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Golden S, Boulware LE, Berkenblit G, et al. Use of Glycated Hemoglobin and Microalbuminuria in the Monitoring of Diabetes Mellitus. Rockville (MD): Agency for Healthcare Research and Quality (US); 2003 Oct. (Evidence Reports/Technology Assessments, No. 84.)

  • This publication is provided for historical reference only and the information may be out of date.

This publication is provided for historical reference only and the information may be out of date.

Cover of Use of Glycated Hemoglobin and Microalbuminuria in the Monitoring of Diabetes Mellitus

Use of Glycated Hemoglobin and Microalbuminuria in the Monitoring of Diabetes Mellitus.

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4Conclusions and Limitations

Among all evidence reporting on the relation between glycemic control and cardiovascular, neurologic, opthamologic, and renal outcomes, there is a strong, graded relation between glycated hemoglobin exposure and the risk of two major microvascular complications of type 1 and type 2 diabetes, retinopathy and nephropathy. These patterns are observed for various measures of glycated hemoglobin (i.e., HbA1c, HbA1, and total GHb). The relation between glycated hemoglobin and macrovascular complications is not as strong as that seen for the microvascular complications, although there are fewer studies examining these outcomes. In general, however, there appears to be a positive relation between glycated hemoglobin and the risk of CAD and PAD, particularly among individuals with type 2 diabetes.

Similarly, among all evidence reporting on the relation between microalbuminuria and cardiovascular and renal outcomes, there appears to be a strong relation between baseline urinary albumin excretion and progression of kidney disease, development of cardiovascular morbidity and mortality, and incidence of all cause death. In addition, there appears to be a graded influence of the degree of urine albumin excretion at baseline and the magnitude of future risk of renal and cardiovascular outcomes.

Glycemic Control

Risk relationship between glycated hemoglobin and retinopathy outcomes

The preponderance of the evidence from cohort studies shows a strong relation between glycated hemoglobin and incident retinopathy, incident proliferative retinopathy and macular edema, and progression of retinopathy. This is confirmed in several randomized clinical trials of individuals with type 1 and type 2 diabetes, which show comparable risk reductions in these outcomes in individuals randomized to intensive therapy, where the HbA1c's were maintained at approximately 7 percent, compared to individuals randomized to conventional therapy, where the mean HbA1c's were maintained at approximately 9 percent. Only a few cohort studies address the relation between glycated hemoglobin and the risk of blindness; however, the majority suggest that increased glycated hemoglobin is a risk factor for blindness in individuals with type 1 diabetes. With the exception of one clinical trial, there are virtually no data on the relation between glycated hemoglobin and risk of blindness in individuals with type 2 diabetes.

Risk relationship between glycated hemoglobin and nephropathy outcomes

The majority of studies evaluating the relation between glycated hemoglobin and the risk of nephropathy have evaluated the risk of developing microalbuminuria. These data show a strong and significant relation between glycated hemoglobin and the risk of microalbuminuria in individuals with type 1 and type 2 diabetes. This is supported by clinical trial data that show significant risk reductions for incident microalbuminuria for individuals randomized to intensive glycemic control, where the mean HbA1c's were maintained at approximately 7 percent, compared to those randomized the conventional glycemic control, where the mean HbA1c's were maintained at approximately 9 percent. While there are less data on the relation between glycated hemoglobin and risk of macroalbuminuria and on the risk of nephropathy progression, several cohort studies and clinical trials support a strong and significant positive association in type 1 and type 2 diabetes. Based on our search strategy and exclusion criteria, the only studies examining the effect of glycated hemoglobin exposure on GFR were cohort studies conducted in individuals with type 1 diabetes. All studies consistently demonstrated that increasing levels of glycated hemoglobin were association with a decline in GFR. There are no clinical trial data examining the GFR outcomes in individuals with type 1 or type 2 diabetes and there are no data on the relation between glycated hemoglobin and GFR in individuals with type 2 diabetes. There are very few studies examining the association between glycated hemoglobin and risk of ESRD.

