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Main topic

Herz 2019 · 44:210–217
https://doi.org/10.1007/s00059-019-4798-3
Published online: 21 March 2019
© Springer Medizin Verlag GmbH, ein Teil von
Springer Nature 2019

P. Valensi1 · C. Meune2

1 Department of Endocrinology, Diabetology, Nutrition, Jean Verdier Hospital, AP-HP, CRNH-IdF, CINFO,
Paris Nord University, Bondy, France

2 Department of Cardiology, Avicenne Hospital, Inserm UMR-942, Paris Nord University, Bobigny, France

Congestive heart failure caused
by silent ischemia and silent
myocardial infarction
Diagnostic challenge in type 2 diabetes

Besides atherosclerotic complications,
heart failure (HF) has emerged in the
past 20 years as a serious cardiovas-
cular complication in patients with
type 2 diabetes mellitus (T2D). Several
epidemiologic studies such as the Fram-
ingham [1], the Reykjavik [2], and the
Strong Heart [3] studies have shown the
increased risk of HF in these patients.
In recent cardiovascular outcome tri-
als (CVOTs) designed in T2D patients
with a history of cardiovascular disease
(CVD) or with several associated risk
factors, the incidence of hospitalization
for HF (hHF) was comparable to the
incidence of acute myocardial infarction
[4].

In diabetic patients, the control of risk
factorsisabletomitigatetheexcessriskof
atheroscleroticcomplicationsbuttherisk
of HF remains high [5]. Thus, HF has be-
come a major challenge in CVD preven-
tion, highlighting the necessary careful
consideration of this outcome in CVOTs.
This should ultimately guide the choice
of antihyperglycemic agents in order to
promote new drugs that can reduce the
risk of HF and to avoid those that may in-
duce/be harmful in HF, which is particu-
larly important in patients with coronary
artery disease (CAD).

Coronary artery disease is the lead-
ing cause of HF in T2D patients. Heart
failure occurs mostly in patients with
known CAD [6]. However, CAD is of-
ten silent and may be detected at a stage
of silent myocardial infarction or using
stress tests of ischemia. Silent myocardi-

al ischemia, particularly when associated
with coronary stenoses, is predictive of
an increased risk of cardiovascular out-
comes. Some data suggest that HF may
occuras a complication of previously un-
detected silent CAD.

The aim of this article is (a) to sum-
marize the data on the risk of congestive
HF in T2D patients with silent myocar-
dial infarction or silent ischemia, and (b)
to report on how to estimate and reduce
this risk.

Heart failure in patients with
CAD and diabetes

Coronary artery disease accounts for half
of the cases of HF, regardless of whether
the patients have diabetes or not [7]. In
theOregonregistry, CADwastwicemore
frequent (41 vs. 18%) and the prevalence
ofhypertensionwashigherindiabeticpa-
tients who developed HF compared with
those who did not [8]. Biochemical and
microcirculatory factors may aggravate
myocardial changes in ischemic HF and
further impair the prognosis of patients
with ischemic HF.

Renal disease may also increase the
risk of HF. In a recent meta-analysis of
CVOTs testing SGLT2 inhibitors that in-
cluded 60% of patients with established
CVD, mostly with CAD, the risk of hHF
in the placebo arms was around four
times greater in the patients with an esti-
mated glomerular filtration rate (eGFR)
of <60ml/min per m2 than in those with
eGFR ≥90ml/min per m2 [9].

Subclinical cardiac autonomic neu-
ropathy(CAN)consistingmainlyinade-
pression of vagal activity and sympa-
thetic overdrive is frequent in patients
with T2D. In a small series of patients
with either prediabetes or diabetes, CAN
was associated with diastolic dysfunction
[10]. In a population of 293 T2D pa-
tients, we showed that patients with both
CAN and silent myocardial ischemia had
a lower left ventricular ejection fraction
(LVEF)andthatCANwasassociatedwith
a reduced diastolic time that could alter
myocardial perfusion (Valensi et al., un-
published data). Thus, CAN might con-
tribute to the excess HF risk in patients
with CAD.

In patients with HF, recent large reg-
istries have demonstrated a significant
association between diabetes and ad-
verse outcomes including CVD death,
all-cause death and hHF, independent
of HF etiology, ischemic or not, or
phenotype [11–15].

