HbA1c Y MICROALBUMINURIA
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  • 1. Agency for Healthcare Research and Quality Evidence Report/Technology Assessment Number 84 Use of Glycated Hemoglobin and Microalbuminuria in the Monitoring of Diabetes Mellitus Summary Overview Chemistry; it systematically reviews the literature identifying the risk relation between testing for Clinical testing to assess levels of disease control glycemic control or urine albumin and these and progression among persons with type 1 and important clinical outcomes. type 2 diabetes mellitus is widely recommended to clinicians to improve patients’ clinical outcomes. Glycemic Control Two important foci of recommendations for the The advent of self-monitoring of blood glucose followup care of individuals with diabetes include (SMBG) has allowed patients to attain glycemic monitoring of glycemic status by measurement of goals more quickly and has revolutionized the care glycated hemoglobin (GHb) and screening for of individuals with diabetes mellitus; however, it kidney disease with urine albumin to assess overall does not provide information regarding glycemic disease progression and to detect potential control over an extended period of time. progression toward end-organ damage. According Measurement of glycated hemoglobin, which first to the American Diabetes Association’s Clinical began in the 1970s, has become the preferred Practice Recommendations, monitoring of method of assessing long-term glycemic control. glycemic status is considered a cornerstone of Of the various GHb fractions, HbA1c is the diabetes care and affects how physicians and preferred standard for measuring glycemic control patients adjust medical therapy as well as over the previous 2-3 months. The American behavioral therapy (e.g., diet and exercise). Diabetes Association began to make treatment Screening for urine albumin among persons with recommendations based on HbA1c following diabetes is also widely recommended for the publication of the results of the Diabetes Control detection and treatment of incipient diabetic and Complications Trial (DCCT) in the 1990s. nephropathy and affects the physician’s The HbA1c has become the gold standard for the implementation of therapy to slow progression of therapeutic management of diabetes mellitus in kidney disease. research and in the clinical setting. Despite widespread recommendations for Glycated hemoglobin testing gives an screening of persons with diabetes for both assessment of long-term glycemic control; but glycemic control and urine albumin, there has not what other prognostic information does it provide been a systematic assembly of the literature to in the management of individuals with diabetes assess the risk relation between tests assessing long- mellitus? Several large, randomized clinical trials term glycemic control or tests assessing the have demonstrated that intensive glycemic control presence of microalbuminuria with cardiovascular, prevents the development and progression of long- peripheral vascular, renal, and neurological term diabetic microvascular complications. In outcomes (all of which represent end-organ effects these studies, glycemic goals were assessed using of long-term diabetes). The report from which glycated hemoglobin as the measure of long-term this summary was developed was commissioned control. Long-term hyperglycemia, as measured by the American Association of Clinical by glycated hemoglobin, is clearly related to the U . S . D E PA R T M E N T O F H E A LT H A N D H U M A N S E R V I C E S • P u b l i c H e a l t h S e r v i c e
  • 2. development of diabetic microvascular complications; however, associated with urinary albumin excretion. Knowledge of the its relation to the development of macrovascular complications pooled magnitude of risk associated with current definitions of is less clear. The relation of glycemic control and cardiovascular microalbuminuria in addition to an improved understanding of disease (CVD) in individuals with diabetes remains the risk relationship of varying levels of baseline albuminuria controversial, with some studies demonstrating a positive with cardiovascular and renal outcomes could have important association and others showing no association. Another implications in screening and treatment recommendations for important issue that is still an area of active investigation in the persons with diabetes. management of diabetes relates to whether there is a threshold effect of glycated hemoglobin for microvascular and/or Reporting the Evidence macrovascular complications. The issue of a threshold effect of This report addresses the following key questions in persons glycated hemoglobin has important implications for where the with type 1 and type 2 diabetes mellitus: HbA1c treatment targets are set to prevent diabetic complications. Glycemic Control Urine Albumin 1. What is the risk relationship between glycated hemoglobin and the subsequent risk of microvascular diabetic complications Screening tests for microalbuminuria are recommended (retinopathy, nephropathy, neuropathy)? annually for patients with type 1 diabetes of greater than 5 2. What is the risk relationship between glycated hemoglobin and years duration and for all patients with type 2 diabetes from the the subsequent risk of macrovascular diabetic complications time of diagnosis. Twenty-four hour collection of urine for (coronary artery disease, cerebrovascular disease, peripheral quantitative assessment of urinary