Treatment of Obesity Hypertension and Diabetes Syndrome

Maria Teresa Zanella, Osvaldo Kohlmann, Jr, Artur Beltrame Ribeiro

Abstract—Obesity has been shown to be an independent risk factor for coronary heart disease. The insulin resistance
associated with obesity contributes to the development of other cardiovascular risk factors, including dyslipidemia,
hypertension, and type 2 diabetes. The coexistence of hypertension and diabetes increases the risk for macrovascular and
microvascular complications, thus predisposing patients to cardiac death, congestive heart failure, coronary heart
disease, cerebral and peripheral vascular diseases, nephropathy, and retinopathy. Body weight reduction increases
insulin sensitivity and improves both blood glucose and blood pressure control. Metformin therapy also improves insulin
sensitivity and has been associated with decreases in cardiovascular events in obese diabetic patients. Antihypertensive
treatment in diabetics decreases cardiovascular mortality and slows the decline in glomerular function. However,
pharmacological treatment should take into account the effects of the antihypertensive agents on insulin sensitivity and
lipid profile. Diuretics and ␤-blockers are reported to reduce insulin sensitivity and increase triglyceride levels, whereas
calcium channel blockers are metabolically neutral and ACE inhibitors increase insulin sensitivity. For the high-risk
hypertensive diabetic patients, ACE inhibition has proven to confer additional renal and vascular protection. Because
hypertension and glycemic control are very important determinants of cardiovascular outcome in obese diabetic
hypertensive patients, weight reduction, physical exercise, and a combination of antihypertensive and insulin sensitizers
agents are strongly recommended to achieve target blood pressure and glucose levels. (Hypertension. 2001;38[part 2]:
705-708.)
Key Words: obesity 䡲 diabetes 䡲 drug therapy

H ypertension is very frequent among obese type 2 dia-

betic patients.1,2 In contrast with hypertension in type 1
ing in increased risk of cardiac death, coronary heart disease,
congestive heart disease, cerebrovascular disease, and periph-
Downloaded from http://ahajournals.org by on March 31, 2019

diabetes,3 hypertension in type 2 diabetes develops even
without renal involvement. The risk of type 2 diabetes and
hypertension are strongly related to obesity and central
distribution of fat.4,5 The constellation of abnormalities that
include obesity, hypertension, type 2 diabetes, and also
dyslipidemia is called metabolic syndrome. Insulin resistance
with hyperinsulinemia is characteristic of the metabolic
syndrome, and this condition has been associated with high
cardiovascular risk, morbidity, and mortality.6 Hyperinsulin-
emia may lead to hypertension and also to an abnormal lipid
profile, thereby predisposing patients to atherosclerosis. The
rise in plasma insulin levels may elevate blood pressure levels
by a variety of mechanisms, including increased sympathetic
activity and sodium retention.7,8 Obesity-induced changes in
the renal medulla, resulting in activation of the renin-angio-
tensin system, may also contribute to sodium retention and
hypertension in visceral obese subjects9
Treatment of Hypertension in
Diabetic Patients
The occurrence of diabetes and hypertension are multiplica-
tive risk factors for macro- and microvascular disease, result-
eral vascular disease.1 Macrovascular complications account
for the majority of deaths in diabetics, and absence of
hypertension is associated with increased survival.10
Because hypertension is a major determinant of cardiovas-
cular events in type II diabetes, tight blood pressure control is
a must in these patients. In fact, in type 2 diabetic patients, the
benefits of tight blood pressure control may be even greater
than the benefits of a more intensive glycemic control, as
shown in the UK Prospective Diabetes Study (UKPDS)
study.11 Nevertheless, clinicians should pursue both blood
pressure and glycemic control, as tightly as possible.
Nonpharmacological Treatment
When obese patients with diabetes present with mild hyper-
tension, nonpharmacological measures should be encour-
aged.12 Among these are body weight reduction, increased
physical activity, decrease in dietary sodium intake, cessation
of smoking, and avoidance of excess alcohol ingestion. Body
weight reduction and increased physical activity will amelio-
rate glucose control by decreasing insulin resistance. How-
ever, despite all of the apparent cardiovascular benefits
associated with weight reduction in obese patients, which

Received March 26, 2001; first decision May 11, 2001; revision accepted May 30, 2001.
From the Nephrology and Endocrinology Divisions, Hospital do Rim e Hipertensão, Federal University of São Paulo, São Paulo, Brasil.
Correspondence to Maria Teresa Zanella, Hospital do Rim e Hipertensão, Federal University of São Paulo, Rua Borges Lagoa 960, 04038-002 São
Paulo SP, Brasil. E-mail tereza.zanella@rimehipertensao.com.br
© 2001 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org

