FDA Issues Guidance for Metformin Use in Renal Impairment

The FDA has issued new guidance for the use of the first-line diabetes drug metformin in patients with renal impairment.

The FDA has issued new guidance for the use of the first-line diabetes drug metformin in patients with renal impairment.

Metformin was approved by the FDA in 1994 for the management of type 2 diabetes. Since its approval, its labeling has warned of a contraindication in elevated serum creatinine (>1.5 mg/dL for males, >1.4 mg/dL for females) due to a risk of lactic acidosis secondary to metformin accumulation.1 Other risk factors for lactic acidosis include contrast dye exposure within 48 hours, chronic or excessive alcohol intake, dehydration, sepsis, acute congestive heart failure, and age.

This absolute contraindication was based on clinical trials of an older biguanide called phenformin, which showed a greater risk of lactic acidosis associated with significant mortality and was subsequently pulled off the market in 1977.2 Although phenformin is no longer available in the United States, it’s still available in European and South American markets.

Notably, the incidence of lactic acidosis associated with metformin is as low as 0.03 cases per 1000 patient-years.

The FDA reviewed several studies to determine whether patients with mild to moderate renal impairment could safely continue on metformin to manage their type 2 diabetes. One of the larger trials reviewed was an observational study of 51,675 type 2 diabetes patients to determine the effect metformin would have on primary outcomes of cardiovascular disease (CVD), all-cause mortality, and acidosis or serious infections with varying degrees of renal function.3

Based on subgroup analyses of patients with varying degrees of renal impairment, the investigators determined that patients with an estimated glomerular filtration rate (eGFR) >45 mL/min/m2 showed no increased risk of CVD, all-cause mortality, acidosis or serious infection and actually showed a reduced risk of all-cause mortality and acidosis or infection. The authors enrolled few patients with an eGFR between 30 mL/min/m2 and 45 mL/min/m2 and made no comment on the drug’s safety or efficacy in this subgroup.

The dosing recommendations suggested by the FDA target eGFR as a more accurate representation of renal status than a single biomarker like serum creatinine. The new recommendations are as follows:

  • Patients with an eGFR ≥60 mL/min/1.73 m2 require no dose adjustments and are able to safely use metformin with annual monitoring.
  • Patients with an eGFR between 45 mL/min/1.73 m2 and 60 mL/min/1.73 m2 may continue treatment but require more frequent renal function monitoring every 3 to 6 months.
  • Patients with moderate chronic kidney disease (eGFR between 30 mL/min/1.73 m2 and 45 mL/min/1.73 m2) aren’t candidates for initiation of metformin, but patients currently maintained on the medication may continue cautiously. The FDA suggests assessing the appropriateness of continuing metformin in this patient population and considering a 50% dose reduction with renal function monitoring every 3 months.
  • The FDA still recommends a contraindication in advanced kidney disease (eGFR <30 mL/min/1.73m2).

It remains to be seen whether more specific dosing recommendations for metformin will be investigated in mild to moderate renal impairment.

References

  • Glucophage (metformin) [prescribing information]. Princeton, NJ: Bristol-Myers Squibb; Jan 2009.
  • Sogame Y, Kitamura A, Yabuki M, Komuro S, Takano M. Transport of biguanides by human organic cation transporter OCT2. Biomed. Pharmacother. 2013;67: 425-430.
  • Ekström N, Schiöler L, Svensson AM, Eeg-Olofsson K, Miao Jonasson J, Zethelius B, et al. Effectiveness and safety of metformin in 51,675 patients with type 2 diabetes and different levels of renal function: a cohort study from the Swedish National Diabetes Register. BMJ Open. 2012;2.pii:e001076.