Current status of aggressive blood glucose and blood pressure control in diabetic hypertensive subjects.

Abstract

Uncontrolled diabetes mellitus (DM) is associated with high cardiovascular morbidity and mortality. The coexistence of hypertension and DM multiplies the diabetic complications manifold. Earlier studies have shown that lowering blood glucose, blood pressure (BP), or both decreases the diabetic complications. On the basis of these results, national and international guidelines have recommended aggressive blood glucose and BP control in patients with DM to glycosylated hemoglobin <7.0% and BP <130/80 mm Hg. However, several recent clinical outcomes trials have demonstrated that lowering glycosylated hemoglobin to <7.0% and BP to <130/80 mm Hg does not add any additional benefit to patients with DM and hypertension and may be detrimental to their health. The consensus of scientific opinion at present is that BP should be reduced to 130 to 139/70 to 80 mm Hg in patients with DM with increased cardiovascular risk. The investigators conducted a Medline search of English-language papers published from 1998 to 2010 regarding aggressive blood glucose and BP control in patients with DM and hypertension, and 15 pertinent reports were selected. In conclusion, a review of recent research findings suggests less aggressive control of glucose and BP, and "the lower the better" may not be defensible at present, until new data become available.

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Current Status of Aggressive Blood Glucose and Blood Pressure
Control in Diabetic Hypertensive Subjects
Steven G. Chrysant, MD, PhD*, and George S. Chrysant, MD
Uncontrolled diabetes mellitus (DM) is associated with high cardiovascular morbidity and
mortality. The coexistence of hypertension and DM multiplies the diabetic complications
manifold. Earlier studies have shown that lowering blood glucose, blood pressure (BP), or
both decreases the diabetic complications. On the basis of these results, national and
international guidelines have recommended aggressive blood glucose and BP control in
patients with DM to glycosylated hemoglobin <7.0% and BP <130/80 mm Hg. However,
several recent clinical outcomes trials have demonstrated that lowering glycosylated he-
moglobin to <7.0% and BP to <130/80 mm Hg does not add any additional benefit to
patients with DM and hypertension and may be detrimental to their health. The consensus
of scientific opinion at present is that BP should be reduced to 130 to 139/70 to 80 mm Hg
in patients with DM with increased cardiovascular risk. The investigators conducted a
Medline search of English-language papers published from 1998 to 2010 regarding aggres-
sive blood glucose and BP control in patients with DM and hypertension, and 15 pertinent
reports were selected. In conclusion, a review of recent research findings suggests less
aggressive control of glucose and BP, and “the lower the better” may not be defensible at
present, until new data become available.© 2011 Elsevier Inc. All rights reserved. (Am J
Cardiol 2011;107:1856–1861)
Diabetes mellitus (DM) is a major cause of cardiovascu-
lar disease (CVD), renal disease, peripheral arterial disease,
and strokes.1–3Also, it is estimated that up to 80% of
patients with DM will eventually develop CVD or die from
it.1Because of this, DM has been considered a “cardiovas-
cular risk equivalent,” conferring the same risk for future
CVD complications, like those who have had previous myo-
cardial infarctions (MIs).4In addition, there is a direct
relation between blood glucose levels and CVD complica-
tions.5,6In contrast, decreases in glucose and glycosylated
hemoglobin (HbA1c) levels are associated with a reduction
of CVD complications.7–9However, besides hyperglyce-
mia, patients with DM have other co-morbid conditions,
such as hypertension and dyslipidemia, which play a sig-
nificant role in the incidence of CVD complications,
whereas decreases of blood pressure (BP) and cholesterol
are associated with a reduction in CVD complications.10–13
On the basis of the proved benefits of tight glucose and BP
control, several national and international guidelines recom-
mend aggressive glucose (HbA1c?7%) and BP control (BP
?130/80 mm Hg), and “the lower the better.”1,14–16How-
ever, recent clinical outcomes trials have shown that this
might not be the case. For this review, we conducted a
Medline search of English-language papers published from
1998 to 2010, and 15 pertinent reports were selected. These
reports, with collateral published research, are discussed in
this review.
