FDA: Metformin Safe for Some Patients With Renal Problems

Robert Lowes and Lisa Nainggolan

April 08, 2016

(Updated April 11 with commentary) In a response to mounting evidence, the US Food and Drug Administration (FDA) announced that the diabetes drug metformin can be used safely in patients with mild and, in some cases, moderate kidney impairment after decades of warning against it. This means that a generic and therefore cheap effective agent for type 2 diabetes should be more widely available for use, as many patients with diabetes also have some form of renal impairment.

Metformin previously had been contraindicated for patients with renal disease or dysfunction, as suggested by serum creatinine levels at or above 1.5 mg/dL for men and 1.4 mg/dL for women or abnormal creatinine clearance.

The FDA now says that after reviewing a number of studies, it has concluded that this contraindication is no longer necessary for certain patients with reduced kidney function. The reason for the contraindication was that patients with reduced renal function are at higher risk of developing lactic acidosis, a very rare side effect associated use of metformin.

There had long been a concern among endocrinologists that many patients with type 2 diabetes were missing out on the benefits of metformin and that the drug was underprescribed because of these concerns, which many believed were unwarranted.

Indeed, prescribing guidance for metformin with regard to its use in different levels of renal impairment varies around the world, and earlier this year, the European Medicines Agency began a review into this issue, with the aim of harmonizing the prescribing information across the EU.

Asked to comment on this new US announcement, Silvio Inzucchi, MD, of Yale Diabetes Center, New Haven, Connecticut, told Medscape Medical News: "I am very pleased that the FDA has made their decision to expand the potential use of metformin to more patients. Evidence has emerged over the past 2 decades that the prior guidelines as related to renal function were overly restrictive and, essentially, prevented the use of this important, effective, and inexpensive generic medicine to hundreds of thousands of patients in the US."

Dr Inzucchi was part of a group, led by Kasia J Lipska, MD, also from Yale, which filed a citizen's petition to the FDA lobbying for such a change in the labeling for metformin.

"We pointed out to the FDA in our petition that while lactic acidosis is a serious…and potentially life-threatening condition, it was indeed no more common in patients prescribed metformin.

"Moreover, surveys showed high rates of metformin use in the real world in patients below the cut points in renal function that the FDA had chosen when metformin was approved in 1995," Dr Inzucchi added. "Despite this fact, lactic-acidosis rates were not observed to have increased. In fact, when a metformin-treated patient develops lactic acidosis, it is almost always due to some other event, such a major hemodynamic or infectious catastrophe. So, metformin is likely an 'innocent bystander' in these situations," he noted.

Another member of the group that submitted the citizen's petition, cardiologist Darren McGuire, MD, MHSc, of the University of Texas Southwestern Medical Center, Dallas, told Medscape Medical News: "From the patient perspective, this is a big win, as it opens access to a large number of patients to metformin, a cheap, generically available, well-tolerated [diabetes agent] with a minimal risk for hypoglycemia." There is also "consistent evidence for modest cardiovascular efficacy" of metformin, so all of these advantages will now be available to patients with mild to moderate kidney disease, who are one of the subgroups of diabetes with highest cardiovascular disease risk, he noted.

In addition, "this represents the process and power of the citizens' petition — a process by which any provider can formally request action of the FDA," noted Dr McGuire.

Dr Lipska's group was not the only one to file a citizen's petition with regard to this issue with FDA. Sean Hennessy, PharmD, PhD, of Perelman School of Medicine, University of Pennsylvania, Philadelphia, and colleagues also filed one, prior to the Yale group.

Dr Hennessy told Medscape Medical News: "Metformin is, simply put, the best-proven oral drug for people living with diabetes.

"However, many people with diabetes also have mild to moderate renal insufficiency, which until now has kept them from taking metformin because of the overly cautious warning statements in the drug's label. FDA's recent decision to remove these…will permit many more patients to take this proven therapy [and] therefore benefit many people living with diabetes."

Measure Renal Function by eGFR; Metformin Still a No-No in Advanced CKD

The FDA is advising metformin manufacturers to revise their label information to incorporate both the new guidance and a new measure of kidney function to determine whether a patient could receive the drug.

The new labels will recommend switching from serum creatinine concentration, a single laboratory parameter, to the glomerular filtration rate estimating equation (eGFR). The agency deems the latter superior because in addition to blood creatinine concentration, it factors in a patient's age, sex, race, and other parameters.

Under the FDA's latest recommendations, clinicians should obtain a patient's eGFR before starting metformin. If the eGFR is below 30 mL/min per 1.73 m2 — defined as advanced renal disease — the drug is contraindicated.

Dr Inzucchi is entirely on board with this advice. Metformin "remains a drug absolutely contraindicated when the eGFR is <30, as they pointed out. Physicians must remember this, and I hope we do not see errors in prescribing if the medical community misinterprets the new guidelines to indicate that renal function is no longer a concern with this drug! It certainly still is," he commented.

He added: "What the guidelines now state is that, essentially, the drug may be used when the eGFR is between 45 and 60 mL/min per 1.73 m2 — ie, mild chronic kidney disease (CKD). When the eGFR falls to between 30 and 45, which is moderate CKD, the FDA appropriately recommends further caution with a careful risk/benefit calculation before deciding to stop or continue the medication."

This advice not to start metformin if the eGFR is already below 45 is, says Dr Inzucchi "very similar to that endorsed by [National Institute for Health and Care Excellence] NICE and in use in the UK."

The FDA states that all patients taking metformin should now have their eGFR checked at least annually. The elderly and others at increased risk for renal impairment should be tested more frequently, the agency adds.

But Advice Needed on a Safety Issue: Dose Adjustment for eGFR 30–45

Dr Inzucchi does have one criticism of the new FDA guidance, however.

"They do not include recommendations for dose adjustment in those with eGFR 30–45. This is what we had recommended in our reviews published on this topic (Diabetes Care. 2011;34:1431-1437; JAMA. 2014;312: 2668-2675). Therein, we advised that the dose be cut in half when eGFR of 45 was reached to minimize any chance of achieving a toxic level in patients with that degree of kidney disease."

For this reason, "I have just submitted a request to the FDA to clarify this specific point — it may be a key safety issue," he told Medscape Medical News.

More information on the metformin announcement of April 8 is available on the FDA's website.

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