There is a substantial amount of clinical data showing the relationship between diabetes and atherosclerosis and its clinical complications (1,2). Cardiovascular disease (CVD) is more common in people with diabetes than in subjects without the disease, and when it is present, it also has a more aggressive course and a worse prognosis (3). The bulk of epidemiological data has firmly established that type 2 diabetes is associated with more than a twofold increased risk for cardiovascular (CV) death. In the case of subjects with type 1 diabetes, in spite of the fact that the CVD rate is significantly lower compared with the population with type 2 diabetes, their relative risk for coronary heart mortality is sevenfold higher than in matched counterparts without the disease (4). Despite all of these data concerning the association of diabetes and CVD, the exact mechanism by which diabetes, and its alterations, is linked to atherosclerosis remains incompletely elucidated. This is especially true in the case of hyperglycemia. The role of nonglycemic factors that accompany the vast majority of patients with type 2 diabetes, such as high blood pressure, dyslipidemia, and hemorreological abnormalities, among others, is much better understood and seems to be independent of glycemia. In addition to this, there have been studies demonstrating that interventions addressed to control these other factors in patients with diabetes effectively reduce CV risk. There also have been data including the use of statins, aspirin, the aggressive management of hypertension, and the use of ACE inhibitors (5,6). Therefore, the positive effects that the control of other factors beyond hyperglycemia exert on CVD are, nowadays, unquestionable. In contrast, to date, the positive effect of intensive glucose management in comparison to nonintensive glucose control on CVD outcomes is still far from proven and seems unlikely to change in the near future (7). As an example, the American Diabetes Association/American Heart Association in their last joint scientific statement on primary prevention of CVD in people with diabetes declared that, “No clinical trials of a glycemic intervention have provided clear-cut evidence that glucose lowering reduces the risk of CVD in subjects with diabetes” (8). Furthermore, one of the latest U.S. Food and Drug Administration announcements on antidiabetic agents clearly concluded that, “There is insufficient information available to determine whether any oral antidiabetic medicine reduces cardiovascular risk” in people affected by diabetes.

Hypertension and dyslipidemia, among other risk factors for CVD, are common in subjects with diabetes. Together, they can explain most, but not all, of the excess of risk of CVD in patients affected by the disease. High blood glucose has long been considered a risk factor for developing atherosclerosis, but data directly relating this alteration to the development and progression of CVD are conflicting. In this context, several glucose-lowering trials in both type 1 and type 2 diabetes showing significant reductions in microvascular complications have systematically failed to achieve significant reductions in macrovascular events (5). Nevertheless, it should also be mentioned that some systematic reviews and metanalysis performed in type 1 and type 2 diabetes (in the case of type 1 diabetes including some studies with few subjects and none or very small number of CV events) have suggested that attempts to improve glycemia reduce the incidence of CVD (9,10).

Before going through “proper” trials evaluating the effects of glycemic control and CVD, the results of the diabetes Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) trial require some comments (11,12). The DIGAMI trial demonstrated that a high-dose insulin infusion followed by 3 months of intensive subcutaneous insulin therapy was associated with a statistically significant reduction in mortality after a 12-month follow-up in patients with diabetes and an acute myocardial infarction (no significant differences in the primary end point at 3 months of follow-up). In the study, high doses of insulin infusion and high blood glucose targets were used during the acute phase of the protocol. Moreover, during the subcutaneous insulin treatment period and conventional clinical targets of glucose control, there were no differences in glucose values as expressed by A1C. Thus, DIGAMI strictly could not be considered a glucose-lowering trial supporting the beneficial effects of glucose control. In addition to this, the results of the unsuccessful DIGAMI-2 trial failed to find significant differences in A1C using different strategies on glucose management in type 2 diabetic subjects and acute myocardial infarction, as well as in mortality and CV outcomes (13). In conclusion, DIGAMI-2 did not provide additional information confirming or denying the beneficial effects of glucose control.

The University Group Diabetes Project (409 participants) may be considered the first glucose-lowering trial evaluating the CV effects of different strategies aimed at glucose control in type 2 diabetes (insulin addressed/not addressed to intensive control, phenformin, tolbutamide, and placebo) (14,15). After 12.5 years of follow-up, there were no differences in CVD events between the intensive control group with insulin, the nonintensive control insulin group, or the placebo. Phenformin and tolbutamide were discontinued because of the development of lactic acidosis and an excess of CV mortality, respectively.

