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Hypoglycemia-associated Mortality Is Not Drug-associated but Linked to Comorbidities

  • Laura Boucai
    Correspondence
    Requests for reprints should be addressed to Laura Boucai, MD, MS, Montefiore Medical Center, Department of Medicine, Division of Endocrinology and Metabolism, 1300 Morris Park Avenue, Belfer Building 701, Bronx, NY 10461
    Affiliations
    Department of Medicine, Montefiore Medical Center and the Albert Einstein College of Medicine, Bronx, NY

    Division of Endocrinology, Montefiore Medical Center and the Albert Einstein College of Medicine, Bronx, NY
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  • William N. Southern
    Affiliations
    Department of Medicine, Montefiore Medical Center and the Albert Einstein College of Medicine, Bronx, NY

    General Internal Medicine, Montefiore Medical Center and the Albert Einstein College of Medicine, Bronx, NY
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  • Joel Zonszein
    Affiliations
    Department of Medicine, Montefiore Medical Center and the Albert Einstein College of Medicine, Bronx, NY

    Division of Endocrinology, Montefiore Medical Center and the Albert Einstein College of Medicine, Bronx, NY
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      Abstract

      Objective

      Although tight glucose control is used widely in hospitalized patients, there is concern that medication-induced hypoglycemia may worsen patient outcomes. We sought to determine if the mortality risk associated with hypoglycemia in hospitalized noncritically ill patients is linked to glucose-lowering medications (drug-associated hypoglycemia) or merely an association mediated by comorbidities (spontaneous hypoglycemia).

      Methods

      A retrospective cohort of patients admitted to the general wards of an academic center during 2007 was studied. The in-hospital mortality risk of a hypoglycemic group (at least 1 blood glucose70 mg/dL) was compared with that of a normoglycemic group using survival analysis. Stratification by subgroups of patients with spontaneous and drug-associated hypoglycemia was performed.

      Results

      Among 31,970 patients, 3349 (10.5%) had at least 1 episode of hypoglycemia. Patients with hypoglycemia were older, had more comorbidities, and received more antidiabetic agents. Hypoglycemia was associated with increased in-hospital mortality (hazard ratio [HR], 1.67; 95% confidence interval [CI], 1.33-2.09; P<.001). However, this greater risk was limited to patients with spontaneous hypoglycemia (HR, 2.62; 95% CI, 1.97-3.47; P<.001) and not to patients with drug-associated hypoglycemia (HR, 1.06; 95% CI, 0.74-1.52; P=.749). After adjustment for patient comorbidities, the association between spontaneous hypoglycemia and mortality was eliminated (HR, 1.11; 95% CI, 0.76-1.64; P=.582).

      Conclusion

      Drug-associated hypoglycemia was not associated with increased mortality risk in patients admitted to the general wards. The association between spontaneous hypoglycemia and mortality was eliminated after adjustment for comorbidities, suggesting that hypoglycemia may be a marker of disease burden rather than a direct cause of death.

