Hypertension in Diabetes

Ankur Jindal
University of Missouri Columbia School of Medicine, Departments of Internal
Medicine, Divisions of Hospital Medicine

Syed Hasan Naqvi

University of Missouri Columbia School of Medicine

Muhammad Waqar Salam

University of Missouri Columbia School of Medicine, Departments of Internal
Medicine, and Endocrinology and Metabolism

James R. Sowers, M.D.

University of Missouri Columbia School of Medicine, Departments of Internal
Medicine, Medical Pharmacology, and Endocrinology and Metabolism, Harry S Truman
Memorial Veterans Hospital

Updated: January 3, 2014

IMPORTANT POINTS
1.
2.
3.
4.

5.
6.

Diabetes is frequently associated with hypertension, and the coexistence of the two disorders
worsens clinical outcomes.
Early detection and appropriate management of hypertension is important to prevent or delay
end organ damage in patients with diabetes.
Blood pressure targets for patients with diabetes have been modified in light of current
evidence
Blood pressure target of 140/80 appears reasonable for most patients with diabetes, but
tighter control may be considered in patients at high risk of stroke, especially if it can be
achieved safely.
Blood pressure targets and treatment should be individualized based on risk factors, treatment
tolerance, and long term benefits.
Simultaneous use of ACE and ARB is not recommended due to worse renal outcomes with
combination therapy.

INTRODUCTION
Statistics from Centers for Disease Control and Prevention (CDC) and National Health and
Nutritional Examination Survey (NHANES) database show that incidence of Type 2 diabetes
mellitus (T2DM) has risen steeply in the last decade. It is estimated that diabetes affects 25.8
million people in the United States, and 67% of individuals aged 20 years or more with
diabetes, have hypertension. Individuals with T2DM often have metabolic de rangements
termed as metabolic syndrome. This metabolic syndrome is a clustering of cardiovascular risk
factors like T2DM, hypertension, dyslipidemia, central obesity, and chronic kidney disease. The
coexistence of hypertension and diabetes increases the risk for CVD, CVA, retinopathy and
nephropathy. Increasing prevalence of obesity, associated diabetes, hypertension and
resulting health care costs are a serious public health concern.

As expected, microvascular as well as macrovascular complications of T2DM, have paralleled the

increased prevalence of diabetes. Diabetes mellitus (DM) continues to be the leading cause of blindness,
end stage renal disease (ESRD) and non-traumatic lower limb amputations in the U.S. While optimal
glycemic control remains paramount particularly in prevention of microvascular complications
(retinopathy, nephropathy, and neuropathy), accompanying metabolic derangements such as
hypertension and dyslipidemia play a pivotal role in the initiation and progression of macrovascular
disease (ischemic heart disease, stroke, and peripheral vascular disease). The appropriate management
of DM, therefore, should comprise a multifaceted approach that targets optimal blood pressure and
lipid management in addition to glycemic control. Here we wi ll discuss the management of hypertension
in patients with diabetes.

Pathophysiology of Hypertension in Diabetes

Hypertension and diabetes coexist and the pathogenesis of hypertension involves maladaptive changes
and complex interactions between autonomic nervous system, mechanical forces, renin-angiotensinaldosterone system (RAAS), and individual and environmental factors. The factors listed below are
involved in the pathogenesis of hypertension and these have been targeted for therapeutic
intervention.

Sedentary lifestyle, excessive caloric intake and insulin resistance

A sedentary lifestyle and excessive calorie intake can lead to increased adiposity which is
associated with increased risk of developing insulin resistance. Insulin resistance is associated
with an increased vascular adhesion molecule expression, oxidative stress, inflammation, and
decreased vascular nitric oxide levels, which in turn promote vascular stiffness resulting in
persistent hypertension.