In the Veterans Affairs Cooperative Study of Diabetes Mellitus (VACSDM), 153 subjects with type 2 diabetes were followed up for a mean of 2.25 years (16,17). This was a pilot feasibility trial in which patients under intensive glucose control (either with insulin or sulfonylureas) achieved a significant reduction in A1C (−2.1% absolute reduction). In spite of this, there was a nonsignificant trend toward an increase in CV events in the group under intensive control.

The Kumamoto study was designed to elucidate whether intensive glucose control (multiple injections of insulin) was associated with a decrease in the frequency (primary prevention) or severity (secondary prevention) of microvascular complications in 110 patients with type 2 diabetes (18). After 8 years and a 2.2% reduction in A1C, in the group receiving intensive control, there were positive results in both primary and secondary prevention of microvascular disease. After evaluating the effect of intensive treatment on CV events (cardiac, cerebrovascular, and peripheral), this was not significant, and this negative result was attributed to the small number of subjects included in the study by the authors.

Undoubtedly, the U.K. Prospective Diabetes Study (UKPDS) is still the landmark study evaluating the effects of glucose control on type 2 diabetes complications (19). Including more than 3,800 subjects, the study demonstrated a 12% significant reduction in a composite of micro- and macrovascular type 2 diabetes–related end points. However, it should be mentioned that UKPDS was underpowered to specifically assess the effect of improving glucose control on CVD. There was a nonsignificant reduction (16%) in the risk of MI and a statistically nonsignificant increase in the risk of stroke (Table 1). The positive effects of using metformin to improve glycemic control is a large claim because it was statistically associated with beneficial effects preventing any diabetes-related end point, diabetes-related mortality, and the frequency of MI (20). However, these results derived from a substudy of UKPDS were limited to overweight type 2 diabetic subjects.

Table 1

Effect of glycemic control on CVD in the UKPDS and DCCT studies

Intensive (rate/100 patient-years)Conventional (rate/100 patient-years)Risk reduction (%)P
End points     
    UKPDS     
        Any diabetes related* 4.09 4.60 12 0.029 
        Myocardial infarction 1.47 1.74 16 0.052 
        Stroke 0.56 0.50 — 0.52 
    Peripheral vascular disease 0.11 0.16 — 0.15 
    DCCT     
        Cardiac 0.06 0.29 78 0.065 
        Peripheral vascular disease 0.43 0.55 22 0.16 
        Combined 0.49 0.84 42 0.082 
Intensive (rate/100 patient-years)Conventional (rate/100 patient-years)Risk reduction (%)P
End points     
    UKPDS     
        Any diabetes related* 4.09 4.60 12 0.029 
        Myocardial infarction 1.47 1.74 16 0.052 
        Stroke 0.56 0.50 — 0.52 
    Peripheral vascular disease 0.11 0.16 — 0.15 
    DCCT     
        Cardiac 0.06 0.29 78 0.065 
        Peripheral vascular disease 0.43 0.55 22 0.16 
        Combined 0.49 0.84 42 0.082 

From Refs. 19 and 24.

*Combined microvascular and macrovascular events.

The use of pioglitazone in type 2 diabetes (secondary prevention) has been evaluated in the PROspective pioglitAzone Clinical Trial In Macrovascular Events (PROactive) (21). It was claimed that the use of the drug was associated with a positive and significant reduction in a secondary composite end point of the study (death, stroke, and MI). Considering that the use of pioglitazone was associated not only with a reduction in A1C, but also triglycerides, the ratio of LDL to HDL, and blood pressure, whether the beneficial effects of pioglitazone were due to the improvement of glucose, to the amelioration of the other CVD risk factors, or to both remains to be elucidated (22).

The milestone study evaluating glucose control improvement and diabetes complications in type 1 diabetes is the Diabetes Control and Complications Trial (DCCT) (23). As a result of this study, intensive management of glycemia with multiple insulin doses is the gold-standard therapy in subjects with the disease to reduce the burden of microvascular complications (primary and secondary prevention). Because of the low rate of macrovascular events during the follow-up, the study lacked enough power to evaluate the effect of glucose control on CVD (24) (Table 1). The DCCT/Epidemiology of Diabetes Interventions and Complications (EDIC) study followed up 1,341 initial participants evaluating CV events (17 years in total after entry in the DCCT). There was a 42% reduction for any CV event and a 57% reduction for CV death, MI, or stroke in the group originally assigned to intensive management (25). In spite of the fact that the authors attributed this positive finding to the DCCT period of intensive glucose control, this piece of data from the DCCT/EDIC study was derived from an epidemiological and observational investigation. While exciting, these results are far from definitive.

