metformin (Glucophage)

Introduction

FDA has recommended voluntary recall of certain extended-release versions of metformin May 2020 due to excessive levels of N-nitrosodimethylamine (NDMA).

Indications

• first line monotherapy for treatment of type 2 diabetes
  • useful in patients with insulin resistance
  • unlikely to be useful as monotherapy when patient has failed therapy with sulfonylurea
• treatment of non-insulin-dependent diabetes in combination with a sulfonylurea
• weight reduction in non-diabetic patients
  • obese patients with hyperglycemia twice as likely to lose at least 5% of body weight with metformin vs placebo
• prediabetes
  • may reduce risk of risk diabetes mellitus type 2 in high-risk patients with prediabetes
  • long-term use may reduce coronary artery calcium in men after 14 years but not women prescribed metformin for prediabetes
• induction of ovulation in patients with polycystic ovary
• may reduce macrovascular complications* including mortality when used for treatment of diabetes mellitus type 2 with or without insulin
• metformin use in patients with sickle cell disease & diabetes mellitus associated with fewer emergency deparment visits & fewer in-hospital adverse events
• metformin reduces risk of dementia in older adults with diabetes mellitus type 2 (RR=0.19)
  • discontinuing metformin is associated with an increased risk of dementia
• reduces risk for both total knee replacement & total hip replacement by 30%
• 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
• proposed as a possible anti-aging drug
  • may reduce cardiovascular risk
  • may reduce cancer risk in type 2 diabetes (RR=0.63)
    • may reduce risk of colorectal cancer (RR=0.85)
    • may reduce risk of liver cancer (RR=0.55)
  • may reduce risk of age-related macular degeneration
• in patients with diabetes mellitus type-2 & asthma, metformin cuts odds of asthma attacks by 30%; adding a GLP-1 receptor agonist reduces odds by another 40%

* does not reduce microvascular complications

* associated with reduced mortality in patients with diabetes plus chronic heart failure, chronic renal failure, or chronic liver disease

Contraindications

• renal failure
  • eGFR <30 mL/minute/1.73 m2
    • may be associated with excess risk (6-7-fold) for lactic acidosis
  • eGFR of 30-60 mL/minute/1.73 m2 reduces metformin clearance, but metformin levels may remain within a safe range
  • serum creatinine > 1.5 mg/dL has been used in past
  • do not initiate metformin therapy if eGFR is < 45 mL/minute
• not necessary to stop metformin in patient receiving iodinated contrast for radiology studies
• acute or chronic metabolic acidosis
• cardiac or respiratory insufficiency likely to cause central hypoxia or reduced peripheral perfusion
• severe infection that could lead to reduced tissue perfusion
• liver disease (including alcoholic liver disease)
• alcohol abuse
• dehydration
• use with caution or not at all in thin elderly
• congestive heart failure NOT a contraindication
• diabetes mellitus type 1
  • does not improve glycemic control in overweight/obese adolescents with diabetes mellitus type 1
• does not prevent fetal macrosomia in obese pregnant women without diabetes mellitus

Pregnancy category: B

• metformin use during pregnancy does not affect offspring growth at 2 years

pregnancy category = b

safety in lactation = ?

Benefit/risk

• number needed to treat to prevent progression of high-risk patients to diabetes mellitus type 2 = 5*

* metformin is less effective than behavioral strategies (>= 150 minutes of moderate physical activity/week) in preventing diabetes mellitus type 2

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

* if starting dose not tolerated, restart at 500 mg QD

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

Pharmacokinetics

• 92-99% protein binding
• 1/2life 6.2 hours
• eliminated by the kidneys
• not likely to cross the blood-brain barrier (see PubChem)

elimination via kidney

1/2life = 6-18 hours

Monitor

• BUN, serum creatinine, GFR baseline & annually
• serum ALT, serum AST (annually)
• complete blood count (CBC) baseline & at least annually
• fasting serum glucose (annually)
• hemoglobin A1c every 3 months
• serum vitamin B12

Adverse effects

• common (> 10%)
  • anorexia, weight loss, nausea/vomiting, flatulence, diarrhea, epigastric fullness, constipation, heartburn
• less common (1-10%)
  • rash, urticaria, photosensitivity, malabsorption of vitamin B12 thus vitamin B12 deficiency, lactic acidosis*, hypoglycemia, taste disturbance
• uncommon (< 1%)
  • blood dyscrasias, aplastic anemia, hemolytic anemia, bone marrow suppression, thrombocytopenia, agranulocytosis
• lowers vitamin B12 levels (50%), increasing serum homocysteine & manifestations of diabetic neuropathy
  • not known if vit B12 supplementation mitigates metformin effect on serum homocysteine &/or diabetic neuropathy
  • association confirmed; clinical significance uncertain
• mild anemia unrelated to vitamin B12
• increased mortality with stage 5 chronic renal failure (RR=1.3)
  • lactic acidosis not influenced
• preconception paternal metformin treatment is associated with genital birth defects in boys
  • paternal monotherapy with metformin does not increase the risk for major congenital malformation
  • association of metformin used in polytherapy likely due to worse parental cardiometabolic risk profilen
  • no association after adjustment for confounders

* Lactic acidosis is an uncommon 3/100,000/year, but sometimes fatal complication related to accumulation of metformin.

• 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
• RR of lactic acidosis = 2.1 for eGFR < 30 mL/minute/1.73 m2

• drug adverse effects of hypoglycemic agents

Drug interactions

• cimetidine increases metformin concentration
• nifedipine & furosemide may increase metformin concentration
• cationic drugs: (i.e. amiloride, digoxin, procainamide, quinidine, ranitidine, triamterene, trimethoprim, vancomycin, morphine) may decrease urinary excretion of metformin
• metformin (esp without Ca+2 supplementation) can lower vitamin B12 levels
• stop metformin prior to iodinated contrast
  • stop 2 days prior to intravenous iodinated contrast*
  • 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*
  • not necessary to stop metformin in patient receiving iodinated contrast for radiology studies

* former recommendations

• drug interaction(s) of fluoroquinolones with hypoglycemic agents

Mechanism of action

• decreases glucose production in liver
• decreases intestinal glucose absorption
• increases peripheral glucose uptake & utilization
• can decrease HgbA1c by 2% (1% more than other hypoglycemic agents, on average); lowers HgbA1c by 1% (in context of 1g/day)
• increases HDL-cholesterol in whites & blacks, but not in hispanics
• metformin activates AMPK
• protein binding to 14-3-3 is regulated by metformin
• loss of serine/threonine kinase LKB1 affects one metformin pathway
• metformin activates protein kinase & MAPKAPK2 (LKB1-independent)
• metformin may diminish IGF1 signaling

Comparative biology

• metformin (0.1% w/w in diet) starting at middle age extends healthspan & lifespan in male mice
  • a higher dose (1% w/w) was toxic
• metformin slows tumor growth & even shrinks posterior fossa ependymomas & extends lifespan in some mice
• 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

Notes

• 10% lower risk of cancer than compared to sulfonylurea
• NDMA is low or undetectable in metformin products

More general terms

• biguanide
• oral hypoglycemic agent

Additional terms

• metformin vs pioglitazone added to sulfonylurea

Component of

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

Database

• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=4091
• PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=14219