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138
CHAPTER 9 Treatment of Primary Hypertension
140/90 mmHg, the addition of a second agent is necessary.
12,15,57,58
It is also
important to note that doubling the dose of monotherapy is less likely to
achieve BP control than using a logical combination.
57,58
Even in patients with
initially well-controlled HTN, a second agent will have to be added over time,
as indicated by the results of the ALLHAT trial,
37
where 76 percent of sub-
jects required two or more agents for BP control. Based on the results of the
ACCOMPLISH trial,
48
a combination of an ACE inhibitor and amlodipine was
associated with a 2 percent absolute risk reduction of cardiovascular death and
major cardiovascular events compared to an ACE inhibitor and thiazide diuretic
combination, despite slightly higher 24-hour BP readings in the amlodipine arm.
In addition to the cardiovascular benefi ts, the ACE inhibitor and CCB com-
bination slowed the progression of chronic kidney disease independently of
the BP pressure-lowering effects.
50
Therefore, individuals treated with a single
antihypertensive medication who have not attained the goal BP should be initi-
ated on a combination of an ACE inhibitor/ARB with a dihydropyridine CCB, or
alternatively an ARB or ACE inhibitor plus a thiazide-like diuretic.
12,15,57
Resistant HTN: Novel invasive approaches
Patients who remain hypertensive after (1) secondary causes of HTN have been
ruled out (Table 9.1), (2) appropriate lifestyle measures have been instituted,
and (3) taking more than three medications with complementary mechanisms,
one of which is a diuretic (with good adherence) are defi ned as having resis-
tant HTN. Medications in such patients should be given at maximally titrated
Table 9.1 Secondary Causes of Hypertension
62
General
Obesity
Poor sleep hygiene (sleep apnea, restless leg syndrome,
63
and others)
Illicit drug use
Coarctation of aorta (children predominantly)
Renovascular
Fibromuscular dysplasia
Renal artery stenosis
Endocrine Causes
Primary aldosteronism
Pheochromocytoma
Renin-producing tumors
Liddle syndrome
Cushing syndrome
Primary hyperparathyroidism
Hyperthyroidism
Hypothyroidism (diastolic HTN)
Glucocorticoid-remediable HTN
Neurogenic HTN
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CHAPTER 9 Treatment of Primary Hypertension
doses, with one being a diuretic appropriate for kidney function. These patients
carry a higher risk of stroke, myocardial infarction, chronic kidney disease, and
congestive heart failure compared with patients with controlled HTN. For
patients with resistant HTN who are already on a combination of medications
including ACE inhibitors/ARBs, CCBs, and thiazide-like diuretic, the addition of
spironolactone has been associated with signifi cant BP reduction.
47,59,60
If the BP is still poorly controlled, beta-blockers with vasodilating properties
(carvedilol, nebivolol), direct vasodilators (hydralazine, nitrates, minoxidil), and
alpha-adrenergic centrally acting agents (clonidine, guanfacine), may be add to
the diuretic, RAAS blocker, and CCB combination.
57
Hydralazine and minoxidil are potent peripheral vasodilators that cause
lower extremity edema, tachycardia, and (rarely) pleural or pericardial effusions;
therefore, when used, they are usually prescribed alongside a beta-blocker and
loop diuretic to minimize these side effects.
61
The use of alpha-1 blockers (e.g.,
doxazosin, terazosin) has been limited by the observation in ALLHAT that dox-
azosin, compared to chlorthalidone, signifi cantly increased the risk of increasing
edema that some people equated with mild heart failure.
37
Note these agents do
not cause sodium retention and the edema is related to peripheral vasodilation.
Sympathetic activation participates in the development of the HTN by promot-
ing the initial BP elevation in the early clinical stages of the disease and maintaining
the BP elevation.
62
The adrenergic overdrive triggers not only elevations in BP
but also contributes over time to cardiac hypertrophy and the metabolic abnor-
malities detected in hypertensive patients. Patients with different stages of HTN
exhibit increased renal as well as central sympathetic nerve activity. Additionally,
baroreceptors become less sensitive to any change in BP in a setting of chronic
HTN. Without the barorefl ex control of elevated BP, continued chronic activa-
tion of the sympathetic nervous system results in chronic HTN.
