Editorial
Dysglycemia and Cardiovascular Risk in the
General Population
Hertzel C. Gerstein, MD, MSc
D iabetes is a metabolic disorder that is diagnosed when
the fasting and/or postload glucose level rises above
well-established thresholds. These thresholds were chosen
because they identified people at particularly high risk for
retinopathy based on epidemiological data. These data also
have shown that people with diabetes and poorly controlled
glucose levels have higher risks of retinopathy than people
with diabetes and well-controlled glucose levels.1,2 Moreover,
recent studies have shown that the relationship between
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chronically elevated glucose levels (as measured by A1c) and
retinal disease is not confined to people with diabetes and is
apparent (although less marked) in people with high glucose
levels that are below the diabetes cutoffs such as those with
impaired glucose tolerance and/or impaired fasting glu-
cose.3–5 Thus, there is a progressive relationship between
glycemia and retinopathy that extends below glucose thresh-
olds for diabetes.
Article p 812
Clearly, diabetes also is a risk factor for many other serious
chronic diseases, including cardiovascular disease.6 Indeed, a
recent meta-analysis of large prospective studies comprising
450 000 people showed that men and women with diabetes
are 2 and 3 times more likely, respectively, to die of coronary
heart disease than men and women without diabetes.7 Other
studies have shown that the degree of glucose elevation
measured by A1c, fasting glucose, or postload glucose is
progressively related to the incidence of cardiovascular out-
comes in people with established diabetes and in people
without diabetes after adjustment for age and varying num-
bers of other risk factors.8 –15 Moreover, several studies that
recruited people from both ambulatory and hospitalized
settings suggest that there may be a stronger relationship
between glycemia and incident cardiovascular outcomes in
people without diabetes than in people with diabetes.8,9,15–17
Such a discrepancy may occur because in people with
established diabetes, markers of glycemia are a measure of
both adequacy of therapy and exposure to hyperglycemia,
whereas they reflect only exposure to hyperglycemia in
The opinions expressed in this article are not necessarily those of the
editors or of the American Heart Association.
From the Department of Medicine and the Population Health Research
Institute, McMaster University and Hamilton Health Sciences, Hamilton,
Ontario, Canada.
Correspondence to Dr H.C. Gerstein, Department of Medicine, Room
3V38, 1200 Main St W, Hamilton, Ontario, L8N 3Z5, Canada. E-mail
gerstein@mcmaster.ca
(Circulation. 2009;119:773-775.)
© 2009 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.108.834408
773
people without diabetes (in whom glucose and A1c levels
are not targets for therapy).
Retinopathy and cardiovascular disease are clearly not the
only outcomes related to progressively higher glucose levels.
This is perhaps best illustrated by epidemiological analyses of
prospective data from the United Kingdom Prospective Dia-
betes Study (UKPDS), which recruited people with a fasting
plasma glucose level ⬎6 mmol/L18 and which therefore
included individuals with newly diagnosed diabetes as well as
some individuals who would be classified as having impaired
fasting glucose and not diabetes based on today’s diagnostic
criteria for diabetes (ie, fasting glucose level ⱖ7 mmol/L). As
noted in the Figure, these analyses showed that progressively
higher A1c levels predicted progressively higher hazards of
severe retinal or renal disease, cataracts, myocardial infarc-
tion, heart failure, amputation or peripheral vascular disease,
stroke, and death. They also showed that the risk relationship
differed with respect to outcome, with a stronger relationship
to some outcomes and a weaker relationship to others (the
Figure). Thus, organ systems may vary in their susceptibility
to damage related to glucometabolic abnormalities, a conclu-
sion strongly supported by the epidemiological analysis
reported in this issue of Circulation.19
Sung et al19 report an analysis of 652 901 Korean men 30
to 64 years of age who were followed up over a 9-year period
with biannual health examinations within the Korean Na-
tional Health Insurance system. They calculated average
glucose levels for participants followed up during this inter-
val of time and grouped them within clinically relevant
categories. They did not analyze fasting glucose level as a
continuous measure; instead, they analyzed the relationship
between categories of average fasting serum glucose levels
and incident myocardial infarction, ischemic stroke, and
hemorrhagic stroke in 570 453 men without any missing data
and reported the hazard after adjustment for age and for other
cardiovascular risk factors. As reported in other studies, they
found a progressive age-adjusted relationship between fasting
glucose levels and both myocardial infarction and stroke that
extended to normal fasting serum glucose levels. The rela-
tionship persisted with adjustment for several risk factors but
was attenuated after additional adjustment for blood pressure,
body mass index, and cholesterol levels. Moreover, the
relationship was stronger for ischemic stroke than for either
myocardial infarction or hemorrhagic stroke. Notably, their
analysis detected an interaction between age and fasting
glucose category in that older men had a stronger relationship
between fasting glucose levels and these cardiovascular
outcomes than younger men. Moreover, for stroke but not
myocardial infarction, there was an interaction between body
mass index and fasting glucose level category.
