Under its Evidence-based Practice Program, the Agency for Healthcare Research and Quality (AHRQ) is developing scientific information for other agencies and organizations on which to base clinical guidelines, performance measures, and other quality improvement tools. Contractor institutions review all relevant scientific literature on assigned clinical care topics and produce evidence reports and technology assessments, conduct research on methodologies and the effectiveness of their implementation, and participate in technical assistance activities.
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Overview / Reporting the Evidence / Methodology / Findings / Future Research / Ordering Information
Clinical testing to assess levels of disease control and progression among persons with type 1 and type 2 diabetes mellitus is widely recommended to clinicians to improve patients' clinical outcomes. Two important foci of recommendations for the followup care of individuals with diabetes include monitoring of glycemic status by measurement of glycated hemoglobin (GHb) and screening for kidney disease with urine albumin to assess overall disease progression and to detect potential progression toward end-organ damage. According to the American Diabetes Association's Clinical Practice Recommendations, monitoring of glycemic status is considered a cornerstone of diabetes care and affects how physicians and patients adjust medical therapy as well as behavioral therapy (e.g., diet and exercise). Screening for urine albumin among persons with diabetes is also widely recommended for the detection and treatment of incipient diabetic nephropathy and affects the physician's implementation of therapy to slow progression of kidney disease.
Despite widespread recommendations for screening of persons with diabetes for both glycemic control and urine albumin, there has not been a systematic assembly of the literature to assess the risk relation between tests assessing long-term glycemic control or tests assessing the presence of microalbuminuria with cardiovascular, peripheral vascular, renal, and neurological outcomes (all of which represent end-organ effects of long-term diabetes). The report from which this summary was developed was commissioned by the American Association of Clinical Chemistry; it systematically reviews the literature identifying the risk relation between testing for glycemic control or urine albumin and these important clinical outcomes.
The advent of self-monitoring of blood glucose (SMBG) has allowed patients to attain glycemic goals more quickly and has revolutionized the care of individuals with diabetes mellitus; however, it does not provide information regarding glycemic control over an extended period of time. Measurement of glycated hemoglobin, which first began in the 1970s, has become the preferred method of assessing long-term glycemic control. Of the various GHb fractions, HbA1c is the preferred standard for measuring glycemic control over the previous 2-3 months. The American Diabetes Association began to make treatment recommendations based on HbA1c following publication of the results of the Diabetes Control and Complications Trial (DCCT) in the 1990s. The HbA1c has become the gold standard for the therapeutic management of diabetes mellitus in research and in the clinical setting.
Glycated hemoglobin testing gives an assessment of long-term glycemic control; but what other prognostic information does it provide in the management of individuals with diabetes mellitus? Several large, randomized clinical trials have demonstrated that intensive glycemic control prevents the development and progression of long-term diabetic microvascular complications. In these studies, glycemic goals were assessed using glycated hemoglobin as the measure of long-term control. Long-term hyperglycemia, as measured by glycated hemoglobin, is clearly related to the development of diabetic microvascular complications; however, its relation to the development of macrovascular complications is less clear. The relation of glycemic control and cardiovascular disease (CVD) in individuals with diabetes remains controversial, with some studies demonstrating a positive association and others showing no association. Another important issue that is still an area of active investigation in the management of diabetes relates to whether there is a threshold effect of glycated hemoglobin for microvascular and/or macrovascular complications. The issue of a threshold effect of glycated hemoglobin has important implications for where the HbA1c treatment targets are set to prevent diabetic complications.
