Management of Hypertension in Obesity and Diabetes

Konstantinos P. Makaritsis, MD, Ph.D
Associate Professor of Internal Medicine
Department of Internal Medicine
University of Thessaly Medical School

Obesity and Hypertension
Overweight and obesity are defined as abnormal or excessive fat
accumulation that may impair health. Body mass index (BMI) is a simple index of
weight-for-height that is commonly used to classify overweight and obesity in adults.
It is defined as a person's weight in kilograms divided by the square of his height in
meters (kg/m2). The WHO definition is: a BMI greater than or equal to 25 is
overweight and a BMI greater than or equal to 30 is obesity (1).
The fundamental cause of obesity and overweight is an energy imbalance
between calories consumed and calories expended. Globally, there has been an
increased intake of energy-dense foods that are high in fat and an increase in
physical inactivity due to the increasingly sedentary nature of many forms of work,
changing modes of transportation, and increasing urbanization (1).
Obese people are at increased risk of diseases such as type 2 diabetes
mellitus, hypertension, dyslipidemia, coronary artery disease, stroke, sleep apnea,
osteoarthritis, gallstones, stress incontinence, depression and certain types of cancer
(2). It has been shown that in white adults, overweight and obesity (and possibly
underweight) are associated with increased all-cause mortality. All-cause mortality is
generally lowest with a BMI of 20.0 to 24.9 (3) (Fig.1).
Screening for overweight and obesity may change patient care in 3 ways.
First, in adults who are found to be obese and also have obesity-related diseases,
modest weight loss (5%–10% of total body weight) may improve control of these
diseases. For example, weight loss in obese adults with type-2 diabetes and
hypertension may improve glycemic and blood pressure control and reduce drug
therapy requirements. Second, in adults who are found to be obese but do not have
obesity-related diseases, lifestyle interventions (e.g., starting an exercise program)
may reduce the risk of these diseases. Third, in adults who are found to be
overweight but are otherwise healthy, promoting healthy lifestyle practices may
prevent them from becoming obese (2).
In 2014, more than 1.9 billion adults, 18 years and older, (39% of adults - 38%
of men and 40% of women) were overweight. Of these over 600 million were obese
(about 13% of the world’s adult population - 11% of men and 15% of women. The
worldwide prevalence of obesity more than doubled between 1980 and 2014.
Overweight and obesity are linked to more deaths worldwide than underweight. In
2013, 42 million children under the age of 5 were overweight or obese. In developing
countries the rate of increase of childhood overweight and obesity has been more
than 30% higher than that of developed countries. However, obesity is preventable
Worldwide, the proportion of adults with a body-mass index (BMI) of 25
kg/m2 or greater increased between 1980 and 2013 from 28·8% to 36·9% in men,
and from 29·8% to 38·0% in women. Prevalence has increased substantially in
children and adolescents in developed countries; 23·8% of boys and 22·6% of girls
were overweight or obese in 2013. The prevalence of overweight and obesity has
also increased in children and adolescents in developing countries, from 8·1% to
12·9% in 2013 for boys and from 8·4% to 13·4% in girls. Since 2006, the increase in
adult obesity in developed countries has slowed down (4).

Among Americans age 20 and older, 154.7 million (two thirds of US adults)
are overweight or obese (BMI of 25.0 kg/m2 and higher): 79.9 million men, 74.8
million women. Of these, 78.4 million (one third of US adults) are obese (BMI of 30.0
kg/m2 and higher): 36.8 million men - 41.6 million women.
The total excess cost related to the current prevalence of adolescent
overweight and obesity is estimated to be $254 billion ($208 billion in lost
productivity secondary to premature morbidity and mortality and $46 billion in
direct medical costs). If current trends in the growth of obesity continue, total
healthcare costs attributable to obesity could reach $861 to $957 billion by 2030,
which would account for 16% to 18% of US health expenditures (5).
Greek financial crisis has been shown to contribute substantially to obesity. In
the last 10 years the level of obesity in children has increased substantially because
of eating habits. The rate of obesity among boys aged 6 to 12 climbed to 14 percent
in 2012 from 9 percent in 2003, and for girls from 9 percent to 13 percent. Greece
has climbed in the first place worldwide in children 5-17 years old who are
overweight or obese (International Association for the study of obesity, 2011).
