Cardiovascular and renal effects of the combination therapy of a GLP-1 receptor  agonist and an SGLT2 inhibitor in observational real-life studies.

Scheen, André

doi:10.1016/j.diabet.2024.101594

Article (Scientific journals)

Cardiovascular and renal effects of the combination therapy of a GLP-1 receptor agonist and an SGLT2 inhibitor in observational real-life studies.

Scheen, André

2025 • In Diabetes and Metabolism, 51 (1), p. 101594

Peer Reviewed verified by ORBi

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https://hdl.handle.net/2268/340414

DOI
10.1016/j.diabet.2024.101594

PubMed
39608670

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Keywords :

Cardiovascular outcome; Combined therapy; GLP-1 receptor agonist; Renal outcome; SGLT2 inhibitor

Abstract :

[en] BACKGROUND: Combining a glucagon-like peptide-1 receptor agonist (GLP-1RA) and an sodium-glucose cotransporter 2 inhibitor (SGLT2i) improved cardiovascular (and renal) prognosis compared to either monotherapy in several post-hoc exploratory analyses of randomized controlled trials (RCTs) versus placebo carried out in patients with type 2 diabetes (T2DM) and high cardiovascular/renal risk. The aim of the present work is to verify if such a benefit of the combined therapy is also present in real-life clinical practice. METHODS: An extended search of the literature was performed to select observational retrospective studies that compared cardiovascular and/or renal outcomes in patients with T2DM treated with a GLP-1RA/SGLT2i combination versus patients treated with either GLP-1RA monotherapy or SGLT2i monotherapy, in addition to standard of care therapy. RESULTS: Nine observational studies showed that a GLP-1RA/SGLT2i combination is associated with a greater reduction in major adverse cardiovascular events (MACEs), hospitalization for heart failure and all-cause-mortality when compared to either GLP-1RA alone or SGLT2i alone, without obvious differences between the two monotherapies, including regarding heart failure. Results were obtained in different populations, including patients with atherosclerotic cardiovascular disease and/or heart failure. Only three observational studies gave information on renal outcomes, with a greater benefit when the GLP-1RA/SGLT2i combination was compared with GLP-1RA alone or SGLT2i alone. CONCLUSION: In real-life conditions, the GLP-1RA/SGLT2i combination reduced cardiovascular and renal outcomes compared with both GLP-1RA monotherapy and SGLT2i monotherapy. Overall, observational studies confirm the results reported in post-hoc exploratory analyses of RCTs versus placebo.

Disciplines :

Endocrinology, metabolism & nutrition
Cardiovascular & respiratory systems

Author, co-author :

Scheen, André ; Université de Liège - ULiège > Département des sciences cliniques

Language :

English

Title :

Cardiovascular and renal effects of the combination therapy of a GLP-1 receptor agonist and an SGLT2 inhibitor in observational real-life studies.

Publication date :

2025

Journal title :

Diabetes and Metabolism

ISSN :

1262-3636

eISSN :

1878-1780

Publisher :

Elsevier Masson, Paris, Fr

Volume :

Issue :

Pages :

101594

Peer reviewed :

Peer Reviewed verified by ORBi

Commentary :

Available on ORBi :

