diabetes research and clinical practice 159 (2020) 107726

Contents available at ScienceDirect

Diabetes Research
and Clinical Practice
journal homepage: www.elsevier.com/locat e/dia bre s

Invited review

Series: Implications of the recent CVOTs in type 2

diabetes
Impact on guidelines: The endocrinologist point of view

André J. Scheen *
Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU Liège, University of Liège, Liège, Belgium
Clinical Pharmacology Unit, CHU Liège, Center for Interdisciplinary Research on Medicines (CIRM), University of Liège, Liège, Belgium

A R T I C L E I N F O A B S T R A C T

Article history: The management of type 2 diabetes mellitus (T2DM) essentially consists in controlling
Received 2 May 2019 hyperglycaemia, together with other vascular risk factors, in order to reduce the incidence
Accepted 8 May 2019 and severity of diabetic complications. Whereas glucose control using classical glucose-
Available online 18 May 2019 lowering agents (except perhaps metformin) largely fails to reduce cardiovascular disease
(CVD), two new pharmacological classes, glucagon-like peptide-1 receptor agonists (GLP-
1RAs) and sodium-glucose cotransporter type 2 inhibitors (SGLT2is), have proven their abil-
Keywords:
ity to reduce major cardiovascular events in patients with established CVD. Furthermore,
Cardiovascular disease
SGLT2is reduced the risk of hospitalisation for heart failure and the progression of renal
GLP-1 receptor agonist
disease. According to the 2018 ADA-EASD consensus report, the choice of a second agent
Guidelines
to be added to metformin should now be driven by the presence or not of atherosclerotic
Heart failure
CVD, heart failure or renal disease, all conditions that should promote the use of a SGLT2i
Chronic kidney disease
or a GLP-1 RA with proven efficacy. Thus endocrinologists have to face a new paradigm in
SGLT2 inhibitor
the management of T2DM, with a shift from a primary objective of glucose control without
Type 2 diabetes
inducing hypoglycaemia and weight gain to a goal of cardiovascular and renal protection,
largely independent of glucose control. Of note, however, the latter remains crucial to
reduce the risk of microangiopathy.
Ó 2019 Published by Elsevier B.V.

Contents

1. Introduction . . . . . . . . . .
2. The classical view . . . . .
3. The new paradigm . . . . .
3.1. Need for detection
3.2. Need for detection
........................................................................... 2
........................................................................... 2
........................................................................... 3
of atherosclerotic cardiovascular disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
of heart failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

* Address: Department of Medicine, CHU Sart Tilman (B35), B-4000 Liège 1, Belgium.
E-mail address: andre.scheen@chuliege.be.
https://doi.org/10.1016/j.diabres.2019.05.005
0168-8227/Ó 2019 Published by Elsevier B.V.
2 diabetes research and clinical practice 159 (2020) 107726

3.3. Need for detection of renal disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

3.4. Need for a collaboration between diabetologists, cardiologists and nephrologists . . . . . . . . . . . . . . . . . . . . . . . . . 4
4. Future perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
4.1. Cardiovascular protection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
4.2. Heart failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
4.3. Renal disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Funding and conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

