Review article 33

Hypertension in diabetes and the risk of cardiovascular

disease
Nirmal Sunkaraa and Chowdhury H. Ahsanb

Hypertension (HTN) is an important risk factor for target goals. Cardiovasc Endocrinol 6:33–38 Copyright ©
cardiovascular disease and its many manifestations. It 2017 Wolters Kluwer Health, Inc. All rights reserved.
shares pathogenic pathways with diabetes and is part of a Cardiovascular Endocrinology 2017, 6:33–38
common metabolic entity, the metabolic syndrome. When
combined with diabetes, HTN has been shown to predict Keywords: diabetes, hypertension, risk of cardiovascular disease

and promote increased risk for cardiovascular disease a

Fellow in Vascular Medicine and Advanced Endovascular and Structural Heart
events over and above each risk factor alone. Of the Interventions, Wellmont CVA Heart Institute Kingsport, Kingsport, Tennessee and
b
Clinical Professor, Director of Cardiac Catheterization Laboratory and
components of this metabolic syndrome, HTN is relatively Cardiovascular Research, School of Medicine, University of Nevada, Las Vegas,
easy to diagnose and thereby more accessible for Nevada, USA

implementing preventive and treatment strategies. The Correspondence to Nirmal Sunkara, MD, 2050 Meadowview parkway, Division of
recent release of Joint National Committee-8 guidelines for Cardiology, Kingsport, Tennessee 37660, USA
e-mail: nirmalsunkara@gmail.com
the treatment of HTN has fueled a debate on treatment
Received 22 October 2016 Accepted 11 January 2017

Introduction [4,7,8]. Because of its high prevalence in the USA [9],

Blood pressure (BP) is the driving force of the circulatory HTN ranks first among the chronic conditions for which
system. William Harvey, physician to Charles I, was the Americans visit a healthcare provider. One of the major
first to accurately describe how the blood circulates through reasons for the impressive reduction in age-adjusted
the human body in his 1628 work ‘De Motu Cordis’ (also stroke mortality (∼62%) and coronary heart disease
known as ‘On the Motion of the Heart and Blood’) [1]. The mortality (∼45%) in the USA since 1972 is the wide-
first published measurement of BP was by clergyman spread acceptance of the need to treat HTN and our
Stephen Hales in 1733 [2]. The pioneering works of increased ability to reduce BP effectively [10].
Thomas Young, Richard Bright, Moahomed, and Sir
Diabetes mellitus (DM) is a known risk factor for CVD
Clifford Allbutt established hypertension (HTN) and its
[11]. HTN and DM are frequently coexisting entities,
association with kidney, heart, and neurological manifes-
causing more damage than each alone. This coexistence
tations [2]. The definition of essential HTN as a clinical
may be linked to a combination of genetics, common
entity was more firmly established, however, only after the metabolic pathophysiologic pathways, and environmental
development of noninvasive methods for measuring BP. At factors. Epidemiologic studies have shown that DM
the beginning of this century, RivaRocci’s sphygmoman- patients are twice as likely to develop HTN relative to
ometer facilitated systolic blood pressure (SBP) measure- those without DM and, conversely, patients with HTN
ment noninvasively and Nicolai Korotkoff’s description are at a 2–3 times higher risk of developing DM com-
of Korotkoff sounds facilitated measurement of diastolic pared with normotensive patients [12,13]. The presence
blood pressure (DBP) and SBP [2,3]. of both increases CVD risk relative to either HTN or
Systemic arterial HTN is the condition of persistent, DM alone.
nonphysiologic elevation of systemic BP. It is currently
defined as a resting SBP of at least 140 mmHg or DBP Epidemiology
(DBP) of at least 90 mmHg or receiving therapy for the HTN is a common problem in patients with both type 1
indication of lowering BP [4]. Historically, HTN and type 2 diabetes; however, the time course of asso-
(BP ≥ 140/90 mmHg) was believed to be the major driver ciation is different [14,15]. In type 1 diabetics, the inci-
of risk for cardiovascular disease (CVD) [5], but BP levels dence of HTN increases progressively with age from 5%
between 120 and 139/80 and 89 mmHg (pre-HTN) are at 10 years to 70% at 40 years and is closely associated
not only more prevalent but also increase cardiovascular with albuminuria. In a study of 981 patients who had type
(CV) risk [6]. Compared with many other risk factors 1 diabetes for 5 or more years, HTN was present in 19%
for stroke, acute myocardial infarction, and heart failure, of patients with normoalbuminuria, 30% with moderately
HTN is among the simplest to diagnose, has the widest increased albuminuria, and 65% with severely increased
variety of treatment options, and (particularly in high-risk albuminuria [15]. The incidence of HTN eventually
individuals) is the most cost-effective preventive strategy reaches 75–85% in patients with progressive diabetic
2162-688X Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/XCE.0000000000000114

Copyright r 2017 Wolters Kluwer Health, Inc. All rights reserved.

