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Published online: December 30, 2020
Reviews in Cardiovascular Medicine
Rev. Cardiovasc. Med. 2020 vol. 21(4), 489–492
©2020 Sabouret et al. Published by IMR Press.
Editorial
New anti-diabetic agents: major advances with
unanswered questions
Pierre Sabouret1,*, Pier Paolo Bocchino2and Giuseppe Biondi-Zoccai3,4
1Heart Institute and ACTION Group, Pitié-Salpétrière, Sorbonne University, 47-83 Boulevard de l'Hôpital, 75013, Paris,
France
2Division of Cardiology, Department of Medical Sciences, University of Turin, “Città della Salute e della Scienza” hospital,
10100, Turin, Italy
3Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, 04100, Latina, Italy
4Mediterranea Cardiocentro, 80100, Napoli, Italy
*Correspondence: cardiology.sabouret@gmail.com (Pierre Sabouret)
DOI:10.31083/j.rcm.2020.04.220
This is an open access article under the CC BY 4.0 license (https://creativecommons.org/licenses/by/4.0/).
Keywords
Diabetes mellitus; SGLT2i; GLP1-RA; heart failure; chronic kidney dis-
ease
During the latest European Society of Cardiology (ESC)
congress, impressive results have been reported regarding the
clinical benefits of sodium-glucose cotransporter 2 inhibitors
(SGLT2i) in heart failure with reduced ejection fraction (HFrEF)
in the EMPagliflozin outcomE tRial in Patients With chrOnic
heaRt Failure With Reduced Ejection Fraction (EMPEROR-
Reduced) and Dapagliflozin on the Incidence of Worsening Heart
Failure or Cardiovascular Death in Patients With Chronic Heart
Failure (DAPA-HF) trials (McMurray et al.,2019;Packer et al.,
2020). A meta-analysis addressing the combined 8474 patients
from both trials showed a 13% relative risk reduction (RRR) of
total mortality (HR [hazard ratio], 0.87; 95% CI [confidence in-
terval], 0.77-0.98), a 14% RRR of cardiovascular death (HR, 0.86;
95% CI, 0.76-0.98), a 25% RRR of cardiovascular death or hos-
pitalizations for heart failure (HR, 0.75; 95% CI, 0.68-0.84) and
a 38% RRR of the composite renal endpoint (HR, 0.62; 95% CI,
0.63-0.90) in the treatment group compared to placebo at a me-
dian follow-up time of 16 months in EMPEROR-Reduced and 18
months in DAPA-HF (Zannad et al.,2020).
After the encouraging results from Empagliflozin, Cardiovas-
cular Outcomes, and Mortality in Type 2 Diabetes (EMPAREG-
OUTCOME) and Dapagliflozin Effect on Cardiovascular Events-
Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58)
trials in diabetic patients with HFrEF (Kato et al.,2019;Zinman et
al.,2015), EMPEROR-Reduced and DAPA-HF demonstrated that
the magnitude of benefits were similar in both diabetic and non-
diabetic HFrEF patients, thus underlining that SGLT2i benefits are
not only mediated by the anti-diabetic pharmacological properties
of these drugs but other biological mechanisms are at work (Mc-
Murray et al.,2019;Packer et al.,2020). Notwithstanding, these
results should not obscure the clinical efficacy of glucagone-like
peptide-1 receptor agonists (GLP1-RA), which come as another
emerging class of anti-diabetic drugs (Gerstein et al.,2019;Marso
et al.,2016b,a).
Despite promising data from randomized controlled trials
(RCT) on SGLT2i and GLP1-RA, some issues remain unresolved.
Indeed, even if these drugs have proven cardioprotective effects,
the underlying mechanisms of action are not yet perfectly under-
stood Fig. 1. The class effect also remains uncertain due to the
pharmacological differences among individual drugs and the het-
erogeneity of the results from RCTs. Moreover, it is still debated
which class provides the greatest prevention against ischemic
events. Indeed, only 3 RCTs, namely EMPAREG-OUTCOME,
Liraglutide Effect and Action in Diabetes: Evaluation of Cardio-
vascular Outcome Results (LEADER) and Peptide Innovation for
Early Diabetes Treatment (PIONEER-6) demonstrated a reduction
of cardiovascular mortality in the treatment group compared to op-
timal medical therapy, whereas all the RCTs showed no difference
in non-fatal myocardial infarction rates between groups (Husain et
al.,2019;Marso et al.,2016a;Zinman et al.,2015). As for stroke,
only dulaglutide was proven to reduce stroke rates in the Dulaglu-
tide and cardiovascular outcomes in type 2 diabetes (REWIND)
trial (Gerstein et al.,2019), but this effect was not observed in other
GLP1-RA or SGLT2i trials. In REWIND, 58 (3.2%) stroke events
were reported in the dulaglutide group (n = 4949) compared to 205
(4.1%) in the placebo group (n = 4952) with a hazard ratio (HR)
of 0.76 (95% CI 0.62-0.94; P= 0.010). Ischemic stroke rates were
decreased by 25% (HR 0.75, 95% CI 0.59-0.94, P= 0.012) with
no impact on hemorrhagic stroke (HR 1.05, 95% CI 0.55-1.99; P
= 0.89) (Gerstein et al.,2020).
