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
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)
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)
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)
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]
