Summary
Evidence Report/Technology Assessment: Number 84
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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
Overview
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.
Glycemic Control
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.
Urine Albumin
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.
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Reporting the Evidence
This report addresses the following key questions in persons
with type 1 and type 2 diabetes mellitus:
Glycemic Control
- What is the risk relationship between glycated hemoglobin and
the subsequent risk of microvascular diabetic complications
(retinopathy, nephropathy, neuropathy)?
- What is the risk relationship between glycated hemoglobin and
the subsequent risk of macrovascular diabetic complications
(coronary artery disease, cerebrovascular disease, peripheral
arterial disease)?
Urine Albumin
- What is the risk relationship between microalbuminuria and
renal function?
- What is the risk relationship between microalbuminuria and
cardiovascular disease and death?
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Methodology
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.
Glycemic Control
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
- Retinopathy—Incident retinopathy was defined as new
onset retinopathy, progression of pre-existing retinopathy,
cataract extraction, incident macular edema, need for focal
or scatter photocoagulation, blindness, or change in visual
acuity.
- Nephropathy—Incident nephropathy was defined as
development of microalbuminuria and progression of
nephropathy as progression from microalbuminuria to
macroalbuminuria or progression to ESRD requiring renal
replacement therapy. Other nephropathy outcomes
included change in glomerular filtration rate/creatinine
clearance.
- Neuropathy—Data on peripheral and autonomic
neuropathy were recorded. Peripheral neuropathy was
defined as an abnormal neurological exam, subjective
symptoms, abnormal biothesiometry, or abnormal nerve
conduction study. Autonomic neuropathy was defined as
abnormal R-R interval, orthostatic hypotension, or resting
tachycardia.
Macrovascular Outcomes
- Coronary artery disease (CAD)—CAD morbidity was
defined as non-fatal myocardial infarction, angina, ischemic
heart disease, congestive heart failure secondary to ischemic
heart disease, coronary artery bypass surgery, and
angioplasty. CAD mortality was defined as fatal
myocardial infarction or sudden cardiac death.
- Cerebrovascular disease—Cerebrovascular morbidity was
defined as non-fatal stroke, transient ischemic attack, or
need for carotid endarterectomy. Cerebrovascular mortality
was defined as fatal stroke.
- Peripheral arterial disease (PAD)—PAD was defined as
claudication, peripheral revascularization procedure
(angioplasty, bypass surgery, stenting), gangrene, limb
amputation, decreased ankle-brachial index, and decreased
arm-toe gradient.
- Others—Outcome data were collected on congestive heart
failure not related to ischemic heart disease and presence of
atherosclerosis (i.e., carotid intimal-medial thickness,
abdominal aortic aneurysm).
Urine Albumin
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:
- Study design.
- Study location.
- Numbers of study subjects enrolled.
- Study exclusion criteria.
- Type of diabetes studied and numbers of persons with each type of diabetes included in study.
- Measurement and definitions of microalbuminuria.
- Descriptive information about study participants (including age
gender, race, duration of diabetes, glycemic control, baseline
diastolic and systolic blood pressure).
- Baseline and followup measures of urinary albumin excretion.
- Baseline and followup measures of kidney function (e.g., serum creatinine,
creatinine clearance, or direct measurement of glomerular
filtration rates).
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
Outcome Variables
- Renal outcomes—Outcomes reflecting decline in renal
function over time were divided into eight categories:
- Change in glomerular filtration rate (GFR) at end of study.
- Rate of change in GFR.
- Change in creatinine clearance at end of study.
- Rate of change in creatinine clearance.
- Change in 1/serum creatinine at end of study.
- Rate of change in 1/serum creatinine.
- Doubling of serum creatinine.
- Need for renal replacement therapy, including dialysis and transplantation.
- Cardiovascular outcomes—Cardiovascular outcomes were
defined as:
- Incidence of all cause death.
- Incidence of composite CVD deaths.
- Incidence of death due to myocardial infarction.
- Incidence of death due to cerebrovascular accident.
- Incidence of CVD morbidity.
- Incidence of composite CVD morbidity and mortality.
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.
Data Abstraction and Analysis
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.
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Findings
Glycemic Control
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?
- The evidence reported supports a strong, graded relation
between GHb 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 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. Compared to the lowest categories of GHb
exposure, the unadjusted relative risks for incident
retinopathy were 4 to 7 times greater in the highest
categories of GHb exposure for type 1 diabetes and 1.5
to 2.5 times greater in individuals with type 2 diabetes.
The unadjusted relative risk for proliferative retinopathy
was 6 to 7 times greater in individuals in the highest
category of GHb exposure compared to the lowest
category for individuals with type 1 diabetes, and the
unadjusted relative risk was 3 to 13 times greater for
individuals with type 2 diabetes although fewer studies
examined this outcome in type 2 diabetes.
- This relation between GHb exposure and retinopathy 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 levels were maintained at approximately 7
percent, compared to individuals randomized to
conventional therapy, where the mean HbA1c levels
were maintained at approximately 9 percent.
