AR Folsom

CL Hart

DD Reid

DECODE Study Group – the European Diabetes Epidemiology Group

EJ Brunner

G. D. Batty

G. Davey Smith

JH Fuller

K Yano

LL Haheim

M. G. Marmot

M. J. Shipley

M. Kivimäki

PK Myint

RJ Jarrett

S Durrleman

SG Wannamethee

WH Pan

Y Hasuo

English

PubMed

Springer - Publisher Connector

SHORT COMMUNICATION
Post-challenge blood glucose concentration and stroke
mortality rates in non-diabetic men in London: 38-year
follow-up of the original Whitehall prospective cohort study
G. D. Batty & M. Kivimäki & G. Davey Smith &
M. G. Marmot & M. J. Shipley
Received: 9 November 2007 /Accepted: 17 March 2008 / Published online: 26 April 2008
# The Author(s) 2008
Abstract
Aims/hypothesis While individuals with diabetes have a
raised risk of stroke, it is unclear whether hyperglycaemia
in non-diabetic populations is related to the development of
this disease.
Methods In this prospective cohort study of 19,019 men,
capillary blood was drawn 2 h after consumption of a
glucose preparation equivalent to 50 g of anhydrous
dextrose. Study participants were then followed for mor-
tality for a maximum of 38 years.
Results During follow-up of 18,406 non-diabetic men,
13,116 deaths occurred (1,189 by stroke). Plots of stroke
mortality rates versus blood glucose identified an upward
inflection in risk of death from stroke at about 4.6 mmol/l.
This upward inflection in risk could be adequately
described using a single linear term above this threshold.
A 1 mmol/l increase in blood glucose after this point was
associated with a 27% increase in risk of death from stroke
(hazard ratio 1.27, 95% CI 1.14–1.42). This increase in risk
was partially attenuated by adjustment for covariates (1.17,
1.04–1.31) but remained statistically significant at conven-
tional levels. Similar observations were made when all-
cause mortality was the outcome of interest, although the
magnitude of the association with blood glucose was
somewhat lower.
Conclusions/interpretation An incremental elevation in
stroke mortality rates occurs with increasing post-challenge
blood glucose.
Keywords Blood glucose .Mortality . Stroke .Whitehall
Introduction
Several population-based cohort studies have shown that
individuals with diabetes have an elevated risk of stroke
relative to people who are diabetes-free [1]. However, it is
unclear whether hyperglycaemia in non-diabetic popula-
tions is also related to the development of stroke: while
some investigators found no relationship between blood
glucose and stroke risk [2, 3], others have reported
increased rates which are confined to the upper end of the
blood glucose spectrum [1, 4, 5].
This apparent discordance in findings may be at least
partially explained by the low number of stroke events in
some studies which limits statistical power. For instance, in
a recent meta-analysis of ten European cohort studies with
individual person data [6], there were fewer than 200 stroke
deaths in men, too small a number to reliably examine the
shape of the relationship between blood glucose and stroke
mortality rates in those who were non-diabetic. This was
also the case in a 10-year follow-up of the Whitehall cohort
study, where only 69 deaths had occurred in diabetes-free
men [7]. With more than 1,100 stroke deaths having
occurred in the intervening 25 years, we now have much
Diabetologia (2008) 51:1123–1126
DOI 10.1007/s00125-008-1005-0
G. D. Batty (*)
MRC Social and Public Health Sciences Unit,
University of Glasgow,
4 Lilybank Gardens,
Glasgow G12 8RZ, UK
e-mail: david-b@sphsu.mrc.ac.uk
M. Kivimäki :M. G. Marmot :M. J. Shipley
Department of Epidemiology and Public Health,
University College London,
London, UK
G. Davey Smith
Department of Social Medicine, University of Bristol,
Bristol, UK
greater statistical power with which to explore this
association.
Methods
Data were collected on 19,019 male government employees
aged from 40 to 69 years when examined between 1967
and 1970, representing a 74% response [8]. Data collection
involved the completion of a study questionnaire and
participation in a medical examination, both of which have
been described in detail elsewhere [8]. In brief, data on civil
service employment grade (an indicator of socioeconomic
position), intermittent claudication, angina, chronic bron-
chitis, marital status, physical activity, cigarette smoking,
height, weight, forced vital capacity, ischaemia, fasting
plasma cholesterol and blood pressure were all determined
using standard protocols. Body mass index was computed
using the usual formula, that is, weight/height2 (kg/m2).
After an overnight fast, capillary blood was drawn 2 h
after consumption of a glucose preparation equivalent to