1. Introduction The aim of this concise review is to describe the changes

Type 2 diabetes mellitus (T2DM) is a complex disease charac-
terized by chronic hyperglycaemia, which gradually increases
over time essentially because of a progressive B-cell failure.
Hyperglycaemia leads to specific microangiopathic complica-
tions and a good glucose control has been shown to reduce
both the incidence and the severity of complications such as
retinopathy, nephropathy and neuropathy [1,2]. However,
T2DM is associated with other cardiovascular risk factors,
such as abdominal obesity, arterial hypertension, dyslipi-
daemia, thrombogenic status, low-grade inflammation, and
oxidative stress [2]. All these risk factors trigger and accelerate
atherothrombosis, which results in cardiovascular disease
(CVD), i.e. coronary heart disease (myocardial infarction),
stroke and peripheral arteriopathy. Almost two-thirds of
patients with T2DM will die from CVD and almost half from
coronary artery disease. A better management of precipitating
factors during the last two decades allowed reducing the inci-
dence of cardiovascular complications, yet the residual risk
remains high in patients with T2DM [3]. Furthermore, chronic
kidney disease (CKD) remains a concern [4,5] and heart failure
(HF) becomes a complication of major interest [6,7], both at
least partly due to the reduction in premature death among
T2DM patients thanks to a a better global management.
Since 2008 and the recommendations by the U.S. Food and
Drug Administration (FDA) [8], the focus in T2DM was placed
on CVD, with the aim first to demonstrate the cardiovascular
safety of new glucose-lowering agents. For this purpose,
numerous cardiovascular outcome trials (CVOTs) were carried
out and several others are still ongoing [9,10]. They demon-
strated the cardiovascular safety of new compounds such as
dipeptidyl peptidase-4 (DPP-4) inhibitors (DPP-4is or gliptins)
[11,12], glucagon-like peptide-1 receptor agonists (GLP-1RAs)
[13,14] and sodium-glucose cotransporter type 2 inhibitors
(SGLT2is) [11,15]. Furthermore, some GLP-1RAs and SGLT2is
demonstrated superiority versus a placebo in T2DM patients
at high risk of CVD, with a significant reduction in major car-
diovascular events (MACEs) [9,10,14,16]. In addition, SGLT2is
also reduced hospitalisation for HF and the progression of
renal disease [17–19]. The positive results on cardiovascular
and renal outcomes profoundly influence the most recent
consensus statement by the American Diabetes Association
(ADA) and the European Association for the Study of Diabetes
(EASD) [20]. In the meantime, other societies of cardiology
[6,21,22] and nephrology [23] also published new algorithms
for the management of patients with T2DM at high risk of car-
diovascular (including HF) and renal complications.
in the management of T2DM, from the classical view to the
recent new paradigm proposed by the ADA-EASD consensus
report. We will also anticipate the potential impact of results
from ongoing clinical trials in patients with HF or CKD, which
might markedly influence further guidelines. Finally, we
emphasize the need for a new perspective by endocrinolo-
gists for the management of patients with T2DM and describe
some practical implications, especially when patients are
considered to be at high risk of CVD, HF or CKD.
2. The classical view
The main objective of diabetes management has been for a
long time to avoid acute (severe hyperglycaemia or hypogly-
caemia) and chronic (vascular) diabetic complications. The
first concern was mainly microangiopathic complications,
especially retinopathy, nephropathy, and neuropathy. It has
been demonstrated that adequate glycaemic control
(assessed by a glycated haemoglobin or HbA1c < 7% or
53 mmol/mol) is able to avoid or at least retard the occurrence
of such complications [1,2]. However, the effects of intensive
glucose control and of commonly used glucose-lowering
agents on macrovascular complications were more controver-
sial [24,25]. Thus, following the results of the STENO-2 study
[26], the focus during the last 15 years was set on a multifac-
torial approach targeting all cardiovascular risk factors,
beyond hyperglycaemia, especially dyslipidaemia, arterial
hypertension and platelet aggregation [27].
In the ADA-EASD consensus report published in 2015 [28],
metformin was considered as the first pharmacological
choice, combined with appropriate lifestyle changes. In case
of failure of metformin monotherapy, the addition of
another glucose-lowering agent was mainly based upon
metabolic criteria, i.e. the efficacy assessed by the reduction
in HbA1c, the effect on body weight, and the risk of hypogly-
caemia, together with the tolerance (mainly gastrointestinal)
profile and the cost of the therapy. Considering all these
items, the clinician may choose between adding a sulphony-
lurea, a thiazolidinedione, a DPP-4i, an SGLT2i, a GLP-1RA or
basal insulin, depending on the patient profile and prefer-
ence and on the main objective (to avoid hypoglycaemia,
weight gain or high cost) [28]. Thus, because of the lack of
evidence from CVOTs and renal studies in 2015, the focus
was not placed on cardiovascular and renal complications
at that time, but rather on safe glucose control, an area
where endocrinologists (diabetologists) may be considered
as experts.
 diabetes research and clinical practice 159 (2020) 107726 3

