Full text of DOI:10.2165/00003495-200262020-00004

Drugs 2002; 62 (2): 285-307
0012-6667/02/0002-0285/$27.50/0
REVIEW ARTICLE
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Treatment of Heart Failure in Patients
with Diabetes Mellitus
Steven J. Lavine and Steven D. Gellman
Harper Hospital, Wayne State University, Detroit, Michigan, USA
Contents
Abstract
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285
1. Pathophysiology of Congestive Heart Failure (CHF) . . . . . . . . . . . . . . . . . . . . . . . . . . . 287
1.1 Definition and Terms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287
1.2 Mechanisms of Left Ventricular (LV) Dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . 288
1.3 Precipitants of CHF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290
2. Diagnosis and Evaluation of Patients with CHF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290
2.1 History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290
2.2 Physical Examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290
2.3 Diagnostic Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291
3. Cardiomyopathy and CHF in Patients with Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . 291
3.1 Diabetes, Hypertension and Cardiovascular Morbidity and Mortality . . . . . . . . . . . . . . 292
3.2 Independent LV Dysfunction in Patients with Diabetes . . . . . . . . . . . . . . . . . . . . . . 292
3.3 Experimental Evidence of Diabetes-Induced LV Dysfunction . . . . . . . . . . . . . . . . . . 293
3.4 The Issue of Calcium Overload . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293
3.5 Ischaemia and Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294
3.6 Insulin Reversibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294
3.7 Glycaemic Control and LV Dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295
4. Management of CHF in Patients with Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297
4.1 Goals of Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297
4.2 Pharmacological Therapy of CHF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298
4.2.1 Inotropic Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298
4.2.2 Diuretics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299
4.2.3 Vasodilators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 300
4.2.4 Angiotensin Converting Enzyme Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . 300
4.2.5 Angiotensin II Receptor Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301
4.2.6 Aldosterone Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301
4.2.7 β-Blockers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301
4.2.8 Calcium Channel Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302
4.3 Therapy of CHF in Patients with Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302
4.4 Pitfalls in Therapy of CHF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302
5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303
Patients with diabetes mellitus have an increased morbidity and mortality from
Abstract
cardiovascular disease. Both coronary artery disease and congestive heart failure
(CHF) are largely responsible for the increased cardiovascular adverse events in
patients with diabetes.
This review discusses the pathophysiology of CHF, the mechanisms of left

286
Lavine & Gellman
ventricular (LV) dysfunction and the neurohormonal mechanisms involved in
both LV dysfunction and CHF. Diabetes with and without hypertension is an
important cause of LV dysfunction and CHF. Diabetes may be responsible for
the metabolic and ultrastructural causes of LV dysfunction, while hypertension
may be responsible for the marked fibrotic changes that are found. Experimental
induction of diabetes in animals has shed light on the biochemical and ultrastruc-
tural changes seen. The role of insulin to reverse both metabolic and structural
changes is reviewed both from experimental data and with the limited amount of
clinical data available.
The therapy of CHF in patients with diabetes is similar to that of patients
without diabetes, with therapy directed toward the use of β-blockers and angio-
tensin converting enzyme (ACE) inhibitors. As the morbidity and mortality are
higher in patients with diabetes, several studies have pointed out the importance
of this subgroup where the opportunity to make a significant clinical impact
exists. A significant opportunity exists to reduce morbidity and mortality with
β-blockers and ACE inhibitors when ischaemia and CHF are both present. How-
ever, studies in patients diabetes have been limited to post hoc subgroup analyses
and rarely as predefined subgroups. Clinical trials involving patients with diabe-
tes with and without hypertension and LV dysfunction are clearly needed in the
future to adequately address the needs of this high risk subgroup.
Patients with diabetes mellitus have an in-
dysfunction termed diabetic cardiomyopathy that
may lead to overt CHF.[10-12] Consequently, in the
presence of comorbid conditions such as coronary
disease or valvular disease, diabetes may also ad-
versely affect the performance of the left ventricle
and contribute to the development of CHF.[1-4] The
high incidence of hypertension in patients with di-
abetes may place them at greater risk for coronary
events and CHF[13] as the incidence and amount of
LV hypertrophy is greater in patients with diabetes
than in patients with hypertension alone. Further-
more, there may be a predilection for increased se-
verity of CHF in women with hypertension and
diabetes,[14] especially in patients who are glucose-
intolerant.[15] Experimentally, in models of com-
bined hypertension and diabetes, there is evidence
of marked fibrosis, interstitial glycoprotein depo-
sition and capillary microaneurysms which have
similarities to human disease.[11,12,16] The combi-
nation of diabetes and hypertension may have dev-
astating effects on the myocardium with hyperten-
sion being responsible for myocardial damage and
diabetes responsible for myocardial cell dysfunc-
tion.[17-19]
creased morbidity and mortality from cardiovascu-
lar disease, especially women who have a risk that
is twice as great as men.[1-4] Specifically, after
myocardial infarction (MI) there is greater left ven-
tricular (LV) dysfunction despite similar infarct
size but infarcts also tend to be larger. The inci-
dence of overt congestive heart failure (CHF) in
patients with similar sized infarcts is greater for
patients with diabetes than for those without.[5-8]
Consequently, in patients with diabetes (a subset
with a higher risk) therapy with angiotensin con-
verting enzyme (ACE) inhibitors offers the oppor-
tunity to increase the myocardial salvage rate and
reduce morbidity after infarction.
In the presence of hypertension and diabetes, the
incidence of LV dysfunction is substantially in-
creased, as is chronic renal insufficiency, which
further increases the morbidity and mortality.[9] As
hypertension and diabetes are important risk fac-
tors for coronary and vascular disease, patients
with diabetes often have concomitant coronary dis-
ease, previous MIs and pre-existing LV dysfunc-
tion. In addition, there exists an independent LV
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Heart Failure in Patients with Diabetes
287
Table I. Aetiologies of heart failure
1. Pathophysiology of Congestive
Heart Failure (CHF)
Myocardial failure
Ischaemic heart disease
Infiltrative diseases (amyloidosis, haemochromatosis)
Inflammatory (myocarditis)
Toxic (chemotherapy)
1.1 Definition and Terms
CHF has been variably defined in a multitude
of reviews. A simple definition proposed in the
1960s was the heart’s inability to pump sufficient
cardiac output to meet the body’s metabolic de-
mands. The compensatory mechanisms called into
action to the meet the body’s metabolic needs lead
to the symptoms, signs and ultimate poor progno-
sis of patients with CHF. CHF has also been clas-
sified into right- or left-sided CHF, and systolic or
diastolic heart failure. The term ‘circulatory con-
gestion’ has been applied to the clinical circum-
stance where cardiac output may be adequate and
there is fluid overload with pulmonary congestion
and/or oedema. The aetiologies of CHF are listed
in table I.
Cardiomyopathy
Valvular
Aortic stenosis or regurgitation
Mitral regurgitation
Mitral stenosis (pulmonary congestion and right heart failure)
Congenital
Pressure overload resulting in right or left ventricular dysfunction
valvular stenosis
conduit stenosis
Volume overload resulting in left or right ventricular dysfunction
valvular regurgitation
left to right shunts with left or right atrial and left ventricular
volume overload
patent ductus arteriosus
ventricular septal defect
atrial septal defect
Although CHF can be conveniently divided into
left- and right-sided failure, these manifestations
of CHF are parallel events more often than serial
events. Traditional teaching has concentrated on
symptoms of left-sided heart failure preceding
manifestation of right-sided failure as two discrete
events in the natural history of CHF. Symptoms of
left-sided failure may coexist early on with mani-
festations of right-sided failure. Traditionally, a
haemodymamic explanation is offered in that left-
sided failure leads to pulmonary congestion with
elevated pulmonary artery pressure and subse-
quent right-sided heart failure. However, neuro-
hormonal adaptations are called into play leading
to salt and fluid retention, circulatory congestion
and leg oedema: a manifestation of right-sided
heart failure. The situation is complicated by coex-
istent right ventricular dysfunction in dilated car-
diomyopathy. The end result is that there is a blend
of both right- and left-sided manifestations of CHF
in any given patient, and these manifestations de-
pend on the aetiology, the degree of neurohormo-
nal stimulation and right ventricular performance.
