Metformin in kidney dysfunction - restriction revised

Metformin is the preferred initial pharmacologic therapy in every patient with type 2 diabetes mellitus who does not have a contraindication or intolerance.  It is recommended as monotherapy after diagnosis, continued when adding other medications (including insulin regimens), and should even be considered to prevent diabetes in certain patients (see who at the bottom).  

Old labeling

From approval, the restriction on metformin related to kidney function was as follows
(because of concern for accumulation and lactic acidosis):

• Contraindicated in renal disease [as suggested by serum creatinine ≥1.5mg/dL (males) and ≥1.4mg/dL (females)] or abnormal creatinine clearance
• It should not be started in ≥80 year olds until accurate creatinine clearance could be attained and adequate renal function confirmed

We now know that simply using serum creatinine as a marker for kidney function is not a good idea.  Creatinine clearnace and glomerular filtration will have widely varying ranges when considering other patient factors like weight/muscle mass, age, gender, and ethnicity - even when the same serum creatinine is present.

New guidelines and labeling

Earlier this year, the 2016 American Diabetes Association guidelines and an FDA alert addressed the issue of using metformin in patients with kidney insufficiency, largely because of a systematic review that was published in 2014.  These authors concluded that:

• In mild-moderate CKD (GFR 30-60mL/min/1.73m2) metformin and lactate concentrations aren't really affected
• The overall incidence of lactic acidosis in metformin users is 3-10/100,000 which is about the same as the overall population with diabetes

So as of 2016, here are the new labeling recommendations from the FDA regarding metformin: 

• Discontinue if GFR <30mL/min/1.73m2 
• Starting therapy with a GFR 30-45mL/min/1.73m2 is not recommended
• If already on therapy, reevaluate use at GFR <45mL/min/1.73m2 with a reduction in maximum dose to 1,000mg per day
• Discontinue if increased risk of lactic acidosis (ie. sepsis, hypotension, hypoxia)
• Discontinue if high risk of AKI (ie. contrast dye if GFR <60mL/min/1.73m2)

Take home point and other notes

These loosened labeling restrictions will hopefully mean that a lot more people can receive metformin and its many benefits.  As a reminder, here are some notes on using this medication:

• In the 10-year followup to the UKPDS trial, metformin reduced diabetes-related death by 30%, MI by 33%, and death from any cause by 27%, compared to conventional therapy (diet) (all patients in this comparison were overweight)
• Associated with weight loss
• Low cost because of generic availability
• Consider metformin to prevent diabetes in those with prediabetes plus BMI >35kg/m2, age <60 years old, women with prior gestational diabetes
• No hypoglycemia
• Patients should discontinue therapy if experiencing nausea, vomiting, or dehydration
• Avoid in hospitalized patients

References

Holman RR, Paul SK, Bethel MA, et al.  10-year follow-up of intensive glucose control in type 2 diabetes.  N Engl J Med  2008;359:1577-89.

Inzucchi SE, Lipska KJ, Mayo H, et al.  Metformin in patients with type 2 diabetes and kidney disease: a systematic review  JAMA  2014;312(24):2668-75.
Metformin-containing drugs: Drug safety communication - revised warnings for certain patients with reduced kidney funciton.  http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm494829.htm  Published April 8, 2016.  Accessed October 6, 2016.
Glucophage (R) [package insert].  Princeton, NJ: Bristol-Myers Squibb Company; 2009.

image from ben alexander