Obesity is recognized as a major cause of high BP, and the combination of
obesity and hypertension is recognized as a pre-eminent cause of CV risk. It is
estimated that at least 75% of the incidence of hypertension is related directly to
obesity. In a survey in Germany, approximately 75% of the hypertensive patients
seen by general practitioners or internists were overweight or obese. A lot of studies
do indicate risk for CVD associated with obesity independent of other risk factors
(diabetes, dyslipidemia, and hypertension). In addition, obesity and hypertension
may have additive effects in increasing risk for CVD (6,7). Data from the long-
standing Framingham Heart Study revealed that compared with normal weight adult
men and women, the multivariable-adjusted relative risks for development of
hypertension in long-term follow-up were 1.48 and 1.70 for overweight men and
women and 2.23 and 2.63 for obese men and women, respectively (8). In CARDIA
study (1358 men & 1321 women), young adults (mean age 25 years at baseline) who
maintained a stable BMI (within 2kg⁄m2 of baseline) at 6 examinations during 15
years had no significant changes in SBP or DBP, whereas those who had an increase
in their BMI≥2kg⁄m2 had substantial increases in BP. Of note, this weight gain was
more important than the baseline weight. Hence, age-related changes in BP may not
be inevitable, and may be caused more by age-related weight gain than aging per se
Pathogenesis - Pathophysiology
How obesity raises blood pressure?
Obesity-associated hypertension is often characterized by increased cardiac
output which appears to be mediated in part through plasma volume expansion and
sodium retention. Neurohumoral mechanisms are also involved (10).
However, a purely hemodynamic etiology, based on increased plasma
volume and increased cardiac output, are not sufficient explanations since the latter
do not account for the increase in peripheral resistance noted in obese hypertensive
patients who exhibit an increase in both kidney and cardiac SNA, when compared
with normotensive obese patients who exhibit an increase in kidney SNA, whereas
sympathetic outflow to the heart is reduced. Pharmacological studies and direct
sympathetic nerve recordings suggest that the SNS may be overactivated in obesity-
associated arterial hypertension (10).
Even though plasma volume and sodium retention are increased, the
systemic RAAS is activated in obesity. Weight loss studies suggest that the local RAAS
in adipose tissue, along with changes in intrarenal physical forces generating from fat
accumulation into the renal medulla, may contribute to the increase in systemic
RAAS activity (7) Table 1. (10).

Table 1. Pathogenesis of Obesity-related Hypertension. (10)
Central obesity & waist to hip ratio
Vague’s observations attracted little attention until the 1980s when
population-based studies in Scandinavia, using waist to hip ratio as a quantifiable
surrogate for the upper body phenotype, demonstrated significant CV risk
(hypertension, myocardial infarction, and type 2 diabetes mellitus) in association
with a high waist to hip ratio (11). It was shown that insulin resistance was also
associated with the upper body phenotype and many subsequent studies showed an
association of insulin levels and ⁄ or insulin resistance with hypertension in both
obese and non-obese people (10).
Visceral adiposity may also have a major role in the occurrence of
hypertension, diabetes mellitus, hyperlipidemia, and atherosclerosis in obese
humans. Recent evidence revealed several biological and genetic differences
between intraabdominal visceral fat and peripheral subcutaneous fat. Visceral
adipose tissue-resident macrophages produce more pro-inflammatory cytokines,
such as TNFα and IL6, but less adiponectin inducing insulin resistance, endothelial
dysfunction and the subsequent atherosclerosis. The rate of visceral fat
accumulation is also different according to the gender and ethnic background, and
may explain the variation in the cardiometabolic risk between different populations.
Interestingly, visceral obesity elicits greater activation of the sympathetic nervous
system (SNS) than subcutaneous obesity does (12).
