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ase Study: Treating Hypertension in Patients With Diabetes

case

1. Evan M. Benjamin, MD, FACP

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Presentation

L.N. is a 49-year-old white woman with a history of type 2 diabetes, obesity, hypertension, and
migraine headaches. The patient was diagnosed with type 2 diabetes 9 years ago when she
presented with mild polyuria and polydipsia. L.N. is 5′4″ and has always been on the large side,
with her weight fluctuating between 165 and 185 lb.

Initial treatment for her diabetes consisted of an oral sulfonylurea with the rapid addition of
metformin. Her diabetes has been under fair control with a most recent hemoglobin A1c of 7.4%.

Hypertension was diagnosed 5 years ago when blood pressure (BP) measured in the office was
noted to be consistently elevated in the range of 160/90 mmHg on three occasions. L.N. was
initially treated with lisinopril, starting at 10 mg daily and increasing to 20 mg daily, yet her BP
control has fluctuated.

One year ago, microalbuminuria was detected on an annual urine screen, with 1,943 mg/dl of
microalbumin identified on a spot urine sample. L.N. comes into the office today for her usual
follow-up visit for diabetes. Physical examination reveals an obese woman with a BP of 154/86
mmHg and a pulse of 78 bpm.
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Questions

1.

What are the effects of controlling BP in people with diabetes?

2.

What is the target BP for patients with diabetes and hypertension?

3.

Which antihypertensive agents are recommended for patients with diabetes?

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Commentary
Diabetes mellitus is a major risk factor for cardiovascular disease (CVD). Approximately two-
thirds of people with diabetes die from complications of CVD. Nearly half of middle-aged people
with diabetes have evidence of coronary artery disease (CAD), compared with only one-fourth of
people without diabetes in similar populations.

Patients with diabetes are prone to a number of cardiovascular risk factors beyond
hyperglycemia. These risk factors, including hypertension, dyslipidemia, and a sedentary lifestyle,
are particularly prevalent among patients with diabetes. To reduce the mortality and morbidity
from CVD among patients with diabetes, aggressive treatment of glycemic control as well as
other cardiovascular risk factors must be initiated.

Studies that have compared antihypertensive treatment in patients with diabetes versus placebo
have shown reduced cardiovascular events. The United Kingdom Prospective Diabetes Study
(UKPDS), which followed patients with diabetes for an average of 8.5 years, found that patients
with tight BP control (< 150/< 85 mmHg) versus less tight control (< 180/< 105 mmHg) had lower
rates of myocardial infarction (MI), stroke, and peripheral vascular events. In the UKPDS, each
10-mmHg decrease in mean systolic BP was associated with a 12% reduction in risk for any
complication related to diabetes, a 15% reduction for death related to diabetes, and an 11%
reduction for MI. Another trial followed patients for 2 years and compared calcium-channel
blockers and angiotensin-converting enzyme (ACE) inhibitors, with or without hydrochlorothiazide
against placebo and found a significant reduction in acute MI, congestive heart failure, and
sudden cardiac death in the intervention group compared to placebo.

The Hypertension Optimal Treatment (HOT) trial has shown that patients assigned to lower BP
targets have improved outcomes. In the HOT trial, patients who achieved a diastolic BP of < 80
mmHg benefited the most in terms of reduction of cardiovascular events. Other epidemiological
studies have shown that BPs > 120/70 mmHg are associated with increased cardiovascular
morbidity and mortality in people with diabetes. The American Diabetes Association has
recommended a target BP goal of < 130/80 mmHg. Studies have shown that there is no lower
threshold value for BP and that the risk of morbidity and mortality will continue to decrease well
into the normal range.

Many classes of drugs have been used in numerous trials to treat patients with hypertension. All
classes of drugs have been shown to be superior to placebo in terms of reducing morbidity and
mortality. Often, numerous agents (three or more) are needed to achieve specific target levels of
BP. Use of almost any drug therapy to reduce hypertension in patients with diabetes has been
shown to be effective in decreasing cardiovascular risk. Keeping in mind that numerous agents
are often required to achieve the target level of BP control, recommending specific agents
becomes a not-so-simple task. The literature continues to evolve, and individual patient
conditions and preferences also must come into play.