50 g of anhydrous dextrose. Blood sugar concentration was
estimated using the ferricyanide reduction micromethod on
an autoanalyser (Technicon method N-9a) [8]. For the study
period (late 1960s) this was a standard protocol for
determining blood glucose levels, as evidenced by other
cohort studies from the same era [9–11]. However, to
interpret our findings, it is necessary to point out that the
blood glucose test was non-standard in several respects: (1)
it was post-challenge; (2) the challenge itself (50 g) was
lower than has been used elsewhere (75 g); (3) capillary
rather than venous was drawn; and (4) whole blood rather
than plasma was assayed.
Participants with self-reported diabetes (48 type 1, 133
type 2 diabetes) did not undergo the glucose tolerance test
and were excluded from these analyses. We also excluded
participants with a blood glucose of ≥11.11 mmol/l (≥200
mg/dl) (n=56), as they were likely to have diabetes [12], as
well as those whose status could not be ascertained owing
to missing data (n=134).
Mortality follow-up until 30 September 2005 was con-
ducted using the National Health Service Central Registry,
with data available for 99.2% of men. We excluded 43 men
whose cause of death was unknown and a further 48 men for
whom data on categorical covariates were missing. Evidence
from two areas suggests that data from death certificates are
accurate. First, in a Scottish cohort [13], investigators
examined the risk factors for stroke death (as recorded from
death certificates) and non-fatal events (as ascertained from
hospital admissions data). The latter can be regarded as a
highly accurate method of ascertaining stroke, given that it is
based on routine test procedures such as computed axial
tomography (‘CAT’) scans. In these analyses, the risk factors
for stroke mortality rates and stroke morbidity were the
same, suggesting that death certificates do indeed provide
valid information on cause. Second, in an autopsy study,
cerebral stroke was found to be correctly recorded on death
certificates in 84% of cases [14].
The present analyses are therefore based on 18,406 men
(17,724 for whom data were complete, 682 for whom data
values on missing continuous covariates were imputed).
Preliminary analyses showed that the main increase in
stroke mortality rates was above the 90th percentile of
blood glucose distribution. We therefore partitioned the
population into three equally sized groups below this point
and four, progressively smaller, groups above it, enabling
any differences in mortality rates either side of this
inflection to be detected. Mortality rates in these groups
were adjusted for age using 5-year age groups using the
direct standardisation method, with the total study popula-
tion as the standard. Using plots created by fitting restricted
cubic regression splines that allow a wide range of non-
linear effects to be estimated [15], we visually inspected the
shape of the relationship between blood glucose (continu-
ous scale) and both stroke and all-cause mortality. Hazard
ratios and accompanying CIs were computed using Cox’s
proportional hazards regression model with follow-up
period as the time scale.
Results
During a maximum of 38 years of follow-up, there were
13,116 deaths, 1,189 of which were ascribed to stroke.
Table 1 and visual inspection of the plots for stroke and all-
cause mortality against the continuous measure of blood
glucose indicated that elevated mortality rates appeared to
begin in the central blood glucose group (about 4.6 mmol/l)
and that the slope after this point could be adequately
described using a single linear term. Below the blood
glucose value of 4.6 mmol/l there was no apparent
relationship between all-cause or stroke mortality rates
and blood glucose. We therefore summarised the relation-
ship between blood glucose and both stroke and all-cause
mortality using a threshold model that matches previous
analyses of the Whitehall study in which coronary heart
disease was the outcome of interest [16]. A 1 mmol/l
increase in blood glucose above the 4.6 mmol/l threshold
was associated with a 27% increase in risk of death from
stroke (hazard ratio 1.27, 95% CI 1.14–1.42) and a 16%
increase in all-cause mortality (1.16, 1.12–1.20). These
elevations in risk were unaffected by adjustment for
employment grade, but were partially attenuated after
controlling for other covariates both in the analyses
featuring stroke (1.17, 1.04–1.31) and in those for total
mortality (1.09, 1.05–1.13).
1124 Diabetologia (2008) 51:1123–1126
Discussion
To our knowledge, this is the largest study to date to examine
the link between blood glucose and stroke mortality rates. We
found an incremental increase in stroke risk above a glucose
