BMJ. 2000 August 12; 321(7258): 405–412.
PMCID: PMC27454
Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study
See editorial "Controlling glucose and blood pressure in type 2 diabetes
" on page 394.
Abstract
Objective
To determine the relation between exposure to glycaemia over time and the risk of macrovascular or microvascular complications in patients with type 2 diabetes.
Design
Prospective observational study.
Setting
23 hospital based clinics in England, Scotland, and Northern Ireland.
Participants
4585
white, Asian Indian, and Afro-Caribbean UKPDS patients, whether
randomised or not to treatment, were included in analyses of incidence;
of these, 3642 were included in analyses of relative risk.
Outcome measures
Primary
predefined aggregate clinical outcomes: any end point or deaths related
to diabetes and all cause mortality. Secondary aggregate outcomes:
myocardial infarction, stroke, amputation (including death from
peripheral vascular disease), and microvascular disease (predominantly
retinal photo-coagulation). Single end points: non-fatal heart failure
and cataract extraction. Risk reduction associated with a 1% reduction
in updated mean HbA1c adjusted for possible confounders at diagnosis of diabetes.
Results
The incidence of clinical complications was significantly associated with glycaemia. Each 1% reduction in updated mean HbA1c
was associated with reductions in risk of 21% for any end point related
to diabetes (95% confidence interval 17% to 24%, P<0 .0001="" 14="" 21="" 27="" 37="" 41="" and="" any="" complications="" deaths="" diabetes="" end="" font="" for="" infarction="" microvascular="" myocardial="" no="" observed="" of="" p="" point.="" related="" risk="" threshold="" to="" was="">
Conclusions
In
patients with type 2 diabetes the risk of diabetic complications was
strongly associated with previous hyperglycaemia. Any reduction in HbA1c is likely to reduce the risk of complications, with the lowest risk being in those with HbA1c values in the normal range (<6 .0="" font="">
Introduction
The
UK prospective diabetes study (UKPDS), a clinical trial of a policy of
intensive control of blood glucose after diagnosis of type 2 diabetes,
which achieved a median haemoglobin A1c (HbA1c) of
7.0% compared with 7.9% in those allocated to conventional treatment
over a median 10.0 years of follow up, has shown a substantial reduction
in the risk of microvascular complications, with a reduction in the
risk of myocardial infarction of borderline significance.1
Complementary information for estimates of the risk of complications at
different levels of glycaemia can be obtained from observational
analyses of data during the study.
In patients
with type 2 diabetes previous prospective studies have shown an
association between the degree of hyperglycaemia and increased risk of
microvascular complications,2,3 sensory neuropathy,3,4 myocardial infarction,2,5,6 stroke,7 macrovascular mortality,8–10 and all cause mortality.9,11–14
Generally, these studies measured glycaemia as being high or low or
assessed glycaemia on a single occasion, whereas repeated measurements
of glycaemia over several years would be more informative.
The
existence of thresholds of glycaemia—that is, concentrations above
which the risk of complications markedly increases—has not been studied
often in patients with type 2 diabetes. The relative risk for myocardial
infarction seems to increase with any increase in glycaemia above the
normal range,15,16 whereas the risk for microvascular disease is thought to occur only with more extreme concentrations of glycaemia.17–19
The diabetes control and complications trial (DCCT) research group
showed an association between glycaemia and the progression of
microvascular complications in patients with type 1 diabetes for
haemoglobin A1c over the range of 6-11% after a mean of six years of follow up.20
No specific thresholds of glycaemia were identified above which
patients were at greater risk of progression of retinopathy, increased
urinary albumin excretion, or nephropathy.19–21 Nor has any threshold of fasting plasma glucose concentration been identified for cardiovascular deaths.22,23
We
evaluated the relation between exposure to glycaemia over time and the
development of macrovascular and microvascular complications and
compared this with the results of the UKPDS trial of a policy of
intensive control of blood glucose control.1
Methods
Participants recruited to the UKPDS
Details are presented in the companion paper (UKPDS 36) published in this issue (see page 412).
Participants in observational analysis
Of 5102 patients, 4585 white, Asian Indian, and Afro-Caribbean patients who had haemoglobin A1c (HbA1c)
measured three months after the diagnosis of diabetes were included in
analyses of incidence rates. Of these, 3642 with complete data for
potential confounders were included in analyses of relative risk.
