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Hypoglycemia Increased Risk for Death in Diabetics with Chronic Kidney Disease:
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".... Patients who had both diabetes and CKD had substantially higher rates of hypoglycemia than either disease state alone.....The incidence of hypoglycemia was higher in patients with CKD versus without CKD....The odds of 1-d mortality were increased at all levels of hypoglycemia....Adjusted odds ratios for 1-d mortality that were associated with glucose values of <50, 50 to 59, and 60 to 69 mg/dl, respectively, versus glucose of >70 mg/dl were...... 6.84, 3.28, and 3.98 for outpatient records from patients with CKD; and 13.28, 7.36, and 4.34 for outpatient records from patients without CKD...."


Frequency of Hypoglycemia and Its Significance in Chronic
Kidney Disease

Clin J Am Soc Nephrol May 7 2009. doi: 10.2215/CJN.00800209
Maureen F. Moen,* Min Zhan, Van Doren Hsu, Lori D. Walker, Lisa M. Einhorn,* Stephen L. Seliger,* and Jeffrey C. Fink* Departments of *Medicine and Epidemiology and Preventive Medicine, School of Medicine, and Pharmaceutical Research Computing, School of Pharmacy, University of Maryland, Baltimore, Maryland
Background and objectives: This study set out to determine the incidence of hypoglycemia in patients with chronic kidney disease (CKD), with and without diabetes, and the association of hypoglycemia with mortality.
Design, setting, participants, & measurements: This was a retrospective cohort analysis of 243,222 patients who had 2,040,206 glucose measurements and were cared for at the Veterans Health Administration. CKD was defined as an estimated GFR of <60 ml/min per 1.73 m2. Hypoglycemia was set at <70 mg/dl. Mortality was measured 1 day after glucose measurement.
Results: The incidence of hypoglycemia was higher in patients with CKD versus without CKD. Among patients with diabetes, the rate was 10.72 versus 5.33 per 100 patient-months and among patients without diabetes was 3.46 versus 2.23 per 100 patient-months, for CKD versus no CKD, respectively. The odds of 1-d mortality were increased at all levels of hypoglycemia but attenuated in CKD versus no CKD. Adjusted odds ratios for 1-d mortality that were associated with glucose values of <50, 50 to 59, and 60 to 69 mg/dl, respectively, versus glucose of >70 mg/dl were 6.09, 4.10, and 1.85 for inpatient records from patients with CKD; 9.95, 3.79, and 2.54 for inpatients records from patients without CKD; 6.84, 3.28, and 3.98 for outpatient records from patients with CKD; and 13.28, 7.36, and 4.34 for outpatient records from patients without CKD.
Conclusions: CKD is a risk for hypoglycemia, with or without diabetes. The excessive mortality associated with hypoglycemia makes this complication a significant threat to patient safety in CKD.
Diabetes is the most common cause of kidney disease worldwide and is a frequent comorbidity in patients with nondiabetic nephropathies (1). A key goal for diabetic treatment in patients with chronic kidney disease (CKD) is rigorous glucose control to prevent ESRD (1); however, diabetes management in the CKD population warrants special considerations. Because insulin is renally cleared, patients who have diabetes and have CKD with reduced GFR (<60 ml/min per 1.73 m2) frequently have lower insulin requirements (2). In addition, degradation of insulin in peripheral tissues is decreased in patients with CKD (3). Patients with CKD and uremia may also become anorexic with suboptimal nutrition, leading to reduction in glycogen stores (4). Moreover, with a decline in renal mass, patients with CKD may experience reduced renal gluconeogenesis (3). Finally, commonly used antidiabetic drugs are renally excreted and have a prolonged half-life in patients with CKD, predisposing them to episodes of hypoglycemia. The confluence of these factors may contribute to a greater risk for hypoglycemia among patients with CKD and may be an unintended consequence of therapy to treat hyperglycemia.
Hypoglycemia can be considered a serious patient safety event with severe health complications, including dizziness, disorientation, slurred speech, convulsions, and death (5,6). In addition, acute hypoglycemia can result in a surge in adrenergic activity, which can result in coronary ischemia, serious cardiac arrhythmias, and sudden death (7). Such adverse consequences of hypoglycemia may at least partially explain the greater risk for cardiovascular disease (CVD) outcomes observed in at least three recent studies of intensive glucose lowering in patients with diabetes (8 –10).