      Keywords

      SEE RELATED COMMENTARY p. 993
      Hyperglycemia in hospitalized patients with and without diabetes is common and has been implicated as a risk factor for increased morbidity and mortality.
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      Elevated admission glucose and mortality in elderly patients hospitalized with heart failure.
      Although a randomized controlled trial of “tight” glycemic control in critically ill patients has demonstrated decreased mortality,
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      Intensive insulin therapy in the critically ill patients.
      other studies have shown no benefits or even increased mortality with this therapeutic approach.
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      • et al.
      Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): effects on mortality at 1 year.
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      • et al.
      Effect of glucose-insulin-potassium infusion on mortality in patients with acute ST-segment elevation myocardial infarction: the CREATE-ECLA randomized controlled trial.
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      • et al.
      Intensive insulin therapy in the medical ICU.
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      • et al.
      Intensive versus conventional glucose control in critically ill patients.
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      • Bloos F.
      • et al.
      Intensive insulin therapy and pentastarch resuscitation in severe sepsis.
      Despite these contradictory results in intensive care unit patients, physicians have widely adopted tight glycemic control in hospitalized patients with hopes of improving outcomes. Enthusiasm for glucose-lowering interventions has been tempered by the concern that treatment-induced hypoglycemia may cause death. Although trials of intensive glucose control have shown higher rates of hypoglycemia than standard glucose management,
      • Van den Berghe G.
      • Wilmer A.
      • Hermans G.
      • et al.
      Intensive insulin therapy in the medical ICU.
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      • Larson R.J.
      Benefits and risks of tight glucose control in critically ill adults: a meta-analysis.
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      • Milants I.
      • et al.
      Intensive insulin therapy in mixed medical/surgical intensive care units: benefit versus harm.
      and hypoglycemia has been associated with increased mortality,
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      • Dellborg M.
      Association between hyper- and hypoglycaemia and 2 year all-cause mortality risk in diabetic patients with acute coronary events.
      • Pinto D.S.
      • Skolnick A.H.
      • Kirtane A.J.
      • et al.
      U-shaped relationship of blood glucose with adverse outcomes among patients with ST-segment elevation myocardial infarction.
      • Kagansky N.
      • Levy S.
      • Rimon E.
      • et al.
      Hypoglycemia as a predictor of mortality in hospitalized elderly patients.
      • Kosiborod M.
      • Inzucchi S.E.
      • Krumholz H.M.
      • et al.
      Glucometrics in patients hospitalized with acute myocardial infarction: defining the optimal outcomes-based measure of risk.
      it is not clear whether hypoglycemia that occurs as a result of glucose-lowering therapy is associated with increased mortality.
      • Drug-associated hypoglycemia is not linked to increased mortality risk in patients admitted to the general medical and surgical wards.
      • The association between spontaneous hypoglycemia and mortality is eliminated after adjustment for comorbidities.
      • Hypoglycemia seems to behave as a marker of disease burden rather than as a direct cause of death, which should reassure clinicians who manage glucose levels in hospitalized patients in the general wards.
      Studies conducted in the outpatient setting usually serve to provide guidance in the management of hospitalized but not critically ill patients. In this regard, 2 multicenter outpatient clinical trials comparing the effects of intensive versus standard glycemic control in patients with advanced type 2 diabetes were completed recently and showed no significant reduction in cardiovascular disease outcomes or any increased mortality with intensive glycemic control.
      • Duckworth W.
      • Abraira C.
      • Moritz T.
      • et al.
      Glucose control and vascular complications in veterans with type 2 diabetes.
      • Patel A.
      • MacMahon S.
      • Chalmers J.
      • et al.
      Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.
      A third outpatient trial, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, was terminated because of increased mortality in participants randomized to receive intensive glycemic therapy.
      • Gerstein H.C.
      • Miller M.E.
      • Byington R.P.
      • et al.
      Effects of intensive glucose lowering in type 2 diabetes.
      However, a post hoc analysis of ACCORD was unable to attribute the excess mortality observed in the intensive therapy group to severe hypoglycemia.
      • Bonds D.E.
      • Miller M.E.
      • Bergenstal R.M.
      • et al.
      The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study.
      Thus, it remains unclear whether hypoglycemia is responsible for increased mortality or just a marker of disease burden.
      To address this important knowledge gap, we designed a retrospective observational study to determine whether hypoglycemia was associated with increased mortality in hospitalized but noncritically ill patients; and whether hypoglycemia associated with various illnesses that occurs in the absence of glucose-lowering therapy (“spontaneous hypoglycemia”) and hypoglycemia associated with initiation of glucose-lowering therapy (“drug-associated hypoglycemia”) carry similar prognostic implications. Specifically, we posited that if hypoglycemia per se were a direct cause of adverse outcomes, it would be expected to be associated with increased mortality regardless of its cause. On the other hand, if hypoglycemia was a marker of disease burden, only spontaneous hypoglycemia would be associated with increased mortality.

      Research Design and Methods

      Study Population

      We examined a retrospective cohort of patients hospitalized at Montefiore Medical Center in Bronx, New York, from January 1 to December 31, 2007. The data assembled were restricted to nonpregnant patients aged 21 years or more and included those with and without the concurrent diagnosis of diabetes who were admitted to the general units. Patients admitted or transferred to medical or surgical intensive care units and patients discharged from the emergency department were excluded from this analysis. For patients with multiple admissions, only the earliest admission was considered as an index hospitalization. Patients were included if their record had at least 1 blood glucose level performed during the period of hospitalization, which yielded a starting data set of 31,970 patients. The diabetes subgroup (n=10,832) included patients with both type 1 and 2 diabetes determined from International Classification of Diseases, 9th Revision, Clinical Modification diagnostic codes of inpatient and outpatient charts.

