Nutrition, Metabolism & Cardiovascular Diseases (2021) 31, 1671e1690

Available online at www.sciencedirect.com

Nutrition, Metabolism & Cardiovascular Diseases

journal homepage: www.elsevier.com/locate/nmcd

POSITION PAPER

Cardiovascular risk management in type 2 diabetes mellitus: A joint

position paper of the Italian Cardiology (SIC) and Italian Diabetes
(SID) Societies*
Angelo Avogaro a, Francesco Barillà b, Franco Cavalot c, Agostino Consoli d,
Massimo Federici b, Massimo Mancone e, Stefania Paolillo f,l, Roberto Pedrinelli g,
Gianluca Perseghin h, Pasquale Perrone Filardi f,l, Roberto Scicali i, Gianfranco Sinagra j,
Carmen Spaccarotella k, Ciro Indolfi k,l,**, Francesco Purrello i,*
a
Dipartimento di Medicina, Sezione di Diabete e Malattia del Metabolismo, Università di Padova, Italy
b
Dipartimento di Medicina dei Sistemi, Università di Roma Tor Vergata, Italy
c
SSD Malattie Metaboliche e Diabetologia, AOU San Luigi Gonzaga, Orbassano (Torino), Italy
d
Department of Medicine and Ageing Sciences and CeSI-Met, University D’Annunzio, Chieti, Italy
e
Dipartimento di Scienze Cliniche, Internistiche, Anestesiologiche e Cardiovascolari, Sapienza Università di Roma, Policlinico Umberto I (Roma), Italy
f
Dipartimento di Scienze Biomediche Avanzate, Sezione di Cardiologia, Università degli Studi di Napoli Federico II, Italy
g
Dipartimento di Patologia Chirurgica, Medica, Molecolare e dell’Area Critica, Università di Pisa, Italy
h
Dipartimento di Medicina e Riabilitazione, Policlinico di Monza, Università degli Studi di Milano Bicocca, Italy
i
Dipartimento di Medicina Clinica e Sperimentale, Università di Catania, Italy
j
Cardiovascular Department ‘Ospedali Riuniti’ and University of Trieste, Trieste, Italy
k
Division of Cardiology, University Magna Graecia, Catanzaro, Italy
l
Mediterranea Cardiocentro, Napoli, Italy

Received 20 February 2021; accepted 23 February 2021

Handling Editor: G. Targher
Available online 6 March 2021

KEYWORDS Abstract Aim: This review represents a joint effort of the Italian Societies of Cardiology (SIC)
Type 2 diabetes; and Diabetes (SID) to define the state of the art in a field of great clinical and scientific interest
Cardiovascular risk; which is experiencing a moment of major cultural advancements, the cardiovascular risk man-
Heart failure agement in type 2 diabetes mellitus.
Data synthesis: Consists of six chapters that examine various aspects of pathophysiology, diag-
nosis and therapy which in recent months have seen numerous scientific innovations and several
clinical studies that require extensive sharing.
Conclusions: The continuous evolution of our knowledge in this field confirms the great cultural
vitality of these two cultural spheres, which requires, under the leadership of the scientific So-
cieties, an ever greater and effective collaboration.
ª 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian
Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II
University. Published by Elsevier B.V. All rights reserved.

*
All authors are alphabetically ordered in the authorship of the manuscript, except for the two corresponding authors.
* Corresponding author.
** Corresponding author. Division of Cardiology, University Magna Graecia, Catanzaro, Italy.
E-mail addresses: indolfi@unicz.it (C. Indolfi), francesco.purrello@unict.it (F. Purrello).

https://doi.org/10.1016/j.numecd.2021.02.029
0939-4753/ª 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical
Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.
1672
Introduction
This review represents a joint effort of the Italian Societies
of Cardiology (SIC) and Diabetes (SID) to define the state of
the art in a field of great clinical and scientific interest,
which is experiencing a moment of major cultural ad-
vancements, with continuous evolution of our knowledge
and several clinical studies that confirm the great cultural
vitality of these two cultural spheres, which requires an
ever greater and effective collaboration. This review con-
sists of six chapters that examine various aspects of
pathophysiology, diagnosis and therapy, which in recent
months have seen numerous scientific innovations that
require extensive sharing.
Coronary artery disease in diabetes
Pathophysiology
Type 2 diabetes mellitus (DM) is characterized by a state of
insulin resistance (IR), hyperinsulinemia, and elevated
plasma glucose levels. This condition associated with
classic cardiovascular (CV) risk factors determines the
development of macrovascular disease even before diag-
nosis of manifest DM. The pathophysiological mechanisms
supporting the concept of a “glycemic continuum” char-
acterized by high fasting glucose values (IFG: impaired
fasting glucose), impaired glucose tolerance (IGT), and DM
are at the basis of the pathophysiology of DM and car-
diovascular disease (CVD) [1]. The development of CVD in
people with IR is a progressive process, characterized by
early endothelial dysfunction and vascular inflammation
that leads to the recruitment of monocytes, the formation
of foam cells and the consequent development of lipid
striae. Over the years, this leads to the formation of
atherosclerotic plaques which, in the presence of a greater
inflammatory content, become unstable with consequent
occlusive or sub-occlusive thrombosis. The atheroma of
patients with DM is richer in lipids, cells, and mediators of
inflammation and thrombi than that of patients not
affected by DM [1].
Endothelial dysfunction
Hyperglycemia and high concentrations of free fatty acids
(FFA) alter the signal transmission pathways involved in
the phosphorylation of endothelial nitric oxide synthase
(eNOS), thus leading to a reduction in nitroxide (NO)
production with consequent endothelial dysfunction and
vascular remodeling.
Macrophage dysfunction
The accumulation of macrophages in adipose tissue,
particularly in patients with visceral obesity, represents a
characteristic process in the context of the pro-
inflammatory state of IR. The polarization of macro-
phages contributes to the development of lipid striae and
vascular damage.
A. Avogaro et al.
Atherogenic dyslipidemia
IR causes an increased inflow of FFA into the liver sec-
ondary to a marked adipose tissue lipolysis. This leads to
greater hepatic production of very-low-density lipopro-
teins (VLDLs) due to the presence of a greater availability
of substrate, a reduction in the degradation of the apoli-
poprotein B-100 (ApoB-100) and an increase in “de novo”
lipogenesis. In T2DM and metabolic syndrome, these
changes lead to a proatherogenic lipid profile character-
ized by high levels of triglycerides (TGs), low levels of
high-density lipoprotein cholesterol (HDL-C), increase in
the synthesis of residual lipoproteins, ApoB, and small and
dense LDLs. This subtype of LDL plays an important role in
atherogenesis by being more prone to oxidation.
Prothrombotic risk
In patients with T2DM, there is a prothrombotic state
characterized by an increased production of plasminogen
activator inhibitor-1 (PAI-1), factors VII and XII, fibrinogen,
and a decrease in tissue plasminogen activator (tPA) levels
[1]. Among the prothrombotic factors that contribute to
the increased risk of CVD events in DM, platelet hyper-
reactivity is of great relevance. A large number of mecha-
nisms contribute to platelet dysfunction, affecting adhe-
sion and activation, as well as the aggregation and stages
of platelet-mediated thrombosis [1].
Reduced regenerative mechanisms
In patients with T2DM, the greatest propensity for CVD is
determined not only by the exposure to more severe CVD
risk factors than in non-diabetic individuals, but also by
the presence of altered cell regeneration processes. Today,
it is believed that in patients with T2DM, a pathological
reduction or dysfunction of endothelial progenitor cells
(EPCs) could prevent the mechanisms of protection from
damage and, therefore, favor the appearance and/or pro-
gression of CVD. In this patient population, the decrease in
the levels of EPC correlates with longer diabetes duration
and poorer metabolic control [2].
Diabetic cardiomyopathy
In patients with T2DM, the presence of IR predisposes to
changes of myocardial structure and function and partially
explains the high prevalence of heart failure (HF) in this
patient population. Patients with unexplained dilated
cardiomyopathy are almost 75% more likely to have
coexisting DM than age-matched control subjects [1].
Prevalence and risk assessment
A meta-analysis of 102 prospective studies showed that
DM confers a double risk for CVD (coronary artery dis-
ease, ischemic stroke, and death from cardio-vascular
causes), regardless of other coexisting CV risk factors. The
risk of CVD events is greater in diabetic women and at a
younger age. This risk is also greater in patients with
long-lasting DM and/or microvascular complications,
Cardiovascular risk and type 2 diabetes mellitus 1673

Table 1 CV risk in patients with DM.

Very high risk Patients with DM and stable CVD or
damage to target organsa
or three or more major risk factorsb
or early onset of long-lasting T1DM (>20
years)
High risk Patients with DM lasting > 10 years
without target organ damage plus
another additional risk factor
Moderate risk Young patients with T1DM and age less
than 35 years or T2DM and age less than
50 years with duration of DM < 10 years
without other risk factors
Modified from 2019 ESC guidelines on diabetes, pre-diabetes, and
CVDs.
a
Proteinuria, renal failure (defined as glomerular filtrate < 30 mL/
min/1.73 m2), left ventricular (LV) hypertrophy, or retinopathy.
b A resting electrocardiogram (ECG) can detect silent
Age, hypertension, dyslipidemia, cigarette smoking, or obesity.
(including those with known CVD) showed that patients
with low plasma NT-proBNP levels (<125 pg/mL) have an
excellent CVD prognosis at short term. The presence of
albuminuria (30e299 mg/day) is associated with an
increased risk of CVD and CKD in both T1DM and T2DM.
EPCs can be considered a CVD risk biomarker in patients
with T2DM. The EPC reduction is associated with greater
carotid-artery intimal medial, suggesting that EPC alter-
ations are an early event and precede the development of
clinical atherosclerosis. EPCs are therefore configured as a
new prototype of CVD risk biomarker that not only reflects
the severity of atherosclerosis, but also has a role in its
development and progression [5].
Electrocardiogram
myocardial infarction (MI) in nearly 4% of people with DM.

Cardiac imaging techniques

including chronic kidney disease (CKD) or proteinuria. It
is important to note that the high risk of coronary artery
disease (CAD) starts at glucose levels below the cut-off
point for diagnosing DM (i.e. <7 mmol/L, <126 mg/dL)
and increases progressively with increasing plasma
glucose levels1. In the presence of DM, the female sex
does not confer a CVD protective effect, as occurs in the
general adult population (Table 1) [3,4].
Screening and use of non-invasive tests for myocardial
ischemia
Biomarkers
The prognostic value of the natriuretic peptide (NT-
proBNP) in an unselected cohort of people with DM
Echocardiography is the first choice to evaluate the
structural and functional abnormalities associated with
DM. Magnetic resonance imaging (MRI) and tissue char-
acterization techniques have shown that patients with DM
without prior CVD exhibit diffuse myocardial fibrosis as a
mechanism of systolic and diastolic ventricular dysfunc-
tion. Computed tomography (CT) is another imaging
technique that provides a non-invasive estimate of the
atherosclerotic load (based on the coronary artery calcium
(CAC) score) and identifies the presence of atherosclerotic
plaques causing significant coronary artery stenosis (CT
coronary angiography (CTCA)). Patients with DM have a
higher prevalence of coronary artery calcifications than
their sex and age-matched counterparts without DM.
While a CAC score of 0 is associated with a favorable

Table 2 Recommendations for the use of laboratory tests, resting ECG and imaging tests for CV risk assessment in asymptomatic patients with
DM.