The Cardiovascular Protective Effects of Intensive
Blood Glucose Control
The pertinent findings from an overview of several clin-
ical trials examining intensive compared to conventional
glucose control on cardiovascular complications are listed
in Table 1.
In the first United Kingdom Prospective Diabetes Study
(UKPDS33),83,867 newly diagnosed subjects with type 2
DM were randomized into an intensive glucose treatment
group with sulfonylurea or insulin, compared to a conven-
tionally treated group with diet modification. The subjects
were followed for 10 years, and the following end points
were prespecified: microvascular complications (nephropa-
thy, retinopathy), DM-related end points (sudden death,
hypoglycemia, hyperglycemia, fatal or nonfatal MI, angina,
heart failure, stroke), and all-cause mortality. At the end of
the study, there were no significant differences between the
2 groups with respect to cardiovascular death and all-cause
mortality. The most significant finding was a 25% decrease
in microvascular complications in the intensively treated
group (Table 1).
The UKPDS34 study9included 1,704 obese patients with
DM randomized to an intensive glucose control with met-
formin, or other agents, and a conventionally treated group
with diet modification. After 10.7 years of observation, inten-
sive treatment resulted in significant decreases in any DM-
related end points and all-cause mortality compared to the
conventionally treated group (Table 1). However, hypoglyce-
mia was more common in the intensively treated groups.
In the Action to Control Cardiovascular Risk in Diabetes
(ACCORD) study,1710,251 high-risk patients with DM
(mean age 62.2 years) were randomized to an intensive-
treatment group (HbA1c?6.0%) or to a standard-therapy
group (HbA1c7.0% to 7.9%) and followed for 3.5 years. At
Oklahoma Cardiovascular and Hypertension Center and the University
of Oklahoma, Oklahoma City, Oklahoma. Manuscript received December
16, 2010; revised manuscript received and accepted February 12, 2011.
*Corresponding author: Tel: 405-721-6662; fax: 405-721-8417.
E-mail address: schrysant@yahoo.com (S.G. Chrysant).
0002-9149/11/$ – see front matter © 2011 Elsevier Inc. All rights reserved.
doi:10.1016/j.amjcard.2011.02.319
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the end of the study, HbA1cvalues were 6.4% and 7.5% in
the intensively and conventionally treated groups, respec-
tively (Table 1). There was no difference in the composite
end point of nonfatal MI, nonfatal stroke, or death from
cardiovascular causes between the 2 groups. However, the
secondary end points of nonfatal MI, nonfatal stroke, death
from cardiovascular causes, and all-cause mortality were
significantly increased in the intensively treated group (Ta-
ble 1). A greater number of subjects in the intensive treat-
ment group developed severe hypoglycemia compared to
the conventionally treated group.
The Action in Diabetes and Vascular Disease: Preterax
and Diamicron Modified Release Controlled Evaluation
(ADVANCE) study18randomized 11,140 subjects with type
2 DM into standard and intensively treated groups. At base-
line, 32.3% of subjects had histories of macrovascular
events, and 10.4% had histories of major microvascular
events. The primary outcomes of the study were a compos-
ite of macrovascular events (death from CVD, nonfatal MI,
or nonfatal stroke) and a composite of microvascular events
(nephropathy, retinopathy). All-cause mortality was a sec-
ondary end point. After a mean follow-up period of 5 years,
the mean HbA1cin the intensively treated group was 6.5%,
compared to 7.3% in the standard-treatment group. There
was no significant difference between the 2 treatment
groups in the incidence of macrovascular events. However,
there were significantly fewer microvascular events in the
intensively treated group (Table 1).
