Should I take metformin?

Metformin, a molecule derived from a French lily, is noted for its mechanism of AMPK activation, which can reduce hepatic glucose output and potentially benefit fatty liver.

While it shows consistent benefits in diabetics and can be prescribed for standard indications and other benefits, its efficacy for extending human lifespan in non-diabetics is not yet convincingly established.

Lifestyle, especially diet, is considered a more powerful factor for health optimization than molecules like metformin, and concerns exist regarding its side effects and potential to abrogate exercise benefits.

Andrew Huberman suggests that supplements, metformin, and GLP-1 agonists can be taken concurrently, but GLP-1s should be introduced separately from metformin to manage potential nausea. Peter Attia notes that gastrointestinal side effects are often manageable with a slow ramp-up.

• 01Rhonda Patrick states that Metformin and berberine share a common mechanism of AMPK activation.
• 02Peter Attia claims that Metformin shows consistent benefits in diabetics compared to non-diabetics of the same age and sex in observational studies.
• 03Peter Attia notes that Metformin's activation of AMPK can lead to the shutdown of glucose production and lipogenesis in the liver, potentially benefiting fatty liver.
• 04Paul Saladino states that many plant molecules have medicinal value, including metformin from a French lily, digitalis, and aspirin from willow bark.
• 05Andrew Huberman claims that supplements, metformin, and GLP-1 agonists can be taken concurrently, but GLP-1s should be introduced separately from metformin to manage potential nausea.
• 06Peter Attia prescribes metformin for standard indications and for other benefits to patients paying out-of-pocket.
• 07Peter Attia states that patients experiencing unmanageable hyperglycemia with metformin were required to discontinue PI3 kinase inhibitor trials.
• 08Paul Saladino claims that achieving insulin-resistant adipocytes through diet or metformin is key to metabolic health, but not with thiazolidinediones.
• 09David Sinclair states that NAD levels decrease in the brain with age due to reduced production by NAMPT and increased degradation by SARM1.
• 10Paul Saladino claims that lifestyle, particularly food choices, is the most significant factor for health optimization, and changing diet is more powerful than using molecules like metformin, resveratrol, or sulforaphane.
• 11David Sinclair states that Metformin, rapamycin, resveratrol, fisetin, quercetin, NMN, and NR are molecules that artificially activate adversity defenses or mimic biological states like low energy and sirtuin activation.
• 12Peter Attia claims that Metformin is a drug that effectively reduces hepatic glucose output and has no myotoxicity, though it can cause gastrointestinal side effects that are often manageable with a slow ramp-up.
• 13David Sinclair states that after one year of treatment in the TRIIM Trial, the Horvath epigenetic clock calculated an average reduction of 2.5 years in blood biomarkers' biological age.
• 14Peter Attia claims that treatment with exenatide and pioglitazone led to a reduction in A1C from 12.2 to 6.1 over three years in a subgroup of symptomatic patients.

David Sinclair states that Metformin can cause metabolic issues and can prevent muscle gain. Peter Attia, Andrew Huberman, and Paul Saladino collectively claim that evidence for metformin extending human lifespan is not convincing, and research is shifting towards rapamycin. Rhonda Patrick states that Metformin abrogates the beneficial effects of daily exercise and inhibits mitochondrial adaptations and improvements in cardiorespiratory fitness after aerobic exercise training in older adults. Paul Saladino claims that Metformin has significant side effects like lowering B12 and does not treat the root cause of diabetes, and that long-term studies on metformin have not demonstrated expected benefits in reducing risks of cancer, diabetes, or cardiovascular disease. Peter Attia and Andrew Huberman note that Metformin failed in the ITP for geroprotective potential. Rhonda Patrick states that Valter Longo would not take metformin due to concerns about blocking central cellular metabolism pathways. Peter Attia claims that the TAME trial will not assess exercise function or cardiorespiratory fitness and that Metformin should not be administered to patients upon arrival at the hospital for COVID-19 treatment due to risk of lactic acidosis. Paul Saladino and David Sinclair state that Metformin carries risks including fatal lactic acidosis, upset stomach, and lack of hunger. Andrew Huberman notes that observational studies may be limited by a lack of matching for medication use between groups. Paul Saladino claims that a pre-diabetic woman with a high grain intake and frequent oil use may have high fasting insulin and be inappropriately prescribed metformin.

The verdict would change if clear dose equivalence between metformin and rapamycin/rapalogs for mTOR inhibition were established, or if the optimal timing for starting geroprotective interventions like senolytics or metformin became certain. Further, if metformin's precise impact on muscle and mitochondrial function were fully known, or if its safety and efficacy for longevity in non-diabetic individuals were definitively established through studies like TAME, the assessment would shift. Additionally, if it were known whether TRIIM Trial treatments reset the entire body's aging clock, or if metformin's potential benefit in non-diabetics clearly outweighed its downside as a weak mitochondrial toxin, the verdict could be altered. Finally, a better understanding of metformin's impact on the microbiome and its potential endocrine-disrupting effects would also influence the assessment.