While lowering BP by any means will help to reduce cardiovascular morbidity, there is evidence
that may help guide the selection of an antihypertensive regimen. The UKPDS showed no
significant differences in outcomes for treatment for hypertension using an ACE inhibitor or a β-
blocker. In addition, both ACE inhibitors and angiotensin II receptor blockers (ARBs)
have been shown to slow the development and progression of diabetic nephropathy.
In the Heart Outcomes Prevention Evaluation (HOPE) trial, ACE inhibitors were found
to have a favorable effect in reducing cardiovascular morbidity and mortality,
whereas recent trials have shown a renal protective benefit from both ACE inhibitors
and ARBs. ACE inhibitors and β-blockers seem to be better than dihydropyridine
calcium-channel blockers to reduce MI and heart failure. However, trials using
dihydropyridine calcium-channel blockers in combination with ACE inhibitors and β-
blockers do not appear to show any increased morbidity or mortality in CVD, as has
been implicated in the past for dihydropyridine calcium-channel blockers alone.
Recently, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack
Trial (ALLHAT) in high-risk hypertensive patients, including those with diabetes,
demonstrated that chlorthalidone, a thiazide-type diuretic, was superior to an ACE
inhibitor, lisinopril, in preventing one or more forms of CVD.

L.N. is a typical patient with obesity, diabetes, and hypertension. Her BP control can
be improved. To achieve the target BP goal of < 130/80 mmHg, it may be necessary
to maximize the dose of the ACE inhibitor and to add a second and perhaps even a
third agent.

Diuretics have been shown to have synergistic effects with ACE inhibitors, and one
could be added. Because L.N. has migraine headaches as well as diabetic
nephropathy, it may be necessary to individualize her treatment. Adding a β-blocker
to the ACE inhibitor will certainly help lower her BP and is associated with good
evidence to reduce cardiovascular morbidity. The β-blocker may also help to reduce
the burden caused by her migraine headaches. Because of the presence of
microalbuminuria, the combination of ARBs and ACE inhibitors could also be
considered to help reduce BP as well as retard the progression of diabetic
nephropathy. Overall, more aggressive treatment to control L.N.'s hypertension will
be necessary. Information obtained from recent trials and emerging new
pharmacological agents now make it easier to achieve BP control targets.
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Clinical Pearls

1.

Hypertension is a risk factor for cardiovascular complications of diabetes.

2.

Clinical trials demonstrate that drug therapy versus placebo will reduce
cardiovascular events when treating patients with hypertension and diabetes.
3.

A target BP goal of < 130/80 mmHg is recommended.

4.

Pharmacological therapy needs to be individualized to fit patients' needs.

5.

ACE inhibitors, ARBs, diuretics, and β-blockers have all been documented to be
effective pharmacological treatment.
6.

Combinations of drugs are often necessary to achieve target levels of BP control.

7.

ACE inhibitors and ARBs are agents best suited to retard progression of
nephropathy.

case

Dan N. is a 19-year-old Caucasian male who presents for a routine office visit to his
family physician, Dr. Nicolette Boca. He complains of episodic wheezing and chest
tightening several days a month, with nocturnal exacerbations every week or
sometimes every 2 weeks for many years. He has difficulty arising and performing at
work on the days following such episodes.

Dan was never diagnosed with asthma or significant allergies, but he has been using
a short-acting ß2-agonist for intermittent wheezing since he was 13 years old. He does not
recall any instances when he has experienced symptom exacerbations or wheezing due to cold
weather, but he has had difficulty breathing during exercise.
No significant irritants have been identified.

Dan’s lung function tests seem to yield confounding results; however, his physician has
diagnosed him with mild persistent asthma based on his symptoms and his frequent use of his
ß2-agonist. She contacts Dr. Gary Rachelefsky, an asthma and allergy specialist, to discuss his
case and the available therapeutic options.

In this case, we will learn the role of the distal airways in asthma and examine the therapeutic
options that are available for patients like Dan. We will apply treatment guidelines in the clinical
setting, with particular emphasis on managing the patient’s symptoms, avoiding any potential
exacerbations of symptoms that interfere with his daily life, and possibly avoiding disease
progression.

Let’s take a look at Dan’s history and a little more detail about his case and see how we might
develop an appropriate treatment plan for him.

case
A 37 y/o black female with a history of asthma, presents to the ER with
tachypnea, and acute shortness of breath with audible wheezing. Patient has taken
her prescribed medications of Cromolyn Sodium and Ventolin at home with no relief
of symptoms prior to coming to the ER. A physical exam revealed the following: HR
110, RR 40 with signs of accessory muscle use. Ausculation revealed decreased
breath sounds with inspiratory and expiratory wheezing and pt was coughing up
small amounts of white sputum. SaO2 was 93% on room air. An arterial blood gas
(ABG) was ordered with the following results: pH 7.5, PaCO2 27, PaO2 75. An aerosol
treatment was ordered and given with 0.5 cc albuterol with 3.0 cc normal saline in a
small volume nebulizer for 10 minutes. Peak flows done before and after the
treatment were 125/250 and ausculation revealed loud expiratory wheezing and
better airflow. 20 minutes later a second treatment was given with the above meds.
Peak flows before and after showed improvements of 230/360 and on ausculation
there was clearing of breath sounds and much improved airflow. RR was 24 at this
time and HR 108. Symptoms resolved and patient was given prescription for inhaled
steroids to be used with current home meds. Instruction was given for use of inhaled
steroids and the patient was sent home.