705
 706 Hypertension September 2001 Part II
include reductions in blood pressure, reductions in left
ventricular mass, and improvement in lipid profile, there is no
evidence that these changes are associated with decreases in
mortality.
Pharmacological Treatment
The choice of pharmacologic agents to treat obese patients
with hypertension and diabetes has to take into account the
effects on body weight, metabolic disturbances, and compli-
cations of diabetes and/or hypertension.
Antidiabetic Therapy
Among the oral antidiabetic agents used in type 2 diabetes,
metformin and the thiazolidinediones have been shown to
improve glucose tolerance by enhancing insulin sensitivity
and to lower blood pressure.13,14 The UKPDS study was
designed to compare the effects of intensive blood glucose
control though different treatment regimens (diet, sulfonyl-
ureas, metformin, and insulin) with conventional treatment on
the micro- and macrovascular complications of diabetes in
⬇4000 patients with type 2 diabetes.15 Over 10 years, the
average glycosylated hemoglobin was 7% in the intensive-
treated group compared with 7.9% in the conventional group.
This resulted in a 12% (P⫽0.029) reduction in any diabetes-
related end point and a 10% in any diabetes-related death
(P⫽0.34) in the intensive-treated group. Most of the risk
reduction in this group was due to a 25% risk reduction in
microvascular endpoints (P⫽0.009). There was no reduction
in macrovascular disease. A 16% decrease in myocardial
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infarction did not reach statistical significance (P⫽0.052). A
subset of 1700 overweight patients (⬎120% ideal body
weight) recruited to the UKPDS were included in a separate
treatment arm that compared intensive blood glucose control
with metformin to conventional therapy. A secondary analy-
sis compared 342 patients allocated to metformin with 951
patients receiving intensive therapy with sulfonylureas or
insulin.16 Over 10 years, the average glycosylated hemoglo-
bin was 7.4% in the metformin-treated group compared with
8.0% in the conventional group. Treatment with metformin
resulted in risk reduction of 32% in any diabetes-related end
points, 42% in diabetes-related death, and 36% in all-cause
mortality. Compared with the group on intensive therapy with
sulfonylureas or insulin, the metformin-treated group also
showed a greater reduction in any diabetes-related end point,
all-cause mortality, and stroke (P⬍0.0034). Compared with
sulfonylureas or insulin therapy, metformin therapy was also
associated with less weight gain, fewer hypoglycemic attacks,
and lower insulin plasma levels. It is not clear, however, if the
improvement in insulin sensitivity induced by metformin
confers long-term cardiovascular benefit compared with that
of other drugs that reduce blood pressure or blood glucose.
Antihypertensive Therapy
As a general rule, the most important objective is to reduce
blood pressure to as near the normal values as possible. The
goal of blood pressure in type 2 diabetes, as suggested by the
Hypertension Optimal Treatment (HOT) trial,17 should be
diastolic blood pressure of ⱕ80 mm Hg; 85 mm Hg was
shown to be less cardioprotective. Similar results have been
published in the UKPDS.18 In this latter study, 1148 patients
treated with either captopril or atenolol were randomized to a
goal blood pressure ⬍150/85 mm Hg (tight group) or ⬍180/
105 mm Hg (less-tight group). At the end of the study, blood
pressure levels in the 2 groups were 144/82 mm Hg and
154/87 mm Hg, respectively. After a follow-up of 8 to 9
years, patients in the lower blood pressure group showed a
24% reduction in diabetes-related end points, including mi-
crovascular disease; 44% less strokes; and 32% reduction in
deaths related to diabetes. They also showed 34% less
occurrence of deterioration in retinopathy compared with that
of the higher blood pressure group. It is important to stress
that 29% of patients in the tight blood pressure control group
required ⱖ3 antihypertensive drugs.
Antihypertensive Agents
ACE Inhibitors and Ang II Antagonists
This family of agents offers a number of advantages, proba-
bly reflecting a major role of angiotensin (Ang) II in the
deterioration of renal function and development of athero-
sclerosis.19,20 In type 1 diabetics, ACE inhibitors (ACE-Is)
have been proven to reduce the velocity of progression to
renal failure21 and are the only antihypertensive agents that
lower protein excretion even when blood pressure is not
lowered.19
Clinically, ACE-Is may not be sufficient to lower blood
pressure, and in addition, other antihypertensive agents may
be needed. ACE-Is have synergistic actions with diuretics and
calcium blockers. Also they have no deleterious effects on
lipid metabolism and may even lower lipid levels through the
improvement of carbohydrate metabolism.22 The mechanism
of the improvement in glucose utilization may involve in-
creases in kinin formation by ACE-I. One possible explana-
tion is that increases in blood flow induced by kinins may
influence insulin sensitivity by promoting better insulin
delivery and glucose uptake by the tissues. In normal rats, we
have demonstrated that the use of a bradykinin inhibitor may
decrease insulin sensitivity.23
A cardioprotective effect of converting enzyme inhibition
was recently shown by the Hope Study, which was designed
to asses the cardiovascular benefits of ramipril in 9297
patients, age ⱖ55 years, who had a previous cardiovascular
event or diabetes plus 1 other cardiovascular risk factor. The
