STATE OF THE ART REVIEW SERIES
REVIEW ARTICLE
Evidence-Based Hypertension Treatment in Patients With Diabetes
Mariana Garcia-Touza, MD;1 James R. Sowers, MD1,2,3
From the Division of Endocrinology, Diabetes & Metabolism, Department of Internal Medicine, University of Missouri;1 the Department of Medical
Physiology and Pharmacology;2 and the Harry S. Truman VA Medical Center, Columbia, MO3
Both impaired glucose tolerance and diabetes are asso-
ciated with substantially increased prevalence of hyperten-
sion, cardiovascular and renal disease. The goal for
hypertension treatment in diabetic patients is in evolution,
because of recent clinical trials. For example, the results of
the recent Action to Control Cardiovascular Risk in Diabe-
tes—BP Arm (ACCORD BP) trial failed to show an addi-
tional benefit on cardiovascular event reduction at a mean
systolic BP of 119 mm Hg. A post hoc analysis of 6,400
patients with type 2 diabetes from the International Vera-
pamil-Trandolapril Study (INVEST) also failed to show addi-
tional cardiovascular risk reduction among patients who
achieved a BP <130 ⁄ 80 mm Hg. While the evidence fails
The association between diabetes and hypertension
(HTN) was first described in residents of Rancho Ber-
nardo, California, aged 50 to 79 years, surveyed from
1972 to 1974. The association was present in both
men and women at all ages, and was the strongest for
persons having the best evidence for diabetes (both
historical and fasting hyperglycemia). Diabetes and
HTN are partially linked to overweight and obesity,
which are prevalent in both conditions.1 Adjustment
for overweight ⁄ obesity reduced the association consid-
erably, but a consistent association remained. The
prevalence of HTN in patients who have type 2 diabe-
tes is up to 3 times higher than in patients without
diabetes.2 This association can be explained, in part,
by the presence of a maladaptive interaction of factors
such as insulin resistance (IR), chronic activation of
the renin-angiotensin-aldosterone system (RAAS), and
the sympathetic nervous system.2,3 The interrelation-
ship between increased adiposity and maladaptive
changes in the heart and kidney in patients with IR
has been called the cardiorenal metabolic syndrome
(CRS).3 Guidelines around the world have been consis-
tent in suggesting that blood pressure (BP) should be
lowered to <130 ⁄ 80 mm Hg in the diabetic popula-
tion. In this article we will review randomized con-
Address for correspondence: Mariana Garcia-Touza, MD, D109 HSC
Diabetes Center, One Hospital Drive, Columbia, MO 65212
E-mail: touzam@health.missouri.edu
This research was supported by the National Institutes of Health (R01
HL73101-01A and R01 HL107910-01) and Veterans Affairs Merit System
0018 (JRS).
Manuscript received: September 1, 2011; Revised: September 19,
2011; Accepted: September 26, 2011
DOI: 10.1111/j.1751-7176.2011.00570.x
Official Journal of the American Society of Hypertension, Inc.
to support a lower BP goal to reduce coronary events,
there was a risk reduction in stroke events both in
ACCORD and the Appropriate Blood Pressure Control in
NIDDM (ABCD) trial. A number of other clinical trials also
demonstrate that when systolic pressures fall to less than
130 mm Hg, a reduction in stroke but not coronary disease
events occurs. Thus, the precise BP goal for diabetic
patients remains unresolved. We would posit that a BP
goal of 135 ⁄ 85 mm Hg may be a reasonable compromise
when viewing the impact of BP reduction on composite
stroke and coronary artery disease in extant trials. J Clin
Hypertens (Greenwich). 2012;14:97–102. 2011 Wiley
Periodicals, Inc.
trolled trials that support a lower BP target in patients
with coexistent diabetes and hypertension.
