Is Metformin Losing Its Luster?

The current black box warning may be overstating the kidney risk. Yet, we need to use some caution. Metformin has a reputation of being a real blockbuster drug and is the primary drug in the treatment of type 2 diabetes. This may be a potential problem due the FDA and the limit placed on it usage. The current label carries a contraindication against the use of metformin when serum creatinine levels exceed 1.4 mg/dl in women or 1.5 mg/dl in men.

Despite its establishment as the first-line therapy for type 2 diabetes, about one-half of the patients currently in the United States do not take it. A major proponent of this is its current labeling, which expresses, for some, unjustifiable concerns about its use for treatment in those with mild to moderate renal insufficiency.

In the last few years, clinicians in the USA have developed an overwhelming consensus that the US Food and Drug Administration (FDA) labeling for metformin could be more lenient and also that it can be expressed in more precise estimated glomerular filtration rates (eGFRs), rather than serum creatinine.

The FDA's initial rationale behind the label was due to resilient evidence that phenformin caused lactic acidosis (another biguanide which has been removed from the US market). Metformin is cleared from the body via the kidneys and for patients with significant renal failure, there were increasing concerns that metformin could potentially build up to relatively high levels that could leave patients to have lactic acidosis. There is now an overwhelming two decades’ worth of research and evidence showing no serious increased risks for lactic acidosis in patients with mild-to-moderately impaired renal function.

The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) have furthermore supported the removal of restrictions on metformin, propagating the notion that practitioners “would continue to prescribe metformin even when the eGFR falls to less than 45 to 60 mL/min/1.73m2, perhaps with dose adjustments to account for reduced renal clearance of the compound. One criterion for stopping the drug is an eGFR of less than 30 ml/min/1.73m2.” It is important to note that patients with chronic kidney disease would require stringent follow-up of renal function.

One of the most recent studies published on the potential impact of metformin eligibility for adults in the United States assessed 3,902 patients with diabetes who partook in the 1999-2010 National Health and Nutrition Examination Surveys. These patients were eligible if the serum creatinine levels met the eligibility markers “of less than 1.4 mg/dl for women and less than 1.5 mg/dl for men along with eGFR categories (likely safe, greater than or equal to 45 mL/min/1.73 m2; contraindicated, less than 30 mL/min/1.73 m2; and indeterminate, 30–44 mL/min/1.73 m2).” Different equations were used to measure eGFR, including: four-variable MDRD, CKD-EPI, CKD-EPI cystain C and Cockroft-Gault with diabetes itself being self-reported or for patients with an A1C greater than 6.5%.

The results of this particular study demonstrated that by replacing the serum creatinine threshold with eGFR thresholds, practitioners were able to expand metformin’s utilization for patients without any significant safety concerns. Findings noted that metformin use amongst patients with an eGFR of 90 ml/min or higher was 90% with a slight drop to 80% with an eGFR of 60 to 90 ml/min. Even with patients with an eGFR below 30 ml/min were found continuing use of metformin; based off of the collected results, an estimation could be made on how many additional people may have benefited from starting therapy (approximately 425,000 patients if the data was from the 60 to 90 ml/min group and almost 560,000 patients if expanded to the 30 to 60 ml/min group). The key main findings of the study include: metformin use has increased in the past decade or so for treatment of type 2 diabetes and implementing eGFR or CrCl rather than serum creatinine thresholds for eligibility of use could considerably expand the utilization of the drug. With greater use of metformin, there is consequently tighter glycemic control, resulting in improvement of healthcare.

Looking forward to the future, additional research is imperative, including prospective randomized trials of metformin at multiple stages of renal injury and a much closer examination of archives of CKD patients taking metformin.