Risk relationship between glycated hemoglobin and neuropathy outcomes

The preponderance of the evidence examining the risk relationship between glycated hemoglobin and neuropathy has shown a strong, positive association between glycated hemoglobin and the risk of peripheral neuropathy in individuals with type 1 diabetes. This has been demonstrated in several cohort studies and confirmed in clinical trials showing a significant risk reduction in the development of peripheral neuropathy in individuals randomized to intensive vs. conventional glycemic control. The association is less clear in individuals with type 2 diabetes because there have only been a few studies in this population and they have yielded conflicting results, with some studies showing a positive association and others showing no association.

There are little data on the relation between glycated hemoglobin and the risk of autonomic neuropathy. The few studies in individuals with type 1 diabetes have all shown a positive association; however, there was only one study addressing this relationship in individuals with type 2 diabetes.

Risk relationship between glycated hemoglobin and macrovascular outcomes

In the cohort studies evaluating cardiovascular outcomes in individuals with diabetes, there was a positive association with glycated hemoglobin exposure; however, the risk estimates are much smaller compared to the risk estimates for the microvascular complications. The preponderance of the evidence from cohort studies shows a positive association between glycated hemoglobin and risk of fatal and non-fatal CAD, particularly among individuals with type 2 diabetes. There are little data on the relation between CAD and glycated hemoglobin among individuals with type 1 diabetes; however most studies have shown a positive association. The relation between glycated hemoglobin and the risk of PAD appears to be strong and positive in individuals with type 1 and type 2 diabetes. The risk relationship between cerebrovascular disease and glycated hemoglobin, which has only been examined among individuals with type 2 diabetes, is less clear. In one clinical trial, there was a non-significant reduction in the risk of cardiovascular disease in individuals with type 2 diabetes. There are very little data on the relation between glycated hemoglobin exposure and CHF or subclinical atherosclerosis, assessed by carotid IMT, making it difficult to draw any conclusions regarding these outcomes.

Threshold effect between glycosylated hemoglobin and diabetic complications

Only a few studies have specifically examined the presence of a threshold effect of glycated hemoglobin on the risk of developing diabetic complications. The majority of these have not found a threshold effect for retinopathy and nephropathy outcomes. There are very little data examining the presence of a threshold effect of glycated hemoglobin on neuropathy and macrovascular outcomes.

Limitations

Our literature review has several limitations. First, the majority of the studies did not use glycated hemoglobin assay methods that were DCCT traceable, indicating that the majority of these measurements were not standardized. Second, there was great heterogeneity in the glycated hemoglobin measurement techniques used, especially for HbA1 and total GHb measurements, making comparisons across studies difficult. Third, our review is subject to publication bias, in that the search was more likely to identify articles that reported a positive association between glycated hemoglobin and outcomes. Fourth, certain outcomes, such as risk of blindness, progression of nephropathy, change in GFR, and certain macrovascular outcomes, were only reported in a few studies, making it difficult to draw definitive conclusions regarding the risk relationships. Finally, our data are limited to examine the risk relation between glycated hemoglobin and microvascular and macrovascular complications below HbA1c of 7 percent because there were very few studies that had exposure data below this cut-point. Therefore, we are still unable, in this report, to address whether there is added benefit to lowering the HbA1c level below the current threshold of 7 percent. Finally, our report focuses on the prognostic value of glycated hemoglobin in predicting clinical outcomes but it does not address the effects of using this test in actual clinical management of patients with diabetes."

Urine Albumin

Relation between baseline urine albumin and renal outcomes

The preponderance of the evidence from both cohort studies and RCTs indicates a strong relation between the presence of microalbuminuria at baseline and renal outcomes among persons with types 1 and 2 diabetes. In addition, there appears to be a graded relation between the total quantity of urine albumin at baseline and progression of renal disease such that persons with macroalbuminuria have faster rates of progression of chronic kidney disease and a greater decrement in kidney function over follow up when compared to persons with lesser degrees of urinary albumin excretion. When employed in RCTs, ACE inhibitor therapy appears to slow rates of progression toward ESRD.

It remains unclear whether currently accepted thresholds for microalbuminuria are ideal in terms of assisting with prediction of risk for renal outcomes. Of all articles assessing the relation between urine albumin and renal outcomes, none reported results pertaining to intermediate cut-off thresholds of urinary albumin (i.e. detectable levels of urine albumin that are too low to qualify as microalbuminuria by current standards or by standards defined by study investigators). Thus, we were unable to assess whether assignment of other thresholds cut-offs could be helpful in predicting increased risk of kidney disease.

