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Disordered glucose metabolism is a common complication of glucocorticoid therapy for acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation (HCT). We aimed to examine the impact of dysglycemia on outcomes in 173 recipients of HCT treated with glucocorticoids for aGVHD. A total of 147 of these patients contributed data to a landmark analysis performed at 12 weeks post-HCT. Median aGVHD onset was 21 days (range: 5–79) after transplant. Median duration of glucocorticoid therapy was 381 days (range: 15–1632). Glucose values were obtained from glucocorticoid initiation date to death or last follow-up, resulting in 11,588 total values. The median (range) for each parameter were: maximum 292 mg/dL (128–694), minimum 75 mg/dL (34–142), average 142 mg/dL (86–327), and standard deviation 46 mg/dL (12–108). Baseline diabetes mellitus predicted significantly greater maximum, mean, and standard deviation. With median follow-up of 20 months (range: 3–55), median overall survival (OS) was 33.7 months (95% confidence interval [CI] 16.4—not reached). On multivariable analysis, maximum, average, or standard deviation of glucose values predicted OS and maximum or average glucose values predicted nonrelapse mortality (NRM). Minimum glucose values of (0–60 mg/dL) were associated with worsened OS and increased NRM. Those patients treated with insulin or oral agents suffered significantly worse OS and increased NRM compared to patients who did not need therapy. Finally, those with sustained maximum values >200 mg/dL despite treatment suffered worse OS and increased NRM. These data suggest an independent adverse effect of dysglycemia in patients treated with glucocorticoids for aGVHD, and argue for stringent glycemic control in this setting.
Acute graft-versus-host disease (aGVHD) is an important complication of allogeneic hematopoietic cell transplantation (HCT) [1–5]. As the accepted initial therapy for aGVHD, high-dose glucocorticoid therapy provides a disappointing complete response rate of 30% to 40% and engenders a burden of serious adverse effects including steroid-induced hyperglycemia, hypertension, fluid retention, cataracts, steroid myopathy and deconditioning, osteopenia, and opportunistic infections [6–10]. The management of aGVHD and later chronic graft-versus-host disease (cGHVD) often results in prolonged treatment with glucocorticoids . In clinical practice, steroid-induced hyperglycemia is a common and often inadequately controlled complication.
In the setting of acute illness, stress hormones, including cortisol and epinephrine, induce hyperglycemia.
Hyperglycemia is also induced by exogenous glucocorticoids. Importantly, hyperglycemia has adverse effects on several critical physiologic functions, leading to decreased immune function [12,13], impaired wound healing [14,15], increased oxidative stress [15–18], procoagulant activity [19,20], and endothelial dysfunction [21,22]. Several retrospective studies have demonstrated that hyperglycemia is associated with adverse medical outcomes including postoperative infections, as well as mortality after adjusting for the severity of illness in several conditions [23–31]. In addition, randomized controlled trials examining intensive strategies for glycemic control have demonstrated a significant mortality benefit for stringent glycemic control both in the setting of diabetic postmyocardial infarction , as well as in critically ill surgical patients . In a randomized trial of critically ill medical patients, intensive glycemic control reduced morbidity including renal injury, time on mechanical ventilation, and length of intensive care unit (ICU) stay; in those with an ICU stay greater than 3 days, in hospital mortality was significantly improved . Thus, there is a robust literature on the impact of hyperglycemia on medical outcomes in several other conditions. Clinical data also supports an adverse effect of both hypoglycemia and increased glucose variability in allied investigation [35–39].
Hammer et al.  have demonstrated the adverse impact of aberrant glucose control, encompassing hyper and hypoglycemia, as well as glycemic variability within the first 100 days after HCT on 200 day nonrelapse mortality (NRM). Although this work demonstrates the impact of aberrant glucose control on early NRM, there are several limitations: glucose values were not obtained beyond day 100 post-HCT; no baseline information on preexisting diabetes was available; most importantly, no information regarding glucocorticoid therapy was examined, but rather the occurrence of GVHD was used as a surrogate for glucocorticoid treatment. Accordingly, the independent effect of glycemic parameters cannot be distinguished from any adverse effect because of steroid treatment alone, including the risk of NRM from immunosuppression and opportunistic infection. In addition, this does not address in particular the common clinical challenge of glucocorticoid-induced dysglycemia in the treatment of aGVHD. Accordingly, we have aimed to examine the independent effect of dysglycemia on outcomes of allogeneic HCT recipients treated with glucocorticoids for aGVHD.
