Meta Information
ID:metformin
Name:Metformin
Schema Version:2.4_uniform_evidence_2026_06_18
Created
2026-05-21T22:30:00Z
Model
phase-a-upgrade-claude-sonnet-4.6
Interactions
Target id:
/condition/renal-impairment
Target name:
Renal Impairment
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Impaired kidney function prevents the proper elimination of metformin, leading to its accumulation and a significantly increased risk of life-threatening lactic acidosis.
Actionable advice:
This should not be used when eGFR is below 30 mL/min/1.73m2; caution and reduced dosage apply for eGFR between 30-45.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Severe renal impairment (eGFR below 30 mL/min/1.73 m 2 )
Label source:
fda_label
Action type:
avoid
Target id:
/procedure/iodinated-contrast-media
Target name:
Iodinated Contrast Media (for CT/Angiogram)
Severity:
major
Interaction type:
adverse
Nature:
temporal
Temporal spacing:
Hours before target:
48
Hours after target:
48
Description:
Iodinated contrast agents used for imaging studies can cause temporary kidney damage, which in combination with metformin can lead to lactic acidosis.
Actionable advice:
Metformin should be stopped at least 48 hours before the procedure and not restarted for 48 hours after, pending stable kidney function.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
having a radiological study with contrast
Label source:
fda_label
Action type:
separate
Target id:
/dietary/alcohol-acute
Target name:
Alcohol (Acute Consumption)
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Alcohol potentiates metformin's effect on lactate metabolism and can significantly increase the risk of life-threatening lactic acidosis, especially with heavy consumption.
Actionable advice:
Binge drinking and chronic heavy alcohol consumption should be avoided while taking metformin.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Alcohol is known to potentiate the effect of metformin on lactate metabolism.
Label source:
fda_label
Action type:
avoid
Target id:
/condition/metabolic-acidosis
Target name:
Metabolic Acidosis
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Metformin is contraindicated in patients with acute or chronic metabolic acidosis, including diabetic ketoacidosis, as it can worsen the condition.
Actionable advice:
This should be strictly avoided in any state of metabolic acidosis.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.
Label source:
fda_label
Action type:
avoid
Target id:
/condition/hepatic-impairment
Target name:
Severe Hepatic Impairment
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
The liver is the primary site for clearing lactate from the blood; severe liver disease impairs this process, dramatically increasing the risk of metformin-associated lactic acidosis.
Actionable advice:
Metformin should not be used in patients with clinical or laboratory evidence of severe hepatic impairment.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
hepatic impairment
Label source:
fda_label
Action type:
avoid
Target id:
/condition/heart-failure
Target name:
Acute or Unstable Heart Failure
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
In acute or unstable heart failure, poor tissue perfusion and oxygenation increase the risk of lactic acidosis with metformin use.
Actionable advice:
Metformin should not be used in patients with acute, decompensated, or unstable congestive heart failure.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
hypoxic states (e.g., acute congestive heart failure)
Label source:
fda_label
Action type:
avoid
Target id:
/procedure/surgery-anesthesia
Target name:
Surgery with General Anesthesia
Severity:
major
Interaction type:
adverse
Nature:
temporal
Temporal spacing:
Hours before target:
48
Hours after target:
48
Description:
The physiological stress of surgery and anesthesia can affect fluid balance and kidney function, increasing the risk of lactic acidosis.
Actionable advice:
Temporarily discontinue metformin before any surgical procedure and restart only after oral intake and renal function have normalized.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
surgery and other procedures
Label source:
fda_label
Action type:
avoid
Target id:
/dietary/meal
Target name:
Any Caloric Meal (Gi Tolerability)
Severity:
major
Interaction type:
requirement
Nature:
temporal
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Taking metformin with a meal significantly reduces gastrointestinal side effects like nausea, diarrhea, and stomach upset by slowing its absorption.
Actionable advice:
Metformin should be taken with a meal to improve tolerability.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
with meals
Label source:
fda_label
Action type:
informational_none
Target id:
/class/carbonic-anhydrase-inhibitors
Target name:
Carbonic Anhydrase Inhibitors (e.g., Topiramate)
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
These drugs can decrease serum bicarbonate and cause metabolic acidosis, significantly increasing the risk of metformin-associated lactic acidosis.