albumin excretion rate is arterial disease)? currently considered the gold standard measurement of microalbuminuria. However, this method is frequently Urine Albumin considered to be cumbersome and difficult to carry out in the outpatient clinical setting, and it is subject to timing and 1. What is the risk relationship between microalbuminuria and collection inaccuracies. Several other methods of testing, which renal function? are considered less difficult to perform in outpatient settings, 2. What is the risk relationship between microalbuminuria and have been studied and have been demonstrated to have varying cardiovascular disease and death? degrees of correlation with 24 hour urine collection for the detection of urinary albumin. These include random or “spot” Methodology testing of a morning urine specimen for urine albumin The Evidence-based Practice Center (EPC) recruited six concentration or albumin-to-creatinine ratio, overnight or technical and community experts to provide input into the “timed” urine collections for estimation of albumin excretion definition of the key questions and to review a draft of the rates, and dipstick testing. While many experts now support report. The EPC also recruited representatives from a range of the use of random or first morning tests for urinary albumin- other stakeholder organizations to serve as peer reviewers of the to-creatinine ratio as a convenient and accurate approach to draft evidence report. These stakeholder organizations included screening patients, there is currently no clear consensus on organizations of physicians, allied health professionals, and standardized testing methods. third party health care payers in addition to consumer In a variety of prospective studies, elevated urinary albumin organizations. excretion has been shown to be associated with increased risk of Because of the divergent content of questions related to progression of kidney disease toward end-stage renal disease glycemic control and urine albumin, two separate teams of (ESRD) as well as increased cardiovascular morbidity, investigators systematically reviewed literature in these two cardiovascular mortality, and total mortality. However, few areas. Investigators from each team executed systematic search studies have systematically ascertained the magnitude of strategies pertinent to each set of questions. Thus, search increase in both renal and cardiovascular risk associated with strategies and studies identified were different for questions on microalbuminuria among persons with type 1 and persons with glycemic control and urine albumin. type 2 diabetes. Moreover, although observations of renal and cardiovascular outcomes among persons classified as having Glycemic Control microalbuminuria by currently accepted standards have been Articles published in the English language from 1966, when reported, it remains unclear whether current definitions of MEDLINE® began indexing, to April 2002 were accessed microalbuminuria are optimal in terms of predicting renal and through PubMed® using MESH and text words for glycated cardiovascular outcomes. It is unclear as well whether there is a hemoglobin, diabetes, and individual diabetic complications, dose-relationship or threshold effect in prediction of outcomes 2
  • 3. including retinopathy, nephropathy, neuropathy, and defined as an abnormal neurological exam, subjective cardiovascular disease. symptoms, abnormal biothesiometry, or abnormal nerve Reviewed studies were restricted to prospective longitudinal conduction study. Autonomic neuropathy was defined as cohort studies, non-concurrent prospective cohort studies, and abnormal R-R interval, orthostatic hypotension, or resting clinical trials that had data on GHb exposure and outcome data tachycardia. on individual microvascular and macrovascular complications Macrovascular Outcomes during at least 1 year of followup in at least 50 participants • Coronary artery disease (CAD)—CAD morbidity was with type 1 and type 2 diabetes. Because the investigators were defined as non-fatal myocardial infarction, angina, ischemic interested in determining the risk relationship between GHb heart disease, congestive heart failure secondary to ischemic exposure and microvascular and macrovascular complications heart disease, coronary artery bypass surgery, and and in re-examining whether a threshold exists for this angioplasty. CAD mortality was defined as fatal relationship, only studies that reported prospective, quantitative myocardial infarction or sudden cardiac death. risk data (i.e., incidence rates, regression coefficients with • Cerebrovascular disease—Cerebrovascular morbidity was standard errors reported separately, relative hazards, relative defined as non-fatal stroke, transient ischemic attack, or odds, relative risk) were included. Retrospective case-control need for carotid endarterectomy. Cerebrovascular mortality studies that reported and compared previous GHb values in was defined as fatal stroke. individuals with a given outcome versus those without a given outcome were excluded. Articles that reported data in • Peripheral arterial disease (PAD)—PAD was defined as graphical form in which specific quantitative values could not claudication, peripheral revascularization procedure be determined were excluded. (angioplasty, bypass surgery, stenting), gangrene, limb amputation, decreased ankle-brachial index, and decreased Other exclusion criteria included review articles, animal or in arm-toe gradient. vitro