More recently, the terms systolic and diastolic
heart failure have been used. Systolic failure refers
to significant left or right ventricular dysfunction
single ventricle, tricuspid atresia
Rhythm disorders
Rapid ventricular response to atrial fibrillation or flutter
Atrioventricular block with slow ventricular escape
Pacemaker (VVI)
Slow and persistent ventricular tachycardia
Pericardial
Constrictive pericarditis
associated with symptoms and signs of left- or
right-sided failure or both. Diastolic dysfunction
has applied to the situation where patients have no
evidence of significant LV systolic dysfunction but
have signs of pulmonary congestion with or with-
out right-sided manifestations. Impedance to LV
filling caused by prolonged relaxation and in-
creased myocardial stiffness occurs in the setting
of coronary artery disease, hypertension, diabetes
and restrictive cardiomyopathy, and is the pur-
ported cause of pure diastolic dysfunction. A
marker for abnormal relaxation may be the trans-
mitral Doppler flow pattern (figure 1) of E to A
reversal. Diastolic dysfunction coexists with sys-
tolic dysfunction, and is manifested by an abnor-
mal pattern of diastolic filling with increased rate
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Lavine & Gellman
and extent of rapid filling, decreased atrial filling
and an increased rate of rapid filling decline. This
pattern may appear normal (pseudonormalised) or
have the appearance of reduced atrial filling
(termed restrictive filling) with both representing
milder and more significant degrees of elevated LV
filling pressures.[20]
Circulatory congestion has been seen in the set-
ting of hyperthyroidism, severe anaemia and fluid
overload (dialysis, postoperative fluid replace-
ment). There is the implication that LV systolic
function is not significantly impaired, although
cardiac output may not be sufficiently high to meet
the body’s metabolic demands. Fluid overload as a
cause of circulatory congestion occurs often in the
setting where the ability to excrete the excess vol-
ume is impaired. Over-vigorous fluid replacement
postoperatively or missed dialysis are prime exam-
ples.
1.2 Mechanisms of Left Ventricular
(LV) Dysfunction
Table II lists the mechanisms associated with
LV dysfunction. These mechanisms have been in-
vestigated both in experimental diabetic and non-
diabetic animals as noted in table II. Cellular adap-
tations include alterations in myocardial blood
flow that may be matched to myocardial oxygen
consumption. In the hypertrophied failing myocar-
dium, there are increased intercapillary distances,
raising the question of ischaemia. This may be of
even greater importance in the scarred ventricle in
patients with coronary disease and/or diabetes. Mi-
tochondrial function may be normal or impaired
depending on the experimental model used and the
stage of CHF in the model. Adenosine triphosphate
(ATP) content, production and turnover may be
normal or variably decreased in patients with CHF.
Alteration of contractile proteins with reduced
ATPase activity has been seen in the rat, as a result
of a change in the myosin isoform which is induced
by diabetes. Similar changes have not been noted
in the human heart.
In patients with increasing LV dysfunction and
CHF there is stimulation of the sympathetic nerv-
ous system and elevation of catecholamine levels
leading to alterations in adrenergic modulation of
myocardial function. Consequently, there is
desensitisation to adrenergic drive and a resultant
down regulation of the myocardial β1-adrenergic
receptor. Furthermore, there is a preponderance of
inhibitory G proteins in the failing heart reducing
cyclic adenosine monophosphate (cAMP) genera-
tion from adrenergic receptor stimulation.[20,21] In
addition, altered myofibrillar calcium responsive-
ness may be responsible for altered contraction
coupled with inadequate calcium removal. Re-
duced calcium uptake by the sarcoplasmic reticu-
lum may lead to reduced calcium release.[22,23]
Alterations in LV chamber and myocardial func-
tion have been well studied, especially with regard
to volume or pressure overload stress. Examination
of a family of Frank Starling curves (figure 2)
demonstrates that with reduced LV contractility
and compensatory LV dilatation, systolic wall
100
80
60
40
20
0
Normal
Abnormal Restrictive
relaxation
Pseudo-
normal
Fig. 1. Normal and abnormal diastolic filling curves obtained
from transmitral pulsed Doppler are demonstrated. Abnormal
filling curves may be an expression of abnormal relaxation (E
to A reversal), an expression of abnormal chamber compliance
(restrictive filling pattern), or combinations of both (pseudonor-
mal filling pattern). Both the restrictive filling pattern and
pseudonormal filling pattern are associated with increased left
ventricular filling pressures.
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Heart Failure in Patients with Diabetes
289
Table II. Mechanisms associated with left ventricular dysfunction
rhythmias and increase mortality. The renin angio-
tensin system is also activated early in the course
of progressive LV dysfunction. Elevated angioten-
sin levels lead to myocardial hypertrophy, intersti-
tial fibrosis, LV dilatation, increased arterial resis-
tance and are a major contributor to progressive
LV dysfunction after MI.[25-28] Because of eleva-
tion of angiotensin, aldosterone is also elevated,
which contributes to interstitial fibrosis, and potas-
sium excretion and depletion. Other peptides (table
II) are activated during progressive LV dysfunc-
tion and can be categorised as vasodilatory,
natiuretic and antimitogenic, or vasoconstrictor,
antinatiuretic and mitogenic.[29-37]
With chronic CHF, there is abnormal reflex
control of the circulation. Blunting of cardiac and
arterial baroreceptor responsiveness and its inhibi-
tion results in increased sympathetic output and
increased angiotensin levels.[38] Abnormalities in
atrial stretch receptors and abnormalities in neuro-
transmitter synthesis, storage and release are also
present. Sodium and fluid retention in patients with
Cellular and Molecular
Nutritive blood flowa
Mitochondrial functiona,b
Energy reservea,b,c
Myofibrilsa,c
Adrenergic receptorsa,b,c
G Proteinsa,b,c
Calciuma,b,c
Remodellinga,b
Neurohormonala,b
Heightened sympathetic nervous activity
Renin angiotensin system and aldosterone
Vasodilatory, natiuretic, antimitogenic peptides
atrial and brain natiuretic factors
nitric oxide
Vasoconstrictive, antinatiuretic, mitogenic peptides
angiotensin II
endothelin
cytokines (tumour necrosis factor)
Other - arginine vasopressin, adrenomedullin, growth hormone
Abnormal reflex controla,b
Disturbances in sodium and water balancea,b
a
b
c
Animal data, nondiabetes.
Human data, nondiabetes.
Animal data, diabetes.
stress increases, which serves as a positive feed-
back loop leading to a further decline in LV sys-
tolic performance. Over time, a process of chamber
remodelling occurs with resultant chamber dilata-
tion, hypertrophy, increased collagen, and intersti-
tial and myocardial fibrous deposition. Myocardial
cell slippage, myocyte necrosis, myocyte apopto-
sis (programmed cell death) and other ultrastruc-
tural changes occur associated with remodelling.
Neurohormonal changes with progressive LV
dysfunction are both a marker and a contributor to
the LV dysfunction and CHF process. Peripheral
noradrenaline (norepinephrine) levels in patients
with CHF are elevated and the level of elevation
correlate with survival.[24] Catecholamines support
the circulation during acute CHF by increasing
heart rate, blood pressure, and both arterial and ve-
nous tone. These processes may become deleteri-
ous if chronic as they increase myocardial oxygen
demand, result in myocyte necrosis, produce ar-
Normal LV function
Congestive heart failure
Compensated heart failure
LV end diastolic volume or pressure
Fig. 2. A family of Frank Starling curves are depicted. The y axis
can be represented by stroke volume, stroke work, or other
ventricular output variables. The x axis can be represented by
end diastolic fibre length, end diastolic volume or pressure, or
other input variables.
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Lavine & Gellman
Table III. Precipitants of congestive heart failure
CHF is well known, and therapeutic efforts are
aimed at maintaining fluid balance. Reductions in
glomerular filtration and renal blood flow result in
vasoconstriction and sodium retention.[39] Com-
pensatory mechanisms to maintain the glomerular
filtration rate include angiotensin II and aldoste-
rone production resulting in vasoconstriction and
sodium retention. Long-term, renal blood flow will
remain depressed and with marked neurohormonal
stimulation will lead to more water retention as a
result of arginine vasopressin excretion.[29] The re-
lease of these vasoconstrictor peptides results in
some production of the vasodilatory peptides but
the vasoconstrictor influences overwhelm the vas-
odilatory factors.
