R e v i e w P a p e r
Hypertension in Diabetes: Treatment
Considerations
Mariela Glandt, MD; Zachary T. Bloomgarden, MD
Treatment of blood pressure in the patient with
diabetes remains a challenge. While data extrapo-
lated from many trials seemed to imply that
lower blood pressures leads to more favorable
cardiovascular outcomes, this paper reviews
newer trials designed to treat to blood pressure
targets below 130 ⁄ 80 mmHg in patients with
long term established diabetes, which showed
that this goal may prove more harmful than
helpful. In clinical practice this may be less rele-
vant due to the fact that less than half of patients
are even at the goal of 130 ⁄ 80. The interaction
between glucose control and blood pressure
control are also discussed, emphasizing the
importance of multifactorial treatment. J Clin
Hypertens (Greenwich). 2011;13:314–318.
ª
2011 Wiley Periodicals, Inc.
H ypertension and diabetes are well-known to
go hand in hand, with a 75% prevalence of
hypertension among persons with diabetes.1 Con-
versely, hypertension is associated with a nearly
5-fold increase in likelihood of diabetes.2
Approximately half of persons with hypertension
have insulin resistance,3 with increased likelihood
of developing diabetes. The combination of both
From the Department of Medicine, Mount Sinai School
of Medicine, New York, NY
Address for correspondence:
Zachary T. Bloomgarden, MD, Department of
Medicine, Mount Sinai School of Medicine, 35 East
85th Street, New York, NY 10028
E-mail: zbloom@gmail.com
Manuscript received December 10, 2010; revised January
25, 2011; accepted January 25, 2011
doi: 10.1111/j.1751-7176.2011.00442.x
314 THE JOURNAL OF CLINICAL HYPERTENSION
hypertension and diabetes in an older population
doubles the risk of stroke, death from cardiovas-
cular (CV) causes, and all-cause mortality when
compared with that of nondiabetic hypertensive
patients.4–8 Furthermore, hypertension is a major
risk factor for progression of diabetic nephrop-
athy,9,10 retinopathy,11 left ventricular hypertro-
phy,12 and heart failure.13
BP TREATMENT FOR PERSONS WITH
DIABETES: EVIDENCE FOR BENEFIT
There is considerable evidence that blood pressure
(BP) lowering reduces the complications of diabetes.
One of the first trials to show the effect of lowering
BP in patients with diabetes was a subtrial of the Uni-
ted Kingdom Prospective Diabetes Study (UKPDS). A
group of 1148 diabetic patients with baseline BP
160 ⁄ 94 mm Hg were randomized to what was at that
time described as tight BP control (<150 ⁄ 85 mm
Hg) with b-blockers or angiotensin-converting
enzyme (ACE) inhibitors as baseline therapy, with
addition of other medications as needed, achieving
mean BP 144 ⁄ 82 mm Hg, or to less tight control
(<180 ⁄ 105 mm Hg), with mean BP 154 ⁄ 87 mm Hg.
Approximately 9 years later, patients assigned to
tight control of BP had a 24% lower risk of all diabe-
tes-related end points, a 32% reduction in death
related to diabetes, a 44% decrease in stroke, and a
37% decrease in microvascular disease.14
An observational analysis of the UKPDS data
showed that the risk of each of the macrovascular
and microvascular complications of type 2 diabetes
was strongly associated with mean systolic BP. On
average, each 10-mm Hg reduction in systolic BP
was associated with a 12% decrease in the risk of
any end point related to diabetes and a 15% reduc-
tion in the risk of death related to diabetes. The
VOL. 13 NO. 4 APRIL 2011
increase in risk showed no evidence of a threshold,
doubling over the range of systolic BP from
<120 mm Hg (median 114 mm Hg) to >160 mm
Hg (168 mm Hg), with the authors concluding,
‘‘There are no natural thresholds under which the
risk of microvascular and macrovascular complica-
tions in diabetes are fully prevented.’’15
The Hypertension Optimal Treatment (HOT)
trial was a large trial of almost 19,000 patients ran-
domized to a target diastolic BP of 90 mm Hg, 85
mm Hg, or 80 mm Hg. Felodipine was used as
baseline therapy, with addition of ACE inhibitors
or b-blockers and diuretics as needed. A subgroup
of 1501 with diabetes attained diastolic BPs of 85
mm Hg, 83 mm Hg, and 81 mm Hg, respectively,
with a 51% reduction in CV end points in the
lower compared with the high BP group.8 Another
major study, the Action in Diabetes and Vascular
Disease: Preterax and Diamicron Modified Release
Controlled Evaluation (ADVANCE) trial, evaluated
antihypertensive therapy with the ACE inhibitor
perindopril and the diuretic indapamide vs placebo
in patients with type 2 diabetes having a baseline
BP 145 ⁄ 81 mm Hg.16 Mean BPs attained were
134 ⁄ 74 mm Hg vs 140 ⁄ 76 mm Hg, leading to a
lower combined rate of major macrovascular and
microvascular events (15.5% vs 16.8%), as well as
reduction in CV mortality (3.8% vs 4.6%) and all-
cause mortality (7.3% vs 8.5%).