RELATIONSHIP BETWEEN HTN,
DYSLIPIDEMIA, AND IR
Insulin is an anabolic hormone that promotes liver,
muscle, and fat tissue glucose uptake and its storage as
glycogen in liver and muscle. Insulin also suppresses
the production of glucose and very low-density lipo-
protein in the liver.4 IR is a condition in which the
insulin metabolic signaling response in skeletal muscle,
liver, and adipose tissue is impaired. IR results from a
genetic predisposition, excess weight (especially central
obesity), and lack of exercise. The state of IR can, in
the absence of adequate b-cell response, lead to hyper-
glycemia, increased advanced glycation end products,
increases in free fatty acids (FFAs), and lipoprotein
abnormalities. This alteration in insulin metabolic sig-
naling leads to increased adhesion molecule expression
and decreased bioavailable nitric oxide (NO) in endo-
thelial cells, as well as increased inflammation and
vascular smooth muscle migration and proliferation.5,6
High levels of FFAs are also detrimental, leading to
increased oxidative stress and diminished endothelial
cell NO bioavailabilty.7,8 The decreased bioavailabilty
of NO reduces endothelial-mediated vasorelaxation
and promotes vascular stiffness. IR is also associated
with inappropriate activation of the RAAS and the
sympathetic nervous system.9 Elevations in angiotensin
II (Ang II) and aldosterone have, in turn, been shown
to promote an impairment in systemic insulin meta-
bolic signaling that leads to endothelial dysfunction
and myocardial functional abnormalities.9,10 These
two factors, decreased bioavailable NO and activation
of the RAAS, promote increased sodium reabsorption
The Journal of Clinical Hypertension Vol 14 | No 2 | February 2012 97
Hypertension Treatment in Diabetes | Garcia-Touza and Sowers

FIGURE 1. Potential effects of insulin resistance on endothelial cell (EC) and skeletal muscle cell (SMC) insulin metabolic signaling. Improved EC
and SMC insulin-stimulated nitric oxide (NO) bioavailability and glucose utilization ultimately improves endothelial function and systemic insulin sensi-
tivity. Akt indicates protein kinase B; eNOS, endothelial NO synthase; FFA, free fatty acids; GLUT4, glucose transporter-4; IR, insulin receptor; IRS-
1, IR substrate-1; PI3-K, phosphoinositol 3-kinase; ROS, reactive oxygen species; TCA, tricarboxylic acid. With permission from Whaley-Connell A,
Sowers JR. Hypertension and insulin resistance. Hypertension. 2009;54:462–464.

and vascular remodeling contributing to the develop-
ment of HTN in diabetes. Further, oxidized low-
density lipoprotein accumulation in the arterial wall
results in decreased arterial elasticity and increased
peripheral vascular resistance (Figure 1).
CONCEPTS REGARDING IMPROVEMENT OF
INSULIN SIGNALING AND SECRETION AND
EFFECTS ON BP IN PERSONS WITH CRS
Both pharmacologic and nonpharmacologic strategies
to improve insulin secretion and metabolic signaling
generally also improve endothelial function and lower
BP. For example, the addition of an Ang II receptor
blocker (ARB) to a diuretic has been shown to
improve insulin secretion in hypertensive patients with
the CRS.11,12 In support of this observation, a recent
report showed that 26 weeks of treatment with an
ARB, valsartan, increased glucose-stimulated insulin
release and insulin sensitivity.12 In this randomized
study, the effects of the ARB or placebo on b-cell
function and insulin sensitivity were assessed in
patients with impaired fasting glucose and ⁄ or impaired
glucose tolerance (IGT), using a combined hyperinsuli-
nemic-euglycemic and hyperglycemic clamp with sub-
sequent arginine stimulation and a 2-hour oral glucose
tolerance test. ARB treatment increased first-phase and
second-phase glucose-stimulated insulin secretion com-
pared with placebo, whereas the enhanced arginine-
stimulated insulin secretion was comparable between
groups. Clamp-derived insulin sensitivity was signifi-
cantly increased with ARB therapy, and this therapy
significantly decreased diastolic BP (DBP) and systolic
BP (SBP) compared with placebo.