      Data Source, Hypoglycemia, and Comorbidities Definition, and Medications

      All data were extracted from the hospital information system using Clinical Looking Glass (version 2.1.5, Bronx, NY). We defined the “hypoglycemia” group as those patients with at least 1 laboratory-documented blood glucose level70 mg/dL. We used this threshold according to the definition provided by the American Diabetes Association.
      Defining and reporting hypoglycemia in diabetes: a report from the American Diabetes Association Workgroup on Hypoglycemia.
      We only used chemistry profiles and excluded patients with point of care glucose values<70 mg/dL because 1) these are entered into the computer system manually by nurses, and they are subject to more data entry errors than those values directly transmitted from the laboratory; 2) we thought we would encounter multiple short and trivial episodes of hypoglycemia evidenced by point of care only in the group receiving antidiabetic agents that would not necessarily be seen in the chemistry profiles and that would not be associated with increased mortality, thus favoring our hypothesis; and 3) we wanted to choose a more conservative approach of clearly documented hypoglycemia in a laboratory chemistry profile that would most likely represent a true episode of hypoglycemia. The “normoglycemia” group consisted of patients with all glucose levels>70 mg/dL. “Spontaneous hypoglycemia” was defined as hypoglycemia occurring in the absence of glucose-lowering interventions; “drug-associated hypoglycemia” was hypoglycemia occurring in patients who were receiving glucose-lowering medications. Comorbidities were determined from International Classification of Diseases, 9th Revision, Clinical Modification codes and, whenever possible, enriched by including patients who met laboratory criteria for disease, and consisted of body mass index, diabetes mellitus, congestive heart failure, myocardial infarction, cerebrovascular accident, cancer, chronic obstructive pulmonary disease, shock, albumin level (as a surrogate for chronic illness, malnutrition, or liver disease when low), white blood cell count, and renal failure defined as a serum creatinine level2 mg/dL. All medications were prescribed electronically and those administered during the patients' hospital stay were abstracted from the database. Antidiabetic oral agents included sulfonylureas, metformin, thiazolidinediones, glucagon-like peptide 1 analogs, and dipeptidyl peptidase 4 inhibitors. Insulin therapy encompassed both human insulin and insulin analogs administered as basal (neutral protamine Hagedorn-protamine insulin or glargine) or bolus (regular insulin or rapid acting analogs).

      Statistical Analysis

      All statistical analyses were performed using STATA/IC (version 10 for Windows; StataCorp LP, College Station, Tex). Baseline demographic and clinical characteristics were compared between patients in the “hypoglycemia” group and patients in the “normoglycemia” group using Pearson chi-square test for categoric variables and Student t test or Mann-Whitney test for continuous variables.
      To determine if hypoglycemia was associated with decreased survival, in-hospital mortality rates were compared between the hypoglycemia group and the normoglycemia group using logistic regression. Mortality analysis was repeated stratified by the presence or absence of diabetes. We further examined the relationship between glycemia and in-hospital mortality using Kaplan-Meier survival estimates in the hypoglycemic and normoglycemic groups and conducted the remaining univariate and multivariate analyses using survival analysis. Proportionality assumptions were tested with Schoenfeld residuals and log-log plots.
      Because we hypothesized that there would be a differential effect of hypoglycemia resulting from treatment with antidiabetic medication (drug-associated hypoglycemia) versus spontaneous hypoglycemia, we explored the interaction between antidiabetic medications and hypoglycemia and conducted separate analyses for subgroups of patients with drug-associated versus spontaneous hypoglycemia. We also conducted sensitivity analyses using a glucose cutoff of 50 mg/dL and performed subanalyses by class of antidiabetic agent to determine the specific effect of drugs known to cause hypoglycemia (ie, sulfonylureas and insulin) on mortality. We examined the association between number of hypoglycemic episodes and mortality in the drug-associated and spontaneous hypoglycemic groups. Patients without hypoglycemic episodes (normoglycemia) served as the reference group and were compared with patients having 1, 2, and 3 or more hypoglycemic episodes.
      Multivariate Cox proportional hazards models were constructed to examine the independent association between hypoglycemia and mortality. We conducted stratified analyses for patients with drug-associated and spontaneous hypoglycemia. Patient characteristics previously demonstrated to be prognostically significant or thought to be clinically important and covariates identified in bivariate analyses as predictors of in-hospital mortality were entered into the models. Covariates included demographic factors: age, sex, self-reported race/ethnicity; comorbidities: body mass index, diabetes mellitus, congestive heart failure, myocardial infarction, cerebrovascular accident, cancer, chronic obstructive pulmonary disease, shock, albumin level (as a surrogate for chronic illness, malnutrition, or liver disease when low), white blood cell count, and renal failure defined as a serum creatinine level2 mg/dL; and number of glucose determinations.
      The literature reports an increase of in-hospital mortality risk of hypoglycemic compared with normoglycemic patients ranging from 60% to 300%.
      • Pinto D.S.
      • Skolnick A.H.
      • Kirtane A.J.
      • et al.
      U-shaped relationship of blood glucose with adverse outcomes among patients with ST-segment elevation myocardial infarction.
      • Kagansky N.
      • Levy S.
      • Rimon E.
      • et al.
      Hypoglycemia as a predictor of mortality in hospitalized elderly patients.
      • Kosiborod M.
      • Inzucchi S.E.
      • Krumholz H.M.
      • et al.
      Glucometrics in patients hospitalized with acute myocardial infarction: defining the optimal outcomes-based measure of risk.
      • Turchin A.
      • Matheny M.E.
      • Shubina M.
      • Scanlon J.V.
      • Greenwood B.
      • Pendergrass M.L.
      Hypoglycemia and clinical outcomes in patients with diabetes hospitalized in the general ward.
      We performed a power calculation with the most conservative estimate of increased mortality risk in the hypoglycemic group. With our actual sample size, we calculated that we would have had 80% power to detect a 60% increase in mortality risk in hypoglycemic subjects compared with normoglycemic subjects using a 2-tailed α of 0.05. All power determinations were calculated using PASS 11 2010 (version 11.0.2, 2010, http://www.ncss.com/pass.html).

