By Annette M. Boyle

LONG BEACH, CA—In recent years, the American Diabetes Association and other organizations have recognized that very low glycemic rates do not provide a cardiovascular benefit and might instead increase mortality risk in the majority of patients. The studies that identified those counterintuitive results did not include diabetic patients with chronic kidney disease, however.

The new research is related to dialysis patients. In this photo, Air Force Mary Bolinger has dialysis equipment in her recreational vehicle as part of a program at the VA Pittsburgh Health System. VA photo

Diabetes not only increases the risk of end stage renal disease (ESRD), it increases mortality rates among those who develop kidney failure. Would historically high glycemic rates continue to affect patients after they transition to dialysis?

Connie Rhee, MD, MSc

Researchers led by Connie Rhee, MD, MSc, and Kam Kalantar-Zadeh, MD, MPH, PhD, both of the Tibpor Rubin VA Long Beach Healthcare System and the University of California-Irvine, recently found that the effects of high glycemic levels persisted much longer than expected. Their study was published in the August issue of Diabetes Care.1

“The avoidance of high glycemic levels in patients with diabetic kidney disease may have lasting benefit in reducing morbidity and mortality even after developing irreversible end-organ damage which required transitioning to dialysis therapy, as if there were a potential ‘metabolic memory’ or ‘legacy effect,’” Rhee told U.S. Medicine.

Understanding the impact of glycemic levels on diabetic patients with chronic kidney disease (CKD) could significantly affect VA care. Between 12,000 and 13,000 veterans transition to maintenance dialysis therapy each year. About 5,000 of those veterans develop end-stage renal disease as a complication of diabetes, she noted.

The study found that diabetic patients with chronic kidney disease who had mean HbA1c levels above 8% in the year before they transitioned to dialysis—the prelude period—had higher mortality rates in the year after they developed ESRD than those who had HbA1c levels between 6% and 7%. Patients with mean A1c between 8% and 9% in the prelude period had a 19% increase in the risk of death in the first year on dialysis, while those with A1c above 9% saw a 50% increase in mortality risk. Mean random glucose levels of 200 mg/dL or greater increased post-ESRD adjusted mortality risk 34% compared to the reference range of 100 mg/dL to 125 mg/dL.

Kam Kalantar-Zadeh, MD, MPH, PhD

The primary takeaway is “that a better control of diabetes in these veterans with advanced chronic kidney disease had far reaching impact even after they transitioned to dialysis,” Kalantar-Zadeh told U.S. Medicine.

Risks of Low HbA1c

While high glycemic levels appear to have long-term sequelae, very low levels also pose their own risks. Both the Kidney Disease Outcomes Quality Initiative (KDOQI) and Kidney Disease: Improving Global Outcomes (KDIGO) guidelines advise against setting a target HbA1c below 7% in individuals at risk of hypoglycemia, including those with Stage 4 or 5 chronic kidney disease and patients on insulin, sulfonylureas and possibly metformin, Rhee noted.

“Note that we did not per se observe that our lowest averaged HbA1c and lowest averaged random glucose categories were associated with improved survival,” Rhee cautioned. The lowest measures and reference ranges had similar mortality rates in the study.

The lowest mean glycemic level seen in the study were in the moderately-low rather than in the hypoglycemic range, which may explain why the lowest levels were not associated with an increase in mortality as seen in previous reports, she said. The team is now researching the impact of very low glycemic levels on post-ESRD outcomes.

Pending the results of the follow-on studies, “we would still caution against aggressive glycemic targets in patients (including veterans) with diabetic kidney disease, including those already on dialysis. Among established dialysis patients, there are a number of studies that have shown a U-shaped association between BOTH lower (HbA1c below 6%) and higher (HbA1c above 8%) glycemic levels with higher mortality risk,” Rhee said.

The researchers studied the records of 52,172 patients in the VA’s national Transition of Care in CKD study who transitioned to dialysis between October 2007 and September 2011. Of those, the 15,549 veterans who had HbA1c or random blood glucose measurements recorded in the prelude year and a diagnosis of diabetes or cause-of-ESRD due to diabetes served as the primary cohort for the Long Beach study.

While guidelines recommend a target HbA1c above 7% in patients with comorbidities and limited life expectancy and those at risk of hypoglycemia, they do not specify the upper limit of the preferred glycemic range for these patients. The finding that mean HbA1c levels above 8% and random glucose measurements above 200 ml/dL in the year before dialysis initiation leads to worse outcomes in patients with diabetes and ESRD may help clinicians set appropriate targets for these patients.

“Based on the existing data and the findings from our study, we recommend that in patients with advanced diabetic kidney disease who may soon require dialysis therapy, a reasonable but not too aggressive glycemic status is associated with improved long-term outcomes that may last even after having transitioned to maintenance dialysis therapy,” Rhee and Kalantar-Zadeh said.

Clinicians may also want to consider the risks of various anti-diabetes medications on this population. The increase in mortality seen in the study was limited to insulin users with HbA1c levels above 8% or mean random glucose levels higher than 200mg/dL, the authors observed. In contrast, they noted that a recent Taiwanese study of diabetes patients on dialysis demonstrated an association between sulfonylurea, meglitinides and thiazolidinediones and elevated risk of myocardial infarction.2

  1. Rhee CM, Kovesdy CP, Ravel VA, Streja E, Brunelli SM, SoohooM, Sumida K, Molnar MZ, Brent GA, Nguyen DV, Kalantar-Zadeh K. Association of Glycemic Status During Progression of Chronic Kidney Disease with Early Dialysis Mortality in Patients with Diabetes. Diabetes Care 2017;40:1050-1057.
  2. Lin TT, Wu CC, Yang YH, et al. Anti-hyperglycemic agents and new-onset acute myocardial infarction in diabetic patients with end-stage renal disease undergoing dialysis. PLoS One 2016;11: e0160436.