34 Cardiovascular Endocrinology 2017, Vol 6 No 1

nephropathy [16]. The risk of HTN is highest in Blacks, mortality in patients with diabetes than in those without
who are also at a much higher risk for renal failure diabetes [27].
because of diabetic nephropathy.
Pathophysiology
Among type 2 diabetics, 39% already have HTN when
Environmental, behavioral, and genetic factors interplay in
newly diagnosed with diabetes. In approximately one-
causing the various components of metabolic syndrome, of
half of these patients, the elevation in BP occurred before
which diabetes and HTN are important components.
the onset of moderately increased albuminuria. HTN was
Multiple genes with small associations have been reported
strongly associated with obesity and the HTN patients
to be associated with diabetes and HTN, including, but
were at an increased risk for CV morbidity and mortality
not limited to, genes encoding angiotensinogen, adreno-
[17]
medullin, apolipoprotein, and α-adductin, to name a
There is considerable overlap between diabetes and few. Interestingly, in studies in Chinese women, single
HTN, reflecting marked overlap in their etiology and nucleotide polymorphisms that predict the development
disease mechanisms. In the Hong Kong Cardiovascular of diabetes were also found to predict the development of
Risk Factor Prevalence Study, only 42% of patients with HTN [28].
diabetes had normal BP and only 56% of patients with
Environmental factors predisposing a fetus to cardiome-
HTN had normal glucose tolerance [18,19]. In the USA
tabolic syndrome in adulthood include the period in utero,
population, HTN occurs in ∼ 30% of patients with type 1
high birth weight, gestational diabetes, and fetal mal-
diabetes and in 50–80% of patients with type 2 diabetes
nutrition [29,30]. Later in life, high intake of sodium,
[20]. 2013–2014 CDC data indicate the prevalence of
alcohol, unsaturated fat, smoking, lack of physical activity,
HTN in adults ages 20 and older in the USA at 33.5%,
and mental stress are examples of an unhealthy lifestyle
increased from 30.9% reported previously [9]. 76 million
predisposing to the cardiometabolic syndrome. HTN and
USA adults are estimated to have HTN; this number is
diabetes considerably share common pathways such as
expected to increase over the next few decades because
obesity, inflammation, oxidative stress, insulin resistance,
of the current pandemic of obesity and aging of the
and mental stress [19]. Obesity is one of the most impor-
population [13].
tant risk factors for HTN and diabetes [31]. Obesity is
African Americans, and especially African American determined by genetic and environmental factors and
women, have a prevalence of HTN that is among the represents an imbalance between energy intake and
highest in the world. Currently, it is estimated that 38.6% expenditure and genetic variations [28]. Currently, more
of African American adults have HTN compared with than one-third (36.5%) of USA adults have obesity and the
32.3% of non-Hispanic Whites and 17.3% of Mexican estimated annual medical cost of obesity was 147 billion
Americans [21,22]. Asian Americans and most other dollars in 2008 [32]. Obesity, especially central, has been
ethnic groups tend to have similar BP levels and HTN shown to be associated with a low-grade inflammatory
prevalence as Whites. The prevalence of HTN increased process [33,34]. This inflammatory process is shown
to a similar extent in all ethnicities during the decade of to predispose to insulin resistance [35–37]. A low-grade
the 1990s. Prevalence rates are similar between men and inflammatory process occurs in both diabetes and HTN
women, but they increase considerably with age, from 7.4 [38]. Even chronic periodontitis is a latent factor in the
to 35.6 to 69.7%, among those aged 18 to 39, 40 to 64, and development of diabetes, HTN, CVDs, and the metabolic
of at least 65 years, respectively [23]. syndrome [39,40]. In this meta-analysis of a total of 19 000
patients, there was a significant dose–response association
The prevalence of HTN and DM is increasing world-
of interleukin-6 levels and C-reactive protein with the risk
wide. 972 (26%) million individuals are estimated to have
of type 2 diabetes [41]. These markers, in addition to
HTN globally and 29.1 million in the USA [24]. WHO
adhesion molecules such as vascular cell adhesion mole-
estimates the number to increase by 60% to 1.56 billion
cule – 1, cellular adhesion molecule – 1, and chemokines,
by 2025 [25]. DM affects estimated 360 million indivi-
are shown to be associated with an increased risk of
duals, with predicted 552 million adults affected by 2030
HTN [42].
[26]. A number of factors, in addition to HTN, contribute
toward the high prevalence of CVD in type 2 diabetic Insulin resistance occurs when normal levels of insulin do
persons. 5000 patients were followed for 12 years in the not trigger the signal for glucose absorption, indicating an
MRFIT trial and we learned that the occurrence of CVD impaired response to insulin in skeletal muscle, liver,
was up to three times more in diabetic men than non- adipose, and CV tissue [43,44]. Insulin resistance arises
diabetic controls, irrespective of systolic pressure, age, because of various genetic, acquired, and environmental
cholesterol, ethnic group, or use of tobacco. This study factors, including obesity [45]. Increased renin angio-
also confirmed that systolic HTN, elevated cholesterol, tensin sympathetic system axis activities may also cause
and cigarette smoking were independent predictors of insulin resistance by the stimulation of angiotensin II
mortality and that the presence of at least one of these type 1 receptors, which trigger increased production of
risk factors had a greater impact on increasing CVD reactive oxygen species in adipocytes, skeletal muscle,