Class Level of
evidence
Routine microalbuminuria evaluation is indicated to identify patients with DM at risk of I B
renal failure or high risk of future CVD
A resting ECG is indicated in patients with DM with hypertension or suspected CVD I C
Evaluation by ultrasound of carotid or femoral atherosclerotic plaques should be IIa B
considered a risk modifier in patients with DM
CAC score could be considered a risk modifier in the evaluation of CV risk of asymptomatic IIb B
patients with DM at moderate risk
CCTA or functional imaging (myocardial scintigraphy, stress MRI, stress IIb B
echocardiography) could be considered in asymptomatic patients with DM as screening
for CVD
ABI index can be considered a risk modifier in the context of CV risk assessment IIb B
Identification of carotid atherosclerotic plaques by CT or MRI could be considered a risk IIb B
modifier in patients with DM at moderate or high CV risk
Supra-aortic trunk echo-Doppler for measurement of carotid-artery intimal medial III A
thickness is not recommended as a screening for CV risk
Routine evaluation of biomarkers is not recommended for CV risk stratification III B
The use of a risk score for the general population is not recommended for the assessment III C
of CV risk in patients with DM
Modificato da 2019 2019 ESC guidelines on diabetes, pre-diabetes, and CVDs.
ABI: ankle brachial index, CAC: coronary artery calcium, CTCA: computed tomography coronary angiography, CV: cardiovascular, CVD: cardio-
vascular disease, DM: diabetes mellitus, ECG: electrocardiogram, MRI: magnetic resonance imaging.
1674
prognosis in asymptomatic subjects with DM, each in-
crease in the CAC score (from 1 to 99 to 100e399
and > 400) is associated with a relative mortality
risk > 25e33%. Coronary stress tests or CT scan could be
also performed in asymptomatic patients at very high risk
(for example, those with peripheral arterial disease or high
calcium score, proteinuria, or renal failure). The evidence
of unstable coronary plaques is an absolute CVD risk factor,
regardless of the presence or absence of DM. The presence
of renal failure is associated with an increase in all-cause
mortality in both diabetic and non-diabetic patients. Table
2 summarizes the recommendations of the latest Euro-
pean Society of Cardiology (ESC) [3] guidelines.
Symptoms and diagnosis in diabetic patients with stable
angina
Coronary heart disease (CAD) is one of the main chronic
complications of DM: it represents the cause of death in
over 50% of this patient population.
Specific symptoms of CVD may be difficult to ascertain
in patients with DM, because of the coexistence of diabetic
neuropathy [6]. In other cases, however, they follow the
classic anginal symptoms [7].
In patients in whom coronary revascularization is futile
due to comorbidities or reduced life expectancy, the
diagnosis of CAD can be performed clinically and treated
with medical therapy alone. In patients with DM in whom
the diagnosis of CAD is uncertain, it is reasonable to treat
these patients with maximal medical therapy and to sug-
gest invasive cardiac procedures only in the case of
recurrent symptoms (ISCHEMIA trial) [8].
DM confers a two-fold increase in the risk of CAD and,
therefore, the control of coexisting CV risk factors for the
prevention of chronic CAD is strongly recommended
(Table 1). Systolic blood pressure (SBP) in patients with
DM should be < 130 mmHg, but not <120 mmHg, and
diastolic blood pressure (DBP) < 80 mmHg, but not
<70 mmHg. Initial antihypertensive treatment should
consist of a combination of a renineangiotensin system
blocker (ACE inhibitors (ACEIs) or ARBs) with either a
calcium channel blocker (CCB) or a thiazide/thiazide-like
diuretic. ACEIs reduce albuminuria and the progression
of diabetic nephropathy, more effectively than other clas-
ses of antihypertensive drugs; all other CV risk factors
should be controlled accordingly, plasma LDL-C levels
should be reduced to <1.8 mmol/L (<70 mg/dL) or reduced
by > 50% if the basal LDL-C values are between 1.8 and
3.5 mmol/L (70 and 135 mg/dL). According to the latest
ESC/European Association for the Study of Diabetes (EASD)
guidelines, the target for LDL-C should be further reduced
to 55 mg/dL amongst DM patients at very high risk. For
most patients with DM and CVD, it is recommended to
maintain target glycated hemoglobin (HbA1c) levels <7%
(<53 mmoL/l) or <6.5%. Major CV safety trials on new
hypoglycemic drugs, such as SGLT2 inhibitors (sodium-
glucose co-transporter-2 or SGLT2-i) and GLP-1 receptor
agonists (glucagon-like peptide-1 receptor agonist or GLP-
A. Avogaro et al.
1RA), have clearly demonstrated a significant reduction in
major adverse cardiovascular events (MACE).
Symptoms and diagnosis in patients with acute coronary
syndromes
Acute coronary syndromes (ACSs) include unstable angina,
MI without ST segment elevation (NSTEMI) and MI with ST
segment elevation (STEMI).
Patients with ACS may present with typical symptoms
of ischemia, such as oppressive chest pain, or with atypical
symptoms, such as wheezing, nausea, unexplained
asthenia, or with a combination of these symptoms.
Diabetic patients
In patients with T2DM, an atypical presentation of symp-
toms can cause a consequent delay in starting treatment.
Often atherosclerotic disease is particularly widespread,
and the coronaries have small caliber. For these reasons,
the diabetic patient has an increased risk of death and
complications (including repeated revascularizations after
PCI). Regarding antithrombotic therapy and reperfusion
strategy, these are similar to those of the non-diabetic
patient. A more aggressive pharmacological strategy is
particularly recommended in these cases, preferring, when
possible, more powerful antiplatelet drugs, such as pra-
sugrel or ticagrelor.
The control of hyperglycemia must be carried out with
insulin therapy.
In the acute phase and in critically ill patients, it is
reasonable to manage hyperglycemia maintaining a blood
sugar concentration of between 120 and 180 mg/dL, thus
avoiding, absolutely, hypoglycemia associated with a
worse prognosis. It is also important, evaluate renal
function (at least for three days after angiography) in pa-
tients receiving metformin (or SGLT2-i).
Management of ACS in diabetic patients
In diabetic patients, the following medical therapy is rec-
ommended during ACS.

Empagliflozin, canagliflozin, and dapagliflozin reduce
CV events in patients with DM and CVD or in those with
very high/high CV risk.

Liraglutide, semaglutide, and dulaglutide reduce CV
events in patients with DM and CVD or who are at high-
risk CV.

Intensive secondary prevention is indicated in patients
with DM and CAD.

Antiplatelet drugs are a cornerstone of secondary CV
prevention.

In high-risk patients without ACS, the combination of
low-dose rivaroxaban and aspirin may be helpful for
CAD.

Aspirin plus reduced dose ticagrelor may be considered
for <3 years after MI.

In patients with DM and multivessel CAD, coronary
anatomy suitable for revascularization and low ex-
pected surgical mortality, these are elements that favor
Cardiovascular risk and type 2 diabetes mellitus 1675

the intervention of aorto-coronary artery bypass graft
(CABG) to percutaneous coronary intervention (PCI).
Angiographic studies have shown that patients with
DM are more likely to have common trunk disease or
multivessel disease and CAD to be more common and
involve small vessels. In addition, the patient with DM
often has other comorbidities, such as renal failure and
cerebrovascular disease, which negatively influence the
outcomes after coronary revascularization. The data in the
literature show that in stable angina, there are no signifi-
cant differences in patients treated with medical therapy
compared with patients treated with revascularization
(BARI 2D study, ISHEMIA) [4e8].
In the context of chronic HF of ischemic origin
(LVEF < 35%), surgical revascularization (CABG) improves
survival compared with medical therapy [9]. In the ACS-
NSTEMI, a meta-analysis of nine randomized clinical tri-
als (9904 patients) [10] showed a similar benefit to 12
months in terms of death, non-fatal MI or hospitalization
for ACS comparing an early invasive strategy compared
with a conservative strategy in patients with and without
DM.
Regarding the revascularization strategy in multivessel
disease, some randomized clinical studies (FREEDOM,
SINTAX) have compared the two revascularization mo-
dalities in patients with DM, in the context of stable
multivessel CAD or with complex coronary stenosis.
Globally, studies have not shown significant differences in
terms of mortality, MI or stroke in the two groups while
repeated revascularizations are more frequent in the PCI-
treated group. Other data in the literature are in favor of
the surgical procedure in particular in patients with
complex CAD (high SINTAX score) [3].
In general, the data available for revascularization in
patients with DM are more favorable to surgery than PCI.
Although it is necessary to underline how a good part of
these studies was done using first generation DES, the
literature data are often conflicting. Among patients with
DM in the EXEL trial (Evaluation of XIENCE vs. Coronary
Artery Bypass Surgery for Effectiveness of Left Main
Revascularization), the primary endpoint of death, MI or
stroke at 3 years occurred in 21.2% of patients in the PCI
arm and 19.4% in the CABG arm (HR 1.04, 95% CI
0.70e1.55). In NSTE-ACSs, limited comparisons between
PCI and CABG are available.
Overall, current evidence indicates that in stable pa-
tients with coronary anatomy suitable for both PCI and
surgery with low predicted mortality, CABG is superior to
PCI in reducing the composite risk of death, MI or stroke.
However, in diabetic patients with low complexity of
coronary anatomy (SYNTAX score < 22), PCI has obtained
results similar to CABG with respect to the death endpoint
and the composite endpoint of death, IM, or stroke.
Therefore, PCI may represent an alternative to CABG in
patients with low complexity of the coronary anatomy,
while CABG is recommended for mediumehigh-
complexity coronary anatomy (SYNTAX score > 22).
In Table 3, the main recommendations of the ESC 2019
guidelines for the choice of coronary revascularization
procedures are reported.
Future perspectives
It is interesting to note that some drugs that started out
as glucose-lowering drugs have proved to be effective in
the treatment of a CV pathology such as HF. As will be
better specified in a later chapter, the results of the
EMPEROR-Reduced trial [11] were recently published.
Treatment with empagliflozin (10 mg daily) reduced the
risk of CV death or hospitalization for HF in patients with
chronic HF and reduced LV ejection fraction (<40%)
compared with placebo. This study confirms published
data from the VERTIS CV [12] and DAPA-HF trials [13]. All
these randomized controlled trials (RCTs) bring further
evidence to support the use of SGLT2 inhibitors and open
great prospects for patients with HF with reduced ejec-
tion fraction, regardless of the presence or absence of
type 2 DM.

Table 3 Main recommendations of the ESC 2019 guidelines for the choice of coronary revascularization procedures.