Pharmacological
Negative inotropic agents
antiarrthymics
calcium channel antagonists
β-blockers
Sodium retaining drugs
Systemic diseases
Anaemia
Thyroid disease
Systemic infection
Ischaemia
Nephropathy
Hemodynamic stresses
Tachycardia; (e.g. atrial fibrillation)
Bradycardia
Hypertension
Patient noncompliance
Medication
1.3 Precipitants of CHF
Salt restriction
Table 3 outlines common precipitants of CHF
and causes of acute decompensation in patients
with pre-existing chronic CHF. An often over-
looked cause of decompensation is noncompliance
with a prescribed medical regimen. These include
salt restriction, medication use and use of alcohol
and drugs (e.g. cocaine) that depress LV systolic
function. Inappropriate medications that promote
fluid retention (e.g. nonsteroidal anti-inflammatory
agents) or with overt negative inotropic properties
(e.g. profanenone, calcium channel antagonists)
are important precipitants. Efforts should be made
to exclude systemic diseases including anaemia,
thyroid disease and infection. In patients with dia-
betes, declining renal function may lead to fluid
retention and pulmonary congestion. Silent myo-
cardial ischaemic events and rapid atrial fibrilla-
tion may be important precipitants in the patient
with diabetes. Haemodynamic factors including
excessive tachycardia, bradycardia and severe hy-
pertension should be sought.
Alcohol or other toxin use
2.1 History
Left-sided symptoms include dyspnea on exer-
tion, orthopnea, paroxysmal nocturnal dyspnea, fa-
tigue, and nocturia. Right-sided symptoms include
leg oedema, fatigue, and abdominal pain and bloat-
ing. Each of these symptoms are not specific for
CHF and can be found in other disease states that
can complicate the diagnosis and care of patients
by being important comorbid conditions. The ex-
tent of each of these symptoms may depend on
whether right- or left-sided CHF is predominant.
Symptoms of fatigue are common and may be
caused by low output, but can also be caused by
fluid and electrolyte disturbances from diuretic
therapy. Most symptoms are related to low cardiac
output, and pulmonary or systemic venous conges-
tion.
2.2 Physical Examination
2. Diagnosis and Evaluation of
Patients with CHF
Findings can be categorised into left-sided find-
ings [presence of an S3, displaced point of maximal
impulse (PMI), mitral regurgitant murmur and pul-
monary crackles on auscultation, or peripheral
hypoperfusion] or right-sided findings (elevated
The presenting history, physical examination
and diagnostic testing in patients with symptoms
and signs suggesting heart failure are similar in
both patients with and those without diabetes.
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Heart Failure in Patients with Diabetes
291
jugular venous pressure, tricuspid regurgitant mur-
mur, hepatomegaly, ascites or oedema). Some
physical findings may be related to the underlying
aetiology of CHF. The vital signs may provide in-
formation in that the heart rate may be excessively
fast with decompensation or slow because of atrio-
ventricular block or another cause. Blood pressure
may be excessively elevated with uncontrolled hy-
pertension or low with overdiuresis or excessive
use of vasodilators. However, oedema can be sec-
ondary to venous insufficiency, liver failure and
nephrotic syndrome (in diabetes) related to albu-
minuria in the nephrotic range.
may be associated with systolic dysfunction and
has been correlated with elevated LV filling pres-
sures, low output and a poor prognostic finding.[20]
Cardiac catheterisation may need to be performed
to assess valvular or ischaemic disease with an
view to correction. Critical aortic stenosis, severe
mitral stenosis and ischaemic LV dysfunction are
important reversible causes of CHF, which can be
identified and eliminated.
Individual clinical criteria alone may not be suf-
ficient to make the diagnosis of CHF. Framing-
ham, Boston and Duke criteria[41,42] have been de-
veloped which combine history, physical
examination and chest radiography into an index
to make the diagnosis of CHF.
2.3 Diagnostic Testing
Laboratory testing should include complete
blood count, serum electrolytes and magnesium,
assessment of renal and hepatic function and, if
indicated, thyroid testing. Assessment of risk fac-
tors for coronary artery disease, including lipids
and glycaemic control in patients with diabetes
should also be performed. A chest radiograph should
be reviewed for cardiac silhouette size, assessment
of pulmonary vasculature and for pleural effusions
or other lung disease. An electrocardiogram should
be performed assessing LV hypertrophy, infarc-
tion, myocardial ischaemia, conduction system
disease and arrythymias. Assessment of LV sys-
tolic and diastolic function and valvular or pericar-
dial disease can be evaluated by two-dimensional
echocardiography and Doppler or radioventric-
ulography (to assess LV function).
3. Cardiomyopathy and CHF in
Patients with Diabetes
Cardiomyopathy has been classified by the
World Health Organization as dilated, hypertro-
phied, restrictive (amyloid), arrhythmogenic right
ventricular dysplasia, and unclassified. Dilated
cardiomyopathy has multiple aetiologies but these
aetiologies can be conveniently categorised into
ischaemic and nonischaemic. Dilated cardiomyop-
athy is associated with left and/or right ventricular
dilatation, elevated LV filling pressures and sys-
tolic dysfunction. Diastolic abnormalities (figure
1) are common and can run the gamut from abnor-
malities of relaxation to abnormalities of chamber
compliance with variable diastolic filling patterns
Table IV outlines the causes of LV dysfunction.
Ischaemic disease is the predominant cause (>50%)
with idiopathic dilated cardiomyopathy being the
cause in an additional 15 to 20% of patients. It is
important to remember that systolic measurements
of LV function may only loosely correlate with
symptoms of dyspnea or exercise tolerance. A full
one-third of patients with CHF have normal sys-
tolic function[40] and are assumed to have diastolic
dysfunction with slowed relaxation. The actual
mechanisms involved have been poorly elucidated.
More severe diastolic dysfunction, consisting of
the pseudonormal and restrictive filling pattern,
Table IV. Aetiologies of left ventricular dysfunction and heart failure
Ischaemic
Valvular
Hypertension
Myocarditis
Viral
Nonviral
HIV
Tachycardia
Alcohol
Diabetes mellitus
Metabolic
Amyloidosis and other infiltrative diseases
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Lavine & Gellman
(abnormal relaxation, pseudonormal or restric-
tive).
LV systolic and diastolic dysfunction have been
noted in patients with type 1 (insulin-dependent)
diabetes mellitus and to a lesser extent in type 2
(noninsulin-dependent) diabetes mellitus, as char-
acterised by a subnormal ejection fraction[48] and
stroke volume,[49] responses to exercise, abnormal
systolic time intervals[50,51] and resting ejection
fractions, and abnormal diastolic function as char-
acterised by an abnormal relaxation filling pat-
tern.[52-55] Diastolic dysfunction (abnormal relax-
ation) is more common and occurs earlier than
systolic dysfunction.[56] Exercise-induced LV dys-
function early in the course of diabetes may be as
a result of the defective and blunted recruitment of
the SNS and impaired sympathetic nervous system
stimulation. This has been demonstrated by PET
(positron emission tomography) scanning with re-
duced MIBG (I-meta-iodobenylguanidine) uptake.
Diabetes has also been implicated in the devel-
opment of significant clinical LV dysfunction in
the absence of coexisting disease processes that
may result in LV dysfunction. Evidence of myo-
cardial hypertrophy, focal areas of fibrosis, capil-
lary microaneurysms and deposition of interstitial
glycoprotein have been reported in patients with
diabetes and CHF without coexisting hypertension
or coronary artery disease.[10,57]
Evidence of systolic or diastolic dysfunction ap-
pears to be related to the duration of diabetes,[54]
the presence of microvascular disease,[53-55] and
autonomic dysfunction.[58] In children with diabe-
tes for an average duration of 5.9 years, prolonga-
tion of LV relaxation was associated with a longer
disease duration and poor control of diabetes.[59]
Conversely, in a study of patients with type 1 and
type 2 diabetes, there was an inverse relationship
between late diastolic filling and glycolated haemo-
globin, and a direct relation between glycolated
haemoglobin, age and early diastolic filling. How-
ever, early diastolic filling was depressed in pa-
tients with type 2 diabetes. Many patients in this
study had autonomic neuropathy.[60] The influence
of autonomic neuropathy was addressed in a study
of 36 patients (24 with type 1 diabetes) of which
12 had neuropathy, 12 did not and 12 were aged-
Cardiomyopathy in patients with diabetes can
present in a variable fashion. As hypertension often
coexists with diabetes, presentations may have el-
ements of dilated, hypertrophied or even restrictive
types of cardiomyopathy depending on the extent
of LV hypertrophy, fibrosis, dilatation and systolic
dysfunction. Unusual causes of CHF associated
with diabetes include acromegaly and haemo-
chromatosis (cardiomyopathy).