Adipokines (mainly leptin, resistin, adiponectin and TNF-alpha) may play a
significant role in the association between obesity and hypertension (13). Leptin
regulates energy intake and expenditure decreasing food intake and upregulating
thermogenesis and energy expenditure through the stimulation of SNA. The effects
of leptin are mediated by two major pathways, positive regulation of anorexigenic α-
MSH and negative regulation of NPY having an orexigenic effect combined with a
reduction of thermogenesis.
In obesity, leptin resistance and hyperleptinemia develop because of
disrupted signaling in leptin receptor-containing neurons in brain areas involved in
food intake regulation, namely the hypothalamic nucleus arcuatus. Leptin action in
the nucleus arcuatus is also important for the control of sympathetic outflow to both
brown adipose tissue and the kidney (12,13). Selective resistance to the metabolic
actions of leptin seems to be present in obesity, whereas its action in stimulation of
sympathetic tone remains unaltered. SNS-stimulating effects of leptin are mainly
demonstrated in the kidney, adrenal gland, and brown adipose tissue.
Hyperleptinemia and leptin resistance thus may be the cause of chronically elevated
SNS in obesity via activation of leptin receptors in hypothalamus and brainstem.
Moreover, in the leptin resistant state, NPY is overexpressed and it is released from
neural sites by sympathetic activation and acts as a vasoconstrictor and thus could
play a role in obesity related hypertension (12).
Insulin has an acute sympatho-excitatory action in both normotensive and
borderline hypertensive subjects, as indicated by increased muscle SNS activity and
heightened norepinephrine levels after insulin administration in several studies.
Insulin might also have a sympatho-excitatory effect directly on the CNS. Insulin
release leads to hypoglycemia, which serves as an activator of the SNS. Moreover,
vasodilator responses to increased muscular glucose uptake and oxygen demands
lead to activation of the baroreceptor reflex and to enhanced muscle SNS activity
Another aspect of insulin infusion is the simultaneous depressor effect of
peripheral vasodilation mediated by a β-adrenergic mechanism. Chronic
hyperinsulinemia has been associated with impairment of the vasodilator action of
insulin. Vasoconstriction in the forearm was reported during insulin infusion in
severe insulin resistance. This finding suggests that hyperinsulinemia promotes
vascular dysfunction. Whether hypertension is caused by excessive amounts of
insulin, resistance to its action or chronically induced trophic vascular effects
remains to be uncovered. Insulin also has a direct action on the kidney to stimulate
sodium retention (14).
Sympathetic activation
Activation of the sympathetic nervous system (SNS) has been considered to
have a crucial function in the pathogenesis of hypertension among obese individuals.
Many studies provide evidence of high muscle SNS activity in obese subjects. High-
caloric intake increases norepinephrine turnover in peripheral tissues and raises
resting plasma norepinephrine concentrations-an indirect measurement of SNS
activity-. High dietary content in fat and carbohydrate has been suggested to acutely
stimulate peripheral α1- and β-adrenergic receptors, leading to elevated sympathetic
activity and hypertension. The mechanisms that have been proposed to be
responsible for an increased SNA in obesity include insulin and leptin, impaired
function of the baroreceptor sensitivity, increased levels of circulating FFAs and Ang
II (14).
The arterial baroreceptors acutely respond to increases in BP by
parasympathetic activation and sympathetic inhibition. A reduced sensitivity of the
arterial baroreflex may occur in long-standing hypertension and obesity, because of
a concomitant increase in central sympathetic outflow and of the effects of
arteriosclerotic lesions leading to an increased stiffness of the large arteries in which
the receptors are located. Impaired baroreflex sensitivity leads to withdrawal of
parasympathetic cardiac modulation, which occurs in obesity even in the absence of
an elevation in arterial pressure. Elevated sympathetic activity did not seem to
account for the increased heart rate in obesity but it appears to be the effect of
decreased parasympathetic activity (14).
Elevated levels of FFAs have been reported in obese hypertensives. Abnormal
distribution of FFAs in obese patients has been found to enhance vascular a-
adrenergic sensitivity and consequently to increase a-adrenergic tone. FFAs inhibit
Na+, K+-ATPase modifying the sodium pump raising vascular smooth muscle tone
and resistance. FFAs act as potent activators of phosphorylation of protein kinase C
(PKC). Other studies have reported a direct action of FFAs released from
phospholipids on ion channels at the cellular membranes of smooth muscle cells and
other tissues (14).
