Hemoglobin A1c Level Control and Risk of ESRD and Mortality in Patients with CKD

Patients with both diabetes and chronic kidney disease (CKD) are at increased risk for death, compared with those with diabetes or CKD alone. Diabetic kidney disease is increasing in prevalence; diabetic nephropathy is the leading cause of end-stage renal disease (ESRD). The ideal level of glycated hemoglobin (hemoglobin A1c [HbA1c]) has not been positively established; results of some clinical trials in the general population have shown an association between intensive glycemic control and adverse outcomes in patients with diabetes. The American Diabetes Association recommends targeting an HbA1c level <7% for most nonpregnant adults and <8% for those at risk for hypoglycemia, extensive comorbid conditions, and long-standing diabetes.

There are few data available assessing the associations between HbA1c levels and clinical outcomes in individuals with CKD; findings from previous studies have been inconsistent. Sankar D. Navaneethan, MD, MS, MPH, and colleagues conducted an observational cohort study designed to examine the associations of HbA1c levels with ESRD and death in a population with diabetes and non–dialysis-dependent CKD who were receiving care in a large healthcare system in the United States. Study results were reported in the American Journal of Kidney Diseases [2017;70(2):191-296].

The outcomes of interest were all-cause and cause-specific mortality, ascertained from the Ohio Department of Health mortality files, and ESRD, ascertained from the US Renal Data System. The study included 6165 patients with diabetes and CKD stages 1 to 5, identified via a pre-existing electronic medical record developed by the Cleveland Clinic.

Inclusion criteria were residents of Ohio with at least one outpatient encounter with a healthcare provider at the Cleveland Clinic and (1) either two estimated glomerular filtration rate (eGFR) values <60 mL/min/1.73 m2 more than 90 days apart or International Classification of Diseases, Ninth Revision codes for various kidney diseases, (2) diabetes treated with oral hypoglycemic agents and/or insulin, and (3) HbA1c measured in the year prior to the second eGFR <60 mL/min/1.73 m2 or a CKD diagnosis. Exclusion criteria were age <18 years and a previous diagnosis of ESRD. Patients meeting inclusion and exclusion criteria from January 1, 2005, to September 15, 2009, were included in the current analysis.

The final cohort included 6165 patients; mean age was 70.1 years, 46.7% were men, and 20.7% were black. Mean body mass index was 32.3 kg/m2; the prevalence of hypertension was 96.3%, malignancy, 17.0%, and coronary artery disease, 96.3%. Mean eGFR was 50.5 mL/min/1.73 m2; 58.8% of patients were in CKD stage 3a, 24.5% were in CKD stage 3b, and 7.4% were in CKD stage 4.

Median follow-up was 2.3 years. During that time, 957 patients died, including 887 pre-ESRD deaths, and 205 patients reached ESRD. In unadjusted competing-risk analyses, there were differences in the incidence of ESRD across different HbA1c levels (P<.001) and differences in all-cause mortality (P<.05). In multivariable Cox proportional hazards regression, there was an independent association between HbA1c level and pre-ESRD mortality. Compared with HbA1c levels of 6% to 6.9%, there was an association between HbA1c level <6% and a higher risk for death (hazard ratio [HR], 1.23; 95% confidence interval [CI], 1.01-1.50); results were similar with HbA1c level ≥9% (HR, 1.34; 95% CI, 1.06-1.69). In adjusted competing-risk model of ESRD, there was no significant difference between baseline HbA1c levels <6% and ≥9% and baseline HbA1c levels of 6% to 9%. In analyses for cause-specific mortality, diabetes accounted for >12% of deaths overall and >19% of deaths among participants with HbA1c levels >9%.

The researchers cited some limitations to the study, including the observational design of the study that made establishment of a causal relationship between HbA1c levels and outcomes impossible; deriving the study population from a single, large integrated health system, possibly limiting the generalizability of the findings; the lack of information on the duration of diabetes and other complications related to diabetes and on newer noninsulin injectable antidiabetic drugs; and the limited number of patients with CKD stage 5.

“In summary, we report increased risk for all-cause mortality among patients with diabetes and CKD who had HbA1c levels <6% and among those who had HbA1c levels ≥9%. By contrast, HbA1c level was not associated with ESRD in this study population. The proportion of deaths due to diabetes increased as HbA1c levels increased. Clinical trials comparing different diabetes control targets and specific medication strategies in patients with established CKD are warranted,” the researchers said.

Takeaway Points

  • Researchers conducted an observational cohort study to examine the associations between hemoglobin A1c (HbA1c) levels and end-stage renal disease (ESRD) and mortality in a population of patients with diabetes and chronic kidney disease (CKD).
  • The study included 6165 patients treated at the Cleveland Clinic (Ohio) for diabetes and CKD; of those, 957 died during a median follow-up of 2.3 years and 205 reached ESRD.
  • HbA1c levels of <6% and ≥9% were associated with higher risk for all-cause mortality compared with HbA1c levels of 6% to 9%.