Metformin (Glucophage)

Indications

  • Non-Insulin Dependent Diabetes Mellitus (see Diabetes Mellitus, [[Diabetes Mellitus]])

Contraindications

  • Chronic Kidney Disease (CKD) (see Chronic Kidney Disease, [[Chronic Kidney Disease]]): due to the predisposition to develop lactic acidosis
    • Cr >1.4 mg/dL in Females (approximately GFR <30 ml/min)
    • Cr >1.5 mg/dL in Males (approximately GFR <30 ml/min)
  • Excessive Ethanol Consumption (see Ethanol, [[Ethanol]]): due to the predisposition to develop lactic acidosis
  • History of Lactic Acidosis (see Lactic Acidosis, [[Lactic Acidosis]])
  • Liver Disease (see End-Stage Liver Disease, [[End-Stage Liver Disease]]): due to the predisposition to develop lactic acidosis
  • Poorly-Controlled Congestive Heart Failure (CHF) (see Congestive Heart Failure, [[Congestive Heart Failure]]): due to the risk of hypoperfusion/hypoxemia, predisposing the development of lactic acidosis
    • Compensated CHF is probably not a contraindication to metformin use

Pharmacology

  • Second-Generation Biguanide Anti-Hyperglycemic Agent
    • Physiologic Effects
      • Increases Insulin Suppression of Gluconeogenesis: decreases hepatic glucose output
      • Decreases Glucagon-Stimulated Gluconeogenesis: decreases hepatic glucose output
      • Increases Uptake of Muscle and Adipose Tissue Glucose Uptake
      • Decreases Insulin Resistance
    • Net Clinical Effects
      • Decreases Fasting and Post-Prandial Blood Glucose by 20-40%
      • Decreases Hemoglobin A1C
      • Decreases Body Weight Slightly
      • Decreases Low Density Lipoprotein (LDL)
      • Increases High Density Lipoprotein (HDL)

Metabolism

  • Renal Metabolism: unmetabolized metformin is actively excreted via proximal tubular transporters
    • Therefore, unmetabolized metformin may accumulate in renal failure
  • Elimination Half-Life (in patients who take multiple doses and have adequate renal function): 5 hrs

Mechanisms of Lactic Acidosis

  • Metformin Promotes the Conversion of Glucose to Lactate in the Small Intestinal Splanchnic Bed
  • Metformin Inhibits Mitochondrial Respiratory Chain Complex 1: decreases hepatic gluconeogenesis from lactate, pyruvate, and alanine
    • Results in additional lactate and substrate for lactate production

Administration

  • PO: start 500 mg qday with evening meal -> if tolerated, add 500 mg dose with breakfast -> escalate dose slowly every 1-2 wks
    • Usual Effective Dose: 1500 to 2000 mg/day per day
    • Maximum Dose: 2550 mg/day (850 mg TID)

Dose Adjustment

  • Hepatic: xxx
  • Renal
    • FDA Advisory Recommendations (4/8/16) [FDA ADVISORY]
      • Before starting metformin, check the patient’s estimated glomerular filtration rate (eGFR)
      • eGFR <30 mL/min/1.73 m2: metformin is contraindicated
      • eGFR 30-45 mL/min/1.73 m2: starting metformin is not recommended
      • In patients started on metformin with eGFR >45 mL/min/1.73 m2:
        • If eGFR later falls below 45 mL/min/1.73 m2, further metformin use should be carefully considered in terms of risks/benefits
        • If eGFR later falls below 30 mL/min/1.73 m2, metformin should be discontinued
      • Discontinue metformin before or at the time of an iodinated contrast imaging procedure in the setting of eGFR 30–60 mL/min/1.73 m2, liver disease, alcohol abuse, congestive heart failure, or intra-arterial iodinated contrast administration
        • Following procedure, assess eGFR at 48 hrs and restart if renal function is stable

Metformin Administration Cautions

  • Metformin Administration Prior to Iodinated Contrast Administration
    • FDA Advisory Recommendations (4/8/16) [FDA ADVISORY]
      • Discontinue metformin before or at the time of an iodinated contrast imaging procedure in the setting of eGFR 30–60 mL/min/1.73 m2, liver disease, alcohol abuse, congestive heart failure, or intra-arterial iodinated contrast administration
        • Following procedure, assess eGFR at 48 hrs and restart if renal function is stable
  • Metformin Administration Prior to Impending Surgery: metformin should probably be discontinued prior to surgery, due to the potential risk for circulatory compromise during surgery

Adverse Effects

Endocrinologic Adverse Effects

  • Hypoglycemia (see Hypoglycemia, [[Hypoglycemia]]): less likely to cause hypoglycemia than sulfonylureas or insulin

Gastrointestinal Adverse Effects

  • Abdominal Discomfort (see Abdominal Pain, [[Abdominal Pain]])
  • Decreased Vitamin B12 Absorption (see Vitamin B12, [[Vitamin B12]]): occurs in 30% of cases (although only rarely causes megaloblastic anemia)
  • Diarrhea (see Diarrhea, [[Diarrhea]])
  • Mild Anorexia (see Anorexia, [[Anorexia]])
  • Metallic Taste in Mouth
  • Nausea (see Nausea and Vomiting, [[Nausea and Vomiting]])

Renal Adverse Effects

Lactic Acidosis (see Lactic Acidosis, [[Lactic Acidosis]])