Renin Angiotensin Aldosterone System (RAAS) activity
Even though plasma volume and sodium retention are increased, the
systemic RAAS is activated in obesity. Moreover, studies in patients under sodium
restriction, which activates the renin–Ang system (RAS), provided evidence for a
presynaptic potentiating effect of Ang II on sympathetic neurotransmission. Several
studies have shown predominantly high levels of plasma renin activity, plasma
angiotensinogen, Ang II and aldosterone values in association with human obesity
Despite remarkable volume expansion and sodium retention in obesity,
several mechanisms are responsible for the RAS activation. Renin secretion by the
kidney seems to be induced by changes in intrarenal physical forces, generating from
fat accumulation around and into the renal medulla. Owing to the actual histologic
changes that cause compression of the medulla, flow rate of the filtrate is
diminished at the loop of Henle leading to prolongation of the time given for sodium
reabsorption. Detection of the decreased amount of sodium, reaching the distal
tubular cells, by the macula densa leads to a rise in renin secretion, through
tubuloglomerular feedback (14).
Adipose cells may represent a major site in which all components of the RAS
are formed. Renin, Ang II, angiotensinogen and Ang II receptors are found in
abundance in adipose mass suggesting that a local tissue Ang system is settled at the
adipocytes level. Angiotensinogen production serves as both a cause and effect of
adipocyte hypertrophy and leads to elevation of BP through the actions of Ang II,
which induce systematic vasoconstriction, direct sodium and water retention and
increased aldosterone production. Another potential mechanism of RAS activation
could be a chronic elevation of sympathetic tone, causing renal vasoconstriction and
renin-dependent chronic hypertension (14).
Increased renal Na reabsorption – Mineralocorticoid Receptor – Aldosterone
Obesity predisposes the kidney to reabsorb sodium by neural (SNS),
hormonal (aldosterone and insulin), and renovascular (angiotensin II) mechanisms.
This enhanced sodium avidity shifts the pressure natriuresis curve to the right,
thereby necessitating higher arterial pressure to excrete the day’s salt intake and
maintain sodium balance and volume homeostasis. This is the basis for the
documented salt sensitivity of obesity related hypertension and underlines the need
for diuretics in the therapeutic regimen (10).
It has been shown that plasma aldosterone in women correlated directly with
visceral adipose tissue, and higher plasma aldosterone values have also been
reported in patients with metabolic syndrome, which is independent of plasma renin
activity. Accumulating studies have elucidated the close relationship between
aldosterone and obesity (15). There is a worse control of BP in obese than lean
hypertensives, which can also be related to excessive aldosterone. Aldosterone
overproduction is an important cause of resistant hypertension and MR blockade has
been shown to effectively reduce BP in such patients (15).
The adipose tissue is an endocrine organ that secretes a variety of
adipokines. Adipocytes are capable of stimulating adrenal aldosterone synthesis
through the secretion of potent aldosterone-releasing factors (ARFs), which are not
yet identified. Nonetheless, the adipose tissue does not express 11 beta hydroxy-
steroid-dehydrogenase 2 (11βHSD2), and mineralocorticoid receptors (MRs) in
adipocytes are predominantly occupied by glucocorticoids which have an essential
function in adipocytes (15). MR activation results in increased renal sodium
reabsorption and excess sodium in the body leading to increased vascular
contraction (16). Figure 2 shows the main mechanisms of obesity associated
hypertension (14).

Management of obesity associated hypertension
Remarkably, current hypertension guidelines do not provide specific
recommendations for the choice of antihypertensive medications in obese patients.
Indeed, there are no large trials addressing the issue. Since a large proportion of
hypertensive patients are overweight or obese, data gathered in large clinical trials
with hard clinical endpoints, which is the foundation of the ESH Guidelines, are at
least in part applicable. However, to address the specific needs of obese patients,
these recommendations have to be modified on the basis of few existing data and
our current understanding of the mechanisms involved in obesity-associated arterial
Currently, recommendations are based on the “Position paper of the Obesity
Society and the American Society of Hypertension” (17), the “Joint statement of the
European Association for the Study of Obesity and the European Society of
Hypertension: obesity and difficult to treat arterial hypertension” (18), and the
“2013 ESH/ESC Guidelines for the management of arterial hypertension” (19).
