Jjmouradjhypertens2008

Review S7

Blood pressure control, risk factors and cardiovascular
prognosis in patients with diabetes: 30 years of progress
Jean-Jacques Mourad and Sylvain Le Jeune

Hypertension is a major co-morbidity for type 2 diabetes, and patients with type 2 diabetes in the Steno-2 study.
an important modifiable risk factor for vascular events. Nevertheless, the major coronary event risk remains high in
Therefore, treatment of diabetes and its risk factors is type 2 diabetes patients, and the results of the ADVANCE
important to minimize complications, and much progress trial provided a step forward in treatment.
has been made over the past 30 years. The UKPDS trial J Hypertens 26 (suppl 3):S7–S13 Q 2008 Wolters Kluwer
showed that intensive glycaemic and blood pressure control Health | Lippincott Williams & Wilkins.
reduced the risk of vascular events. In the HOT study, the
Journal of Hypertension 2008, 26 (suppl 3):S7–S13
addition of aspirin to patients with diabetes and controlled
hypertension decreased the risk of myocardial infarction. Keywords: diabetes mellitus, hypertension, risk factors, treatment
Blood pressure control with angiotensin-converting enzyme
Hypertension Unit, Avicenne University Hospital (AP-HP) and Paris 13 University
inhibitors in MICRO–HOPE also showed significant (EA 3412), 93000 Bobigny, France
reductions in the risk of vascular complications, and blockers
Correspondence to Jean-Jacques Mourad, Avicenne University Hospital,
of the renin–angiotensin system produced substantial renal 125 route de Stalingrad, 93009 Bobigny Cedex 09, France
protective effects in patients with hypertension and diabetes. E-mail: jean-jacques.mourad@avc.aphp.fr

Statin therapy in the HPS and CARDS studies was effective in
Sponsorship: Funding for preparation of this paper was provided by Servier.
the primary prevention of cardiovascular disorders. Finally, an
Conflicts of interest: J-J.M. has undertaken consultancies for almost all
intensive multifactorial intervention achieved sustained pharmaceutical companies that develop antihypertensive medications, including
reduction in the risk of vascular complications and death in Servier.

Diabetes and hypertension: risk factors In particular, hypertension is a major co-morbid condition
for cardiovascular disease for diabetes, and an important risk factor for the devel-
Diabetes mellitus is a major global health problem, with a opment of cardiovascular and renal disease in patients
prevalence of approximately 246 million individuals world- with diabetes. In an observational study of the UKPDS
wide [1]. By 2025, this number is predicted to increase to trial [5], a continuous positive correlation was seen
approximately 350 million people, particularly in develop- between systolic blood pressure and the occurrence of
ing regions of the world, an increase of more than 50%. macrovascular and microvascular events (Fig. 2). More-
Patients with diabetes are at an increased risk of developing over, it is estimated that 68% of coronary events globally
macrovascular (e.g. cardiovascular disease) and microvas- are attributable to diabetes or hypertension [6]. The
cular (e.g. nephropathy and retinopathy) complications, coexistence of hypertension and diabetes provides an
which result in a significant decrease in life expectancy. In a additive increase in the risk of vascular events. The
recent retrospective analysis [2], the life expectancy of men ¨
Swedish Goteborg study, which followed 754 men with
and women with diabetes aged 50 years or older was hypertension for at least 25 years, found that men with
decreased by 7.5 and 8.2 years, respectively, compared both conditions had a 66% greater risk of stroke or
with equivalent non-diabetic individuals. The occurrence myocardial infarction compared with men with hyperten-
of macrovascular complications is more common, cardio- sion alone [7]. The strong association between diabetes
vascular disease being responsible for up to 80% of the total and other cardiovascular risk factors emphasizes the need
mortality in patients with type 2 diabetes [3]. A marked for comprehensive, integrated therapeutic management
increase in microvascular complications is also seen, how- programmes to reduce the risk of complications and
ever, with 75% of patients with diabetes from the UK increase life expectancy. Significant progress in the mana-
Prospective Diabetes Study (UKPDS) having a renal event gement of diabetes has been made over the past 30 years,
over a 20-year period (Fig. 1) [4]. largely as a result of the numerous studies that have
demonstrated the importance of specific drug interven-
Diabetes is associated with a number of cardiovascular tions, the need to combine drug treatment with close
risk factors, which include hypertension, dyslipidaemia, monitoring, and the aggressive treatment of any co-
hypercholesterolaemia and abnormalities in fibrinolysis. existing cardiovascular risk factors. The major advances