Concerning the renal outcomes, RCTs on individual SGLT2i
and GLP1-RA molecules demonstrated their protective role
against worsening renal function, likely due to an increase of natri-
uresis and glycosuria, reduced proteinuria, decrease in glomerular
Fig. 1. Overview of the effects of SGLT2i (A) and GLP1-RA (B) on heart, kidney and metabolic pathways. GLP1-RA, glucagone-like peptide-1
receptor agonists; HBA1c, glycated haemoglobin; HDL, high-density lipoprotein; SGLT2, sodium-glucose cotransporter 2.
oxidative stress leading to an improved glomerular renal function
Fig. 1 (Gerstein et al.,2019;Kato et al.,2019;Marso et al.,2016b,a;
Zinman et al.,2015). However, which drug class should be con-
sidered for first-line antidiabetic therapy in patients with chronic
kidney disease is still a matter of debate as the most protective
agents against worsening renal function are still argued.
Lastly, whether a combination therapy with these agents is ef-
fective on cardiovascular and/or renal outcomes in diabetic and
non-diabetic patients is yet to be assessed in clinical trials (Table 1)
and, should it be proved true, their safety and cost-effectiveness
will eventually need to be confirmed by post-marketing analyses.
Of note, retinopathy complications (vitreous hemorrhage, blind-
490 Sabouret et al.
Table 1. Trials evaluating the combination of GLP1RA with SGLT2i.
Study DURATION 8
(Packer et al.,2020)
DECREASE (IJzerman ,
2020)
EXANDA
(Kautzky-Willer ,
2020)
RESILIENT (Uni-
versitätsklinikum
Hamburg-
Eppendorf. ,
2020)
NCT03018665 (Wang ,2017)
Number 2017-004709-42 NCT03361098 NCT03007329 NCT03419624 NCT03018665
Treatment group ExenatideQW Exenatide BID ExenatideQW ExenatideQW Exenatide
+ Dapagliflozin + Dapagliflozin + Dapagliflozin + Dapagliflozin + Metformin
Comparator group Placebo + Placebo + Placebo + Placebo + BIAsp30
Dapagliflozin Dapagliflozin Dapagliflozin Dapagliflozin + Metformin
Patient’s T2 diabetes, T2 diabetes, T2 diabetes, T2 diabetes, T2 diabetes,
Characteristics HbA1c 8-12% BMI >
30 kg/m2
HbA1c 7-10%, BMI 30-40
kg/m2
HbA1c 6.5-11%,
BMI ≥ 25 kg/m2
HbA1c 8-11% BMI
≥ 30 kg/m2
HbA1c 8-14% BMI ≥ 24-40
kg/m2
Primary end-
points
Changes in HbA1c Differences in neuronal
activity in central reward and
satiety activity in response to
food
Change in hepatic
lipid content
Differences in
weight and HbA1c
Rate of Inducing Diabetes +
Change of Rate of Maintaining
Diabetes Remission + Time of
Maintaining Diabetes
Remission
Status Published Recruiting Recruiting Ongoing Recruiting
T2 : Type 2; HbA1c : glycosylated Hemoglobin; IR:insulin resistance.
ness or conditions requiring treatment with an intravitreal agent
or photocoagulation) may be higher with GLP1-RA as reported
for semaglutide compared to placebo in the Trial to Evaluate Car-
diovascular and Other Long-term Outcomes with Semaglutide in
Subjects with Type 2 Diabetes (SUSTAIN 6) (HR 1.76, 95% CI
1.11-2.78; P= 0.02) (Huang and Lee,2020;Marso et al.,2016a).
