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Tuesday, November 29, 2011

HbA1c Must Be Just Right in Diabetic Kidney Disease

By Todd Neale, Senior Staff Writer, MedPage Today
Published: November 28, 2011
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner
Among patients with diabetes and stage 3 or 4 chronic kidney disease, glycated hemoglobin levels that are too low are associated with worse clinical outcomes, just as are levels that are too high, an observational study showed.

Higher glycated hemoglobin (HbA1c) levels at baseline were associated with greater risks of death, progression of kidney disease, new end-stage renal disease, cardiovascular events, and all-cause hospitalization (P<0.001 for all trends), according to Marcello Tonelli, MD, of the University of Alberta in Edmonton, and colleagues.
Action Points  

  • Among patients with diabetes and stage 3 or 4 chronic kidney disease, higher glycated hemoglobin (HbA1c) levels at baseline were associated with greater risks of death, progression of kidney disease, new end-stage renal disease, cardiovascular events, and all-cause hospitalization.
  • Low HbA1c levels of less than 6.5% were also associated with an increased mortality risk.
But for mortality in particular, an HbA1c level that was too low -- less than 6.5% -- also was associated with an elevated risk, they reported in the Nov. 28 issue of Archives of Internal Medicine.
Those findings are largely consistent with two observational studies reported earlier this month at the annual meeting of the American Society of Nephrology, which showed that HbA1c values outside a 6% to 9% range were associated with increased mortality in diabetic patients with end-stage renal disease.
Noting the limitations of observational data, however, Tonelli and colleagues said that randomized controlled trials are needed to confirm whether overly intensive therapy worsens outcomes in patients with diabetes and chronic kidney disease.
Targeting HbA1c levels lower than 7% has been shown to slow the progression of diabetic kidney disease, and the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (KDOQI) suggests that goal for all diabetic patients, regardless of kidney function.
But patients with chronic kidney disease have been mostly excluded from glycemic control trials and a co-chair of the KDOQI work group on diabetes and chronic kidney disease suggested at the ASN meeting that the upcoming revision of the guidelines -- based on research reported since the last update in 2007 -- will include higher targets for these patients.
The ACCORD trial showed that intensive glycemic control to a target less than 6% increased mortality in higher-risk patients with type 2 diabetes. That trial excluded patients with elevated creatinine levels, and thus, most patients with chronic kidney disease.
"As with participants in the ACCORD trial, it is plausible that patients with diabetes and chronic kidney disease who are treated to an HbA1c level lower than 6.5% might experience iatrogenic harm owing to serious hypoglycemic events or too precipitous a fall in average glucose," Tonelli and colleagues wrote.
Using hospitalization and claims data from Alberta, the researchers identified 23,296 patients with stage 3 or 4 chronic kidney disease and type 1 or 2 diabetes. They were stratified by glycemic control based on the first HbA1c measurement completed during the study period.
The median HbA1c at baseline was 6.9%. About one in every 10 patients (11%) had a value greater than 9%.
Through a median follow-up of nearly four years, 16% of the patients died, 49% were hospitalized, 16% had a cardiovascular event, 6% had a progression of kidney disease defined by a doubling of serum creatinine, and 2% developed end-stage renal disease.
After adjustment for age, sex, baseline kidney function, individual and neighborhood income, comorbidities, and residence location, higher HbA1c values were associated with an elevated risk of all five outcomes.
The association with mortality was U-shaped, however, with greater risks at HbA1c levels lower than 6.5% and higher than 8%.
And the relationship with incident end-stage renal disease was significantly stronger in patients with milder chronic kidney disease at baseline (P<0.001 for the interaction), which "may represent a 'point of no return' for kidney function -- beyond which better glycemic control may simply not be enough to prevent progressive kidney function loss," Tonelli and colleagues wrote.
But, in an accompanying editorial, David Goff Jr., MD, PhD, of Wake Forest University in Winston-Salem, N.C., pointed out that severity of renal dysfunction was not a significant modifier of the relationship between glycemic control and a doubling of serum creatinine levels.
"The lack of internal consistency for these two renal outcomes [incident end-stage renal disease and disease progression] raises some uncertainties regarding the clinical importance of the differential association of HbA1c level with end-stage renal disease between stage 3 and stage 4 chronic kidney disease," he wrote.
Goff also called for randomized controlled trials to better inform the discussion about the best approaches for managing risk factors in patients with advanced kidney disease.
But, he added, "in the absence of strong evidence specific to patients with advanced chronic kidney disease and diabetes, prudent practice may be to pursue at least moderately intensive risk factor management while minimizing the potential for serious adverse effects of the treatment regimens."
Tonelli and colleagues acknowledged some limitations of their analysis, including the retrospective design, the inability to control for several potential confounders, the use of a single measurement of serum creatinine to define chronic kidney disease, and the inability to distinguish between type 1 and 2 diabetes.
The study was funded by an operating grant from the Heart and Stroke Foundation of Canada, and by an interdisciplinary team grant from the Alberta Heritage Foundation for Medical Research (AHFMR). Tonelli and three of his co-authors were supported by career salary awards from the AHFMR. Tonelli was also supported by a Government of Canada Research Chair. Four of the study authors were supported by a joint initiative between Alberta Health and Wellness and the Universities of Alberta and Calgary.
The authors reported that they had no conflicts of interest.
Goff is an ACCORD investigator. He has received compensation as a member of the Operations Committee for a trial of a glucose-lowering medication marketed by Merck. He serves as a Data and Safety Monitoring Board member for a trial of a glucose- lowering medication marketed by Takeda.


Primary source: Archives of Internal Medicine
Source reference:
Shurraw S, et al "Association between glycemic control and adverse outcomes in people with diabetes mellitus and chronic kidney disease: a population-based cohort study" Arch Intern Med 2011; 171: 1920-1927.


Additional source: Archives of Internal Medicine
Source reference:
Goff D Jr. "Glycemic control and cardiorenal outcomes in patients with advanced chronic kidney disease: relative or absolute risks?" Arch Intern Med 2011; 171: 1927-1928.


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Higher, Lower HbA1c Levels Associated With Worse Outcomes In CKD With Diabetes.

MedPage Today Share to FacebookShare to Twitter (11/29, Neale) reports, "Among patients with diabetes and stage 3 or 4 chronic kidney disease, glycated hemoglobin levels that are too low are associated with worse clinical outcomes, just as are levels that are too high," according to a study Share to FacebookShare to Twitter in the Nov. 28 issue of Archives of Internal Medicine. "Higher glycated hemoglobin (HbA1c) levels at baseline were associated with greater risks of death, progression of kidney disease, new end-stage renal disease, cardiovascular events, and all-cause hospitalization (P<0.001 for all trends)." However, "for mortality in particular, an HbA1c level that was too low -- less than 6.5% -- also was associated with an elevated risk." An accompanying editorial Share to FacebookShare to Twitter "called for randomized controlled trials to better inform the discussion about the best approaches for managing risk factors in patients with advanced kidney disease."
 

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