Silent CAD and risk of heart
failure in diabetic patients

High prevalence of silent CAD in
diabetes

Up to 50% of myocardial infarctions are
undetected at the time of occurrence and
are discovered later during routine care
or when cardiovascular symptoms have
emerged [16] or are revealed by car-
diac imaging. The prevalence of silent
myocardialinfarctionindiabeticpatients

210 Herz 3 · 2019

as detected by resting electrocardiogra-
phy (ECG) is about 4% and markedly
higherwhenusingcardiacmagneticreso-
nanceimagingormyocardialsingle-pho-
tonemissioncomputedtomography[17].
Theincidenceofsilentmyocardialinfarc-
tion as detected by ECG is higher in dia-
beticpatientswithahistoryofmyocardial
infarction[17]. IntheFIELDstudy, silent
myocardial infarction detected on rou-
tine standard ECG accounted for more
than one third of the first cases of myo-
cardial infarction and two thirds of cases
after a first myocardial infarction [18].
In the RECORD study, a retrospective
analysis of ECGs showed that one third
of prevalent and one quarter of inci-
dent myocardial infarctions were unrec-
ognized [19]. In a population of 9243
participants from the ARIC (Atheroscle-
rosis RiskinCommunities)studyinclud-
ing 8% with diabetes, about one half of
all myocardial infarctions were clinically
silent (detected on ECG reading), and
the proportion of diabetic patients was
twice greater among the patients with
silent or clinical myocardial infarction
than among those without myocardial
infarction [20]. However, a limitation to
these studies is related tothe ECG criteria
usedforthedetectionofsilentmyocardial
infarction. The sensitivity and specificity
of Q waves have been questioned in stud-
ies that attempted to correlate Q waves
with myocardial damage evaluated by
positron emission tomography, scintig-
raphy, and magnetic resonance imaging
[21, 22]. The reason may be that Q waves
can resolve with time, and several non-
ST segment elevation myocardial infarc-
tions (NSTEMI) do not have Q waves on
ECGs [23].

In asymptomatic diabetic patients
with other risk factors, the prevalence of
silent myocardial ischemia detected by
stress tests is variable in the literature,
mostly reported to be around 20–30%
[24–27]. This discrepancy is explained
partly by differences in patient selection
and choice of stress tests. The prevalence
of silent myocardial ischemia progres-
sively decreases in the diabetic popula-
tion probably in line with an improved
risk factor control [28]. Regarding the
screening methods, the combination of
exercise ECG with an imaging technique

(myocardial perfusion imaging or stress
echocardiography) provides incremental
diagnostic value [29]. Silent myocardial
ischemia is associated with significant
coronary stenoses on angiography in
40–90% of cases, meaning that ischemia
may also result from functional disorders
including endothelial dysfunction [30],
abnormal microcirculation, and reduced
coronary reserve [31, 32].

Coronary artery disease may also
be detected using computed tomogra-
phy (CT), which allows for noninvasive
estimation of the coronary calcifica-
tion (using the coronary artery calcium
[CAC] score) and detection of coronary
atherosclerotic plaques and stenosis (CT
coronary angiography). A CAC score of
>400 Agatston units (AU) that may affect
around 20% of asymptomatic diabetic
patients [33] was shown to increase the
risk of all-cause mortality more than four
times [34]. The CAC score is synergistic
with myocardial perfusion scintigra-
phy for the prediction of cardiovascular
events [35]. Screening patients for silent
myocardial ischemia should be limited
to very high risk patients such as those
with evidence of peripheral artery dis-
ease, proteinuria, or renal failure. A
high CAC score may also be used as
a first-line test to identify very high risk
patients who may justify being screened
for silent myocardial ischemia [36].