 774 Circulation February 17, 2009
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The large number of participants and outcomes is a clear
strength of this study. First, it allowed the investigators to
examine the relationship between fasting glucose levels and
different types of cardiovascular disease. Their observation of
different relationships to myocardial infarction, ischemic
stroke, and hemorrhagic stroke clearly supports the conclu-
sion that the impact of glycemia on outcomes varies accord-
ing to the outcome being assessed and extends it to different
subtypes of stroke and to the general population. Second, the
weaker relationship to myocardial infarction than to ischemic
stroke may not have been apparent in smaller studies that did
not have sufficient numbers of strokes to divide people
according to the type of stroke. This finding should lead to
further analyses in women and in other populations. Third,
the large sample facilitated exploration of the role of con-
founders. The fact that adjusting for blood pressure choles-
terol and body mass index attenuates the relationship between
glucose and myocardial infarction to a greater extent than
between glucose and ischemic stroke is interesting but unex-
plained. If anything, one would expect that adjustment for
blood pressure would attenuate the relationship with stroke,
which tends to be more strongly associated with blood
pressure than myocardial infarction.
Of note, this study was conducted in relatively healthy men
within the general Korean population whose 9-year incidence
of myocardial infarction and stroke was quite low at 0.6% and
1.7%, respectively (ie, ⬍0.2%/y). Its results may therefore
not be directly applicable to women, to older or sicker people,
or to other populations with a higher risk for cardiovascular
disease. Indeed, the interaction with age in which there was a
stronger relationship between fasting glucose levels
⬎5.5 mmol/L and myocardial infarction in older versus
younger people suggests that the importance of dysglycemia
as a cardiovascular risk factor may be greater in people at
higher risk of cardiovascular disease. It would also have been
very interesting if the risk for cardiovascular outcomes across
progressively higher fasting glucose levels (measured as a
continuous variable) had been presented in addition to the
Figure. The relationship between updated A1c
and the multivariable adjusted hazard of various
chronic consequences of diabetes in partici-
pants in the UKPDS based on the reported dif-
ference per 1% higher A1c level.1 The hazard
ratio of an A1c of 6% was set at 1.0. Line A,
Amputation or death resulting from peripheral
vascular disease (43% per 1%); B, retinal or
renal disease (37% per 1%); C, cataract extrac-
tion (19% per 1%); D, heart failure (16% per
1%); E, myocardial infarction (14% per 1%) and
all-cause death (14% per 1%); and F, stroke
(12% per 1%). The same results are shown on a
linear scale (left) and a log scale (right).
risk across discrete categories of fasting glucose. Such an
analysis would be relevant in light of the spline distribution of
the data (Data Supplement Figure I in the article by Sung et al19),
which is consistent with a progressive versus a threshold
relationship between fasting glucose levels and both myocardial
infarction and ischemic stroke.