Prior research suggested that thiazide diuretics
reduce insulin sensitivity. For example, the Study of
Trandolapril ⁄ Verapamil and IR (STAR) trial13 tested
the hypothesis that a fixed-dose combination of
trandolapril ⁄ verapamil sustained release (T ⁄ V) was
superior to a fixed-dose combination of losartan ⁄
hydrochlorothiazide (L ⁄ H) on glucose tolerance in
hypertensive patients with IGT. The study showed that
in patients with IGT, normal kidney function, and
HTN, the fixed-dose combination of T ⁄ V reduced the
risk of new-onset diabetes compared with an L ⁄ H-
based therapy. These data suggested that diuretics had
adverse effects on insulin secretion and ⁄ or insulin sen-
sitivity. Further, these data collectively suggest that
RAAS blockers improve insulin secretion ⁄ sensitivity
and ⁄ or IR and may partly negate some of the detri-
mental metabolic effects of thiazide diuretics.11–13
EVIDENCE-BASED MEDICAL TREATMENT IN
PATIENTS WITH HTN AND DIABETES
The current guidelines for diabetes care issued by the
American Diabetes Association and other committees
around the world recommend a BP goal
<130 ⁄ 80 mm Hg in patients with diabetes. One of
the first studies to provide information on optimal
threshold and targets for administering antihyperten-
sive medication to patients with diabetes was the
Pretereax and Diamicron MR Controlled Evaluation
(ADVANCE) trial.14 This trial was designed to

98 The Journal of Clinical Hypertension Vol 14 | No 2 | February 2012 Official Journal of the American Society of Hypertension, Inc.

evaluate the risks of major microvascular disease and
macrovascular events in individuals with type 2 diabe-
tes, which would be reduced by intensive glucose con-
trol using a sulfonylurea-based regimen targeting a
hemoglobin A1c of 6.5%: additional BP-lowering
using a single-pill combination of an angiotensin-con-
verting enzyme (ACE) inhibitor (perindopril) and a
diuretic (indapamide). A total of 11,140 patients from
Europe, Canada, Asia, and Australia were randomly
assigned to the BP- and glucose-lowering arms. The
study ended after 4.3 and 5.5 years, respectively. Com-
pared with placebo, additional BP-lowering of 5.6 ⁄ 2.2
mm Hg was associated with reductions of 9% in the
primary end point, 18% in cardiovascular death, 14%
in total mortality, and 21% in total renal events
(P<.01). The study investigators concluded that
additional BP-lowering and intensive glucose control
produced independent benefits and, when combined,
they significantly reduced cardiovascular mortality and
improved renal outcomes.
The result of the Ongoing Telmisartan Alone and in
Combination With Ramipril Global Endpoint Trial
(ONTARGET)15 was published in the New England
Journal of Medicine in 2008. In this study, 25,588
patients were enrolled in a multicenter, double-blinded
randomized trial in 40 countries. The study enrolled
patients older than 55 years with coronary, peripheral,
or cerebrovascular disease or diabetes with end-organ
damage. They were randomized to ramipril, telmisar-
tan, or both. The primary outcome of the study was a
composite of cardiovascular death, myocardial infarc-
tion (MI), stroke, or hospitalization for heart failure.