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 HTN in diabetes and the risk of CVD Sunkara et al. 35

and CV tissue of obese individuals [46]. Insulin resis- patients may enable later reduction in the dose or the
tance is a prothrombotic state characterized by an eleva- number of antihypertensive agents.
tion of PAI-1 and fibrinogen levels, leading to an
Drug therapy in hypertensive diabetic patients has been
increased risk of CV events [47]. Insulin resistance may
shown to be protective on the basis of results from multiple
be the result of an overproduction of proinflammatory
trials, including United Kingdom Prospective Diabetes
cytokines (e.g. interleukin-6, tumor necrosis factor, and
C-reactive protein) and a relative deficiency of anti- Study (UKPDS), ADVANCE, and Hypertension Optimal
inflammatory cytokines (e.g. adiponectin) [48]. Most Treatment, as well as meta-analyses of these and other
patients with type 2 diabetes are insulin resistant and trials [56–63]. In this meta-analysis of 40 trials, compared
about half of those with essential HTN are insulin with placebo in 100 354 patients, antihypertensive therapy
resistant [49,50]. Therefore, insulin resistance is an reduced mortality related to CVD, myocardial infarction,
important common link between diabetes and HTN. and stroke. A 10 mmHg reduction in systolic pressure with
antihypertensive therapy was associated with a hazard ratio
Diabetes has also been shown to cause volume expan- (HR) for death of 0.87 [95% confidence interval (CI):
sion, induced by both insulin and increased glucose load 0.78–0.96] and a HR for total CVD of 0.89 (95% CI:
in the proximal tubule, leading to sodium retention and 0.83–0.95). However, analyses that divided patients
thereby increasing BP levels [51]. Protein glycation in according to their baseline systolic pressures showed that,
diabetes also predisposes to vascular stiffness, leading to with the exception of stroke, the benefit of anti-
a reduction in arterial distensibility and an increase in hypertensive therapy was limited to those whose initial
systolic pressure [52]. systolic pressures greater than 140 mmHg. The benefit of
reduction in stroke was observed even in BP less than
Treatment 140 mmHg systolic. For most outcomes, no class of drugs
This includes nonpharmacologic interventions to prevent was superior to the others [56]. However, calcium channel
HTN and pharmacologic interventions treating HTN. The blockers reduced the risk of stroke compared with others
American Diabetes Association 2015 guidelines recom- [relative risk (RR) 0.86, 95% CI: 0.97–0.77] and β-blockers
mend that for patients with a SBP of 120–139 mmHg, or a were shown to increase the risk of stroke compared with
diastolic pressure of 80–89 mmHg, nonpharmacologic other agents (RR 1.25, 95% CI: 1.05–1.50).
methods should be used to reduce BP, such as weight The UKPDS, using captopril or atenolol as the primary
reduction, increased consumption of fresh fruits, vege- therapy, evaluated a goal BP of less than 150/85 versus