- Only a few 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 cohort study and
one clinical trial, there are virtually no data on the
relation between glycated hemoglobin and risk of
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 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. Compared to individuals in the lowest
category of GHb exposure, those in the highest category
had an unadjusted increased risk of microalbuminuria
that was 3 to 9 times greater for type 1 diabetes and an
increased risk of microalbuminuria that was 1.4 to 8
times greater for 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, as noted above, the
mean HbA1c levels were maintained at approximately 7
percent, compared to those randomized to conventional
glycemic control, where the mean HbA1c levels were
maintained at approximately 9 percent. Among
individuals with type 1 diabetes, the unadjusted relative
risk reductions were 34 percent to 43 percent, compared
to 60 percent to 74 percent for individuals with type 2
diabetes.
- Although fewer data exist on the relation between
glycated hemoglobin and risk of macroalbuminuria and
on the relation between glycated hemoglobin and the
risk of nephropathy progression, several cohort studies
and clinical trials support a strong and significant
positive association in individuals with type 1 and type 2
diabetes.
- The only studies identified by the search strategy and
inclusion criteria examining the effect of GHb exposure
on GFR were cohort studies conducted in individuals
with type 1 diabetes. All studies consistently
demonstrated that increasing levels of glycated
hemoglobin were associated with a decline in GFR.
There are no clinical trial data examining the GFR
outcomes and no data on the relation between glycated
hemoglobin and GFR in individuals with type 2
diabetes.
- Very few studies examined the association between
glycated hemoglobin and the risk of ESRD.
- Among individuals with type 1 diabetes, there appears
to be a strong, positive association between glycated
hemoglobin and the risk of peripheral neuropathy in
both cohort studies and clinical trials; however, the
evidence of an association between glycated hemoglobin
and peripheral neuropathy in individuals with type 2
diabetes yields conflicting results.
- There are fewer data on the association between glycated
hemoglobin and the risk of autonomic neuropathy. In
individuals with type 1 diabetes, there appears to be a
positive association. There are also very limited data on
the relation between glycated hemoglobin and the risk
of autonomic neuropathy in individuals with 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?
- In the cohort studies evaluating cardiovascular outcomes
in individuals with diabetes, there was a positive
association with GHb 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 coronary
artery disease, particularly among individuals with type
2 diabetes. Compared to those in the highest category
of GHb exposure, the unadjusted risk of fatal and non-fatal
coronary artery disease was 50 percent to 70
percent (relative risk, 1.5 to 1.7) greater than for those
in the lowest category of exposure.
- There are few 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. Compared to those in
the lowest category of GHb exposure, the unadjusted
risk of PAD was 5 to 6 time greater in individuals in the
highest category of exposure among individuals with
type 1 diabetes, and the risk was 2 to 4 times greater
among individuals with 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.
- There are very few data on the relation between GHb
exposure and congestive heart failure or subclinical
atherosclerosis, assessed by carotid intimal-medial
thickness, making it difficult to draw any conclusions
regarding these outcomes.
- Only a few studies have examined the presence of a
threshold effect of glycated hemoglobin on the risk of
developing diabetic complications (i.e., a level of glycated
hemoglobin above which there is a non-constant or
exponential increase in risk of complications). The
majority of these studies have not found a threshold
effect for retinopathy and nephropathy outcomes but,
rather, have demonstrated a continuous risk of
complications with increasing GHb levels. There are
very few studies that have attempted to examine the
presence of a threshold effect of glycated hemoglobin on
neuropathy and macrovascular outcomes.
Urine Albumin
1. What is the risk relationship between microalbuminuria and
renal function?
- Eleven studies reported on this question. The analyses
had important limitations including broad variation in
methods of assessing levels of urine albumin excretion as
well as substantial heterogeneity in reporting of renal
outcomes.
- The preponderance of evidence suggests that the
presence of microalbuminuria at baseline is associated
with progression of chronic kidney disease.
- The relation of urine albumin excretion at baseline to
progression of chronic kidney disease appears graded;
higher levels of urine albumin excretion at baseline are
associated with a greater magnitude of decrease in renal
function as well as a faster rate of decline in renal
function over time.
2. What is the risk relationship between microalbuminuria,
cardiovascular disease, and death?
- Nineteen studies reported on cardiovascular morbidity
and mortality, and 24 reported on all-cause mortality.
The analyses had important limitations including broad
variation in methods of assessing levels of urine albumin
excretion as well as few studies focusing on disease-specific
cardiovascular morbidity or mortality.
- The preponderance of evidence from these studies
demonstrates an association between microalbuminuria
at baseline and increased risk of cardiovascular
morbidity, cardiovascular mortality, and all-cause
mortality.
- The relation of urine albumin excretion at baseline to
cardiovascular morbidity, cardiovascular mortality, and
all-cause mortality appears graded; greater levels of urine
albumin excretion at baseline are independently
associated with a greater magnitude of risk of
cardiovascular morbidity, cardiovascular mortality, and
all-cause mortality over time.
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Future Research
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.
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Ordering Information
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. 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 is also online on the National Library of Medicine Bookshelf.
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AHRQ Publication No. 03-E048
Current as of July 2003