Happy Friday!
We are going to take a detour from peptide land today in the name of longevity.
A new paper just landed in The Journal of Clinical Endocrinology & Metabolism that confirms something I have had a hunch about for the last two years.
A team from Juntendo University in Tokyo asked why SGLT2 inhibitors produce benefits far greater than their glucose-lowering effects can explain.
So what's actually happening underneath the hood with these drugs, and does it touch aging itself?
Read it here: https://doi.org/10.1210/clinem/dgag207
I've been running empagliflozin or dapagliflozin for two years now, and my bloodwork has improved dramatically over that stretch. I've watched it happen on paper, year over year.
Here's what they found in the paper.
Mechanisms
Your kidney filters sugar out of your blood, then a transporter grabs it and pulls it back in. SGLT2 inhibitors block that transporter.
Now the sugar leaves. As a result, you pee out 50 to 100 grams of glucose a day.
Your body notices the missing fuel and adapts like you're fasting.
It shifts toward burning fat and making ketones.
Ketones are your backup fuel, and one of them, beta-hydroxybutyrate, does a second job as a signal. It calms inflammation and tells your mitochondria to clean house.
So you get a fasting-like state while eating normally.
AMPK and SIRT1 go UP. Those are your energy and repair sensors.
Metformin raises AMPK.
Rapamycin suppresses mTOR.
SGLT2 inhibitors kill both these birds with one stone.
But even beyond that, the part of this article that made me sit up is the work on senescence.
Senescent cells are damaged cells that won't die.
They sit in your tissue leaking inflammatory garbage that ages everything around them.
Clearing them out is the hottest trend in longevity right now.
Senescent cells, aka zombie cells, hide by wearing a molecule called PD-L1.
Essentially it’s a "don't eat me" flag.
Cancer cells run the same con, which is why PD-L1 is a multibillion-dollar oncology target.
SGLT2 inhibition raises AMPK. AMPK tears that flag down.
Your T cells and NK cells suddenly see the zombies and clear them out.
The drug pulls the mask off, and your immune system does the work.
In mice, canagliflozin cleared senescent cells from visceral fat within 1 week.
The researchers tried to reproduce that with ketones alone.
It didn't work.
Insulin didn't work.
Fixing their diet didn't work either.
Which means you cannot get this effect from fasting or keto.
It's a separate lever, and until this work nobody knew it existed.
The human outcome data backs the whole picture.
Around 14% fewer major cardiac events.
A third fewer heart failure hospitalizations.
Kidney outcomes improved 28% to 39%.
Liver fat down 10% to 30%.
Lower dementia risk in observational data. And it all works in people without diabetes.
Those percentages are disease endpoints in sick people, not lifespan numbers.
The lifespan extension data is in mice.
A trial measuring biological age using an epigenetic clock is underway right now, and hopefully that gives us even more insight.
But AMPK doesn't care whether you're sick.
Senescent cells accumulate in everyone starting in your thirties. That machinery is running in all of us.
Stacking for the Win
Here's where I'll get ahead of the data and tell you what I think.
If you're already on a GLP-1 and an SGLT2, you may be sitting on the most powerful longevity combination available right now.
The two classes work through totally different machinery.
SGLT2 inhibitors mostly cut heart failure and kidney events.
GLP-1s mostly cut strokes and heart attacks.
So what happens when people run both?
A 2025 systematic review and meta-analysis in Diabetologia pooled the data. Combination versus monotherapy came out to a 50% lower relative risk of all-cause mortality and a 74% lower relative risk of cardiovascular death.
That's observational cohort data, and the authors themselves rate the certainty as low. It's in people with type 2 diabetes.
But we have two drug classes with different mechanisms, both hitting AMPK and inflammation and senescence from different angles, with the best mortality signal in the business.
Affordability
For the last two years, it has been quite pricey to get SGLT2s from your doctor, and many people have resorted to sourcing their stash from online pharmacies from India.
But, in February, that all changed.
Generic dapagliflozin went up on TrumpRx.gov starting at $8 a month. Get your doctor to write you a script, print a coupon, and hand it to your pharmacist.
This is currently how I get mine.
Empagliflozin has no generic yet and won't until 2027 or so, and the brand name, Farxiga, on the same site starts at $35.
If you have insurance, check your copay first, because it might already beat both.
Ten years ago, a longevity protocol meant supplements with zero outcome data and a lot of hope.
Now we have a drug with randomized human endpoints, twelve years of safety surveillance, millions of people already on it, and a mechanism reaching into core aging biology that costs eight bucks per month.
Final Thoughts
For years, many people in this space have argued about metformin dosing and rapamycin protocols (honestly I’m so over the metformin debate at this point, I gave up a long time ago trying to convince people to take it LOL).
Meanwhile, a drug class with better human outcome data than either one has been sitting in the diabetes aisle getting ignored, because it came with the wrong label on the box.
Is the case closed yet? I would say no.
But I am saying that SGLT2 inhibitors deserve a seat at the table for the conversation of longevity.
Two years in, I plan to continue leaning on reta/tirz + dapagliflozin or empagliflozin to extend healthspan.
And of course, I will continue using those right alongside the tried-and-tested BHRT.
Have a fantastic weekend and thank you for supporting my work!
Best,
Hunter Williams
Further Reading
Katsuumi G, Minamino T. Dissecting out the unexpected effects of SGLT2 inhibitors on human aging. J Clin Endocrinol Metab. 2026;111(8):2154-2165. https://doi.org/10.1210/clinem/dgag207
Effectiveness and safety of combining SGLT2 inhibitors and GLP-1 receptor agonists in type 2 diabetes: a systematic review and meta-analysis of cohort studies. Diabetologia. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12686040/