level of 4.6 mmol/l in a non-diabetic population of employed
men. This is consistent with a previous report from the
Whitehall study in which coronary heart disease mortality, an
outcome with a similar pathophysiology to stroke, was the
endpoint of interest [16]. Although attenuated, the associa-
tion between blood glucose and stroke remained after control
for a range of covariates, as it did for total mortality.
The present study has a number of strengths. These
include: (1) cohort size, which offers higher statistical
power than many others; (2) minimal loss to follow-up,
thereby reducing the likelihood of selection bias; and (3)
measurement of a range of physiological and behavioural
covariates which permit consideration of confounding.
At the same time, our study is not without weaknesses.
First, because blood glucose, confounders and mediators
may fluctuate over time, it is preferable to have more than a
single baseline measurement. In this regard, surviving
members of the original Whitehall study have recently been
re-surveyed; unfortunately, however, blood glucose was not
measured. Second, we were not able to investigate the blood
glucose–stroke mortality gradient in women, which might
plausibly be of a different shape to that seen in men. Third,
given the similarities in the pathophysiology of coronary heart
disease and ischaemic stroke, a stronger relationship between
blood glucose and the latter rather than between blood glucose
and haemorrhagic stroke would be anticipated. However, as
death certificates in the UK do not reliably identify stroke sub-
types, we were unable to examine this hypothesis.
A fourth potential weakness is that some of the factors
for which we controlled (such as blood pressure and body
mass index) could be components of the same constellation
Table 1 Hazard ratios (95% CIs) for the relationship of post-challenge blood glucose with stroke and all-cause mortality rates: the original
Whitehall study
Blood glucose (mmol/le) Hazard ratio per
1.0 mmol/l
increase above
4.6 mmol/l
threshold
2.50–3.78 3.79–4.22 4.23–4.94 4.95–5.28 5.29–5.72 5.73–6.78 6.79–11.10
Population,
n (%)
5,663 (31) 5,469 (30) 5,390 (29) 825 (4) 540 (3) 382 (2) 137 (1) 4,027 (22)
All-cause mortality
Deaths (n) 4,056 3,852 3,766 594 416 312 122 2,922
Mortality ratea 30.4 30.6 30.5 31.2 34.1 36.3 43.2 –
Model Ab 1.0 (ref) 1.00
(0.96–1.04)
1.01
(0.95–1.07)
1.04
(0.96–1.14)
1.17
(1.06–1.29)
1.32
(1.18–1.49)
1.63
(1.36–1.95)
1.16
(1.12–1.20)
Model Bc 1.0 1.01
(0.97–1.06)
1.00
(0.95–1.04)
1.03
(0.95–1.13)
1.15
(1.04–1.27)
1.28
(1.14–1.44)
1.62
(1.35–1.94)
1.15
(1.10–1.19)
Model Cd 1.0 1.02
(0.98–1.07)
1.01
(0.97–1.06)
1.04
(0.95–1.14)
1.14
(1.02–1.29)
1.21
(1.08–1.36)
1.32
(1.10–1.58)
1.09
(1.05–1.13)
Stroke mortality
Deaths (n) 358 345 335 64 44 29 14 274
Mortality ratea 2.7 2.9 2.7 3.4 3.6 3.3 3.7 –
Model Ab 1.0 (ref) 1.04
(0.90–1.21)
1.02
(0.88–1.19)
1.30
(1.00–1.70)
1.44
(1.06–1.98)
1.45
(0.99–2.11)
2.25
(1.32–3.83)
1.27
(1.14–1.42)
Model Bc 1.0 1.04
(0.90–1.21)
1.02
(0.88–1.18)
1.30
(1.00–1.70)
1.44
(1.06–1.97)
1.46
(1.00–2.13)
2.21
(1.29–3.77)
1.27
(1.13–1.42)
Model Cd 1.0 1.04
(0.90–1.21)
1.02
(0.88–1.19)
1.27
(0.97–1.66)
1.37
(1.00–1.87)
1.24
(0.85–1.82)
1.76
(1.02–3.02)
1.17
(1.04–1.31)
Stroke deaths were coded according to the eighth, ninth (430–439 for both) or tenth revision (I60–I69) of the International Classification of
Diseases
a Age-adjusted mortality rates are expressed per 1,000 person-years
b Age-adjusted
c Adjusted for age and employment grade
d Adjusted for age, employment grade, disease at study entry, physical activity, smoking habit, marital status, forced expiratory volume in 1 s
(height-adjusted), systolic blood pressure, diastolic blood pressure, height, body mass index (linear and quadratic terms) and plasma cholesterol
e 1 mmol/l=18 mg/100 ml
ref, referent category
Diabetologia (2008) 51:1123–1126 1125
of risk factors that is indicated by a raised post-load glucose
level. The use of data from an occupational cohort
represents a fifth problem, namely the issue of the general-
isability our findings. In this respect, however, the fact that
results for common risk factor–disease associations
reported in the Whitehall study (e.g. blood pressure and
obesity as predictors of cardiovascular disease) are very
similar to those apparent in general population-based
studies suggests that our results are indeed generalisable.
One final potential problem is that, as described, the
post-challenge blood glucose test used in the Whitehall
study at baseline in the 1960s is non-standard in compar-
ison to present day protocols. The characteristics of this test
explain why blood glucose levels found at baseline in the
