IMR Press / RCM / Volume 21 / Issue 4 / DOI: 10.31083/j.rcm.2020.04.220
Open Access Editorial
New anti-diabetic agents: major advances with unanswered questions
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1 Heart Institute and ACTION Group, Pitié-Salpétrière, Sorbonne University, 47-83 Boulevard de l’Hôpital, 75013, Paris, France
2 Division of Cardiology, Department of Medical Sciences, University of Turin, “Città della Salute e della Scienza” hospital, 10100, Turin, Italy
3 Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, 04100, Latina, Italy
4 Mediterranea Cardiocentro, 80100, Napoli, Italy
*Correspondence: (Pierre Sabouret)
Rev. Cardiovasc. Med. 2020, 21(4), 489–492;
Submitted: 19 October 2020 | Revised: 6 December 2020 | Accepted: 8 December 2020 | Published: 30 December 2020
Copyright: © 2020 Sabouret et al. Published by IMR Press.
This is an open access article under the CC BY 4.0 license (

No abstract present

Diabetes mellitus
heart failure
chronic kidney disease

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 (Packer et al., 2020; McMurray et al., 2019). 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 interval], 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 hospitalizations 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 median 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, Cardiovascular 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 (Zinman et al., 2015; Kato et al., 2019), 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 (Packer et al., 2020; McMurray et al., 2019). 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., 2016a, b).

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 understood Fig. 1. The class effect also remains uncertain due to the pharmacological differences among individual drugs and the heterogeneity 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 Cardiovascular Outcome Results (LEADER) and Peptide Innovation for Early Diabetes Treatment (PIONEER-6) demonstrated a reduction of cardiovascular mortality in the treatment group compared to optimal medical therapy, whereas all the RCTs showed no difference in non-fatal myocardial infarction rates between groups (Zinman et al., 2015; Marso et al., 2016a; Husain et al., 2019). As for stroke, only dulaglutide was proven to reduce stroke rates in the Dulaglutide 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).

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.

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 natriuresis and glycosuria, reduced proteinuria, decrease in glomerular oxidative stress leading to an improved glomerular renal function Fig. 1 (Zinman et al., 2015; Kato et al., 2019; Gerstein et al., 2019; Marso et al., 2016a, b). However, which drug class should be considered 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 effective 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, blindness 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 Cardiovascular 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) (Marso et al., 2016a; Huang and Lee, 2020).

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 (Universitätsklinikum 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 endpoints 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.

Future studies are warranted to better assess the pharmacological 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 critically reviewed the manuscript. All authors read and approved its final version.


There are no acknowledgments to disclose.



Conflict of Interest

Dr. Sabouret reports consulting or lecture fees from Amgen, 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.

Cosentino, F., Grant, P. J., Aboyans, V., Bailey, C. J., Ceriello, A., Delgado, 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 Document 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. Minerva 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 inhibitors 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., Pedersen, 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) ( Identifier NCT03361098). Available at: (Accessed: 12 December 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., Desai, 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 diabetes. 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 Exenatide Versus Dapagliflozin and Placebo on Ectopic Lipids in Patients With Uncontrolled Type 2 Diabetes Mellitus. (EXENDA) ( Identifier NCT03007329). Available at: (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 Dapagliflozin Plus Exenatide in Obese Insulin-resistant Patients ( Identifier: NCT03419624). Available at: (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 Therapy on Diabetes Remission in Subjects With Newly Diagnosed Type 2 Diabetes Who Are Overweight or Obese ( Identifier: NCT03018665). Available at: (Accessed: 12 December 2020).
Zannad, F., Ferreira, J. P., Pocock, S. J., Anker, S. D., Butler, J., Filippatos, 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.
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