The Veterans Affairs Diabetes Trial (VADT) was an
open-label trial19comparing the effects of intensive and
conventional treatment on glucose control and cardiovascu-
lar outcomes in 1,791 veterans with type 2 DM. In this
study, 40% of subjects had previous cardiovascular events at
the time of enrollment. The primary outcome included a com-
posite of MI, stroke, death from cardiovascular causes, con-
gestive heart failure, surgery for vascular disease, inoperable
coronaryarterydisease,andamputationforischemicgangrene.
The aim was to reduce HbA1cby 1.5% from baseline with
intensive treatment. After 5.6 years of observation, HbA1cwas
6.9% in the intensively treated group compared to 8.4% in the
conventionally treated group. There was no significant differ-
ence between the 2 groups in any component of the primary
outcome or in death from any cause (Table 1).
Cardioprotective Effects of Aggressive Blood Pressure
Control
Hypertension is a well-recognized major risk factor for
CVD, stroke, and renal failure, and a major meta-analysis of
1 million hypertensive subjects demonstrated a direct and
Table 1
Cardiovascular end points of intensive versus conventional glucose control in patients with type 2 diabetes mellitus
Studyn Age
(years)
TreatmentFollow-Up
(years)
Results
IntensiveConventionalIntensive Conventional RR or HR p Value
UKPDS338
3,867 54Sulfa, insulin Diet10.0HbA1c
Any DM end
point
Microvascular
All-cause death
HbA1c
Any DM end
point
Microvascular
All-cause death
HbA1c
7.0%
35.3%
7.9%
38.5%
RR
12%0.029
8.2%
17.9%
7.4%
10.3%
10.6%
18.7%
8.0%
38.9%
25%
6%
RR
32%
0.0099
0.44
UKPDS349
1,70453 MetforminDiet 10.7
0.0023
2.5%
5.3%
6.4%
9.2%
21.7%
7.5%
29%
36%
HR
0.19
0.011
ACCORD17
10,25162Any antidiabetic
drug
Any antidiabetic
drug
3.4
Composite end
point
Nonfatal MI
Nonfatal stroke
All-cause death
HbA1c
6.9%0.90 0.16
3.6%
1.3%
5.0%
6.5%
4.6%
1.2%
4.0%
7.9%
0.76
1.06
1.22
HR
0.04
0.74
0.041
ADVANCE18
11,14066Maximum doses of
metformin,
rosiglitazone,
glimepiride
Standard doses of
same drugs
4.9
Microvascular
Macrovascular
All-cause death
HbA1c
9.4%
10.3%
8.89%
6.9%
10.9%
10.6%
9.6%
8.4%
0.86
0.94
0.93
HR
0.01
0.32
0.28
VADT19
1,791 60 Maximum doses of
metformin ?
rosiglitazone or
glimepiride ?
rosiglitazone
Half of maximum
dose of same
drugs
5.6
Major CV event
All-cause death
29.5%
11.4%
33.5%
10.6
0.88
1.07
0.41
0.08
CV ? cardiovascular; HR ? hazard ratio; RR ? risk reduction.
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sustained effect of BP on CVD and strokes from 115/75 to
160/100 mm Hg or higher, regardless of age or gender.20A
complementary meta-analysis also showed a direct effect of
BP reduction, with decreases in CVD and strokes, although
BP did not decrease to ?130/80 mm Hg.21
The first studies to demonstrate a beneficial effect of BP
reduction in patients with DM and hypertension were the
Hypertension Optimal Treatment (HOT) study10and UK-
PDS38,11respectively. Subsequently, several studies were
conducted testing the significance of very tight BP control
on CVD complications in subjects with type 2 DM. All
these studies are listed in Table 2.
The HOT study10was the first to evaluate the long-term
cardiovascular effects of 3 different levels of diastolic BP in
patients with hypertension. In this study, 18,790 subjects
with hypertension were randomized to target diastolic BPs
of ?90, ?85, and ?80 mm Hg and followed for 3.8 years.