3. The new paradigm peripheral artery disease, including revascularisation. How-

The results from recent CVOTs that have investigated DPP-4is,
GLP-1RAs and SGLT2is [9–11] led to an updated consensus
report by the ADA and the EASD published in 2018 [20]. It pro-
posed a new paradigm for the management of hyperglycaemia
in patients with T2DM not well controlled with lifestyle and
metformin monotherapy depending on the presence or not of
comorbidities (Fig. 1) [20]. This new strategy has been endorsed
by several other national diabetes societies or study groups
[22,29]. Among patients with T2DM who have established
ASCVD, SGLT2is or GLP-1 RAs with proven cardiovascular ben-
efit are recommended as part of glycaemic management. In
patients in whom HF coexists or is of special concern, SGLT2is
are preferably recommended. For patients with T2DM and
CKD, with or without CVD, the use of an SGLT2i shown to
reduce CKD progression should be considered. If contraindi-
cated or not preferred, a GLP-1 RA shown to reduce CVD (and
possibly CKD progression) may alternatively be used [20].
Results appear more homogeneous across SGLT2is [30] than
among GLP-1RAs [14,31], although some controversy still per-
sists. In patients without ASCVD, HF or CKD, classical criteria
pointed out in 2015 [28] are still valid with the aims to avoid
hypoglycaemia, weight gain or excessive cost [20]. This new
view in the management of T2DM will obviously change both
the reasoning and clinical practice of endocrinologists.
3.1. Need for detection of atherosclerotic cardiovascular
disease
ASCVD is easy to detect in patients who already had a MACE
such as myocardial infarction or stroke, or symptomatic
ever, EMPA-REG OUTCOME enrolled a significant proportion
of patients with established ASCVD but without previous CV
event while LEADER recruited 18.6% of patients aged
60 years with CV risk factors, but without known cardiovas-
cular complications. For endocrinologists, it may be a difficult
task to detect asymptomatic ASCVD. Two basic questions
arise: first, which patients should be screened and, second,
which simple tests should be used [27]? Screening of asymp-
tomatic ASCVD should primary focus on T2DM patients who
cumulate multiple risk factors, such as long duration of the
disease, abdominal adiposity, hypertension, dyslipidaemia,
smoking in order to increase the return of the screening pro-
cedure [32]. The traditional basic tests for the diagnosis of
ASCVD, mainly silent coronary artery disease, consist in elec-
trocardiogram, echocardiography and exercise (stress) test.
This strategy requires a collaboration between endocrinolo-
gists and cardiologists at least for high risk patients [21,27].
3.2. Need for detection of heart failure
HF is increasingly prevalent in patients with T2DM, yet
endocrinologists only recently were sensitized to this under-
estimated complication [6,7]. While HF with reduced left ven-
tricular ejection fraction is more easily to be recognized, most
patients with T2DM (generally combined with arterial hyper-
tension) have HF with preserved ejection fraction (‘‘diastolic
HF”), partially due to cardiomyopathy independent of severe
ASCVD [6,7]. This type of HF is generally more difficult to be
detected. Indeed, symptoms such as fatigue, dyspnoea, ankle
oedema are not specific and rather common in T2DM patients
who are generally overweight/obese, and the task is even

Lifestyle + meormin :
if HbA1c above target

With CVD or CKD Without CVD or CKD

Need to
ASCVD HF or CKD Need to avoid Need to reduce
promote
predominates predominates hypoglycaemia cost
weight loss

Preferably iSGLT2 DPP-4i

GLP-1RA
(si eGFR adequate)
or
GLP-1RA GLP-1RA SU
SGLT2i (if eGFR
If not possible (*) :
adequate) SGLT2i TZD
GLP-1AR with SGLT2i
with proven CVD
proven CVD
benefit TZD
benefit