The lack of positive effects of glycemic control on CVD complications in diabetes in the above-mentioned trials that, up to now have assessed this topic, could be due to different factors: low number of subjects included, low number of CV events, not lengthy enough follow-up, low efficacy of therapies that have been used, the degree to which glucose reduction might reduce CVD events has not been achieved, or just because the effect of glycemic control on CVD is superfluous in comparison with the effect of controlling other risk factors in diabetes. Under this context, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, which was designed to determine whether intensively lowering blood glucose (below current recommendations) would reduce the risk of CV events or death from CVD, specifically in people with type 2 diabetes who were at a particularly high risk, recently has shown that this strategy is associated with an increased risk of death. Therefore, the degree to which glucose reduction may safely reduce CVD remains unclear.

In conclusion, currently, the relationship (if there is any) between glucose control and CVD in diabetes is still a matter of controversy. The results of the effect of intensive glucose control in comparison with usual management of major CV events are still inconclusive. In the meantime, an overall strategy toward risk management for our patients with type 1 and type 2 diabetes should place appropriate emphasis on blood pressure and lipid control to reduce the leading complications of diabetes.

The publication of this supplement was made possible in part by unrestricted educational grants from Eli Lilly, Ethicon Endo-Surgery, Generex Biotechnology, Hoffmann-La Roche, Johnson & Johnson, LifeScan, Medtronic, MSD, Novo Nordisk, Pfizer, sanofi-aventis, and WorldWIDE.

No potential conflicts of interest relevant to this article were reported.

