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metformin (Glucophage)

FDA has recommended voluntary recall of certain extended-release versions of metformin May 2020 due to excessive levels of N-nitrosodimethylamine (NDMA). [52] Indications: 1) first line monotherapy for treatment of type 2 diabetes a) useful in patients with insulin resistance b) unlikely to be useful as monotherapy when patient has failed therapy with sulfonylurea 2) treatment of non-insulin-dependent diabetes in combination with a sulfonylurea 3) weight reduction in non-diabetic patients [7,25] - obese patients with hyperglycemia twice as likely to lose at least 5% of body weight with metformin vs placebo [44] 4) prediabetes [9,28] - may reduce risk of risk diabetes mellitus type 2 in high-risk patients with prediabetes [9,28] - long-term use may reduce coronary artery calcium in men after 14 years but not women prescribed metformin for prediabetes [41] 5) induction of ovulation in patients with polycystic ovary 6) may reduce macrovascular complications* including mortality when used for treatment of diabetes mellitus type 2 with or without insulin [17,22,33] 7) metformin use in patients with sickle cell disease & diabetes mellitus associated with fewer emergency deparment visits & fewer in-hospital adverse events [45] 8) metformin reduces risk of dementia in older adults with diabetes mellitus type 2 (RR=0.19) [54,65] - discontinuing metformin is associated with an increased risk of dementia [66] 9) reduces risk for both total knee replacement & total hip replacement by 30% [61] 10) mitigation of Covid-19 severity - metformin reduces hospitalizations/death from Covid-19 through 28 days by 58%, emergency department visits/hospitalizations/death through 14 days by 42%, & long COVID through 10 months by 42% by reducing SARS CoV2 viral load [67] 11) proposed as a possible anti-aging drug [29,30] a) may reduce cardiovascular risk b) may reduce cancer risk in type 2 diabetes (RR=0.63) [39] - may reduce risk of colorectal cancer (RR=0.85) [64] - may reduce risk of liver cancer (RR=0.55) [64] c) may reduce risk of age-related macular degeneration [57] * does not reduce microvascular complications [17] * associated with reduced mortality in patients with diabetes plus chronic heart failure, chronic renal failure, or chronic liver disease [40] Contraindications: 1) renal failure - eGFR <30 mL/minute/1.73 m2 [42] - may be associated with excess risk (6-7-fold) for lactic acidosis [27] - eGFR of 30-60 mL/minute/1.73 m2 reduces metformin clearance, but metformin levels may remain within a safe range [27,31] - serum creatinine > 1.5 mg/dL has been used in past - do not initiate metformin therapy if eGFR is < 45 mL/minute 2) not necessary to stop metformin in patient receiving iodinated contrast for radiology studies [47] 3) acute or chronic metabolic acidosis 4) cardiac or respiratory insufficiency likely to cause central hypoxia or reduced peripheral perfusion 5) severe infection that could lead to reduced tissue perfusion 6) liver disease (including alcoholic liver disease) 7) alcohol abuse 8) dehydration [11] 9) use with caution or not at all in thin elderly 10) congestive heart failure NOT a contraindication [13] 11) diabetes mellitus type 1 - does not improve glycemic control in overweight/obese adolescents with diabetes mellitus type 1 [35] 12) does not prevent fetal macrosomia in obese pregnant women without diabetes mellitus [36] Pregnancy category: B - metformin use during pregnancy does not affect offspring growth at 2 years [62] Benefit/risk: - number needed to treat to prevent progression of high-risk patients to diabetes mellitus type 2 = 5 [9]* * metformin is less effective than behavioral strategies (>= 150 minutes of moderate physical activity/week) in preventing diabetes mellitus type 2 [9] Dosage: - start with 850 mg PO QD or 500 mg BID - max 2250 mg/day - most effective dose 1000 mg BID - concurrent calicum supplementation recommended [18] * if starting dose not tolerated, restart at 500 mg QD [63] Tabs: 500 & 850 mg. Glucophage XR: once a day dosing; max 2000 mg/day Dosage adjustment in renal failure: - max dose 1000 mg/day for eGFR 30-45 mL/minute/1.73 m2 [27] Pharmacokinetics: 1) 92-99% protein binding 2) 1/2life 6.2 hours 3) eliminated by the kidneys 4) not likely to cross the blood-brain barrier (see PubChem) Monitor: 1) BUN, serum creatinine, GFR baseline & annually [21,37] 2) serum ALT, serum AST (annually) 3) complete blood count (CBC) baseline & at least annually [21] 4) fasting serum glucose (annually) [19] 5) hemoglobin A1c every 3 months [20] 