014 and 2017
- 19:13 – 20:36
Why Drug Names Are So Hard to Pronounce
In response to a question from the host, Peter explains that complicated generic names are deliberate. The generic name is free for anyone to use, so companies want people to remember the brand name instead.
- •Generic names are free to use once a drug is off patent
- •Brand names such as Jardiance, Crestor and Lipitor are easier to remember
- •Companies want doctors and patients to associate the brand name with the drug
- 20:36 – 23:32
Cardiovascular Benefits Beyond Glycemic Control
Peter says scientists are especially excited about SGLT2 inhibitors compared with metformin, citing the ITP and clinical trial data. SGLT2 inhibitors improve outcomes in heart failure patients even without type 2 diabetes, possibly through blood pressure reduction.
- •The public is more interested in metformin, but scientists see more promise in SGLT2 inhibitors
- •The ITP found a clear difference between them
- •They reduce hospitalization and death in heart failure with reduced ejection fraction
- •They improve outcomes in heart failure with preserved EF
- •Benefits appear even in people without type 2 diabetes
- 23:32 – 27:07
Question on SGLT2 Inhibitors as Geroprotective Molecules
The host asks what is known about SGLT2 inhibitors as potential geroprotective molecules, noting that many questions come from people interested in longevity rather than diabetes. The sneak peek then ends with a membership pitch.
- •Questions come from people interested in geroprotection, not just diabetics
- •Same pattern of interest as with metformin
- •The full answer is in the premium version of the AMA
