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Metformin appears safe for patients with mild to moderate CKD
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Clinicians may expand the use of metformin in patients with type 2 diabetes with mild to moderate kidney disease cautiously, based on literature showing limited evidence of increased risk for lactic acidosis, according to a review published in JAMA.
“Our systematic review found that the actual risk of lactic acidosis in metformin-treated patients is essentially equivalent to the background rate in patents whose type 2 diabetes is being treated with other drugs,” Silvio E. Inzucchi, MD, of Yale University School of Medicine, told Endocrine Today. “Moreover, in the rare circumstance where a metformin-treated patient does develop lactic acidosis, there is usually another explanation for the metabolic decompensation.”
Silvio E. Inzucchi
The data suggest that the drug can be continued when estimated glomerular filtration rates drop below 60 mL/min/1.73 m2, Inzucchi said. When eGFR reaches 45 mL/min/1.73 m2, the dose should be reduced by half and stopped when eGFR reaches 30 mL/min/1.73 m2.
“These recommendations are similar to those already in widespread use in the United Kingdom,” Inzucchi said.
He and colleagues searched MEDLINE and Cochrane databases for articles published between 1950 and 2014 pertaining to metformin, kidney disease and lactic acidosis. The researchers included 65 articles, of 818 initially identified, comprising pharmacokinetic/metabolic studies, large case series, retrospective studies, meta-analyses and a clinical trial.
The investigators found that metformin levels generally remain in the therapeutic range, with lactate concentrations not considerably increased, when used in patients with mild to moderate CKD (30-60 mL/min per 1.73m2).
Overall incidence of lactic acidosis in patients treated with metformin varies (approximately 3 per 100,000 to 10 per 100,000 person-years) across studies and is indistinguishable from the overall diabetes population.
The researchers found limited data suggesting an elevated risk for lactic acidosis in metformin-treated patients with CKD; further, they found no randomized controlled trials evaluating the safety of the drug in patients with significantly impaired kidney function.
Population-based studies demonstrate that metformin may be prescribed counter to prevailing renal guidelines in up to one in four patients with type 2 diabetes, according to the researchers. In most reports, the use is not linked to increased rates of lactic acidosis.
Observational studies suggest metformin could potentially benefit macrovascular outcomes, even in patients with renal contraindications.
“When investigators have retrospectively assessed outcomes in those patients with kidney disease who took metformin in violation of the guidelines, their clinical outcomes were generally better than those not being treated with metformin,” Inzucchi said.
The FDA currently recommends halting the use of metformin when serum creatinine reaches 1.5 mg/dL in men or 1.4 mg/dL in women, he said.
“Current prescribing guidelines for metformin are antiquated,” Inzucchi said. They fail to reflect both modern reporting of kidney function as well as pathophysiologic understanding of lactic acidosis relative to metformin and current prescribing patterns, he added.
“Millions of patients with type 2 diabetes in the United States are being deprived of access to this inexpensive, safe and effective drug because of the prevailing guidelines,” Inzucchi said.
He noted that his group, backed by more than 100 US diabetes experts, has already petitioned the FDA to act based on available data.
“A randomized trial in type 2 diabetes patients with mild to moderate CKD would be great,” Inzucchi said. “But this would likely require too many patients over too many years to be feasible — a direct reflection of how rare lactic acidosis really is in this population.”
For more information:
Silvio E. Inzucchi, MD, can be reached at the Section of Endocrinology, Yale School of Medicine, 333 Cedar St., New Haven, CT 06520; email: silvio.inzucchi@yale.edu.
Disclosure: Inzucchi reports serving as a consultant for Boehringer Ingelheim, Bristol-Myers Squibb, Janssen, Merck and Novo Nordisk; serving as speaker for Merck; and receiving nonfinancial support from Takeda. Please see the study for the full list of the other researchers’ financial disclosures.
Perspective
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Kenneth Cusi, MD, FACP, FACE
I fully support expanding the use of metformin to people whose estimated glomerular filtration rates (eGFRs) are between 30 and 60 mL/min/1.73 m2. This medication is inexpensive, effective and well-tolerated. Most clinicians believe it is very safe, even beyond the label restrictions, but the medicolegal aspects of prescribing outside the label indications make physicians reluctant to use the drug in many patients who could benefit from it.
In fact, we already are using metformin in many people who have impaired kidney function, whether we know it or not. About one in six adults with diabetes have reduced eGFRs, and that rate is doubled for patients 65 years or older (De Boer IH. JAMA. 2011.305:2532-2539).
Among the key findings of this review is that in most studies, the concentrations of lactic acid among those on metformin are similar, or slightly higher, than those on other medications, but never in the range where there is of risk for lactic acidosis. Pivotal early studies at the time of drug approval showed that lactate metabolism is really not affected in healthy patients with diabetes who are taking metformin (Cusi K. J Clin Endocrinol Metab. 1996.81:4059-4067). Many studies since then have also shown the drug to be safe in patients with renal impairment with eGFRs in the range of 30 to 60 mL/min/1.73 m2.
In another challenge to current dogma, a recent study by Zhang and colleagues (Hepatology. 2014.60:2008-2016.) found improved survival with continuation of metformin in patients with diabetes and cirrhosis (a contraindication to metformin) although restricted to patients with nonalcoholic steatohepatitis (NASH).
With close monitoring, the benefits of metformin should be extended to the estimated 2.5 million people with eGFRs in the 30 to 60 mL/min/1.73 m2 that are not receiving the drug with the current restrictions. It is time for the FDA to reconsider the current guidelines, and a good first step would be to adopt metformin guidelines similar to those currently used in Canada and United Kingdom.
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