Of these, 1,501 had DM. A retrospective analysis of this
group showed that the group randomized to diastolic BP
?80 mm Hg had a 51% reduction in strokes compared to
the group randomized to diastolic BP ?90 mm Hg (risk
reduction 1.43, p ? 0.005). The actual achieved diastolic
BPs were 85.2 and 81.1 mm Hg for those subjects ran-
domized to diastolic BP ?90 and ?80 mm Hg, respec-
tively (Table 2).
The UKPDS38 randomized 1,148 patients with type 2
DM and hypertension into less tight and tight BP control
and followed them for 8.4 years. The achieved BPs at the
end of the study were 154/87 mm Hg for the less tight group
and 144/82 mm Hg for the tight group. The tight BP group
had significantly lower incidence of the prespecified end
points related to DM (fatal and nonfatal MIs), death related
to DM, and all-cause mortality (Table 2). However, the
achieved BP in the tight control group was much higher
than 130/80 mm Hg, as is currently recommended.15,16
The Appropriate Blood Pressure Control in Diabetes
(ABCD) study12was a prospective trial evaluating the ef-
fects of intensive versus moderate BP control in patients
with DM and hypertension the progression of diabetic ne-
phropathy, retinopathy, and cardiovascular events. In this
study, 470 patients aged 58 years were randomized into 2
BP groups and followed for 5.3 years. The actual achieved
BPs at the end of the study were 132/78 and 138/86 mm Hg
for the intensively and moderately treated groups, respec-
tively. Intensive BP treatment resulted in no difference in
the progression of renal disease or albuminuria. However, it
resulted in a 48% reduction in all-cause deaths (Table 2).
The ADVANCE study22evaluated the effects of aggres-
sive BP control on major vascular events in 11,140 high-risk
patients with type 2 DM. The baseline BP for the whole
group was 145/81 mm Hg, and emphasis was given to
systolic BP reduction. All patients were receiving back-
ground antihypertensive treatment. They were randomized
to more aggressive treatment with perindopril plus indap-
amide or placebo. After 4.3 years of observation, BP in the
aggressively treated group was reduced to 139.4/78.8 mm
Hg, or ?5.6/2.2 mm Hg compared to the control group.
This resulted in significant decreases in macrovascular and
microvascular complications, but no decrease in all-cause
mortality compared to the control group (Table 2).
A subanalysis of the International Verapamil-Trandola-
pril Study (INVEST) examined the effects of tight BP
control on cardiovascular complications in patients with
hypertension and type 2 DM.23This substudy of 6,400
high-risk patients with DM evaluated the effects of tightly
controlled systolic BP (?130 mm Hg) to usual control of
130 to ?140 mm Hg or uncontrolled systolic BP (?140 mm
Hg). At the end of 2.7 years of follow-up, 12.7%, 12.6%,
and 19.8% of patients with tight systolic BP control, usual
BP control, and uncontrolled BP experienced the primary
event (all-cause death, nonfatal MI, or nonfatal stroke), with
no difference among the 3 BP groups.
The ACCORD study24examined the effects of intensive
versus standard systolic BP control on the primary compos-
ite outcome of nonfatal MI, nonfatal stroke, or death from
cardiovascular causes in subjects with type 2 DM. In this
Table 2
Cardiovascular end points of aggressive blood pressure control in patients with type 2 diabetes mellitus
StudynAge
(years)
Follow-Up
(years)
BP (mm Hg)CV End PointsRR (%) p Value
Aggressive Less Aggressive
HOT10
1,50161.5 3.881.1 (diastolic) 85.2 (diastolic)CVD
Stroke
Composite end point
DM death
Stroke
Microvascular
CVD
All-cause death
CVD
Macrovascular ? microvascular
All-cause death
CVD
All-cause death
Composite end point
All-cause death
Stroke
ND
51
24
32
44
37
ND
48.6
ND
9
14
ND
ND
ND
ND
47
NS
0.005
0.005
0.019
0.013
0.009
NS
0.037
NS
0.04
0.03
NS
NS
NS
NS
0.01
UKPDS3811
1,14856.0 8.4144/82 154/87
ABCD12
470 58.05.3132/78 138/86
ADVANCE22
11,14066.04.3 139/79145/81
INVEST23
6,40066.0 2.7
?130 (systolic)
?140 (systolic)
ACCORD24
4,73362.0 4.7119.3 (systolic)133.5 (systolic)
ND ? no difference. Other abbreviations as in Table 1.