Screening tests for microalbuminuria are recommended annually for patients with type 1 diabetes of greater than 5 years duration and for all patients with type 2 diabetes from the time of diagnosis. Twenty-four hour collection of urine for quantitative assessment of urinary albumin excretion rate is currently considered the gold standard measurement of microalbuminuria. However, this method is frequently considered to be cumbersome and difficult to carry out in the outpatient clinical setting, and it is subject to timing and collection inaccuracies. Several other methods of testing, which are considered less difficult to perform in outpatient settings, have been studied and have been demonstrated to have varying degrees of correlation with 24 hour urine collection for the detection of urinary albumin. These include random or "spot" testing of a morning urine specimen for urine albumin concentration or albumin-to-creatinine ratio, overnight or "timed" urine collections for estimation of albumin excretion rates, and dipstick testing. While many experts now support the use of random or first morning tests for urinary albumin-to- creatinine ratio as a convenient and accurate approach to screening patients, there is currently no clear consensus on standardized testing methods.
In a variety of prospective studies, elevated urinary albumin excretion has been shown to be associated with increased risk of progression of kidney disease toward end-stage renal disease (ESRD) as well as increased cardiovascular morbidity, cardiovascular mortality, and total mortality. However, few studies have systematically ascertained the magnitude of increase in both renal and cardiovascular risk associated with microalbuminuria among persons with type 1 and persons with type 2 diabetes. Moreover, although observations of renal and cardiovascular outcomes among persons classified as having microalbuminuria by currently accepted standards have been reported, it remains unclear whether current definitions of microalbuminuria are optimal in terms of predicting renal and cardiovascular outcomes. It is unclear as well whether there is a dose-relationship or threshold effect in prediction of outcomes associated with urinary albumin excretion. Knowledge of the pooled magnitude of risk associated with current definitions of microalbuminuria in addition to an improved understanding of the risk relationship of varying levels of baseline albuminuria with cardiovascular and renal outcomes could have important implications in screening and treatment recommendations for persons with diabetes.
This report addresses the following key questions in persons with type 1 and type 2 diabetes mellitus:
The Evidence-based Practice Center (EPC) recruited six technical and community experts to provide input into the definition of the key questions and to review a draft of the report. The EPC also recruited representatives from a range of other stakeholder organizations to serve as peer reviewers of the draft evidence report. These stakeholder organizations included organizations of physicians, allied health professionals, and third party health care payers in addition to consumer organizations.
Because of the divergent content of questions related to glycemic control and urine albumin, two separate teams of investigators systematically reviewed literature in these two areas. Investigators from each team executed systematic search strategies pertinent to each set of questions. Thus, search strategies and studies identified were different for questions on glycemic control and urine albumin.
Articles published in the English language from 1966, when MEDLINE® began indexing, to April 2002 were accessed through PubMed® using MeSH® and text words for glycated hemoglobin, diabetes, and individual diabetic complications, including retinopathy, nephropathy, neuropathy, and cardiovascular disease.
Reviewed studies were restricted to prospective longitudinal cohort studies, non-concurrent prospective cohort studies, and clinical trials that had data on GHb exposure and outcome data on individual microvascular and macrovascular complications during at least 1 year of followup in at least 50 participants with type 1 and type 2 diabetes. Because the investigators were interested in determining the risk relationship between GHb exposure and microvascular and macrovascular complications and in re-examining whether a threshold exists for this relationship, only studies that reported prospective, quantitative risk data (i.e., incidence rates, regression coefficients with standard errors reported separately, relative hazards, relative odds, relative risk) were included. Retrospective case-control studies that reported and compared previous GHb values in individuals with a given outcome versus those without a given outcome were excluded. Articles that reported data in graphical form in which specific quantitative values could not be determined were excluded.
Other exclusion criteria included review articles, animal or in vitro studies, non-English language, and studies in which the design was unclear.
Exposure Variables
Glycated hemoglobin—Data were abstracted on the biochemical method of measurement, whether the method was traceable to the DCCT standard and/or whether the lab was certified by the National Glycohemoglobin Standardization Program (NGSP), and how glycated hemoglobin was reported (i.e., HbA1c, HbA1, total GHb).
Diabetes mellitus—Data were extracted on the type of diabetes that study participants had and the method of diagnosis/confirmation.