Complete data were required for all participants included in the
multivariate observational analyses. For this reason there are fewer
(3642) participants in these analyses than in the clinical trial,
despite the inclusion of patients not randomised in the trial. Their
characteristics are presented in table table1.1.
Characteristics
of patients included in proportional hazards model measured after three
month dietary run-in after diagnosis of diabetes and those included in
UKPDS glucose control study.1 Figures are means (SD) unless stated otherwise
Participants in UKPDS blood glucose control study
After
a three month dietary run-in period patients were stratified on the
basis of fasting plasma glucose concentration and body weight. The 3867
patients who had fasting plasma glucose concentrations between 6.1 and
15.0 mmol/l and no symptoms of hyperglycaemia were randomised to a
policy of conventional glucose control, primarily with diet, or to an
intensive policy with sulphonylurea or insulin.1,24–26
The aim in the group allocated to conventional control (n=1138) was to
obtain fasting plasma glucose concentration <15 alt="[gt-or-equal, slanted]" border="0" but="" concentrations="" if="" img="" l="" mmol="" rose="" src="http://europepmc.org/corehtml/pmc/pmcents/ges.gif" title="" to="">15
mmol/l or symptoms of hyperglycaemia developed patients were
secondarily randomised to non-intensive use of these pharmacological
treatments, with the aim of achieving fasting plasma glucose
concentrations <15 a="" achieve="" aim="" allocated="" and="" been="" concentration="" control="" details="" effect="" elsewhere.="" fasting="" glucose="" group="" have="" in="" intensive="" l="" mmol="" n="2729)" of="" on="" pharmacological="" plasma="" primarily="" published="" single="" sup="" symptoms.="" the="" their="" to="" treatment.="" treatments="" was="" with="" without="">1
Biochemical methods
Biochemical methods have been reported previously.27 Haemoglobin A1c
was measured by high performance liquid chromatography (Biorad Diamat
automated glycosylated haemoglobin analyser), the range for people
without diabetes being 4.5% to 6.2%.27,28 Baseline variables are quoted for measurements after the initial dietary run-in period.
Glycaemic exposure
Exposure to glycaemia was measured firstly at baseline as haemoglobin A1c concentration and secondly over time as an updated mean of annual measurements of haemoglobin A1c
concentration, calculated for each individual from baseline to each
year of follow up. For example, at one year the updated mean is the
average of the baseline and one year values and at three years is the
average of baseline, one year, two year, and three year values.
Clinical complications
The
clinical end points and their definitions are shown in the box in the
companion paper (UKPDS 36) published in this issue (see page 412).
Statistical analysis
Incidence rates by category of glycaemia
The
unadjusted incidence rates were calculated by dividing the number of
people with a given complication by the person years of follow up for
the given complication within each category of updated mean haemoglobin A1c concentration and reported as events per 1000 years of follow up.29
The categories were defined (median values in parentheses) as: <6 6-="" 7-="" 8-="" 9-="" alt="[gt-or-equal, slanted]" and="" border="0" img="" src="http://europepmc.org/corehtml/pmc/pmcents/ges.gif" title="">10% (10.6%) over the range of updated mean haemoglobin A1c
of 4.6-11.2% (1st-99th centile). Follow up time was calculated from the
end of the initial period of dietary treatment to the first occurrence
of that complication or loss to follow up, death from another cause, or
to the end of the study on 30 September 1997 for those who did not have
that complication. Hence, follow up time is equivalent to duration of
diabetes. For myocardial infarction and stroke for participants who had a
non-fatal followed by a fatal event, the time to the first event was
used. The rates were therefore for single and not recurrent events. The
median follow up time for all cause mortality was 10.4 years.
We calculated adjusted incidence rates for each category of updated mean haemoglobin A1c
using a Poisson regression model adjusted for male sex, white ethnic
group, age at diagnosis 50-54 years, and duration of diabetes 7.5-12.5
years and expressed in events per 1000 person years of follow up. These
parameters were chosen to reflect the median age and duration of
diabetes and the modal ethnic group and sex.
Hazard ratio and risk reduction
To assess potential associations between updated mean haemoglobin A1c
and complications we used proportional hazards regression (Cox) models.
