Bringing Metformin to Over 2 Million More Patients

Twitter summary: New research challenging an FDA restriction on metformin, potential benefit for 2+ million patients

In 1994, one of the biggest breakthrough drugs in type 2 diabetes finally made its way to the US. The drug was called metformin, and since its approval, it has gained prominence as the safest, least costly (it’s generic!), and one of the most effective first-line drugs to treat type 2 diabetes. Metformin’s global impact has made its benefits clear, as it is estimated to be the most prescribed diabetes medication worldwide.

As with many drugs, the 1994 approval of metformin in the US came with some uncertainties. In this case, the FDA had concerns that metformin (which is partially cleared from the body through the kidneys) would accumulate in the bloodstream of patients with reduced kidney function, putting them at risk for lactic acidosis – a serious, life-threatening condition if left untreated (lactic acidosis happens when too much acid builds up in the bloodstream). As a result, the FDA’s approved label for metformin prohibits its use for people with mild to moderate kidney disease (though it can still be taken off-label).

However, a recent study published in JAMA at the end of 2014 is finally challenging this restriction. After reviewing 65 articles on metformin use in patients with kidney impairment, a team at the Yale University School of Medicine concluded that the current FDA restriction may be overly cautious and lacks adequate clinical evidence to support it. The researchers found that even for people at the most extreme cut-off of moderate kidney impairment (an eGFR of 30 ml/min/1.73m²), metformin use did not appear to lead to an increased risk for lactic acidosis. (Kidney function is assessed by a blood test called  ‘eGFR,’ which estimates how much blood passes through the kidneys’ filter system each minute. It’s measured in the slightly clunky units of “ml/min/1.73m²”. An eGFR of 30-59 ml/min/1.73m² is classified as moderate kidney damage, and normal kidney function is anything better than 90 ml/min/1.73m². For our full run-down in kidneys and eGFR, you can read our learning curve here.  In the Yale work, observational studies investigating the link between metformin and lactic acidosis have found no significant relationship, and people with mild to moderate kidney impairment using metformin off-label have reported no apparent adverse effects. In short, the researchers found that metformin, at appropriate doses, should be safe to use in people with mild to moderate kidney impairment.

Under the FDA’s current restriction, many health care providers must prescribe metformin off-label for patients with kidney impairment, making it more difficult for patients to access this valuable treatment. As we understand it, providers do prescribe metformin for this purpose, and the guidelines in the UK recommend an expanded label as well. An expanded label that allows for the cautious and well-monitored use of metformin in these populations would better reflect current medical research and allow for increased access to patients. Although the FDA restriction may seem minor, the reality is that as many as 2.5 million patients living with diabetes and kidney impairment are unable to access metformin if doctors follow the labeled use. Making the drug available for many more patients could have a profound impact.

More research on metformin demonstrates that it may also be useful in other populations. JDRF has invested $2.8 million in a research grant to the T1D Exchange to study metformin in overweight adolescents with type 1 diabetes to help improve blood sugar control. Metformin also has the potential to delay or prevent diabetes for the 86 million Americans with prediabetes, but the FDA doesn’t currently have an approval pathway for prediabetes drugs. It’s time we address how our regulatory process affects access to critical therapies and treatments and to continue to work collaboratively with the FDA to provide them feedback from patients directly. As this important paper demonstrates, sticking with the status quo is no longer enough.

Appendix: Based on their findings, the authors suggest a possible new guideline for prescribing metformin that would allow cautious use with some dose adjustment in people with mild to moderate renal impairment: