Hemodialysis International 2014; 18:423–432
High Hemoglobin A1c levels and glycemic variability increase risk of severe hypoglycemia in diabetic hemodialysis patients Mark E. WILLIAMS,1 Rajesh GARG,2 Weiling WANG,3 Ronilda LACSON,2 Franklin MADDUX,3 Eduardo LACSON, Jr3 1
Joslin Diabetes Center, Boston, Massachusetts, USA; 2Brigham and Women’s Hospital, Boston, Massachusetts, USA; 3Fresenius Medical Care, North America, Waltham, Massachusetts, USA
Abstract While hyperglycemia is central to the pathogenesis and management of diabetes mellitus, hypoglycemia and glucose variability also contribute to outcomes. We previously reported on the relationship of glycemic control to outcomes in a large population of diabetic end-stage renal disease (ESRD) patients. Recognizing that ESRD is a risk factor for severe hypoglycemia, we have now analyzed the association between glycosylated hemoglobin A1c (HgbA1c) levels and glycemic variability in those with hypoglycemia. This is a retrospective study of patients with diabetes enrolled in a large hemodialysis program. Hypoglycemia was identified from hospital discharge diagnostic codes. Glycemic variability was assessed by the standard deviation of HgbA1c and glucose levels over time. Hypoglycemia as a discharge diagnosis was documented in 4.1% of patients. Higher baseline HgbA1c was associated with greater risk for hypoglycemia hospitalization, a finding confirmed by time-lagged HgbA1c levels drawn a quarter earlier. Higher baseline HgbA1c categories were also associated with greater variability in HgbA1c levels during the analysis period. Similarly, greater glucose variability was associated with higher mean glucose levels by trend analysis. High, not low, HgbA1c levels are associated with greater risk of severe hypoglycemia, which may derive from glucose variability in the setting of treatment for hyperglycemia. High HgbA1c and glycemic variability are associated with increased risk of hypoglycemia in individuals with diabetes and ESRD. Key words: Hypoglycemia, dialysis, diabetes, hemoglobin A1c
INTRODUCTION Diabetes mellitus is a leading cause of end-stage renal disease (ESRD),1 now accounting for nearly 50% of Correspondence to: M. E. Williams, MD, Renal Unit, Joslin Diabetes Center, 1 Joslin Place, Boston MA 02215 U.S.A. E-mail: [email protected] Funding: No external funds
incident dialysis patients in the United States (URSDS). A large body of data indicates that hyperglycemia is central to the development of both micro- and macrovascular complications of diabetes.2 Rigorous glycemic control is therefore a priority in the overall management of patients with diabetes and chronic kidney disease (CKD). However, diabetes has also been depicted as a condition of “dysglycemia”, with two components in addition to hyperglycemia: hypoglycemia and glucose variability,3 each
© 2013 International Society for Hemodialysis DOI:10.1111/hdi.12110
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Williams et al.
contributing to the overall risk of diabetes outcomes beyond hyperglycemia alone. Hypoglycemic events can be serious or even dangerous to patients, and are known to limit the degree of glycemic control possible in patients with diabetes. Aggressive treatment of hyperglycemia may create a greater risk of hypoglycemia and glucose variability, demonstrated in intensively treated patients in large clinical trials (ACCORD, ADVANCE, NICE-SUGAR).4–6 In fact, a recent proposal defined “potential overtreatment creating risk for hypoglycemia” as a threshold of glycosylated hemoglobin A1c (HgbA1c) under 7.0%.7 Although two recent large observational studies with differing methodologies reached somewhat contrasting conclusions with regard to the role of glycemic control in diabetic patients on chronic hemodialysis,8,9 they both highlighted the risks associated with low HgbA1c levels, suggesting that very low glycemic levels may add to risk of mortality. Consistent glycemic control is difficult to achieve in ESRD, specifically because of altered glucose metabolism, fluctuating insulin resistance, impaired insulin secretion, and decreased insulin degradation, as well as because of effects on drug metabolism, adding further complexity to glycemic management. In addition, a wide intrapatient variability is not uncommon day-today with regards to food intake, adherence to glycemic control prescriptions, and cognitive ability relative to the dialysis schedule. These factors not only create unique challenges for glycemic control, but also increase the risk of hypoglycemia and glucose variability in ESRD. We therefore sought to further evaluate the clinical implications of HgbA1c levels with regard to hypoglycemia and glycemic variability in a large national ESRD database.
METHODS This is a retrospective study of data obtained from dialysis information systems that collect information for all patients enrolled in the hemodialysis program of Fresenius Medical Care, North America between October 1 and December 31, 2002.10 The diagnosis of diabetes mellitus was based on either diabetes as the cause of ESRD or on reporting of diabetes as a comorbidity during the baseline period of October 1 to December 31, 2002. Patients with no available HgbA1c during this baseline period were excluded. The study investigators had no influence over the frequency of HgbA1c determinations, which were ordered by the individual nephrologists. All HbgA1c values were measured using the Roche Cobra Integra 800 whole-blood immunoturbidimetric assay (standardized according to the Diabetes Complications Control Trial/ National Glycohemoglobin Standardization Program),
424
performed by a single laboratory (Spectra Laboratories, Rockleigh, NJ, USA). Patient demographic and case-mix variables were collected as of December 31, 2002. These included diabetes type (type 1 or 2), insulin use as determined using i-SCOUT natural language software,11 age, gender, race, dialysis vintage, body surface area (BSA; from height and weight), and vascular access type (native fistula, graft, or catheter). All available laboratory results for the last quarter of 2002 for HgbA1c, eKt/V (fractional urea clearance), hemoglobin, albumin, creatinine, calcium, phosphorus, and white blood cell count were collected. The patient’s 3-month average value was used for each test in the analyses. In addition, all available random blood glucose measurements (most with one result each month) on patients with HgbA1c levels obtained in the last quarter of 2002, drawn within the previous 90 days from the date of the HgbA1c, were analyzed. Most patients had three determinations each quarter. Over the next three years, subsequent HgbA1c levels and hospitalization rates were collected until death, withdrawal from dialysis, or end of calendar year 2005. We also searched for all-cause hospitalizations and looked for hospitalizations with one discharge diagnosis of hypoglycemia within the database that specified International Classification of Diseases 9 codes for hypoglycemia (250.3, 250.8, 251.0, 251.1, 251.2, 962.3). Patients with > = one documented hypoglycemic diagnosis were assumed to be cases, and the remainder became “controls”. Baseline characteristics and laboratory results from patients that experienced hypoglycemia were compared with those patients without them, using t tests or chisquare tests, as appropriate. The standard Cox models were utilized to evaluate the association between HgbA1c levels and hypoglycemia events presented as: unadjusted, adjusted for case-mix, and adjusted for case-mix and laboratory variables. As a sensitivity analysis, we performed a time-dependent Cox model utilizing a one–quarter-lagged HbA1c as a predictor variable to evaluate whether the previous quarter’s HbA1c level, presumably a major determinant for the subsequent quarter’s treatment intensity, would be associated with hypoglycemia-related hospitalization risk. The primary analysis included the association between hypoglycemia-related hospitalization and glycemic variability according to HgbA1c levels. We analyzed glycemic variability by determining the standard deviation (SD) of within-subject HgbA1c levels of available values during the follow-up period along with adjustment according to mean HgbA1c levels. Stepwise logistic regression models
Hemodialysis International 2014; 18:423–432
Predictors of hypoglycemia in hemodialysis patients
(entry at univariate P ≤ 0.1) with all available variables were constructed to determine significant associates of hypoglycemia-related hospitalizations. Logistic regression models were used to determine the association between SD of HgbA1c and the occurrence of hypoglycemiarelated hospitalization events. Because of a non-normal distribution of HgbA1c, a repeat analysis was performed using log-normal HgbA1c, with no difference in the statistical results. Data are presented as unadjusted, mean HgbA1c-adjusted, and case-mix plus laboratory, and mean HgbA1c-adjusted models. All analyses were performed using SAS 9.1 or higher (SAS Institute, Cary, NC, USA; http://www.sas.com).
RESULTS Out of 76,178 ESRD patients on hemodialysis at the Fresenius Medical Care during the study period, 38,701 (50.8%) patients had a diagnosis of diabetes mellitus. Of
these, 13,827 (35.7%) patients were excluded because no HgbA1c was available during the 3-month baseline period. Included in the analysis were all 24,751 chronic in-center hemodialysis patients with diabetes mellitus active on January 1, 2003 and having at least one HbA1c in the preceding quarter. Of the study cohort with diabetes, 75% had diabetes as the cause of their kidney disease based on their Medicare 2728 form. Hypoglycemia as a discharge diagnosis of hospitalization was documented in 4.1% of patients (N = 1017; i.e., “cases”). Baseline characteristics of the entire cohort and of groups with and without hypoglycemia-related hospitalizations are presented in Table 1. For the entire cohort, mean age was 63.7 years, slightly over half were women, 36.4% were black, 5.5% had type 1 diabetes, and BSA was 1.86 m2; eKt/V was 1.41, serum albumin 3.82 g/dL, hemoglobin 11.71g/dL, and HgbA1c 6.77%. Patients with hypoglycemia tended to be younger (61.6 vs. 63.8 years), but with slightly less BSA (1.81 vs. 1.86 m2), with
Table 1 Baseline characteristics of the entire cohort and of groups with and without hypoglycemia-related hospitalizations Characteristics N (%) Age* (years) % Female Race White Black Other Type I diabetes* (%) Vintage (days) Body surface area* (m2) Access type Fistula Graft Catheter Unknown % Insulin at baseline * Type I DM Type II DM * Laboratory results HD dose (eKt/V) Albumin (g/dL) Hemoglobin (g/dL) Calcium (mg/dL) * Phosphorus (mg/dL) Creatinine (mg/dL) White blood cell count Hemoglobin A1C* (%)
All patients
Hypoglycemia-related hospitalization
Without hypoglycemia-related hospitalization
24,751 63.7 (12.1) 51.5%
1,017 (4.1%) 61.6 (13.6) 51.9%
23,734 (95.9%) 63.8 (12.1) 51.5%
53.1% 36.4% 10.6% 5.5% 1,048 (948) 1.86 (0.25)
50.0% 39.2% 10.8% 10.8% 1,029 (900) 1.81 (0.24)
53.2% 36.2% 10.6% 5.3% 1,049 (950) 1.86 (0.25)
29.9% 45.7% 23.6% 0.8% 47.0% 68.0% 45.8%
29.4% 46.0% 23.6% 1.0% 54.3% 73.6% 51.9%
29.9% 45.7% 23.6% 0.7% 46.7% 67.5% 45.6%
1.41 (0.29) 3.82 (0.38) 11.71 (1.10) 9.29 (0.70) 5.60 (1.45) 8.22 (2.67) 7.77 (2.87) 6.77 (1.71)
1.42 (0.30) 3.79 (0.40) 11.68 (1.04) 9.21 (0.70) 5.66 (1.48) 8.20 (2.45) 7.82 (2.24) 7.35 (1.96)
1.41 (0.29) 3.82 (0.38) 11.72 (1.10) 9.29 (0.70) 5.60 (1.45) 8.22 (2.67) 7.77 (2.90) 6.75 (1.70)
Data presented as mean (SD), * P < 0.001 between two groups. DM, diabetes mellitus; HD, hemodialysis.
Hemodialysis International 2014; 18:423–432
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Williams et al.
over-representation of type 1 diabetes (10.8% vs. 5.3%) and insulin use (54.3% vs. 46.7%); of note, hypoglycemia cases had higher mean of HgbA1c values (7.35% vs. 6.75%; all P < 0.001). All other case-mix factors and laboratory results were similar, except for serum calcium (9.21 vs. 9.29, P < 0.001). The multivariable stepwise logistic model indicated that HgbA1c, BSA, diabetes type, insulin use, male sex, and serum calcium were associated with hypoglycemia-related hospitalization, as shown in Table 2. The frequency distribution of the HgbA1c results for the entire cohort is shown by the red line connecting the dots in Figure 1A, along with the breakdown by HgbA1c category of hazard ratios for time to hypoglycemia-related hospitalization. Higher baseline HgbA1c was associated with greater risk for hypoglycemia-related hospitalization, shown in Figure 1A. Time-dependent HgbA1c levels drawn one-quarter earlier confirmed the greater risk of hypoglycemia-hospitalization for high levels, shown in Figure 1B. Log transformation of HgbA1c data (not shown) did not change the results. The association of higher baseline HgbA1c and hypoglycemia-related hospitalization was present both in patients with type 1 and 2 diabetic (Figure 2A,B). All-cause hospitalization risk did not differ according to HgbA1c categories (data not shown). We then evaluated the role of glycemic variability as a risk factor for hypoglycemia hospitalization in the cohort. The distribution of SDs of the 3-year HgbA1c according to baseline HgbA1c levels is shown in Figure 3. Higher baseline HgbA1c categories were associated with greater mean SDs of HgbA1c levels during the analysis period. In addition, the odds ratio of hypoglycemia hospitalization increased sequentially comparing those with increasing SDs of HgbA1c to the group with the lowest variability (Figure 4). As with HgbA1c, greater glucose variability was also associated with higher mean glucose levels by trend analysis (Figure 5). There was good, statistically significant correlation between SD for HgbA1c and SD for glucose levels over the follow period (r = 0.54, P < 0.0001).
Over 12 quarters (3 years) of analysis, distribution of HgbA1c values in the study population remained constant, except for a decrease in the proportion of patients within the lowest HgbA1c category over time (Figure 6). Use of insulin rose steadily in incident patients throughout the 12-quarter observation period.
DISCUSSION This study highlights three new observations: (i) high HgbA1c levels are associated with high risk of hypoglycemia-related hospitalization in diabetic patients on hemodialysis; (ii) variability in chronic glycemic control (SD for HgbA1c) is associated with high risk of hypoglycemia related hospitalization; (iii) higher glycemic variability (SD for HgbA1c as well as SD for glucose levels) is associated with high glycemic levels. We have previously suggested that HgbA1c targets in ESRD patients should be individualized, with less stringent goals being appropriate for older patients and others with greater comorbidities and reduced life expectancy.8 Also to be considered are the presence of risk factors for the occurrence of hypoglycemia. We previously reported that HgbA1c levels, the most widely used index of glycemic control, were below 7% in 65%, 5–6% in 28%, and below 5% in 11% of diabetic hemodialysis patients from a large national ESRD database.8 A similar distribution was reported from a second large ESRD database by KalantarZadeh et al.9 We also previously reported that both low and high extremes of HgbA1c were associated with hospitalization risk in diabetic ESRD patients.12 These data extend previous observations by indicating that a major risk factor for severe hypoglycemia resulting in hospitalization is poor overall glycemic control, as evidenced by the greater risk associated with high HgbA1c categories. Related to this risk are the use of insulin and increased glycemic variability. While an association between low HgbA1c and hypoglycemia was anticipated,13 the association between high HgbA1c and hypoglycemia was an unexpected finding. In the United
Table 2 Multivariate stepwise logistic regression analysis of hypoglycemia-related hospitalizations Steps 1 2 3 4 5 6
Entered variables
P value (final model)
HgbA1c (%) BSA (m2) DM type −2 Calcium (mg/dL) Insulin use at baseline Gender (male)