3.1 Diabetes, Hypertension and
Cardiovascular Morbidity and Mortality
The combination of hypertension and diabetes
clinically presents additive risks to patients. The
incidence of CHF is substantial in patients over the
age of 65 years, being at least 40%. As hyperten-
sion and MI are important additional causes of
CHF in patients with diabetes, the value of calcium
channel antagonists and ACE inhibitors has been
studied in four trials. The Appropriate Blood Pres-
sure Control in Diabetes (ABCD) trial[43] demon-
strated fewer moderate or severe events with ACE
inhibitors compared with calcium channel antago-
nists. The importance of addressing blood pressure
lowering in patients with diabetes is well illustrated
in the Systolic Hypertension in Europe (SYS-
EUR) study[44,45] where patients with diabetes
demonstrated a 55% and 73% reduction in mortal-
ity and total events (including MI and CHF) com-
pared with 26% and 38% in patients without dia-
betes. Similarly, in the Hypertension Optimal
Treatment (HOT) study,[46] blood pressure lower-
ing demonstrated reduced mortality in a subgroup
of patients with diabetes. In the UK Prospective
Diabetes Study (UKPDS),[47] more intensive blood
pressure lowering resulted in fewer morbid events
(24%) and lower mortality (32%).
3.2 Independent LV Dysfunction in
Patients with Diabetes
Clinically, independent LV dysfunction associ-
ated with diabetes has been termed ‘diabetic car-
diomyopathy’. Clinical and subclinical evidence of
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Heart Failure in Patients with Diabetes
293
matched controls. The patients with autonomic
neuropathy had reduced exercise tolerance and re-
duced early diastolic filling.[61] Mechanisms ex-
perimentally that have been cited to be responsible
for the abnormal systolic and diastolic function in-
clude abnormalities of glucose and fatty acid trans-
port, intracellular calcium overload, coronary
microangiopathy, interstitial and perivascular fi-
brosis, and autonomic neuropathy. In addition, en-
dothelial dysfunction, advanced end-stage glyca-
tion products, decreased nitric oxide, reduced
autoregulation and diffuse atherosclerosis all lead
to reduced myocardial contraction efficiency.
dependent stimulation of adenyl cyclase was re-
duced.[69] Diabetic (rat) hearts have a decreased
ability to regulate ATP synthesis, which was asso-
ciated with decreased relaxation.[70]
3.4 The Issue of Calcium Overload
These functional alterations in the rat were as-
sociated with alterations in intracellular calcium
homeostasis. In addition, the sarcolemmal and the
sarcoplasmic reticular calcium transporters have
been found to be depressed.[71] Consequently,
cytoplasmic calcium content may be increased and
the calcium outward current altered resulting in
prolonged action potential duration and increased
myocardial stiffness.[72] However, work in isolated
diabetic myocytes have noted that resting intracel-
lular calcium may not be increased. Although re-
sponses to isoproterenol were abnormal in resting
and electrically-stimulated diabetic myocytes, di-
rect calcium activators produced a normal twitch
response.[73,74] Although there may be some con-
troversy as to whether intracellular calcium was
increased, there was a reduction in calcium sensi-
tivity as a result of shifts in myosin light chains and
troponin I sensitivity.[71]
The importance of calcium overload as a cause
of cardiac muscle dysfunction has been evaluated
in diabetic (rat) hearts without addressing insulin
deficiency and hyperglycaemia. Inhibition of al-
dose reductase, which blocks the over-utilised polyol
pathway, improved relaxation rates in diabetic
papillary muscles. The mechanisms of action may
be related to improvement in defective calcium
handling by the sarcoplasmic reticulum[67] and a
reduction in protease (which damage myocardial
cells) release. Hyperglycaemic diabetic rats treated
with verapamil demonstrated improved indices of
LV contraction and relaxation, increased myosin
ATPase levels and reduced ultrastructural distor-
tion compared with untreated diabetic rats.[75]
Microvascular spasm has been suspected as an
aetiological factor in the interstitial, arteriolar and
capillary alterations seen in diabetes and in cardio-
myopathy.[11,12,76,77] Verapamil has been demon-
strated to slow the rate of cardiomyopathy and
3.3 Experimental Evidence of
Diabetes-Induced LV Dysfunction
Experimental diabetes mellitus has been in-
duced by sequential injections of alloxan or
streptozotocin into dogs, rats, rabbits and pigs.
Regan[62,63] evaluated LV functional responses
to afterload (angiotensin infusion) and preload
(volume) challenges in dogs 9 to 11 months after
diabetes was induced. These diabetic dogs demon-
strated a marked increase in LV end diastolic pres-
sure for small volume or systolic pressure incre-
ments suggesting abnormal LV chamber stiffness
despite normal systolic function. These functional
responses were associated with an altered compo-
sition of the myocardium consisting of increased
triglycerides, cholesterol and interstitial glycopro-
tein [periodic acid-Schiff (PAS)+].
Data from streptozotocin-induced diabetes mel-
litus in rats demonstrated abnormal relaxation,
stiffness and abnormal systolic function in the pap-
illary muscles of diabetic rats.[64-67] These func-
tional alterations were associated with a predomi-
nance of the myosin subtype V3 which has reduced
calcium ATPase activity,[66-68] reduced calcium
uptake by the sarcoplasmic reticulum (ATPase-
dependent) and increased calcium content of the
cytoplasm.
Experimental diabetes has also been produced
in pigs where decreased catecholamine respon-
siveness has been noted. β-receptor density was
normal but receptor-dependent and G protein-
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294
Lavine & Gellman
myocytolysis in the Syrian hamster, presumably by
reducing microvascular spasm.[76] The hyperten-
sive diabetic rat also demonstrates histological fo-
cal areas of spasm and patchy interstitial fibrosis
suggesting that widespread microvascular spasm
plays an important role in the pathogenesis of the
hypertensive diabetic cardiomyopathy seen in
rats.[11-12]
3.6 Insulin Reversibility
Prevention or partial prevention of systolic and
diastolic dysfunction can be demonstrated with in-
sulin therapy in experimental diabetes in the rat.
Prevention of these functional changes are associ-
ated with near normalisation of the levels of myo-
sin calcium ATPase, normalisation of the myosin
subtype, and a near normal collagen content of the
myocardium and arterioles.[66,82-84] These changes
appear to correlate with the plasma glucose level.[85]
Insulin also influences calcium homeostasis with
normalisation of sarcolemmal and sarcoplasmic
reticulum-dependant calcium uptake,[18] and normal-
ised glucose transport rates.[86,87] Using isolated
myocytes from severely diabetic rats, Ren and
Davidoff[88] demonstrated prolongation of contrac-
tion and relaxation as early as 4 to 6 days after
induction of diabetes, which was reproduced in
normal cultured rat myocytes exposed to a diabetes-
like serum.[89] These isolated myocyte findings
suggest rapid onset of myocardial dysfunction
which may be amenable to reversibility with
normalisation of glucose levels.
Compositional changes can also be reversed
with insulin therapy. The increased interstitial and
perivascular deposition of extracellular matrix can
be prevented when insulin therapy is begun within
3 days after the induction of diabetes in the rat and
only partially reversed (33% improvement) if insu-
lin therapy is delayed 12 weeks.[80] Finally, diabe-
tes also increases the presence of free radicals,
which may contribute to myocardial damage and
dysfunction. This increase was reversed with an
antioxidant, which improved LV performance in
the diabetic rat.[90]
3.5 Ischaemia and Diabetes
Experimentally, diabetes also sensitises the
myocardium to ischaemic insults. Diabetic rats
without ketosis demonstrated a greater reduction in
systolic function with coronary hypoperfusion than
nondiabetic rats.[52] Similarly, coronary ischaemia
produced by balloon inflation of the left anterior
descending artery in dogs with induced diabetes
resulted in reduced LV compliance compared with
nondiabetic dogs. Stroke volume and stroke work
were also reduced in the diabetic dogs. These ab-
normalities in diastolic function may be related to
the interstitial glycoprotein deposition which prob-
ably contributes to increased diastolic stiffness.[78]
In experimental diabetes in the rat, morphologic
changes were often absent but heart weight as a
function of bodyweight was increased. The volume
of extracellular components increased three-fold
and the volume of capillaries fell, resulting in in-
creased oxygen diffusion distance to mitochondria,
increasing the potential for ischaemia.[79] Myofib-
ril volume also fell[80] and advanced glycosylation
end products of collagen increased resulting in a
stiff ventricle.[81]
Clinically, there is excess mortality with coro-
nary artery disease, MI and CHF in patients with
diabetes. Noninfarcted myocardium appears to
have reduced compensatory ability, which may be
related to coronary artery disease, reduced vas-
odilatory reserve and abnormal metabolism of
myocardial substrate. Reinfarction and recurrent
events are more common in patients with diabetes.