since 27 January 2026

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Bibliography

Scheen, A.J., Sodium-glucose co-transporter type 2 inhibitors for the treatment of type 2 diabetes mellitus. Nat Rev Endocrinol 16:10 (2020), 556–577.
Marilly, E., Cottin, J., Cabrera, N., Cornu, C., Boussageon, R., Moulin, P., et al. SGLT2 inhibitors in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials balancing their risks and benefits. Diabetologia 65 (2022), 2000–2010.
Nauck, M.A., Quast, D.R., Wefers, J., Meier, J.J., GLP-1 receptor agonists in the treatment of type 2 diabetes - state-of-the-art. Mol Metab, 46, 2021, 101102.
Sattar, N., Lee, M.M.Y., Kristensen, S.L., Branch, K.R.H., Del Prazto, S., Khurmi, N.S., et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials. Lancet Diabetes Endocrinol 9 (2021), 653–662.
Davies, M.J., Aroda, V.R., Collins, B.S., Gabbay, R.A., Green, J., Maruthur, N.S., et al. Management of hyperglycaemia in type 2 diabetes, 2022. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 65 (2022), 1925–1966.
Marx, N., Federici, M., Schütt, K., Müller-Wieland, D., Ajjan, R.A., Antunes, M., et al. 2023 ESC Guidelines for the management of cardiovascular disease in patients with diabetes. Eur Heart J 44 (2023), 4043–4140.
Kidney Disease: improving Global Outcomes Diabetes Work G. KDIGO 2022 clinical practice guideline for diabetes management in chronic kidney disease. Kidney Int 102 (2022), S1–S127.
Cherney, D.Z.I., Udell, J.A., Drucker, D.J., Cardiorenal mechanisms of action of glucagon-like-peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors. Med 2 (2021), 1203–1230.
Gourdy, P., Darmon, P., Dievart, F., Halimi, J.M., Guerci, B., Combining glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) in patients with type 2 diabetes mellitus (T2DM). Cardiovasc Diabetol, 22, 2023, 79.
Scheen, A.J., GLP-1 receptor agonists and SGLT2 inhibitors in type 2 diabetes: pleiotropic cardiometabolic effects and add-on value of a combined therapy. Drugs, 2024, 10.1007/s40265-024-02090-9.
Lajara, R., Combination therapy with SGLT-2 inhibitors and GLP-1 receptor agonists as complementary agents that address multi-organ defects in type 2 diabetes. Postgrad Med 131 (2019), 555–565.
Castellana, M., Cignarelli, A., Brescia, F., Perrini, S., Natalicchio, A., Laviola, L., Giorgino, F., Efficacy and safety of GLP-1 receptor agonists as add-on to SGLT2 inhibitors in type 2 diabetes mellitus: a meta-analysis. Sci Rep, 9, 2019, 19351.
Guo, M., Gu, J., Teng, F., Chen, J., Ma, X., Chen, Q., et al. The efficacy and safety of combinations of SGLT2 inhibitors and GLP-1 receptor agonists in the treatment of type 2 diabetes or obese adults: a systematic review and meta-analysis. Endocrine 67 (2020), 294–304.
Tuersun, A., Hou, G., Cheng, G., Efficacy and safety of the combination or monotherapy with GLP-1 receptor agonists and SGLT-2 inhibitors in type 2 diabetes mellitus: an update systematic review and meta-analysis. Am J Med Sci 368 (2024), 579–588.
Clegg, L.E., Penland, R.C., Bachina, S., Boulton, D.W., Thuresson, M., Heerspink, H.J.L., et al. Effects of exenatide and open-label SGLT2 inhibitor treatment, given in parallel or sequentially, on mortality and cardiovascular and renal outcomes in type 2 diabetes: insights from the EXSCEL trial. Cardiovasc Diabetol, 18, 2019, 138.
Lam, C.S.P., Ramasundarahettige, C., Branch, K.R.H., Sattar, N., Rosenstock, J., Pratley, R., et al. Efpeglenatide and clinical outcomes with and without concomitant sodium-glucose cotransporter-2 inhibition use in type 2 diabetes: exploratory analysis of the AMPLITUDE-O trial. Circulation 145 (2022), 565–574.
Neves, J.S., Borges-Canha, M., Vasques-Novoa, F., Green, J.B., Leiter, L.A., Granger, C.B., et al. GLP-1 receptor agonist therapy with and without SGLT2 inhibitors in patients with type 2 diabetes. J Am Coll Cardiol 82 (2023), 517–525.