In summary, a fasting glucose level above normal is a
progressive risk factor for cardiovascular outcomes, and the
magnitude of the risk rises with age and is greater for
ischemic stroke than for myocardial infarction or hemor-
rhagic stroke. Whether specifically targeting lower fasting
glucose levels can reduce cardiovascular outcomes remains
unknown. Some clues may reside in the 10-year-long UK-
PDS, which randomized people with newly diagnosed diabe-
tes and few other cardiovascular risk factors to a policy of
targeting a fasting plasma glucose ⬍6 mmol/L versus a
conventional policy targeting a fasting plasma glucose
⬍15 mmol/L.18,20 This study reported a clear reduction in
myocardial infarction and death in a subset of obese partici-
pants allocated to metformin as the means of glucose lower-
ing, with nonsignificant cardiovascular effects in the other
participants.20 However, after 9 years of passive follow-up,
all participants experienced a 13% and 15% reduction in
death and myocardial infarction, respectively, and the subset
given metformin retained the benefit observed during the
active treatment phase.21 Conversely, 3 large trials varying in
duration from 3.5 to 6.3 years have recently reported the
effect of targeting an A1c level below 6%22,23 or 6.5%24 versus
less intensive glucose lowering in a very different population
of people with well-established diabetes (ie, of a mean
duration of 8 to 12 years) and several additional cardiovas-
cular risk factors. All 3 used a menu of drugs to lower both
fasting and postprandial glucose levels and did not detect a
clear cardiovascular benefit; indeed, 1 trial22 was stopped
early because of increased mortality. Taken together, these
trials suggest that any benefit of glucose lowering may be
greatest in people with early dysglycemia, a question that
is being tested in the ongoing Outcome Reduction With an
 Gerstein
Initial Glargine Intervention (ORIGIN) clinical trial,
which has randomized ⬎12 500 people with impaired
fasting glucose, impaired glucose tolerance, or early dia-
betes to 1 injection of insulin glargine that is titrated to a
fasting plasma glucose ⱕ5.3 mmol/L versus standard
care.25 Data from this and other trials underway will clarify
the therapeutic implications of epidemiological observa-
tions such as those published in this issue.19
Disclosures
Dr Gerstein’s institution receives funding from Sanofi-Aventis to
conduct the ORIGIN trial of the effect of lowering fasting glucose
levels with glargine insulin on cardiovascular outcomes. Dr Gerstein
holds the McMaster Population Health Research Institute Chair in
Diabetes (sponsored by Aventis).
References
1. Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA,
Hadden D, Turner RC, Holman RR. Association of glycaemia with
Downloaded from http://circ.ahajournals.org/ by guest on December 27, 2017
macrovascular and microvascular complications of type 2 diabetes
(UKPDS 35): prospective observational study. BMJ. 2000;321:405– 412.
2. Expert Committee on the Diagnosis and Classification of Diabetes
Mellitus. Report of the Expert Committee on the Diagnosis and Classi-
fication of Diabetes Mellitus. Diabetes Care. 1997;20:1183–1197.
3. Wong TY, Liew G, Tapp RJ, Schmidt MI, Wang JJ, Mitchell P, Klein R,
Klein BE, Zimmet P, Shaw J. Relation between fasting glucose and
retinopathy for diagnosis of diabetes: three population-based cross-
sectional studies. Lancet. 2008;371:736 –743.
4. Diabetes Prevention Program Research Group. The prevalence of reti-
nopathy in impaired glucose tolerance and recent-onset diabetes in the
Diabetes Prevention Program. Diabet Med. 2007;24:137–144.
5. Gerstein HC, Pogue J, Mann JF, Lonn E, Dagenais GR, McQueen M,
Yusuf S. The relationship between dysglycaemia and cardiovascular and
renal risk in diabetic and non-diabetic participants in the HOPE study: a
prospective epidemiological analysis. Diabetologia. 2005;48:1749 –1755.
6. Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, McQueen
M, Budaj A, Pais P, Varigos J, Lisheng L. Effect of potentially modifiable
risk factors associated with myocardial infarction in 52 countries
(the INTERHEART study): case-control study. Lancet. 2004;364:
937–952.
7. Huxley R, Barzi F, Woodward M. Excess risk of fatal coronary heart
disease associated with diabetes in men and women: meta-analysis of 37
prospective cohort studies. BMJ. 2006;332:73–78.
8. Selvin E, Coresh J, Golden SH, Brancati FL, Folsom AR, Steffes MW.
Glycemic control and coronary heart disease risk in persons with and
without diabetes: the Atherosclerosis Risk in Communities Study. Arch
Intern Med. 2005;165:1910 –1916.
9. Khaw KT, Wareham N, Bingham S, Luben R, Welch A, Day N. Asso-
ciation of hemoglobin A1c with cardiovascular disease and mortality in
adults: the European Prospective Investigation Into Cancer in Norfolk.
Ann Intern Med. 2004;141:413– 420.
