In Diabetes With CKD, Moderate Glycemic Control May Be Ideal

November 30, 2011 — In patients with diabetes mellitus (DM) and chronic kidney disease (CKD), hemoglobin A_1c (HbA_1c) targets that fall between 7% and 9% may be associated with decreased risk for adverse outcomes, whereas levels either above or below this range may increase this risk, according to a new study.

"[W]e found strong and independent associations between higher levels of HbA_1c and multiple clinically relevant outcomes, including mortality, [cardiovascular] events, hospitalization, and progression to kidney failure," write Sabin Shurraw, MD, from the University of Alberta in Edmonton, Canada, and colleagues, in an article published in the November 28 issue of the Archives of Internal Medicine.

"Our findings are consistent with the hypothesis that (as in the general population of patients with DM) better glycemic control in patients with stage 3 to 4 CKD tends to improve clinical outcomes, but that overly intensive therapy (ie, HbA_1c target level lower than 7%) may be harmful," they write.

However, although risk reduction for 4 outcomes was associated with better glycemic control among patients with both stage 3 and 4 CKD, findings for a fifth outcome, end-stage renal disease (ESRD), showed that the association between better glycemic control and reduced risk was actually weaker for those with stage 4 CKD compared with for those with stage 3 disease.

The study used data on patients with both DM and CKD from the Alberta Kidney Disease Network and the provincial health ministry from 2005 through 2006 to examine the association between glycemic control and adverse outcomes.

CKD was identified through routine serum creatinine measurements and was defined as an estimated glomerular filtration rate (eGFR) of less than 60.0 mL/minute per 1.73 m².

A total of 23,296 patients met criteria for the study, most (n = 21,155) with stage 3 CKD (eGFR, 30.0 – 59.9 mL/minute per 1.73 m²), and 2141 with stage 4 CKD (eGFR, 15.0 – 29.9 mL/minute per 1.73 m²).

The median HbA_1c level was 6.9% (range, 2.8% – 20.0%), and 11% of the participants had an HbA_1c level higher than 9%.

The primary outcome for the study was all-cause mortality, with other outcomes being cardiovascular events, hospitalizations, progression of kidney disease (based on a doubling of serum creatinine level), and ESRD.

During the median follow-up period of 3.8 years (range, 1 – 51 months), 16% of patients died, 49% were hospitalized, 16% had any cardiovascular event, 6% had progression of kidney disease, and 2% developed ERSD.

The analysis was adjusted for the following potential confounders: age, sex, index eGFR, individual health insurance premium level (a marker for individual level income), median neighborhood income, comorbidity, and residence location.

The researchers found that for both stage 3 and stage 4 CKD, higher HbA_1c levels were associated with an increased risk for all-cause mortality, cardiovascular events, hospitalizations, and progression of kidney disease (P < .001), but for the ERSD outcome, the magnitude of this association was weaker among those with stage 4 CKD compared with those with stage 3 CKD.

Specifically, for both stages of CKD, HbA_1c levels above 9% were associated with significantly higher all-cause mortality than HbA_1c levels below 7% (adjusted hazard ratio [HR], 1.35; 95% confidence interval [CI], 1.21 – 1.50), although there was a U-shape to this association, in that HbA_1c levels greater than 8% or lower than 6.5% were associated with increased mortality compared with levels of 7%.

"As with participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, it is plausible that patients with DM and CKD who are treated to an HbA_1c level lower than 6.5% might experience iatrogenic harm owing to serious hypoglycemic events or too precipitous a fall in average glucose," the authors speculate.

Similarly, for both stages 3 and 4 CKD, HbA_1c levels higher than 9%, compared with those lower than 7%, were associated with an increased risk for hospitalization (adjusted relative risk [RR], 1.44 [95% CI, 1.36 – 1.52] and 1.25 [95% CI, 1.01 – 1.54], respectively), as well as with progression of kidney disease (adjusted HR, 1.77 [95% CI, 1.48 – 2.13] and 1.40 [95% CI, 1.17 – 1.67], respectively).

However, for ERSD, the higher HbA_1c level was associated with more risk among in patients with stage 3 CKD (adjusted HR, 2.52 [95% CI, 1.58 – 4.02]) compared with those with stage 4 CKD (adjusted HR, 1.13 [95% CI, 0.80 – 1.59]).

"We speculate that this finding 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," the authors write.

In an invited commentary accompanying the paper, David C. Goff, MD, PhD, writes that the findings "underscore the importance of considering relative and absolute risks (or benefits) when examining potential subgroup differences in risk (or treatment) effects."

If one were to look at the data according to estimated adjusted absolute risks, the difference in risk for ESRD between good and poor glycemic control would be 0.60% in patients with stage 3 CKD and 1.41% in patients with stage 4 CKD, noted Dr. Goff, who is from the Department of Epidemiology and Prevention at Wake Forest School of Medicine in Winston-Salem, North Carolina.

"From this perspective, intensive glucose control might lead to greater absolute prevention of ESRD in stage 4 CKD than in stage 3 CKD, an inference that conflicts with the speculation of the authors based on considering relative risk (and potential relative risk reduction) alone."

However, acknowledging that the overall study results "emphasize the importance of a high HbA_1c level as a risk marker for cardiovascular and renal outcomes," Dr. Goff suggests that "[i]n the absence of strong evidence specific to patients with advanced CKD and DM, 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."

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. Four authors were supported by career salary awards from the foundation. One author was also supported by a Government of Canada Research Chair. Four authors were supported by a joint initiative between Alberta Health and Wellness and the Universities of Alberta and Calgary. Dr. 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.