Outcome Variables
Microvascular Outcomes
Macrovascular Outcomes
Articles published in the English language from 1966 to April 2002 were identified by searching PubMed® using MeSH® and text words for diabetes, proteinuria, and cardiovascular or renal outcomes. To obtain additional references not otherwise identified through the electronic search, the investigators searched bibliographies of relevant primary and review articles from the electronic search.
After identification of citations through PubMed®, all abstracts were reviewed for relevance by a single abstractor. All articles to be potentially included in the final review underwent double review by study authors for data abstraction. Differences in opinion were resolved through consensus adjudication. Data abstracted included the following:
For randomized controlled trials featuring medication interventions (e.g., ACE inhibitors vs. other anti-hypertension agents), the type of medication, dose, and frequency were also recorded.
Exposure Variables
Microalbuminuria was classified according to the method of ascertainment in each study. Studies reporting only on persons with macroalbuminuria (levels greater than those defined above, unless authors defined microalbuminuria in some other fashion) were excluded from analysis.
Outcome Variables
Coronary artery disease, cerebrovascular disease, peripheral arterial disease, and other outcome variables (congestive heart failure not related to ischemic heart disease and presence of atherosclerosis) are the same as described for glycemic control.
Two investigators reviewed titles and abstracts of identified articles and appropriate studies were selected for data abstraction. Articles chosen for abstraction were reviewed by two reviewers to ensure that all relevant data had been obtained and were correct.
1. What is the risk relationship between glycated hemoglobin and the subsequent risk of microvascular diabetic complications (retinopathy, nephropathy, neuropathy) in individuals with type 1 and type 2 diabetes?
2. What is the risk relationship between glycated hemoglobin and macrovascular diabetic complications (coronary artery disease, cerebrovascular disease, and peripheral arterial disease) in individuals with type 1 and type 2 diabetes?
1. What is the risk relationship between microalbuminuria and renal function?
2. What is the risk relationship between microalbuminuria, cardiovascular disease, and death?
For research on glycemic control, future cohort studies and clinical trials should focus on studying the relation between GHb exposure and the risk of macrovascular complications. Fewer data are available on these outcomes than on microvascular outcomes; however, more data are also needed on the relation between glycated hemoglobin and the risk of neuropathy, particularly the risk of peripheral and autonomic neuropathy in individuals with type 2 diabetes.
For research on urine albumin, future work should seek to define the optimal and most feasible tests for measuring microalbuminuria and to standardize measurement of microalbuminuria. Future research should also characterize the nature of the relation (e.g. threshold versus linear) between microalbuminuria and outcomes. In addition, further work is needed to understand whether currently accepted definitions of microalbuminuria are optimal in predicting future renal and cardiovascular outcomes.
Extension of research in both these areas has important future implications for gaining improved understanding of the role of glycemic control in the prevention of the cardiovascular sequelae as well as for future development of guidelines for screening practices among persons with type 1 and type 2 diabetes mellitus.
The full evidence report from which this summary was taken was prepared for AHRQ by the Johns Hopkins Evidence-based Practice Center, Baltimore, MD, under contract No. 290-97-0006. It is expected to be available in late summer 2003. At that time, printed copies may be obtained free of charge from the AHRQ Publications Clearinghouse by calling 800-358-9295. Requesters should ask for Evidence Report/Technology Assessment No. 84, Use of Glycated Hemoglobin and Microalbuminuria in the Monitoring of Diabetes Mellitus.
The Evidence Report can also be downloaded as a zipped file online at: www.ahrq.gov/clinic/evrptfiles.htm#glyca.
AHRQ Publication No. 03-E048
Current as of July 2003
Internet Citation:
Use of Glycated Hemoglobin and Microalbuminuria in the Monitoring of Diabetes Mellitus. Summary, Evidence Report/Technology Assessment: Number 84. AHRQ Publication No. 03-E048, July 2003. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/epcsums/glycasum.htm
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