      Results

      Baseline Characteristics

      We identified 31,970 patients with at least 1 blood glucose determination during their hospitalization (mean age 61±17.8 years, 58% were female). Self-designated race/ethnicity was available in 92.6% of patients (whites: 23.6%, blacks: 32.2%, Hispanics: 36.8%, unknown: 7.4%). Table 1 presents baseline patient characteristics of those subjects who did (n=3349) and did not (n=28,621) develop hypoglycemia during their hospital stay. The proportion of female patients was similar between the 2 groups. There was a higher percentage of non-Hispanic blacks in the hypoglycemic group. Compared with patients who did not develop hypoglycemia, those with hypoglycemic events were older, had a lower body mass index, had more comorbidities including diabetes, and received more insulin, sulfonylureas, or a thiazolidinedione. There were fewer patients in the hypoglycemia group receiving metformin.
      Table 1Patient Characteristics by Glycemia Status
      Hypoglycemia (n=3349)Normoglycemia (n=28,621)P Value
      Demographic data
       Age in years, mean (SD)64.1 (17.3)60.6 (17.9)<.001
       Female sex, n (%)1918 (57.3)16,765 (58.6).15
       Whites, n (%)732 (21.9)6829 (23.9).01
       Blacks, n (%)1234 (36.9)9045 (31.6)<.001
       Hispanics, n (%)1179 (35.2)10,577 (36.9).047
      Clinical data
       Body mass index, mean (SD)27.1 (7.5)29.1 (7.8)<.001
       Diabetes, n (%)1717 (51.3)9115 (31.9)<.001
       Congestive heart failure, n (%)944 (28.2)3984 (14.0)<.001
       Myocardial infarction, n (%)311 (9.3)2005 (7.1)<.001
       Cerebrovascular accident, n (%)318 (9.5)2038 (7.2)<.001
       Cancer, n (%)389 (11.6)2355 (8.3)<.001
       Shock, n (%)75 (2.24)134 (0.47)<.001
       Chronic obstructive pulmonary disease, n (%)775 (23.2)5969 (21.0).004
       White blood cell count, median (IQR)9.2 (6.8-12.8)8.7 (6.7-11.7)<.001
       Albumin, mean (SD)3.46 (0.71)3.85 (0.56)<.001
       Renal failure, n (%)804 (24.1)1968 (7.0)<.001
      In-hospital medications
       Sulfonylureas, n (%)342 (10.2)1570 (5.5)<.001
       Metformin, n (%)169 (5.1)1737 (6.1).02
       Thiazolidinediones, n (%)132 (3.9)922 (3.22).03
       DPP-4i/GLP-1, n (%)4 (0.12)33 (0.12).95
       Any insulin, n (%)1447 (43.2)4650 (16.3)<.001
       Any oral, n (%)480 (14.3)3154 (11.0)<.001
       Any oral or insulin, n (%)1635 (48.8)6670 (23.3)<.001
      SD=standard deviation; IQR=interquartile range; DPP-4i=dipeptidyl peptidase 4 inhibitor; GLP-1=glucagon-like peptide 1.
      Overall, 3349 patients (10.5%) developed a total of 5884 episodes of hypoglycemia. Spontaneous hypoglycemia occurred in 1714 patients, and drug-associated hypoglycemia occurred in 1635 individuals. Among patients with diabetes, those treated with insulin experienced higher rates of hypoglycemia compared with those not treated with insulin (23.7% [1447/6097 patients] vs 7.4% [1902/25,873], P<.001).