Recommendations in accordance with the extension of CAD CABG PCI

Monovasal CAD Class and level of evidence Class and level of evidence
without involvement of proximal anterior interventricular IIb C IC
branch
with involvement of proximal anterior interventricular branch IA IA
Bi-vessel CAD Class and level of evidence Class and level of evidence
without involvement of proximal anterior interventricular IIb C IC
branch
with involvement of proximal anterior interventricular branch IB IC
Tri-vessel CAD Class and level of evidence Class and level of evidence
with low complexity disease (SINTAX score 0e22) IA IIb A
with disease of intermediate or high degree of complexity IA III A
(SINTAX Score > 22)
Left main CAD Class and level of evidence Class and level of evidence
with low complexity disease (SINTAX score 0e22) IA IA
with intermediate degree disease of complexity (SINTAX score 22 IA IIa A
e32)
with high degree disease of complexity (SINTAX score  33) IA III B
1676
Management of hyperglycemia in diabetic patients with
cvd
Glucose-lowering drugs: efficacy and safety
Effective glycemic control plays an important role in pre-
venting chronic complications of DM. An expanding list of
drugs is nowadays available for lowering blood glucose;
these, however, differ in terms of efficacy and especially in
terms of CV safety profile. The latest American Diabetes
Association (ADA)/EASD consensus statement [14] lists the
following class of drugs: metformin, sulfonylureas (SUs),
and metiglinides, pioglitazone, DPP-IV inhibitors, SGLT2
inhibitors, GLP-1 receptor agonists, and insulin analogs.
Metformin is the most commonly prescribed oral
glucose-lowering agent worldwide and is recommended
as first-line therapy by the ADA/EASD, and International
Diabetes Federation [15]. Metformin has been used for
over 50 years and its safety profile is well known [14]. It is
usually very well tolerated (less than 5% of patients have to
discontinue the drug due to gastrointestinal intolerance)
and it is counter-indicated only in severe renal or respi-
ratory insufficiency. Metformin absolute efficacy in terms
of HbA1c lowering depends mostly (as for all diabetes
drugs) on the starting HbA1c level. On average, in T2DM
patients naïve to pharmacological treatment, the HbA1c
reduction is between 0.5 and 0.9% [16].
Whether metformin represents the first line treatment
in the vast majority of patients with T2DM, this concept
has been lately challenged by the most recent ESC and
EASD guidelines [17]. Indeed, this document suggests that
in T2DM patients with atherosclerotic CVD or at high or
very high CV risk, GLP-1 receptor agonists or SGLT2 in-
hibitors should represent the first line of treatment.
However, the efficacy of other diabetes drugs on HbA1c
reduction has mostly been tested as add on to metformin.
On the basis of network meta-analyses [18], it seems fair to
state that the efficacy of the different non-insulin diabetes
drugs on HbA1c reduction is fairly similar among different
agents and it results on an average HbA1c reduction be-
tween 0.7 and 1.0%. However, it should be noted that the
cited network meta-analyses did not include studies con-
ducted with SGLT2 inhibitors and with the latest weekly
GLP-1 receptor agonists (which appear to be more potent
and able to reduce HbA1c by as much as 2.5%). Never-
theless, they did show a trend demonstrating a greater
potency of GLP-1 receptor agonists (relative to other
classes) in reducing HbA1c.
SUs use has been associated with weight gain (although
modest in most cases) and with increased risk of hypo-
glycemia. Hypoglycemia risk is greater with glibenclamide
and less with gliclazide, but all SUs can induce hypogly-
cemia, which can be severe. Several retrospective obser-
vational studies have demonstrated a relationship
between SUs use and increased CV risk [19e21]. However,
still conflicting data are present on this specific topic, as
subsequently discussed.
Pioglitazone does not induce hypoglycemia. Its use is
associated with a 2e4 kg weight increase, but with
A. Avogaro et al.
favorable changes in adipose tissue distribution. Pioglita-
zone affects bone remodeling and an increased risk of
bone fractures has been reported in pioglitazone-treated
patients [22]. The drug also induces water retention and
it is associated with increased risk of hospitalization for
HF. In patients with ascertained CVD pioglitazone
decreased the risk of MACE, and its use seems to be
associated with a decreased risk of stroke as well, as
subsequently reported.
DPP-IV inhibitors do not induce hypoglycemia or
weight gain. They seem to be the best tolerated class of
blood glucose-lowering drugs. Several RCTs have proven
their CV safety, although a signal has been reported for
increased risk of HF hospitalization with the use of sax-
agliptin and alogliptin [23,24]. Such a signal has not been
confirmed in additional studies and has never been
detected for other molecules of the class, such as sita-
gliptin, linagliptin, and vildagliptin.
SGLT2 inhibitors do not induce hypoglycemia and their
use is associated with weight loss. A modest but significant
decrease in BP is also common with SGLT2 inhibitors,
which are also generally very well tolerated. The most
common side effect is genital mycotic infection related to
glycosuria, usually benign and responding to topical
treatment. In older and frail patients, caution needs to be
used for possible volume depletion. Relative to CV risk,
SGLT2 inhibitors are not only safe but, as discussed in the
next section, their use is also associated with protection
against MACE and even more against HF events [25].
GLP-1 receptor agonists do not induce hypoglycemia
and their use is associated with significant weight loss,
particularly pronounced with the latest weekly formula-
tion. Although an oral formulation has very recently been
approved for human use, GLP-1 receptor agonists pres-
ently available have to be administered subcutaneously
with either daily or weekly injections. As for SGLT2 in-
hibitors, also GLP-1 receptor agonist’s use has been asso-
ciated with a modest, but significant decrease in BP. They
are generally well tolerated; the most common side effects
are nausea and, less frequently, vomit and diarrhea.
Nausea might occur in up to 20e25% of patients, but it
generally subsides after the first week of treatment. Rela-
tive to CV risk, although their use is associated with a
modest increase in heart rate, GLP-1 receptor agonists are
not only safe, but also their use appears associated with
protection against MACE, and, in particular, against
atherosclerotic events [26].
It is a common notion that insulin treatment is the
most potent treatment for reducing HbA1c and eventually,
if adequately titrated, insulin treatment should bring to
target the greater majority of T2DM patients. However, in
clinical practice, it is often very difficult to appropriately
titrate insulin, due to hypoglycemia, weight gain, and pa-
tients’ compliance. This has been observed in clinical trials
as well: all studies in which treatment intensification by
basal insulin was compared with treatment intensification
by GLP-1 receptor agonists, failed to demonstrate superi-
ority of insulin treatment [27,28]. Patients treated with
GLP-1 receptor agonists achieved at least the same HbA1c
Cardiovascular risk and type 2 diabetes mellitus
reduction as patients treated with basal insulin, but with
less hypoglycemic events and less weight gain.
Glucose-lowering drugs: data on cardiovascular risk
A fair amount of data exists currently on glucose-lowering
drugs and CV risk, although the more extensive informa-
tion has mostly been gathered for DPP-IV inhibitors, SGLT2
inhibitors, and GLP-1 receptor agonists. In fact, since 2008
and 2012, the Food and Drug Administration (FDA) and the
European Medicines Agency (EMA), respectively, have
required CV outcomes trials (CVOTs) for novel glucose-
lowering drugs to assess CV safety.
The only study demonstrating an effect of metformin in
reducing diabetes-related endpoints, including MI, is the
UKPDS 34 [29]. This study, however, was performed only
in obese patients and data on metformin-treated patients
were compared with those obtained in SUs or insulin-
treated patients. Thus, although metformin has been
credited with protective effects toward CV risk, hard evi-
dence for this is still lacking.
Regarding SUs, concerns about their CV safety have
been raised from several observational retrospective
studies. An analysis of 127,555 patients from the Nation-
wide OsMed Health-DB Database showed that use of a
DPP-IV inhibitor was associated with a reduced risk of
hospitalization for HF compared with SUs use [19]. Similar
results were obtained by Mogensen et al. in the analysis of
a Danish registry, showing that the risk for all-cause
mortality and CV mortality was lower in patients
exposed to incretin-based therapies in combination with
metformin compared with patients exposed to SUs in
combination with metformin [20]. Thus, it would seem
that patients treated with SUs are at greater risk of CVD
compared with those exposed to more innovative treat-
ments. As far as RCTs are concerned, Bain et al. recently
conducted a Bayesian meta-analysis of 82 RCTs, finding an
increased risk in all-cause mortality and CV-related mor-
tality for SUs vs. all other treatments [21]. Thus, on the
basis of the available data, no convincing association be-
tween all-cause mortality or CV mortality and SUs use in
people with T2DM has been clearly demonstrated. On the
other hand, it appears that SUs do not exert any protective
action toward CV risk.
Relationships between CV risk and pioglitazone use
were explored in the first CVOT performed with a glucose-
lowering drug [30]. In particular, the use of pioglitazone in
diabetic individuals with ascertained CVD was associated
with a significant 16% decrease in the risk of occurrence of
a composite endpoint, including all-cause death, non-fatal
MI, and non-fatal stroke. However, pioglitazone treatment
was associated with a 41% increase in the risk of HF. HF-
related mortality was not significantly different in pa-
tients exposed to pioglitazone or to placebo. Thus, thia-
zolidinediones (TZDs) are not recommended in patients
with HF [17]. In a more recent study in a cohort of non-
diabetic insulin-resistant patients who had suffered a
recent stroke, pioglitazone treatment significantly
decreased by 24% the risk of a recurrent stroke [31].
1677
CVOTs conducted with DPP-IV inhibitors have firmly
established CV safety of this class of drugs. In all of these
trials, DPP-IV inhibitors were not inferior to placebo on the
occurrence of MACE [32]. In none of these trials, however,
DPP-IV inhibitors were found superior to placebo in terms
of protection toward the occurrence of CV events. DPP-IV
inhibitors do not offer as well any protection against the
risk of hospitalization for HF. As a matter of fact, for the
molecules saxagliptin and alogliptin, a signal was observed
for a greater risk of hospitalization for HF as compared
with placebo [10,11]. Such a signal was not observed for
sitagliptin and linagliptin, which appear totally and truly
neutral in terms of CV events. ESC/EASD guidelines do not
recommended saxagliptin use in patients with T2DM and a
high risk of HF [17].
CVOTs conducted with SGLT2 inhibitors have not only
firmly established CV safety of this class of drugs, but have
clearly demonstrated CV protection [25]. SGLT2 inhibitors
are responsible of a 10e12% reduction in the risk of the
occurrence of MACE. This risk reduction was significant in
diabetic patients with established CVD, while it was less
pronounced in diabetic patients who had not experienced
a previous CV event. On the other hand, in all CVOTs
conducted with SGLT2 inhibitors, a significant and pro-
found reduction of more than 30% in the risk of hospital-
ization for HF has been observed. This remarkable
reduction appears to be present and to be of the same
magnitude in patients with or without previous history of
HF. Moreover, interestingly, among patients with HF and a
reduced ejection fraction, the risk of worsening HF or
death from CV causes was lower among those who
received dapagliflozin than among those who received
placebo, regardless of the presence or absence of diabetes
[33]. In addition, data from the aforementioned trials
consistently show an SGLT2 inhibitors effect in slowing the
decline of glomerular filtration rate as well as a positive
impact on several kidney-related composite outcomes.
These kidney-protective effects appear to be present
regardless of the status of kidney function at baseline and
regardless of the presence or the absence of history of
previous CV events [25].
As noted for SGLT2 inhibitors, CVOTs conducted with
GLP-1 receptor agonists have not only firmly established
CV safety of this class of drugs, but have clearly demon-
strated CV protection, mainly in terms of atherosclerotic
events. Meta-analyses on the CV effects of GLP-1 receptor
agonists reported a significant average 12% reduction in
the risk of MACE [26]. GLP-1 receptor agonists also reduce
total mortality by 11%, CV mortality by 12%, and stroke by
16% [26]. This effect was clearly demonstrated for liraglu-
tide, semaglutide, dulaglutide, and albiglutide. Less strong
appear the data obtained with exenatide once a week, but
a definite trend for a decrease in the occurrence of the
above-mentioned primary endpoint was observed also
with this molecule [34]. On the other hand, in the trial
conducted with lixisenatide, no protective effect was
observed in patients exposed to the drug [35]. Reasons for
the observed differences among the different molecules
have not been clearly elucidated. Differences in the design
1678
of studies and in the characteristics of the enrolled pa-
tients have been invoked, but it is likely that pharmaco-
kinetics of the different molecules also play an important
role. The protective effects of GLP-1 receptor agonists
treatment against MACE occurrence have been clearly
demonstrated in patients with established CVD. Some
studies, however, enrolled a sufficient number of patients
without history of previous CV events, which allowed to
observe a protective effect of GLP-1 receptor agonists also
in high CV risk diabetic patients who had not experienced
previous CV events [26]. In none of the studies, a decrease
in the rate of hospitalization for HF was observed.
Glucose-lowering drugs to be used in patients with
cardiovascular disease
On the basis of what has been summarized above, the
following statements could be proposed relative to the use
of each class of glucose-lowering drugs in diabetic patients
with CVD:
Metformin use is safe in patients with CVD, however,
there is limited evidence that it might exert protection
against CV events. Caution needs to be used in patients
with impaired kidney function and the drug should not be
administered in presence of estimated glomerular filtra-
tion rate (eGFR) <30 mL/min/1.70 m2 for the potential risk
of lactic acidosis [14]. According to ESC/EASD guidelines
[17], in patients with CVD or at high/very high CV risk
already on metformin, it should not be used as mono-
therapy, since an SGLT2 inhibitor or/and a GLP-1 receptor
agonist needs to be part of the treatment strategy in these
patients to reduce the risk of CV events. In T2DM drug-
naïve patients with the previous reported characteristics,
an SGLT2 inhibitor or/and a GLP-1 receptor agonist should
be used as the first line treatment with the subsequent
addition of metformin to reach HbA1c targets.
SUs should not be used in patients with CVD. Although
no definite evidence exists for these drugs to be harmful in
patients with CVD, they do increase the risk of hypogly-
cemia, and patients with CVD are those in whom hypo-
glycemia must be mostly avoided. Besides, no study has
demonstrated that SUs might help preventing further CV
events in diabetic patients.
Pioglitazone could be used in diabetic patients with
CVD. Its use is associated with a significant reduction in CV
risk. However, pioglitazone does induce fluid retention
and it might increase the risk of hospitalization for HF.
Therefore, TZDs are not recommended in patients with HF.
The use of pioglitazone should be always combined with
either an SGLT2 inhibitor or a GLP-1 receptor agonist.
DPP-IV inhibitors could be used in diabetic patients
with CVD. They might particularly find use in the elderly
patients, given their excellent tolerability profile and their
overall safety. On the other hand, they do not seem to have
per se any protective effect toward recurrence of CV events
or hospitalization for HF. They should be used as combi-
nation therapy with SGLT2 inhibitors, being the rational
for associating them with GLP-1 receptor agonists very
poor.
A. Avogaro et al.
SGLT2 inhibitors are one of the two classes of drugs of
choice in diabetic patients with CVD. Nowadays, most
guidelines and consensus statements [1,4] dictate that a
diabetic patient with CVD must be treated with SGLT2
inhibitors (or GLP-1 receptor agonists). In patients with a
known HF diagnosis, or at risk for HF, treatment with an
SGLT2 inhibitor need be considered as first line therapy.
Similarly, SGLT2 inhibitors should be considered in pa-
tients with an initial impairment in kidney function.
GLP-1 receptor agonists are the other class of drugs of
choice in diabetic patients with CVD. Since it appears that
the CV protection associated with the use of these drugs is
present also in patients at high CV risk who have not yet
experienced a CV event, use of GLP-1 receptor agonists
with demonstrated CV protective effects should be
considered in all diabetic patients at high risk of CVD. As a
matter of fact, most guidelines [1,4] dictate that diabetic
patients with CVD must be treated with a GLP-1 receptor
agonist (or an SGLT2 inhibitor).
Although ample evidence exists that GLP-1 receptor
agonists are not inferior to basal insulin in lowering
HbA1c and in percent of patients who can be brought to
target, in a number of diabetic patients, insulin will be
required to achieve a sufficient glycemic control. Insulin
treatment does not increase CV risk. However, given the
protective CV effects exerted by SGLT2 inhibitors and
GLP-1 receptor agonists, a drug of one of these two
classes (chosen according to patient’s characteristics)
need to be used in combination with insulin in diabetic
patients with CVD.
In conclusion, in diabetic patients with CVD:

It is of the outmost importance to achieve good glyce-
mic control without increasing hypoglycemia risk;

It is mandatory to include in the diabetes treatment
strategy drugs with demonstrated CV protective effects,
such as SGLT2 inhibitors and GLP-1 receptor agonists;

GLP-1 receptor agonists seem to be more potent than
SGLT2 inhibitors in reducing HbA1c and body weight,
thus they should be preferred in patients with CVD in
worse glycemic control and or in need to lose weight.
They are not the drug of choice in patients at high risk
of HF;

SGLT2 inhibitors do have a protective action toward
MACE in patients with established CVD, significantly
reduce HF-related outcomes, and are associated with
slower progression of kidney function impairment.
Therefore, they should be preferred in patients with a
known diagnosis of HF, or in patients at high risk of HF,
and/or in patients with impaired renal function;

Use of GLP-1 receptor agonists and SGLT2 inhibitor in
combination is already approved. At present no study
has explored yet CV outcomes in diabetic patients
treated with both GLP-1 receptor agonists and SGLT2
inhibitors. As the mechanisms responsible for CV
protection are probably different between SGLT2 in-
hibitors and GLP-1 receptor agonists, the use of these
drugs in combination might potentially amplify the
benefit.
Cardiovascular risk and type 2 diabetes mellitus
Management of dyslipidemia in diabetic subjects with
cardiovascular disease
Low-density lipoprotein cholesterol: what are the
optimal levels?
DM is one of the most important environmental patho-
genic factors in the development of CVD. Lipid metabolism
abnormalities are frequent in patients with DM, causing
increased total cholesterol and low-density lipoprotein
cholesterol (LDL-C), TG levels, and reduced levels of high-
density lipoproteins (HDLs). These changes are primarily
due to the effect of IR on lipolysis with an increase in FFA
and VLDLs. For this reason, diabetic patients are frequently
exposed to increased levels of large VLDL particles and
chylomicrons, which generate highly atherogenic remnant
particles (small and dense LDL particles rich in TGs and
dense HDL). Epidemiological, genetic, and clinical studies
have shown that LDL-C is the etiopathogenetic factor
responsible for the development of CVD. Circulating ox-
LDL concentrations are related to the increase in serum
LDL levels, which generate about 90% of circulating ApoB.
Plasma LDL concentrations depend on the amount of
cholesterol coming from food or synthesized by the he-
patocytes and on the liver’s ability to catabolize circulating
LDL.
The first recommendations aimed at lowering LDL
levels to reduce CV risk date back to the early 2000s when
the National Heart, Lung and Blood Institute sponsored the
Heart Protection Studies [36], carried out by the National
Cholesterol Education Program (NCEP). These studies
demonstrated a linear relationship between low LDL levels
and reduced risk of CV events. Another important finding
was observed in newborns, who presented physiological
LDL levels between 20 and 40 mg/dL and thus a very low
probability of developing atherosclerosis. In view of these
demonstrations, LDL target values  100 mg/dL, or even
better  70 mg/dL, were already then recommended in
secondary prevention, especially if the risk of CV events
was very high. The Cholesterol Treatment Trialists’
Collaboration study [37] definitively showed that in pa-
tients with a history of CVD, a reduction of 1 mmol/L of
LDL reduced the risk of coronary events by 23% and CV
events by 21%, in 5 years of follow-up.
Based on this evidence, the 2011 and 2016 ESC guide-
lines for the management of dyslipidemias recommended
(Class I/B) LDL target values < 70 mg/dL (1.8 mmol/L) or
baseline values reduced by 50%, if LDL level was between
70 and 135 mg/dL in patients at high CV risk, including
diabetic patients with a history of CVD.
The IMPROVE-IT study (IMProved Reduction of Out-
comes: Vytorin Efficacy International Trial) [38] showed
for the first time that a reduction of LDL below the values
already considered optimal (<70 mg/dL) in these patient
settings, led to a greater reduction in the primary endpoint
(reduced CV mortality, MI, stroke, and need for myocardial
revascularization; p Z 0.016) in 7 years of follow-up. Pa-
tients treated with simvastatin plus ezetimibe achieved an
LDL target of 53.2 mg/dL compared with 69.9 mg/dL in
1679
those treated with statin (p < 0.001). This study provided
important evidence to further emphasize the primacy of
LDL-C lowering as a strategy to prevent CHD, so “the lower
the better.”
The results of the two trials FOURIER (Further Cardio-
vascular Outcomes Research With PCSK9 Inhibition in
Subjects With Elevated Risk) and ODYSSEY Outcome
(Evaluation of Cardiovascular Outcomes After an Acute
Coronary Syndrome During Treatment With Alirocumab)
[39,40], which studied the effect of monoclonal antibodies
on the reduction of both LDL and CV events in patients
with very high risk of CV, were more surprising than those
obtained by IMPROVE-IT. These studies showed that sub-
jects treated with the PCSK9 receptor inhibitors yielded
LDL target values < 50 mg/dL, which are difficult to ach-
ieve with high doses of statins or with statins plus ezeti-
mibe and this led to an additional benefit of CV events
reduction.
With reference to these three trials [38e40], the Euro-
pean Task Force recommended a further reduction in LDL-
C target values in high-risk patients in order to reach
values of <55 mg/dL (<1.4 mmol/L), or baseline values
reduced by 50%, if the patients were not on statin treat-
ment. Most of diabetic patients fall under this definition.
However, LDL target values < 40 mg/dL (<1 mmol/L) are
recommended in patients with a medical history of ACS,
who experience a second vascular event within 2 years
while taking maximally tolerated statin-based therapy.
Low-density lipoprotein cholesterol: which drug to treat?
LDL-C-lowering treatment is the key stone of diabetic
patients with prior CVD. However, it should be empha-
sized that any pharmacological treatment must always be
accompanied by lifestyle changes in order to reduce the
overall CVD risk.
Statins are still a cornerstone of lipid-lowering therapy
in all patients with DM, both in primary or in secondary
prevention for CVD. Statins often allow, in particular when
they are administered at high doses and associated with
ezetimibe, to reach the set treatment target of LDL-C in
most patients.
In clinical trials involving patients with DM, statins
have been shown to significantly reduce CVD risk and
improve prognosis. In addition to this, statins have been
shown to reduce the 5-year incidence of major CVD
events. The risk was reduced by 23% for each 1 mmol/L of
reduction in the LDL-C level, regardless of the baseline
level [41]. Evidence reported in the literature shows that in
patients at very high risk of CVD, especially those with DM,
high-intensity statins should be preferred due to their
greater efficacy in reducing LDL-C levels, as well as the risk
of CVD events. In fact, atorvastatin and rosuvastatin yield a
50% reduction in LDL-C levels compared with 30% that can
be obtained using a moderate-intensity statin.
The addition of ezetimibe (a drug that inhibits intestinal
cholesterol absorption by blocking the NiemannePick C1-
like protein) yields a further 24% reduction in LDL-C levels
with the extra benefit that it also reduces the risk of CVD
1680
events. The IMPROVE-IT study [38] showed that in patients
with DM, a therapy combined with ezetimibe reduced the
relative risk (RR) for CVD events by 15% and the absolute
risk by 5.5%. This benefit was more marked in diabetic pa-
tients than in normoglycemic subjects; possible explana-
tions of this beneficial effect are the platelet inhibition due
to ezetimibe (the platelet aggregation activity is increased
in diabetic subjects), a reduction in the
cholesterolecholesterol ratio (increased in the diabetic
subject) or a reduction in oxidative stress (increased in the
diabetic subject). It should be emphasized that the combi-
nation of statins and ezetimibe has become the treatment
of choice in these patients as LDL target levels are achieved
more easily, and it is therefore becoming the elective
medical treatment, also in patients who develop ACS.
Particular attention should be paid to patients aged 85
years. In these cases, the guidelines recommend caution in
the administration of high doses of statins, particularly if
they are high-intensity drugs, as they may not improve life
expectancy while increasing the risk of adverse effects.
The ADA guidelines [41] recommend assessment of the
lipid profile in all patients receiving lipid-lowering treat-
ment, initially and after 4e12 weeks of therapy and then
annually to assess response to therapy, adherence and
possible changes to be made to the therapy. If long-term
statin treatment is poorly tolerated or if the LDL-C levels
are not optimal, the administration of monoclonal anti-
bodies, evolocumab or alirocumab, is strongly
recommended.
These drugs inhibit the PCSK9 protein, which plays an
important role in the lipid metabolism and in the cell cycle
of LDL receptors (LDLR). The latter can be internalized
within the cell, whether or not linked to PCSK9. The
complexes that also contain PCSK9 are degraded intracel-
lularly, in particular at the lysosomal level. The complexes
that do not contain PCSK9 release the LDL content into the
cell, but recycle the receptor that goes to the cell surface
ready for a new transport.
The discovery and availability on the market of these
drugs was a novelty of great importance in the treatment
of dyslipidemia, as they have a higher cholesterol-lowering
efficacy than statins, however, they are still very expensive.
Some RCTs [39,40] evaluated the efficacy and safety of
subcutaneous administration of evolocumab 140 mg twice
a month and alirocumab in doses of 75 mg or 150 mg
twice a month for 12 weeks. Both alirocumab and evolo-
cumab effectively reduced baseline values LDL levels by
approximately 60% in patients with very high CV risk,
including diabetes patients. It furthermore seems, that
PCSK9 inhibitors also effectively reduce TG levels while
increasing HDL and ApoA-I levels. An even more inter-
esting fact is that unlike statins, alirocumab and evolocu-
mab can reduce Lp(a) plasma concentrations by 30%e40%.
This effect might explain the further reduction of CV
events obtained with these drugs in patients at very high
risk, who have already achieved LDL target values
(<70 mg/dL). The data on the safety of these drugs are