Potential confounding risk factors included in all Cox models were sex,
age, ethnic group, smoking (current/ever/never) at time of diagnosis of
diabetes, and baseline high and low density lipoprotein cholesterol,
triglyceride, presence of albuminuria (> 50 mg/l measured in a single
morning urine sample) measured after three months' dietary treatment,
and systolic blood pressure represented by the mean of measures at two
and nine months after diagnosis. The hazard ratio was used to estimate
the relative risk. At each event time, the updated mean haemoglobin A1c
value for individuals with an event was compared with the updated value
of those who had not had an event by that time. The updated mean value
was included as a time dependent covariate to evaluate glucose exposure
during follow up.20,29,30
It was included as a categorical variable in the categories of
glycaemia listed above, with the lowest category (<6 1.0="" a="" alt="[gt-or-equal, slanted]" and="" as="" assigned="" border="0" category="" hazard="" highest="" img="" of="" ratio="" reference="" src="http://europepmc.org/corehtml/pmc/pmcents/ges.gif" the="" title="" with="">9%. (This is reflected in the point estimates as shown in figures figures33 and and4.)4.) Separate models, with updated mean haemoglobin A1c as a continuous variable, were used to determine reduction in risk associated with a 1% reduction in haemoglobin A1c (see regression lines in figures figures33 and and4).4).
We evaluated the presence of thresholds by visual inspection. The 95%
confidence intervals were calculated on the basis of the floating
absolute risk.31 Log linear relations are reported by convention.1,32 The risk reduction associated with a reduction of 1% updated mean haemoglobin A1c
was calculated as 100% minus the reciprocal of the hazard ratio
expressed as a percentage. The risk reduction from the continuous
variable model associated with a 1% reduction in observed haemoglobin A1c
was compared with the risk reduction seen in the UKPDS intervention
trial of an intensive versus a conventional policy of blood glucose
control, for which no adjustment for potential confounders was required
as they were balanced by randomisation.1
Hazard
ratios, with 95% confidence intervals as floating absolute risks, as
estimate of association between category of updated mean haemoglobin A1c concentration and any end point or deaths related to diabetes and all cause mortality. Reference ...
Hazard
ratios, with 95% confidence intervals as floating absolute risks, as
estimate of association between category of updated mean haemoglobin A1c concentration and myocardial infarction, stroke, microvascular end points, cataract extraction, ...
To assess whether the association between mean updated haemoglobin A1c and complications was independent of randomisation, separate models included mean updated haemoglobin A1c
and randomisation to either intensive or conventional policy, as well
as all potential confounders listed above. The model for all end points
related to diabetes included 3005 individuals.
Statistical analyses were performed with SAS version 6.12.33
Results
The
risk of each of the microvascular and macrovascular complications of
type 2 diabetes and cataract extraction was strongly associated with
hyperglycaemia as measured by updated mean haemoglobin A1c.
The incidence rates for any end point related to diabetes, adjusted for
age, sex, ethnic group, and duration of diabetes, increased with each
higher category of updated mean haemoglobin A1c, with no evidence of a threshold and with a threefold increase over the range of updated mean haemoglobin A1c of <6 5.6="" alt="[gt-or-equal, slanted]" border="0" img="" median="" src="http://europepmc.org/corehtml/pmc/pmcents/ges.gif" title="" to="">10% (median 10.6%) (figs (figs11 and and2).2). The unadjusted and adjusted incidence rates are shown in table table2.2. Figure Figure22
shows the adjusted incidence rates for myocardial infarction and
microvascular end points. The increase in the incidence rate for
microvascular end points was greater over the range of increasing
glycaemia than was the increase in the incidence rate for myocardial
infarction. Thus at near normal concentrations of updated mean
haemoglobin A1c the risk of myocardial infarction was twice
to three times that of a microvascular end point, whereas in the highest
category of haemoglobin A1c concentration (![[gt-or-equal, slanted]](https://lh3.googleusercontent.com/blogger_img_proxy/AEn0k_sv9mYZg_EiIVykLlUJUIndiWx03mxVy4P7GPc23ij0z7WL5LyrD6e3WEjboe36BNfDxJlr3QngDE9n6koWpgYrdC4XAqV9tANsaO83_uq_qC7_Bns=s0-d)
10%) the risks were of the same order.
10%) the risks were of the same order. 
Incidence rate and 95% confidence intervals for any end point related to diabetes by category of updated mean haemoglobin A1c concentration, adjusted for age, sex, and ethnic group, expressed for white men aged 50-54 years at diagnosis and with ...
Incidence
rates and 95% confidence intervals for myocardial infarction and
microvascular complications by category of updated mean haemoglobin A1c concentration, adjusted for age, sex, and ethnic group, expressed for white men aged 50-54 years ...