Fig. 1 – Management of type 2 diabetes according to the ADA-EASD 2018 consensus report (adapted from Ref. [20]). (*) SGLT2i
not tolerated or contraindicated or if eGFR less than adequate. ASCVD: atherosclerotic cardiovascular disease. CVD:
cardiovascular disease. DPP-4i: dipeptidyl peptidase-4 inhibitor. GLP-1RA: glucagon-like receptor agonist. HF: heart failure.
eGFR: estimated glomerular filtration rate. SGLT2i: sodium-glucose cotransporter type 2 inhibitor. SU: sulphonylurea. TZD:
thiazolidinedione.
4 diabetes research and clinical practice
more difficult in the elderly population. In case of suspicion of
HF, a measurement of natriuretic peptide is recommended,
although this attitude is not commonly adopted by most
endocrinologists yet and may also vary between countries
among cardiologists [6,7]. A normal value excludes the diag-
nosis of HF (high sensitivity) whereas an elevated value
should lead to further exams to be performed by the cardiol-
ogist to confirm the diagnosis of HF (moderate specificity). An
echocardiography is the recommended procedure that can
easily differentiate HF with reduced or preserved ejection
fraction.
Whereas the benefit of SGLT2is in T2DM patients at risk to
develop HF appears consistent in all three CVOTs with
SGLT2is [17–19], independently of the presence of HF at base-
line [30], the place of GLP-1RAs appears more controversial
[33]. Indeed, no significant reduction in hospitalisation for
HF was detected in CVOTs with GLP-1RAs (especially in LEA-
DER) [34] and two small studies (FIGHT and LIVE) with liraglu-
tide in T2DM patients with established HF failed to
demonstrate any positive effects (review in [33]). Neverthe-
less, the ADA-EASD consensus report recommends the
administration of a GLP-1RA that has proven cardiovascular
protection in patients with HF when the use of an SGLT2i is
not possible (for instance in case of estimated glomerular fil-
tration rate or eGFR < 60 ml/min/1.73 m2) [20]. Because the
evidence is still rather weak, further studies are required to
support this statement.
3.3. Need for detection of renal disease
Diabetic nephropathy is a classical complication of diabetes,
although nondiabetic kidney disease may also coexist with
T2DM [5]. Endocrinologists were increasingly interested in
detecting this complication since the discovery of microalbu-
minuria as a simple marker of early CKD and a validated indi-
cator of prognosis of more severe renal disease. The interest
was even increased following the demonstration of the
remarkable renoprotective effect of blockers of the renin-
angiotensin system [35]. Both SGT2is and GLP-1RAs, added
to RAS blockers, have been shown to reduce microalbumin-
uria and proteinuria in patients with T2DM, although SGLT2is
appear to exert a stronger protective effect on hard clinical
outcomes [36].
The estimation of renal function, which is apparently easy
using the creatinine assay, raises some difficulties in clinical
practice [37]. One of the practical reason is that several meth-
ods have been proposed across years, with the creatinine
clearance using the Gault-Cockroft formula, the eGFR esti-
mated using the MDRD (‘‘Modification of Diet in Renal Dis-
ease”) formula and more recently the CKD-EPI (‘‘Chronic
Kidney Diabetes Epidemiology Collaboration”) equation, all
methods that may result in slightly different results [37]. Cur-
rently, the nephrologists recommend the use of the CKD-EPI
equation, which appears to be more accurate with less poten-
tial biases, but this method is not very popular among
endocrinologists yet.
One additional difficulty is that eGFR may fluctuate from
time to time, being influenced not only by the chemical assay
of serum creatinine, but also by a variety of physiological
159 (2020) 107726
(level of hydration, for instance) or pharmacological (use of
nonsteroidal anti-inflammatory agents or blockers of the
renin-angiotensin system, for instance) confounding factors.
Furthermore, SGLT2is may transiently reduce eGFR within
the first few weeks of administration [35]. Because the use
of SGLT2i is currently restricted in patients with low eGFR
(no initiation if eGFR < 60 ml/min/1.73 m2 and treatment
interruption recommended if eGFR falls < 45 ml/min/1.73 m2),
difficulties in evaluating renal function may render the task of
the clinician (including endocrinologists) somewhat haz-
ardous. However, considering positive results from recent
CVOTs [17–19,30,38], reinforced by CREDENCE [39] (see below),
this limitation based on eGFR for initiating and continuing
SGLT2i therapy might change in a near future. This will most
probably occur when the results of further ongoing trials with
SGLT2is that specifically target the population with CKD will
be available (see section ‘‘Future perspectives”).
There is no restriction in the use of GLP-1RAs in patients
with moderate to severe CKD [40], yet this pharmacological
class has not proven its ability to avoid the progression of
renal disease, at least with a rather short follow up of
<4 years, in contrast to the impressive demonstration by
SGLT2is [36].
3.4. Need for a collaboration between diabetologists,
cardiologists and nephrologists
Most patients with T2DM are managed by primary care physi-
cians, who play a crucial role in the prevention, early detec-
tion, control and access to the right multidisciplinary
interventions [41]. However, when the disease progresses,
the management becomes more difficult, not only to main-
tain adequate and safe glucose control, but also to take into
account a variety of complications such as CVD, HF and
CKD, co-morbidities that may segregate and also coexist with
microangiopathic complications, so that the role of specialist
then becomes more important [42]. As emphasized in a report
from the European Society of Cardiology Cardiovascular
Roundtable, addressing cardiovascular risk in T2DM requires
a better collaboration between diabetologists and cardiolo-
gists [21]. Considering the increasing importance of CKD in
T2DM [4,5,35] and the specific action of SGLT2is to slow down
the progression of renal disease [36], a closer collaboration
between endocrinologists and nephrologists may also
become mandatory [43].
4. Future perspectives
Available CVOTs mainly focused on T2DM patients with
established ASCVD and not specifically recruited patients
without ASCVD or patients with HF or CKD. Furthermore,
the primary endpoint in these trials was the reduction in
major cardiovascular events (MACE-3 points: cardiovascular
mortality, nonfatal myocardial infarction, nonfatal stroke),
while effects on hospitalisation for HF or progression of renal
disease were only secondary or exploratory endpoints. Thus,
there remains some doubt in T2DM patients without ASCVD
(so-called primary prevention) as well as in patents with HF
or CKD (Fig. 2).
 diabetes research and clinical practice 159 (2020) 107726 5

