The contribution of malglycemia to mortality among allogeneic hematopoietic cell transplant recipients

Abstract

Allogeneic hematopoietic cell transplantation (HCT) continues to be associated with substantial rates of nonrelapse mortality (NRM). Numerous factors influence glucose metabolism among HCT recipients. We hypothesized that "malglycemia," defined as hyperglycemia, hypoglycemia or increased glycemic variability, is associated with increased mortality in HCT patients. In a retrospective cohort study Cox regression was used to assess the association of malglycemia after transplant with day 200 NRM. A total of 66,062 blood glucose (BG) measurements from 1175 adult allogeneic HCT recipients between 2000 and 2005 at the Fred Hutchinson Cancer Research Center were evaluated (median 0.55 values per patient-day, range: 0.09-3.62). Overall, there were 215 cases of NRM by day 200 post-HCT and 601 deaths from any cause throughout observation. After adjustment for previously identified factors associated with NRM, all 3 components of malglycemia were associated with increased NRM when individually modeled as time-dependent covariates. Specifically, the hazard ratio for death was 1.93 for BG >200 mg/dL (P = .0009) and 2.78 for BG >300 (P = .0004) compared with BG 101-150 mg/dL. A minimum BG </=89 was associated with a risk of day 200 NRM 2.17 times that of a minimum BG >89 (P < .0001). The upper quartile of glucose variability was associated with a 14.57-fold increase in risk of NRM by day 200 relative to the first quartile (P < .0001). These retrospective data indicate that malglycemia is associated with mortality following HCT. The applicability of these findings to other situations and whether correcting malglycemia in HCT can lead to reductions in mortality remain to be determined.

Figure 1

Distribution of blood glucose values across all patients from days 0-100^{* *}Values less than 30 and greater than 300 are assigned values of 30 and 300, respectively, for plotting purposes

Figure 2

Figure 2a. Relationships Between Malglycemia and Day 200 Non-Relapse Mortality Figure 2a. (i) Hazard ratio (HR) of day 200 non-relapse mortality (NRM) as a function of blood glucose (BG) relative to a value of 103 mg/dl (where the hazard of NRM attains its minimum) after adjusting for glycemic variability and minimum BG. (ii) HR of day 200 NRM as a function of glycemic variability (measured as the standard deviation) relative to a value of 29 mg/dl (the median standard deviation) after adjusting for individual and minimum blood glucose values. (iii) HR of day 200 NRM as a function of minimum blood glucose (BG) relative to a value of 90 mg/dl (the median minimum value) after adjusting for glycemic variability and individual BG value. Solid line represents the HR, dotted lines represent point-wise 95% confidence limits. Figure 2b. Relationship Between Malglycemia and Composite Infection Endpoint Figure 2b. (i) Hazard ratio (HR) of failure for the composite infection endpoint as a function of blood glucose (BG) relative to a value of 103 mg/dl after adjusting for glycemic variability and minimum BG. (ii) HR of failure for the composite infection endpoint as a function of glycemic variability (measured as the standard deviation) relative to a value of 29 mg/dl (the median standard deviation) after adjusting for individual and minimum blood glucose values. (iii) HR of failure for the composite infection endpoint as a function of minimum BG relative to a value of 90 mg/dl (the median minimum value) after adjusting for glycemic variability and individual BG value. Solid line represents the HR, dotted lines represent point-wise 95% confidence limits.

Figure 2

Figure 2a. Relationships Between Malglycemia and Day 200 Non-Relapse Mortality Figure 2a. (i) Hazard ratio (HR) of day 200 non-relapse mortality (NRM) as a function of blood glucose (BG) relative to a value of 103 mg/dl (where the hazard of NRM attains its minimum) after adjusting for glycemic variability and minimum BG. (ii) HR of day 200 NRM as a function of glycemic variability (measured as the standard deviation) relative to a value of 29 mg/dl (the median standard deviation) after adjusting for individual and minimum blood glucose values. (iii) HR of day 200 NRM as a function of minimum blood glucose (BG) relative to a value of 90 mg/dl (the median minimum value) after adjusting for glycemic variability and individual BG value. Solid line represents the HR, dotted lines represent point-wise 95% confidence limits. Figure 2b. Relationship Between Malglycemia and Composite Infection Endpoint Figure 2b. (i) Hazard ratio (HR) of failure for the composite infection endpoint as a function of blood glucose (BG) relative to a value of 103 mg/dl after adjusting for glycemic variability and minimum BG. (ii) HR of failure for the composite infection endpoint as a function of glycemic variability (measured as the standard deviation) relative to a value of 29 mg/dl (the median standard deviation) after adjusting for individual and minimum blood glucose values. (iii) HR of failure for the composite infection endpoint as a function of minimum BG relative to a value of 90 mg/dl (the median minimum value) after adjusting for glycemic variability and individual BG value. Solid line represents the HR, dotted lines represent point-wise 95% confidence limits.

Figure 2

Figure 2a. Relationships Between Malglycemia and Day 200 Non-Relapse Mortality Figure 2a. (i) Hazard ratio (HR) of day 200 non-relapse mortality (NRM) as a function of blood glucose (BG) relative to a value of 103 mg/dl (where the hazard of NRM attains its minimum) after adjusting for glycemic variability and minimum BG. (ii) HR of day 200 NRM as a function of glycemic variability (measured as the standard deviation) relative to a value of 29 mg/dl (the median standard deviation) after adjusting for individual and minimum blood glucose values. (iii) HR of day 200 NRM as a function of minimum blood glucose (BG) relative to a value of 90 mg/dl (the median minimum value) after adjusting for glycemic variability and individual BG value. Solid line represents the HR, dotted lines represent point-wise 95% confidence limits. Figure 2b. Relationship Between Malglycemia and Composite Infection Endpoint Figure 2b. (i) Hazard ratio (HR) of failure for the composite infection endpoint as a function of blood glucose (BG) relative to a value of 103 mg/dl after adjusting for glycemic variability and minimum BG. (ii) HR of failure for the composite infection endpoint as a function of glycemic variability (measured as the standard deviation) relative to a value of 29 mg/dl (the median standard deviation) after adjusting for individual and minimum blood glucose values. (iii) HR of failure for the composite infection endpoint as a function of minimum BG relative to a value of 90 mg/dl (the median minimum value) after adjusting for glycemic variability and individual BG value. Solid line represents the HR, dotted lines represent point-wise 95% confidence limits.