0263-6352 ß 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI:10.1097/01.hjh.0000334072.97080.33

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

S8 Journal of Hypertension 2008, Vol 26 (suppl 3)

Fig. 1

100

Proportion of patients (%)
80
Any renal event

60

Microalbuminuria
40
Reduced creatinine
clearance

20 Macroalbuminuria

Doubling of
serum creatinine
0
5 10 15 20
Years after randomization

Proportion of patients with renal events during the follow-up of UKPDS (4031 patients followed during 20 years). Reproduced with permission from
The American Diabetes Association [4]. Copyright # 2006 American Diabetes Association.

in the treatment and understanding of diabetes of the explore the effects of intensive blood glucose control on
past 30 years are reviewed in this article. the development of complications in patients with type 2
diabetes. In 1991 the scope of the trial was broadened to
30 years of progress in diabetes: from UKPDS examine the effects of intensive blood pressure control.
to ADVANCE
The UKPDS is one of the longest and largest clinical trials Glycaemic and blood pressure control in UKPDS
ever conducted. When it commenced in 1977 it aimed to The primary part of diabetes care is the control of blood
glucose levels. It is clear that tight glycaemic control slows
Fig. 2 the progression of microvascular disease, but it remains
uncertain if intensive glycaemic control alone has a
50
beneficial effect on major vascular events. In UKPDS
33 the difference in the incidence of macrovascular events
between the intensive glycaemic control group (fasting
Adjusted incidence per 1000 person years (%)

plasma glucose <6 mmol/l) and the conservative therapy
40
group was only of borderline significance (Fig. 3a) [8].
However, a subsequent analysis of data from the UKPDS
trial [9] revealed that each 1% reduction in mean haemo-
globin A1c was associated with significant reductions in the
30
incidence of myocardial infarction (14%; P < 0.0001) and
stroke (12%; P ¼ 0.035). Intensive control was highly
effective for the prevention of microvascular events. After
10 years of follow-up, haemoglobin A1c in the intensive
20
treatment group was reduced by 11% relative to the
conservative group, resulting in a 25% reduction in the
relative risk (RR) of microvascular events [RR 0.75; 95%
10
confidence interval (CI) 0.60–0.93; P ¼ 0.0099). In con-
trast, there was no significant change in the risk of stroke,
although a trend towards significance was seen with the
risk of myocardial infarction (RR 0.84; 95% CI 0.71–1.00;
0
P ¼ 0.052) [8]. It is, however, plausible that a longer period
110 120 130 140 150 160 170 of observation would lead to a significant benefit in terms
of macrovascular events.
The relatonship between mean systolic blood pressure (mmHg) and the
incidence of myocardial infarction or microvascular events in the The American Diabetes Association and the American
UKPDS trial. & Myocardial infarction; microvascular endpoints.
Reproduced with permission from Adler et al. [5]. Association of Clinical Endocrinologists currently recom-
mend maintaining haemoglobin A1C at less than 7% or


Blood pressure control and cardiovascular prognosis in diabetes Mourad and Le Jeune S9

Fig. 3

(a) Proportion of patients with events during the follow-up of UKPDS 33 [8]; 3867 patients with diabetes over 10 years. Conventional group
(haemoglobin A1c 7.9%); intensive group (haemoglobin A1c 7%). (b) Proportion of patients with events during the follow-up of UKPDS 38 [14];
3867 patients with diabetes over 10 years. Conventional group (154/87 mmHg); intensive group (144/82 mmHg).