Arnott, C., Neuen, B.L., Heerspink, H.J.L., Figtree, G.A., Kosiborod, M., Lam, C.S., et al. The effects of combination canagliflozin and glucagon-like peptide-1 receptor agonist therapy on intermediate markers of cardiovascular risk in the CANVAS program. Int J Cardiol 318 (2020), 126–129.
Cahn, A., Wiviott, S.D., Mosenzon, O., Murphy, S.A., Goodrich, E.L., Yanuv, I., et al. Cardiorenal outcomes with dapagliflozin by baseline glucose-lowering agents: post hoc analyses from DECLARE-TIMI 58. Diabetes Obes Metab 23 (2021), 29–38.
Cannon, C.P., Pratley, R., Dagogo-Jack, S., Mancuso, J., Huyck, S., Masiukieewicz, U., et al. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med 383 (2020), 1425–1435.
Bhatt, D.L., Szarek, M., Pitt, B., Cannon, C.P., Leiter, L.A., McGuire, D.K., et al. Sotagliflozin in patients with diabetes and chronic kidney disease. N Engl J Med 384 (2021), 129–139.
Neuen, B.L., Fletcher, R.A., Heath, L., Perkovic, A., Vaduganathan, M., Badve, S., Cardiovascular, et al. kidney and safety outcomes with GLP-1 receptor agonists alone and in combination with SGLT2 inhibitors in type 2 diabetes: a systematic review and meta-analysis. Circulation 150 (2024), 1781–1790.
Mantsiou, C., Karagiannis, T., Kakotrichi, P., Malandris, K., Avgerinos, I., Liakos, A., et al. Glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors as combination therapy for type 2 diabetes: a systematic review and meta-analysis. Diabetes Obes Metab 22 (2020), 1857–1868.
Li, C., Luo, J., Jiang, M., Wang, K., The efficacy and safety of the combination therapy with GLP-1 receptor agonists and SGLT-2 inhibitors in type 2 diabetes mellitus: a systematic review and meta-analysis. Front Pharmacol, 13, 2022, 838277.
Apperloo, E.M., Neuen, B.L., Fletcher, R.A., Jongs, N., Anker, S.D., Bhatt, D.L., et al. Efficacy and safety of SGLT2 inhibitors with and without glucagon-like peptide 1 receptor agonists: a SMART-C collaborative meta-analysis of randomised controlled trials. Lancet Diabetes Endocrinol 12 (2024), 545–557.
Ahmad, A., Sabbour, H., Effectiveness and safety of the combination of sodium-glucose transport protein 2 inhibitors and glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes mellitus: a systematic review and meta-analysis of observational studies. Cardiovasc Diabetol, 23, 2024, 99.
Jensen, M.H., Kjolby, M., Hejlesen, O., Jokobsen, P.E., Vestergaard, P., Risk of major adverse cardiovascular events, severe hypoglycemia, and all-cause mortality for widely used antihyperglycemic dual and triple therapies for type 2 diabetes management: a cohort study of all Danish users. Diabetes Care 43 (2020), 1209–1218.
Wright, A.K., Carr, M.J., Kontopantelis, E., Leelarathna, L., Thabit, H., Emsley, R., et al. Primary prevention of cardiovascular and heart failure events with SGLT2 inhibitors, GLP-1 receptor agonists, and their combination in type 2 diabetes. Diabetes Care 45 (2022), 909–918.
Riley, D.R., Essa, H., Austin, P., Preston, F., Kargbo, I., Hernandez Ibarburu, G., et al. All-cause mortality and cardiovascular outcomes with sodium-glucose co-transporter 2 inhibitors, glucagon-like peptide-1 receptor agonists and with combination therapy in people with type 2 diabetes. Diabetes Obes Metab 25 (2023), 2897–2909.
Dave, C.V., Kim, S.C., Goldfine, A.B., Glynn, R.J., Tong, A., Patorno, E., Risk of cardiovascular outcomes in patients with type 2 diabetes after addition of SGLT2 inhibitors versus sulfonylureas to baseline GLP-1RA therapy. Circulation 143 (2021), 770–779.
Lopez, P.D., Bhatia, K., Bohra, C., Mahmood, K., Baruch, L., Eng, C., Benefits of adding glucagon-like peptide 1 receptor agonists to sodium-glucose co-transporter 2 inhibitors in diabetic patients with atherosclerotic disease and heart failure. Am J Cardiol 181 (2022), 87–93.
Simms-Williams, N., Treves, N., Yin, H., Lu, S., Yu, O., Pradhan, R., et al. Effect of combination treatment with glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors on incidence of cardiovascular and serious renal events: population based cohort study. BMJ, 385, 2024, e078242.