Life style management of obesity associated hypertension
Life style management of obesity related hypertension consists of weight
loss, diet modification, salt restriction, physical activity (exercise), alcohol
moderation and behavioral modification.
Weight Loss
Systematic reviews consistently report a decrease in SBP of about 1 mm Hg
per kg of weight loss with follow-up of 2 to 3 years. There is attenuation in the
longer-term, with a decrease of about 6 mm Hg in SBP per 10 kg of weight loss (17).
Meta-analyses and systematic reviews that compare various dietary
approaches do not favor a specific diet for weight reduction. Appropriate diets for
the management of obesity related hypertension are rich in potassium, calcium and
magnesium, and fiber and low in salt and saturated fat. In terms of foods, these diets
promote consumption of vegetables, fruits, low-fat dairy products, whole grains,
nuts, poultry, and fish and discourage salt, red meats, sweet foods, and sugary
drinks. Mediterranean diet is also associated with benefits in relation to CV risk,
weight control, and BP (17).
Low-Salt Diets
Salt sensitivity is commonly associated with obesity. The usual salt intake is
between 9 and 12 g/day in many countries and it has been shown that reduction to
about 5 g/day has a modest (1–2mmHg) SBP-lowering effect in normotensive
individuals and a somewhat more pronounced effect (4–5mmHg) in hypertensive
individuals. A daily intake of 5– 6 g of salt is thus recommended for the general
population. The effect of sodium restriction is greater in black people, older people
and in individuals with diabetes, metabolic syndrome or CKD, and salt restriction
may reduce the number and doses of antihypertensive drugs. The effect of reduced
dietary salt on CVD events remains unclear, although the long-term follow-up
showed a reduced salt intake to be associated with lower risk of CV events (18,19).
Physical Activity
Aerobic exercise can reduce weight and BP, but when exercise is the only
intervention, weight losses are small, with an estimated change of 1.6 kg in
moderate-intensity programs continued for 6 to 12 months. In a meta-analysis that
included assessment of ambulatory BP it was reported that in studies lasting 4 to 52
weeks, with physical activity as the only intervention, aerobic exercise reduced BP by
3 ⁄ 2.4 mm Hg. The change affected daytime (3.3 ⁄ 3.5 mm Hg) but not nighttime (0.6
⁄ 1.0 mm Hg) BP. The effect on BP was independent of the estimated weight loss of
1.2 kg. However, when aerobic exercise is combined with calorie restriction for
weight control, the effects on ambulatory BP can be substantial (17).
The pressor effect of alcohol has been established in clinical trials, with an
estimated increase in SBP of 1 mm per 10 g of alcohol. Drinking alcohol at low to
moderate levels is associated with lower risk of atherosclerotic disease. Moderation
of heavier daily alcohol intake to no more than one standard drink in women and
two standard drinks in men appears prudent, with potential benefits for both weight
gain and BP. Combination of alcohol moderation and weight reduction in overweight
and obese hypertensive drinkers, achieved a 14 ⁄ 9 mm Hg BP reduction compared
with controls who maintained usual weight and drinking habits (17).
Although smokers tend to have lower body weight, they may gain weight
because of clustering of adverse health behaviors. Smoking increases BP acutely,
with an associated rise in arterial stiffness that lasts longer in hypertensive men (17).
Drug treatmnet of obesity associated hypertension
As in individuals with diabetes and chronic kidney disease, many authorities
have recommended lower target BPs for obese individuals. This recommendation is
partially due to the constellation of risk factors associated with obesity and the
metabolic syndrome, and is also attributed to the fact that hypertension in obese
patients has proven more difficult to control than hypertension in the non-obese
population. In fact, even modest weight loss increases the likelihood of achieving
goal BPs (20). Although logical, there is no strong evidence to support lowering BP
much beyond the defined 140 ⁄ 90 mm Hg threshold (19).
