U. Rabbits have been paramount source breeding so much like, well, rabbits, that rabbit boards have been set up to deal with the population of them in specific areas. S. Food and Drug Administration prescribing guidelines for metformin contraindicate its use in men and women with serum creatinine concentrations ?1. 5 and ?1. 4 mg/dL (?132 and ?123 µmol/L), respectively. In a patient tolerating and controlled with this medication, should it automatically be discontinued as the creatinine rises beyond these cut points over time? Stopping metformin often results in poorly controlled glycemia and/or the need for other agents with their own adverse-effect profiles. Moreover, is the now widespread use of estimated glomerular filtration rate (eGFR) in lieu of serum creatinine levels creating even more confusion, especially in those with abnormalities in one but not the other indirect measure of renal function?
Based on statistical inference, the estimated upper limit of true incidence was 4. 3 and 5. 4 cases per 100,000 patient-years in the metformin and nonmetformin groups, respectively. This investigation suggests that lactic acidosis is extremely rare and the incidence does not differ in those treated with metformin versus other agents.
CONCLUSIONS AND RECOMMENDATIONS
Although metformin is eliminated renally, and accumulation may conceivably lead to lactic acidosis, there currently is limited systematic evidence to substantiate continued reliance on the creatinine-based contraindications in use in the U. S. Indeed, in the modern era of eGFR, this measure of glomerular filtration appears to give a more reliable estimate of renal dysfunction. Metformin-associated lactic acidosis is exceedingly rare based on the available literature, and even though the use of metformin has not been comprehensively assessed in individuals with CKD, there is extensive evidence that this agent often is used without adverse effects in those with mildly to moderately reduced renal function. In the context of rising concerns regarding other glucose-lowering therapies (), safety restrictions over the use of metformin in this population may result in the drug being stopped prematurely and unnecessarily in some patients. This may lead to significant deterioration in glycemic control and/or the need for other glucose-lowering medications, which present their own safety concerns. An evidence-based approach to prescribing metformin in this group appears warranted, taking into account the current pervasive use of eGFR in clinical care.
We therefore suggest that the current guidelines for metformin use in the U. S. be updated. These recommendations should include eGFR thresholds that are generally consistent with the National Institute for Health and Clinical Excellence guidelines in the U. K. and those endorsed by the Canadian Diabetes Association and the Australian Diabetes Society (). Metformin may be continued (or initiated) with eGFR <60 mL/min per 1. 73 m2, but renal function should be monitored closely (every 3–6 months). The dose of metformin should be reviewed and reduced (e. g. , by 50% or to half-maximal dose) in those with eGFR <45 mL/min per 1. 73 m2, and renal function should be monitored closely (every 3 months). Metformin should not be initiated in patients at this stage, however. The drug should be stopped once eGFR falls to <30 mL/min per 1. 73 m2. Additional caution is required in patients with anticipated significant fluctuations in renal status or those at risk for abrupt deterioration in kidney function, based on previous history, other comorbidities, albuminuria, and medication regimen (e. g. , potent diuretics or nephrotoxic agents).