Metformin Ups Mortality in Advanced Kidney Disease

Veronica Hackethal, MD

July 01, 2015

A Taiwanese study is the first to link use of metformin to increased risk of death in patients with type 2 diabetes and advanced kidney disease.

"In a national registry of patients with type 2 diabetes and stage 5 chronic kidney disease [CKD], metformin users compared with nonusers…had a significantly higher risk of death from all causes; however, metformin use was not associated with a greater occurrence of metabolic acidosis," say Szu-Chun Hung, MD,from Taipei Tzu Chi Hospital, Taiwan, and colleagues, in their paper published online June 18 in Lancet Diabetes Endocrinology.

"Our findings have important therapeutic implications, supporting the current recommendations that metformin should not be used in patients with stage 5 chronic kidney disease [serum creatinine > 5.3 mg/dL or estimated glomerular filtration rate (eGFR) < 15 mL/min/1.73 m2]," they write

More research is needed to determine whether patients with less severe chronic kidney disease can continue metformin using dose adjustments, they add.

Although considered first-line therapy for type 2 diabetes, use of metformin in patients with anything more than mild renal impairment (chronic kidney disease stages 1 and 2) is generally not recommended because of the risk for lactic acidosis.

However, guidance on this differs around the world. The US Food and Drug Administration (FDA) carries a boxed warning against metformin use in women with serum creatinine ≥ 1.4 mg/dL and men with serum creatinine ≥ 1.5 mg/dL, equating to eGFR less than 60 mL/min/1.73 m2 (CKD stages 3, 4, and 5).

But the UK National Institute for Health and Care Excellence (NICE) guidance allows metformin use in patients with CKD stage 3a as well as stages 1 and 2 (eGFR > 45 mL/min/1.73 m2).

Consequently, many experts argue that the risk of lactic acidosis with metformin is being overstressed, particularly in the United States, leading to underuse of the medication. In January 2015, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) issued a joint statement saying that the FDA labeling may be too restrictive.

First to Assess Risk of Metformin in Advanced Kidney Disease

Dr Hung and colleagues say that given the discussion on safe prescribing of metformin in renal failure, a relaxation of clinical practice has occurred, which means that many type 2 diabetes patients with stages 1 to 3 CKD (eGFR > 30 mL/min) now do receive metformin.

And there is starting to be debate about whether the drug could even be given to some patients with stage 4 or 5 CKD, they note.

Taiwan, until recently, was one of very few nations where metformin administration was allowed for all patients with type 2 diabetes and CKD, irrespective of the severity of renal impairment. However, in June 2009, Taiwan instituted similar restrictions to the US FDA.

Therefore, using pre-2009 data, the researchers were able to assess the risks and benefits of metformin in this advanced kidney disease patient population.

They performed a retrospective observational study covering the period from January 2000 until June 2009, when the Taiwan Food and Drug Administration began restricting metformin use.

They included patients with type 2 diabetes and stage 5 chronic kidney disease and available data in Taiwan's national health insurance research database. Using propensity-score matching, the authors matched 813 metformin users and 2349 nonusers in a ratio of 1:3.

Metformin Upped Hospital Admission for Cardiovascular Disease

Death from any cause occurred in 53% (n = 434) of metformin users compared with 41% (n = 1012) of nonusers, and multivariate analyses revealed metformin as an independent risk factor for mortality (adjusted hazard ratio [HR], 1.35; P < .0001).

And there was an increased risk of death with increasing metformin dose, with the highest risk among those prescribed over 1000 mg/day (HR, 1.57; P = .048 for trend).

But there was no significant difference in the rate of metabolic acidosis between the groups, occurring in 4% of both (36 metformin users vs 86 nonusers; adjusted HR, 1.30 P = .19).

The increased risk of death with metformin use remained consistent across all subgroups and sensitivity analyses, but the risk of metabolic acidosis remained nonsignificant.

"Our results corroborate previous observations that no relevant link is present between metformin and lactic acidosis, even in patients with stage 5 chronic kidney disease," the researchers observe.

Despite this, mortality was still increased among those on metformin, and although causes of death were not available in their database, "we found that metformin use compared with no use was associated with a significantly higher risk of hospital admission attributable to cardiovascular diseases before death (HR, 1.86; P < .0001)," they note.

However, compared with nonusers, metformin users had a 24% decreased risk of end-stage renal disease (HR, 0.76; P < .0001).

"Additional studies are required to understand the exact mechanisms of increased mortality in these patients," the researchers conclude.

Minority Opinion? Existing FDA Guidance Is Correct...

In an editorial accompanying the study, Kamyar Kalantar-Zadeh, MD, MPH, of the University of California, Irvine School of Medicine in Orange, and Connie Rhee, MD, of University of California, Los Angeles Fielding School of Public Health, say: "The findings of Hung and colleagues give us little doubt that metformin use leads to excess deaths in patients with type 2 diabetes and advanced CKD."

And although they acknowledge the increase in metabolic acidosis seen with metformin in this study was not significant, Dr Kalantar-Zadeh told Medscape Medical News that, in his opinion, "the renal levels that are already well established and recognized by the FDA metformin package insert for decades shall continue to be valid and credible."

Metformin-induced lactic acidosis can be potentially fatal in patients with and without chronic kidney disease, he pointed out, and carries a mortality rate of 40% to 50% or higher.

In addition, patients with diabetes and mild kidney disease are more susceptible to acute kidney injury and accelerated decline in kidney function, but guidelines do not often consider this vulnerability when assessing risk for acidosis. Patients with chronic kidney disease also have comorbidities that increase their acidosis risk, Dr Kalantar-Zadeh noted.

"The safest approach," he advised, is to prescribe metformin only if eGFR > 60 mL/min/1.73 m2 (CKD stage 1 or 2). He offered the following guidance from his own practice:

  • Metformin is "absolutely" contraindicated in patients with eGFR < 45 mL/min (CKD stage 3b, 4, and 5), regardless of serum creatinine.

  • It is "relatively" contraindicated if eGFR falls between 45 to 60 mL/min (CKD stage 3a), although it is better not to give metformin in this range.

  • If creatinine is ≥ 1.4 mg/dL in women and ≥1.5 mg/dL in men, metformin should be discontinued regardless of eGFR.

  • If both serum creatinine and eGFR are normal but the patient is at high risk for acute kidney injury, metformin is contraindicated.

"I am likely a small minority here, as the majority of endocrinologists and also many nephrologists appear to push for relaxation of metformin against the 1.4- and 1.5-mg/dL [creatinine] threshold, which I feel has become the 'new style' of thinking," Dr Kalantar-Zadeh emphasized.

But, he said, "In my opinion, safety overrides all other considerations. Let's learn from the thalidomide story and not sacrifice safety."

The authors and editorialists report no relevant financial relationships.

Lancet Diabetes Endocrinol. Published online June 18 2015. Abstract, Editorial

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