Prognosis of silent CAD in diabetic
patients and risk of HF

The risk of cardiovascular events in di-
abetic patients was reported to be as
high after silent and clinical myocar-
dialinfarction(aroundfourfoldincrease)
compared to diabetic patients without
myocardial infarction [18]. Only a few
studies, including the Rotterdam, Heart
Framingham, and ARIC studies, exam-
ined the risk of incident HF in silent
myocardial infarction as a separate out-
come. For instance, in the ARIC study,
after a median follow-up of 13 years the
incidence rate of hHF was higher in both
thegroupofparticipantswithclinicaland
with silent myocardial infarction than
in those without myocardial infarction
(30.4, 16.2, and 7.8 per 1000 person-
years, respectively; p< 0.001), with the

same trend noted for patients with or
without diabetes [20]. As recently sum-
marized[37], allthesestudiesreachedthe
conclusion that silent myocardial infarc-
tion is associated with an increased risk
of HF, independent of usual risk factors,
which suggests that the changes in struc-
ture and function of cardiomyocytes in
the ischemic heart and other unidenti-
fied mechanisms need to be considered
and targeted to prevent the occurrence
of HF.

Silent myocardial ischemia is a strong
predictorofcardiovascularoutcomes[38,
39], and adds to the prediction of an
event above and beyond routine assess-
ment of risk prediction [40]. The prog-
nosis is worse when the extent of myo-
cardial perfusion defects on scintigraphy
is large [39] and when silent myocar-
dial ischemia is associated with signifi-
cant coronary stenoses on angiography
[38], a high CAC score [35], or cardiac
autonomic neuropathy [41]. However,
no prospective study has ever reported
a higher occurrence of HF in patients
withdetectedsilentmyocardialischemia,
which might be due to underpowered
studies, to the lack of attention to this
outcome, or to a too-short follow-up. In
patientswithHF,however, previouslyun-
recognized CAD often seems to be in-
volved. In a series of 136 patients under
75 years hospitalized for HF in the UK,
invasive coronary angiography was un-
dertaken in 99 cases; CAD was consid-
ered to be the etiology of HF in 71 of the
patients while in 18 of these 71 patients
the ischemic etiology was not recognized
prior to angiography [42]. In a Japanese
study, 155 consecutive patients hospital-
ized with HF, of whom 65 patients had
diabetes, underwent invasive coronary
angiography. In the study cohort, 59
patients had coronary stenoses, diabetes
was more prevalent in the group with
stenoses (63% vs. 29%), and diabetes was
the only independent predictor of steno-
sis [43]. Thisstronglysuggeststhatprevi-
ous silent CAD was often present, which
supports performing coronary imaging
in diabetic patients with HF and with-
out clear etiology so as to confirm the
presence of coronary stenosis.

Herz 3 · 2019 211

Abstract · Zusammenfassung

Herz 2019 · 44:210–217 https://doi.org/10.1007/s00059-019-4798-3
© Springer Medizin Verlag GmbH, ein Teil von Springer Nature 2019

P. Valensi · C. Meune

Congestive heart failure caused by silent ischemia and silent myocardial infarction. Diagnostic
challenge in type 2 diabetes

Abstract
In asymptomaticpatients with type 2 diabetes
(T2D), the prevalence of silent myocardial
infarction on routine electrocardiograms is
about 4% while for silent myocardial ischemia
it is 20–30%. Some studies showed that
silent myocardial infarction is associatedwith
an increased risk of incident heart failure
(HF), whereas no prospective study has ever
reported such a risk in patients with silent
myocardial ischemia. In patients with HF, how-
ever, previously unrecognized coronary artery
disease (CAD) often seems to be involved.
Brain natriuretic peptide (BNP) and N-terminal
pro-BNP (NT-proBNP) levels represent first-line
diagnostic tools for patients with suspected
HF and might also serve as biomarkers

for silent CAD. Echocardiography provides
a detailed report of cardiac alterations that
includes changes suggestive of ischemia,
heart failure, and left ventricular dysfunction
in addition to strong prognostic indices.
Diabetic patients with silent myocardial
infarction or silent myocardial ischemia
should be screened for asymptomaticchanges
in left ventricular function or structure.
In patients with silent CAD, all risk factors
need to be better controlled and the choice
of antihyperglycemic agents adjusted. In
patients with congestive HF and no obvious
cause of HF, invasive coronary angiography
(or noninvasive computed tomography
angiography) should be performed to detect

CAD, since the finding of CAD may involve
revascularization and requires additional
treatments including antiplatelet agents
and statins. Future research is needed to
examine the cost effectiveness of screening
for silent myocardial ischemia as part of HF
risk assessment, and to identify preventive
therapies to lower the risk of HF among
patients with silent myocardial infarction.