The primary composite outcome was related to base-
line SBP: SBP changes from baseline to event and aver-
age in-trial SBP. The results showed that the risk of
myocardial infarction did not increase with baseline
SBP and was unaffected by subsequent SBP change. In
contrast, stroke risk progressively increased with base-
line SBP and decreased with reduction. In patients
with baseline SBP <130 mm Hg, cardiovascular mor-
tality increased with further SBP reduction. A J curve
(nadir around 130) (Figure 2) occurred in the relation-
FIGURE 2. Relative risk of the primary outcome and of the main sec-
ondary outcome. The primary composite outcome was death from car-
diovascular causes, myocardial infarction, stroke, or hospitalization for
heart failure. The main secondary outcome was death from cardiovas-
cular causes, myocardial infarction, or stroke, which was used as the
primary outcome in the Heart Outcomes Prevention Evaluation (HOPE)
trial 5. The P value is for the comparison with the noninferiority mar-
gins. With permission from Buchner N, Banas B, Kramer BK. Telmisar-
tan, ramipril, or both in patients at high risk of vascular events. N Engl
J Med. 2008;359:426–427.
Official Journal of the American Society of Hypertension, Inc.
Hypertension Treatment in Diabetes | Garcia-Touza and Sowers
ship between in-treatment SBP and all outcomes
except stroke.16 The conclusion of this study was that
in high-risk patients, the benefits from SBP-lowering
<130 mm Hg are determined by a reduction of stroke,
myocardial infarction is unchanged, and cardiovascu-
lar mortality is unaffected or increased.
The Action to Control Cardiovascular Risk in Dia-
betes (ACCORD) BP trial arm17 evaluated the effect
of targeting an SBP of 120 mm Hg, as compared with
a goal of 140 mm Hg, among patients with type 2 dia-
betes at high risk for cardiovascular events. A total of
4733 participants were randomly assigned to intensive
therapy (BP <120 mm Hg) or standard therapy (BP
<140 mm Hg), with the mean follow-up being
4.7 years. The intensive antihypertensive therapy in
the ACCORD BP trial did not considerably reduce the
primary cardiovascular outcome or the rate of death
from any cause. The intensive arm of BP control
reduced the rate of total stroke and nonfatal stroke. In
this context, the estimated number needed to treat
with intensive BP therapy to prevent one stroke over
5 years was 89. There were indicators of possible
harm associated with intensive BP control (systolic
<120 mm Hg), including a rate of serious adverse
events in the intensive arm.
The observational subgroup analysis of the Interna-
tional Verapamil SR-Trandolapril Study (INVEST)
was published in 2010.18 Participants in this study
were at least 50 years old and had diabetes and
coronary artery disease. Patients received a first-line
therapy of either a calcium antagonist or b-blocker
followed by an ACE inhibitor, a diuretic, or both to
achieve SBP <130 mm Hg and DBP <85 mm Hg. The
study had 3 groups: tight control, SBP <130 mm Hg;
usual control, between 140 mm Hg to 130 mm Hg;
and uncontrolled, 140 mm Hg. Patients in the usual
control group (140–130 mm Hg) had a cardiovascular
event rate of 12.6% vs 19.8% for the uncontrolled
group (>140 mm Hg). However, little difference
existed between those with usual control and those
with tight control (>130 mm Hg). The author con-
cluded that tight control of SBP <130 ⁄ 80 mm Hg was
not associated with improved cardiovascular outcomes
compared with usual control and emphasis should be
placed on maintaining SBP between 130 mm Hg and
139 mm Hg.
Guidelines currently suggest that the primary antihy-
pertensive drug strategy in patients with diabetes
should include an ARB or an ACE inhibitor.19,20 If the
baseline BP is >150 ⁄ 90 mm Hg, a second agent
should be added, preferably a thiazide diuretic,
because they can add cardiovascular protection.21,22
However, recent evidence suggests that calcium chan-
nel blockers, especially amlodipine can comparatively
reduce cardiovascular events.23 To test the advantages
of these two types of combination therapies, the
Avoiding Cardiovascular Events In Combination Ther-
apy in Patients Living With Systolic Hypertension
(ACCOMPLISH) trial24 was conducted. The trial
The Journal of Clinical Hypertension Vol 14 | No 2 | February 2012 99
Hypertension Treatment in Diabetes | Garcia-Touza and Sowers
compared treatment outcomes of ACE inhibitor plus
amlodipine and ACE inhibitor plus hydrochlorothia-
zide combinations.25 The study was performed in very
high-risk hypertensive patients, half of whom had
diabetes, and found that the amlodipine-based combi-
nation was more effective than thiazide-based thera-
pies in reducing a composite of fatal and nonfatal
cardiovascular events.