      Unadjusted Association Between Hypoglycemia and Mortality

      Figure 1 shows that patients with hypoglycemia had significantly higher in-hospital mortality than patients without hypoglycemia (4.39% [147/3,349] vs. 1.06% [304/28,621], P<.001). Both diabetic and nondiabetic patients with hypoglycemia had significantly increased in-hospital mortality compared with patients without hypoglycemia. Nondiabetic patients with hypoglycemia had approximately double the mortality rate than diabetic patients with hypoglycemia (5.88% vs 2.97%, P<.001).
      Figure thumbnail gr1
      Figure 1Percent in-hospital mortality by glycemia status among all patients, patients with diabetes, and patients without diabetes. *P<.001 for all hypoglycemic versus normoglycemic patients. †P<.001 for nondiabetic hypoglycemic patients versus diabetic hypoglycemic patients.
      Patients with hypoglycemia had significantly higher mortality compared with normoglycemic patients (HR, 1.67; 95% CI, 1.33-2.09; P<.001, Table 2). However, the association between hypoglycemia and mortality was markedly different among subjects who developed it spontaneously versus those who developed it after glucose-lowering therapy (P=.001 for hypoglycemia×antidiabetic medications interaction). Among patients not treated with insulin or oral antidiabetic agents (spontaneous hypoglycemia), those with hypoglycemia had significantly higher mortality compared with those who did not develop hypoglycemia (HR, 2.62; 95% CI, 1.97-3.47; P<.001). In contrast, among patients treated with insulin or oral antidiabetic agents (drug-associated hypoglycemia), mortality hazards were similar between those who did and did not develop hypoglycemia (HR, 1.06; 95% CI, 0.74-1.52; P=.749). Sensitivity analyses using a glucose cutoff of 50 mg/dL showed similar results. Table 3 shows a subgroup analysis by drug class. The specific group who developed hypoglycemia associated with sulfonylureas or insulin did not have an increased mortality hazard compared with the normoglycemic group taking the same drugs. The small number of deaths observed in patients receiving metformin, thiazolidinediones, and sulfonylureas likely reflects the fact that oral drugs are discouraged during hospitalization and insulin is preferentially used.
      Table 2Unadjusted In-Hospital Mortality of All Hypoglycemic Patients, Patients with Spontaneous Hypoglycemia, and Patients with Drug-Associated Hypoglycemia Compared with Normoglycemic Patients
      HRNo. of DeathsP Value95% CI
      All hypoglycemic patients1.67451<.0011.33-2.09
       Spontaneous hypoglycemia2.62287<.0011.97-3.47
       Drug-associated hypoglycemia1.06164.7490.74-1.52
      HR=hazard ratio; CI=confidence interval.
      Table 3Subanalysis of In-Hospital Mortality of Patients Who Developed Hypoglycemia Compared with Normoglycemic Patients by Class of Antidiabetic Drug
      HRNo. of DeathsP Value95% CI
      Sulfonylureas0.9014.8800.23-3.48
      Metformin1.285.8550.09-17.7
      Thiazolidinediones0.0141
      Any insulin0.98158.9070.68-1.40
      Any sulfonylurea or insulin0.97163.8670.68-1.39
      HR=hazard ratio; CI=confidence interval.
      Of the 3349 patients with hypoglycemia, 64.3% had 1 episode, 19.1% had 2 episodes, and 16.6% had 3 or more episodes. We found an association between the number of spontaneous hypoglycemic episodes and in-hospital mortality (P for trend<.001), but there was no significant association between the number of drug-associated hypoglycemic events and in-hospital mortality (P for trend=.562, Table 4).
      Table 4Number of Hypoglycemic Episodes and In-Hospital Mortality
      HRP Value95% CI
      Spontaneous hypoglycemia
      P for trend<.001.
       1 episode1.73.0061.17-2.57
       2 episodes3.78<.0012.32-6.15
       ≥3 episodes4.86<.0013.11-7.60
      Drug-associated hypoglycemia
      P for trend=.562.
       1 episode0.99.9620.64-1.54
       2 episodes1.12.6830.64-1.96
       ≥3 episodes1.15.5960.68-1.94
      HR=hazard ratio; CI=confidence interval.
      low asterisk P for trend<.001.
      P for trend=.562.