Increased intra-vascular volume:

Intra vascular volume is determined by total body sodium content. Sodium is the major
extracellular cation in human beings, and it has osmotic activity which helps determine
effective arterial blood volume. A mismatch between sodium intake and sodium loss can lead
to a positive sodium balance. This results in increased sodium concentration in intravascular
compartment. Increased sodium concentration in the intravascular compartment leads to
influx of water along the osmotic gradient, thus leading to increased intravascular volume. The
resultant increased venous return to heart, results in increased cardiac output in accordance
with Frank Starling Law, and this eventually leads to elevated arterial pressure.
Increased blood pressure increases glomerular filtration and promotes urinary salt excretion.
This increased salt excretion in a state of elevated blood pressure has been termed pressure
natriuresis. Pressure natriuresis helps restore total body sodium content.
ESRD is another disease entity in which volume overload contributes to hypertension.
Hypertension in ESRD is often difficult to control, unless normal or near normal volume status
is restored, which can often be achieved with dialysis.

Premature vascular aging :

Changes in vessel lumen and elasticity affect the ease with which blood can flow through
blood vessels. Minimal reduction in the lumen of the blood vessel is associated with an
exponential increase in the resistance to blood flow. In patients with hypertension, structural
and functional changes can reduce lumen of small arteries and arterioles. Vascular remodeling,
low grade inflammation, vascular fibrosis and atherosclerosis result in decreased pliability of

the blood vessels, thus increasing peripheral vascular resistance, which eventually leads to
hypertension. In patients with diabetes, accelerated atherosclerosis leads to premature
vascular aging, characterized by enhanced vascular smooth muscle contraction, rigidity and
resistance. These maladaptive vascular changes subsequently contribute to the de velopment
of hypertension.

Autonomic nervous system dysregulation:

Autonomic nervous system is an important determinant of blood pressure levels. Both
sympathetic and parasympathetic activity helps in regulation of blood pressure.
Increased sympathetic activity leads to increased heart rate, force of contraction of ventricles,
peripheral vascular resistance, and fluid retention. These physiological and pathological
changes promote blood pressure elevation. Decreased parasympathetic outflow also results i n
increased heart rate, thus contributing to pathogenesis of hypertension. Central obesity,
insulin resistance, sleep apnea and resistant hypertension are often accompanied by increased
sympathetic nervous system activity. Further, activation of the sympathetic nervous system
promotes insulin resistance and risk of T2DM. Reduction in central sympathetic outflow, which
can be achieved by renal denervation, is associated with improved insulin sensitivity, better
glycemic control and reductions in blood pressure.
Renin angiotensin aldosterone system (RAAS):
RAAS plays an important role in the pathogenesis of hypertension via effects of angiotensin II
and aldosterone. Angiotensin II is a potent vasoconstrictor and has a direct effect on the
vascular smooth muscle. Angiotensin II also stimulates production of aldosterone, which
promotes sodium and water retention. Understanding the physiology of RAAS is very
important as it is the target for angiotensin converting enzyme (ACE) inhibitors and
angiotensin II receptor blockers (ARBs), which are cornerstones of blood pressure
management in individuals with diabetes.
Renin is a proteolytic enzyme found in the juxtaglomerular cells in the kidney. Renin cleaves
angiotensinogen to angiotensin I. ACE acts on angiotensin I and transforms it to angiotensin II.
Production and release of renin is tightly regulated by many interdependent factors such as
renal perfusion pressure, sodium chloride concentration in distal tubule of nephron, and
stimulation of renin secreting cells by sympathetic nervous system.
Decreased renal perfusion pressure in a state of dehydration or decreased intravascular
volume, promotes release of renin. The release of renin results in a cascade of steps,
culminating in increased production of angiotensin II. Increased angiotensin II results in
vasoconstriction and also stimulates secretion of aldosterone and thus restores intravascular
volume by increasing sodium and water retention.
Obesity and insulin resistance are associated with the inappropriate activation of RAAS and the
sympathetic nervous system. Increased adiposity has also been associated with high levels of
plasma aldosterone suggesting that obesity is a condition characterized by activated RAAS.
Angiotensin II and aldosterone have been shown to inhibit insulin metabolic signaling in
classical insulin sensitive tissues and this likely plays a role in reduced endothelial-mediated
vascular relaxation and the development of hypertension. Angiotensin II and aldosterone may
also promote insulin resistance through non-genomic mechanisms like activation of serine

kinases and increased serine phosphorylation of critical insulin signaling molecule, insulin
receptor substrate protein 1, causing impaired phosphatidylinositol 3-kinase engagement and
protein kinase B stimulation.

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