Incidence of complications in patients with type 2 diabetes by category of updated mean haemoglobin A1c
concentration (%). Rates per 1000 person years' follow up adjusted in
Poisson regression model to white men aged 50 to 54 years at diagnosis ...
The estimated hazard ratios associated with different categories of updated mean haemoglobin A1c concentration, relative to the lowest category, are shown as log linear plots in figures figures33 and and4.4.
Mortality related to diabetes and all cause mortality were both
strongly associated with glycaemia (P<0 .0001="" a="" complications="" each="" evaluated="" haemoglobin="" increasing="" mean="" of="" risk="" rose="" sub="" the="" updated="" with="">1c
Observational
analysis of relation between glycaemic exposure and complications of
diabetes as estimated by decrease in risk for 1% reduction in
haemoglobin A1c (HbA1c) concentration, measured at baseline and as updated mean, controlled for age ...
There
was no indication of a threshold for any complication below which risk
no longer decreased nor a level above which risk no longer increased.
The updated mean haemoglobin A1c showed steeper relations than did baseline haemoglobin A1c (table (table3),3), and when both glycaemic variables were included in a model for all complications of diabetes only updated mean haemoglobin A1c reached significance (P<0 .0001="" font="">
Discussion
This
observational analysis shows highly significant associations between
the development of each of the complications of diabetes, including
mortality, across the wide range of exposure to glycaemia that occurs in
patients with type 2 diabetes. This association remained after
adjustment for other known risk factors, including age at diagnosis,
sex, ethnic group, systolic blood pressure, lipid concentrations,
smoking, and albuminuria. Each 1% reduction in haemoglobin A1c
was associated with a 37% decrease in risk for microvascular
complications and a 21% decrease in the risk of any end point or death
related to diabetes. The association with glycaemia was less steep for
stroke and heart failure, for which blood pressure is a major
contributing factor.32,34,35 In patients within the lowest category of updated mean haemoglobin A1c the incidence of myocardial infarction was higher than that of microvascular disease.5
These results suggest that, in these people, the effect of
hyperglycaemia itself may account for at least part of the excess
cardiovascular risk observed in diabetic compared with non-diabetic
people beyond that explained by the conventional risk factors of
dyslipidaemia, hypertension, and smoking.36
The rate of increase of relative risk for microvascular disease with
hyperglycaemia was greater than that for myocardial infarction, which
emphasises the crucial role of hyperglycaemia in the aetiology of small
vessel disease and may explain the greater rate of microvascular
complications seen in populations with less satisfactory control of
glycaemia.
Relation to trial data
This
observational analysis provides an estimate of the reduction in risk
that might be achieved by the therapeutic lowering of haemoglobin A1c
by 1.0%, but it is important to realise that epidemiological
associations cannot necessarily be transferred to clinical practice.
Tissue damage from previous hyperglycaemia may not promptly be overcome,
but the results are not inconsistent with those achieved by the policy
of intensive glucose control in the clinical trial.1
This suggests that the reduction in glycaemia obtained over a median 10
years of follow up of the trial, comparing median haemoglobin A1c
7.0% with 7.9%, provided much of the benefit that could be expected
from that degree of improved glycaemic control. Our results suggest that
intensive treatment with sulphonylurea or insulin does not have an
effect beyond that of lowering blood glucose concentration with respect
to altering risk. The 16% risk reduction (P=0.052) in myocardial
infarction in the clinical trial in the group allocated to a policy of
intensive blood glucose control (associated with a 0.9% difference in
haemoglobin A1c) was similar to the 14% risk reduction seen
in the epidemiological analysis, which was associated with a 1%
reduction in concentration of updated mean haemoglobin A1c.
The UKPDS clinical trial evaluated a policy of intensive glucose control
based primarily on single pharmacological treatments to enable
evaluation of the individual treatments. Now that the UKPDS has shown
that improved glucose control reduces the risk of complications and that
the treaments used are safe in clinical practice, a larger reduction in
haemoglobin A1c might be achieved by the earlier use of
combination treatments or by the use of newer treatments, which could
further reduce the risk of myocardial infarction.
The
observational analysis extends the range of hyperglycaemia studied in
the UKPDS by including participants who, throughout the study, had near
normal glucose concentrations on dietary treatment alone and
participants who could never be treated by dietary treatment alone.37
The UKPDS population was likely to be at lower risk of complications
than other diabetic populations. Hence, the incidence rates we report
are perhaps lower than might be observed in other diabetic populations
as the cohort was newly diagnosed with diabetes, excluded old or ill
patients, and contained a small proportion (6%) of participants with
impaired fasting glycaemia.38 None the less, the decrease in relative risk is unlikely to be different from other diabetic populations.