No epidemiologic studies have examined the incidence of hypoglycemia among patients with CKD, determined its significance, or estimated to what extent it might contribute to the excessive mortality rate associated with CKD. In this study, our primary objective was to examine a large national cohort of patients to determine the incidence of hypoglycemia in patients with versus without CKD, both with and without diabetes. We also examined the association of hypoglycemia with subsequent near-term mortality in this population.
In a national cohort of veterans observed during 1 yr, the diagnoses of CKD and diabetes both were independent risk factors for hypoglycemia of any severity. CKD and diabetes interacted significantly, leading to a greater risk for mild to severe hypoglycemia in the presence of both diseases than that with diabetes, with or without CKD, is largely related to use of diabetic therapies; however, in the case of patients without diabetes and with CKD, the underlying cause for hypoglycemia is not entirely clear. The association between hypoglycemia and mortality was striking and consistent with the anticipated consequences of this metabolic disturbance. The “dose-response” relationship between severity of hypoglycemia and risk for mortality supports the likelihood of a causal relationship; however, the reduced risk for mortality in patients with CKD was unexpected and could relate to an unmeasured increased intensity and quality of care in this patient population relative to patients without CKD.
The higher frequency of hypoglycemia in both CKD subgroups with and without diabetes and the associated increased mortality may account for some portion of the excess cardiovascular morbidity and mortality seen in CKD. Studies demonstrate that hypoglycemia is associated with cardiac disturbances and an increased incidence of death (7,18). In addition, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study in 2008 showed that patients who had type 2 diabetes and were on an intensive glucose-lowering program had an increased rate of death from all causes and from CVD compared with patients who received standard therapy (8). It is plausible that the increased mortality in the intensive treatment arm could be attributable to hypoglycemia, although this was not entirely clear in ACCORD. Both the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) and the Veterans Affairs Diabetes Trial (VADT) found that severe hypoglycemia was more common in an intensive glucose-lowering group than a control group, but the two treatment groups had similar mortality rates (9,10).
As with all retrospective analyses, there are some inherent limitations to consider. The data set was based on administrative data, which is subject to data recording errors and the potential for nonrandom differences in frequency of laboratory measures between exposure groups. Conversely, a large administrative data set, such as that examined here, offers an opportunity to examine relatively uncommon events such as those related to patient safety. Differences in severity of illness and comorbidity may have led to more hospitalizations and frequency of laboratory measurements, and increased surveillance may lead to detection of more hypoglycemia in high-risk groups; however, our findings on the impact of hypoglycemia showed similarly significant trends for both inpatient and outpatient records, with the latter representing a setting in which such factors would likely be less of a factor. Moreover, the patient population was preselected to have at least one hospitalization, ensuring a higher degree of comparability between those with and without hypoglycemia than if the entire population of veterans were chosen. In addition, variations in illness severity were further adjusted for with the CCI. The choice of examining the association between hypoglycemia and 1-d mortality is likely to have limited the influence of other factors that may confound the causal relationship between this metabolic disturbance and mortality at a more distant point in time. In addition, it is important to consider whether the findings from this study of veterans are generalizable to other populations, especially given the predominance of men in this population.
Despite the relatively low proportion of women in the study, the absolute number is still relatively large (9928) and offers a reasonable sample of women from which the results can be generalized. Finally, the study is limited by the lack of medication records to elucidate the mechanism by which hypoglycemia occurs in this population. Details of medication use were not available, and such information would substantially increase the analytic complexity of an analysis.
CKD is a significant risk factor for the development of hypoglycemia with or without the presence of diabetes, but the risk is greatest in patients with CKD and diabetes. The risk for death, whether experienced in or out of the hospital, is increased within 1 d of a hypoglycemic event. Although the extent to which the increased risk for hypoglycemia is iatrogenic or due to medical therapy is unknown, this metabolic disturbance should be considered an important patient safety outcome in CKD or diabetes populations.
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