Future studies are warranted to better assess the pharmacolog-
ical properties, efficacy and safety of SGLT2i and GLP1-RA in
order to optimize the management of both diabetic patients and
non-diabetic individuals with heart failure against a background
of optimal medical treatmsent (Cosentino et al.,2020;Di Lullo et
al.,2020).
Author contributions
Pierre Sabouret and Giuseppe Biondi Zoccai conceived the
study. Pierre Sabouret and Pier Paolo Bocchino did the literary
search and wrote the first draft of the manuscript. All authors crit-
ically reviewed the manuscript. All authors read and approved its
final version.
Acknowledgment
There are no acknowledgments to disclose.
Funding
None.
Conflict of Interest
Dr. Sabouret reports consulting or lecture fees from Am-
gen, AstraZeneca, Bayer, Bristol-Myers Squibb, Novartis, Pfizer,
Servier, Vifor, Sanofi Regeneron, outside the submitted work. Dr.
Biondi-Zoccai has consulted for InnovHeart, Milan, Meditrial,
Rome, and Replycare, Rome, all in Italy, outside the submitted
work. Dr. Bocchino has no conflicts of interest to declare.
Submitted: October 19, 2020
Revised: December 06, 2020
Accepted: December 08, 2020
Published: December 30, 2020
References
Cosentino, F., Grant, P. J., Aboyans, V., Bailey, C. J., Ceriello, A., Del-
gado, V., Federici, M., Filippatos, G., Grobbee, D. E., Hansen, T. B.,
Huikuri, H. V., Johansson, I., Jüni, P., Lettino, M., Marx, N., Mellbin,
L. G., Östgren, C. J., Rocca, B., Roffi, M., Sattar, N., Seferović, P.
M., Sousa-Uva, M., Valensi, P., Wheeler, D. C.; ESC Scientific Doc-
ument Group. (2020) 2019 ESC Guidelines on diabetes, pre-diabetes,
and cardiovascular diseases developed in collaboration with the EASD.
European Heart Journal 41, 255-323.
Di Lullo, L., Bellasi, A., Guastamacchia, E., Triggiani, V., Ronco, C.,
Lavalle, C., Di Iorio, B. R., Russo, D., Cianciolo, G., La Manna, G.
and Settembrini, S. (2020) Glifozines and cardiorenal outcomes. Min-
erva Cardioangiologica 68, 188-196.
Gerstein, H. C., Colhoun, H. M., Dagenais, G. R., Diaz, R., Lakshmanan,
M., Pais, P., Probstfield, J., Riesmeyer, J. S., Riddle, M. C., Rydén,
L., et al. (2019) Dulaglutide and cardiovascular outcomes in type 2
diabetes (REWIND): a double-blind, randomised placebo-controlled
trial. The Lancet 394, 121-130.
Gerstein, H. C., Hart, R., Colhoun, H. M., Diaz, R., Lakshmanan, M.,
Botros, F. T., Probstfield, J., Riddle, M. C., Rydén, L., Atisso, C. M.,
Dyal, L., Hall, S., Avezum, A., Basile, J., Conget, I., Cushman, W. C.,
Hancu, N., Hanefeld, M., Jansky, P., Keltai, M., Lanas, F., Leiter, L. A.,
Lopez-Jaramillo, P., Muñoz, E. G. C., Pogosova, N., Raubenheimer, P.
J., Shaw, J. E., Sheu, W. H. and Temelkova-Kurktschiev, T. (2020) The
effect of dulaglutide on stroke: an exploratory analysis of the REWIND
trial. The Lancet Diabetes & Endocrinology 8, 106-114.
Huang, C. Y. and Lee, J. K. (2020) Sodium-glucose co-transporter-2 in-
hibitors and major adverse limb events: A trial-level meta-analysis
including 51 713 individuals. Diabetes, Obesity and Metabolism 22,
2348-2355.
Husain, M., Birkenfeld, A. L., Donsmark, M., Dungan, K., Eliaschewitz,
F. G., Franco, D. R., Jeppesen, O. K., Lingvay, I., Mosenzon, O., Ped-
Volume 21, Number 4, 2020 491
ersen, S. D., Tack, C. J., Thomsen, M., Vilsbøll, T., Warren, M. L. and
Bain, S. C. (2019) Oral semaglutide and cardiovascular outcomes in
patients with type 2 diabetes. New England Journal of Medicine 381,
841-851.
IJzerman, R. G. (2020) DECREASE: Dapagliflozin Plus Exenatide on
Central REgulation of Appetite in diabeteS typE 2 (DECREASE)
(Clinicaltrials.gov Identifier NCT03361098). Available at: https://cl
inicaltrials.gov/ct2/show/NCT03361098 (Accessed: 12 Decem-
ber 2020).