promising, as the risk of dementia due to cerebral amyloid
accumulation is avoided.
A. Avogaro et al.
The effect of PCSK9 inhibitors is enhanced by the as-
sociation with statins and/or ezetimibe with effectiveness
on the reduction of LDL levels ranging from 75% to 85%. On
the one hand statins reduce LDL levels, but on the other
they increase the expression on the hepatocytes of the
PCSK9 receptors which are antagonized by evolocumab
and alirocumab.
The effects on CV outcomes of these drugs were
assessed in the FOURIER [39] and ODYSSEY Outcomes
trials [40]. The FOURIER trial enrolled 27.564 patients (40%
of whom with diabetes) with a medical history of CVD and
an additional CV risk factor. All patients were receiving the
maximum tolerated dose of statins and presented LDL
values  70 mg/dL (non-HDL > 100 mg/dL). They were
randomly selected to receive treatment with evolocumab
or placebo. Patients treated with evolocumab experienced
a 59% LDL reduction (with a mean reduction from 92 to
30 mg/dL) compared with the placebo group. During the
2.2 years of follow-up alirocumab reduced the composite
endpoint of CV death, MI and stroke by 20% and the RR by
15%; the results were similar in patients with and without
diabetes. However, because the basal risk was higher in
diabetes, the absolute risk reduction was greater in dia-
betes patients (2.7% at 3 years), than in those without
diabetes.
The ODYSSEY Outcome study enrolled 18,924 patients
with recent acute MI or unstable angina. They were
receiving statin therapy and presented LDL levels  70 mg/
dL (non-HDL > 100 mg/dL and ApoB levels > 80 mg/dL).
The patients were randomly selected for treatment with
alirocumab or placebo, and underwent a mean follow-up
of 2.8 years. The patient group receiving alirocumab
experienced a decrease in LDL levels from 92 to 48 mg/dL,
with a relative decrease in the risk of CHD, death, nonfatal
MI, ischemic stroke or unstable angina by 15% (HR 0.85%).
Both studies showed a reduced all-cause mortality rate,
but no significant reduction in CV mortality. It is probable
that the observation period was too short to permit a more
accurate assessment of the effect on outcomes of both
drugs.
Management of hypertriglyceridemia
Lifestyle changes and weight control are the first impor-
tant therapeutic options in the treatment of hyper-
triglyceridemia. Aerobic exercise and a diet free of
saturated fats, alcohol, and simple sugars, are the first
recommended measures to reduce plasma concentration
of TG and increase HDL levels.
Different therapeutic options, such as fibrates and
omega-3 fatty acids, are also available for treatment of
hypertriglyceridemia. As for fibrates, they should be
considered in patients with low HDL and high TG levels.
However, the clinical benefits of fibrates on high TG levels
are still being debated. In patients with type 2 DM and TG
values < 200 mg/dL, the FIELD study (Fenofibrate Inter-
vention and Event Lowering in Diabetes) [42] showed that
fenofibrate in combination with statins reduces CVD
events (non-fatal MI) by more than 25%, with no
Cardiovascular risk and type 2 diabetes mellitus
significant efficacy on CVD mortality. However, recent data
have shown how a common genetic variant on peroxisome
proliferator-activated receptor alpha (PPAR-alpha)dcan
modulate the CVD benefits of fenofibrates and could
identify those diabetic subjects who would benefit most
with such therapy.
Pemafibrate, a selective PPAR-alpha agonist, was able to
improve glucose control and plasma lipid profile, to reduce
low-grade inflammatory state, with an overall protective
effect on atherosclerosis. In patients with DM and hyper-
triglyceridemia, treatment with pemafibrate for 24 weeks
reduced serum TG levels by 45%. In addition to being very
well tolerated, pemafibrate has proved its effectiveness in
increasing HDL and ApoA-I levels and improving the li-
poprotein profile in favor of less atherogenic lipoprotein
subclasses. Therefore, PPAR-alpha receptor agonists asso-
ciated or not with statins are recommended by the current
guidelines in the treatment of hypertriglyceridemia in
patients with DM [43].
Regarding omega-3 fatty acids, data from literature on
the reduction of CVD events are conflicting. The Reduction
of Cardiovascular Events with Icosapent
EthyleIntervention Trial (REDUCE-IT) [44] assessed the
effect of icosapent ethyl 2 g BID on CVD events in 8179
high-risk patients, already on lipid-lowering statin therapy
during a mean follow-up of 4.9 years. This study showed a
20% reduction of serum TG levels, a significant 25%
reduction in the composite endpoint of the study and a
4.8% reduction in the absolute CVD risk. In the treated
group of patients, there was a 1% increase in hospitaliza-
tions due to atrial flutter or fibrillation. However, omega-3
fatty acid (icosapent ethyl) administration 4 gr/day is also
recommended by the current guidelines to treat hyper-
triglyceridemia in patients with DM who are already
treated with statins.
Management of hypertension in t2dm diabetic subjects
with cardiovascular disease
Reference blood pressure in type 2 diabetic patients
according to the latest guidelines
Systemic hypertension is the most prevalent CVD risk
factor in the world and a key target for effective CVD
prevention and its frequent coexistence with type 2 DM
makes BP control in that high-risk subset a major clinical
issue. However, effective BP control requires shared defi-
nitions of BP targets but treatment goals for hypertensive
and diabetic patients have shifted periodically from more
to less lenient thresholds over the last 30 years. Concor-
dant with that trend, the American College of Cardiology
(ACC)/American Heart Association (AHA) Task Force on
Clinical Practice Guidelines released in its 2017 document
a Class I recommendation for 130/80 mmHg as treatment
goal in diabetic patients [45]. That indication, which
departed from preceding less demanding targets, was
influenced by the 2015 publication of the Systolic Blood
Pressure Intervention Trial (SPRINT) that showed for the
first time the additional CV benefits of lowering SBP below
1681
120 mm Hg as compared with the more
conventional < 140 mmHg target [46]. However, diabetics
were excluded from SPRINT since the effect of achieving
lower BP targets (SBP < 120 mm Hg) in hypertensive and
diabetic participants had been tested with negative results
in the BP arm of the Action to Control Cardiovascular Risk
in Diabetes (ACCORD) trial [47]. For several reasons
including that seemingly contradictory evidence, the call
of the ACC/AHA panel to more aggressive attitudes did not
receive uniform acceptance. For example, while the Can-
ada’s 2018 guidelines for diagnosis, risk assessment, pre-
vention, and treatment of hypertension incorporated the
ACC/AHA panel proposal [48]. However, the 2018 joint ESC
and European Diabetes Association guidelines confirmed
140/90 mmHg as the preferred threshold for hypertensive
T2DM patients with the option to lower SBP values below
130 mmHg if tolerated but warning against BP below 120/
80 mmHg [17]. Not dissimilarly, the 2019 ADAstandards of
medical care supported the lower 130/80 mmHg thresh-
olds in high-risk patients, provided their safe attainment
although still recommending the 140/90 mmHg target
[49]. Quite in contrast, the 2019 National Institute for
Health and Clinical Excellence (NICE) proposed a single BP
target < 140/90 mmHg for all diabetic hypertensive adults
under 80 years old [50].
In front of this rather inconsistent series of evidence-
driven guidelines, it seems useful to revise in brief the
scientific evidence in favor or against the current BP tar-
gets in hypertensive patients with T2DM.
Why to pursue lower blood pressure targets in
hypertensive patients with t2dm
The ACC/AHA recommendation for stricter BP targets are
supported by pooled post-hoc analyses of the ACCORD-BP
and SPRINT studies [51e53], the two only RCTs which have
insofar succeeded in a clear separation of BP values in large
randomized cohorts of patients targeted to either strict
(SBP < 120 mmHg) or conventional (<140/90 mmHg) BP
standards. Those reports [51e53] confirmed the benefits of
stricter BP control even in diabetics [51e53] although at
expense of higher rates of serious adverse events (see
below). No evidence was found for the so called J-curve
phenomenon [54], i.e. an increased mortality from coro-
nary ischemia as BP is reduced below some critical level
[54]. The conclusion was strengthened by the reduced
rates of mortality and major vascular events in T2DM pa-
tients with baseline BP < 120/70 mmHg on treatment with
perindoprileindapamide as compared with placebo in a
post-hoc analysis of the Action in Diabetes and Vascular
Disease: Preterax and Diamicron Modified Release
Controlled Evaluation (ADVANCE) trial [55]. That conclu-
sion is consistent with the by now dated results of both the
Hypertension Optimal Treatment (HOT) [56] and the UK
Prospective Diabetes Study (UKPDS) trials [57]. In the
former, in fact, diabetics targeted at DBP < 80 mmHg
showed a 51% reduction in major CV events as compared
with the <90 mmHg target group [57] while in the latter
achieving DBP levels targeted concurrently with a SBP
1682
target <130 mmHg (mean achieved BP:144/82 mmHg)
was associated with a better outcome.
Why to maintain more lenient blood pressure targets in
hypertensive patients with t2dm
The adoption of more conservative SBP
targets < 140 mmHg in hypertensive and diabetic patients
is supported by evidence not weaker than that quoted in
the previous paragraph. A systematic review and meta-
analysis of over 100,000 study participants by Emdin et al.
reported a significantly lower RR of mortality (13%), CV
events (11%), CHD (12%), stroke (27%), albuminuria (17%),
and retinopathy (13%) in patients with baseline
SBP  140 mmHg. However, for baseline SBP < 140 mmHg,
additional SBP lowering did not reduce CV or CHD events
although stroke, retinopathy, and progression of albu-
minuria declined by further decrements in SBP [58], a
conclusion in substantial agreement with two additional
meta-analyses [59,60]. A more negative outlook was pre-
sented by Brunström and Carlberg who, in their analysis of
49 trials including 73,738 participants, most with T2DM,
while confirming the improved outcome of patients on
anti-hypertensive treatment with a baseline SBP of
140e150 mmHg, reported an increased risk of CV mor-
tality and MI for SBP < 130 mmHg [61]. That conclusion is
in line with the post-hoc analysis of the diabetic patients
with CAD enrolled in the International Verapamil SR-
Trandolapril Study (INVEST) study [62] as well as those