Actionable advice:
Concomitant use should be avoided if possible; acid-base balance should be monitored closely if use is necessary.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Carbonic anhydrase inhibitors may increase risk of lactic acidosis.
Label source:
fda_label
Action type:
avoid
Target id:
/biomarker/vitamin-b12
Target name:
Vitamin B12
Severity:
moderate
Interaction type:
diminishing
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Long-term metformin use interferes with the calcium-dependent absorption of the vitamin B12-intrinsic factor complex in the small intestine, leading to deficiency.
Actionable advice:
Vitamin B12 levels are best monitored annually, and supplementation is a good idea if levels are low or borderline.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Metformin may lower vitamin B 12 levels.
Label source:
fda_label
Action type:
monitor
Target id:
/intervention/resistance-training
Target name:
Resistance Training
Severity:
moderate
Interaction type:
diminishing
Nature:
temporal
Temporal spacing:
Hours before target:
12
Hours after target:
12
Description:
Metformin activates AMPK, which can interfere with the mTOR pathway crucial for muscle protein synthesis and hypertrophy stimulated by resistance exercise.
Actionable advice:
To maximize muscle gains, consider skipping your metformin dose on days you perform resistance training or separate the dose by 12+ hours.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
metformin can blunt resistance exercise-induced muscle hypertrophy and protein synthesis, likely through sustained activation of AMP-activated protein kinase (AMPK) and consequent suppression of mammalian target of rapamycin complex 1 (mTORC1) signaling.
Label source:
Han et al. 2026, PMID 41751275. Directly supports AMPK->mTORC1-suppression blunting of hypertrophy.
Action type:
separate
Target id:
/class/cationic-drugs-renal-secretion
Target name:
Cationic Drugs (e.g., Amiloride, Digoxin, Morphine)
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
These drugs compete with metformin for elimination by the kidneys, which can lead to dangerously high metformin levels in the blood.
Actionable advice:
This is best used with caution, and it is a good idea to monitor renal function closely; dose adjustments may be needed.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Drugs that reduce metformin clearance (such as ranolazine, vandetanib, dolutegravir, and cimetidine)
Label source:
fda_label
Action type:
adjust_with_prescriber
Target id:
/class/diuretics
Target name:
Diuretics (Water Pills)
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Diuretics can reduce kidney function by causing dehydration, which impairs metformin clearance and increases the risk of lactic acidosis.
Actionable advice:
Kidney function should be monitored regularly, and adequate hydration is important when taking diuretics with metformin.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Thiazides and other diuretics
Label source:
fda_label
Action type:
monitor
Target id:
/class/nsaids
Target name:
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Regular use of NSAIDs can decrease kidney function, which reduces metformin clearance and increases the risk of accumulation and lactic acidosis.
Actionable advice:
NSAID use is best limited, and kidney function is best monitored if long-term use is necessary.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Exact phrase from label:
These data indicate a dose-dependent decline in eGFR and underscores the need to conservatively dose or avoid NSAIDs in patients who are high risk to prevent a more rapid decline in eGFR.
Label source:
fda_label_inferred
Action type:
monitor
Target id:
/intervention/ketogenic-diet
Target name:
Ketogenic Diet
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
While there is concern of developing lactic ketoacidosis when taking metformin and berberine together, clinical evidence suggests that they synergize to produce better blood glucose lowering for diabetics.
Actionable advice:
Extreme caution is warranted, and it is important to talk to a physician before combining metformin with a ketogenic diet.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Exact phrase from label:
The ketogenic diet may act synergistically with metformin, as it also effectively lowers blood glucose concentrations and improves insulin sensitivity [19,277]. The first preclinical study demonstrated a possible beneficial synergy of KD and metformin with respect to anti-cancer effects, specifically in the treatment of triple-negative breast cancer (TNBC).
Label source:
natmed_pro
Action type:
informational_none
Target id:
/intervention/berberine
Target name:
Berberine
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Berberine and metformin share similar mechanisms for lowering blood sugar (AMPK activation), and taking them together can increase the risk of hypoglycemia (low blood sugar).
Actionable advice:
Berberine and metformin are best not taken together unless under strict medical supervision with frequent glucose monitoring.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Healthcare providers may consider cautioning patients about supplementing metformin pharmacotherapy with goldenseal to avoid risks for undesired changes in glycemic control. Trial Registration: ClinicalTrials.gov identifier: NCT05081583.