  • Epidemiology
    • Incidence: 9 cases per 100,000 person-years of metformin exposure (compared to 40-64 cases per 100,000 person-years of phenformin exposure) (see Phenformin, [[Phenformin]])
      • Systematic reviews suggest that the incidence of lactic acidosis is very low [MEDLINE], although is it not clear from the trial data as to how many patients had contraindications to metformin use (such as significant chronic kidney disease)
  • Risk Factors
    • Administration of Intravenous Iodinated Contrast
    • Chronic Kidney Disease (CKD) (see Chronic Kidney Disease, [[Chronic Kidney Disease]])
      • Lactic acidosis usually occurs in the setting of baseline chronic kidney disease (although it may occur in patients with normal renal and hepatic function in the setting of an overdose)
    • Congestive Heart Failure (CHF) (see Congestive Heart Failure, [[Congestive Heart Failure]])
    • Dehydration
    • Hypoxemia (see Hypoxemia, [[Hypoxemia]])
    • Maternally-Inherited Diabetes and Deafness (MIDD) Syndrome
    • Sepsis (see Sepsis, [[Sepsis]])
  • Mechanism
    • Metformin Accumulates and Inhibits Oxidative Phosphorylation: inhibits hepatic Cori cycle conversion of lactate into glucose
    • In the Setting of Renal Failure, Excess Lactate Cannot Be Adequately Cleared by the Kidneys
  • Diagnosis: lactate levels are usually <2 mmol/L (but may be higher in patients with patients with other risk factors for lactic acidosis)
  • Treatment: bicarbonate hemodialysis can correct the acidosis and remove metformin
  • Prognosis: metformin-induced lactic acidosis has a high case-fatality rate (approximately 45%)
    • Neither arterial lactate nor plasma metformin concentrations predict mortality

Metformin Overdose

Diagnosis

  • Metformin Level
    • Rarely available
    • Serum metformin concentration does not often correlate with the severity of the poisoning or outcome

Clinical Manifestations

Endocrinologic Manifestations

  • Hypoglycemia (see Hypoglycemia, [[Hypoglycemia]]): uncommon, unless other hypoglycemic agents are ingested

Gastrointetsinal Adverse Effects

Renal Manifestations

Treatment

  • Treatment of Hypoglycemia (see Hypoglycemia, [[Hypoglycemia]]): as required
  • Gastrointestinal Decontamination with Activated Charcoal: recommended in acute overdose (unlikely to be effective in patients with toxicity associated with chronic use)
  • Sodium Bicarbonate (see Sodium Bicarbonate, [[Sodium Bicarbonate]]): use should be reserved for patients with pH <7.15 -> aim to maintain the pH >7.15, until the acute toxicity resolves
  • Hemodialysis (with Bicarbonate Buffer) (see Hemodialysis, [[Hemodialysis]]): hemodialysis corrects the acidosis and to a lesser extent, removes metformin
    • Has been successfully used in both acute overdose and toxicity associated with chronic use
    • Indicated for patients with severe metabolic acidosis (pH >7.10), severe illness, and presence of renal insufficiency
    • Continuous vene-venous hemodialysis (CVVHD) should only be used in patients who are too hemodynamically unstable to tolerate intermittent hemodialysis: as CVVHD is less effiecient at removing metformin than intermittent hemodialysis

References

  • Biguanide-associated lactic acidosis. Case report and review of the literature. Arch Intern Med. 1992 Nov;152(11):2333-6 [MEDLINE]
  • Re-evaluation of a biguanide, metformin: mechanism of action and tolerability. Pharmacol Res. 1994 Oct-Nov;30(3):187-228 [MEDLINE]
  • Metformin. N Engl J Med. 1996 Feb 29;334(9):574-9 [MEDLINE]
  • Incidence of lactic acidosis in metformin users. Diabetes Care. 1999 Jun;22(6):925-7 [MEDLINE]
  • Evaluation of prescribing practices: risk of lactic acidosis with metformin therapy. Arch Intern Med. 2002 Feb 25;162(4):434-7 [MEDLINE]
  • Frequency of inappropriate metformin prescriptions. JAMA. 2002 May 15;287(19):2504-5 [MEDLINE]
  • Metformin and thiazolidinedione use in Medicare patients with heart failure. JAMA. 2003 Jul 2;290(1):81-5 [MEDLINE]
  • The phantom of lactic acidosis due to metformin in patients with diabetes. Diabetes Care. 2004 Jul;27(7):1791-3 [MEDLINE]
  • Comparative outcomes study of metformin intervention versus conventional approach the COSMIC Approach Study. Diabetes Care. 2005 Mar;28(3):539-43 [MEDLINE]
  • Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev. 2010 Apr 14;(4):CD002967. doi: 10.1002/14651858.CD002967.pub4 [MEDLINE]
  • Systematic review of current guidelines, and their evidence base, on risk of lactic acidosis after administration of contrast medium for patients receiving metformin. Radiology Jan 2010; 254:261-269
  • Limitations of metformin use in patients with kidney disease: are they warranted? Diabetes Obes Metab. 2010 Dec;12(12):1079-83. doi: 10.1111/j.1463-1326.2010.01295.x [MEDLINE]
  • Metformin usage in type 2 diabetes mellitus: are safety guidelines adhered to? Intern Med J. 2014 Mar;44(3):266-72. doi: 10.1111/imj.12369 [MEDLINE]
  • Metformin in patients with type 2 diabetes and kidney disease: a systematic review. JAMA. 2014 Dec 24-31;312(24):2668-75. doi: 10.1001/jama.2014.15298 [MEDLINE]
  • FDA Advisory (4/8/16) [FDA ADVISORY]