CKD hHF MACE-3 pts

SECONDARY PREVENTION
T2DM IN T2DM WITH CVD
(EMPA-REG OUTCOME,
+ CANVAS, DECLARE-TIMI 58)
CVD ONGOING STUDIES
(VERTIS-CV)

T2DM + PRIMARY PREVENTION

CV RISK FACTORS IN T2DM
(CANVAS, DECLARE-TIMI 58 :
subpopulaons)

T2DM OR NON DIABETIC

? ? +
ONGOING STUDIES
(DAPA-HF, DELIVER,
EMPEROR-REF & -PEF)
HEART FAILURE (REF & PEF)

T2DM WITH CKD

T2DM OR NON DIABETIC (CREDENCE)
+ ONGOING STUDIES
(DAPA-CKD,
CKD ( eGFR & albuminuria) EMPA-KIDNEY, SCORED)

Fig. 2 – Schematic illustration of the already demonstrated and potential beneficial effects of SGLT2 inhibitors. CKD: chronic
kidney disease. CV: cardiovascular. CVD: cardiovascular disease. eGFR: estimated glomerular filtration rate. hHF:
hospitalisation for heart failure: MACE-3 points: major cardiovascular events (composite of cardiovascular mortality,
myocardial infarction, stroke). T2DM: type 2 diabetes mellitus. REF: reduced ejection fraction: PEF: preserved ejection fraction.