      Adjusted Association Between Hypoglycemia and Mortality

      After multivariate adjustment for age, sex, race, and number of glucose determinations (Table 5, model 1), the association between hypoglycemia and mortality remained significantly different for patients with spontaneous hypoglycemia versus those with drug-associated hypoglycemia (P<.001 for adjusted interaction). Spontaneous hypoglycemia was significantly associated with higher risk of mortality (HR, 2.84; 95% CI, 2.14-3.76; P<.001), whereas drug-associated hypoglycemia was not (HR, 0.95; 95% CI, 0.66-1.36; P=.762). To determine if the association between hypoglycemia and mortality was attenuated after adjustment for comorbidities, we constructed serial regression models. In model 1, we adjusted for patient demographics and found a strong and significant association between spontaneous hypoglycemia and mortality (HR, 2.84; 95% CI, 2.14-3.76; P<.001). In contrast, in model 2, after adjustment for patient demographics and comorbidities, the association between spontaneous hypoglycemia and mortality was eliminated (HR, 1.11; 95% CI, 0.76-1.64; P=.582, Table 5, model 2). Among patients with drug-associated hypoglycemia, the relationship between hypoglycemia and mortality remained nonsignificant after adjustment for comorbidities (HR, 0.72; 95% CI, 0.45-1.13; P=.155).
      Table 5Adjusted In-Hospital Mortality of Patients with Spontaneous Hypoglycemia and Patients with Drug-Associated Hypoglycemia Compared with Normoglycemic Patients
      HRNo. of DeathsP Value95% CI
      Model 1
       Spontaneous hypoglycemia2.84287<.0012.14-3.76
       Drug-associated hypoglycemia0.95164.7620.66-1.36
      Model 2
       Spontaneous hypoglycemia1.11171.5820.76-1.64
       Drug-associated hypoglycemia0.72114.1550.45-1.13
      HR=hazard ratio; CI=confidence interval.
      Model 1: hypoglycemia adjusted by age, sex, race, and number of glucose determinations. Model 2: hypoglycemia adjusted by age, sex, race, body mass index, diabetes mellitus, congestive heart failure, myocardial infarction, cerebrovascular accident, cancer, chronic obstructive pulmonary disease, shock, white blood cell count, albumin, creatinine, and number of glucose determinations.