High Hemoglobin A1c levels and glycemic variability increase risk of severe hypoglycemia in diabetic hemodialysis patients Mark E. WILLIAMS,1 Rajesh GARG,2 Weiling WANG,3 Ronilda LACSON,2 Franklin MADDUX,3 Eduardo LACSON, Jr3 1
Joslin Diabetes Center, Boston, Massachusetts, USA; 2Brigham and Women’s Hospital, Boston, Massachusetts, USA; 3Fresenius Medical Care, North America, Waltham, Massachusetts, USA
Abstract While hyperglycemia is central to the pathogenesis and management of diabetes mellitus, hypoglycemia and glucose variability also contribute to outcomes. We previously reported on the relationship of glycemic control to outcomes in a large population of diabetic end-stage renal disease (ESRD) patients. Recognizing that ESRD is a risk factor for severe hypoglycemia, we have now analyzed the association between glycosylated hemoglobin A1c (HgbA1c) levels and glycemic variability in those with hypoglycemia. This is a retrospective study of patients with diabetes enrolled in a large hemodialysis program. Hypoglycemia was identified from hospital discharge diagnostic codes. Glycemic variability was assessed by the standard deviation of HgbA1c and glucose levels over time. Hypoglycemia as a discharge diagnosis was documented in 4.1% of patients. Higher baseline HgbA1c was associated with greater risk for hypoglycemia hospitalization, a finding confirmed by time-lagged HgbA1c levels drawn a quarter earlier. Higher baseline HgbA1c categories were also associated with greater variability in HgbA1c levels during the analysis period. Similarly, greater glucose variability was associated with higher mean glucose levels by trend analysis. High, not low, HgbA1c levels are associated with greater risk of severe hypoglycemia, which may derive from glucose variability in the setting of treatment for hyperglycemia. High HgbA1c and glycemic variability are associated with increased risk of hypoglycemia in individuals with diabetes and ESRD. Key words: Hypoglycemia, dialysis, diabetes, hemoglobin A1c
INTRODUCTION Diabetes mellitus is a leading cause of end-stage renal disease (ESRD),1 now accounting for nearly 50% of Correspondence to: M. E. Williams, MD, Renal Unit, Joslin Diabetes Center, 1 Joslin Place, Boston MA 02215 U.S.A. E-mail: [email protected] Funding: No external funds
incident dialysis patients in the United States (URSDS). A large body of data indicates that hyperglycemia is central to the development of both micro- and macrovascular complications of diabetes.2 Rigorous glycemic control is therefore a priority in the overall management of patients with diabetes and chronic kidney disease (CKD). However, diabetes has also been depicted as a condition of “dysglycemia”, with two components in addition to hyperglycemia: hypoglycemia and glucose variability,3 each
© 2013 International Society for Hemodialysis DOI:10.1111/hdi.12110
423
Williams et al.
contributing to the overall risk of diabetes outcomes beyond hyperglycemia alone. Hypoglycemic events can be serious or even dangerous to patients, and are known to limit the degree of glycemic control possible in patients with diabetes. Aggressive treatment of hyperglycemia may create a greater risk of hypoglycemia and glucose variability, demonstrated in intensively treated patients in large clinical trials (ACCORD, ADVANCE, NICE-SUGAR).4–6 In fact, a recent proposal defined “potential overtreatment creating risk for hypoglycemia” as a threshold of glycosylated hemoglobin A1c (HgbA1c) under 7.0%.7 Although two recent large observational studies with differing methodologies reached somewhat contrasting conclusions with regard to the role of glycemic control in diabetic patients on chronic hemodialysis,8,9 they both highlighted the risks associated with low HgbA1c levels, suggesting that very low glycemic levels may add to risk of mortality. Consistent glycemic control is difficult to achieve in ESRD, specifically because of altered glucose metabolism, fluctuating insulin resistance, impaired insulin secretion, and decreased insulin degradation, as well as because of effects on drug metabolism, adding further complexity to glycemic management. In addition, a wide intrapatient variability is not uncommon day-today with regards to food intake, adherence to glycemic control prescriptions, and cognitive ability relative to the dialysis schedule. These factors not only create unique challenges for glycemic control, but also increase the risk of hypoglycemia and glucose variability in ESRD. We therefore sought to further evaluate the clinical implications of HgbA1c levels with regard to hypoglycemia and glycemic variability in a large national ESRD database.