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study, 4,733 high-risk subjects were randomized to systolic
BP ?120 mm Hg or standard control of systolic BP (?140
mm Hg) and followed for 4.7 years. At the end of the study,
systolic BP in the intensive control group was 119.3 mm Hg
and in the standard control group was 133.5 mm Hg. The
annual rate of the primary composite outcome was 1.8% in
the intensive control group, compared to 2.09% in the stan-
dard control group (p ? 0.20). However, the annual rates of
stroke, a prespecified secondary outcome, were 0.32% and
0.53% in the intensive and standard systolic BP control
groups, respectively, accounting for a stroke reduction of
39.6% (p ?0.01; Table 2).
Discussion
From the evidence presented here, it appears that aggres-
sive glucose and BP control in subjects with type 2 DM and
hypertension does not provide any additional benefits in
CVD complications to standard glucose and BP control,
with the exception of stroke. It also may increase the inci-
dence of adverse events. With respect to glucose control,
observational studies and meta-analyses have shown that
hyperglycemia increases cardiovascular and renal compli-
cations in patients with DM1–3,5,6and that DM is associated
with a 2 to 4 times higher incidence of CVD, and up to 80%
of patients with diabetes will eventually die from it.1The
injurious effects of hyperglycemia on the vascular system
are traditionally divided into microvascular and macrovas-
cular complications. Microvascular complications include
diabetic retinopathy, neuropathy, and nephropathy, whereas
macrovascular complications include coronary artery dis-
ease, peripheral arterial disease, and cerebrovascular dis-
ease. Clinical and experimental evidence suggests a direct
relation of hyperglycemia with microvascular disease
through several mechanisms, including the aldose reductase
(polyol pathway), reactive oxygen species, advanced glyca-
tion end products, decreased nitric oxide production, and
endothelial cell dysfunction. Also, reduction of glucose lev-
els is associated with either regression or arrest of progres-
sion of microvascular complications. In contrast, hypergly-
cemia by itself is not associated with macrovascular disease,
because this process is an interplay of hyperglycemia and
dyslipidemia in association with endothelial cell dysfunc-
tion and other factors. In addition, treatment of hyperglyce-
mia, exclusive of other cardiovascular risk factor interven-
tion, is inadequate to reverse or reduce the complex
atherosclerotic process. These complications were signifi-
cantly reduced with glucose lowering in the UKPDS stud-
ies, especially microvascular disease complications.8,9
These observations led to the notion that more aggressive
glucose lowering will produce greater results, and “the
lower the better.” However, recent large clinical outcomes
trials have shown that this might not be the case.17–19These
studies have shown that aggressive lowering of HbA1cto
?7.0% did not result in any additional benefit with respect
to microvascular and macrovascular complications and in-
creased the incidence of severe hypoglycemia and risks of
vascular events and death.25
Besides glucose control, BP control is also very impor-
tant in addition to other cardiovascular risk factors. National
and international guidelines15,16recommend the reduction
of BP in patients with DM and hypertension to ?130/80
mm Hg, although there is no hard evidence for this recom-
mendation. The only evidence for the beneficial cardiovas-
cular and stroke effects of aggressive BP control came from
the HOT10and ACCORD24studies for diastolic and systolic
BP, respectively. However, in the HOT study, the lowest
diastolic BP achieved was 81.1 mm Hg, which is higher
than the currently recommended 80 mm Hg.15,16Also, in
the UKPDS38 study,11the final BP in the intensively treated
group was 144/82 mm Hg, compared to 154/87 mm Hg in
the less intensively treated group. This intensive BP control
was associated with significant reduction of macrovascular
complications, although it was much higher than the cur-
rently recommended BP. However, this beneficial effect
was lost when BP control was not sustained long term.26In
addition, recent clinical outcomes trials have not demon-
strated any superior beneficial effect of aggressive com-
pared to less aggressive BP control with respect to cardio-
vascular outcomes in subjects with hypertension and type 2
DM.13,23,24Although there is incontrovertible evidence that
any reduction of BP in patients with DM and hypertension
results in reduction of cardiovascular and renal complica-
tions, aggressive systolic BP reduction to ?130 mm Hg
does not appear to be protective, and it may lead to a higher
cardiovascular event rate.24Aggressive BP control in these
subjects will often require ?3 different drug combinations,
which will increase side effects and decrease adherence to
treatment.