Label source:
natmed_pro
Action type:
avoid
Target id:
/class/hyperglycemic-agents
Target name:
Drugs that Raise Blood Sugar (e.g., Corticosteroids)
Severity:
moderate
Interaction type:
diminishing
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Certain medications like corticosteroids, thiazide diuretics, and some antipsychotics can raise blood glucose levels, making metformin less effective.
Actionable advice:
Blood glucose is best monitored closely, and the metformin dosage is best adjusted as needed when starting or stopping these medications.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Drugs Affecting Glycemic Control
Label source:
fda_label
Action type:
adjust_with_prescriber
Target id:
/intervention/zone-2-exercise
Target name:
Endurance Exercise (Zone 2)
Severity:
minor
Interaction type:
diminishing
Nature:
temporal
Temporal spacing:
Hours before target:
12
Hours after target:
12
Description:
Some evidence suggests metformin may slightly reduce the gains in cardiorespiratory fitness (VO2 max) and mitochondrial adaptations from aerobic exercise.
Actionable advice:
To maximize aerobic adaptations, consider separating your metformin dose from endurance workouts by at least 12 hours.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Compared with exercise alone, metformin was associated with smaller improvements in VO2peak (MD -1.19 [95% CI -2.33 to -0.04])
Label source:
Etayo-Urtasun et al. 2026 meta-analysis, PMID 42051241. Supports metformin attenuating aerobic-fitness (VO2peak) gains; the mitochondrial-mechanism wording is a reasonable extension.
Action type:
informational_none
Target id:
/intervention/folate
Target name:
Folate (Vitamin B9)
Severity:
minor
Interaction type:
diminishing
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Metformin may slightly reduce the absorption of folate, a B-vitamin related to B12 metabolism, potentially affecting homocysteine levels.
Actionable advice:
Adequate folate intake through diet or supplementation may help, especially if B12 levels are also low.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Metformin is associated with maternal vitamin B12 deficiency and antifolate like activity.
Label source:
natmed_pro
Action type:
informational_none
Target id:
/class/glucose-lowering-supplements
Target name:
Glucose-Lowering Supplements (e.g., Chromium, Cinnamon)
Severity:
minor
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Various supplements can also lower blood glucose, and combining them with metformin may increase the risk of hypoglycemia.
Actionable advice:
It is a good idea to check blood sugar levels carefully when adding any new glucose-lowering supplement to a regimen.
Validation status:
unvalidatable
Evidence tier:
tier_e
Evidence basis:
unvalidatable
Evidence anchors:
Source url:
Scientific literature support not found
Exact phrase from label:
Label source:
natmed_pro
Action type:
monitor
Target id:
/biomarker/egfr
Target name:
eGFR (Kidney Function)
Severity:
major
Interaction type:
requirement
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
eGFR is the critical biomarker for assessing kidney function to determine if metformin can be used safely and at what dose.
Actionable advice:
eGFR should be checked before starting metformin and at least annually thereafter to ensure continued safety.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
estimated glomerular filtration rate (eGFR)
Label source:
fda_label
Action type:
monitor
Target id:
/intervention/coenzyme-q10
Target name:
Coenzyme Q10
Severity:
minor
Interaction type:
diminishing
Nature:
absolute
Description:
Metformin's effects on mitochondrial function via AMPK activation may lead to a reduction in the body's Coenzyme Q10 levels over time.
Actionable advice:
Consider supplementing with Coenzyme Q10, especially if experiencing fatigue or muscle pain.
Validation status:
validated_via_class_inference
Evidence tier:
tier_c
Evidence basis:
class_inference_summary
Evidence anchors:
Source url:
Established mechanism / class pharmacology (no single primary source quoted)
Exact phrase from label:
Mechanistic inference: metformin can modestly lower circulating CoQ10 (statin-like and AMPK/mitochondrial effects are described), so co-supplementing CoQ10 is sometimes suggested; effect is small and not firmly established.
Label source:
Class inference
Action type:
informational_none
Temporal spacing:
Hours before target:
0
Hours after target:
0
Derived From
metformin_systemic_healthspan
Provenance Note
Interactions duplicated from 'metformin_systemic_healthspan'. Scope-suffix reconciliation.