Keywords
Diabetes mellitus, adult-onset · Coronary
artery disease · Antihyperglycemic agents ·
Risk assessment · Prognosis

Kongestive Herzinsuffizienz durch stumme Ischämie und stummen Herzinfarkt. Diagnostische
Herausforderung bei Typ-2-Diabetes

Zusammenfassung
Bei asymptomatischen Patienten mit Typ-
2-Diabetes (T2D) liegt die Prävalenz des
stummen Herzinfarkts im Routineelektro-
kardiogramm etwa bei 4%, die Prävalenz
der stummen Myokardischämie dagegen
bei 20–30%. In einigen Studien zeigte sich,
dass ein stummer Herzinfarkt mit einem
erhöhten Risiko für eine neu auftretende
Herzinsuffizienz (HF) einhergeht, jedoch ist
ein solches Risiko bei Patienten mit stummer
Myokardischämie bisher nicht in einer
prospektiven Studie dokumentiert worden.
Bei Patienten mit HF scheint häufig eine
zuvor unbekannte koronare Herzkrankheit
(KHK) mitbeteiligt zu sein. Für Patienten mit
Verdacht auf HF stellen die Werte für BNP
(„brain natriuretic peptide“) und NT-proBNP
(„N-terminal pro-BNP“) die diagnostischen
Parameter der ersten Wahl dar, die sich auch

als Biomarker für eine stumme KHK eignen
könnten. Die Echokardiographie ermöglicht
zusätzlich zu soliden prognostischen
Anhaltspunkten einen detaillierten Einblick
in kardiale Veränderungen einschließlich
Hinweisen auf Ischämie, Herzinsuffizienz
und linksventrikuläre Dysfunktion. Patienten
mit Diabetes und stummem Herzinfarkt
oder stummer Myokardischämie sollten
auf asymptomatische Veränderungen der
linksventrikulären Funktion oder Struktur hin
gescreent werden. Bei Patienten mit stummer
KHK müssen alle Risikofaktoren besser einge-
stellt und die Auswahl antihyperglykämischer
Substanzen angepasst werden. Bei Patienten
mit kongestiver HF und ohne offensichtliche
Ursache der HF sollte eine invasive Koro-
narangiographie (oder eine nichtinvasive
Computertomographie-Angiographie)zur

Diagnose der KHK durchgeführt werden.
Denn die Feststellung einer KHK könnte
auch eine Revaskularisierung beinhalten und
erfordert eine zusätzliche Behandlung mit
Thrombozytenaggregationshemmern und
Statinen. Zukünftige Untersuchungen sind
erforderlich, um die Wirtschaftlichkeit des
Screenings auf stumme Myokardischämie als
Teil der HF-Risikobeurteilung zu ermitteln
und präventive Behandlungen zur Senkung
des HF-Risikos bei Patienten mit stummem
Herzinfarkt zu identifizieren.

Schlüsselwörter
Diabetes mellitus mit Beginn im Erwach-
senenalter · Koronare Herzkrankheit ·
Antihyperglykämische Substanzen ·
Risikobeurteilung· Prognose

Association between silent CAD
and echocardiographic changes

In a large population of asymptomatic
T2Dpatients, wescreenedforsilentmyo-
cardial ischemia by stress scintigraphy
andperformedinvasivecoronaryangiog-
raphy in those who had silent myocar-
dial ischemia. All patients underwent
echocardiography at rest, and we showed
that in patients with silent myocardial is-

chemia, the positive predictive value of
LV hypertrophy associated with another
echocardiographic abnormality (includ-
ing LV dilatation, systolic dysfunction,
and hypokinesia) for CAD was 63% [44].
Inaddition, among the normotensive pa-
tients the prevalence of LV hypertrophy
and hypokinesia was 30% and 13%, re-
spectively, in those with CAD as com-
pared with 24% and 5% in those without
CAD [45]. Therefore, the presence of LV

hypertrophy with another abnormality
should raise the possibility of silent CAD.
Such echocardiographic alterations may
indicatetheroleofischemicdiseaseinLV
remodeling and a potentially increased
risk of HF.