less than 6.5%, respectively [10,11]. Blood pressure vascular events, but also prevents or reduces microvas-
lowering has been shown to reduce the incidence of cular complications. In the UKPDS trial, the use of an
stroke and myocardial infarction in the general popu- ACE inhibitor or a beta-blocker reduced the risk of
lation [12], and improve symptoms associated with microvascular, and some macrovascular events [14].
microalbuminuria and overt nephropathy in patients with The Heart Outcomes Prevention Evaluation (HOPE)
type 1 diabetes [13]. Therefore, strict blood pressure trial published in 2000 [15] demonstrated a decrease in
control is important in patients with diabetes, especially the risk of both macro- and microvascular events with the
in those with co-morbid hypertension. In UKPDS 38 [14], use of an ACE inhibitor (ramipril) in patients at high risk
intensive treatment with tight blood pressure control of a cardiovascular event. The diabetic subgroup of the
(target blood pressure <150/85 mmHg) using the angio- HOPE trial (MICRO–HOPE) [16] also showed that
tensin-converting enzyme (ACE) inhibitor captopril or ramipril significantly reduced the risk of the composite
the beta-blocker atenolol significantly reduced the risk of primary endpoint of myocardial infarction, stroke and
microvascular events (RR 0.63; 95% CI 0.44–0.89; cardiovascular mortality by 25% (P ¼ 0.0004), compared
p ¼ 0.0092), but not myocardial infarction, compared with placebo; the risk reduction for each of these indi-
with conservative therapy using less intensive blood vidual outcomes was found to be significant (Fig. 4). In
pressure control (blood pressure <180/105 mmHg) addition, the risk of overt nephropathy was reduced by
(Fig. 3b). The risk of stroke was also significantly reduced 24% in the ramipril group (P ¼ 0.027). The results of
in the intensive group (RR 0.56; 95% CI 0.35–0.89; MICRO–HOPE further reinforced the importance of
p ¼ 0.013); this outcome is in agreement with an earlier blood pressure control for the therapeutic management
meta-analysis, which showed a stroke risk reduction of of patients with diabetes, and clearly demonstrated
42% [12]. the benefits of ACE inhibitors in this population, for
the reduction of cardiovascular and renal disease. More
Blood pressure control in MICRO–HOPE recently, the Antihypertensive and Lipid-Lowering
Blockade of the renin–angiotensin–aldosterone system Treatment to Prevent Heart Attack Trial (ALLHAT)
by ACE inhibitors or angiotensin II receptor blockers [17] showed that the risk of cardiovascular events was
(ARB) not only treats hypertension and reduces cardio- decreased with the thiazide-type diuretic chlorthalidone



Fig. 4

Proportion of patients with diabetes with events during the follow-up of the MICRO–HOPE study; 3577 patients with diabetes with a follow-up of
more than 4.5 years (60% of patients had coronary events). Placebo group (142/79 mmHg); ramipril group (142/80 mmHg) [16].