METHODS This is a retrospective study of data obtained from dialysis information systems that collect information for all patients enrolled in the hemodialysis program of Fresenius Medical Care, North America between October 1 and December 31, 2002.10 The diagnosis of diabetes mellitus was based on either diabetes as the cause of ESRD or on reporting of diabetes as a comorbidity during the baseline period of October 1 to December 31, 2002. Patients with no available HgbA1c during this baseline period were excluded. The study investigators had no influence over the frequency of HgbA1c determinations, which were ordered by the individual nephrologists. All HbgA1c values were measured using the Roche Cobra Integra 800 whole-blood immunoturbidimetric assay (standardized according to the Diabetes Complications Control Trial/ National Glycohemoglobin Standardization Program),
424
performed by a single laboratory (Spectra Laboratories, Rockleigh, NJ, USA). Patient demographic and case-mix variables were collected as of December 31, 2002. These included diabetes type (type 1 or 2), insulin use as determined using i-SCOUT natural language software,11 age, gender, race, dialysis vintage, body surface area (BSA; from height and weight), and vascular access type (native fistula, graft, or catheter). All available laboratory results for the last quarter of 2002 for HgbA1c, eKt/V (fractional urea clearance), hemoglobin, albumin, creatinine, calcium, phosphorus, and white blood cell count were collected. The patient’s 3-month average value was used for each test in the analyses. In addition, all available random blood glucose measurements (most with one result each month) on patients with HgbA1c levels obtained in the last quarter of 2002, drawn within the previous 90 days from the date of the HgbA1c, were analyzed. Most patients had three determinations each quarter. Over the next three years, subsequent HgbA1c levels and hospitalization rates were collected until death, withdrawal from dialysis, or end of calendar year 2005. We also searched for all-cause hospitalizations and looked for hospitalizations with one discharge diagnosis of hypoglycemia within the database that specified International Classification of Diseases 9 codes for hypoglycemia (250.3, 250.8, 251.0, 251.1, 251.2, 962.3). Patients with > = one documented hypoglycemic diagnosis were assumed to be cases, and the remainder became “controls”. Baseline characteristics and laboratory results from patients that experienced hypoglycemia were compared with those patients without them, using t tests or chisquare tests, as appropriate. The standard Cox models were utilized to evaluate the association between HgbA1c levels and hypoglycemia events presented as: unadjusted, adjusted for case-mix, and adjusted for case-mix and laboratory variables. As a sensitivity analysis, we performed a time-dependent Cox model utilizing a one–quarter-lagged HbA1c as a predictor variable to evaluate whether the previous quarter’s HbA1c level, presumably a major determinant for the subsequent quarter’s treatment intensity, would be associated with hypoglycemia-related hospitalization risk. The primary analysis included the association between hypoglycemia-related hospitalization and glycemic variability according to HgbA1c levels. We analyzed glycemic variability by determining the standard deviation (SD) of within-subject HgbA1c levels of available values during the follow-up period along with adjustment according to mean HgbA1c levels. Stepwise logistic regression models
Hemodialysis International 2014; 18:423–432
Predictors of hypoglycemia in hemodialysis patients
(entry at univariate P ≤ 0.1) with all available variables were constructed to determine significant associates of hypoglycemia-related hospitalizations. Logistic regression models were used to determine the association between SD of HgbA1c and the occurrence of hypoglycemiarelated hospitalization events. Because of a non-normal distribution of HgbA1c, a repeat analysis was performed using log-normal HgbA1c, with no difference in the statistical results. Data are presented as unadjusted, mean HgbA1c-adjusted, and case-mix plus laboratory, and mean HgbA1c-adjusted models. All analyses were performed using SAS 9.1 or higher (SAS Institute, Cary, NC, USA; http://www.sas.com).