Diagnosis of heart failure

According to the recent guidelines of the
European Society of Cardiology (ESC),

212 Herz 3 · 2019

Symptoms and signs of HF
NT-proBNP ≥ 125 ng/l or BNP ≥ 35 ng/l

Cardiac imaging
EF

Cardiac remodeling
Left atrial pressure

Relaxation

HFrEF, HFpEF, or HFmrEF

Known symptomatic CAD
Hypertension

Known silent CAD detected on Q
waves or previous screening tests:

– stress ECG test or myocardial
perfusion imaging or stress

echocardiography
– CAC, CT angiography, or invasive

coronary angiography

CAD of insufficient severity
to account for CHF

or no clear etiology of HF

Invasive coronary
angiography

Revascularization
in patients with
high ischemic

burden

Medical treatments
BP control

Statins
Anti-platelet therapy

Lifestyle and patient
education

Smoking cessation, weight
loss, advice for diet and

encouragement to physical
activity or rehabilitation

program

HFrEF
1st line: ACEI & beta-blockers

Other treatments:
MRA, ARNi, Ivabradine

Devices
Symptomatic (diuretics)

HFpEF: symptomatic (diuretics)

Anti-hyperglycemic therapy
Avoid hypoglycemia

No glitazone
SGLT2 inhibitor

or GLP1-RA except for HFrEF
Metformin and insulin if

necessary

Etiological assessment

Exclusion of acute coronary syndrome
(e.g. by high-sensitivity Troponin assay)

Fig. 1 8 Diagnostic andtherapeutic workflow in diabeticpatientswith congestive heart failure andsilentcoronary artery
disease. ACEI angiotensin-converting enzyme inhibitors, ARNi angiotensin receptorneprilysin inhibitor, BPbloodpressure,
CAC coronary artery calcium score,CAD coronary artery disease,CHF congestiveheartfailure,CT computedtomography,
EF ejection fraction,HFrEF/HFpEF/HFmrEF heart failure with reduced/preserved/mid-range ejection fraction, MRA mineralo-
corticoidreceptorantagonist, NT-proBNPN-terminal pro-brain natriureticpeptide,SGLT2sodium–glucose cotransporter2

chronic HF should be diagnosed in the
presence of signs and symptoms, mainly
dyspnea, together with evidence of ab-
normal heart function (. Fig. 1). Indica-
tors of cardiac dysfunction may be LVEF
<40% for HF with reduced EF (HFrEF),
orincreasednatriureticpeptides(NP)as-
sociated with heart structural alteration
and abnormal diastolic function for HF
with preserved EF (HFpEF), or HF with
mid-range EF (HFmrEF) [46]. The im-
portance of asking questions to patients
whodonotcomplainofsymptomsissup-
ported by a recent study including 581
patients with T2D (mean age, 72 years,
65% with hypertension, 19% with CAD).
Heart failure was systematically looked
for (clinical symptoms and signs, LV dys-
function on cardiac ultrasound) and di-
agnosed in 28% of patients, mostly as
HFpEF, with CAD being considered the
most common cause after hypertension
[6].

According to these recent guidelines,
ECG and NP (brain natriuretic peptide
[BNP] and N-terminal pro-BNP [NT-
proBNP]) are first-line recommended
tools; echocardiography should be per-

formed later, except if HF has been
otherwise ruled out [46]. Such a strat-
egy may hold limitations. First, these
guidelines are focused on patients with
symptomatic HF. The detection of LV
dysfunction at a preclinical stage might
offer the opportunity to identify earlier
patients at high risk, thereby allowing
preventive treatment to mitigate the
prognosis, a hypothesis that warrants
confirmation. Second, one should not
consider that the detection of ischemia
and HF should be performed separately.
Biomarkers (i.e., NP) and ECG are not
specific to HF, but rather offer the op-
portunity to detect both ischemia (see
next section) and/or HF, and therefore
should be considered in all T2D patients.
Third, the sensitivity of these diagnostic
tools is not uniform, as for the detection
of ischemia.