This case is an example of what many people with asthma experience. The
following discussion will cover the etiology, pathogenesis, signs and symptoms,
diagnosis, and treatment of asthma. Complete the following sections and take the
quiz to check your understanding.

Learning Objectives

After completing the sections below, you should be able to:

1. list different ways asthma is diagnosed.

2. explain how a proper forced expiratory test is to be performed.
3. list the 3 primary pathologic reactions during as asthmatic episode.
 4. differentiate the two types of asthma.
5. recognize chest x-ray changes seen with asthma.
6. recognize the signs and symptoms of asthma.
7. describe some of the equipment necessary for an exercise test.
8. discuss why and how a bronchoprovocation test is done.
9. discuss which values are most often used when testing for asthma.
10. recommend the appropriate drug therapy of an asthmatic patient for
chronic treatment or for an acute attack.
11. recognize the commonly used bronchodilation agents.
12. list the side effects related to the different asthma medications.

References

Presentation
R.C. is a 57-year-old man with type 2 diabetes first diagnosed 2 years ago. Other
medical problems include obesity and hypothyroidism. He has a history of heavy
alcohol use but quit drinking alcohol 2 years ago. He presents now for routine follow-
up and is noted to have a blood pressure of 168/100 mmHg. He is asymptomatic.

Physical exam reveals a height of 5 feet, 8 inches, weight of 243 lb, blood pressure of
160/100 mmHg, and a regular pulse of 84 beats/min. There is no retinopathy or
thyromegaly. There is no clinical evidence of congestive heart failure or peripheral
vascular disease.

Laboratory evaluation reveals trace protein on urinalysis, blood urea nitrogen of 14

mg/dl, serum creatinine of 1.2 mg/dl, random serum glucose of 169 mg/dl, normal
electrolytes, and normal thyroid-stimulating hormone levels. A 24-h urine collection
reveals a urinary albumin excretion rate of 250 mg/day.

Questions

1. Does this patient have renal disease?

2. Should his blood pressure be treated?
3. What treatment strategy should be used?

Commentary
Diabetic nephropathy is a clinical syndrome characterized by albuminuria,
hypertension, and progressive renal insufficiency. Diabetic nephropathy is the most
common cause of end-stage renal disease (ESRD) in Western countries, accounting
for ~35% of all new ESRD cases in the United States. The life expectancy of patients
with diabetic ESRD is <50% at 3 years, despite improvements in dialysis and renal
transplantation.

Early detection and treatment of albuminuria is essential in diabetes. A normal

urinary albumin excretion rate (UAER) ranges from 0 to 30 mg/day. Overt
albuminuria or macroalbuminuria is defined as a UAER >300 mg/day. Many studies
have shown that a UAER >30 mg/day is abnormal and can be used to predict the
development of overt albuminuria or diabetic nephropathy and both microvascular
and macrovascular disease. As a result, the term "microalbuminuria" was coined to
refer to a UAER of 30–299 mg/day.

Many organizations, including the American Diabetes Association, recommend

regular screening for microalbuminuria. Type 1 diabetic patients should be screened
5 years after diagnosis of diabetes and after puberty. People with type 2 diabetes
should be screened from the time of diagnosis, since many type 2 diabetic patients
have had undiagnosed disease for some time. If the initial screening is negative, then
annual screenings are indicated.

Traditional urinary dipsticks are insensitive at detecting albuminuria <300 mg/day.

Spot urine samples may be assayed for microalbuminuria and creatinine and a ratio
>30 µg/mg or mg/g is abnormal. Newer methods, such as Micral-Test II test strips (Boehringer
Mannheim, Mannheim, Germany), permit reliable semiquantitative determination of
microalbuminuria and can be used in the office for dipstick screening of diabetic patients.

Transient elevations in urinary albumin excretion may be associated with marked hyperglycemia,
acute febrile illness, exercise, hypertension, heart failure, and urinary tract infection. If the initial
test is elevated, these and other potential causes of renal disease should be considered and
ruled out. Because there is also marked day-to-day variability in urinary albumin excretion, a
positive test should be confirmed on a subsequent occasion before designating a patient as
having persistent microalbuminuria.

Patients identified with persistent microalbuminuria should be aggressively treated both with
respect to glycemic and blood pressure control. Patients are considered to be hypertensive if their
blood pressure is >140/90 mmHg. The goal for the management of hypertensive diabetic patients
is to keep the blood pressure <130/85 mmHg.