Finally, ischaemia is less well tolerated. Overt sys-
tolic dysfunction occurs late in the course of dia-
betes and is associated with advanced microvascu-
lar complications and hypertension.
Reversibility of abnormal LV function in dia-
betic dogs was somewhat less complete. Pogatsa et
al.[64] demonstrated that induced diabetes mellitus
in the dog resulted in an increased thermostability
of collagen without other histologic changes. Insulin-
treated diabetic dogs still demonstrated some in-
crease in diastolic stiffness which was intermediate
in level between healthy control dogs and untreated
dogs with diabetes. However, the degree of revers-
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Heart Failure in Patients with Diabetes
295
ibility of systolic and diastolic functional changes
may be related to the extent of histologic changes.
microvascular ischaemia and LV infarction. Eight
weeks after embolisation, dogs have a dilated left
ventricle with moderate LV dysfunction, increased
LV mass and increased LVEDP. Histopathology
(figure 3) revealed diffuse but patchy fibrosis (re-
placement-fibrosis) emanating from microsphere
occluded arterioles in the perivascular interstitial
areas are found in all levels of the myocardium.[91]
As this model of LV dysfunction shares some
histological characteristics of human diabetic car-
diomyopathy, we combined this model of LV dys-
function with the canine model of diabetes of
Regan et al.[62,63] We determined the effect of ex-
perimentally induced diabetes mellitus at different
levels of glycaemic control on LV systolic and di-
astolic function by inducing diabetes in 7 dogs
(with previously induced LV dysfunction) and ad-
3.7 Glycaemic Control and LV Dysfunction
Although the role of glycaemic control in the
healthy left ventricle has importance, patients with
diabetes often have concomitant hypertension,
coronary artery disease and LV dysfunction. There
are no clinical studies to date that can answer this
important question. An animal model of both type
1 diabetes and LV dysfunction was used to examine
the relationship between glycaemic control and LV
function. In our animal laboratory, we have used a
canine model of chronic ischaemic LV dysfunc-
tion. In this model, 50 micron occlusive micro-
spheres were injected in sequential dosages into
the left main coronary artery resulting in diffuse
Fig. 3. A haematoxylin and eosin (low and high power) stain of myocardium with a microsphere in the field with interstitial and
myocardial fibrosis (pale area) distributed in a patchy fashion throughout the myocardium.
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Lavine & Gellman
justing daily insulin dosages to achieve ‘poor
glycaemic control’ (250 mg/dl to 400 mg/dl; 6.5 to
10.3 mmol/L) for 3 months followed by ‘good
glycaemic control’ (100 mg/dl to 150 mg/dl; 2.6 to
3.9 mmol/L) for the next 3 months. After 3 months
of ‘poor glycaemic control’ (figure 4), LV size and
LV end diastolic pressure increased and LV sys-
tolic performance declined. After three additional
months of good control (figure 5), LV function re-
verted to the baseline level of LV dysfunction. In
summary, this data suggests that glycaemic control
has a modulating influence on LV systolic function
and LV filling pressures.[92]
There had been limited clinical information and
primarily observational studies regarding the influ-
ence of glycaemic control on LV systolic and dias-
tolic function, and has exclusively focused on type
1 diabetes. Hausdorf et al.[93] demonstrated that
levels of glycosylated haemoglobin correlated di-
rectly with the isovolumic relaxation period and
inversely with systolic function in asymptomatic
children with diabetes over a 2 year period. In pa-
tients with type 2 diabetes, insulin improved rest-
ing measure of LV systolic function and increased
ejection fraction with exercise. The change in fast-
ing glucose levels and glycosylated haemoglobin
correlated with changes in the PEP/LVET (pre-
ejection period/LV ejection time).[94] However, the
effect of glycaemic control in a patient group with
type 2 diabetes demonstrated improvement in non-
invasive indices of relaxation and early diastolic
filling only in patients where retinopathy was not
present.[95]
endpoints, the DCCT demonstrated a 41% reduc-
tion (nonsignificant) in the combined endpoint of
peripheral vascular and cardiovascular events with
intensive insulin therapy.[96] The influence of gly-
caemic control on cardiovascular morbidity and
mortality has not been clearly determined. The
University Group Diabetes Program in a post hoc
subgroup analysis noted a 35% cardiovascular
mortality in the placebo group and a 17% (variable
insulin dose) and a 21% (fixed insulin dose) mor-
tality in the groups who received insulin (nonsig-
nificant).[97]
The applicability of the implications of glycae-
mic control to patients with type 2 diabetes seems
reasonable except that insulin (insulin resistance)
may be an atherosclerotic promoting factor. Pre-
liminary data from two studies have yielded con-
flicting results. The Veteran Affairs Cooperative
Study on glycaemic control and complications
(VACSDM) demonstrated a 32% cardiovascular
event rate in patients who received intensive treat-
ment versus a 20% event rate in patients who re-
Baseline LV dysfunction
Poor glycemic control
*
p < 0.05
*
*
*
These observational studies suggest that histo-
logical and microvascular changes are associated
with long standing diabetes as are disturbances of
LV systolic and possibly diastolic function. Addi-
tional information can be gleaned from randomised
clinical trials investigating the role of glycaemic
control. The Diabetes Control and Complications
Trial (DCCT) indicated that intensive glycaemic
control reduced the onset and progression of reti-
nopathy, nephropathy and neuropathy (microvas-
cular complications) in patients with type 1 diabe-
tes. Although not powered to address these
EDA
LVEDP
AEF
Fig. 4. The effect of poor glycaemic control on left ventricular
(LV) size (EDA), LV end diastolic pressure (LVEDP) and systolic
function (AEF-area ejection fraction) are shown at baseline LV
dysfunction and after 3 months of poor glycaemic control. (Units
for y axis are cm2, mmHg and %).
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Drugs 2002; 62 (2)

Heart Failure in Patients with Diabetes
297
ceived usual care (p = 0.1).[98] However, the inci-
dence of pre-existing coronary disease was greater
in the group who received intensive treatment. The
Finnish studies demonstrated that cardiovascular
mortality (coronary) is linearly related to glycae-
mic control irrespective of the mode (insulin ther-
apy) of glycaemic control.[99] In the presence of
acute MI, insulin-glucose infusion followed by
strict glycaemic control was a predictor of reduced
mortality in the Diabetes and Insulin-Glucose In-
fusion in Acute Myocardial Infarction (DIGAMI)
study.[100]
Baseline LV dysfunction
Good glycemic control
4. Management of CHF in
Patients with Diabetes
EDA
LVEDP
AEF
4.1 Goals of Therapy
Fig. 5. The influence of good glycaemic control on left ventric-
ular (LV) size (EDA), LV end diastolic pressure (LVEDP) and
systolic function (AEF-area ejection fraction) are shown at base-
line LV dysfunction and after 3 months of poor followed by 3
additional months of good glycaemic control. (Units for y axis
are cm2, mmHg and %).
Therapy of patients with CHF in part is related
to the underlying pathophysiology. Of prime con-
sideration is the treatment of the underlying cause
of LV dysfunction and the removal of all precipi-
tating factors. The goals of therapy include the
short-term relief of both pulmonary and systemic
congestion, and the long-term slowing of the pro-
gression and potentially reversing the course of LV
dysfunction and prolonging survival. Short term
relief of symptoms can be accomplished by non-
pharmacological approaches (relief of ischaemia
and salt restriction) and pharmacological therapy.