Useful antihypertensive agents in the management of obesity associated
hypertension include RAAS inhibitors (Angiotensin-converting enzyme inhibitors and
angiotensin receptor blockers), calcium channel blockers, diuretics (Low-dose
thiazide or thiazide-like agent and loop diuretics [if required]), potassium–sparing
agents and all agents potentiated by weight loss. With the exception of vasodilatory
beta blockers, avoid β-blockers except for specific cardiac indications (18,19).
RAAS inhibitors
Inhibitors of the renin-angiotensin-system are considered first-line
antihypertensive agents for most patients. Because of their broad spectrum of
beneficial effects, angiotensin-converting enzyme inhibitors are currently considered
to be the most appropriate drug for antihypertensive treatment of obese patients.
Angiotensin receptor blockers can be utilized in patients who do not tolerate
angiotensin-converting enzyme inhibition. Cleary, renin-angiotensin system blockade
in patients with obesity-related hypertension is unlikely to worsen glucose or lipid
metabolism (18,19).
Calcium channel blockers
Dihydropyridine calcium channel blockers are effective in lowering blood
amlodipine/benazepril vs. hydrochlorothiazide/benazepril in a hypertensive patient
population with a considerable number of obese patients (mean BMI 31.0 kg/m2 in
both groups). The trial was terminated early due to reduced cardiovascular mortality
with the amlodipine/benazepril combination. The observation that obese patients
are more likely to experience peripheral edema with dihydropyridine calcium
channel blocker treatment compared with lean patients is a potential limitation
Diuretic agents could be used with respect to the well described
hypervolemia and sodium retention in obesity. Combination of low-dose thiazide
diuretics with renin– angiotensin system blockers may reduce hyperkalemia risk
while improving blood pressure control. Consideration should be given to the
impairment of insulin sensitivity and deterioration of glucose metabolism that could
be caused by high dose thiazide diuretics. Overall, thiazide diuretics may not be the
first choice for most obese hypertensive patients. However, in patients not
responding to monotherapy, thiazide diuretics are a reasonable second or third
antihypertensive drug (18,19).
Mineralocorticoid Receptor (MR) blockers
More than half of the obese hypertensive patients are treated with two or
more antihypertensive drugs. A recent study in patients with resistant hypertension,
adding the mineralocorticoid antagonist spironolactone in doses of 25–100 mg/day
showed a 16/9mmHg reduction in ambulatory blood pressure performed after a
median interval of 7 months. Remarkably, higher waist circumference was
associated with better response to spironolactone (21). These findings point to the
special role of aldosterone in obesity associated hypertension (18).
Beta adrenergic receptor blockers
Beta-blockers reduce cardiac output and renin activity, both of which are
frequently increased in obese patients. Beta-blockers alone, or in combination with
alpha-adrenoreceptor blockers, were more effective in decreasing blood pressure in
obese than in lean hypertensive individuals. Limitations for the use of beta-blockers
are related to their potential negative effects on glucose metabolism and body
weight. Beta-blockers with vasodilating properties, such as carvedilol or nebivolol,
may be less likely to worsen glucose metabolism (18,19).
Bariatric medical treatment of obesity in hypertensives
Many therapeutic targets have been recently identified, on both the intake
and the expenditure side of the energy balance equation, thereby providing hope
that new agents, with limited off-target effects, may become available in the future
(17). Table 2 shows the bariatric agents currently used.

Table 2. Bariatric agents used in Obesity-related Hypertension. (17)
Obesity-related hypertension is an important public health issue. As the
prevalence of obesity increases, the prevalence of hypertension with its associated
CV risk will increase as well. Primary prevention is the long-term goal for diminishing
the prevalence of obesity, control of both obesity and hypertension in the
population at risk is the overriding current challenge.