compared with the ACE inhibitor lisinopril in patients with with diabetes, probably as a result of the smaller dia-
hypertension with or without diabetes. As a result, thiazide betic patient sample size [11,23]. Furthermore, aspirin
diuretics are one of the recommended first-line therapies had no substantial effects on stroke and mortality in
in patients with hypertension and diabetes, without overt patients either with or without diabetes. The real
nephropathy, with ACE inhibitors one of the leading degree of efficacy of aspirin for the prevention of
options for add-on treatment [18]. cardiovascular events in patients with diabetes thus
remains uncertain, and additional specific trials of
Blood pressure control and aspirin therapy in HOT aspirin administration in patients with diabetes are
The effectiveness of tight blood pressure control for the required. Certainly, evidence indicating that diabetes
prevention of macrovascular events was further shown in is a prothrombotic condition continues to accumulate. A
a diabetic subgroup of the Hypertension Optimal Treat- recent review [24] reported that insulin resistance
ment (HOT) trial [19]. In HOT, patients randomly is accompanied by the loss of control of platelet acti-
assigned to antihypertensive treatment with a diastolic vation and increased levels of a variety of coagulation
blood pressure goal of less than 80 mmHg had a 51% factors and the fibrinolytic inhibitor, plasminogen acti-
reduction in major cardiovascular events compared with vator inhibitor 1. As diabetes develops, the fibrin struc-
those randomly assigned to a diastolic blood pressure ture/function of fibrinogen is altered, resulting in a
target of less than 90 mmHg. The current blood press- reduction in permeability, clot lysis and enhanced clot
ure target of 130/80 mmHg recommended for patients rigidity. These haemostatic abnormalities generate a
with hypertension and diabetes in all major guidelines prothrombotic phenotype, suggesting the importance
[10,11,18] has been heavily influenced by these land- of antithrombotic therapy as a prevention strategy in
mark studies. Before the publication of these studies patients with diabetes. Current American Diabetes
‘fair’ or ‘acceptable’ blood pressure levels for individuals Association guidelines recommend the use of aspirin
with diabetes were as high as 160/95 mmHg or less therapy in patients with diabetes who have a history
[20]. (secondary prevention) or are at risk (primary preven-
tion) of cardiovascular disease [10].
Clinical trials have also shown that aspirin reduces the
incidence of stroke and myocardial infarction in patients Renal protection in IDNT
with a history of cardiovascular disease [21,22]. The Diabetic nephropathy is a common complication of
HOT trial showed that the addition of low-dose aspirin diabetes, which results in a decline in renal function
to antihypertensive treatment reduced major cardiovas- and consequent progression to end-stage renal disease
cular events by 15% (P ¼ 0.03) and myocardial infarc- (ESRD) in the absence of specific intervention. Arterial
tion by 36% (P ¼ 0.001), compared with placebo, in blood pressure also plays an important role in the devel-
patients with treated hypertension [19]. A separate opment of renal damage; hypertension appears to be a
subgroup analysis showed that although aspirin statisti- determining factor of progression to ESRD. Therefore,
cally significantly reduced the risk of major cardiovas- the tight control of hypertension is essential to reduce
cular events and myocardial infarction in patients with- the risk of development and progression of diabetic
out diabetes it did not show such an effect in patients nephropathy.



As described above, the use of ACE inhibitors in both the or greater [28]. Daily treatment with simvastatin was found
UKPDS and MICRO–HOPE studies reduced the risk of to reduce significantly the incidence of major coronary
microvascular events. In the Irbesartan Diabetic Nephro- (27%) and vascular (22%; both p < 0.0001) events, includ-
pathy Trial (IDNT) [25], the renoprotective effects of the ing stroke (24%; p ¼ 0.01), compared with placebo after
ARB irbesartan were demonstrated in patients with hy- 4.8 years of follow-up. This risk reduction in major
pertension with nephropathy caused by type 2 diabetes. vascular events was also seen in diabetic patients with
After 2.6 years of follow-up, the risk of a doubling of the hypertension within the HPS population. The Collabora-
serum creatinine concentration was decreased by 33% tive Atorvastatin Diabetes Study (CARDS) [29] showed
(p ¼ 0.003) and 37% (p < 0.001) in irbesartan and amlodi- that atorvastatin effectively reduced the risk of cardio-
pine recipients, respectively, compared with placebo vascular events, including acute coronary events and
(Fig. 5). Moreover, the relative risk of ESRD was 23% stroke, in patients with type 2 diabetes without elevated
lower in the irbesartan group compared with either the LDL-cholesterol levels and with no previous history of
placebo or amlodipine groups; this was found to be margin- cardiovascular disease (Fig. 6). After a follow-up period of
ally significant (both p ¼ 0.07). An analysis [26] of the 3.9 years, the risk of a major cardiovascular event was
cardiovascular endpoints that were reported in the IDNT significantly reduced in the atorvastatin group compared
study failed to show a cardioprotective effect with irbe- with the placebo group [hazard ratio (HR) 0.63; 95% CI
sartan; no difference in the cardiovascular event rates were 0.48–0.83; p ¼ 0.001]. This outcome was driven by signi-
seen between the irbesartan, placebo and amlodipine ficant reductions in the risk of acute coronary events
groups (29.7%, 32.5% and 28.3% of patients, respectively). (HR 0.64; 95% CI 0.45–0.91) and stroke (HR 0.52; 95%
CI 0.31–0.89).
Lipid-lowering therapy: HPS and CARDS
The increased risk of cardiovascular morbidity and The results of HPS and CARDS established the effec-
mortality in patients with diabetes emphasizes the need tiveness of statin therapy for the primary prevention of
for aggressive lowering of all modifiable risk factors. In macrovascular events in patients with diabetes regardless
these individuals, low-density lipoprotein (LDL) choles- of cholesterol levels, and statins have become the first-
terol is a strong predictor of coronary heart disease as in choice agent for primary prevention in these patients.
the general population. Plasma concentrations of total Those studies also emphasized the need for tight control
and LDL-cholesterol in patients with diabetes are, how- of the multiple risk factors present in patients with
ever, typically similar to those in the general population, diabetes.
which may explain the low prescription rates of lipid-
lowering therapies for patients with diabetes in the past Multifactorial intervention and mortality: Steno-2
[27]. Trials of intensified interventions for single risk factors in
patients with type 2 diabetes, which include UKPDS and
Two major studies have demonstrated the benefits of CARDS, have demonstrated efficacy in reducing the
statins for the prevention of macrovascular events in development and progression of both micro- and macro-
patients with diabetes, which has led to the wide use of vascular complications. On the basis of these findings,
this lipid-lowering therapy in such individuals. The Heart treatment guidelines were modified to recommend an
Protection Study (HPS) included almost 6000 patients intensified multifactorial approach to the treatment of
with diabetes and total cholesterol levels of 3.5 mmol/l type 2 diabetes.