PROVIDING RENAL PROTECTION AND
PREVENTION OF MICROALBUMINURIA IN
DIABETES
Patients with HTN and diabetes have a 7-fold greater
risk for progressing to end-stage renal disease (ESRD)
and 2 to 4-fold greater risk of developing cardiovascu-
lar disease. There are data suggesting that RAAS inhi-
bition and BP control have added renoprotective and
cardioprotective effects. The Bergamo Nephrologic
Diabetic Complications Trial (BENEDICT)26 found
that in patients with type 2 diabetes, HTN, and nor-
moalbuminuria, ACE inhibitor therapy with trando-
lapril plus verapamil or trandolapril alone delayed the
onset of microalbumninuria. This effect was significant
even after adjustment for baseline and follow-up DBP
and SBP, proving a specific renoprotective effect
of ACE inhibitor therapy. The recently published
ROADMAP trial27 investigated whether treatment
with an ARB would delay or prevent the occurrence
of microalbuminuria in patients with type 2 diabetes,
HTN, and normoalbuminuria. The BP target was
<130 ⁄ 80 mm Hg and was achieved in nearly 80% of
patients taking olmesartan and 71% of patients taking
placebo. The patients were followed for a median of
3.2 years. The primary outcome was the amount of
time until the first onset of microalbuminuria and the
secondary end point was the onset of renal and cardio-
vascular events. Olmesartan was associated with
delayed onset of microalbuminuria. Fewer patients in
the olmesartan group than in the placebo group had
nonfatal cardiovascular events (3.6% compared with
4.1%) but a greater number had fatal cardiovascular
events (0.7% compared with 0.1%). It is difficult to
interpret this finding and it may be related to chance.
The fatal cardiovascular events were more common in
patients with known preexisting coronary heart disease
and who were either in the lowest quartile of BP or
the highest quartile of BP reduction during follow-up.
This finding was also described in the ONTARGET
trial and has been called the J-curve effect. In the
Nephropathy Trial (ORIENT), a higher rate of death
from cardiovascular causes was also noticed. Because
of these findings, the Food and Drug Administration is
reviewing these data.
The trials described above have clearly shown a ben-
efit in the prevention and delayed progression of
microalbuminuria in patients with HTN and diabetes.
But it remains unclear whether the prevention of
nephropathy and retinopathy will be slowed by early
administration of drugs that block the RAAS. The
100 The Journal of Clinical Hypertension Vol 14 | No 2 | February 2012
Diabetic Retinopathy Candersartan Trial (DIRECT)
evaluated the effect of candesartan in the prevention
of microalbuminuria in patients who were normoten-
sive and normoalbuminuric with type 1 or type 2 dia-
betes. The research program comprised 3 related
studies to investigate the effect of candesartan on the
incidence of retinopathy in type 1 or type 2 diabetic
patients who were normotensive and normoalbuminu-
ric. Pooled results showed that the annual rate of
change in albuminuria was 5.53% lower (confidence
interval, 0.73%–10.14%) with candesartan than
placebo. The conclusion of the study was that for
4.7 years candesartan did not prevent microalbuminu-
ria in normotensive patients with type 1 or type 2 dia-
betes. A limitation of the study was the fact that it
was powered for retinal and not renal end points.28 In
2009, a multicenter study was published that involved
285 normotensive patients with type 1 diabetes and
normoalbuminuria who were randomly assigned to
receive losartan (100 mg) daily, enalapril (20 mg)
daily, or placebo and follow-up for 5 years. The pri-
mary end point of the study showed a change in the
fraction of glomerular volume occupied by mesangium
in kidney biopsy specimens. The retinopathy end point
was a progression on the retinopathy severity scale.
