Evidence Growing Metformin Safe in Many With Diabetes and CKD

Kristin Jenkins

June 05, 2018

More evidence supporting the "cautious use" of metformin in selected patients with type 2 diabetes and mild to moderate chronic kidney disease (CKD) is emerging.

A new analysis of two large retrospective patient cohorts in the United States shows there was no significant association between metformin therapy and incident lactic acidosis in those with an estimated glomerular filtration rate (eGFR) of at least 30 mL/min/1.73 m2.

Rates of acidosis in metformin users with an eGFR range of 30 to 44 or 45 to 59 mL/min/1.73 m2 were comparable with those in patients who had never been treated with metformin, according to Benjamin Lazarus, MBBS, MPH, from Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, and colleagues.

This was the case even after controlling for confounding variables, such as age, comorbid conditions, cardiovascular risk factors, serum bicarbonate levels, and concomitant medications, including insulin, the study authors say in their report, published June 4 in JAMA Internal Medicine.

"These findings support the recent expansion of the eGFR thresholds for metformin use by the [US Food and Drug Administration (FDA)], and recommendations from other regulatory bodies, which suggest that metformin can be used when eGFR is 45 to 59 mL/min/1.73 m2 and cautiously when eGFR is 30 to 44 mL/min/1.73 m2," they write.

In an invited commentary, Chester B. Good, MD, MPH, from the Veteran Affairs Center for Medication Safety in Hines, Illinois, and Leonard M. Pogach, MD, from the Department of Veterans Affairs New Jersey Healthcare System in East Orange, say this study "increases our confidence that metformin is safe to use in patients with mild to moderate CKD."

Caveats Critical With Metformin and Moderate CKD

Metformin has been the first-line treatment of choice for type 2 diabetes in the United States and Europe for decades, the researchers note.

However, its use in patients with CKD has been contraindicated until quite recently, when the FDA decided in 2016 to permit the use of metformin in patients with mild CKD (eGFR, 45 mL/min/1.73 m2 or greater).

When the eGFR falls to between 30 and 45, which is moderate CKD, the FDA recommends further caution with a careful risk/benefit calculation before deciding to stop or continue the medication.

Metformin use is still contraindicated in those with advanced CKD (eGFR <30 mL/min/1.73 m2).

Despite this change in recommendations, about 1 million eligible patients in the United States do not receive guideline-directed metformin therapy, possibly because of "uncertainty regarding the risk of acidosis in patients with [CKD]," Lazarus and colleagues say.

And despite the reassurance from this new study, Good and Pogach say many questions still remain, including how the benefits and risks of metformin in patients with CKD stack up against those observed with newer medications for type 2 diabetes that also offer cardiovascular protection, such as liraglutide (Victoza; Novo Nordisk) and empagliflozin (Jardiance; Boehringer Ingelheim Pharmaceuticals, Inc).

In the meantime, they emphasize that "caveats are critical" in patients with moderate CKD with an eGFR between 30 and 45 mL/min/1.73 m2.

"At a minimum, patients in this category should have a repeated eGFR measurement given the limitation in the accuracy of a single eGFR determination," they write.

And those "at higher risk for dehydration due to concomitant medication use (especially sodium-glucose co-transporter inhibitors and diuretics), social circumstances, and comorbid conditions should be carefully monitored for symptoms or worsening renal function."

Most Patients Will Opt for Metformin When Pros and Cons Are Explained

Discussing a suitable treatment strategy with patients is likely to present a significant clinical challenge, especially in cases in which the use of metformin differs from conventional wisdom or from current FDA guidelines, Good told Medscape Medical News.

"Concepts like absolute and relative risk, for both risks and benefits, can be challenging for patients to understand and for physicians to explain in a clear but succinct fashion," he explained. "Diabetes educators and clinical pharmacists can be invaluable as part of this process."

Good and Pogach predict that when all the therapeutic avenues are laid out, most patients will opt for metformin.

"Metformin offers low cost, excellent tolerability for most patients, likely benefit in patients with moderate CKD, many years of clinical experience to uncover adverse events, and is recommended as first-line therapy by both the American Diabetes Association and the American College of Physicians."

Newer agents have a role when additional therapy is needed, and when patients are unable to tolerate metformin or are otherwise unsuitable candidates, they indicate.

Asked for comment, Robert A. Gabbay, MD, PhD, chief medical officer at Joslin Diabetes Center in Boston, Massachusetts, agreed this study provides "further evidence on the safety of metformin in patients with diabetes and chronic kidney disease," and he reiterated the endorsements of its use in this patient population by the FDA and American Diabetes Association.

However, the clinical questions that remain are unlikely to be answered by randomized controlled trials, he added.

Study Results

For the study, Lazarus and colleagues looked at a primary community-based cohort of 75,413 patients with diabetes who were receiving primary care in the Geisinger Health System, which included time-dependent assessment of eGFR stage from January 2004 until January 2017.

Mean participant age was 60.4 years, and 51% were women. During the median follow-up of 5.7 years, there were 2335 hospitalizations with acidosis.

The researchers then replicated the results in a second cohort that included 67,578 new users of metformin and 14,439 new sulfonylurea users between 2010 and 2015. The MarketScan data were sourced from 350 private US health systems.

When compared with alternate diabetes management, the analysis showed that time-dependent metformin use was not associated with incident acidosis overall (adjusted hazard ratio [HR], 0.98). It was also not associated with incident acidosis in patients with eGFR 45 to 59 mL/min/1.73 m2 (adjusted HR, 1.16) and eGFR 30 to 44 mL/min/1.73 m2 (adjusted HR, 1.09).

An increased risk for acidosis was seen with metformin use at eGFR less than 30 mL/min/1.73 m2 (adjusted HR, 2.07), however.

These results were also consistent for incident acidosis in those with eGFR 30 to 44 mL/min/1.73 m2 for the following groups: new metformin users compared with new sulfonylurea users (adjusted HR, 0.77), in a propensity-matched cohort (adjusted HR, 0.71), after exclusion of baseline insulin users (adjusted HR, 1.16), and in the replication cohort (adjusted HR, 0.86).

"In 2 real-world clinical settings, metformin use was associated with acidosis only at eGFR less than 30 mL/min/1.73 m2. Our results support cautious use of metformin in patients with type 2 diabetes and eGFR of at least 30," they conclude.

Funding for this study was provided by the National Institutes of Health. Lazarus has disclosed no relevant financial relationships. One coauthor has disclosed that he is chair of the FDA's Peripheral and Central Nervous System Advisory Committee and has relationships with MesaRx Innovations, Monument Analytics, and OptumRx. The other authors and Gabbay have disclosed no relevant financial relationships.

JAMA Intern Med. Published June 4, 2018. Article abstract, Commentary extract

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