BP GOALS
Although these and other trials showed benefits of
lowering BP, none of them were designed to treat
to targets below 130 ⁄ 80 mm Hg. Less than half of
patients with diabetes achieve a BP at such a cur-
rently recommended goal,17 with those not at goal
often at substantially higher levels.18
Hypertension guidelines set out by the Seventh
Report of the Joint National Committee on Preven-
tion, Detection, Evaluation, and Treatment of High
Blood Pressure,19 the World Health Organization,20
the British Hypertension Society,21 the European
Society of Hypertension ⁄ European Society of Cardi-
ology,22 the American Heart Association,23 and the
American Diabetes Association24 all advocate treat-
ing BP to <130 ⁄ 80 mm Hg for patients with diabe-
tes mellitus, assuming that treating to such targets
will achieve the reduction in CV morbidity and mor-
tality predicted from epidemiologic observational
studies. The evidence for such treatment may not
be as conclusive as has been thought, with meta-
analyses showing nonsignificant trends for reduction
in mortality and total CV events comparing 85 mm
Hg vs 90 mm Hg diastolic BP in diabetes.25
VOL. 13 NO. 4 APRIL 2011
The BP arm of the Action to Control Cardiovas-
cular Risk in Diabetes (ACCORD) trial prospec-
tively investigated whether lower BP at such levels
further reduced CV events in high-risk patients with
type 2 diabetes followed during an 8-year period.26
In the hypertension arm of the trial, 4733 patients
aged 40 to 79 with type 2 diabetes were randomly
assigned to intensive therapy, targeting a systolic
BP of <120 mm Hg, or standard therapy, targeting
a BP of <140 mm Hg. The patients had diabetes
for an average of 10 years. During the follow-up
period of 4.7 years, the average systolic BP was
119 mm Hg in the intensively treated group and
133.5 mm Hg in the standard therapy group. No
significant differences were found between the
intensive group and the standard group in rates of
a combined end point of nonfatal myocardial
infarction, nonfatal stroke, or death from CV
causes (208 CV events in the intensive group, 237
events in the standard group). The two study
groups did not differ with respect to most of the
secondary outcomes, although there were signifi-
cant differences in the rate of total stroke, at
0.32% vs 0.53% per year. The intensively treated
group was, however, more likely to experience side
effects, such as hypotension, hypokalemia, and in
particular worsening of renal function, with eleva-
tion in creatinine in 561 vs 367 participants,
although none of the events were said to have
caused serious complications.
An observational subgroup analysis of the Inter-
national Verapamil SR and Trandolapril Study
(INVEST) trial27 that analyzed data on 6400
patients with diabetes and established coronary
artery disease also suggests that lowering BP to
<130 ⁄ 80 mm Hg may cause harm. Patients were
followed during a 5-year period, receiving initially
either a calcium antagonist or b-blocker, followed
by an ACE inhibitor, a diuretic, or both to achieve
a systolic BP of <130 mm Hg and a diastolic BP of
<85 mm Hg. Patients were categorized as having
tight control if they could maintain their systolic
BP at <130 mm Hg; usual control if it ranged from
130 mm Hg to <140 mm Hg; and uncontrolled if
it was 140 mm Hg. Total mortality was 22.8%
in the tight control vs 21.8% in the usual control
group.
Another study, Ongoing Telmisartan Alone and
in Combination With Ramipril Global Endpoint
Trial (ONTARGET), analyzed the impact of BP on
CV events in high-risk patients with atherosclerotic
disease or diabetes with organ damage. In this
study, 37.5% of the patients had diabetes and
treated hypertension. The study analyzed the
THE JOURNAL OF CLINICAL HYPERTENSION 315
 relationship between baseline BP and its changes
with treatment on subsequent CV outcomes.
Among study participants who were randomized to
ramipril, telmisartan, or both, there was a J-shaped
pattern of CV mortality, with nadir at 130 mm
Hg, and of myocardial infarction, with nadir at
126 mm Hg, although, as in ACCORD, the risk of
stroke continued to decrease at lower BP levels.28
A Cochrane library meta-analysis is currently
underway to determine whether there is a reduction
in total mortality and morbidity associated with
treatment of BP to ‘‘lower targets’’ as compared
with ‘‘standard targets,’’ defining lower targets as a
BP 130 ⁄ 80 mm Hg.29 At the present time,
however, for people with long-standing diabetes,
especially those with established CV disease, we
should be concerned as to whether BP <130 ⁄ 80
mm Hg may cause harm. Whether such aggressive
management of BP would be beneficial for patients
who are younger or have had a shorter duration of
diabetes has not been studied. With the low event
rate in such populations, dauntingly large trials
would be required to address this question.
BP VS GLYCEMIC TREATMENT: IS ONE
MORE IMPORTANT THAN THE OTHER?