recruited in the ONgoing Telmisartan Alone and in Com-
bination with Ramipril Global Endpoint Trial (ONTARGET)
and the Telmisartan Randomised AssessmeNt Study in ACE
intolerant subjects with CVD (TRANSCEND) [63].
Conclusions
Waiting for definitive randomized trials allowing to sup-
port or refute to target SBP below 130 mmHg in hyper-
tensive patients with diabetes, some points may perhaps
help professional providers in their daily clinical
endeavors.
First, lowering BP below 140/90 mmHg is certainly not
a banal achievement in the light of how large is the
number of untreated or uncontrolled hypertensive and
diabetic patients. On that purpose, RAAS blockers ACEIs or
ARBs, particularly in patients with evidence of end-organ
damage (albuminuria and LV hypertrophy) in fixed com-
bination with a dihydropiridine CCB, usually amlodipine,
and thiazide (or thiazide like) diuretics will achieve that
target in most patients, assuming that they adhere to
prescribed medications.
Second, the lower BP target in T2DM will likely asso-
ciate with decreasing benefits in relative terms but abso-
lute risk reduction will be almost certainly larger in
diabetics than non-diabetics because of their higher
baseline CV risk. Stricter BP control will almost certainly
reduce further stroke incidence, which is not little thing
considering the large contribution of stroke to mortality
and permanent invalidity among hypertensive people and
A. Avogaro et al.
the ability to reduce this effect remains the most impres-
sive benefit of antihypertensive therapy.
Third, a J-curve phenomenon might perhaps increase
coronary events at DBP levels <70 mmHg and this possi-
bility has to be taken in careful account when planning a
therapeutic strategy in hypertensive and diabetic patients.
However, all the available meta-analyses and post-hoc
evaluation of previous studies are flawed by the lack of a
priori stratification of patients in well-defined BP strata
such as those attained in SPRINT and ACCORD BP. More-
over, the concept of the J-curve is subject to reverse cau-
sality by which low BP may merely represent a marker of
underlying diseases (congestive HF or cancer) rather than
actively contribute to incident events.
Fourth, care must be taken to serious adverse effects of
stricter BP control will facilitate syncopes and falls
particularly in fragile elderly patients in whom an
aggressive BP lowering strategy is to avoided. Targeting BP
to lower limits may in the long-term deteriorate metabolic
control [64] and deteriorate renal function [65] although
this negative event does not seem to impact on long-term
clinical outcomes [22].
Antiplatelet therapy for cv prevention in diabetes
patients
The role of low-dose aspirin (acetyl salicylic aciddASA),
now well established in secondary CV prevention, is much
debated in primary prevention, where its use is not rec-
ommended by the guidelines, with the exception of
particular risk conditions.
According to CV risk calculators, DM, especially if
associated with the presence of other factors, causes an
increased CV risk, sometimes similar to that conferred by
previous CV events. For this reason, the indication for ASA
in primary prevention in patients with DM represents an
important point of discussion.
In the aspirin risk/benefit ratio, the reduction in the
incidence of colon cancer together with the reduction in
CV events must not be forgotten, while, on the other hand,
the increase in the incidence of bleeding must be taken
into account.
Aspirin for primary prevention: randomized clinical
trials
In subjects with DM, the risk of CV events is 2e4 times
greater than in non-diabetic subjects. Daily administration
of ASA has been a cornerstone for many years in CV pre-
vention for patients with DM. Moreover, the most recent
evidence has questioned the usefulness of the ASA in
primary prevention considering the correct balancing of
risk/benefit ratio.
In a meta-analysis by the Antithrombotic Trialists’
Collaboration (2002), among 4961 patients with diabetes
in nine trials, antiplatelet therapy was associated with a 7%
reduction in serious vascular events and none of the trials
reported major extra-cranial bleeds [66].
Cardiovascular risk and type 2 diabetes mellitus
A 2009 meta-analysis conducted by the same group,
analyzed the use of aspirin as single anti-aggregating
agent in primary prevention and documented a 12%
decrease in CV events, mainly due to the 23% reduction in
non-fatal coronary events. However, no significant varia-
tion in the proportional effect of aspirin was found be-
tween the groups of patients with high CV risk, including
those affected by DM. Moreover, the net effect on stroke
was not significant (instead, with a significant increase in
hemorrhagic strokes), as well as the effect on CV mortality.
In contrast, aspirin treatment was associated with an in-
crease in intra-cranial bleeding, major gastrointestinal
bleeding and extra-cranial bleeding, amplifying the effect
of pre-existing risk factors for bleeding, such as age, dia-
betes, cigarette smoking, and high BP, which were also risk
factors for CAD [67]. A limitation of this meta-analysis is
the reduced number of events analyzed in the subgroup of
diabetic subjects.
The analysis of over 1000 diabetic patients enrolled in
the Primary Prevention Project confirmed a 10% reduction
trend in major CV events in subjects treated with aspirin,
but it was not statistically significant [68]. The Women’s
Health Study included 39,876 healthy women (at the time
of enrollment), aged 45 or more, randomizing them to
aspirin or placebo, with a 10-year follow-up. Aspirin
showed no significant effects on the reduction of acute MI
and CV mortality rates, regardless of the presence of dia-
betes [69]. In the POPAPAD trial, a 2  2 design study, 1276
subjects with type 1 or 2 diabetes, asymptomatic for CVD,
were randomized to 100 mg aspirin with or without a mix
of antioxidants and followed for 6.7 years. No differences
in CV events and mortality were observed between the
groups, nor interaction between aspirin and antioxidants
[70]. In the Japanese Primary Prevention Project (JPPP),
conducted in the 2005e2007 period, 14,644 subjects aged
60 and 85 years, affected by hypertension, dyslipidemia, or
diabetes (approximately 1/3), were randomized to aspirin
100 mg daily or placebo. The study was stopped before the
programmed deadline (approximately 5 years of average
follow-up) for futility: in primary prevention aspirin had
no impact on the composite endpoint of CV mortality, non-
fatal stroke, and non-fatal MI [71].
In the Japanese Primary Prevention of Atherosclerosis
with Aspirin for Diabetes (JPAD), 2539 subjects with type 2
diabetes were randomized to receive ASA 81 or 100 mg
daily or placebo in primary prevention. The study ended in
2008 with a 20% reduction in CV events, not statistically
significant (68 vs. 86, p Z 0.16) [72]. At the 10-year follow-
up, there was no reduction in CV events, with increase in
gastrointestinal bleeding [73]. In the ASCEND trial, con-
ducted in Great Britain, 15,480 type 2 diabetics with no
established history of CVD were randomized to aspirin or
placebo with or without a combination of omega-3 fatty
acids, the average follow-up was 7.4 years. The results of
the analysis showed a 12% significant reduction in major
CV events in the aspirin group (8.5% vs. 9.6%; rate ratio,
0.88; 95% confidence interval [CI], 0.79e0.97; p Z 0.01).
However, the benefit was largely offset by major bleeding,
with a 29% increase compared with control (4.1% with
1683
aspirin vs. 3.2% with placebo: rate ratio, 1.29; 95% CI
1.09e1.52; p Z 0.003); most of them were gastrointestinal
or otherwise extra-cranial [74].
The results of a recent meta-analysis by Scally et al.
showed that proton pump inhibitors can confer substantial
protection from gastrointestinal bleeding and peptic ulcer,
regardless of whether or not NSAIDs are used [75]. It
should be highlighted that in the ASCEND study only one-
fourth of the subjects were treated with a pump inhibitor:
a greater use of these drugs may improve the riskebenefit
ratio of aspirin in primary prevention. The 2019 ESC/EASD
guidelines on prediabetes, diabetes, and CVD indicate ASA
75e100 mg/day for primary prevention in subjects with
DM and high or very high CV risk, with the absence of
clear contraindications (Class IIb, Level A). For subjects
with moderate CV risk, primary prevention treatment is
not recommended (Class III; Level B). A very high risk is
configured by DM associated with confirmed CVD and/or
organ damage, or by the coexistence of three or more
major risk factors or in the case of type 1 DM with disease
duration of more than 20 years. The high risk, on the other
hand, is reached in DM with disease duration > 10 years
without organ damage, associated with any other risk
factor.
The guidelines also emphasize that in subjects treated
with ASA, proton pump inhibitors should be considered to
prevent gastrointestinal bleeding (Class IIa; Level A) [76].
DAPT in diabetic patients: which drugs to use and for
how long
The association of ASA and a P2Y12 receptor antagonist is
prescribed for the treatment of ischemic heart disease,
especially in a fixed-term regimen after coronary angio-
plasty. As discussed, diabetic and non-diabetic patients
derive particular benefit in terms of ischemic recurrence
from the single anti-aggregation in the context of sec-
ondary prevention, in which therapy with ASA
(75e100 mg/day) or clopidogrel (75 mg/day) sine die is
recommended. Therefore, the debate on the use of dual
antiplatelet therapy (DAPT) in particular risk conditions
and again on its duration after myocardial revasculariza-
tion is particularly challenging, especially in patients at
very high risk. Once again, DM represents a factor capable
of increasing both ischemic recurrence and bleeding;
therefore, the careful balance of risk/benefit is not a simple
goal.
In the CHARISMA trial, the addition of clopidogrel to
ASA for 28 months in stable patients with a history of AMI,
stroke, or peripheral arterial disease, reduced CV events
similarly in diabetics and non-diabetic subjects, but with
an effect balanced by an increased risk bleeding in di-
abetics; the protective action of DAPT was also reduced in
the subgroup with diabetic nephropathy [77].
A meta-analysis by Gargiulo et al., in 2016 analyzed the
effect of DAPT (ASA þ thienopyridine) for 6 months
compared with 12 months in patients undergoing PCI with
drug-eluted stent implantation, in the presence or absence
of DM. Although DM was an independent predictor of
1684
ischemic recurrence, DAPT for 12 months, when compared
