Published: 10 December 2015

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Metformin - Renal Impairment and Risk of Lactic Acidosis

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Prescriber Update 36(4): 56-57
December 2015

Metformin is recommended as the first line oral hypoglycaemia medicine for patients with type 2 diabetes in international guidelines¹. However, use has been restricted in patients with renal impairment due to the increased risk of lactic acidosis.

The New Zealand metformin data sheets have recently been updated to allow for the use of metformin in patients with stable renal impairment. The contraindication cut-off level for creatinine clearance has changed from <60 mL/min to <15 mL/min. Patients with renal impairment MUST take a lower dose of metformin to avoid toxic concentrations. The maximum daily dose to be used in renal impairment is specified in the metformin data sheet, according to degree of impairment.

The metformin data sheets can be found on the Medsafe website (www.medsafe.govt.nz/Medicines/infoSearch.asp).

Lactic acidosis

Lactate is produced by most tissues and is rapidly cleared by the liver. Levels of lactate increase as a consequence of intracellular acidosis and help to slow down the onset of acidosis. High lactate levels are generally considered to be those above 4 mmol/L². Lactic acidosis is a condition of high lactate and a pH below 7.35².

There are many causes of elevated lactate including²:

• sepsis and septic shock
• regional tissue ischaemia for example due to burns
• anaerobic muscle activity for example as a result of seizures
• use of drugs such as alcohol
• use of medicines such as metformin or linezolid
• diabetic ketoacidosis
• cardiac arrest
• trauma
• liver dysfunction.

Risk factors for the development of lactic acidosis in patients taking metformin include ³:

• renal impairment
• acute kidney injury for example due to dehydration
• hepatic insufficiency
• poorly controlled diabetes
• alcohol intoxication
• acute tissue hypoxia for example in sepsis.

Symptoms of lactic acidosis are generally non-specific and include malaise, myalgia, muscle cramps, respiratory distress, nausea, vomiting and abdominal pain³.

The general nature of the symptoms can make diagnosis difficult and may be confused with other causes, which may in turn result in lactic acidosis. The difficulty in determining the cause of lactic acidosis in some cases has led to debate about the existence of metformin associated lactic acidosis (MALA). However, the occurrence of lactic acidosis in people who have taken an overdose of metformin provides evidence that MALA does occur³.

The incidence of lactic acidosis in patients taking metformin is also difficult to estimate. A Cochrane review failed to identify any cases of lactic acidosis in patients taking metformin ⁴. Whereas, a Dutch observational study found an incidence of 47 cases of MALA per 100,000 patient years⁵. The Centre for Adverse Reactions Monitoring (CARM) has received 19 cases of lactic acidosis in patients taking metformin to 30 October 2015.

The mortality of MALA is high. Previous estimates were around 50% ⁶. However, more recently the estimate has been revised to 25% ⁷. The decrease in mortality may be due to changes in clinical practice including better use of haemodialysis to remove metformin ⁷. Of the19 cases of lactic acidosis reported to CARM, 12 patients (63%) were reported to have died.

Using Metformin Safely in Patients with Renal Impairment

Metformin is not metabolised and is entirely cleared by renal excretion. Studies have indicated that plasma levels of metformin below 5 mg/L are not associated with lactic acidosis ⁸.

Since metformin metabolism is entirely dependent on renal function a dose reduction is required in patients with stable renal impairment. The new advice on metformin doses in renal impairment is derived from a population pharmacokinetic study⁸. This study included patients with varying levels of renal impairment (Table 1)⁸.

Table 1: Maximum recommended doses of metformin^3,8

Renal function (creatinine clearance )	Maximum daily metformin dose
15-30 mL/min	500 mg
30-60 mL/min	1000 mg
60¬-120 mL/min	2000 mg

Renal function should be measured at least twice a year in patients with renal impairment taking metformin³. Dosage adjustments should be made as and when necessary. For more information see the metformin data sheets.

Information for Patients

Patients should be informed of the symptoms of lactic acidosis and acute kidney injury and told to seek medical attention if these occur. Patients should be warned against excessive alcohol intake.

References

1. National Institute for Health and Care Excellence. 2009. Type 2 diabetes: The management of type 2 diabetes. NICE Guideline CG87.2009. URL: www.nice.org.uk/guidance/cg87/resources/the-management-of-type-2-diabetes-975693927877 (accessed 3 November 2015).
2. Andersen LW, Mackenhauer J, Roberts JC, et al. 2013. Etiology and therapeutic approach to elevated lactate levels. Mayo Clinic proceedings 88: 1127-1140.
3. Apotex NZ Ltd. 2015. Apotex Metformin Data Sheet 5 August 2015. URL: www.medsafe.govt.nz/profs/datasheet/m/Metformintab.pdf (accessed 17 November 2015).
4. Salpeter SR, Greyber E, Pasternak GA, et al. 2010. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane database of systematic reviews: CD002967.
5. van Berlo-van de Laar IR, Vermeij CG, Doorenbos CJ. 2011. Metformin associated lactic acidosis: incidence and clinical correlation with metformin serum concentration measurements. Journal of Clinical Pharmacy and Therapeutics 36: 376-382.
6. Pillans P. 1998. Metformin and Fatal Lactic Acidosis. Prescriber Update 16: 22-24.URL: www.medsafe.govt.nz/profs/PUarticles/5.htm (accessed 18 November 2015).
7. Kajbaf F, Lalau JD. 2014. Mortality rate in so-called "metformin-associated lactic acidosis": a review of the data since the 1960s. Pharmacoepidemiology and Drug Safety 23: 1123-1127.
8. Duong JK, Kumar SS, Kirkpatrick CM, et al. 2013. Population pharmacokinetics of metformin in healthy subjects and patients with type 2 diabetes mellitus: simulation of doses according to renal function. Clinical Pharmacokinetics 52: 373-384.