Kato, E. T., Silverman, M. G., Mosenzon, O., Zelniker, T. A., Cahn, A.,
Furtado, R. H. M., Kuder, J., Murphy, S. A., Bhatt, D. L., Leiter, L.
A., McGuire, D. K., Wilding, J. P. H., Bonaca, M. P., Ruff, C. T., De-
sai, A. S., Goto, S., Johansson, P. A., Gause-Nilsson, I., Johanson, P.,
Langkilde, A. M., Raz, I., Sabatine, M. S. and Wiviott, S. D. (2019)
Effect of dapagliflozin on heart failure and mortality in type 2 diabetes
mellitus. Circulation 139, 2528-2536.
Marso, S. P., Bain, S. C., Consoli, A., Eliaschewitz, F. G., Jódar, E., Leiter,
L. A., Lingvay, I., Rosenstock, J., Seufert, J., Warren, M. L., Woo,
V., Hansen, O., Holst, A. G., Pettersson, J. and Vilsbøll, T. (2016b)
Semaglutide and cardiovascular outcomes in patients with type 2 dia-
betes. New England Journal of Medicine 375, 1834-1844.
Marso, S. P., Daniels, G. H., Brown-Frandsen, K., Kristensen, P., Mann, J.
F. E., Nauck, M. A., Nissen, S. E., Pocock, S., Poulter, N. R., Ravn, L.
S., Steinberg, W. M., Stockner, M., Zinman, B., Bergenstal, R. M. and
Buse, J. B. (2016a) Liraglutide and cardiovascular outcomes in type 2
diabetes. The New England Journal of Medicine 375, 311-322.
Kautzky-Willer, A. (2020) Effects of Combined Dapagliflozin and Exe-
natide Versus Dapagliflozin and Placebo on Ectopic Lipids in Patients
With Uncontrolled Type 2 Diabetes Mellitus. (EXENDA) (Clinicaltri-
als.gov Identifier NCT03007329). Available at: https://clinicaltria
ls.gov/ct2/show/NCT03007329 (Accessed: 12 December 2020).
McMurray, J. J. V., Solomon, S. D., Inzucchi, S. E., Køber, L., Kosiborod,
M. N., Martinez, F. A., Ponikowski, P., Sabatine, M. S., Anand, I. S.,
Bělohlávek, J., et al. (2019) Dapagliflozin in patients with heart failure
and reduced ejection fraction. The New England Journal of Medicine
381, 1995-2008.
Packer, M., Anker, S. D., Butler, J., Filippatos, G., Pocock, S. J., Carson,
P., Januzzi, J., Verma, S., Tsutsui, H., Brueckmann, M., et al. (2020)
Cardiovascular and renal outcomes with empagliflozin in heart failure.
The New England Journal of Medicine 383, 1413-1424.
Universitätsklinikum Hamburg-Eppendorf. (2020) The Potential of Da-
pagliflozin Plus Exenatide in Obese Insulin-resistant Patients (Clini-
caltrials.gov Identifier: NCT03419624). Available at: https://clin
icaltrials.gov/ct2/show/NCT03419624 (Accessed: 12 December
2020).
Wang, G. X. (2017) A Study of the Effect of Glucagon-like Peptide
1(GLP-1) Receptor Agonist in Combination With Metformin Ther-
apy on Diabetes Remission in Subjects With Newly Diagnosed Type
2 Diabetes Who Are Overweight or Obese (Clinicaltrials.gov Identi-
fier: NCT03018665). Available at: https://clinicaltrials.gov/ct2/
show/NCT03018665 (Accessed: 12 December 2020).
Zannad, F., Ferreira, J. P., Pocock, S. J., Anker, S. D., Butler, J., Filip-
patos, G., Brueckmann, M., Ofstad, A. P., Pfarr, E., Jamal, W. and
Packer, M. (2020) SGLT2 inhibitors in patients with heart failure with
reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced
and DAPA-HF trials. The Lancet 398, 819-829.
Zinman, B., Wanner, C., Lachin, J. M., Fitchett, D., Bluhmki, E., Hantel,
S., Mattheus, M., Devins, T., Johansen, O. E., Woerle, H. J., Broedl, U.
C. and Inzucchi, S. E. (2015) Empagliflozin, cardiovascular outcomes,
and mortality in Type 2 diabetes. New England Journal of Medicine
373, 2117-2128.
492 Sabouret et al.
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