Similarly both nonpharmacological and pharma-
cological approaches can be employed for long-
term therapy. Attention should directed at reducing
the standard coronary risk factors (hypercholester-
olaemia, hypertension, smoking, etc.). The transi-
tion between LV dysfunction and CHF is being
vigorously investigated at the present time. Efforts
to influence remodelling processes are being pur-
sued. Reduced progression to overt CHF and re-
duced hospitalisation for CHF have been demon-
strated in the prevention arm of the Studies of Left
Ventricular Dysfunction Prevention (SOLVD)
trial with the use of ACE inhibitors.[101] At the
present time no other pharmacologic agent has
been demonstrated to halt the transition from LV
dysfunction to CHF.
The presence of diabetes adds an additional fac-
tor that has been recognised as an adverse prognos-
tic indicator in general for cardiovascular disease.
The incidence and extent of coronary disease are
increased as is the incidence of LV dysfunction.
Vigorous attention to glycaemic control and hyper-
tension may be beneficial with regard to coronary
disease and CHF, but randomised clinical trials
have been underpowered and not designed to ad-
dress these issues. In the UKPDS study, intensive
treatment resulted in a reduced risk of MI (p =
0.052).[102] Many trials demonstrating symptom-
atic and survival benefit with either ACE inhibitors
or β-blockers do not have predefined subgroups of
patients with diabetes. However, as it is this sub-
group who has the highest risk profile for CHF and
mortality, interventions designed to reduce risk in
the CHF population as a whole may very well have
their greatest benefit in the patient with diabetes
and LV dysfunction.
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298
Lavine & Gellman
4.2 Pharmacological Therapy of CHF
ejection fraction, reduces symptoms of CHF, im-
proves exercise capacity and decreases the number
of CHF hospitalisations [Digitalis Investigation
Group (DIG) trial].[108,119] Although there are few
data in patients with NYHA Class IV CHF, digoxin
appears to work across the spectrum and in patients
with diabetes (a specified subgroup in this
study).[108] However, it has a neutral effect on mor-
tality.[108] Digoxin may be of particular use in pa-
tients with CHF and atrial fibrillation when its ef-
fects on the AV node can be used to control the
heart rate. Sensitivity to the toxic effects of digoxin
are more likely to manifest themselves with vol-
ume depletion, and potassium and magnesium de-
pletion, which may occur with diuresis.
Sympathomimetic agents have been used to
support the circulation acutely and for acute de-
compensated CHF. Dobutamine, dopamine and
epinephrine (adrenaline) are primarily intravenous
agents. Phosphodiesterase type III inhibitors have
been used intravenously for similar purposes.
However, oral milrinone was found to increase
mortality and has been withdrawn [Prospective
randomised milrinone survival evaluation (PROM-
ISE) study] from clinical use,[109] although intrave-
nous milrinone continues to be used.
The majority of therapeutic agents for CHF
have similar or better efficacy in patients with dia-
betes as in those without. As a general principle,
patients with diabetes and especially those with
concomitant hypertension represent a subgroup
with a high incidence of coronary artery disease
and greater degree of LV dysfunction. Efficacious
agents may be especially useful in this important
subgroup (tables V and VI).
4.2.1 Inotropic Agents
Digoxin has been used as an inotropic agent for
over 30 years. Its efficacy has only been recently
established. Its action involves inhibition of mono-
valent cation transport resulting in increased avail-
ability of myocardial calcium. Neurohormonal
modulation, amelioration of autonomic dysfunc-
tion with enhancement of parasympathetic stimu-
lation and restoration of baroreceptor stimulation
are some of its salutary actions. Therapeutic end-
points with digoxin have been difficult to achieve
in the past because of digitalis intoxication. At-
tempts to optimise therapy based on digoxin con-
centrations will lead to increased toxicity without
significant improvement in therapeutic effect.
In patients with New York Heart Association
(NYHA) Class II to III CHF, digoxin increases
Table V. Heart failure and mortality prevention trialsa
Trial
Drug treatments
Mortality
MI
CHF
Adverse
events
Stroke
Appropriate Blood Pressure Control in Diabetes Enalapril vs nisoldipine
Reduced
Reduced
Reduced
Reduced
(ABCD)[43]b
Heart Outcomes Prevention Evaluation
(HOPE)[103]c
Ramipril vs placebo
Reduced
Reduced
Reduced
Reduced
Reduced
Hypertension Optimal Treatment (HOT)[46]c
Felodipine vs ACE
Reduced Reduced
inhibitors + β-blockers
Studies Of Left Ventricular Dysfunction
Prevention (SOLVD)[101]
Enalapril vs nisoldipine
University Group Diabetes Program (UDGP)[97]b Insulin vs placebo
Reduced
Diabetes Mellitus Insulin Glucose Infusion in
Acute Myocardial Infarction (DIGAMI)[100]b
Insulin-glucose infusion vs Reduced
placebo
a
b
c
Results are for patients with diabetes, but were also true for patients without diabetes.
Diabetes study.
Diabetes subgroup.
CHF = congestive heart failure; MI = myocardial infarction.
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Heart Failure in Patients with Diabetes
299
Table VI. Heart failure and therapeutic trials
Trial
Mortality
CHF
Hospitalisations Exercise
Capacity
Angiotensin converting enzyme inhibitors
Survival and Ventricular Enlargement (SAVE)[104]
Studies of Left Ventricular Dysfunction Treatment (SOLVD)[101]
Reduced
Reduced
Reduced
Reduced
Reduced
Reduced
Reduced
Cooperative North Scandinavian Enalapril Survival
(CONSENSUS)[105]
Vasodilator Heart Failure Trial (V-HEFT II)[106]
Trandolapril Cardiac Evaluation (TRACE)[107]a
Inotropes
Reduced
Reduced
Reduced
Reduced
Digitalis Investigation Group (DIG)[108]a
Reduced
Increased
Increased
Prospective Randomised Milrinone Survival Evaluation
(PROMISE)[109]
Increased
Aldosterone antagonists
Randomised Aldactone Evaluation Study (RALES)[110]
Reduced
Reduced
Reduced
Reduced
β-Blockers
Metoprolol Randomised Intervention Trial in Congestive Heart
Failure (MERIT-HF)[111]
Metoprolol in Dilated Cardiomyopathy (MDC)[112]
The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II)[113]
Reduced
Reduced
Reduced
Reduced
Reduced
Prospective Randomised Evaluation of Carvedilol on Symptoms
and Exercise (PRECISE)[114]
Increased
Increased
Multicenter Oral Carvedilol Heart Failure Assessment (MOCHA)[115] Reduced
Reduced
Calcium channel antagonists
Prospective Randomised Amlodipine Survival Evaluation[116]
The Danish Verapamil Infarction Trial II (DAVIT-II)[117]
Neutral
Reduced if no
CHF
Multicenter Diltiazem Post Infarction Trial (MDIPIT)[118]
Increased if CHF
a
Diabetes subgroup.
CHF = congestive heart failure.
4.2.2 Diuretics
uresis. Furosemide (20 to 80mg as a single dose)
and bumetanide (1 to 3mg as a single dose) are two
examples of loop diuretics. Their actions are in the
ascending limb of the loop of Henle where they
inhibit transport of sodium and chloride. Potas-
sium depletion is common. Other diuretic classes
(e.g. thiazides) inhibit sodium and chloride trans-
port in the distal tubule. Their diuretic effect is
more modest and less effective in patients with re-
nal dysfunction. Their use may augment the effects
of furosemide but at the expense of marked potas-
sium depletion. Potassium sparing diuretics in-
clude triamterene and spironolactone, which is an
inhibitor of type I mineralocorticoid and gluco-
corticoid receptors. Secondary hyperaldosteron-
ism occurs in the setting of CHF, especially with
loop diuretic use. Spironolactone is useful in re-
In patients with CHF, renal adaptations to the
reduced cardiac output occur mediated by the
many neurohormonal changes. Glomerular filtra-
tion may be reduced when CHF is associated with
renovascular disease. Glomerular filtration may be
dependent on the the relative vasoconstriction of
the afferent vs the efferent arterioles. There is no
long-term data on the use of diuretics in CHF. Di-
uretics have been used in CHF as background ther-
apy in clinical trials along with digoxin. Diuretics
are a mainstay of therapy for volume overload and
act by blocking ion transport in the loop of Henle
or distal tubule. The activity of diuretics in the
proximal tubule and collecting duct is usually less.