Relation between baseline urine albumin and all-cause mortality

The preponderance of the evidence from both cohort studies and RCTs demonstrates an independent association between microalbuminuria at baseline and all-cause mortality for persons with types 1 and 2 diabetes. In some cases, greater than two to three fold increases in risk of all-cause mortality were identified for persons with microalbuminuria at baseline when compared to their counterparts with normoalbuminuria after adjustment for potential confounding factors. In addition, there appears to be a graded relation between the total quantity of urine albumin at baseline and total mortality such that greater levels of urine albumin at follow up are related to greater risk of all-cause mortality.

It remains unclear whether currently accepted thresholds for microalbuminuria are ideal in terms of assisting with prediction of risk of all-cause mortality. However, in five studies analyzing intermediate levels of urine albumin excretion, there appeared to be a graded influence on the degree of urine albumin present at baseline and the incidence of all-cause mortality at follow up. These data suggest that prediction of increased risk of future risk of death may be possible at levels of urinary albumin excretion that are lower than thresholds currently used to define microalbuminuria.

Relation between baseline urine albumin and CVD events

The preponderance of the evidence from cohort studies and RCTs demonstrates an independent association between microalbuminuria at baseline and CVD events at follow up for persons with types 1 and 2 diabetes. Both disease specific (myocardial infarction and cerebrovascular accidents) and composite CVD death outcomes were increased among persons with microalbuminuria when compared to their counterparts with normoalbuminuria. Persons with microalbuminuria also had increased risk of composite measures of CVD mortality and morbidity in most studies. In some cases, greater than two to three fold increases in risk of CVD morbidity outcomes were identified for persons with microalbuminuria at baseline when compared to their counterparts with normoalbuminuria after adjustment for potential confounders. Similarly, in some studies, two to seven-fold increases in risk of CVD mortality was reported for persons with microalbuminuria at baseline versus their counterparts with normoalbuminuria at after adjustment for potential confounders. In addition, there appears to be a graded relation between levels of urinary albumin excretion at baseline such that greater levels of baseline urinary albumin excretion are related to greater risk of all cardiovascular outcomes.

It remains unclear whether currently accepted thresholds for microalbuminuria are ideal in terms of assisting with prediction of risk of cardiovascular morbidity and mortality. However, in four studies analyzing intermediate levels of urine albumin excretion, there appears to be a graded influence on the degree of urine albumin present at baseline and the incidence of cardiovascular morbidity and mortality at follow up. These data suggest that prediction of increased risk of future risk of death may be possible at levels of urinary albumin excretion that are lower than thresholds currently used to define microalbuminuria.

Limitations

Limitations of this review deserve mention. First, we found that the methods of measurement of urinary albumin, definitions for microalbuminuria, the measures used to describe urinary excretion rates, and outcomes reported varied substantially in these studies. This variability in ascertainment of exposure and outcomes should be taken into account when interpreting the aforementioned conclusions. Second, the ascertainment of urinary creatinine and urinary albumin can occur via a variety of biochemical measurement assays (e.g. for urinary albumin, immunonephelometry, immunoturbidimetry, radioimmunoassay, and others; for urine creatinine, colorimetric and enzymatic methods), which we did not take into account in this report. Variation in use of such assays to measure urine albumin or creatinine excretion could further affect the comparability of urinary albumin excretion measures. Third, study participants' baseline characteristics varied widely across studies, including important characteristics such as participants' diabetes durations at study inception and level of glucose control. (Tables 2, 3) While many studies reporting adjusted risk estimates controlled for these factors at baseline, others did not, which may affect our ability to compare the magnitude of outcomes across studies. Fourth, while this report focuses on the prognostic value of testing for urine albumin, it does not address the utility of such tests in affecting the clinical management of persons with diabetes. Finally, while this report presents most data on the risk relation between the presence of urine albumin at baseline and clinical outcomes at follow up in the format of comparative relative risks, the use of absolute risk estimates may be more appropriate in guiding clinical decisions. Notwithstanding these limitations, the associations we report appear to be consistent across studies and consistent across types of measurement of urine albumin excretion (e.g. timed urine samples versus random urine samples). More formal analyses are needed to understand how these features of study design and measurement of urinary albumin excretion rates may relate to the magnitude of the associations summarized above.

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