4.1. Cardiovascular protection
Most T2DM patients included in CVOTs with SGLT2is had
established CVD (all patients in EMPAREG OUTCOME) [17]
and only CANVAS [18] and DECLARE-TIMI 58 [19] included a
significant number of patients without established CVD. The
results of a meta-analysis of all three trials suggest that the
reduction in MACE-3 points was significant in patients with
established CVD (so called secondary prevention), but not in
patients without CVD (so-called primary prevention), at least
at rather short-term (4 years of follow-up) [30]. Similarly, in
LEADER, liraglutide significantly reduced the incidence of
MACEs in T2DM patients with established CVD (82% of the
population) but not in patients with only CVD risk factors
(18% of recruited patients) [34]. In the ADA-EASD 2018 consen-
sus report, no specific place was reserved to SGLT2is or GLP-1
RAs in T2DM patients without ASCVD (and without HF or
CKD). The question thus arises whether a cardiovascular pro-
tection might be expected when a longer follow up would be
achieved. This is important because the majority of T2DM
patients supervised by endocrinologists are without known
CVD, yet they will probably die from CVD in the long-term.
The next still ongoing trial VERTIS-CV that is comparing ertu-
gliflozin versus placebo has also included patients with estab-
lished CVD (similar to the population enrolled in EMPA-REG
OUTCOME) [44], and thus will not answer this question. In
contrast, the next CVOT to be published with a GLP-1 RA,
REWIND, has the particularity of a recruitment of a large
majority (about 70%) of T2DM patients in primary prevention
[45]. A press release published on November 5, 2018 informed
that dulaglutide demonstrates superiority in reduction of
MACEs versus placebo for a broad range of people with
T2DM [46]. Of note, these results were already anticipated in
the 2019 ACC/AHA Guideline on the Primary Prevention of
Cardiovascular Disease; indeed, it is stated that ‘‘for adults
with T2DM and additional ASCVD risk factors it may be rea-
sonable to initiate a SGLT2i or a GLP-1RA to improve gly-
caemic control and reduce CVD risk (class IIB)” [22].
Another question of importance in the management of
patients at high cardiovascular risk is what to do with
patients with established CVD who are rather well controlled
with metformin. From a classical endocrinologist point of
view, if adequate glucose control is reached in metformin-
treated patients (for instance HbA1c < 7%), no further
glucose-lowering agent should be added. However, consider-
ing the new paradigm proposed by the new ADA-EASD con-
sensus report, it seems reasonable to consider the addition
of a drug that has proven its ability to improve the prognosis,
based on hard clinical endpoints including mortality, inde-
pendently of improvement of glucose control [47]. This is
especially important because in the previous guidelines [28],
acceptable HbA1c target may be increased from 7%
(53 mmol/mol) to around 8% (64 mmol/mol) in patients with
established CVD. In the CVOTs, patients with HbA1c > 7%
(53 mmol/mol) were included and no difference in the out-
come could be detected between patients with HbA1c < 8–
8.5% versus > 8–8.5% (64–69 mmol/mol) [47]. Furthermore, in
a post-hoc analysis of EMPA-REG OUTCOME, the cardiovascu-
lar protection was independent of baseline HbA1c and HbA1c
reduction during the trial [48].
Finally, while metformin remains the first-line recom-
mended medication for T2DM, there are no robust data prov-
6 diabetes research and clinical practice
ing its efficacy for either macro or microvascular disease out-
comes. As a consequence, despite the long clinical experience
and the low cost with this biguanide, the time may come to
reconsider the primacy of metformin in the management of
T2DM in patients with ASCVD, especially if HF is present [49].
4.2. Heart failure
As already mentioned, all CVOTs showing that SGLT2is
reduced the incidence of hospitalisation for HF were per-
formed in T2DM patients with ASCVD or multiple CVD risk
factors, but not specifically in patients with HF. HF was men-
tioned by investigators in around 10% of patients at baseline,
but not specifically confirmed (no natriuretic peptide mea-
surements, no echocardiography). In absence of specific
investigations, it is impossible to decide whether those
patients included while having HF had reduced or preserved
left ventricular ejection fraction.
Several dedicated studies are ongoing that evaluate the
effects of empagliflozin (EMPEROR reduced, EMPEROR pre-
served) [50] and dapagliflozin (DAPA-HF, DELIVER) in
patients with reduced or preserved left ventricular ejection
fraction, respectively [6,51]. Endocrinologists will be inter-
ested to know that these trials devoted to HF will include
not only patients with T2DM but also non-diabetic individ-
uals. This is explained by the fact that the reduction in
hospitalisation for HF in available CVOTs appeared to be
independent of the glucose control status. If ongoing trials
would confirm positive results in non-diabetic patients,
these agents, which were initially developed as glucose-