RESULTS Out of 76,178 ESRD patients on hemodialysis at the Fresenius Medical Care during the study period, 38,701 (50.8%) patients had a diagnosis of diabetes mellitus. Of
these, 13,827 (35.7%) patients were excluded because no HgbA1c was available during the 3-month baseline period. Included in the analysis were all 24,751 chronic in-center hemodialysis patients with diabetes mellitus active on January 1, 2003 and having at least one HbA1c in the preceding quarter. Of the study cohort with diabetes, 75% had diabetes as the cause of their kidney disease based on their Medicare 2728 form. Hypoglycemia as a discharge diagnosis of hospitalization was documented in 4.1% of patients (N = 1017; i.e., “cases”). Baseline characteristics of the entire cohort and of groups with and without hypoglycemia-related hospitalizations are presented in Table 1. For the entire cohort, mean age was 63.7 years, slightly over half were women, 36.4% were black, 5.5% had type 1 diabetes, and BSA was 1.86 m2; eKt/V was 1.41, serum albumin 3.82 g/dL, hemoglobin 11.71g/dL, and HgbA1c 6.77%. Patients with hypoglycemia tended to be younger (61.6 vs. 63.8 years), but with slightly less BSA (1.81 vs. 1.86 m2), with
Table 1 Baseline characteristics of the entire cohort and of groups with and without hypoglycemia-related hospitalizations Characteristics N (%) Age* (years) % Female Race White Black Other Type I diabetes* (%) Vintage (days) Body surface area* (m2) Access type Fistula Graft Catheter Unknown % Insulin at baseline * Type I DM Type II DM * Laboratory results HD dose (eKt/V) Albumin (g/dL) Hemoglobin (g/dL) Calcium (mg/dL) * Phosphorus (mg/dL) Creatinine (mg/dL) White blood cell count Hemoglobin A1C* (%)
All patients
Hypoglycemia-related hospitalization
Without hypoglycemia-related hospitalization
24,751 63.7 (12.1) 51.5%
1,017 (4.1%) 61.6 (13.6) 51.9%
23,734 (95.9%) 63.8 (12.1) 51.5%
53.1% 36.4% 10.6% 5.5% 1,048 (948) 1.86 (0.25)
50.0% 39.2% 10.8% 10.8% 1,029 (900) 1.81 (0.24)
53.2% 36.2% 10.6% 5.3% 1,049 (950) 1.86 (0.25)
29.9% 45.7% 23.6% 0.8% 47.0% 68.0% 45.8%
29.4% 46.0% 23.6% 1.0% 54.3% 73.6% 51.9%
29.9% 45.7% 23.6% 0.7% 46.7% 67.5% 45.6%
1.41 (0.29) 3.82 (0.38) 11.71 (1.10) 9.29 (0.70) 5.60 (1.45) 8.22 (2.67) 7.77 (2.87) 6.77 (1.71)
1.42 (0.30) 3.79 (0.40) 11.68 (1.04) 9.21 (0.70) 5.66 (1.48) 8.20 (2.45) 7.82 (2.24) 7.35 (1.96)
1.41 (0.29) 3.82 (0.38) 11.72 (1.10) 9.29 (0.70) 5.60 (1.45) 8.22 (2.67) 7.77 (2.90) 6.75 (1.70)
Data presented as mean (SD), * P < 0.001 between two groups. DM, diabetes mellitus; HD, hemodialysis.
