Happy Tuesday!
Before getting into today’s email, I want to first start by saying THANK YOU!
We recently crossed 100,000 readers of these emails. It wasn’t too long ago that I was ecstatic to see 200 people open my emails. All the more thanks to you for being a supporter!
To celebrate, I'm running a giveaway starting today. There will be six winners, totaling $3,000 in prizes.
Here's what's on the table:
2 winners get $500 gift cards to BioStack Labs, my go-to for clean longevity supplements
2 winners get $500 gift cards to Vanguard Labs, for any bloodwork panel you want to run (through Quest Diagnostics)
2 winners get $500 gift cards to Blushield USA, to grab one of their EMF protection devices
You can enter the giveaway by clicking this link.
Now, back to today’s message on metformin.
The longevity community keeps telling you metformin is dead.
In my opinion, they're wrong based on data that keeps pouring in.
Metformin has been in the longevity crosshairs for a few years now. GLP-1s have stolen the spotlight (and rightfully so in my opinion).
The "metformin blunts exercise" headlines make everyone nervous.
Nonetheless, I keep taking my 500mg a day.
Why? Because the data keeps stacking in its favor.
Every few months, another paper drops showing metformin does something useful.
Lower dementia risk. Lower cancer incidence. Longer lifespan in primates. Reduced cardiovascular mortality.
Today, I want to walk you through the last year of research around metformin.
Then I want to explain why I think metformin still earns a spot in a longevity stack in 2026, even in an era of SGLT2s and GLP-1s.
Let's get into it.
New Data Points
Let’s take a look at what has emerged over the last 1-2 years.
Lifespan and aging clocks. A 2024 primate study showed deceleration across DNA methylation, transcriptome, and proteome markers. Multiple yeast and mouse studies this year reinforced the mechanism through chromatin regulation, retrotransposon dynamics, and mitochondrial stress response.
Cardiovascular mortality. A 2024 meta-analysis of 33 studies and 58,271 patients showed metformin use was associated with a 10% reduction in all-cause mortality and an 11% reduction in cardiovascular mortality in patients with pre-existing cardiovascular disease. A 2025 PLoS One meta-analysis of over 300,000 patients showed a 16% reduction in all-cause mortality and 12% reduction in cardiovascular events when metformin was combined with SGLT2 inhibitors or GLP-1 receptor agonists.
Dementia and Alzheimer's. The Zheng et al. UK cohort of 210,237 participants in 2025 showed longer metformin use correlated with greater dementia risk reduction. The Taiwan 2025 cohort showed a 53% reduction in dementia risk. An August 2025 Alzheimer's & Dementia paper found that metformin combined with DPP-4 inhibitors showed the lowest cumulative dementia risk at 15 years compared to other oral combination therapies.
Cancer. A 2025 Medicina meta-analysis synthesized observational and RCT data through October 2024. Metformin showed protective associations across multiple cancer types, particularly breast, prostate, colorectal, and pancreatic. A December 2025 meta-analysis in Cancer Treatment and Research Communications showed metformin reduced all-cause and cancer-specific mortality in colorectal cancer patients.
Exceptional longevity. The Women's Health Initiative target trial emulation showed 30% higher odds of reaching age 90 on metformin versus sulfonylurea.
Mechanism. A Mendelian randomization study using UK Biobank data showed metformin's effects on PhenoAge are genetically linked to GPD1 and AMPKγ2 targets. This suggests the geroprotective effects extend beyond glycemic lowering alone.
But What About…?
There are five main criticisms I see across metformin. Let’s break them down honestly.
1. Metformin blunts exercise adaptations.
This is the most-cited concern in the longevity space. And it's real, with caveats.
The Konopka lab at UW-Madison published a 2018 study showing that metformin attenuated the increase in VO2max after 12 weeks of aerobic exercise in older adults.
A 2025 follow-up in the Journal of Applied Physiology using mice confirmed that metformin suppresses skeletal muscle mitochondrial respiration and transcriptional adaptations to aerobic exercise.
A November 2025 Rutgers study in the Journal of Clinical Endocrinology and Metabolism showed that metformin blunted gains in vascular insulin sensitivity after 16 weeks of exercise training in adults at risk for metabolic syndrome.
HOWEVER, these studies used 1500 to 2000 mg daily.
The older studies showed high individual variability in response. Some people had normal adaptations on metformin. Some had reduced adaptations. The effect size is population-level, not individual.
At 500 mg, the evidence for blunted adaptations is much thinner. The dose-response relationship on mitochondrial complex I inhibition is not linear, and lower doses appear to provide most of the AMPK activation benefit with far less mitochondrial suppression.
I take 500 mg. I train hard. My performance markers keep improving. For me, it’s anecdotal, but it aligns with the dose-response literature.
2. The DPPOS data didn't show a mortality benefit.
The long-term follow-up of the Diabetes Prevention Program Outcomes Study found no significant difference in cardiovascular or all-cause mortality between the metformin and placebo groups after 19 to 21 years.
This is often cited as proof that metformin doesn't work.
The reality is messier. Out-of-study metformin use was high in the placebo arm because participants developed diabetes and got prescribed metformin. Adherence dropped in the original metformin arm over time. The lifestyle intervention arm also diluted the signal. And DPPOS enrolled prediabetic adults, not the general population.
3. B12 deficiency.
Long-term metformin use increases the risk of B12 deficiency. The 2025 All of Us Research Program study of 14,808 adults showed long-term users had a 67% higher likelihood of B12 deficiency than non-users.