6) serum vitamin B12 [18] Adverse effects: 1) common (> 10%) - anorexia, weight loss, nausea/vomiting, flatulence, diarrhea, epigastric fullness, constipation, heartburn 2) less common (1-10%) - rash, urticaria [56], photosensitivity, malabsorption of vitamin B12 [18,38] thus vitamin B12 deficiency, lactic acidosis*, hypoglycemia, taste disturbance 3) uncommon (< 1%) - blood dyscrasias, aplastic anemia, hemolytic anemia, bone marrow suppression, thrombocytopenia, agranulocytosis 4) lowers vitamin B12 levels (50%), increasing serum homocysteine & manifestations of diabetic neuropathy [18] - not known if vit B12 supplementation mitigates metformin effect on serum homocysteine &/or diabetic neuropathy - association confirmed; clinical significance uncertain [8] 5) mild anemia unrelated to vitamin B12 [55] 6) increased mortality with stage 5 chronic renal failure (RR=1.3) - lactic acidosis not influenced [31] 7) preconception paternal metformin treatment is associated with genital birth defects in boys [60] - paternal monotherapy with metformin does not increase the risk for major congenital malformation [68] - association of metformin used in polytherapy likely due to worse parental cardiometabolic risk profilen [68] - no association after adjustment for confounders [21] * Lactic acidosis is an uncommon 3/100,000/year, but sometimes fatal complication related to accumulation of metformin. [11,16] - conditions that contribute to acidosis or effect the elimination of metformin should be monitored - 12.9 for eGFR < 45 mL/min vs 8.6 for eGFR > 60 mL/min [53] - RR of lactic acidosis = 2.1 for eGFR < 30 mL/minute/1.73 m2 [42] Drug interactions: 1) cimetidine increases metformin concentration 2) nifedipine & furosemide may increase metformin concentration 3) cationic drugs: (i.e. amiloride, digoxin, procainamide, quinidine, ranitidine, triamterene, trimethoprim, vancomycin, morphine) may decrease urinary excretion of metformin 4) metformin (esp without Ca+2 supplementation) can lower vitamin B12 levels [10] 5) stop metformin prior to iodinated contrast - stop 2 days prior to intravenous iodinated contrast [14,37]* - stop before an iodinated oral contrast imaging procedure in patients with GFR 30-60 mL/minute/1.73 m2, a history of liver disease, alcoholism, or heart failure [37]* - not necessary to stop metformin in patient receiving iodinated contrast for radiology studies [45] * former recommendations Mechanism of action: 1) decreases glucose production in liver 2) decreases intestinal glucose absorption 3) increases peripheral glucose uptake & utilization 4) can decrease HgbA1c by 2% (1% more than other hypoglycemic agents, on average) [24]; lowers HgbA1c by 1% (in context of 1g/day) [58] 5) increases HDL-cholesterol in whites & blacks, but not in hispanics [32] 6) metformin activates AMPK [46] 7) protein binding to 14-3-3 is regulated by metformin [46] 8) loss of serine/threonine kinase LKB1 affects one metformin pathway [46] 9) metformin activates protein kinase & MAPKAPK2 (LKB1-independent) [46] 10) metformin may diminish IGF1 signaling [30] Comparative biology: - metformin (0.1% w/w in diet) starting at middle age extends healthspan & lifespan in male mice [34] - a higher dose (1% w/w) was toxic - metformin slows tumor growth & even shrinks posterior fossa ependymomas & extends lifespan in some mice [59] - metformin is neuroprotective in elderly male cynomolgus macaques (Macaca fasciucularis), preserving brain structure & enhancing cognition - geroprotective effects on primate neurons are partially mediated by activation of Nrf2, a transcription factor with anti-oxidant functions [70] Notes: - 10% lower risk of cancer than compared to sulfonylurea [23] - NDMA is low or undetectable in metformin products [48]

Interactions

drug interactions drug adverse effects of hypoglycemic agents

Related

metformin vs pioglitazone added to sulfonylurea

General

biguanide oral hypoglycemic agent

Properties

MISC-INFO: elimination route KIDNEY 1/2life 6-18 HOURS pregnancy-category B safety in lactation ?

Database Correlations

PUBCHEM correlations

References

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Component-of

Actoplus Met (metformin, pioglitazone) alogliptin/metformin (Kazano) canagliflozin/metformin (Invokamet) dapagliflozin/metformin empagliflozin/linagliptin/metformin (Trijardy XR) glipizide/metformin (Metaglip) glyburide/metformin (Glucovance) linagliptin/metformin (Jentadueto XR) metformin/repaglinide (PrandiMet) metformin/rosiglitazone (Avandamet) metformin/saxagliptin (Kombiglyze XR) metformin/sitagliptin; januvia/metformin (Janumet)