Lack of thresholds
We
observed no thresholds of glycaemia for any type of complication of
diabetes. This suggests that there is no specific target value of
haemoglobin A1c for which one should aim but that the nearer to normal the haemoglobin A1c concentration the better. In reality, it is difficult to obtain and maintain near normal concentrations of haemoglobin A1c in patients with type 2 diabetes, particularly in those with a high concentration of haemoglobin A1c at diagnosis of diabetes.37
Intensification of treatment by adding insulin to improve the
relatively modest reduction in glycaemia achieved with oral
hypoglycaemic treatments can be constrained by reluctance from patients
and providers because, in part, of side effects such as hypoglycaemia or
weight gain. These observational analyses, together with the results of
the clinical trial, however, indicate that any improvement in a raised
haemoglobin A1c concentration is likely to reduce the risk of diabetic complications.
The magnitude of the risk reduction associated with a 1% reduction in haemoglobin A1c
concentration for myocardial infarction and microvascular disease
(mostly retinopathy) was consistent with that observed in a cohort of
patients from Wisconsin.2 As in this analysis, a stronger association with haemoglobin A1c
concentration was observed for amputation than for ischaemic heart
disease, possibly because glycaemia increases the risk of microvascular
disease, neuropathy, and peripheral arterial disease, each of which
increases the risk of amputation.4,8,18,39–41 The estimated 14% decrease in all cause mortality per 1% reduction in haemoglobin A1c concentration was similar to that seen in other studies that have assessed glycaemia as haemoglobin A1c as a continuous variable (per 1% change) in multivariate proportional hazards models.9
Summary
Both
the observational and clinical trial analyses of an intensive glucose
control policy suggest that even a modest reduction in glycaemia has the
potential to prevent deaths from complications related to diabetes as
cardiovascular and cerebrovascular disease account for 50-60% of all
mortality in this and other diabetic populations.8,42–47
Individuals with very high concentrations of glycaemia would be most
likely to benefit from reduction of glycaemia as they are particularly
at risk from the complications of type 2 diabetes, but the data suggest
that any improvement in glycaemic control across the diabetic range is
likely to reduce the risk of diabetic complications.
Acknowledgments
The
cooperation of the patients and many NHS and non-NHS staff at the
centres is much appreciated. We thank Mr Dick Jelfs for the measurement
of haemoglobin A1c. Details of participating centres can be found on the BMJ 's website.
Footnotes
Professor Turner died unexpectedly after completing work on this paper
Funding:
The major grants for this study were from the UK Medical Research
Council, the British Diabetic Association, the UK Department of Health,
The National Eye Institute and The National Institute of Digestive,
Diabetes and Kidney Disease in the National Institutes of Health, United
States, The British Heart Foundation, Novo Nordisk, Bayer,
Bristol-Myers Squibb, Hoechst, Lilly, Lipha, and Farmitalia Carlo Erba.
Details of other funding companies and agencies, the supervising
committees, and all participating staff can be found on the BMJ's website.
Competing
interests: AIA has received fees for speaking from Bristol-Myers
Squibb, SmithKline Beecham, and Pfizer. IMS has received support for
attending conferences from Zeneca and Hoechst and fees for speaking from
Hoechst. CAC has received support for attending conferences from
Bristol-Myers Squibb, Novo Nordisk, and Pfizer and fees for speaking
from Bristol-Myers Squibb and Novo Nordisk. DRM has received fees for
speaking from Bristol-Myers Squibb, Novo Nordisk, SmithKline Beecham,
and Lilly and research funding from Lilly. SEM has received support for
attending conferences from Bayer and Novo Nordisk. RRH has received fees
for consulting from Bayer, Boehringer Mannheim, Bristol-Myers Squibb,
Hoechst, Lilly, Novo Nordisk, Pfizer, and SmithKline Beecham; support
for attending conferences from Bayer, Bristol-Myers Squibb, Hoechst,
Lilly, Lipha, Novo Nordisk, and SmithKline Beecham; and research funding
from Bayer, Bristol-Myers Squibb, Lilly, Lipha, and Novo Nordisk.
Details of participating centres, staff, and committees and additional funding agencies are on the BMJ's website.
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