with DAPT for only 6 months, did not reduce the ischemic
risk, increasing the risk of bleeding both in patients with
DM and in the non-diabetic group [78].
Clopidogrel (loading dose of 300 mg followed by
75 mg/day for 9 months) vs. placebo in addition to ASA
therapy in subjects with NSTEMI has been studied in the
CURE trial, showing similar efficacy in diabetic compared
with non-diabetic subjects [79]. In the TRITON-TIMI-38
trial, 13,608 patients with mediumehigh-risk ACS were
randomized to receive prasugrel (loading dose 60 mg,
maintenance dose 10 mg/day) or clopidogrel (loading dose
300 mg, dose maintenance 75 mg/day) for a period be-
tween 6 and 15 months after PCI. Prasugrel compared with
clopidogrel reduced MACE in diabetic subjects by 30%, in
non-diabetic subjects by 14% (approximately 19% in the
global study population), however, it led to a significant
increase in the bleeding rate [80]. In the PLATO trial,
ticagrelor (loading dose of 180 mg followed by 90 mg
twice a day) compared with clopidogrel in subjects with
ACS reduced MACE after 1 year in both diabetic and non-
diabetic patients (RR reduction (RRR), respectively, 12%
and 17%), with a modest increase in the risk of bleeding
[81]. There is therefore no particular evidence in favor of
the use of a specific P2Y12 inhibitor compared with
another, to be associated with aspirin in the diabetic
population.
As regards the duration of treatment with dual anti-
aggregation, the DAPT study assessed the efficacy beyond
one year, for 30 months, of the therapy with prasugrel or
clopidogrel vs. single anti-aggregation with ASA in patients
undergoing DES implantation for stable CAD or ACS. Pro-
longed therapy with thienopyridines significantly reduced
the risk of intra-stent thrombosis and other MACE, how-
ever, leading to increased bleeding risk. The RRR was
slightly lower for MI in patients with diabetes than in
those without diabetes (P interaction Z 0.02) with ho-
mogeneous results for other ischemic and safety endpoints
[82].
In the PEGASUS-TIMI 54 study, treatment with tica-
grelor 90 or 60 mg  2/day in addition to ASA vs. ASA
alone in subjects with a history of IMA in the previous 1e3
years, led to a reduction of MACE in both diabetic and
nondiabetic subjects, with a greater absolute benefit in
diabetes, and a better clinical benefit with 60 mg  2/day
ticagrelor compared with 90 mg  2/day, thanks to a
similar reduction of ischemic events associated with a
lower risk of bleeding. In patients with diabetes, prolonged
ticagrelor therapy reduced CV mortality by 22% and MI
mortality by 34% [83]. The THEMIS-PCI trial enrolled pa-
tients with type 2 DM and stable CAD previously treated
with PCI (patients with previous stroke or MI were
excluded). The active arm received ticagrelor in addition to
aspirin, with a reduction in the incidence of CV death, MI,
and stroke, but an increase in major bleeding. The inci-
dence of a combined endpoint (death from all causes, MI,
stroke, fatal bleeding, or intracranial hemorrhage) was
similar in the ticagrelor group compared with the placebo
group (10.1% vs. 10.8%; HR 0.93; 95% CI, 0.86e1.02) [84].
A. Avogaro et al.
The evidence therefore shows that a platelet inhibition
with P2Y12 inhibitors in diabetics after ACS, due to the
higherisk profile, should be indicated for 1 year, especially
in subjects without a high risk of bleeding [85].
ESC guidelines 2019 recommend (Class I; Level A) the
use of ticagrelor or prasugrel in addition to ASA for 1 year
in diabetic subjects with ACS undergoing PCI or CABG.
Prolonged treatment with DAPT beyond 1 year can be
considered in selected patients with type 2 DM and
ischemic heart disease (acute or chronic) who have well-
tolerated DAPT for 12 months in the absence of major
bleeding complications (Class IIa; Level A). Finally, the
addition of a second anti-thrombotic agent to the ASA in
long-term secondary prevention should be considered in
patients without a high risk of bleeding (Class IIa; Level A)
[76].
Last, in the COMPASS trial, the effectiveness of the addition
of the factor Xa inhibitor rivaroxaban, 2.5 mg  2/day in
addition to ASA 100 mg/day or monotherapy at a dosage of
5 mg  2/day was compared with ASA 100 mg/day in patients
with stable atherosclerotic vasculopathy. The study was
interrupted prematurely after an average 2.3-year follow-up
for superiority of rivaroxaban 2.5 mg  2/day þ ASA
compared with ASA alone in the reduction of the primary
composite endpoint (CV death, stroke, or MI) [86]. A sub-
analysis by Bhatt et al. revealed a similar RRR between dia-
betic and non-diabetic subjects. However, due to the higher
basal risk in diabetic subjects, the absolute reduction appears
greater in patients with diabetes (2.3% vs.1.4% for the primary
3-year endpoint) [87].
Heart failure and type 2 diabetes mellitus
Epidemiology and prognosis of heart failure in diabetic
patients
A close bidirectional interaction exists between HF and
DM. DM is frequently observed in HF patients with a
prevalence ranging from 10% to 30% and up to 40% in
hospitalized HF subjects [88]. Similarly, a state of IR, even
in absence of overt DM, is frequently reported in HF, with
an observed prevalence of about 70% [89]. Conversely,
symptomatic or asymptomatic LV dysfunction is a com-
mon cardiac finding in DM. The prevalence of HF in the
general population is approximately 1e2%, rising up to
12e30% in diabetic patients [90]. Unrecognized HF is also
frequent in DM (25% HF with reduced ejection fraction,
HFrEF; 75% HF with preserved ejection fraction, HFpEF).
Pathophysiology of heart failure in diabetic patients
Two different forms of HF can be observed in DM. The first
is a typical myocardial dysfunction consequent to CAD
with no specific characteristics and quite similar to the
general population. The other one is a typical manifesta-
tion of DM known as diabetic cardiomyopathy, a distinc-
tive cardiac dysfunction of diabetic patients, characterized
by a cardiac dysfunction that occurs in absence of CAD,
uncontrolled hypertension, significant valvular heart
Cardiovascular risk and type 2 diabetes mellitus
disease, and congenital heart disease. The typical cardiac
phenotype of diabetic cardiomyopathy is characterized by
a restrictive disease with LV hypertrophy and diastolic
dysfunction. Conventionally, two stages are recognized: an
early stage characterized by LV concentric hypertrophy,
increased myocardial stiffness and filling pressures, and
impaired diastolic function, and a late stage characterized
by myocardial fibrosis, progression of diastolic dysfunc-
tion, and systolic impairment. Seferovic et al. [91] pro-
posed that with this classification we are probably facing
with two distinct phenotypes of diabetic cardiomyopathy,
as a restrictive/HFpEF phenotype and a dilated/HFrEF
phenotype rather than with two successive stages of the
same disease. The pathophysiologic mechanism underly-
ing diabetic cardiomyopathy are still under investigation
and many hypotheses were proposed, as 1) change in
substrate metabolism and cardiac lipotoxicity, 2) endo-
thelial and microvascular dysfunction, 3) advanced gly-
cated end-products deposition, and 4) inappropriate
neurohormonal response.
Basically, all the above-described mechanisms are
accompanied by mitochondrial dysfunction, endoplasmic
reticulum stress, and impaired calcium handling, contrib-
uting to the occurrence and progression of diabetic car-
diomyopathy and might represent in the next future
potential new therapeutic targets.
Treatment of heart failure in patients with type 2
diabetes mellitus
In 2019, the ESC developed in collaboration with the EASD,
new practice guidelines for the management of patients
affected by DM and CVDs [17]. The majority of HF treat-
ment beneficial effects, reported in RCTs, are consistent
with and without DM at baseline. ACEIs and beta-blockers
are recommended in symptomatic patients with HFrEF
and DM, to reduce the risk of HF hospitalization and death
(Class of Recommendation IA). The addition of a mineral-
ocorticoid receptor antagonist (MRA) is indicated in HFrEF
diabetic patients who remain symptomatic despite a
maximum tolerated dose treatment with ACEIs and beta-
blockers (Class of Recommendation IA). Sacubitril/valsar-
tan is indicated in HFrEF in replacement of ACEIs to reduce
the risk of HF hospitalization and death in patients still
symptomatic, despite treatment with ACEIs, beta-blockers,
and MRAs (Class of Recommendation IB). Regarding other
drugs, angiotensin receptor blockers (ARBs) are indicated
in HFrEF symptomatic patients not tolerating ACEIs,
whereas diuretics are recommended in all HF forms in
presence of signs and/or symptoms of fluid congestion, to
improve symptoms; ivabradine should be considered in
patients with HFrEF and DM in sinus rhythm, with a
resting heart rate  70 bpm, who remain symptomatic
despite treatment with maximal tolerated dose of beta-
blockers, ACEIs/ARBs, and MRAs, or in patients not toler-
ating beta-blockers to control heart rate. Aliskiren is not
recommended in HFrEF and DM because of a higher risk of
hypotension, worsening renal function, hyperkalemia, and
stroke.
1685
Recommendations for devices and revascularization
procedures, and for ICD/CRT are the same as in the general
population, whereas cardiac revascularization with sur-
gery has shown similar beneficial effects in HFrEF patients
with and without DM, and is recommended for patients
with two- or three-vessel coronary disease, including a
significant left anterior descending stenosis. Heart trans-
plantation could be considered in end-stage HF, however,
DM-transplanted patients have a decreased likelihood of
long-term survival.
Prevention of heart failure by glucose-lowering drugs
Anti-diabetic drugs with potential negative effects
TZDs are contraindicated in patients with overt HF because
rosiglitazone and pioglitazone trials showed higher risk of
hospitalization for HF (HHF), even if mortality was not
affected. Initial data about dipeptidyl-peptidase 4 in-
hibitors (DPP4-i) suggested that they may have deleterious
effects, however, a neutral effect was observed with sita-
gliptin (TECOS) [92] and linagliptin (CARMELINA) [93]
treatments. We have no RCTs specifically designed to test
the CV effects of SUs, but based on prospective and
retrospective observational studies, it was suggested that
SUs have higher risk of HHF when compared with met-
formin and similar to that of TZDs [94]. With this respect,
the pragmatic trial TOSCA did not show different outcomes
comparing pioglitazone and SUs (mainly gliclazide) [95]
and, more recently, CAROLINA showed no CVD difference