A series of subjects with biopsy-confirmed aGVHD treated with glucocorticoids were identified by retrospective analysis of allogeneic HCT recipients from 2004 to 2008 at the Moffitt Cancer Center. This study was approved by the University of South Florida’s institutional review board. The following data was gathered in all cases, and considered as pre-HCT variables: diagnosis of diabetes prior to HCT, age, condition requiring transplantation, Center for International Blood and Marrow Transplant Research (CIBMTR) risk category, remission status at time of transplant, donor/recipient sex matching, donor relation, degree of HLA disparity, conditioning regimen utilized, aGVHD prophylaxis regimen, stem cell source, CD34+ cell dose/kg body weight, and cytomegalovirus (CMV) status of donor and recipient. As well, body mass index (BMI) was calculated for each subject at time of HCT as weight (kg)/(height in meters)2. Standard definitions (underweight <18.5, normal weight 18.5–24.9, overweight 25–29.9, and obesity 30 and greater) were utilized to categorize individual subjects’ BMI. All baseline variables were considered as covariates in pre-HCT multivariate models.
For each subject, the following was also collected and considered as post-HCT variables: maximum aGVHD grade reached in duration of follow-up ; first-line glucocorticoid dose/kg body weight utilized; the occurrence of refractory aGVHD (defined as either grade progression within 3 days from initiation of glucocorticoids or failure to achieve at least 1 grade improvement after 5 days of glucocorticoid therapy); maximum cGVHD grade in duration of follow-up ; and sum of weekly steroid dose in mg/kg of body weight. In cases where intravenous methylprednisolone was utilized, the dose was computed as prednisone equivalent. Additionally, summary parameters (maximum, minimum, average, and standard deviation) were calculated for the glucose data available for each subject from the date of glucocorticoid initiation until death or last follow-up time. Glucose values were obtained randomly, rarely fasting, from both the inpatient and outpatient setting, and do not contain measurements obtained by patient self monitoring. Each of these glucose parameters was considered as post-HCT variables in analyses. As well, treatment for hyperglycemia (insulin or oral agents) post-HCT and glycemic control group membership were considered as post-HCT variables.
The following definitions were utilized to create hyperglycemia treatment groups: The proportion of total glucose values for each subject >200 mg/dL was calculated, and a median value for this proportion for all subjects in the analysis was determined. A control group was defined as those who did not receive any treatment (insulin and/or oral agents) and in whom the proportion of glucose measurements >200 was smaller than the median value (0.1136, range: 0–0.913). The second group (well controlled) was treated with insulin and/or oral agents and had a proportion of values >200 less than this median. The final group (poorly controlled) was treated with these agents, but had a proportion of values >200 greater than this median.
Baseline characteristics were summarized using descriptive statistics including mean, median, and standard deviation for continuous measures, and frequencies for categoric variables. Glucose measurements were summarized by the parameters maximum, minimum, average, and standard deviation. The relationship between the glucose data (maximum, minimum, average, and standard deviation) and the presence of preexisting diabetes mellitus was examined using the Wilcoxon rank-sum test.
The relationship between these related glucose parameters (maximum, minimum, average, standard deviation) was examined using Fisher’s exact test. Each of these parameters was significantly related with the others. As well, there was a significant relationship between the hyperglycemia treatment group (control group, well controlled, poorly controlled), and each of these glucose parameters by Cochran-Armitage trend test. There was also a significant relationship between treatment (receipt of insulin and/or oral agents) and each of these glucose parameters by Cochran-Armitage trend test. Accordingly, separate multivariable analyses were considered where only 1 of the above related variables were entered.
A landmark analysis was performed at 12 weeks post-HCT. As 26 subjects died prior to this time point, only 147 of the original 173 subjects contributed data to the landmark analysis. Overall survival (OS) was estimated using the Kaplan-Meier method from the 12-week landmark. Survival curves among subgroups were compared using the log-rank test. Accounting for competing risk events, the cumulative incidence of primary disease relapse and NRM was calculated by the Gray method . For the outcomes of OS, the relationship between this outcome and all baseline variables was examined first employing univariable analysis. Again, for each of these outcomes, Cox proportional hazard modeling was employed with baseline variables as covariates. For cumulative incidence of NRM, a subdistribution hazards regression model by the method of Fine  and Gray  was utilized for univariable and multivariable analysis. Those variables with P-value of .2 or less in univariable analysis were selected for construction of the multivariable model. The backward selection procedure with a P-value cutoff of .1 was utilized. Separate multivariate analyses were conducted to examine pre- and post-HCT variables as defined earlier. Given the significant relationships between glucose parameters, hyperglycemia treatment group membership, and insulin/oral agent treatment, each of these variables was considered independent of the others in separate multivariate models.