The treatment of choice for hypertensive diabetic patients with or without microalbuminuria
remains angiotensin-converting enzyme (ACE) inhibitors. Only captopril (Capoten) is approved
for the treatment of diabetic nephropathy, but all ACE inhibitors appear to be effective. Fosinopril
(Monopril) has a dual route of elimination and therefore may have an advantage over other ACE
inhibitors, particularly when used for patients with renal insufficiency or failure.

Once started, renoprotective therapy should be continued indefinitely. ACE inhibitors have been
shown to prevent or slow the progression from microalbuminuria to overt nephropathy. Studies
have also shown that the renoprotective effects of ACE inhibitors go beyond those expected from
blood pressure reduction by itself. Additionally, the renoprotective effects apply to both
normotensive and hypertensive patients with microalbuminuria. Therefore, the indication for ACE
inhibition can be persistent microalbuminuria, regardless of blood pressure. Discontinuing therapy
will result in a recurrence of microalbuminuria.

In addition to aggressively managing blood pressure, attempts need to be made toward lifestyle
modifications. These include meticulous control of blood glucose, seeking counseling to stop
smoking, maintaining optimal body weight, following an appropriate diet, and exercising regularly.

Clinical Pearls

1. Screen diabetic patients for microalbuminuria.

2. Recognize hypertension in diabetic patients with a blood pressure >140/90 mmHg.
3. ACE inhibition is the preferred treatment of microalbuminuria and/or hypertension.
4. Counsel diabetic patients on lifestyle modifications, including blood glucose control, weight
control, smoking cessation, diet, and exercise

CASE
A 44 year old moderately dehydrated man was admitted with a two day history of
acute severe diarrhoea. Electrolyte results (in mmol/l): Na+ 134, K+ 2.9, Cl- 113,
HCO3- 16, urea 12.3, creatinine 0.30 mmol/l. Anion gap 8.

Arterial Blood Gases

pH 7.31

pCO2 33 mmHg

pO2 - not given

HCO3 16 mmol/l

K+ 2.1 mmol/l
Assessment
Firstly, the initial clinical assessment

The possibilities suggested by the history of severe diarrhoea with hypovolaemia are:

* Hyperchloraemia with normal anion-gap acidosis due to the diarrhoea

* Acute pre-renal renal failure with elevated urea and creatinine
* Acute lactic acidosis (high anion gap acidosis) due to peripheral circulatory
failure.

Secondly, the acid-base diagnosis

Looking at the results systematically:-

1. pH: A net acidaemia is present so an acidosis must be present to have caused

this.
2. Pattern: Both the pCO2 & HCO3 are low - this pattern is found in respiratory
alkalosis and in metabolic acidosis. Now we know that an acidosis must be present
(because of the acidaemia), so therefore the diagnosis is metabolic acidosis
3. Clues:
* The normal anion gap with an elevated chloride suggests a normal anion gap
acidosis.
* The elevated urea & creatinine is noted but this has not been sufficient to
elevate the anion gap so there has not been significant retention of acid anions.
* There is no evidence to support the co-existence of a high AG acidosis and a
normal AG acidosis. The delta ratio is slightly negative and certainly not in the range
which would suggest a combined acidosis.
4. Compensation: Here we ask is the respiratory compensation appropriate? The
maximal amount of respiratory compensation takes 12-24 hours to occur so sufficient
time has elapsed. The expected pCO2 (by Rule 5) is (1.5 x 16 + 8) which is 32
mmHg. This is close to the actual measured value of 33mmHg, so no primary
respiratory disorder is present. This is consistent with the history as there was no
evidence of a respiratory disorder.
5. Formulation: The acid-base diagnosis is a normal anion gap metabolic acidosis
with appropriate respiratory compensation.
6. Confirmation: This is no investigation which can assist here. A lactate level would
have been useful to totally exclude any lactic acidosis.

Finally, the clinical diagnosis

This patient has acute diarrhoea causing a mild normal anion gap metabolic acidosis.
The volume loss is probably responsible for pre-renal azotaemia.
Comments

Pertinent points were the acidaemia, elevated chloride, normal anion gap and the
elevation of urea and creatinine. Note that this laboratory has calculated the anion
gap as (Na + K) - (Cl + HCO3).

Some pre-renal renal failure is present but there is no evidence of a high anion gap
acidosis due to renal failure. As a general guideline, acidosis usually does not occur in
renal failure until GFR is less than 20 mls/min (or a creatinine level of about 0.30-0.35
mmol/l). Similarly tissue perfusion is still adequate enough to prevent development of
a lactic acidosis. Hypovolaemia results in secondary hyperaldosteronism which
increases sodium reabsorption but increases excretion of K+ resulting in
hypokalaemia.

http://www.anaesthesiamcq.com/AcidBaseBook/ab9_6.php#cases
for dehydation incxludes all drug nd their contraindictiohn