Both BNP and NT-proBNP are rec-
ommended as first-line tools for patients
with suspected HF with a threshold value
of125ng/lforNT-proBNPand35ng/lfor
BNP. Suchlow values offer very high sen-
sitivity(94–98%)andshouldallowforthe
detection of patients with symptomatic

HF but also those with LV dysfunction
only [47]. Furthermore, NT-proBNP
might also serve as a biomarker for silent
CAD. Indeed, in asymptomatic patients
with T2D, we reported that plasma NT-
proBNP in the third tertile (≥38pg/ml)
of our study population predicted silent
CADwithasensitivityof59%andaspeci-
ficity of 67%, independently of LV func-
tion and structure [48].

The recommendation to perform
echocardiography only when the diag-
nosis remains uncertain or as a confir-
mation tool may not be suitable in the
specific contextofT2Dpatients. A recent
echocardiographic study that included
842 patients from two distinct cohorts
identified three clusters of patients [49].
Cluster 1 were patients with low comor-
bidity, less myocardial hypertrophy and
diastolic dysfunction, high LVEF and
myocardial strain. Cluster 2 were elderly
patients, predominantly female, with
high blood pressure, obesity, they had
the best myocardial strain but the most
altered diastolic function. Cluster 3 were
male patients with similar age, hyperten-
sion, and obesity to cluster 1; they had

Herz 3 · 2019 213

Main topic

the maximal myocardial hypertrophy,
dilatation, and reduced strain. During
follow-up, clusters 2 and 3 had increased
cardiovascular mortality or hospitaliza-
tions[49]. Thesedatasuggestthatclinical
characteristics are not accurate enough
for risk stratification of patients and that
a large proportion of patients should un-
dergo echocardiography that is coupled
with strain imaging. The large diffusion
of strain imaging on most recent ultra-
sound machines will allow for its general
use. As cited earlier, echocardiography
provides a very detailed report of cardiac
alterations that includes modifications
suggestive of ischemia, heart failure, and
LV dysfunction in addition to strong
prognostic indices. Myocardial strain
imaging will improve both the detection
of LV dysfunction as well as of ischemia
as offered by echocardiography.

Coronary imaging is strongly recom-
mended for diabetic patients without
a clear etiology of HF so as to detect pre-
viously unknown or silent CAD, since
the finding of CAD is important not
only for revascularization but for addi-
tional treatments including anti-platelet
therapy and statins.

Therapeutic implications

Lifestyle and medical preventive
treatments in patients with silent
CAD or silent HF

LikeinclinicalCAD,preventivemeasures
targeting lifestyle changes need to be
strongly advocated in patients with silent
CAD in order to reduce the risks of ma-
jor events (. Fig. 1). This includes smok-
ing cessation, advice for diet, and en-
couragementforphysical activity. Statins
targeting low-density lipoprotein (LDL)
cholesterol levels under 70mg/dl, blood
pressure control, and renin-angiotensin
system (RAS)inhibitors as first-line ther-
apy are also logical.

The impactofa cardioprotective treat-
ment has recently been suggested by the
PONTIAC trial performed with high-
riskT2DpatientswithNT-proBNPlevels
>125ng/l but no obvious cardiac disease
[50]. The T2D patients were random-
ized to a control group or an intensified
treatment group in which all patients

received an angiotensin-converting en-
zyme (ACE) inhibitor and a beta-blocker
agent. After 12 months of follow-up, the
patientsintheintensifiedgrouphadmore
active treatment at higher dosage and
a reduction in cardiovascular mortality/
hospitalization. A confirmation study is
ongoing. If the results are replicated, pa-
tients should be screened and their treat-
ment up-titrated based on biomarkers.

Regarding aspirin, the ASCEND trial
[51] has recently shown that in diabetic
patients older than 40 years in primary
prevention, aspirin decreases the rate of
cardiovascular events but is associated
with a clear increase in major bleeding,
resulting in a nonsignificant difference
in overall mortality. Thus, the system-
atic use of low-dose aspirin should not
be recommended in diabetic patients in
primary prevention. A possible benefi-
cial effect in very high-risk patients such
as those with silent myocardial ischemia
is unknown and has to be specifically
studied.