Loop diuretics are perhaps the most commonly
used diuretics resulting in a prompt and brisk di-
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300
Lavine & Gellman
storing diuresis when secondary hyperaldosteron-
ism occurs with loop diuretic use. More recently,
spironolactone at low nondiuretic doses (25mg)
demonstrated a salutary effect on CHF, hospital-
isations and survival in the Randomized Aldactone
Evaluation Study (RALES).[110] Metolazone, a
thiazide-like diuretic, with some proximal tubule
effect has been used at a dose of 2.5 to 10 mg/day
to augment the effect of loop diuretics.
Diuretics are helpful in avoiding volume over-
load, but can lead to potassium depletion, prerenal
azotemia and other electrolyte disorders which can
become more acute in the setting of renal insuffi-
ciency (especially in patients with diabetes). Dif-
fuse oedema or anasarca can result in diuretic re-
sistance as a result of nonabsorption secondary to
bowel oedema. Diuretics can also impair glucose
tolerance (thiazides) and in the presence of renal
insufficiency (loop diuretics) may lead to hyper-
kalaemia and renal insufficiency with volume de-
pletion secondary to distal tubular renal acidosis.
of hypertension, CHF and diabetic nephropathy.
Their cardiovascular and renal actions are targeted
at reversing the effects of angiotensin II. These in-
clude antagonising the increased sympathetic out-
flow, vascular and smooth muscle cell hypertro-
phy, endothelial dysfunction, increased oxidative
stress, atherosclerotic and thrombotic effects, and
aldosterone production. Renal function may be ad-
versely impacted by their use as 10% of patients
will have an increase of serum creatinine by 0.3
units. Renal atherosclerosis and efferent arteriole
constriction contribute to the decrease in renal
function.[39] This class of drugs are excreted by the
kidney and may accumulate in patients with renal
insufficiency made worse by hypotension and re-
duced glomerular filtration.
SOLVD, Survival and Ventricular Enlargement
(SAVE), the Cooperative North Scandinavian En-
alopril Survival Study (CONSENSUS) and VHEFT-
II are clinical trials that have demonstrated im-
proved survival in patients with CHF with ACE
inhibitors.[101,104-106,120] Subdivisions into patient
groups with and without diabetes were not system-
atically performed in these trials. However, the
Heart Outcomes Prevention Evaluation (HOPE)
study of patients at high risk for cardiovascular
events but with ejection fractions >40% and no
CHF, demonstrated a marked risk reduction in MI,
death and stroke, and a 22% reduction in the inci-
dence of new CHF.[103,121] The effects were more
marked in patients with diabetes. Similarly, in the
Trandolapril Cardiac Evaluation (TRACE) study,
patients receiving trandolapril who had a previous
MI and had LV dysfunction with and without CHF
demonstrated a 27% increase in life expectancy.
Patients with diabetes after infarction are a high
risk group with ≥50% mortality over 6 months in
the TRACE study. These salutary findings on mor-
tality were more marked in the subgroup with dia-
betes. In patients with diabetes, there was a reduc-
tion in cardiovascular death (44%), sudden death
(54%) and progression to CHF (62%) with
trandolapril.[107] Very clearly, patients with diabe-
tes (irrespective of type and insulin use) and LV
dysfunction secondary to coronary artery disease
4.2.3 Vasodilators
Although vasodilators were popular at one time
for the treatment of CHF, they have been largely
supplanted by ACE inhibitors. α-Blockers includ-
ing prazosin have early impressive haemodynamic
effects that wane as a result of tachyphylaxis. They
demonstrate no survival effect [Vasodilator Heart
Failure Trial (V-HEFT)] and their use has largely
been abandoned.[120] The nonspecific vasodilator,
hydralazine (approximately 300 mg/day) when
combined with isosorbide dinitrate, improved sur-
vival, increased ejection fraction and reduced
symptoms of CHF.[120]
However, the effects were not as salutary as
those seen with ACE inhibitors in VHEFT-II.[106]
The use of nitrates alone may assist with symptoms
of pulmonary congestion and angina in patients
with LV dysfunction and coronary disease.
4.2.4 Angiotensin Converting Enzyme Inhibitors
ACE inhibitors inhibit the conversion of angio-
tensin I to angiotensin II. Bradykinin degradation
is also inhibited resulting in increased levels which
may be responsible for the cough sometimes seen
with their use. They are now used for the treatment
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Heart Failure in Patients with Diabetes
301
derive an ant-ischaemic effect and an effect on pro-
gression to CHF (anti-remodelling) that appear to
be interrelated. The effects on mortality, reinfarc-
tion, stroke and CHF appear to be a class effect. It
is important to administer maximal tolerated doses
of the ACE inhibitor as most trials uptitrate the
specific drug.
tients with CHF, LV dysfunction and coronary dis-
ease, the data for AT1-receptor antagonists are lim-
ited. At the present time, patients unable to tolerate
ACE inhibitors should receive isosorbide dinitrate
and hydralazine, a combination with a positive ef-
fect on mortality.[120]
4.2.6 Aldosterone Antagonists
Aldosterone stimulation in patients with CHF
results in increased sodium and water retention,
increased potassium and magnesium loss, in-
creased sympathetic and reduced parasympathetic
nervous system stimulation, and increased colla-
gen synthesis. ACE inhibitor therapy does not ant-
agonise aldosterone production. Angiotensin II
production can occur through the chymase path-
way despite ACE inhibitor therapy.[133,134] To test
the influence of aldosterone on CHF symptoms
and mortality (RALES study), patients with CHF
were randomised to spironolactone 12.5 to 25mg
or placebo in addition to maintenance therapy
(ACE inhibitor, diuretic, digoxin, but a low use of
β-blocker). Mortality was reduced from 46% to
35% in the treatment group and CHF hospital-
isations were reduced 35%.[110]
4.2.5 Angiotensin II Receptor Antagonists
These agents block the angiotensin II type 1 re-
ceptor (AT1) but do not influence the unopposed
angiotensin II type 2 receptor (AT2) stimulation.
AT2 receptor stimulation results in vasodilatation,
an antigrowth and antiproliferative effect but an
increase in apoptosis.[122] In CHF, glomerular
filtration is under the control of both the afferent
and efferent arteriole constriction and a low ultra-
filtration coefficient.[123] The renal vasculature
arborises so the arterial pressure needs to be 65
mmHg at entry into the glomerulus with 35 mmHg
needed to transport across the glomerular base-
ment membrane. When the effects of angiotensin I
are blocked with ACE inhibitors, glomerular filtra-
tion rate improves as a result of increased perfu-
sion, reduced afferent tone and adequate efferent
tone. AT1-receptor antagonists affect the glomeru-
lar efferent tone to a lesser extent than ACE inhib-
itors, which reduces renal problems.[124,125] How-
ever, patients who have ACE inhibitor renal
intolerance may also have intolerance to AT1-
receptor antagonists. In the Evaluation of Losartan
in the Elderly (ELITE) trial, <10% of patients had
a 0.3 unit increase in their serum creatinine.[126]
Monotherapy with an AT1-receptor antagonist
decreased the mean pulmonary capillary pressure
by 6.3 mmHg. Higher doses added no further
haemodynamic benefit acutely, but resulted in less
mortality and chronic CHF.[127-130] Both drug
classes have been used in combination in the treat-
ment of CHF and have resulted in additive de-
creases in the mean pulmonary capillary pressure
with little hypotension.[131] The ELITE trial dem-
onstrated that losartan had a lower mortality asso-
ciated with its use compared with captopril,[126]
which were not confirmed in the ELITE II trial.[132]
Although ACE inhibitors improve survival in pa-
4.2.7 β-Blockers
β-Blockers have progressed from being contra-
indicated in patients with CHF to being important
agents that have symptomatic and survival bene-
fits. Multiple trials performed have demonstrated
efficacy and safety in patients with Class II to III
CHF.[111-115,135-140] Ejection fraction generally im-
proves over 3 months with variable improvements
in exercise tolerance.[135,136] In most trials of symp-
tomatic patients with ejection fractions <40%,
background therapy consisted of an ACE inhibitor,
a diuretic and digoxin. Both selective and non-
selective agents have been used.