present study seem lower than expected, for instead of the
75 g glucose challenge employed today, a 50 g challenge
was used. Moreover, to simplify data interpretation, we
excluded men with a blood glucose of ≥11.11 mmol/l, as
they were deemed likely to have diabetes. It should also be
noted that men in this cohort were surveyed in the 1960s
when, due to the lower prevalence of obesity, diabetes and
raised blood glucose were much less common than they are
today. Following on from this, it is possible that the
threshold we identified for an increased risk of total and
stroke mortality is higher in more recently established
cohorts that have used contemporary test procedures.
In conclusion, the incremental elevation in stroke and
all-cause mortality rates occurring with increases in post-
challenge blood glucose concentrations above a threshold
of 4.6 mmol/l warrants further examination in large-scale
studies, particularly in women.
Acknowledgements The original screening of the Whitehall study
was funded by the Department of Health and Social Security and the
Tobacco Research Council. D. Batty is a Wellcome Trust fellow, M.
Marmot is a MRC Research Professor, M. Shipley is supported by the
British Heart Foundation and M. Kivimaki is supported by the
Academy of Finland.
Duality of interest The authors declare that there is no duality of
interest associated with this manuscript.
Open Access This article is distributed under the terms of the
Creative Commons Attribution Noncommercial License which per-
mits any noncommercial use, distribution, and reproduction in any
medium, provided the original author(s) and source are credited.
References
1. Wannamethee SG, Perry IJ, Shaper AG (1999) Nonfasting serum
glucose and insulin concentrations and the risk of stroke. Stroke
30:1780–1786
2. Folsom AR, Rasmussen ML, Chambless LE et al (1999) Prospective
associations of fasting insulin, body fat distribution, and diabetes
with risk of ischemic stroke. The atherosclerosis risk in communities
(ARIC) study investigators. Diabetes Care 22:1077–1083
3. Haheim LL, Holme I, Hjermann I, Leren P (1995) Nonfasting
serum glucose and the risk of fatal stroke in diabetic and
nondiabetic subjects. 18-year follow-up of the Oslo Study. Stroke
26:774–777
4. Hart CL, Hole DJ, Davey Smith G (1999) Risk factors and
20-year stroke mortality in men and women in the Renfrew/Paisley
study in Scotland. Stroke 30:1999–2007
5. Myint PK, Sinha S, Wareham NJ et al (2007) Glycated
hemoglobin and risk of stroke in people without known diabetes
in the European Prospective Investigation into Cancer (EPIC)-
Norfolk prospective population study: a threshold relationship?
Stroke 38:271–275
6. DECODEStudyGroup – the EuropeanDiabetes EpidemiologyGroup
(2001) Glucose tolerance and cardiovascular mortality: comparison of
fasting and 2-hour diagnostic criteria. Arch Intern Med 161:397–405
7. Fuller JH, Shipley MJ, Rose G, Jarrett RJ, Keen H (1983)
Mortality from coronary heart disease and stroke in relation to
degree of glycaemia: the Whitehall study. BMJ 287:867–870
8. Reid DD, Hamilton PJS, McCartney P et al (1974) Cardiorespi-
ratory disease and diabetes among middle-aged male civil
servants. Lancet 1:469–473
9. Pan WH, Cedres LB, Liu K et al (1986) Relationship of clinical
diabetes and asymptomatic hyperglycemia to risk of coronary heart
disease mortality in men and women. Am J Epidemiol 123:504–516
10. Yano K, Kagan A, McGee D, Rhoads GG (1982) Glucose
intolerance and nine-year mortality in Japanese men in Hawaii.
Am J Med 72:71–80
11. Jarrett RJ, Keen H, McCartney M et al (1978) Glucose tolerance
and blood pressure in two population samples: their relation to
diabetes mellitus and hypertension. Int J Epidemiol 7:15–24
12. Fuller JH, Shipley MJ, Rose G, Jarrett RJ, Keen H (1980)
Coronary-heart-disease risk and impaired glucose tolerance. The
Whitehall study. Lancet 1:1373–1376
13. Hart CL, Hole DJ, Davey Smith G (2000) Comparison of risk
factors for stroke incidence and stroke mortality in 20 years of
follow-up in men and women in the Renfrew/Paisley Study in
Scotland. Stroke 31:1893–1896
14. Hasuo Y, Ueda K, Kiyohara Y et al (1989) Accuracy of diagnosis
on death certificates for underlying causes of death in a long-term
autopsy-based population study in Hisayama, Japan; with special
reference to cardiovascular diseases. J Clin Epidemiol 42:577–584
15. Durrleman S, Simon R (1989) Flexible regression models with
cubic splines. Stat Med 8:551–561
16. Brunner EJ, Shipley MJ, Witte DR, Fuller JH, Marmot MG
(2006) Relation between blood glucose and coronary mortality
over 33 years in the Whitehall Study. Diabetes Care 29:26–31
1126 Diabetologia (2008) 51:1123–1126