between linagliptin and glimepiride [96], even if in these
studies the prevalence of HF at baseline was very low.
Finally, even if it is recognized that insulin may exert a
dose-dependent sodium retention effect at the renal level
[97] and several retrospective observational studies re-
ported poorer prognosis in patients with HF treated with
insulin, specific RCTs are lacking. Said that, the RCTs of CVD
safety with insulin glargine (ORIGIN) [98] and degludec
(DEVOTE) [99] did not detect a higher risk of HHF.
Anti-diabetic drugs with positive effects
2019 ESC/EASD guidelines recommend sodium glucose
transport protein-2 inhibitors as first choice in HF patients,
naïve to metformin. There are many RCTs focused of CV
effects of glucagon-like peptide 1-receptor agonists (GLP-
1RA), but there is a lack of focus on HF. Based on a recent
meta-analysis, these drugs showed a small protective ef-
fect on HHF (HR 0.91, 95% CI 0.83e0,99, p Z 0.02), sug-
gesting that these may be considered safe drugs in patients
with HF [26,100].
Since 2008 and 2012, the FDA and the EMA, respec-
tively, have required CVOTs for novel glucose-lowering
drugs to assess CV safety. Unexpected favorable results
have been obtained from CVOTs on sodium-glucose
cotransporter-2 inhibitors (SGLT-2i), also named gli-
flozins, in term of HF outcomes prevention.
The first published study, the EMPA-REG OUTCOME
trial [101] treated 7020 type 2 DM patients at high CV risk
with empagliflozin or placebo on top on usual anti-
diabetic therapy for a median of 3.1 years and
1686
demonstrated, in empagliflozin-treated patients, signifi-
cantly lower rates of death from CV causes (3.7 vs. 5.9%,
respectively, 38% RR reduction), lower rates of hospitali-
zations for HF (2.7 vs. 4.1%, respectively, 35% RR reduction),
together with a reduced risk of all-cause death. Similar
safety and tolerability profile in empagliflozin and placebo
groups was observed. A retrospective analysis of the
EMPA-REG OUTCOME trial [102] analyzed the effects of
empagliflozin in diabetic patients having HF at baseline
(n Z 706, 10.1%). The investigators reported significantly
lower rates of HF hospitalizations or CV death with
empagliflozin vs. placebo (5.7% vs. 8.5%, respectively, HR
0.66; p < 0.0001), corresponding to a number needed to
treat of 35 over 3 years. Subgroup analysis revealed that
the benefits of HF outcomes of empagliflozin were inde-
pendent from the presence of HF at baseline excluding that
trial results were driven by patients already having HF at
enrollment. Similarly, the CANagliflozin cardioVascular
Assessment Study (CANVAS) [103] compared canagliflozin
300 mg vs. placebo. CANVAS program included two trials:
CANVAS and CANVAS-R, this last designed to evaluate
renal endpoints. Entirely, 10,142 patients (4330 in CANVAS
and 5812 in CANVAS-R) were enrolled and followed for 3.6
years. Differently from EMPA-REG OUTCOME, only 2/3 of
the enrolled population had CVD at baseline (65.6%). The
rate of the primary outcome (composite of CV death, non-
fatal MI, or stroke) was lower with canagliflozin vs. pla-
cebo (26.9 vs. 31.5 participants per 1000 patient-years; HR
0.86; 95% CI 0.75e0.97; p < 0.001 for non-inferiority;
p Z 0.02 for superiority). No significant differences were
found for the single components of the primary outcome
when individually considered. HF hospitalizations were
significantly reduced with canagliflozin (HR 0.67, 95% CI
0.52e0.87) with a 33% RR reduction. Moreover, canagli-
flozin showed beneficial effects on progression of albu-
minuria (HR 0.73; 95% CI 0.67e0.79) and on renal
outcomes (HR 0.60; 95% CI 0.47e0.77). Serious adverse
events were less common in the canagliflozin group;
however, there was a higher risk of amputation of toes,
feet, or legs with canagliflozin than placebo (6.3 vs. 3.4
participants per 1000 patient-years, HR 1.97; 95% CI
1.41e2.75). A recent analysis on this specific point [104],
showed that anticipated risk factors for amputation were
identified in patients that underwent amputation during
the trial, such as prior amputation history, peripheral
vascular disease and neuropathy, but no specific etiological
mechanism or at-risk subgroup for canagliflozin was
identified. Thus, the FDA suggests that canagliflozin is not
recommended in patients with conditions at risk for future
amputation. Moreover, for the CANVAS, a subanalysis on
HF outcomes has been published, analyzing patients hav-
ing HF at baseline (14.4%) [105]. Canagliflozin reduced the
risk of CV death or HF hospitalizations across a broad
range of different patient subgroups, however, benefits
were greater in those with HF history at baseline. The last
published trial, the Multicenter Trial to Evaluate the Effect
of Dapagliflozin on the Incidence of Cardiovascular Events
(DECLARE-TIMI58) [106] enrolled 17.160 diabetic patients
to dapagliflozin 10 mg or placebo with a median follow-up
A. Avogaro et al.
of 4.2 years. Fifty-nine percent (n Z 10.186) of enrolled
patients were on primary CV prevention. In efficacy ana-
lyses, dapagliflozin did not result in a lower rate of MACE
(8.8% vs. 9.4% in the placebo group; HR 0.93; 95% CI
0.84e1.03; p Z 0.17), but showed a lower rate of CV death
or hospitalization for HF (4.9% vs. 5.8%; HR 0.83; 95% CI
0.73e0.95; p Z 0.005), which mainly reflected a lower
rate of HF hospitalization (HR 0.73; 95% CI 0.61e0.88); no
between-group difference in CV death was observed (HR
0.98; 95% CI 0.82e1.17). A DECLARE-TIMI58 subanalysis
[107] investigated the impact of baseline EF on the clinical
benefit of dapagliflozin in 11.6% of patients with HF at
baseline (3.9% with HFrEF and 7.7% with HFpEF). Dapagli-
flozin reduced HF hospitalizations in patients with and
without HFrEF and CV death and all-cause mortality in
patients with HFrEF. The mechanisms underlying these
effects are unknown and many potential contributors have
been advocated, including effects on plasma volume,
arterial stiffness, sympathetic nervous system modulation,
and cardiac remodeling [108]. The interesting aspect of
gliflozins is the early effect on HF outcomes with a benefit
in few weeks/months after drugs begin. This suggests an
early beneficial neurohumoral/hemodynamic effect that
significantly impacts on CV protection.
Recently, ertugliflozin data have been presented (eVal-
uation of ERTugliflozin effIcacy and Safety CardioVascular
outcome trialdVERTIS-CV), but the trial, that confirmed
the efficacy on a gliflozin on HF outcomes, but has some
controversial points, has not yet been published.
European guidelines [17] suggest the use of gliflozins
(or GLP-1, depending on patients’ profile) as first choice in
diabetic patients with known CVD or at high CV risk, or as
second choice in patients already taking metformin. Since
for patients in the so-called primary prevention the risk
profile of atherosclerotic CVD and HF may be largely
overlapping, estimates of risk of future development of HF
are needed in parallel with the well-known for the CV
atherosclerotic events [109].
Glucose-lowering drugs for heart failure treatment in
non-diabetic subjects
After the interesting results obtained in term of CV pro-
tection with gliflozins, a dense trials program started to
assess the benefit of these drugs in HF patients indepen-
dently from the presence of DM. The first published study
was the Study to Evaluate the Effect of Dapagliflozin on the
Incidence of Worsening Heart Failure or Cardiovascular
Death in Patients With Chronic Heart Failure (DAPA-HF)
[33] evaluating the efficacy of dapagliflozin vs. placebo in
4.744 HFrEF patients on a composite of worsening HF
(hospitalization or an urgent visit resulting in intravenous
therapy) with a median follow-up of 18.2 months, and on
top of HF recommended treatment. Enrolled patients had a
median EF of 31%, were mostly distributed among NYHA
Classes I and II, and only 42% of them had a known diag-
nosis of DM. The primary endpoint occurred in 386 (16.3%)
dapagliflozin patients and in 502 (21.2%) placebo subjects
Cardiovascular risk and type 2 diabetes mellitus
(HR 0.74; 95% CI 0.65e0.85; p < 0.001) with a significant
RR reduction of 26% and a number needed to treat of 21.
A small (11%) subgroup of enrolled patients were
treated with sacubitril/valsartan, and in these patients,
there were no different favorable effects of dapaglifozin
compared with patients not receiving this combination.
Thus, although additional data in larger number of pa-
tients are warranted, the beneficial effects of dapaglifozin
appear to be incremental to those of optimized HF treat-
ment, including neprilysin inhibition. Dapagliflozin also
improved quality of life and HF symptoms perception, and
its effect was maintained regardless the presence or
absence of DM. This demonstration of the CV benefits of
dapagliflozin in patients without DM provides support for
prior suggestions that such treatment has beneficial ac-
tions other than glucose-lowering.
Recently, the results of the EMPEROR-Reduced trial
have been published, confirming the observation of DAPA-
HF study on the beneficial effects of a gliflozin in HFrEF
patients independently from the presence of diabetes at
baseline [110].
FDA granted priority review for the use of dapagliflozin
in HFpatients, thus in the next future, gliflozins will be
introduced as HF-specific drugs newly changing the ther-
apeutic and prognostic pathway of such a complex disease.
An interesting clinical issue is how to combine SGLT2-i
with ongoing HF treatment. A strict control of renal
function, electrolytes, body weight, and BP is necessary in
combination treatments. SGLT2-i are not recommend in
presence of hypovolemia, however, in euvolemic condi-
tions, attention should be focused on BP trend over time,
reducing diuretics dose, if possible, in case of symptomatic
hypotension. Specific attention needs to be paid in case of
conditions leading to dehydration (fever, gastroenteritis,
and surgical stress) when SGLT2-i and diuretics are used in
combination. With this respect, it was suggested to avoid
starting the treatment in these conditions [111]. If a com-
bination therapy with diuretics is present, SGLT2-i may be
initiated without changing the dose of thiazide diuretics,
meanwhile the dose of loop diuretics should be reduced by
a half taking into consideration the re-introduction of the
previous dose in the case of gain of weight of BP [111].
Conflicts of interest
The authors declare that they have no known competing
financial interests or personal relationships that could
have appeared to influence the work reported in this
paper.
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