Metoprolol demonstrated a 34% decrease in
risk of transplant in the Metoprolol in Dilated Car-
diomyopathy (MDC) trial[141] and 34% decrease in
mortality in the Metoprolol CR/XL Randomized
Intervention Trial in Congestive Heart Failure
(MERIT-HF) study.[111,137] Bisoprolol use resulted
in a 34% decrease in hospitalisation [the Cardiac
Insufficiency Bisoprolol Study (CIBIS)] and a
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Drugs 2002; 62 (2)

302
Lavine & Gellman
34% decrease in mortality in CIBIS-II, which was
similar whether LV dysfunction was caused by is-
chaemic or nonischaemic aetiologies.[113,137] Car-
vedilol use demonstrated a 65% decrease in mor-
tality and hospitalisation with a 38% reduction in
death.[140] Both the Prospective Randomised Eval-
uation of Carvedilol on Symptoms and Exercise
(PRECISE) and Multicenter Oral Carvedilol Heart
Failure Assessment (MOCHA) trials demonstrated
a reduction in the combined endpoint of mortality
and hospitalisation of 39-49%. The MOCHA trial
demonstrated that higher dosages were more ad-
vantageous.[114,140] With regard to patients in Class
IV CHF, there is no data for efficacy and there is a
concern regarding decompensation. Subgroup
analysis of some of these trials demonstrated sim-
ilar efficacy in patients with diabetes as those with-
out.
The general rule is to start at very low doses
(metoprolol 6.25mg or carvedilol 3.125mg) and to
uptitrate. Careful scrutiny for symptoms of fatigue,
bodyweight gain, decreased exercise tolerance and
hypotension is required. Alteration of diuretic dose
can address hypotension and bodyweight gain.
Continued deterioration should prompt a search for
the precipitants of CHF including noncompliance
of medication, ischaemia, arrhythmias and infec-
tion. Efforts should be made not to discontinue the
β-blocker since their proven efficacy with regard
to CHF hospitalisation and mortality is size-
able.[140] The presence of diabetes does not pose a
relative contraindication to the use of β-blockers.
On the contrary, β-blockers may be even more im-
portant in this subgroup of patients.
using a combined endpoint.[117] Amlodipine
showed no adverse effects when used in the Pro-
spective Randomized Amlodipine Survival Evalu-
ation (PRAISE) study.[116] This is important be-
cause amlodipine is a commonly-used agent in the
therapy of hypertension in patients with CHF.
4.3 Therapy of CHF in
Patients with Diabetes
There are no specific trials that address this is-
sue. In fact, subgroup analysis of patients with di-
abetes are rarely addressed unless the trial involves
patients with ischaemic disease or after MI. Diabe-
tes and hypertension are important adverse risk fac-
tors in ischaemic heart disease and CHF. Efforts to
address ischaemia in this high risk group with ther-
apies that are efficacious for CHF and are anti-
ischaemic, antithrombotic and improve endothelial
and vasodilator function are likely to make great
impact on the morbidity and mortality of patients
with diabetes. Other clinical trials have demon-
strated that effective therapies generate the greatest
impact on subgroups with the highest risk: patients
with diabetes and hypertension. Antidiabetic ther-
apies that produce tight glycaemic control may im-
prove the microvascular complications associated
with diabetes, but have uncertain impact on macro-
vascular complications and LV systolic and dias-
tolic function. It is these issues that require more
investigation to maximise the impact of CHF ther-
apy in patients with diabetes.
4.4 Pitfalls in Therapy of CHF
The most important pitfall is not recognising the
presence of CHF. Not all patients will present with
classic symptoms and signs. The presence of LV
dysfunction is an important clue. However, dias-
tolic dysfunction can be an important cause of con-
gestive symptoms. The presence of coronary artery
disease, hypertension with LV hypertrophy, or
even infiltrative diseases including amyloidosis
can produce congestive symptoms with preserved
LV systolic function.
4.2.8 Calcium Channel Antagonists
Enthusiasm for the use of calcium channel an-
tagonists in patients with CHF has largely waned.
Trials have demonstrated efficacy, no benefit, or
even harm in subgroups of patients with CHF after
MI. The earliest trial was the Multicenter Diltiazem
Post Infarction Trial (MDIPIT) which used dil-
tiazem after MI and demonstrated increased mor-
tality post infarction in patients with CHF.[118] Ver-
apamil in the Danish Verapamil Infarction Trial II
(DAVIT-II) did show benefit in patients with CHF
Although the cornerstone of CHF therapy are
ACE inhibitors, diuretics are commonly employed
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Drugs 2002; 62 (2)

Heart Failure in Patients with Diabetes
303
to treat pulmonary congestion and may produce
either symptoms of fatigue with overuse or conges-
tion with underuse. ACE inhibitor dose adminis-
tration needs to be maximised based on clinical
trials. Use of dosages that are too low is common
and prevents the full effect from these agents being
gained. Not all patients will tolerate ACE inhibitor
therapy because of adverse effects, primarily
coughing. Although AT1-receptor antagonists are
possible alternatives to ACE inhibitors, clinical tri-
als do not yet support their widespread use. How-
ever, the combination of isosorbide dinitrate and
hydralazine does improve symptoms and mortal-
ity, as shown in the V-HEFT trial.[107]
Therapy for CHF should include an assessment
of the quality of life and long term goals of pa-
tients. Very simply, therapies aimed at reducing
long term mortality are paramount. Not all these
therapies will reduce symptoms, nor will all thera-
pies aimed at reducing symptoms improve mortal-
ity. However, all therapies aimed at reducing con-
gestion should be mortality neutral.
of hyperinsulinaemia, which may result from in-
creased efforts to control glycaemia, may have ath-
erosclerotic and growth promoting potential on
vascular lesions. Little if any data exist with regard
to agents (metformin or thiazolidinediones) that
improve insulin sensitivity. Nevertheless, glycae-
mic control is important to the overall health of
patients. Experimental data may suggest that
hyperglycaemia can be responsible for exacerbat-
ing LV dysfunction. Furthermore, CHF is a state
where high levels of catecholamines exist that can
adversely effect glycaemic control.
Exacerbation of CHF in patients with diabetes
has many potential causes. The presence of poorly
controlled atrial fibrillation, hypertension, infec-
tion and ischaemia are examples. Nephropathy as-
sociated with diabetes can result in fluid retention,
hypertension and increased symptoms of pulmo-
nary congestion. Efforts to treat these symptoms
may be hampered by a lack of response to diuretics
and worsening renal function produced by ACE
inhibitors, resulting a in dosage reduction in or ces-
sation of this latter drug.
5. Conclusions
Management of patients with diabetes and CHF
is similar to patients without diabetes. As patients
with diabetes represent a high risk subset of pa-
tients with CHF, efforts to maximise therapy will
have a substantially greater impact on hospitalisa-
tion and mortality than other subsets of patients.
Dosages of ACE inhibitors should be maximised
to achieve the greatest benefit. For those patients
who are unable to tolerate this class of drug,
hydralazine and nitrates according to the dose ad-
ministration of the V-HEFT trial should be used.
To date, there is insufficient data on the effects of
AT1-receptor antagonists on CHF hospitalisation
and mortality to recommend them as alternative
therapy. β-blockers should also be employed in pa-
tients with class II to III CHF to reduce long-term
mortality. Although there has been previous con-
cern in patients with diabetes that β-blockers may
mask hypoglycaemic episodes and worsen glycae-
mic control, the benefits in patients with diabetes
and CHF with this class of drug are substantial. As
concomitant coronary artery disease is often pres-
The diagnosis of CHF in patients with diabetes
is no different than in patients without diabetes.
However, diastolic dysfunction is common early
on in patients with diabetes. The clinician should
be alerted to this possibility and investigate symp-
toms of dyspnea realising that they may represent
pulmonary congestion. As patients with type 2 di-
abetes often have concomitant hypertension, the
increased incidence of fibrosis, abnormal relax-
ation, and reduced myocardial and chamber com-
pliance often results in pulmonary congestion on
exertion. Rapid atrial fibrillation may exacerbate
diastolic dysfunction by producing episodes of
pulmonary congestion and haemodynamic decom-
pensation.
The presence of diabetes in patients with CHF
provides some unique considerations. Glycaemic
control reduces the progression of microvascular
complications, but whether it has salutary effects
on vascular disease, coronary artery disease, and
systolic and diastolic function is unclear. The role
© Adis International Limited. All rights reserved.
Drugs 2002; 62 (2)

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Correspondence and offprints: Dr Steven J. Lavine, Cardio-
vascular Center, University of Florida-Jacksonville, 655
West 8th Street, Jacksonville, Florida 32209, USA.
E-mail: Steven.Lvine@jax.ufl.edu
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Drugs 2002; 62 (2)