The change in mesangial fractional volume per glo-
merulus over the 5-year period did not differ signifi-
cantly between the placebo group and the enalapril or
losartan groups. The 5-year cumulative incidence of
microalbuminuria was 6% for the placebo group; the
incidence was higher in the losartan group (17%) but
not with enalapril (4%). When compared with pla-
cebo, the odds of retinopathy progression by 2 or
more steps was reduced by 65% with enalapril and by
70% with losartan, independent of changes in BP. The
conclusion of the study showed that early blockade of
the RAAS in patients with type 1 diabetes did not
slow nephropathy progression but slowed the progres-
sion of retinopathy.29
DISCUSSION
All current guidelines recommend a BP goal in patients
with diabetes <130 ⁄ 80 mm Hg to reduce cardiovascu-
lar events and the progression of diabetic nephropathy.
This recommendation is based mainly in the Hyperten-
sion Optimal Treatment (HOT) and ADVANCE tri-
als.30 Lamentably, the level of evidence used for these
guidelines is level C. The ACCORD and ONTARGET
trials did not find any benefit on improved cardiovas-
cular outcome with BP <130 ⁄ 80 mm Hg, but did find
a benefit determined by reduction of stroke. In the
INVEST trial, SBP <130 mm Hg was also not associ-
ated with improved cardiovascular outcomes when
compared with SBP <139 mm Hg. Post hoc analysis
of these trials demonstrated that the benefit of lower-
ing BP levels on cardiovascular risk reduction is lost
when SBP levels fall below 130 mm Hg. There is an
increase in cardiovascular events at SBP <120 mm Hg,
which is called the J-curve effect. The J-curve effect
Official Journal of the American Society of Hypertension, Inc.

evident in the INVEST and ONTARGET studies
showed an increased risk when lowering BP
<130 mm Hg in patients older than 50 years who
have long-standing HTN and coronary disease.31 Con-
temporary evidence suggests that a BP target around
130 ⁄ 80 mm Hg in patients with diabetes is reasonable
and possible to achieve in clinical practice. Indeed, the
ACCORD study demonstrated that targeting this BP
goal resulted in fewer strokes, a devastating complica-
tion that is more common in patients with diabetes.17
However, physicians should be careful in older dia-
betic patients with a history of coronary artery disease
and ⁄ or long-standing diabetes. In this group, lowering
SBP to a level around 120 mm Hg may cause
increased mortality. Thus, as for the level of glycemic
control, the BP goals should be individualized in
patients with diabetes.
CONCLUSIONS
There is agreement and a good level of evidence that
the first line of therapy for HTN in patients with dia-
betes should be an ARB or an ACE inhibitor to reduce
the risk of developing microalbuminuria and protein-
uria and to minimize progression of proteinuria. If the
initial BP is >150 ⁄ 90 mm Hg or the reduction in BP is
not achieved with one therapy, a second agent should
be added. The ACCOMPLISH trial showed that the
amlodipine-based combination was more effective than
a thiazide-based combination in reducing cardiovascu-
lar events. These nondihydropyridine calcium channel
blockers have the benefit of a neutral effect on
glycemic control when compared with b-blockers and
diuretics, which worsen insulin sensitivity.32 In this
regard, the American Society of Hypertension recom-
mends using first- and second-line antihypertensive
agents that do not worsen preexisting metabolic condi-
tions. There is no evidence to support the use of ACE
inhibitors or ARBs in normotensive patients with type
1 or type 2 diabetes to prevent or delay the develop-
ment of microalbuminuria or nephropathy, but this
therapy has been shown to reduce the progression of
retinopathy in diabetic patients.
Acknowledgments and disclosures: The authors would like to thank Brenda
Hunter for her assistance in editing this manuscript.
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