Among more than 1.3 million veterans who did not have diabetes, those with blood urea nitrogen (BUN) levels above a certain cut point were more likely to develop type 2 diabetes during a 5-year follow-up, irrespective of their kidney function.
This study of “big data” is the first to show that BUN is an independent risk factor for diabetes in humans, and it confirms findings in mice, senior author Ziyad Al-Aly, MD, from the VA St Louis Health Care System, Missouri, told Medscape Medical News.
The article, by Yan Xie, also from VA St Louis Health Care System, and colleagues, was published online December 11 in Kidney International.
The researchers found that seven more patients per 1000 patients were diagnosed with diabetes per year in the group of patients with high BUN (> 25 mg/dL), compared with the group of patients with low BUN (< 25 mg/dL).
This difference is “not astronomically high,” said Dr Al-Aly, “but it is significant from a public-health perspective.”
When kidneys are failing, they lose their ability to rid the body of urea — a breakdown product of protein metabolism — and levels of urea in the blood rise, Dr Al-Aly noted. But patients can also have a high urea level with normal kidney function (a normal estimated glomerular function [eGFR]), by eating a lot of red meat, for example.
Moreover, some studies have shown that reduced red-meat consumption reduces the risk of diabetes, Dr Al-Aly continued. The current study suggests that differences in urea levels might explain some of this finding.
However, it is too early to prescribe medications to lower blood urea levels in patients with high levels of this metabolite, he cautioned, since it’s not known if this would lower their risk of diabetes. Further studies are needed.
In the meantime, “eating a healthy diet is good, in general,” Dr Al-Aly noted, so advising patients with a high BUN to make “dietary modifications to try to reduce protein consumption in the hope this would reduce urea and also reduce the risk of diabetes might not be an unreasonable approach.”
Would Findings in Mice Be Replicated in Humans?
A study in mice by another of the authors, Vincent Poitout, professor at Université de Montréal, Quebec, and colleagues (J Clin Invest. 2016;126:3598–3612), sparked the current study, said Dr Al-Aly.
“They did amazing work. They showed that in mice, urea suppresses insulin secretion and also reduces insulin sensitivity,” suggesting that high urea levels are associated with incident diabetes.
To investigate this in humans, the researchers identified 1,1337,452 veterans who were part of the VA Health Care System database in 2003 and did not have diabetes at baseline and followed them until 2008.
The study outcome was incident type 2 diabetes, defined based on ICD9 codes, plus having either a prescription for an antidiabetic agent or an HbA1c > 6.4%.
At study entry, 91% of patients had a BUN < 25 mg/dL and 9% had a high BUN level.
The patients were mainly men (95%), and most were white (82%). A third were obese. Three-quarters had four or more outpatient clinic visits per year.
Overall, they had a mean age of 66; those with a high BUN were older than the others (mean age of 77 vs 65). More than 300,000 patients were younger than 50.
At study entry, most patients (83%) had never used medications such as corticosteroids that increase the risk of diabetes.
It’s Not the Kidney Problem Causing Diabetes, It’s Urea
During a median follow-up of 4.93 years, there were 172,913 new cases of diabetes.
Patients with a high BUN had a 23% higher risk of developing diabetes compared with the other patients (hazard ratio, 1.23; 95% CI, 1.21–1.25).
There were 2989 new cases of diabetes per year for every 100,000 patients with low urea levels vs 3677 new cases of diabetes per year for every 100,000 patients with high urea levels, said Dr Al Aly.
“This means that for every 100,000 people, there would be 688 more cases of diabetes each year in those with higher urea levels,” he added.
The risk of incident diabetes was significantly increased in patients with a BUN > 25 mg/dL at all levels of eGFR.
Among patients with a high BUN, even patients with eGFR > 60 mL/min/1.73 m2 had an increased risk of developing diabetes (hazard ratio, 1.27).
“Our results were almost an exact replica of the mouse study. The results showed a clear relationship between urea levels and risk of diabetes. It’s not the kidney problem that is causing the risk of diabetes. It’s urea,” Dr Al-Aly reiterated.
Healthcare practitioners who deal with patients with diabetes or kidney disease — such as primary-care physicians, diabetologists, and nephrologists — should be paying some attention to urea, but “this is really not the end of the story,” he said.
“We need to determine if lowering BUN would lower their risk.”
In addition, “future research should examine whether higher levels of urea are associated with poorer diabetes control and poorer outcomes among diabetic patients and whether elevated levels of urea are associated with an increased risk of failure of oral hypoglycemic agents and increased need for insulin,” the authors suggest.
The study was funded by a grant from the US Department of Veterans Affairs. The authors have no relevant financial relationships.
Kidney Int. Published online December 11, 2017. Article
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