      Discussion

      In this large group of patients hospitalized in the general wards, hypoglycemia was associated with greater risk of in-hospital mortality, but this association only occurred in those who developed it spontaneously. In contrast, hypoglycemia that occurred with initiation of antidiabetic medications was not associated with higher in-hospital mortality. These findings suggest that hypoglycemia in hospitalized patients may be a marker of disease burden rather than a direct cause of death, results that should reassure clinicians who manage glucose levels in hospitalized patients in the general wards.
      Additional evidence that hypoglycemia may not cause mortality is provided in our multivariate analyses. Although the unadjusted analyses suggested a strong and significant association between spontaneous hypoglycemia and mortality, this association disappeared after adjusting for patient comorbidities. This suggests that spontaneous hypoglycemia may be a marker of disease burden and used to identify a susceptible host with multiple comorbidities, but it might not be a direct cause of mortality. Our findings contrast with epidemiologic studies conducted mainly in type 1 diabetic subjects, which have rendered hypoglycemia responsible for increased mortality.
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      Acute complications and drug misuse are important causes of death for children and young adults with type 1 diabetes: results from the Yorkshire Register of diabetes in children and young adults.
      A recent report of a young type 1 diabetic subject wearing a retrospective (non-real-time) continuous subcutaneous glucose monitoring system documented the occurrence of hypoglycemia at the time of the patient's death.
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      Although drug-associated hypoglycemia is known to have deleterious effects on the central nervous system,
      • Cryer P.E.
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      we did not find an association between drug-associated hypoglycemia and mortality in univariate or multivariate analyses.
      Our results support many observational studies that found that hypoglycemia was common during hospitalization, and it was strongly associated with in-hospital mortality.
      • Finfer S.
      • Chittock D.R.
      • Su S.Y.
      • et al.
      Intensive versus conventional glucose control in critically ill patients.
      • Pinto D.S.
      • Skolnick A.H.
      • Kirtane A.J.
      • et al.
      U-shaped relationship of blood glucose with adverse outcomes among patients with ST-segment elevation myocardial infarction.
      • Kagansky N.
      • Levy S.
      • Rimon E.
      • et al.
      Hypoglycemia as a predictor of mortality in hospitalized elderly patients.
      • Kosiborod M.
      • Inzucchi S.E.
      • Krumholz H.M.
      • et al.
      Glucometrics in patients hospitalized with acute myocardial infarction: defining the optimal outcomes-based measure of risk.
      • Turchin A.
      • Matheny M.E.
      • Shubina M.
      • Scanlon J.V.
      • Greenwood B.
      • Pendergrass M.L.
      Hypoglycemia and clinical outcomes in patients with diabetes hospitalized in the general ward.
      • Shilo S.
      • Berezovsky S.
      • Friedlander Y.
      • Sonnenblick M.
      Hypoglycemia in hospitalized nondiabetic older patients.
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      • Barton M.K.
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      • Roman S.H.
      Mortality in hospitalized patients with hypoglycemia and severe hyperglycemia.
      • Kosiborod M.
      • Inzucchi S.E.
      • Goyal A.
      • et al.
      Relationship between spontaneous and iatrogenic hypoglycemia and mortality in patients hospitalized with acute myocardial infarction.
      Most studies, however, include critically ill patients. Two previous studies conducted among elderly patients (>70 years of age) admitted to critical care and general ward units reported an association between hypoglycemia and in-hospital mortality.
      • Kagansky N.
      • Levy S.
      • Rimon E.
      • et al.
      Hypoglycemia as a predictor of mortality in hospitalized elderly patients.
      • Shilo S.
      • Berezovsky S.
      • Friedlander Y.
      • Sonnenblick M.
      Hypoglycemia in hospitalized nondiabetic older patients.
      Because elderly patients are at increased risk of developing comorbidities, the authors hypothesized that comorbidities, rather than hypoglycemia itself, would be responsible for the observed excess mortality. In these studies, and in others,
      • Fischer K.F.
      • Lees J.A.
      • Newman J.H.
      Hypoglycemia in hospitalized patients Causes and outcomes.
      • Stagnaro-Green A.
      • Barton M.K.
      • Linekin P.L.
      • Corkery E.
      • deBeer K.
      • Roman S.H.
      Mortality in hospitalized patients with hypoglycemia and severe hyperglycemia.
      it was not possible to determine if hypoglycemia was a direct cause of mortality. Our report extends these observations to a younger population with fewer comorbidities as such found in the general hospital wards. One study excluded patients admitted to the intensive care unit
      • Turchin A.
      • Matheny M.E.
      • Shubina M.
      • Scanlon J.V.
      • Greenwood B.
      • Pendergrass M.L.
      Hypoglycemia and clinical outcomes in patients with diabetes hospitalized in the general ward.
      and showed an association between hypoglycemia and mortality. However, the authors could not distinguish between patients who developed hypoglycemia spontaneously versus those who developed it as a consequence of glucose-lowering therapies.
      • Turchin A.
      • Matheny M.E.
      • Shubina M.
      • Scanlon J.V.
      • Greenwood B.
      • Pendergrass M.L.
      Hypoglycemia and clinical outcomes in patients with diabetes hospitalized in the general ward.
      Kosiborod et al
      • Kosiborod M.
      • Inzucchi S.E.
      • Goyal A.
      • et al.