10. Khaw KT, Wareham N, Luben R, Bingham S, Oakes S, Welch A, Day N.
Glycated haemoglobin, diabetes, and mortality in men in Norfolk cohort
of European Prospective Investigation of Cancer and Nutrition
(EPIC-Norfolk). BMJ. 2001;322:1– 6.
Fasting Glucose, Stroke, and Myocardial Infarction 775
11. Danaei G, Lawes CM, Vander HS, Murray CJ, Ezzati M. Global and
regional mortality from ischaemic heart disease and stroke attributable to
higher-than-optimum blood glucose concentration: comparative risk
assessment. Lancet. 2006;368:1651–1659.
12. Lawes CM, Parag V, Bennett DA, Suh I, Lam TH, Whitlock G, Barzi F,
Woodward M. Blood glucose and risk of cardiovascular disease in the
Asia Pacific region. Diabetes Care. 2004;27:2836 –2842.
13. Brunner EJ, Shipley MJ, Witte DR, Fuller JH, Marmot MG. Relation
between blood glucose and coronary mortality over 33 years in the
Whitehall Study. Diabetes Care. 2006;29:26 –31.
14. Held C, Gerstein HC, Yusuf S, Zhao F, Hilbrich L, Anderson C, Sleight
P, Teo K. Glucose levels predict hospitalization for congestive heart
failure in patients at high cardiovascular risk. Circulation. 2007;115:
1371–1375.
15. Gerstein HC, Swedberg K, Carlsson J, McMurray JJ, Michelson EL,
Olofsson B, Pfeffer MA, Yusuf S. The hemoglobin A1c level as a
progressive risk factor for cardiovascular death, hospitalization for heart
failure, or death in patients with chronic heart failure: an analysis of the
Candesartan in Heart failure: Assessment of Reduction in Mortality and
Morbidity (CHARM) program. Arch Intern Med. 2008;168:1699 –1704.
16. Kosiborod M, Rathore SS, Inzucchi SE, Masoudi FA, Wang Y, Havranek
EP, Krumholz HM. Admission glucose and mortality in elderly patients
hospitalized with acute myocardial infarction: implications for patients
with and without recognized diabetes. Circulation. 2005;111:3078 –3086.
17. Goyal A, Mahaffey KW, Garg J, Nicolau JC, Hochman JS, Weaver WD,
Theroux P, Oliveira GB, Todaro TG, Mojcik CF, Armstrong PW,
Granger CB. Prognostic significance of the change in glucose level in the
first 24 h after acute myocardial infarction: results from the CARDINAL
study. Eur Heart J. 2006;27:1289 –1297.
18. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-
glucose control with sulphonylureas or insulin compared with conven-
tional treatment and risk of complications in patients with type 2 diabetes
(UKPDS 33). Lancet. 1998;352:837– 853.
19. Sung J, Song Y-M, Ebrahim S, Lawlor D. Fasting blood glucose and the
risk of stroke and myocardial infarction. Circulation. 2009;119:812– 819.
20. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive
blood glucose control with metformin on complications in overweight
patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352:854 – 865.
21. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-Year
follow-up of intensive glucose control in type 2 diabetes. N Engl J Med.
2008;359:1577–1589.
22. Action to Control Cardiovascular Risk in Diabetes Study Group. Effects
of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;
358:2545–2559.
23. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD,
Zieve FJ, Marks J, Davis SN, Hayward R, Warren SR, Goldman S,
McCarren M, Vitek ME, Henderson WG, Huang GD, for the VADT
Investigators. Glucose control and vascular complications in veterans
with type 2 diabetes. N Engl J Med. 2009;360:129 –139.
24. ADVANCE Collaborative Group. Intensive blood glucose control and
vascular outcomes in patients with type 2 diabetes. N Engl J Med.
2008;358:2560 –2572.
25. Origin Trial Investigators. Rationale, design, and baseline characteristics
for a large international trial of cardiovascular disease prevention in
people with dysglycemia: the ORIGIN Trial (Outcome Reduction With
an Initial Glargine Intervention). Am Heart J. 2008;155:26 –32.
KEY WORDS: Editorials 䡵 epidemiology 䡵 glucose 䡵 myocardial infarction
䡵 risk factors 䡵 stroke
 Dysglycemia and Cardiovascular Risk in the General Population
Hertzel C. Gerstein

Circulation. 2009;119:773-775
doi: 10.1161/CIRCULATIONAHA.108.834408
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