A 2025 cross-sectional study found that the average duration of metformin use leading to B12 deficiency was 13.6 years.
This is a real concern, but the solution is easy. Take methylcobalamin. Test B12 annually. The 2025 ADA guidelines now formally recommend B12 screening for patients on doses above 1500 mg or with a duration of more than 4 years.
At 500 mg, the risk is lower, but I still supplement.
4. GI side effects.
About 20-30% of people experience GI distress with metformin. Nausea, diarrhea, cramping.
The solution? Start low. Use the extended-release formulation. Titrate slowly. Take with food. Most people adjust within two weeks.
If you don't adjust, it's not the drug for you.
5. Lactic acidosis.
Real but rare. Risk is concentrated in patients with significant kidney disease, heart failure, or alcohol use disorder. In healthy adults at prophylactic doses, the risk is negligible.
Why SGLT2s Might Make Metformin Obsolete
SGLT2 inhibitors are better than metformin at almost everything metformin claims to do.
The SGLT2 class extends median lifespan in male mice by 14% in the NIA Interventions Testing Program. Metformin's ITP results were weaker and inconsistent.
A meta-analysis of 21 randomized trials and over 70,000 patients showed SGLT2 inhibitors reduce all-cause mortality by 14% compared to comparators. A Taiwan observational study of 140,000 patients showed SGLT2 users had a 60% lower mortality risk versus DPP-4 users.
SGLT2s reduce heart failure hospitalization, chronic kidney disease progression, atrial fibrillation, non-alcoholic fatty liver disease, gout, atherosclerotic cardiovascular disease, and cancer mortality.
Dr. Nir Barzilai, the architect of the TAME trial and metformin's most prominent scientific advocate, co-authored a 2024 paper ranking SGLT2 inhibitors as the top gerotherapeutic class on the market.
SGLT2 inhibition triggers a mild fasting-mimetic state. Glucose gets excreted in urine. Ketones rise. AMPK activates. Autophagy increases. Inflammation decreases. Senescent cell burden drops. The drug basically tricks the body into thinking it's practicing mild caloric restriction.
A 2024 two-stage meta-analysis in Advances in Therapy showed that metformin outperformed SGLT2 inhibitors on all-cause mortality by a small margin.
But for most longevity-focused users, SGLT2s probably do more.
They hit more pathways. They have stronger outcome data. They don't blunt exercise to the same degree.
Could SGLT2s make metformin obsolete? Possibly, over the next decade. I wouldn't be shocked at all.
The Metformin + GLP-1 + SGLT2 Stack
The three drugs hit different pathways.
Metformin activates AMPK through mitochondrial complex I inhibition and improves hepatic insulin sensitivity.
GLP-1 receptor agonists improve glucose-dependent insulin secretion, reduce appetite, decrease inflammation, and provide cardiovascular protection independent of weight loss.
SGLT2 inhibitors excrete glucose in urine, induce mild ketosis, and improve renal and cardiac function.
All these pathways complement each other.
A 2024 systematic review in Cardiovascular Diabetology examined outcomes of triple therapy.
Patients on SGLT2 inhibitors plus GLP-1 receptor agonists plus metformin had the lowest risk of major adverse cardiovascular events, all-cause mortality, and severe hypoglycemia compared to any dual combination.
A December 2025 meta-analysis in Diabetologia of 18 cohort studies and 1,164,774 participants compared SGLT2 inhibitor plus GLP-1 receptor agonist combination therapy to monotherapy with either drug.
The combination was associated with a 50% lower risk of all-cause mortality, a 74% lower risk of cardiovascular mortality, a 44% reduction in major adverse cardiovascular events, and a 33% reduction in heart failure hospitalizations.
The CARDIAB cohort study of 138,397 patients with type 2 diabetes and atherosclerotic cardiovascular disease showed that patients on both SGLT2 inhibitors and GLP-1 receptor agonists had an 83% lower all-cause mortality risk compared to patients on neither.
Adding metformin as background therapy further sharpens the effect.
A July 2025 Circulation actuarial analysis estimated that combination therapy with SGLT2 inhibitors, GLP-1 receptor agonists, and background metformin in patients with type 2 diabetes and albuminuria resulted in a 33% reduction in all-cause mortality and a 36% reduction in cardiovascular mortality.
At age 50, this translated to an estimated 2.7 additional years of event-free survival.
These are population-level effects in patients with diabetes.
The data for non-diabetic longevity users is much thinner, but the mechanistic case is strong.
Final Thoughts
At 500 mg daily, metformin is cheap, safe, well-studied, and adds a complementary mechanism to my stack.
It's no longer the strongest anti-aging drug on the market. SGLT2s probably are.
But I don't have to pick one drug. I can run metformin alongside other interventions and get the compounding benefit.
The exercise-blunting concern is real at higher doses and in some individuals. At 500 mg, with the dose-response literature, and with my own training markers holding steady, I'm comfortable.
The B12 concern can be addressed with a sublingual supplement and annual testing.
The primate aging data, the exceptional longevity signal in women, the dementia risk reduction, the cancer signal, and the mortality reduction in combination therapy all argue for keeping metformin in the stack.
If I had to pick one drug for longevity and I was diabetic, I'd pick an SGLT2.
If I had to pick one drug and I wasn't diabetic, I'd still pick an SGLT2 off-label.
But I don't have to pick one. And neither do you.
For me, metformin earns its 500 mg a day.
Best,
Hunter Williams
Further Reading
I made a webpage to include all the updated studies. You can visit by clicking here.