Hemodialysis International 2014; 18:423–432
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Williams et al.
over-representation of type 1 diabetes (10.8% vs. 5.3%) and insulin use (54.3% vs. 46.7%); of note, hypoglycemia cases had higher mean of HgbA1c values (7.35% vs. 6.75%; all P < 0.001). All other case-mix factors and laboratory results were similar, except for serum calcium (9.21 vs. 9.29, P < 0.001). The multivariable stepwise logistic model indicated that HgbA1c, BSA, diabetes type, insulin use, male sex, and serum calcium were associated with hypoglycemia-related hospitalization, as shown in Table 2. The frequency distribution of the HgbA1c results for the entire cohort is shown by the red line connecting the dots in Figure 1A, along with the breakdown by HgbA1c category of hazard ratios for time to hypoglycemia-related hospitalization. Higher baseline HgbA1c was associated with greater risk for hypoglycemia-related hospitalization, shown in Figure 1A. Time-dependent HgbA1c levels drawn one-quarter earlier confirmed the greater risk of hypoglycemia-hospitalization for high levels, shown in Figure 1B. Log transformation of HgbA1c data (not shown) did not change the results. The association of higher baseline HgbA1c and hypoglycemia-related hospitalization was present both in patients with type 1 and 2 diabetic (Figure 2A,B). All-cause hospitalization risk did not differ according to HgbA1c categories (data not shown). We then evaluated the role of glycemic variability as a risk factor for hypoglycemia hospitalization in the cohort. The distribution of SDs of the 3-year HgbA1c according to baseline HgbA1c levels is shown in Figure 3. Higher baseline HgbA1c categories were associated with greater mean SDs of HgbA1c levels during the analysis period. In addition, the odds ratio of hypoglycemia hospitalization increased sequentially comparing those with increasing SDs of HgbA1c to the group with the lowest variability (Figure 4). As with HgbA1c, greater glucose variability was also associated with higher mean glucose levels by trend analysis (Figure 5). There was good, statistically significant correlation between SD for HgbA1c and SD for glucose levels over the follow period (r = 0.54, P < 0.0001).
Over 12 quarters (3 years) of analysis, distribution of HgbA1c values in the study population remained constant, except for a decrease in the proportion of patients within the lowest HgbA1c category over time (Figure 6). Use of insulin rose steadily in incident patients throughout the 12-quarter observation period.
DISCUSSION This study highlights three new observations: (i) high HgbA1c levels are associated with high risk of hypoglycemia-related hospitalization in diabetic patients on hemodialysis; (ii) variability in chronic glycemic control (SD for HgbA1c) is associated with high risk of hypoglycemia related hospitalization; (iii) higher glycemic variability (SD for HgbA1c as well as SD for glucose levels) is associated with high glycemic levels. We have previously suggested that HgbA1c targets in ESRD patients should be individualized, with less stringent goals being appropriate for older patients and others with greater comorbidities and reduced life expectancy.8 Also to be considered are the presence of risk factors for the occurrence of hypoglycemia. We previously reported that HgbA1c levels, the most widely used index of glycemic control, were below 7% in 65%, 5–6% in 28%, and below 5% in 11% of diabetic hemodialysis patients from a large national ESRD database.8 A similar distribution was reported from a second large ESRD database by KalantarZadeh et al.9 We also previously reported that both low and high extremes of HgbA1c were associated with hospitalization risk in diabetic ESRD patients.12 These data extend previous observations by indicating that a major risk factor for severe hypoglycemia resulting in hospitalization is poor overall glycemic control, as evidenced by the greater risk associated with high HgbA1c categories. Related to this risk are the use of insulin and increased glycemic variability. While an association between low HgbA1c and hypoglycemia was anticipated,13 the association between high HgbA1c and hypoglycemia was an unexpected finding. In the United
Table 2 Multivariate stepwise logistic regression analysis of hypoglycemia-related hospitalizations Steps 1 2 3 4 5 6
Entered variables
P value (final model)
HgbA1c (%) BSA (m2) DM type −2 Calcium (mg/dL) Insulin use at baseline Gender (male)