studies, non-English language, and studies in which the design was unclear. • Others—Outcome data were collected on congestive heart failure not related to ischemic heart disease and presence of Exposure Variables atherosclerosis (i.e. carotid intimal-medial thickness, Glycated hemoglobin—Data were abstracted on the abdominal aortic aneurysm). biochemical method of measurement, whether the method was Urine Albumin traceable to the DCCT standard and/or whether the lab was certified by the National Glycohemoglobin Standardization Articles published in the English language from 1966 to Program (NGSP), and how glycated hemoglobin was reported April 2002 were identified by searching PubMed® using (i.e. HbA1c, HbA1, total GHb). MESH and text words for diabetes, proteinuria, and Diabetes mellitus—Data were extracted on the type of cardiovascular or renal outcomes. To obtain additional diabetes that study participants had and the method of references not otherwise identified through the electronic diagnosis/confirmation. search, the investigators searched bibliographies of relevant primary and review articles from the electronic search. Outcome Variables After identification of citations through PubMed®, all Microvascular Outcomes abstracts were reviewed for relevance by a single abstractor. All • Retinopathy—Incident retinopathy was defined as new articles to be potentially included in the final review underwent onset retinopathy, progression of pre-existing retinopathy, double review by study authors for data abstraction. Differences cataract extraction, incident macular edema, need for focal in opinion were resolved through consensus adjudication. Data or scatter photocoagulation, blindness, or change in visual abstracted included the following: 1) study design, 2) study acuity. location, 3) numbers of study subjects enrolled, 4) study exclusion criteria, 5) type of diabetes studied and numbers of • Nephropathy—Incident nephropathy was defined as persons with each type of diabetes included in study, 6) development of microalbuminuria and progression of measurement and definitions of microalbuminuria, 7) nephropathy as progression from microalbuminuria to descriptive information about study participants (including age, macroalbuminuria or progression to ESRD requiring renal gender, race, duration of diabetes, glycemic control, baseline replacement therapy. Other nephropathy outcomes diastolic and systolic blood pressure), 8) baseline and followup included change in glomerular filtration rate/creatinine measures of urinary albumin excretion, and 9) baseline and clearance. followup measures of kidney function (e.g., serum creatinine, • Neuropathy—Data on peripheral and autonomic creatinine clearance, or direct measurement of glomerular neuropathy were recorded. Peripheral neuropathy was filtration rates). For randomized controlled trials featuring 3
  • 4. medication interventions (e.g., ACE inhibitors vs. other anti- Findings hypertension agents), the type of medication, dose, and frequency were also recorded. Glycemic Control Exposure Variables 1. What is the risk relationship between glycated hemoglobin and • Urine albumin—Data were abstracted on the biochemical the subsequent risk of microvascular diabetic complications method of urine measurement, including the timing of (retinopathy, nephropathy, neuropathy) in individuals with urine specimens and the cutoffs used to define different type 1 and type 2 diabetes? levels of urine albumin exposure at baseline. • The evidence reported supports a strong, graded relation Microalbuminuria was classified according to the method between GHb exposure and the risk of two major of ascertainment in each study. Studies reporting only on microvascular complications of type 1 and type 2 persons with macroalbuminuria (levels greater than those diabetes, retinopathy and nephropathy. These patterns defined above, unless authors defined microalbuminuria in are observed for various measures of glycated some other fashion) were excluded from analysis. hemoglobin (i.e., HbA1c, HbA1, and total GHb). • Diabetes mellitus—Data were extracted on study • The preponderance of the evidence from cohort studies participants’ type of diabetes and the reported method of shows a strong relation between glycated hemoglobin diagnosis/confirmation of diabetes within each study. and incident retinopathy, incident proliferative Outcome Variables retinopathy and macular edema, and progression of • Renal outcomes—Outcomes reflecting decline in renal retinopathy. Compared to the lowest categories of GHb function over time were divided into eight categories: 1) exposure, the unadjusted relative risks for incident change in glomerular filtration rate (GFR) at end of study, retinopathy were 4 to 7 times greater in the highest 2) rate of change in GFR, 3) change in creatinine clearance categories of GHb exposure for type 1 diabetes and 1.5 at end of study, 4) rate of change in creatinine clearance, 5) to 2.5 times greater in individuals with type 2 diabetes. change in 1/serum creatinine at end of study, 6) rate of The unadjusted relative risk for proliferative retinopathy change in 1/serum creatinine, 7) doubling of serum was 6 to 7 times greater in individuals in the highest creatinine, or 8) need for renal replacement therapy, category of GHb exposure compared to the lowest including dialysis and transplantation. category for individuals with type 1 diabetes, and the unadjusted relative risk was 3 to 13 times greater for • Cardiovascular