The document summarizes evidence on the relationship between glycated hemoglobin (HbA1c) levels and microalbuminuria in monitoring diabetes. It finds:
1) HbA1c is strongly associated with increased risk of retinopathy and nephropathy. Risk rises with higher HbA1c levels.
2) Microalbuminuria is associated with increased risk of declining renal function and cardiovascular disease outcomes like death. However, studies have not systematically assessed the exact risk relationship or determined optimal definitions of microalbuminuria.
3) The report systematically reviews literature on glycemic control and microalbuminuria testing to evaluate their ability to predict diabetes complications and inform clinical guidelines.
Prescribed medication order and communication skills.pptx
Glycasum
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