A claim you hear on longevity podcasts

Does metformin lower disease risk in type 2 diabetes?

The claim checked: Among people with type 2 diabetes, metformin lowers the risk of cancer, heart disease and frailty Hear it at 27:51

What do the studies say?

Not enough evidence

The one study, from Danish registries, found people starting metformin for type 2 diabetes did not match the survival of people without diabetes.

Computed from 1 study that test this point, each judged by two readers, in full. Fewer than 3 sources so far. 3 more studies are waiting for a full read and do not count yet.

What was said on the podcast?

“Type 2 diabetics that go on metformin, on average, live longer than people that don't have Type 2 diabetes. And they're protected against diseases. So if you're susceptible to cancer, or heart disease, frailty, those on metformin reduce their risk of those diseases”

David Sinclair, Lifespan · The Science Behind Why We Age | Lifespan with Dr. David Sinclair #1 · 27:51 on YouTube
Comes up in 7 episodes of the show.

Point 1 of 2 Not enough evidence

People with type 2 diabetes on metformin live longer than people without type 2 diabetes (retrospective, adjusted)

Agree 0

None.

Partly agree 0

None.

Disagree 1

other primary study · 2022

“Treatment initiation by metformin monotherapy in Type 2 diabetes was not associated with survival equal or superior to that of the general population without diabetes.”

Reassessing the evidence of a survival advantage in Type 2 diabetes treated with metformin compared with controls without diabetes: a retrospective cohort study. Int J Epidemiol
Who: Danish adults from national health registers: a 5% random sample of singletons and the Danish Twin Registry; incident type 2 diabetes initiated on metformin monotherapy vs matched people (or co-twins) without diabetes
PMID 36287641

Point 2 of 2 Mixed

In retrospective studies metformin lowers the risk of cancer, heart disease, Alzheimer's and frailty

One study, in older male veterans, found metformin slowed age-related disease; four found no lower risk of cancer, dementia or frailty. Five were mixed, and one of those, a large review, called the observational data largely unreliable.

Computed from 10 studies that test this point, each judged by two readers, in full. 5 more studies are waiting for a full read and do not count yet.

Agree 1

other primary study · 2017

“Metformin slowed ARC development in old men with T2D, and these effects varied by ARC phenotype.”

Differential effects of metformin on age related comorbidities in older men with type 2 diabetes. J Diabetes Complications
Who: Male US veterans aged >=65 with type 2 diabetes and free of age-related comorbidities in 2002-2003
PMID 28190681

Partly agree 5

systematic review · 2021

“Observational evidence on metformin seems largely unreliable.”

Metformin and health outcomes: An umbrella review of systematic reviews with meta-analyses. Eur J Clin Invest
Who: Meta-analyses of observational studies and RCTs of metformin in any population (mostly diabetic, cancer, PCOS, obese)
PMID 33709434

other primary study · 2010 · landmark

“In this observational study in a population of women with type 2 diabetes, we found a decreased risk of breast cancer in women who used metformin for several years, whereas no such effect was seen for short-term use.”

Long-term metformin use is associated with decreased risk of breast cancer. Diabetes Care
Who: Women aged 30-79 with type 2 diabetes using oral antidiabetes drugs in the UK General Practice Research Database (1994-2005)
PMID 20299480

pooled analysis · 2024 · landmark

“Metformin may be associated with a decreased risk of many cancer types, but high heterogeneity and risk of publication bias limit confidence in these results.”

Association of metformin use and cancer incidence: a systematic review and meta-analysis. J Natl Cancer Inst
Who: observational studies (mostly in people with type 2 diabetes) comparing metformin users with nonusers for cancer incidence
PMID 38291943

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other primary study · 2024 · landmark

“Furthermore, among the subgroup of subjects who developed frailty, those who received metformin exhibited a significant decrease in frailty levels (p<0.0001).”

Prediabetes Increases the Risk of Frailty in Prefrail Older Adults With Hypertension: Beneficial Effects of Metformin. Hypertension
Who: pre-frail hypertensive adults aged >65 with MoCA <26 in Avellino, Southern Italy; metformin subgroup = those with prediabetes who became frail
PMID 38752357

pooled analysis · 2024 · landmark

“Metformin, thiazolidinediones, pioglitazone, GLP1RAs and SGLT2is were associated with significant reduction in risk of dementia.”

Diabetes, antidiabetic medications and risk of dementia: A systematic umbrella review and meta-analysis. Diabetes Obes Metab
Who: Individuals with diabetes (cohort/case-control studies from 7 countries), mean/median age 58.3-80.6 years; plus 100 systematic reviews in the umbrella review
PMID 37869901

Disagree 4

pooled analysis · 2020

“The pooled adjusted OR for PD was 1.66 (95% CI 1.14 to 2.42); that for AD was 0.9 (95% CI 0.47 to 1.73); and that for dementia was 0.96 (95% CI 0.85 to 1.09) ( figure 4 ).”

Association between metformin and neurodegenerative diseases of observational studies: systematic review and meta-analysis. BMJ Open Diabetes Res Care
Who: Observational studies (13 cohorts, 3 cross-sectional, 3 case-control) of mostly people with diabetes/hyperglycaemia exposed vs not exposed to metformin
PMID 32719079

controlled trial · 2021

“Among DPPOS participants who completed frailty assessments in Years 8 and 10, approximately 12–14 years after DPP randomization, there was no difference in the odds of frailty between the metformin and placebo arms.”

Association of Intensive Lifestyle and Metformin Interventions With Frailty in the Diabetes Prevention Program Outcomes Study. J Gerontol A Biol Sci Med Sci
Who: DPP/DPPOS participants at high risk of diabetes (age >=25, impaired glucose, BMI >=24), mean age 63 at frailty assessment
PMID 33428709

pooled analysis · 2017

“The studies least likely to be affected by bias did not support a causal effect of metformin on cancer risk.”

Metformin and cancer in type 2 diabetes: a systematic review and comprehensive bias evaluation. Int J Epidemiol
Who: observational (case-control and cohort) studies of people with type 2 diabetes comparing metformin users with non-users or users of other diabetes drugs, outcome overall or site-specific cancer
PMID 28031313

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other primary study · 2013

“In our population-based study, use of metformin was not associated with an altered risk of esophageal cancer.”

Case-control analysis on metformin and cancer of the esophagus. Cancer Causes Control
Who: UK GPRD patients aged 40-89 years with incident esophageal cancer 1994-2010, and matched controls (age, sex, calendar time, practice, years of history); predominantly Caucasian
PMID 23820930

What else was said but not tested?

Whether this holds without diabetes is unknown; TAME is testing it

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