outcomes—Cardiovascular outcomes were individuals with type 2 diabetes although fewer studies defined as: 1) incidence of all cause death, 2) incidence of examined this outcome in type 2 diabetes. composite CVD deaths, 3) incidence of death due to • This relation between GHb exposure and retinopathy is myocardial infarction, 4) incidence of death due to confirmed in several randomized clinical trials of cerebrovascular accident, 5) incidence of CVD morbidity, individuals with type 1 and type 2 diabetes, which show and 6) incidence of composite CVD morbidity and comparable risk reductions in these outcomes in mortality. individuals randomized to intensive therapy, where the Coronary artery disease, cerebrovascular disease, peripheral HbA1c levels were maintained at approximately 7 arterial disease, and other outcome variables (congestive heart percent, compared to individuals randomized to failure not related to ischemic heart disease and presence of conventional therapy, where the mean HbA1c levels atherosclerosis) are the same as described for glycemic control were maintained at approximately 9 percent. (see above). • Only a few studies address the relation between glycated Data Abstraction and Analysis hemoglobin and the risk of blindness; however, the majority suggest that increased glycated hemoglobin is a Two investigators reviewed titles and abstracts of identified risk factor for blindness in individuals with type 1 articles and appropriate studies were selected for data diabetes. With the exception of one cohort study and abstraction. Articles chosen for abstraction were reviewed by one clinical trial, there are virtually no data on the two reviewers to ensure that all relevant data had been obtained relation between glycated hemoglobin and risk of and were correct. blindness in individuals with type 2 diabetes. • There are very few studies examining the relation between glycated hemoglobin and the incidence of cataracts. • The majority of studies evaluating the relation between glycated hemoglobin and the risk of nephropathy have 4
  • 5. evaluated the risk of developing microalbuminuria. of autonomic neuropathy in individuals with type 2 These data show a strong and significant relation diabetes. between glycated hemoglobin and the risk of 2. What is the risk relationship between glycated hemoglobin and microalbuminuria in individuals with type 1 and type 2 macrovascular diabetic complications (coronary artery disease, diabetes. Compared to individuals in the lowest cerebrovascular disease, and peripheral arterial disease) in category of GHb exposure, those in the highest category individuals with type 1 and type 2 diabetes? had an unadjusted increased risk of microalbuminuria • In the cohort studies evaluating cardiovascular outcomes that was 3 to 9 times greater for type 1 diabetes and an in individuals with diabetes, there was a positive increased risk of microalbuminuria that was 1.4 to 8 association with GHb exposure; however, the risk times greater for type 2 diabetes. This is supported by estimates are much smaller compared to the risk clinical trial data that show significant risk reductions for estimates for the microvascular complications. incident microalbuminuria for individuals randomized • The preponderance of the evidence from cohort studies to intensive glycemic control, where, as noted above, the shows a positive association between glycated mean HbA1c levels were maintained at approximately 7 hemoglobin and risk of fatal and non-fatal coronary percent, compared to those randomized to conventional artery disease, particularly among individuals with type glycemic control, where the mean HbA1c levels were 2 diabetes. Compared to those in the highest category maintained at approximately 9 percent. Among of GHb exposure, the unadjusted risk of fatal and non- individuals with type 1 diabetes, the unadjusted relative fatal coronary artery disease was 50 percent to 70 risk reductions were 34 percent to 43 percent, compared percent (relative risk, 1.5 to 1.7) greater than for those to 60 percent to 74 percent for individuals with type 2 in the lowest category of exposure. diabetes. • There are few data on the relation between CAD and • Although fewer data exist on the relation between glycated hemoglobin among individuals with type 1 glycated hemoglobin and risk of macroalbuminuria and diabetes; however most studies have shown a positive on the relation between glycated hemoglobin and the association. risk of nephropathy progression, several cohort studies and clinical trials support a strong and significant • The relation between glycated hemoglobin and the risk positive association in individuals with type 1 and type 2 of PAD appears to be strong and positive in individuals diabetes. with type 1 and type 2 diabetes. Compared to those in the lowest category of GHb exposure, the unadjusted • The only studies identified by the search strategy and risk of PAD was 5 to 6 time greater in individuals in the inclusion criteria examining the effect of GHb exposure highest category of exposure among individuals with on GFR were cohort studies conducted in individuals type 1 diabetes, and the risk was 2 to 4 times greater with type 1 diabetes. All studies consistently among individuals with type 2 diabetes. demonstrated that increasing levels of glycated hemoglobin were associated with a decline in GFR. • The risk relationship between cerebrovascular disease There are no clinical trial data examining the GFR and glycated hemoglobin, which has