62,63
Preclinical and clinical studies have shown that novel invasive approaches
(renal sympathetic denervation treatment [RDT] and barorefl ex activation
therapy [BAT] with the Barostim device) result in signifi cantly better BP control
despite intensive ongoing medical therapy, reduced left ventricular mass, and
improved glycemic control over time.
62
The Barostim, formerly the Rheos Hypertension System, is a new implant-
able carotid sinus baroreceptor stimulator. The prospective, randomized,
double-blind Rheos Pivotal Trial
63
evaluated BAT in 265 patients with resistant
HTN for 21 months. Early BAT yielded a decrease in systolic BP of 26 mmHg
at 6 months and 35 mmHg at 12 months, while delayed BAT yielded 17-mmHg
and 33-mmHg decreases, respectively. After 1-year follow-up, 81 percent of
the study participants had a systolic BP drop of at least 10 mmHg from before
the implant. Moreover, 63 percent of these subjects reached a systolic BP of
less than 140 mmHg, with an average systolic BP drop of 44 mmHg. The main
procedure-related side effects were associated with carotid sinus lead place-
ment and transient or permanent nerve injury.
64
The safety and effi cacy of RDT using a radiofrequency ablation catheter
was tested in the Symplicity HTN-2 multicenter, prospective, randomized trial
(Fig. 9.1).
65,66
One hundred six patients with a baseline systolic BP of 160 mmHg or
more and an estimated GFR of above 45 mL/min/1.73 m
2
were randomly allocated
in a one-to-one ratio to undergo RDT with previous treatment or to maintain
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140
CHAPTER 9 Treatment of Primary Hypertension
Primary Endpoint: 6-month Office BP
RDN (n=49) Control (n=51)
33/11 mmHg
difference between
renal denervation therapy (RDN)
and Control (P<0.0001)
10
0
–10
–20
Δ from Baseline to
6 Months (mmHg)
–30
–40
–50
–32
Systolic
• 84% of RDN patients had ≥ 10 mmHg reduction in SBP
• 10% of RDN
p
atients had no reduction in SBP
–12
Diastolic
Systolic Diastolic
01
Figure 9.1 Primary outcome and safety profi le from Symplicity HTN-2 Trial.
60
previous treatment alone. The absolute home-based BP difference between
groups was 22/12 mmHg. There were no serious complications related to the
device or procedure; however, the study had some methodological limitations.
The ongoing Symplicity HTN-3 is expected to provide more robust data on
the safety and effi cacy of RDT.
67
Offi ce systolic BP is the primary end point, but
it will also have 24-hour ambulatory BP data in participants as a prespecifi ed
secondary end point.
67
It is still too early to determine whether one approach is
better than the other and who is an ideal candidate for which procedure. These
novel approaches will not eliminate the need for antihypertensive medications,
but they are expected to effectively reduce BP in combination with medications
to levels below 140/90 mmHg and potentially reduce the risk for stroke, myo-
cardial infarction, and chronic kidney disease.
Conclusion
HTN is a well-established independent risk factor for the development of cardio-
vascular events and progression of chronic kidney disease. BP reduction signifi cantly
decreases HTN-related morbidity and mortality. Effective BP control requires
mandatory implementation of lifestyle modifi cations (low-sodium diet, exercise)
as well as appropriate selection of medications. With the increasing prevalence of
obesity, initial combination therapy is becoming more the rule. Antihypertensive
therapy should be tailored to the patient’s risk factors and adjusted based on toler-
ability, effi cacy, and cost. Novel invasive approaches for BP control in patients with
resistant HTN effectively reduced BP in the fi rst clinical studies and thus emerge as
promising approaches for patients with resistant HTN.