Review of several clinical trials has demonstrated that
systolic BP ?130 mm Hg is difficult to achieve, as dem-
onstrated in Figure 1, despite the use of multiple drug
combinations.27In addition, low BP may cause a J-shaped
curve effect in subjects with high cardiovascular risk, such
as patients with DM and hypertension and especially the
Figure 1. Number of drugs needed to lower systolic BP (SBP) to ?130 mm
Hg in several clinical trials. Adapted with permission from Cardiol Clin.27
AASK ? African American Study of Kidney Disease and Hypertension;
ABCD ? Appropriate Blood Pressure Control in Diabetes; ALLHAT ?
Antihypertensive Lipid-Lowering Treatment to Prevent Heart Attack Trial;
CKD ? chronic kidney disease; CONVINCE ? Controlled Onset Vera-
pamil Investigation of Cardiovascular End Points; IDNT ? Irbesartan
Diabetic Nephropathy Trial; MDRD ? Modification of Diet in Renal
Disease; RENAAL ? Reduction of Endpoints in NIDDM With the An-
giotensin II Antagonist Losartan.
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elderly. A post hoc analysis of the results of the Pravastatin
or Atorvastatin Evaluation and Infection Therapy–Throm-
bolysis In Myocardial Infarction 22 (PROVE-IT–TIMI
22)28showed a J- or U-shaped curve effect between systolic
BP of 110 to 130 mm Hg and diastolic BP of 70 to 90 mm
Hg with respect to the composite primary outcome of death,
MI, unstable angina, revascularization after 30 days, and
stroke (Figure 2). These were patients with acute coronary
syndromes, and the lowest event rates were observed with
systolic BP of 130 to 140 mm Hg and diastolic BP of 70 to
80 mm Hg. On the basis of all the recent data presented, one
wonders whether the current recommendations of scientific
societies for aggressive glucose and BP control are defen-
sible. The consensus of scientific opinion at present is that
systolic BP should be reduced to levels of 130 to 139 mm
Hg and diastolic BP to levels of 70 to 80 mm Hg in patients
with increased cardiovascular risk. With respect to glucose
control, HbA1cshould be maintained close to 7.0%.
Whether these observations will be sustained or incorpo-
rated in the new scientific guidelines remains to be seen.
More definitive answers to these questions will come from
future studies, such as the Systolic Blood Pressure Interven-
tion Trial (SPRINT), sponsored by National Institutes of
Health, which addresses tight BP control in subjects without
DM, as well as studies correlating central aortic pressure
with peripheral arterial pressure.
In closing, it should be emphasized that treatment of
hyperglycemia and hypertension should be combined with
lifestyle changes and proper diet. It should also address
other risk factors, such as dyslipidemia and the metabolic
syndrome.
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Adapted with permission from Circulation.28
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