tables, and low-fat dairy products, exercise, salt restriction, less than 180/105 [57]. At a median 8.4-year follow-up,
and avoidance of smoking and excess alcohol ingestion. patients with lower BP showed a 24% reduction in
Pharmacological agents should be initiated in patients who diabetes-related endpoints, including microvascular dis-
develop HTN (BP ≥ 140/90 mmHg) [53]. ease (37 vs. 49%), a 32% reduction in deaths related to
Although there are no well-controlled studies of diet and diabetes, 44% fewer strokes, and a 34 and 47% reduction
exercise in the treatment of elevated BP or HTN in in significant deterioration in retinopathy and visual
individuals with diabetes, The Dietary Approaches to acuity, respectively. After 9 years of follow-up, 29% of
Stop Hypertension study evaluated the impact of healthy patients in the group assigned to tighter control required
dietary patterns in individuals without diabetes and has three or more drugs to continue to achieve target BP [64].
shown antihypertensive effects similar to those of phar- These significant improvements were lost within 2 years
macological monotherapy with reduced BP by 5.5 mmHg of termination of tight BP control. In a subsequent
and DBP by 3.0 mmHg (P < 0.001) [54]. The lifestyle observational report utilizing data from the UKPDS trial,
changes advocated include reducing excess body weight, there was an inverse correlation between the updated
restricting sodium intake (2300 mg/day), increasing con- mean SBP and the aggregate endpoint at the 10-year
sumption of fruits and vegetables (8–10 servings/day) and follow-up for any complication related to diabetes [65].
low-fat dairy products (2–3 servings/day), avoiding Each 10 mmHg reduction in systolic pressure was asso-
excessive alcohol consumption (no > 2 servings/day in ciated with a 12% risk reduction; the lowest risk occurred
men and no > 1 serving/day in women), and increasing at a systolic pressure below 120 mmHg [65]. However,
activity levels. These lifestyle (nonpharmacological) UKPDS was not designed to assess the efficacy of
strategies may also positively affect glycemia and lipid systolic pressures below 140 mmHg.
control and should be encouraged.
In the Hypertension Optimal Treatment trial, which
As HTN places diabetic patients at high risk for CV evaluated target diastolic pressures of ≤ 90, ≤ 85, or
complications, in all diabetic patients with persistent BP ≤ 80 mmHg, in the diabetic subgroup of 3000 patients,
above 140/90 mmHg, early treatment of HTN is impor- but not in other patients, the RR of a CV event was
tant both to prevent CVD and to minimize progression of significantly reduced in less than or equal to 80 mmHg
renal disease and diabetic retinopathy [55]. Successful group compared with less than or equal to 90 mmHg
implementation of nonpharmacologic therapy in these group (RR 0.49, 95% CI: 0.29–0.81) [61].

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36 Cardiovascular Endocrinology 2017, Vol 6 No 1