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141
CHAPTER 9 Treatment of Primary Hypertension
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58. Wald DS, Law M, Morris JK, Bestwick JP, Wald NJ. Combination therapy versus
monotherapy in reducing blood pressure: meta-analysis on 11,000 participants
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61. Ferdinand KC. A compendium of antihypertensive therapy. J Clin Hypertens
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145145
Chapter 10
Therapy for Type 2 Diabetes
Kathleen Yip and Sangeeta Kashyap
Epidemiology
The Centers for Disease Control and Prevention (CDC) estimates that
25.8 million people, or 8.3 percent of the U.S. population, have diabetes mel-
litus. Type 2 diabetes mellitus (T2DM) accounts for 90 to 95 percent of all cases
of diabetes, and the number of people with T2DM has been projected to triple
by 2050.
1
Health costs have been estimated at $174 billion in direct and indirect
costs. T2DM is the seventh leading cause of death and the leading cause of
blindness, chronic renal disease, and nontraumatic lower limb amputations.
Up to 90 percent of T2DM patients are obese, defi ned as a body mass index
(BMI) of 30 kg/m
2
or more. However, this can differ by racial groups. Nearly
100 percent of Pima Indians and certain Pacifi c Islander groups who have T2DM
are obese, while this holds true for only approximately 30 percent of Chinese
and Japanese patients. Regardless, patients with a lower or normal BMI may
have increased abdominal adiposity, which is associated with insulin resistance
and cardiovascular risk.
Previously, patients with T2DM were considered to have a “mild” form of
diabetes compared to patients with immunologic destruction of pancreatic islet
cells that results in T1DM, and could thus be managed satisfactorily with nutri-
tional guidance and exercise. As a result, tight glycemic control was not a treat-
ment goal for these patients. However, patients with both subtypes are at risk
for microvascular (e.g., retinopathy, nephropathy, and neuropathy) and macro-
vascular (e.g., coronary, cerebrovascular, peripheral vascular) complications.
According to the American Diabetes Association, diagnosis should be based
on one of the following: a glycated hemoglobin (HbA1c) of at least 6.5 percent,
a fasting plasma glucose of at least 126 mg/dL (7.0 mmol/L), a 2-hour plasma
glucose at least 200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test,
or a random plasma glucose at least 200 mg/dL. Results diagnostic of diabetes
should be confi rmed via repeat testing unless the diagnosis is clear based on the
symptoms of hyperglycemia.
2
Lifestyle issues
T2DM is a chronic and progressive disease that is not fully understood. The
pathophysiology revolves around diminished muscle, adipose, and liver sen-
sitivity to insulin and superimposed pancreatic beta-cell failure, resulting in
hyperglycemia and systemic metabolic dysfunction.
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CHAPTER 10 Therapy for Type 2 Diabetes
Insulin is a peptide hormone released from beta cells in the pancreas in
response to elevated blood glucose levels and the presence of incretins such
as gastric-inhibitory peptide (GIP) and glucagon-like peptide-1 (GLP-1), small
peptide hormones secreted from the intestines. Through the incretin effect,
these hormones stimulate increased insulin release when glucose is taken orally
compared to intravenously. When insulin binds to its respective receptor, it
assists in regulating glucose uptake, nutrient metabolism, and tissue growth and
proliferation. In normal physiological states, insulin stimulates glucose uptake
and storage in primarily skeletal and adipose tissues to maintain euglycemia.
When blood glucose levels remain elevated in a prediabetic individual, insulin
production can be increased, compensating to maintain euglycemia. Over time,
beta cells in the pancreas progressively fail and the individual cannot produce
suffi cient amounts of insulin.
3
Additionally, glucagon secreted from alpha cells in
the pancreas increases while concurrently incretin hormones become less effec-
tive, worsening hyperglycemia. Insuffi cient insulin combined with insulin resis-
tance in adipose and skeletal tissue can lead to a diagnosis of T2DM. Current
therapeutic strategies target both beta-cell failure and insulin resistance.
As stated previously, up to 90 percent of T2DM patients are also obese
and typically accumulate visceral fat, which is distinct from subcutaneous fat.