only been outcomes and no data on the relation between glycated examined among individuals with type 2 diabetes, is less hemoglobin and GFR in individuals with type 2 clear. diabetes. • There are very few data on the relation between GHb • Very few studies examined the association between exposure and congestive heart failure or subclinical glycated hemoglobin and the risk of ESRD. atherosclerosis, assessed by carotid intimal-medial thickness, making it difficult to draw any conclusions • Among individuals with type 1 diabetes, there appears regarding these outcomes. to be a strong, positive association between glycated hemoglobin and the risk of peripheral neuropathy in • Only a few studies have examined the presence of a both cohort studies and clinical trials; however, the threshold effect of glycated hemoglobin on the risk of evidence of an association between glycated hemoglobin developing diabetic complications (i.e. a level of glycated and peripheral neuropathy in individuals with type 2 hemoglobin above which there is a non-constant or diabetes yields conflicting results. exponential increase in risk of complications). The majority of these studies have not found a threshold • There are fewer data on the association between glycated effect for retinopathy and nephropathy outcomes but, hemoglobin and the risk of autonomic neuropathy. In rather, have demonstrated a continuous risk of individuals with type 1 diabetes, there appears to be a complications with increasing GHb levels. There are positive association. There are also very limited data on very few studies that have attempted to examine the the relation between glycated hemoglobin and the risk 5
  • 6. presence of a threshold effect of glycated hemoglobin on Future Research neuropathy and macrovascular outcomes. For research on glycemic control, future cohort studies and Urine Albumin clinical trials should focus on studying the relation between 1. What is the risk relationship between microalbuminuria and GHb exposure and the risk of macrovascular complications. renal function? Fewer data are available on these outcomes than on • Eleven studies reported on this question. The analyses microvascular outcomes; however, more data are also needed on had important limitations including broad variation in the relation between glycated hemoglobin and the risk of methods of assessing levels of urine albumin excretion as neuropathy, particularly the risk of peripheral and autonomic well as substantial heterogeneity in reporting of renal neuropathy in individuals with type 2 diabetes. outcomes. For research on urine albumin, future work should seek to • The preponderance of evidence suggests that the define the optimal and most feasible tests for measuring presence of microalbuminuria at baseline is associated microalbuminuria and to standardize measurement of with progression of chronic kidney disease. microalbuminuria. Future research should also characterize the • The relation of urine albumin excretion at baseline to nature of the relation (e.g. threshold versus linear) between progression of chronic kidney disease appears graded; microalbuminuria and outcomes. In addition, further work is higher levels of urine albumin excretion at baseline are needed to understand whether currently accepted definitions of associated with a greater magnitude of decrease in renal microalbuminuria are optimal in predicting future renal and function as well as a faster rate of decline in renal cardiovascular outcomes. function over time. Extension of research in both these areas has important 2. What is the risk relationship between microalbuminuria, future implications for gaining improved understanding of the cardiovascular disease, and death? role of glycemic control in the prevention of the cardiovascular • Nineteen studies reported on cardiovascular morbidity sequelae as well as for future development of guidelines for and mortality, and 24 reported on all-cause mortality. screening practices among persons with type 1 and type 2 The analyses had important limitations including broad diabetes mellitus. variation in methods of assessing levels of urine albumin excretion as well as few studies focusing on disease- Ordering Information specific cardiovascular morbidity or mortality. The full evidence report from which this summary was taken • The preponderance of evidence from these studies was prepared for AHRQ by the Johns Hopkins Evidence-based demonstrates an association between microalbuminuria Practice Center, Baltimore, MD, under contract No. 290-97- at baseline and increased risk of cardiovascular 0006. It is expected to be available in late summer 2003. At morbidity, cardiovascular mortality, and all-cause that time, printed copies may be obtained free of charge from mortality. the AHRQ Publications Clearinghouse by calling 800-358- • The relation of urine albumin excretion at baseline to 9295. Requesters should ask for Evidence Report/Technology cardiovascular morbidity, cardiovascular mortality, and Assessment No. 84, Use of Glycated Hemoglobin and all-cause mortality appears graded; greater levels of urine Microalbuminuria in the Monitoring of Diabetes Mellitus. albumin excretion at baseline are independently Internet users will be able to access the report online through associated with a greater magnitude of risk of AHRQ’s Web site at www.ahrq.gov. cardiovascular morbidity, cardiovascular mortality, and all-cause mortality over time. www.ahrq.gov AHRQ Pub. No. 03-E048 July 2003 ISSN 1530-440X