Treating hypertension in the obese requires addressing the obesity as part of
the therapeutic plan. Lifestyle management is required in every case, with a focus on
weight loss and risk reduction. Treatment of obesity with caloric restriction and
sodium restriction works if extreme enough, but it is not a feasible long-term
strategy. In most patients, additional therapies including medications, aggressive
diet counseling and behavioral techniques, and sometimes bariatric surgery will be
Given the volume expansion and the neurohumoral activation in obesity-
associated arterial hypertension, renin-angiotensin system inhibitors, calcium
channel blockers, diuretics, and beta blockers are reasonable choices, along with MR
inhibitors (spironolactone) in resistant hypertension. However, when choosing
antihypertensive medications metabolic side effects should be taken into
Management of Hypertension in Diabetes mellitus
Diabetes Mellitus and Hypertension
High BP is a common feature of both type 1 and type 2 diabetes. Prevalence
of hypertension in diabetic patients is very high reaching 66% and 72% in diabetic
men and women, respectively (22). Masked hypertension is not infrequent in
diabetics, so that monitoring 24-h ambulatory BP in apparently normotensive
patients with diabetes may be a useful diagnostic procedure (19,23).
High BP in diabetics substantially increases the risk of macro- and
microvascular complications, doubling the risk of all-cause mortality and stroke,
tripling the risk of coronary heart disease and significantly increasing the progression
of diabetic nephropathy, retinopathy, and neuropathy. In these patients, a
difference of 5 mmHg in either SBP or DBP increases the risk of cardiovascular events
or death by 20% to 30%. Cardiovascular mortality is increased in individuals with
type 2 diabetes, across the whole range of blood pressure values, and this effect is
most noticeable within the normal range of blood pressure values (24).
Patients enrolled in UKPDS were newly diagnosed type 2 diabetic patients
with a relatively low prevalence of background risk factors and no prior history of
cardiovascular disease. In the intensive glucose control arm during the first 10 years,
8.4% of the patients died of either fatal myocardial infarction or sudden death,
signifying the importance of coronary heart disease as a primary determinant
outcome even in patients with tight glycemic control managed in a clinical trial (25).
Indeed, in a study evaluating the influence of diabetes on mortality following acute
coronary syndrome, it was shown that mortality at 30 days and 1 year following
acute coronary syndrome was significantly higher among patients with diabetes than
without diabetes presenting with unstable angina/NSTEMI and STEMI (26). The
impact of diabetes on cardiovascular mortality was studied in MRFIT, where a total
of 347,978 men, 35 to 57 years old, were screened to assess predictors of
cardiovascular disease (CVD) mortality among men with and without diabetes, and
to assess the effect of diabetes on CVD death. It was also evaluated the effect of 3
CV risk factors, serum cholesterol, systolic blood pressure, and reported number of
cigarettes smoked per day. The outcome measure was CVD mortality. The relative
risk for CVD death in participants with none of the risk factors was 5.10 for diabetics
compared to nondiabetics. With all 3 risk factors, the relative risk for CVD death was
2.64 for diabetics compared to nondiabetics (27).
Diabetes type 2 is the major cause of chronic kidney disease (28). Diabetic
patients with both hypertension and proteinuria experience an extremely high
mortality risk: 11-fold for men and 18-fold for women with type 1 diabetes and 5-
fold for men and 8-fold for women with type 2 diabetes (29).
Management of hypertension in diabetic patients
In diabetic patients with hypertension, the cardiovascular benefits of
antihypertensive treatment are mainly due to the achieved BP values, rather than
specific drug classes. However, many trials have shown that the renoprotective
effects of ACE inhibitors and ARBs are independent of BP control. Antihypertensive
treatment in diabetes exerts a major protective effect against renal complications,
whereas evidence of a similar effect on eye and neural complications is less
consistent (19).
The Hypertension Optimal Treatment (HOT) trial demonstrated fewer
cardiovascular events with tighter control of diastolic blood pressure in patients with
diabetes. One objective of the HOT trial was to assess the optimum target diastolic
blood pressure in the treatment of hypertension. In the subgroup of patients with
diabetes there was a 51% reduction in major cardiovascular events in target group
<80 mmHg compared with target group <90 mmHg (30).