Impact of coronary revascular-
ization in patients with silent
CAD

In the Swedish heart failure registry from
2003to2011, theimpactofischemicheart
disease onmortalityinpatients withT2D
was beneficially influenced by previous
revascularization[15]. Asaconsequence,
the adequate identification of patients
with silent CAD is pivotal. Some ran-
domized clinical trials have evaluated the
impact of screening for silent myocardial
ischemia in diabetic patients and showed
no differences in cardiac death and un-
stable angina at follow-up in those who
underwent stress testing or CT coronary
angiography compared with the current
standard of care based on the strict con-
trol of risk factors [39, 52]. However, in
a meta-analysis of five randomized con-
trolled trials including 3299 participants,
there was a trend with screening toward
a nonsignificant reduction in event rates
of nonfatal myocardial infarction (rela-
tive risk, 0.65; p= 0.062) and hHF (rel-
ative risk, 0.61; p= 0.1) [53]. This result
deserves being tested in larger, appro-
priately powered trials, and the benefit
of coronary revascularization in patients

withsilentmyocardialinfarctionorsilent
myocardial ischemia needs to be evalu-
ated specifically.

Effect of glycemic control in
diabetic patients with silent CAD

In the UKPDS epidemiological analysis,
a 1% drop in HbA1c levels was associated
with a 16% reduction in HF risk [54]. In
a pilot study, improvement of glycemic
control with insulin therapy was sug-
gested to improve myocardial diastolic
function and perfusion in T2D patients
[55]. However, a meta-analysis of ran-
domized trials of intensive glucose treat-
ment did not show any benefit of inten-
sive treatment on the reduction of either
hHF-orHF-relatedmortality[56]. Inthe
Veterans Affairs Diabetes Trial, intensive
glucose-lowering therapy reduced CVD
events only in patients with a CAC score
of <100 AU, which suggests a lack of
benefit in those with silent CAD [57].
When targeting a stricter glycemic con-
trol, avoidanceofhypoglycemiaiscrucial
in patients with silent as well as clinical
CAD and in HF patients, as it was shown
to be detrimental, in order to avoid sym-
pathetic activation and reduce the risk
of arrhythmia and recurrent congestive
episodes.

A more novel issue concerns the spe-
cific effects of antihyperglycemic medi-
cations on CVD events. Insulin seems
to be a good choice in diabetic patients
withcongestiveHF.IntheORIGINstudy,
insulin glargine treatment at a moderate
dose was not associated with a higher
risk of cardiovascular complications in-
cluding HF [58]. Regarding other “old”
antihyperglycemic classes, observational
studies have shown that the HF inci-
dencewaslowerinpatientsonmetformin
treatment compared with sulfonylureas.
In the REACH registry including thou-
sands of diabetic patients with diffuse ar-
terial disease, patients on metformin had
a 33% lower mortality and the results re-
mained significant in patients with HF
[59]. Metformin is no longer contraindi-
cated in patients with congestive HF pro-
vided they do not have advanced kidney
failure. Glitazones often induce edema
and, in particular in patients with pre-
vious myocardial infarction and/or HF,

214 Herz 3 · 2019

can lead to congestive HF, subsequently
to increased renal sodium tubular reab-
sorption and hypervolemia [60]; they are
contraindicated in patients with clinical
HF[46]. Ameta-analysisincludingseven
randomized double-blind trials reported
a 45% reduction in the relative risk of HF
with acarbose versus placebo in patients
with T2D [61].

In most of the recent CVOTs, more
than 50% of the T2D patients included
had CAD. Regarding dipeptidyl pep-
tidase-4 (DPP4) inhibitors, only the
SAVOR trial that tested saxagliptin re-
ported an increase (+27%) in the rate of
hHF, mostly in patients with a history of
HF or elevated plasma pro-BNP levels
[62], while in the TECOS study there
was no concern about an increase in
hHF with sitagliptin [63]. Glucagon-
like peptide 1 (GLP-1) receptor ago-
nists showed a significant reduction
of major events with liraglutide in the
LEADER study [64], with semaglutide
in the SUSTAIN-6 study [65], and with
albiglutide in the HARMONY study [66]
but they had no effect on hHF. How-
ever, in two recent studies in patients
with HFrEF, cardiovascular prognosis
was impaired in patients on liraglu-
tide [67, 68]. Testing sodium–glucose
co-transporter (SGLT2) inhibitors, the
EMPA-REG OUTCOME study (with
empagliflozin) and the CANVAS study
(with canagliflozin) both showed a 35%
drop in hHF rate [69, 70], which resulted
mainly from volume depletion.

In clinical practice, the …

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