Fig. 5

End stage of renal disease p = 0.003

Doubling of creatinine p = 0.07

Cardiovascular events NS

0 10 20 30
% patients

Proportion of patients with events during the follow-up of the IDNT study; 1715 patients with hypertension and proteinuria (>900 mg/24 h, creatinine
1–3 mg/dl) with a follow-up of more than 2.6 years. Placebo group (144/80 mmHg); irbesartan group (141/78 mmHg) [25].



Fig. 6

Proportion of patients with events during the follow-up of the CARD study; 2838 patients with diabetes with one or more other risk factor
(hypertension, retinopathy, albuminuria, smoking). Placebo group; atorvastatin group [29].

The Steno-2 study was designed to evaluate the effect on assessed the effects of fixed combination therapy, using
cardiovascular disease of multiple drug combination an ACE inhibitor and a diuretic, on vascular disease in a
therapy and behavioural modification, aimed at several large, diverse population of patients with type 2 diabetes.
modifiable risk factors in type 2 diabetes patients with ADVANCE also evaluated the effects of intensive
microalbuminuria [30,31]. After a mean follow-up of glycaemic control with a gliclazide-based antihypergly-
13.3 years, significant reductions in the risk of death from caemic and standard glycaemic control on the same
any cause (HR 0.54; 95% CI 0.32–0.89; P ¼ 0.02), the risk outcomes. The results of the blood pressure arm of the
of death from cardiovascular causes (HR 0.43; 95% CI ADVANCE trial discussed in more detail later in this
0.19–0.94; P ¼ 0.04) and the risk of a cardiovascular event supplement provide a clear step forward for the routine
(HR 0.41; 95% CI 0.25–0.67; P < 0.001) were demons- treatment of patients with diabetes.
trated with intensive therapy versus conventional
therapy [30]. In addition, significantly fewer patients in Acknowledgements
the intensive versus the conventional therapy groups The authors would like to thank Max Chang, Wolters
developed diabetic retinopathy (RR 0.57; 95% CI Kluwer Health, for his assistance in the writing and
0.37–0.88; P ¼ 0.01) or diabetic nephropathy (RR 0.4; editing of this manuscript.
95% CI 0.25–0.77; P ¼ 0.004), and significantly fewer
progressed to ESRD (one versus six; P ¼ 0.02). References
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