lowering (antidiabetic) agents, will be captured by cardiolo-
gists in a near future, and thus might, at least partially
and perhaps largely, escape endocrinologist’s speciality in
the future.
4.3. Renal disease
Among all glucose-lowering agents, SGLT2is are those that
raise the greatest interest as far as nephroprotection in
T2DM patients is concerned [36]. In available CVOTs [17–19],
renal events were only considered as a secondary rather than
a primary outcome and none of them specifically included
patients with CKD, except in the recently published trial CRE-
DENCE [39] (see below). On the contrary, patients with moder-
ate to severe CKD were excluded in several studies, especially
in DECLARE-TIMI 58 trial [19]. Nevertheless, a significant pro-
portion of patients included in EMPA-REG OUTCOME and in
CANVAS had eGFR between 30 and 60 ml/min/1.73 m2. The
reduction in MACE-3 points and hospitalisation for HF was
observed in those patients with moderate CKD both in
EMPA-REG OUTCOME [52] and CANVAS [53]. Furthermore, in
prespecified exploratory analyses, empagliflozin [54] and
canagliflozin [55] treatment was associated with a reduced
risk of sustained loss of kidney function, attenuated eGFR
decline, and a reduction in albuminuria. A meta-analysis of
the results of all three trials showed that the cardiovascular
and renal protection was observed independently of baseline
eGFR [30]. However, an interaction between baseline renal
159 (2020) 107726
function and the clinical benefit of SGLT2is was observed.
Specifically, there was a significantly lesser reduction in pro-
gression of renal disease but a significantly greater reduction
in hospitalisation for HF and a trend for a greater reduction in
MACEs in T2DM patients with worse baseline renal function
[30].
CREDENCE is a double-blind, randomized trial that
assigned patients with T2DM and albuminuric CKD to receive
canagliflozin at a dose of 100 mg daily or placebo [39]. All the
patients had an eGFR of 30 to <90 ml per minute per 1.73 m2
and albuminuria (ratio of albumin [mg] to creatinine [g],
>300 to 5000) and were treated with renin-angiotensin system
blockade. In this specific population, the risk of kidney failure
and cardiovascular events was lower in the canagliflozin
group than in the placebo group at a median follow-up of
2.62 years [39]. These results were not available at the time
of the ADA-EASD consensus report [20]. They pave the road
for the use of SGLT2is in T2DM patients with moderate CKD,
which might result in a larger use of these agents, even in
patients with eGFR between 30 and 60 ml/min/1.73 m2 in
future guidelines.
Finally, other trials in patients with CKD are ongoing,
with the particularity of having included subjects with but
also without T2DM [56,57]: this is the case for EMPA-
KIDNEY [58] and DAPA-CKD [56,57]. Thus, these ongoing
dedicated renal outcome trials will provide further guidance
on the potential clinical role of SGLT2is in slowing the
development and progression of renal impairment in indi-
viduals with T2DM. Furthermore, they will evaluate
whether this renal protection also occurs independently of
the presence of diabetes and thus of the glucose status. If
yes, this will of course open new perspectives for the use
of SGLT2s in patients with CKD and the interest for this
pharmacological class might be increasingly shifted from
endocrinologists to nephrologists [23,43], in a similar
way as the expected shift to cardiologists as already
mentioned [21].
5. Conclusion
The choice of glucose-lowering agents was, for a long time,
based upon classical efficacy and safety criteria, especially
the ability to reduce HbA1c, if possible without inducing
hypoglycaemia and increasing body weight, together with
an acceptable tolerance profile and a bearable cost. Since
the demonstration that some new glucose-lowering agents
can improve cardiovascular and renal prognosis, at least in
T2DM patients at high cardiovascular risk, and the revolution-
ary views that these favourable effects were largely indepen-
dent of the glucose-lowering effects, endocrinologists have to
face a new paradigm as summarized in the 2018 ADA-EASD
consensus report. This will drastically change the manage-
ment of T2DM, at least in patients at high CVD or CKD risk,
although implementation in real life practice will probably
take some time. Furthermore, new trials in specific popula-
tions, especially with HF and CKD, are still ongoing, whose
results may further profoundly influence guidelines in a near
future.
 diabetes research and clinical practice
Funding and conflict of interest
No sources of funding were used to assist in the preparation
of this manuscript. No conflicts of interest are directly rele-
vant to the content of this manuscript.
A.J. Scheen has received lecturer/scientific advisor/clinical
investigator fees from AstraZeneca, Boehringer Ingelheim, Eli
Lilly, Janssen, Merck Sharp & Dohme, Novartis, NovoNordisk,
Sanofi-Aventis and Servier. He worked as clinical investigator
in TECOS, EMPA-REG OUTCOME, LEADER, CANVAS-R,
DECLARE-TIMI 58 and HARMONY OTCOME cardiovascular
outcome trials.
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