1.
Beckman
JA
,
Creager
MA
,
Libby
P
:
Diabetes and atherosclerosis: epidemiology, pathophysiology, and management
.
JAMA
2002
; 
287
:
2570
2581
2.
Creager
MA
,
Luscher
TF
,
Cosentino
F
,
Beckman
JA
:
Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: Part I
.
Circulation
2003
; 
108
:
1527
1532
3.
Haffner
SM
,
Lehto
S
,
Ronnemaa
T
,
Pyorala
K
,
Laakso
M
:
Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction
.
N Engl J Med
1998
; 
339
:
229
234
4.
Laing
SP
,
Swerdlow
AJ
,
Slater
SD
,
Burden
AC
,
Morris
A
,
Waugh
NR
,
Gatling
W
,
Bingley
PJ
,
Patterson
CC
:
Mortality from heart disease in a cohort of 23,000 patients with insulin-treated diabetes
.
Diabetologia
2003
; 
46
:
760
765
5.
Huang
ES
,
Meigs
JB
,
Singer
DE
:
The effect of interventions to prevent cardiovascular disease in patients with type 2 diabetes mellitus
.
Am J Med
2001
; 
111
:
633
642
6.
Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy
.
Lancet
2000
; 
355
:
253
259
7.
Selvin
E
,
Marinopoulos
S
,
Berkenblit
G
,
Rami
T
,
Brancati
FL
,
Powe
NR
,
Golden
SH
:
Meta-analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus
.
Ann Intern Med
2004
; 
141
:
421
431
8.
Buse
JB
,
Ginsberg
HN
,
Bakris
GL
,
Clark
NG
,
Costa
F
,
Eckel
R
,
Fonseca
V
,
Gerstein
HC
,
Grundy
S
,
Nesto
RW
,
Pignone
MP
,
Plutzky
J
,
Porte
D
,
Redberg
R
,
Stitzel
KF
,
Stone
NJ
:
Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association
.
Diabetes Care
2007
; 
30
:
162
172
9.
Stettler
C
,
Allemann
S
,
Juni
P
,
Cull
CA
,
Holman
RR
,
Egger
M
,
Krahenbuhl
S
,
Diem
P
:
Glycemic control and macrovascular disease in types 1 and 2 diabetes mellitus: meta-analysis of randomized trials
.
Am Heart J
2006
; 
152
:
27
38
10.
Lawson
ML
,
Gerstein
HC
,
Tsui
E
,
Zinman
B
:
Effect of intensive therapy on early macrovascular disease in young individuals with type 1 diabetes: a systematic review and meta-analysis
.
Diabetes Care
1999
; 
22
(
Suppl. 2
):
B35
B39
11.
Malmberg
K
,
Ryden
L
,
Efendic
S
,
Herlitz
J
,
Nicol
P
,
Waldenstrom
A
,
Wedel
H
,
Welin
L
:
Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): effects on mortality at 1 year
.
J Am Coll Cardiol
1995
; 
26
:
57
65
12.
Malmberg
K
,
Ryden
L
,
Hamsten
A
,
Herlitz
J
,
Waldenstrom
A
,
Wedel
H
:
Effects of insulin treatment on cause-specific one-year mortality and morbidity in diabetic patients with acute myocardial infarction: DIGAMI Study Group: Diabetes Insulin-Glucose in Acute Myocardial Infarction
.
Eur Heart J
1996
; 
17
:
1337
1344
13.
Malmberg
K
,
Ryden
L
,
Wedel
H
,
Birkeland
K
,
Bootsma
A
,
Dickstein
K
,
Efendic
S
,
Fisher
M
,
Hamsten
A
,
Herlitz
J
,
Hildebrandt
P
,
MacLeod
K
,
Laakso
M
,
Torp-Pedersen
C
,
Waldenstrom
A
:
Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity
.
Eur Heart J
2005
; 
26
:
650
661
14.
Knatterud
GL
,
Klimt
CR
,
Levin
ME
,
Jacobson
ME
,
Goldner
MG
:
Effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. VII. Mortality and selected nonfatal events with insulin treatment
.
JAMA
1978
; 
240
:
37
42
15.
Effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. VIII. Evaluation of insulin therapy: final report
.
Diabetes
1982
; 
31
(
Suppl. 5
):
1
81
16.
Abraira
C
,
Emanuele
N
,
Colwell
J
,
Henderson
W
,
Comstock
J
,
Levin
S
,
Nuttall
F
,
Sawin
C
:
Glycemic control and complications in type II diabetes: design of a feasibility trial: VA CS Group (CSDM)
.
Diabetes Care
1992
; 
15
:
1560
1571
17.
Abraira
C
,
Colwell
JA
,
Nuttall
FQ
,
Sawin
CT
,
Nagel
NJ
,
Comstock
JP
,
Emanuele
NV
,
Levin
SR
,
Henderson
W
,
Lee
HS
:
Veterans Affairs Cooperative Study on glycemic control and complications in type II diabetes (VA CSDM): results of the feasibility trial
.
Diabetes Care
1995
; 
18
:
1113
1123
18.
Ohkubo
Y
,
Kishikawa
H
,
Araki
E
,
Miyata
T
,
Isami
S
,
Motoyoshi
S
,
Kojima
Y
,
Furuyoshi
N
,
Shichiri
M
:
Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study
.
Diabetes Res Clin Pract
1995
; 
28
:
103
117
19.
U.K. Prospective Diabetes Study (UKPDS) Group
.
Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)
.
Lancet
1998
; 
352
:
837
853
20.
U.K. 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.
Dormandy
JA
,
Charbonnel
B
,
Eckland
DJ
,
Erdmann
E
,
Massi-Benedetti
M
,
Moules
IK
,
Skene
AM
,
Tan
MH
,
Lefebvre
PJ
,
Murray
GD
,
Standl
E
,
Wilcox
RG
,
Wilhelmsen
L
,
Betteridge
J
,
Birkeland
K
,
Golay
A
,
Heine
RJ
,
Koranyi
L
,
Laakso
M
,
Mokan
M
,
Norkus
A
,
Pirags
V
,
Podar
T
,
Scheen
A
,
Scherbaum
W
,
Schernthaner
G
,
Schmitz
O
,
Skrha
J
,
Smith
U
,
Taton
J
:
Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial
.
Lancet
2005
; 
366
:
1279
1289
22.
Yki-Jarvinen
H
:
The PROactive study: some answers, many questions
.
Lancet
2005
; 
366
:
1241
1242
23.
Diabetes Control and Complications Trial Research Group
.
The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus
.
N Engl J Med
1993
; 
329
:
977
986
24.
Effect of intensive diabetes management on macrovascular events and risk factors in the Diabetes Control and Complications Trial
.
Am J Cardiol
1995
; 
75
:
894
903
25.
Nathan
DM
,
Cleary
PA
,
Backlund
JY
,
Genuth
SM
,
Lachin
JM
,
Orchard
TJ
,
Raskin
P
,
Zinman
B
:
Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes
.
N Engl J Med
2005
; 
353
:
2643
2653