      Relationship between spontaneous and iatrogenic hypoglycemia and mortality in patients hospitalized with acute myocardial infarction.
      recently found increased mortality risk among patients with acute myocardial infarction developing hypoglycemia spontaneously, but not among those developing hypoglycemia as a consequence of glucose-lowering therapy. Our results show a similar differential association but in noncritically ill patients. In addition, we provide further evidence that hypoglycemia behaves as a marker of disease rather than as a direct cause of death by showing that an increased number of hypoglycemic episodes is associated with greater risk of hospital death only among patients developing hypoglycemia spontaneously. Moreover, when comorbidities are included in a multivariate model, the association between spontaneous hypoglycemia and mortality disappears.
      Studies performed in outpatient populations also are pertinent when examining the role of hypoglycemia as a contributor to adverse outcomes versus a marker of disease burden. Two outpatient studies in individuals with type 2 diabetes showed no mortality benefit of tight glycemic control,
      • Duckworth W.
      • Abraira C.
      • Moritz T.
      • et al.
      Glucose control and vascular complications in veterans with type 2 diabetes.
      • Patel A.
      • MacMahon S.
      • Chalmers J.
      • et al.
      Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.
      whereas a third study, ACCORD, was prematurely stopped because of increased mortality in patients randomized to receive intensive glycemic therapy.
      • Gerstein H.C.
      • Miller M.E.
      • Byington R.P.
      • et al.
      Effects of intensive glucose lowering in type 2 diabetes.
      A post hoc analysis of ACCORD, however, could not attribute the excess mortality observed in the intensive therapy arm to severe hypoglycemia,
      • Bonds D.E.
      • Miller M.E.
      • Bergenstal R.M.
      • et al.
      The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study.
      suggesting that there are alternative explanations to the observed association between tight glycemic control and mortality independent of hypoglycemia. Some of the mechanisms contributing to increased mortality postulated by the ACCORD investigators include the magnitude or the speed of the reduction in glycated hemoglobin levels or the development of adverse effects due to undetected interactions of various drug classes.
      • Gerstein H.C.
      • Miller M.E.
      • Byington R.P.
      • et al.
      Effects of intensive glucose lowering in type 2 diabetes.
      Recently, the authors from ADVANCE also studied the association between hypoglycemia and mortality, and they concluded that although hypoglycemia may contribute to adverse outcomes, it is just as likely to be a marker of disease burden.
      • Zoungas S.
      • Patel A.
      • Chalmers J.
      • et al.
      Severe hypoglycemia and risks of vascular events and death.
      In our study, the fact that the association between spontaneous hypoglycemia and mortality disappeared after adjustment for comorbidities and the fact that the number of hypoglycemic events was not associated with higher mortality risk in patients treated with antidiabetic agents (despite a higher rate of hypoglycemic events in this group) suggest that hypoglycemia may not be a cause of mortality but rather a marker of poor prognosis in hospitalized patients.
      Our study has several strengths. First, it was conducted in a highly diverse racial and ethnic patient base, which should enhance the generalizability of our results. Second, we had a large data set that allowed us to perform sensitivity analyses using a lower glucose threshold (50 mg/dL) and subanalyses to examine the impact of different drug classes on hospital mortality. Finally, we designed a methodology that would allow us to distinguish mortality risks among hypoglycemic patients receiving and not receiving antidiabetic drugs.
      Despite its strengths, our study has several limitations. Because our analysis is retrospective and we were not able to document hypoglycemia at the time of death, we are not able to establish causality. However, prospective randomized trials are precluded for ethical reasons. In addition, we could not confirm a temporal relation between the administration of drugs and the occurrence of the hypoglycemic event. Despite the fact that drug-associated hypoglycemia was not associated with increased mortality, this study does not provide evidence that intensive therapy of hyperglycemia is beneficial in the general ward setting. An appropriately powered clinical trial of tight glycemic control in noncritically ill patients would be the adequate methodology to answer this question. Given the lack of randomization of our groups, we cannot exclude the possibility that antidiabetic agents might have been prescribed to an overall healthier population who tolerated hypoglycemia better and did not show evidence of increased mortality. Finally, the specific cause of hypoglycemia in patients who developed it spontaneously could not be established, and the specific cause of death could not be determined, so we considered all-cause mortality.

      Conclusions

      Our study shows that although hypoglycemia is associated with increased in-hospital mortality among patients admitted to the general wards, this risk is confined to patients with spontaneous hypoglycemia. In contrast, drug-associated hypoglycemia is not associated with higher in-hospital mortality. Although hypoglycemia remains an undesirable event and should be avoided when possible, these data suggest that hypoglycemia behaves as a marker of disease burden rather than as a direct cause of death.

      Acknowledgments

      The authors thank Drs Harry Shamoon, Norman Fleischer, and Martin I. Surks, Albert Einstein College of Medicine, for critically reading the manuscript and providing helpful suggestions.

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