Metformin Label Too Restrictive on Renal Grounds, Limits Use

Miriam E Tucker

January 08, 2015

Metformin is being underprescribed in patients with type 2 diabetes because of unwarranted concerns about its use in those with mild to moderate renal insufficiency, a new database analysis suggests.

Despite recommendations to use metformin as first-line therapy for type 2 diabetes, about half of patients in the United States don't take it, and this new research confirms that the drug's labeling is behind a large proportion of its nonuse.

The US label carries a contraindication against use of metformin when serum creatinine levels exceed 1.4 mg/dL in women or 1.5 mg/dL in men.

"Clinicians and patients should be aware that common prescribing practices are too conservative and lead physicians and patients to underuse metformin in patients with mild to moderate kidney disease. In fact, metformin is still safe in many of these patients and remains a superior option for treating type 2 diabetes," lead author Dr James H Flory (Weill Cornell Medical College, New York) told Medscape Medical News.

Indeed, over the past few years there has been an emerging consensus that the US Food and Drug Administration (FDA) labeling for metformin is too strict with regard to mild/moderate renal impairment. Both Dr Flory's group at Cornell and a team at Yale have filed citizen petitions with the FDA requesting that the renal cutoff be relaxed and also that it be expressed in the more accurate estimated glomerular filtration rates (eGFRs), rather than serum creatinine.

Dr Flory published the findings online January 5 as a research letter in JAMA Internal Medicine, along with Dr Sean Hennessy (University of Pennsylvania, Philadelphia).

ADA and EASD Support Removal of Restrictions on Metformin

The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) also address this issue in a new joint position statement, "Management of hyperglycemia in type 2 diabetes, 2015: A patient-centered approach" (Diabetes Care. 2015;38:140-149).

The document cites "increasing evidence that the current cutoff points for renal safety [for metformin] in the US…may be overly restrictive."

According to the ADA/EASD, "Many practitioners would continue to prescribe metformin even when the eGFR falls to less than 45 to 60 mL/min/1.73 m 2, perhaps with dose adjustments to account for reduced renal clearance of the compound. One criterion for stopping the drug is an eGFR of <30 mL/min/1.73 m2. Of course, any use in patients with [chronic kidney disease] mandates diligent follow-up of renal function."

Metformin Use Plummets as eGFR Drops

In their research, Drs Flory and Hennessey analyzed 2011–2012 data from the National Health and Nutrition Examination Survey. Of more than 10 million people using oral diabetes drugs, 90.4% of patients with an eGFR greater than 90 mL/min/1.73 m2 were using metformin. But the drug's use dropped successively at eGFRs of >60 to 90, >45 to 60, and 30 to 45 mL/min/1.73 m2, to 80.6% of patients, 57.4%, and 48.6%, respectively.

For patients with eGFR less than 30 mL/min/1.73 m2, the level at which metformin use is not recommended, the rate of metformin use was 17.9%.

The doctors estimate that extending the 90.4% rate of use in patients with normal kidney function to those with eGFRs >60 to 90 mL/min/1.73 m2 would enable an extra 425,000 people to take metformin. Further prescribing metformin to those with eGFRs down to 30 mL/min/1.73 m2 would bring in another 560,000.

They point out that these numbers are likely underestimates, since the NHANES database doesn't include people with type 2 diabetes who aren't taking any oral diabetes drugs. But of course, in some patients, a low eGFR may be associated with other factors, such as undocumented heart failure, that account for the nonprescribing.

"The Evidence…Is Very Convincing"

The rationale behind the current FDA label for metformin was established in 1994, when there was strong evidence that phenformin, another biguanide since removed from the US market, caused lactic acidosis, Dr Flory told Medscape Medical News.

"The FDA was cautious and assumed metformin might have the same problem phenformin did. Metformin is cleared from the body by the kidneys, so in patients with renal failure there was a concern that metformin might build up to relatively high levels and that those would be the patients who got lactic acidosis. The FDA cutoffs were chosen based on pharmacokinetic data to provide a margin of safety to ensure that this couldn't happen," he explained.

But now, there have been 2 decades of research showing no increased risk for lactic acidosis in patients with mild to moderately impaired renal function, he said, pointing, for example, to a recent systematic review by the Yale group (JAMA. 2014;312(24): 2668-2675.)

"The evidence…is very convincing once you go through all of it," he told Medscape Medical News.

Asked about potential liability, Dr Flory responded, "I am not qualified to give legal advice, so all I can say is that many diabetes specialists, including myself, routinely prescribe metformin to patients with mild to moderate renal failure. I have never heard of this leading to a lawsuit. Personally, I feel that the risk of liability seems low enough that it's worth taking to provide better care for patients."

Dr Flory has no relevant financial relationships. Dr Hennessy reports consulting for Abbott Laboratories, Hoffmann-La Roche, Novartis, Bayer Healthcare, AstraZeneca, and Bristol-Myers Squibb; receiving research support from AstraZeneca and Bristol-Myers Squibb; and receiving institutional support from Pfizer and Sanofi to support pharmacoepidemiology training.

JAMA Intern Med. Published online January 5, 2015. Abstract

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