From 327 total allogeneic HCTs performed at the center between 2004 and 2008, 173 subjects were identified by retrospective review to have aGVHD treated with glucocorticoids. Of these, 147 contributed data at the 12-week landmark analysis. The baseline characteristics of these 147 subjects are summarized in Table 1. At a median of 21 days (range: 5–79) post-HCT, glucocorticoid therapy was initiated for the treatment of aGVHD. The starting prednisone dose was most commonly (72% of subjects) 1 mg/kg body weight. The total prednisone exposure was a median of 3.8 (range: 1.12–15) mg/kg at 4 weeks. The median duration of glucocorticoid treatment was 381 days (range: 15–1632).
All available glucose values from date of glucocorticoid initiation until death or last follow-up were abstracted for each patient, resulting in 13,170 total values for the original 173 subjects. For the cohort of 147 included in the landmark analysis, this included 11,588 total individual values. There was a median of 61 values (range: 8–405) per patient. For each subject, maximum, minimum, average, and standard deviation of glucose values were determined. Summary values are depicted in Figure 1.
Seven patients in this series had preexisting type II diabetes mellitus prior to HCT; 5 were treated with oral hypoglycemic agents, and 2 also required insulin therapy. Those patients with baseline diabetes had greater maximum (median 460 versus 287 mg/dL, P = .006), average (median 227 versus 145 mg/dL, P ≤.001), and standard deviation glucose values (median 76 versus 47 mg/dL, P = .01) than nondiabetics.
With a median follow-up of time of 20 months (range: 3–55), median OS from initiation of glucocorticoid therapy was 33.7 months (95% confidence interval [CI] 16.4—not reached). Univariate analyses examining the relationship between glucose parameters as well as glucose treatment groups (control group, well controlled, and poorly controlled) are represented in Figure 2. All of the posttransplant glycemic parameters significantly predicted OS in separate multivariate analyses (Table 2). Maximum glucose, average glucose, and standard deviation of glucose values demonstrated a linear relationship, with increasing hazard for death for stepwise increase in these variables. Minimum glucose level demonstrated a nonlinear relationship, wherein there was an increased hazard for death in both the 0–60 mg/dL and 81–150 mg/dL ranges in comparison to a reference of 61–80 mg/dL. Of patients without baseline diabetes pre-HCT, those who received treatment with insulin or oral agents suffered an increased hazard for death. As previously defined, hyperglycemia treatment group was also significantly associated with poor OS: in comparison to the control group, those treated with insulin/oral agents, and particularly those with poorly controlled hyperglycemia despite this treatment suffered increased hazard for death. The sum of steroid exposure did not remain a significant predictor of OS on multivariate modeling. As well, BMI was not a significant predictor of OS. The maximal severity of cGVHD, as well as the occurrence of glucocorticoid-refractory aGVHD remained independent predictors of OS in the post-HCT multivariate model, and thus the impact of the mentioned glycemic parameters and hyperglycemia treatment variables were adjusted by cGVHD and refractory aGVHD.
All glucose parameters demonstrated significant relationships with the cumulative incidence of NRM on univariate analysis (Figure 3). In separate multivariate analyses, stepwise increases in maxium and average glucose were associated with increased hazard for NRM. Those with minimum values of 0–60 suffered increased NRM compared to the reference range of 61–80. Those treated with insulin or oral agents suffered significantly increased NRM. Finally, in comparison to the control group, those treated with insulin and/or oral agents with poor glycemic control suffered significantly greater NRM (Table 3). The impact of these variables was adjusted by refractory aGVHD, which remained a significant predictor of NRM in the multivariate model.
In the management of both aGVHD and cGVHD after allogeneic HCT, patients are commonly exposed to a prolonged duration of therapy with high-dose glucocorticoids. Many complications and late effects of this therapy have been well described [6–10]. The problem of aberrant glucose control with glucocorticoid therapy after HCT, however, remains inadequately examined despite its common occurrence in clinical practice. Basic investigation has demonstrated the adverse impact of hyperglycemia on several vital physiologic functions, and clinical data from allied disciplines have demonstrated the adverse impact of hyperglycemia, as well as both hypoglycemia and glycemic variability on disease outcomes. Accordingly, we aimed to investigate the independent prognostic impact of glycemic control on outcome in a series of patients with aGVHD treated with glucocorticoids after HCT.