In the ADVANCE trial, in 11 000 patients with type 2 mortality with aggressive therapy (≤ 115 mmHg) and
diabetes, a fixed combination of perindopril-indapamide higher adverse events related to antihypertensive
was compared with placebo. A target BP was not used to agents [69].
guide protocol therapy, and all other agents, except
Conducted in nondiabetic patients at increased CV
angiotensin-converting enzyme inhibitors and thiazides,
risk, The Systolic Blood Pressure Intervention Trial
were initiated at the discretion of the treating clinicians.
(SPRINT) showed that targeting a systolic pressure less
After a mean of 4.3 years, in addition to a decrease in the
than 120 mmHg compared with less than 140 mmHg
mean BP by 5.6/2.2 mmHg, major microvascular and
reduced CV events and mortality when using automated
macrovascular events were lower as well as CV mortality
oscillometric blood pressure (AOBP). AOBP readings
and all-cause mortality (15.5 vs. 16.8, 3.8 vs. 4.6 and 7.3
were typically 5–10 mm lower than with manual mea-
vs. 8.5, respectively) [62]. During the 6-year post-trial
surement. The mean systolic pressure was 121 mmHg in
open-label follow-up in 8494 of the trial patients, those
the intensive lowering group [70].
who had been assigned perindopril-indapamide had a
lower death rate during the cohort phase (15.3 vs. 16.7%) Data from NHANES 2001–2010 indicate that ∼ 78% of
as well as a lower incidence of major CV events (13.3 vs. hypertensive individuals were aware of their elevated
14.2%) [66]. On combining both the trial and the cohort BP, 73.7% of them were receiving antihypertensive
phases (∼10 years of follow-up), all-cause mortality was therapy, but only 48.4% had a BP of less than
significantly lower among those in the treatment group 140/90 mmHg – the level considered to be ‘controlled’ or
(HR 0.91, 95% CI: 0.84–0.99) [66]. at goal. The prevalence of antihypertensive medication
use increased from 63.5% in 2001 to 2002 to 77.3% in
The normotensive Appropriate Blood Pressure Control in
2009 to 2010 (Ptrend < 0.01). Most notably, there was a
Diabetes Trial evaluated enalapril or nisoldipine treated
large increase in the use of multiple antihypertensive
to a target DBP of 10 mmHg below baseline. The mean
agents (from 36.8 to 47.7%, Ptrend < 0.01) [71]. In com-
BP in the intensive group was 128 ± 0.8/75 ± 0.3 versus
parison with monotherapy, single-pill combinations and
137 ± 0.7/81 ± 0.3 mmHg in the moderate group. At 5 years,
multiple-pill combinations were associated with 55 and
there was no difference between the two groups in crea-
26% increased likelihoods of BP control, respectively. By
tinine clearance, which was the primary endpoint, but
the 2009–2010 time period, 47% of all hypertensive
reductions in some secondary endpoints, such as progres-
patients and 60% of treated hypertensive patients had
sion of retinopathy (34 vs. 46%), microalbuminuria, and
achieved BP control. However, higher treated but
macroalbuminuria. There was no reduction in the rate of all
uncontrolled HTN rates continued to persist among
CV events, although there was a significant reduction in
older Americans, non-Hispanic Blacks, diabetic patients,
stroke (P = 0.03) [67].
and those with chronic kidney disease. Also, Mexican
The Action to Control Cardiovascular Risk in Diabetes Americans with HTN were still less likely to take anti-
Blood Pressure Trial (ACCORD BP) also evaluated a hypertensive medication than non-Hispanic Whites with
lower treatment goal. This study randomized 4733 HTN [71].
patients with type 2 diabetes who had CVD or at least two
Joint National Committee-8 came up with the following
additional risk factors for CVD to either intensive therapy
recommendations for the treatment of HTN in diabetic
(goal SBP < 120 mmHg) or standard therapy (goal
patients after analyzing available data for treatment goals.
SBP < 140 mmHg). At a mean follow-up of 4.7 years, no
significant difference in the annual rate of the primary
(1) In patients with HTN and diabetes, pharmacologic
composite outcome of nonfatal myocardial infarction,
treatment should be initiated when BP is
nonfatal stroke, or death from CV causes (1.87 vs. 2.09%,
140/90 mmHg or higher, irrespective of age.
HR 0.88, 95% CI: 0.73–1.06), annual all-cause mortality
(2) Initial antihypertensive treatment should include
rate (1.28 vs. 1.19%), or in the rate of death from CV causes
a thiazide diuretic, a calcium channel blocker, an
(0.52 vs. 0.49%) was observed. The annual rates of total
angiotensin-converting enzyme inhibitor, or angio-
stroke and nonfatal stroke (0.32 vs. 0.53%, HR 0.59, 95%
tensin receptor blocker in the general non-Black
CI: 0.39–0.89, for total stroke and 0.3 vs. 0.47%, HR 0.63,
population or a thiazide diuretic or a calcium channel
95% CI: 0.41–0.96, for nonfatal stroke) were lower in the
blocker in the general Black population.
intensive treatment group. Moreover, the intensive group
(3) If the target BP is not reached within 1 month after
also had a higher rate of an increase in serum creatinine of
initiating therapy, the dosage of the initial medication
more than 1.5 mg/dl in men or more than 1.3 mg/dl in
should be increased or a second medication should
women and severe adverse effects related to treat-
be added.
ment [68].
The SANDS trial of 499 American Indian men and The American Diabetes association has similar recom-
women with type 2 diabetes and no history of previous mendations, but recognizes the need for additional data
CVD events showed no difference in clinical CV in special subgroups and supports lower targets in special

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 HTN in diabetes and the risk of CVD Sunkara et al. 37

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