Visceral fat is more metabolically active, increasing the transport of free fatty
acids from adipose tissue to the liver, stimulating liver gluconeogenesis and
decreasing skeletal muscle insulin sensitivity. Concurrently at the cellular level,
there may be decreased insulin binding to its receptor and defects in its down-
stream insulin signaling, causing decreased glucose disposal. Lifestyle manage-
ment involves decreasing intra-abdominal fat and increasing muscle insulin
sensitivity.
A large number of clinical trials have focused on glycemic control and pre-
vention (Table 10.1).
Of note, the Diabetes Prevention Program (DPP) study pointed to the con-
siderable advantages of lifestyle modifi cation for disease progression. Over an
average follow-up of 2.8 years, lifestyle modifi cations lowered the risk of devel-
oping T2DM by 58 percent, while treatment with metformin alone conferred a
31 percent risk reduction compared to placebo.
4
The lifestyle modifi cation pro-
gram was defi ned as a weight loss of at least 7 percent and at least 150 minutes
of physical activity per week. Look AHEAD (Action for Health in Diabetes)
was a multicenter randomized clinical trial comparing the effects of intensive
lifestyle modifi cations (exercise and decreased caloric intake) versus a control
condition of diabetes support and education on diabetes and cardiovascular
disease and mortality. Results 4 years into the trial showed that lifestyle inter-
ventions produced substantial weight loss and improvement of cardiovascular
risk factors, including blood pressure and lipids.
5
However, the trial was halted
due to no difference in treatment effects on overall mortality. The results from
these two large trials point to some overt benefi ts of a healthy diet and rigor-
ous aerobic exercise.
At the cellular level, aerobic exercise causes contraction of skeletal muscle,
stimulating translocation of GLUT4, a glucose transporter, to the cell surface
and promoting cellular uptake of glucose. This mechanism is separate from that
of insulin on skeletal muscle. T2DM patients should be encouraged especially to
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CHAPTER 10 Therapy for Type 2 Diabetes
Table 10.1 Summary of Major Randomized Controlled Trials for Glycemic Control and Prevention in T2DM Patients
Trial Population Intervention Outcome Goal HbA1c Results
ACCORD
47
10,251 patients with
HbA1c ≥ 7.5% and high
cardiovascular risk
Intensive or standard
therapy
Intensive therapy:
HbA1c < 6%
Standard therapy:
HbA1c 7.0–7.9%
Intensive therapy: 6.4%
Standard therapy: 7.5%
Intensive medical therapy reduced 5-year
nonfatal myocardial infarctions but
increased 5-year mortality.
ADVANCE
48
11,140 patients Intensive or standard
glucose control
HbA1c ≤ 6.5%
Intense control: 6.5%
Standard control: 7.3%
10% relative reduction in macrovascular
and microvascular events but increase in
hypoglycemic episodes.
Kumamoto
49
110 Japanese patients Multiple vs.
conventional insulin
injection treatment
Reduction of
microvascular DM
outcomes
Multiple injections: 7.1%
Conventional injections: 9.4%
Multiple insulin injection therapy delays
onset and progression of microvascular
DM complications.
UKPDS-33
50
3,867 newly diagnosed
patients
Intensive sulfonylurea
or insulin therapy vs.
diet
Target FPG
< 6 mmol/L (108.1
mg/dL)
Medical therapy: 7.0%
Diet: 7.9%
Signifi cant weight gain and number of
hypoglycemic episodes with sulfonylurea or
insulin use; 12% decrease in DM end points,
especially microvascular.
UKPDS-34
51
1,704 overweight
patients
Intensive metformin
vs. diet
Target FPG
< 6 mmol/L
Metformin: 7.4%
Diet: 8.0%
Signifi cant risk reduction of 32% for diabetes-
related end point, 42% for diabetes-related
death, 36% for all-cause mortality.
VADT
52
1,791 military veteran
patients
Intensive vs. standard
therapy
Absolute HbA1c
reduction of 1.5% in
intensive group
Intensive therapy: 6.9%
Standard therapy: 8.4%
No signifi cant effect on rate of major
cardiovascular events, death, or
microvascular complication with exception
of progression of albuminuria.
FPG, fasting plasma glucose.
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