In this series of HCT recipients treated with glucocorticoids for aGVHD, we have examined the impact of glycemic control on OS and NRM in several ways. First, we have examined the impact of individual glycemic parameters that summarize the glucose data for each patient. These analyses demonstrate the adverse impact of each: first, multivariate modeling confirmed an independent adverse impact of stepwise increases in maximum glucose on both OS and NRM. Strikingly, those with a maximum glucose of >400 mg/dL had an independent hazard for nonrelapse death >9 times that of the reference group of 101–200 mg/dL. The directionality of this effect is also in keeping with that reported by Hammer et al. , but the magnitude of the effect here is even greater; in multivariate analysis accounting for the covariates of severity of disease, patient age at HCT, type of donor, year of HCT, and presence of grades II–IV aGVHD, the hazard ratio (HR) for NRM in the group with maximum glucose values >300 in that study was 2.78. As well, step-wise increases in average glucose conferred an increased hazard in multivariate models of NRM and OS. These findings are in keeping with the adverse impact of hyperglycemia documented in medical and surgical outcome data from allied investigations [25–27,30,31]. Similarly, multivariate modeling has confirmed the independent adverse impact of increased glucose variability, here represented by the standard deviation of glucose values, on OS. Finally, those with minimum glucose values below the reference range suffered a significantly worse OS and NRM.
In addition to examining the impact of individual summary glucose parameters on OS and NRM, we have also here examined the association between hyperglycemia treatment and its success and these outcomes. Of those without baseline diabetes, treatment with insulin or oral agents post-HCT was associated with significantly worsened OS and NRM. Importantly, this therapy was significantly related to the earlier mentioned glycemic parameters; treatment with these agents was strongly dependent upon the degree of hyperglycemia. Therefore, the effect observed likely reflects the associated severity of hyperglycemia. As well, we have examined the impact of poor glycemic control among those who have received treatment for hyperglycemia. Compared to the reference no treatment group, those who had poor glycemic control despite such therapy—defined by sustained values >200 mg/dL—suffered significantly worsened OS and NRM.
These findings demonstrate the adverse association of dysglycemia with OS and NRM in the setting of glucocorticoid therapy for aGVHD. This data complements that of Hammer et al. , but offers novel information in the following ways: First, patients studied here differ in that they include exclusively those with aGVHD treated with glucocorticoids. Second, glucose values were obtained for each subject from the onset of glucocorticoid therapy until the last contact or death; glucose values were only obtained to day 100 as a predictor of 200 day NRM in the former study. In addition, we have demonstrated here that those with baseline diabetes mellitus had significantly greater maximum and average glucose values, as well as variation in serum glucose values, thereby identifying an especially high risk group. Next, we have importantly demonstrated the adverse effect of the studied glycemic parameters, independent from the adverse impact of glucocorticoid therapy. We have also demonstrated that poor glycemic control despite insulin or oral agent therapy is associated with worse outcome. Finally, we have confirmed the adverse impact of these glycemic parameters on NRM, but also have for the first time shown a robust association with OS.
As these data demonstrate an adverse association between dysglycemia incurred in the setting of glucocorticoid therapy for aGVHD and outcomes, efforts to limit this burden are of importance. In regard to the management of dysglycemia, the data here suggest the following: first, these findings support the importance of routine assessment of glycemic control and its requisite management. This is likely best achieved in the setting of a multidisciplinary team, for example, including a transplant physician, nurse, nutritionist, and endocrinologist, to address the patient’s diet, activity, glycemic control, and the associated therapy. Those with baseline diabetes constitute an especially vulnerable group that requires particular attention. Next, the data suggest potential targets in the management of this complication: As minimum values below 60 mg/dL are associated with both worsened OS and increased NRM, these low values should be minimized. Accordingly, a major goal of therapy should be to restrict severe low values in the management of hyperglycemia. Next, as maximum values >200 are associated with worsened OS and NRM, a goal of therapy should be to limit maximum values to below 200 as possible. Finally, data demonstrating the adverse impact of increased glucose variability suggest that minimizing this variation should be another therapeutic goal. The optimal agents (eg, oral hypoglycemic drugs, insulin therapy) and schedule to achieve this control, avoid hypoglycemia, and reduce variability remain to be determined. As well, this retrospective analysis has demonstrated the independent association of glycemic parameters and hyperglycemia treatment group membership with the outcomes of OS and NRM; however, definitive conclusions regarding optimal glycemic control in this setting would require an adequately powered prospective randomized trial examining a strict glycemic control strategy. Finally, efforts at more stringent glycemic control are reactive in nature: efforts toward ameliorating the underlying problem, namely, more effective aGVHD prevention, primary therapy, avoidance of glucocorticoid-refractory aGVHD, as well as investigation into nonglucocorticoid or glucocorticoid-sparing approaches, may help limit these adverse effects of glucocorticoids.
Financial disclosure: The authors have nothing to disclose.