In diabetic patients with hypertension, it has been
argued that intensive BP control is more beneficial
than tight glucose control.14,30 For stroke, any dia-
betic end point, death from diabetes, and microvas-
cular complications, treating hypertension led to
much greater relative risk reductions than treating
hyperglycemia. If, however, one looks in the
UKPDS at the relationship between end points at
increasing levels of hemoglobin A1c and of BP, the
patterns are remarkably similar.15,31
Current guidelines recommend a multifactorial
approach with simultaneous targeting of elevated
BP and glucose levels in individuals with type 2 dia-
betes. However, it is not known whether combining
BP lowering and glucose control can reduce the risk
of vascular complications to a greater extent than
either treatment alone. Since therapy of each of the
risk factors is known to reduce the risk of complica-
tions and the presence of both risk factors markedly
increases the risk over the presence of just one, there
is potential for achieving a major reduction in the
incidence of the complications of diabetes by treat-
ing both blood glucose and BP. Analysis of outcome
among the 887 hypertensive patients in UKPDS ran-
domized to both the glycemia and hypertension
intervention arms of the study provides insight per-
taining to this question.32 Of the 887 patients, 87
were allocated to conventional glucose ⁄ less tight BP,
316 THE JOURNAL OF CLINICAL HYPERTENSION
155 to conventional glucose ⁄ tight BP, 231 to inten-
sive glucose ⁄ less tight BP, and 414 to both the inten-
sive glucose and tight BP intervention groups. For
the ‘‘any diabetes–related end point,’’ diabetes-
related mortality, and all-cause mortality, patients
allocated to both intensive glucose and to tight BP
control had significantly fewer events than those
allocated to either group alone or neither. Similar
trends were seen for other end points, serving as
important evidence for multifactorial treatment for
the prevention of complications of type 2 diabetes.
An explanation for the apparently lesser effect of
the glycemic intervention may be the progressive
worsening over time of glycemic control in the
UKPDS, regardless of the glycemic treatment to
which a given person had been assigned.33 The
treatment of hypertension may not require the same
degree of progressively greater intervention in reduc-
ing complications.
Interestingly, the UKPDS 10-year follow-up
study shows ongoing benefit of the original glyce-
mic intervention, although the glycemic differences
between the intensive and conventional group dis-
appeared after the first year of follow-up, with per-
sistence in the decreased risk of microvascular
complications noted at the end of the original study
and significant 15% and 13% risk reductions for
myocardial infarction and total mortality, respec-
tively.34 This legacy effect of earlier glucose control
is reminiscent of what was observed in the Diabetes
Control and Complications Trial ⁄ Epidemiology of
Diabetes Intervention and Complications (DCCT ⁄
EDIC) study in patients with type 1 diabetes.35
Although post-trial changes in BP were also similar
in the intervention and control groups, there did
not seem to be a ‘‘memory effect’’ of tight BP con-
trol.36 After a median 8.0 years of post-trial follow-
up, nearly all the significant relative risk reductions
found during the trial in the group receiving tight
BP control were lost.
The ADVANCE study was a 22 factorial inter-
vention with both BP and glycemia treatment, pro-
viding another opportunity to look at the combined
effect of both interventions.37 During the duration of
4.3 years, BP was reduced by an average  standard
error of the mean of 7.10.3 mm Hg systolic and
2.90.2 mm Hg diastolic in patients assigned to
joint treatment compared with those assigned to nei-
ther treatment (P<.001). Similarly, hemoglobin A1c
was reduced by 0.61%0.02% after 4.3 years of
follow-up in patients assigned to joint treatment
compared with those assigned to neither treat-
ment (P<.001). Comparing the 4 resultant groups,
glucose-intensive and glucose-standard with and
VOL. 13 NO. 4 APRIL 2011
without perindopril ⁄ indapamide, patients assigned
to both intensive glucose and BP-lowering, compared
with the standard glucose and placebo BP inter-
vention, had significant 18% and 24% reductions in
total and CV mortality, and a 28% reduction
in renal events, in particular with 54% reduction in
likelihood of new-onset macroalbuminuria.
The concept of multifactorial intervention among
persons with diabetes was most dramatically shown
in the Steno-2 trial of diabetic patients with microal-
buminuria. Therapy targeting hyperglycemia, hyper-
tension, dyslipidemia, microalbuminuria, cigarette
use, and the need for antithrombotic medication,
while achieving systolic BP goal in less than half and
glycemic goal in less than one fifth of patients, led to
>50% reductions in CV disease, nephropathy, and
retinopathy end points during an 8-year period38
and to a nearly 50% reduction in total mortality at
13 years.39
CONCLUSIONS
With the high correlation of diabetes and hyperten-
sion and the strong association of the latter with a
variety of diabetic complications, it is instructive to
review the evidence of benefit of BP-lowering in
this group. A variety of interventions have been
shown to be beneficial across the spectrum of com-
plications. Some proposals regarding goals of BP-
lowering may not be fully evidence-based, and it
seems possible that excessively aggressive measures
may lead to adverse outcome, but it is striking to
observe the evidence of beneficial interaction of BP
and glycemic treatment, with further benefit of
combined lipid, BP, and glycemic treatment. A rea-
sonable strategy then may be to pursue BP-lowering
in persons with diabetes with attention to potential
renal and CV adverse effects that might necessitate
less aggressive treatment, while continuing at the
same time to appropriately treat to glycemic and
lipid goals based on careful clinical evaluation of
the patient’s needs.
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