Post-challenge blood glucose concentration and stroke mortality rates in non-diabetic men in London: 38-year follow-up of the original Whitehall prospective cohort study

Crossref

Batty, GD

Kivimaki, MJ

Davey Smith, G

Marmot, MG

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Accuracy of diagnosis on death certificates for underlying causes of death in a long-term autopsy-based population study in Hisayama, Japan; with special reference to cardiovascular diseases.

Cardiorespiratory disease and diabetes among middle-aged male civil servants.

Chambless LEetal(1999)Prospective associations of fasting insulin, body fat distribution, and diabetes with risk of ischemic stroke. The atherosclerosis risk in communities (ARIC) study investigators. Diabetes Care

Comparison of risk factors for stroke incidence and stroke mortality in 20 years of follow-up in men and women in the Renfrew/Paisley Study in Scotland.

Coronary-heart-disease risk and impaired glucose tolerance. The Whitehall study.

Flexible regression models with cubic splines.

Glucose intolerance and nine-year mortality in Japanese men in Hawaii.

Glucose tolerance and blood pressure in two population samples: their relation to diabetes mellitus and hypertension.

Glucose tolerance and cardiovascular mortality: comparison of fasting and 2-hour diagnostic criteria.

Glycated hemoglobin and risk of stroke in people without known diabetes in the European Prospective Investigation into Cancer (EPIC)-Norfolk prospective population study: a threshold relationship?

Mortality from coronary heart disease and stroke in relation to degree of glycaemia: the Whitehall study.

Nonfasting serum glucose and insulin concentrations and the risk of stroke.

Nonfasting serum glucose and the risk of fatal stroke in diabetic and nondiabetic subjects. 18-year follow-up of the Oslo Study.

Relation between blood glucose and coronary mortality over 33 years in the Whitehall Study. Diabetes Care 29:26–31 1126 Diabetologia

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Post-challenge blood glucose concentration and stroke mortality rates in non-diabetic men in London: 38-year follow-up of the original Whitehall prospective cohort study

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