primary outcome was a composite of myocardial infarction,
stroke, or death from cardiovascular causes. Over a mean
period of 5 years, the relative risk of any primary end point
was 0.78 (P⬍0.001) in the ramipril-treated group.24 In the
3577 diabetic patients without clinical proteinuria included in
this study, ramipril lowered the risk of the combined primary
outcome by 25% (P⫽0.0004), myocardial infarction by 22%
(P⫽0.01), stroke by 33% (P⫽0.074), cardiovascular death by
37% (P⫽0.0001), total mortality by 24% (P⫽0.004), and
overt nephropathy by 24% (P⫽0.027).25 The benefits of
ramipril in this study were greater than those that would be
expected from the observed effects in blood pressure. The
inhibition of Ang II formation or the increase in bradykinin
concentrations are possibly some of the mechanisms involved
in the protective effect of the ACE-I on the arterial wall.
 Zanella et al
Close monitoring of potassium levels in the blood is
warranted when patients have decreased renal function.
Hyperkalemia is a frequent cause of suspension of ACE-I in
patients with diabetic nephropathy. Diabetic patients appear
to be more prone to develop hyperkalemia probably because
of a decrease in aldosterone production.26
Blockade of the renin-angiotensin system with Ang II
blockers, from both experimental and clinical data, appear to
be equally protective as ACE-I. Ongoing clinical trials in type
2 diabetics will give us a more definite answer as to their role
in clinical practice.27
Diuretics
These agents, together with salt restriction, are most fre-
quently needed to control blood pressure in diabetic obese
patients. The association with ACE-I enhances the antihyper-
tensive effect and reduces the chances of hypokalemia that
may worsen insulin resistance.28,29 More recently, the use of
low-dose (12.5 to 25 mg) thiazide therapy has been shown to
reduce metabolic disturbances consequent to diuretic thera-
py.30 Results from the Systolic Hypertension in the Elderly
Patient (SHEP) study have shown that chlorthalidone therapy
(doses 12.5 to 25 mg) was twice as effective in preventing
cardiovascular events in diabetics than in nondiabetic hyper-
tensive patients.31 In clinical practice, it is almost impossible
to control blood pressure in diabetic patients without the use
of diuretics. Most frequently, thiazides have to be replaced by
more potent loop diuretics to control blood pressure, espe-
cially when renal damage progresses.
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␤-Blockers
Increases in insulin resistance in obese patients occur during
␤-blocker therapy.32 However, in clinical practice, ␤-blockers
are frequently used to correct tachycardia, to help lower blood
pressure, and to assist in secondary prevention of myocardial
infarction. In the UKPDS, despite being associated with
greater weight gain, atenolol was as effective as captopril in
protecting against vascular disease.33
Calcium Channel Blockers
Calcium channel blockers are very efficacious in lowering
blood pressure and are metabolically neutral for glucose and
lipid profiles. The HOT trial showed a cardiovascular protec-
tive effect of the long-acting dihydropyridine calcium blocker
felodipine.17 In this large study (⬇19 000 subjects), patients
were randomized to 3 target diastolic blood pressures:
ⱕ90 mm Hg, ⱕ85 mm Hg, and ⱕ80 mm Hg. In a subset of
1501 diabetic hypertensive patients, the relative risk of a
cardiovascular event was reduced in the ⱕ80 mm Hg group
compared with the ⱕ90 mm Hg group (relative risk, 0.49).
The placebo-controlled Systolic Hypertension in Europe
Trial (Syst-Eur Trial)34 analyzed the effect of nitrendipine in
systolic hypertension in the elderly. In the diabetic patients
(n⫽492; 10% of total patients studied), blood pressure was
8.6/3.9 mm Hg lower in the nitrendipine group than in the
placebo group. After a median follow-up of 2 years, active
treatment reduced cardiovascular events by 69%, cardiovas-
cular mortality by 76%, and overall mortality by 55%. These
reductions were greater than those observed in the nondia-
betic patients in the study. However, according to the results
Obesity, Hypertension, and Diabetes 707
of Fosinopril Amlodipine Cardiovascular Events Trial
(FACET) and Appropriate Blood Pressure Control in Diabe-
tes (ABCD) clinical trials,35,36 calcium channel blockers do
not appear to be as protective against coronary disease as
ACE-Is.
Because high blood pressure levels are important determi-
nants of cardiovascular outcomes in obese diabetic hypertensive
patients, a more strict control of blood pressure is strongly
recommended. In diabetic patients with normal renal function,
goal systolic blood pressure should be ⬍130 mm Hg; a goal
diastolic blood pressure, ⬍85 mm Hg.3,19 –21 However, if pa-
tients have renal insufficiency and excrete ⬎1 to 2 grams
protein/24 hours, goal blood pressure control should be 120/
75 mm Hg.22 For renal and vascular protection of the hyperten-
sive diabetic patients, the blockade of the renin-angiotensin
system seems to be important. Because poor glycemic control
has proven to contribute to vascular lesions, for the insulin
resistant obese patients, the administration of insulin-sensitizer
agents are preferred. The goal of therapy should be the reduction
of glycosylated hemoglobin to values ⬍7% when the upper limit
of the method of determination is near 6%. Because these targets
are difficult to achieve, body weight reduction, physical exer-
cise, and a combination of several antihypertensive and antidi-
abetic agents are usually necessary.
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