Lower systolic blood pressure resulted in slower rates of decline in
glomerular filtration rate (GFR) in patients with diabetic and non-diabetic renal
disease. The beneficial impact from achieved control of systolic blood pressure (SBP)
was demonstrated in a meta-analysis of the 9 major clinical trials in diabetic and
non-diabetic renal diseases (31).
In UKPDS a comparison of tight glucose control, HbA1c=7% (achieved was
8.2%) vs tight blood pressure control <150/85 mmHg (achieved 144/82 mmHg)
revealed that blood pressure reduction contributed to a greater extent to the
relative reduction of cardiovascular events (32). However, recent evidence suggests
that combining effective blood glucose (HbA1c to 6.5-7%) and BP control increases
protection, particularly of the kidney.
The “optimal” BP target for people with diabetes is still the object of much
debate. Previous randomized controlled trials demonstrated the favorable effects of
“tight” BP control on cardiovascular outcomes, but achieved SBP in the intervention
groups was never lower than 130 mmHg. The issue is further complicated by data
from post hoc analyses (INVEST & ONTARGET), suggesting that intensive BP lowering
might cause an increased risk of cardiovascular events, the so-called J-curve (33,34).
Before the ACCORD-BP trial, in no randomized trial in diabetic patients has
SBP been brought down to below 130mmHg with proven benefits, and this has also
been very difficult to achieve in the majority of the patients. However, the ACCORD-
BP trial, showed no improvement in the composite primary outcome of nonfatal MI,
stroke, or CV death in the intensive BP-lowering arm (<120 mmHg), but showed
significant decrease in non-fatal stroke events. Nevertheless, the ACCORD trial could
be regarded as inconclusive, given the small number of observed events (the actual
event rate was 2.09% vs 4% planned) and was underpowered to determine a
significant advantage of one BP target over the other (35).
People with diabetes and hypertension should be treated to a systolic blood
pressure (SBP) goal of <140 mmHg. Lower systolic targets, such as <130 mmHg, may
be appropriate for certain individuals, such as younger patients, if they can be
achieved without undue treatment burden. Individuals with diabetes should be
treated to a diastolic blood pressure (DBP) <90 mmHg. Lower diastolic targets, such
as <80 mmHg, may be appropriate for certain individuals, such as younger patients,
if they can be achieved without undue treatment burden (36).
Patients with blood pressure >120/80 mmHg should be advised on lifestyle
changes to reduce blood pressure. Patients with confirmed office-based blood
pressure higher than 140/90 mmHg should, in addition to lifestyle therapy, have
prompt initiation and timely subsequent titration of pharmacological therapy to
achieve blood pressure goals (36).
Lifestyle therapy for elevated blood pressure consists of weight loss, if
overweight or obese; a Dietary Approaches to Stop Hypertension (DASH)-style
dietary pattern including reducing sodium and increasing potassium intake;
moderation of alcohol intake; and increased physical activity (36).
Pharmacological therapy for patients with diabetes and hypertension should
comprise a regimen that includes either an ACE inhibitor or an angiotensin receptor
blocker (ARB). If one class is not tolerated, the other should be substituted.
Multiple-drug therapy (including a thiazide diuretic and ACE inhibitor/ARB, at
maximal doses) is generally required to achieve blood pressure targets. Multiple-
drug therapy (including a thiazide diuretic and ACE inhibitor/ARB, at maximal doses)
is generally required to achieve blood pressure targets. If ACE inhibitors, ARBs, or
diuretics are used, serum creatinine/estimated glomerular filtration rate (eGFR) and
serum potassium levels should be monitored (36).
In pregnant patients with diabetes and chronic hypertension, blood pressure
targets of 110–129/65–79 mmHg are suggested in the interest of optimizing long-
term maternal health and minimizing impaired fetal growth. ACE inhibitors and ARBs
are contraindicated during pregnancy (36).
An important caveat is that most patients with hypertension require multiple
drug therapy to reach treatment goals (37-40). Identifying and addressing barriers to
medication adherence (such as cost and side effects) should routinely be done. If
blood pressure remains uncontrolled despite confirmed adherence to optimal doses
of at least three antihypertensive agents of different classifications, one of which
should be a diuretic, clinicians should consider an evaluation for secondary forms of
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