Marfella, R., Prattichizzo, F., Sardu, C., Rambaldi, P.F., Fumagalli, C., Marfella, L.V., et al. GLP-1 receptor agonists-SGLT-2 inhibitors combination therapy and cardiovascular events after acute myocardial infarction: an observational study in patients with type 2 diabetes. Cardiovasc Diabetol, 23, 2024, 10.
Garcia-Vega, D., Cinza-Sanjurjo, S., Eiras, S., Gonzalez-Juanatey, J.R., Combined sodium-glucose-transporters inhibitors and glucagon-like-peptide receptor agonist compared with monotherapy improves long-term survival: a real-world registry. Am J Med 137 (2024), 761–769 e1.
Patel, R., Wadid, M., Makwana, B., Kumar, A., Khadke, S., Bhatti, A., et al. GLP-1 Receptor agonists among patients with overweight or obesity, diabetes, and HFpEF on SGLT2 Inhibitors. JACC Heart Failure 12 (2024), 1814–1826.
Kobayashi, K., Toyoda, M., Tone, A., Kawanami, D., Suzuki, D., Tsuriya, D., et al. Renoprotective effects of combination treatment with sodium-glucose cotransporter inhibitors and GLP-1 receptor agonists in patients with type 2 diabetes mellitus according to preceding medication. Diab Vasc Dis Res, 20, 2023, 14791641231222837.
Muta, Y., Kobayashi, K., Toyoda, M., Tone, A., Suzuki, D., Tsuriya, D., et al. Influence of the combination of SGLT2 inhibitors and GLP-1 receptor agonists on eGFR decline in type 2 diabetes: post-hoc analysis of RECAP study. Front Pharmacol, 15, 2024, 1358573.
Mann, J.F.E., Rossing, P., Bakris, G., Belmar, N., Bosch-Traberg, H., Busch, R., et al. Effects of semaglutide with and without concomitant SGLT2 inhibitor use in participants with type 2 diabetes and chronic kidney disease in the FLOW trial. Nat Med 30 (2024), 2849–2856.
Khera, R., Aminorroaya, A., Dhingra, L.S., Thangaraj, P.M., Pedroso Camargos, A., Bu, F., et al. Comparative effectiveness of second-line antihyperglycemic agents for cardiovascular outcomes: a large-scale, multinational, federated analysis of the LEGEND-T2DM study. J Am Coll Cardiol 84 (2024), 904–917.
Zareini, B., Gerds, T.A., Sorensen, K.K., Clemmensen, K.K.B., Kvist, K., David, J.P., et al. Benefit of dual therapy with GLP-1 RA and SGLT2i on cardiovascular outcomes in type 2 diabetes. Diabetes, 72, 2023 :200-LB.
Pandey, A., Khan, M.S., Patel, K.V., Bhatt, D.L., Verma, S., Predicting and preventing heart failure in type 2 diabetes. Lancet Diabetes Endocrinol 11 (2023), 607–624.
Belli, M., Barone, L., Bellia, A., Sergi, D., Lecis, D., Prandi, F.R., et al. Treatment of HFpEF beyond the SGLT2-is: does the addition of GLP-1 RA improve cardiometabolic risk and outcomes in diabetic patients?. Int J Mol Sci, 23, 2022, 14598.
Ostrominski, J.W., Solomon, S.D., Vaduganathan, M., Heart failure with preserved ejection fraction therapy: combining sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide-1 receptor agonists. Eur Heart J 45 (2024), 2748–2751.
Scheen, A.J., Delanaye, P., Acute renal injury events in diabetic patients treated with SGLT2 inhibitors: a comprehensive review with a special reference to RAAS blockers. Diabetes Metab, 48, 2022, 101315.
Delanaye, P., Scheen, A.J., Epidemiology of acute kidney injury adverse events with SGLT2 inhibitors: a meta-analysis of observational cohort studies. Diabetes Epidemiol Manag, 3, 2021, 100021.
Lui, D.T.W., Au, I.C.H., Tang, E.H.M., Cheung, C.L., Lee, C.H., Woo, Y.C., et al. Kidney outcomes associated with sodium-glucose cotransporter 2 inhibitors versus glucagon-like peptide 1 receptor agonists: a real-world population-based analysis. EClinicalMedicine, 50, 2022, 101510.
Fadini, G.P., Longato, E., Morieri, M.L., Bonora, E., Consoli, A., Fattor, B., et al. Comparative renal outcomes of matched cohorts of patients with type 2 diabetes receiving SGLT2 inhibitors or GLP-1 receptor agonists under routine care. Diabetologia 67 (2024), 2585–2597.
Suzuki, Y., Kaneko, H., Nagasawa, H., Okada, A., Fujiu, K., Jo, T., et al. Comparison of estimated glomerular filtration rate change with sodium-glucose cotransporter-2 inhibitors versus glucagon-like peptide-1 receptor agonists among people with diabetes: a propensity-score matching study. Diabetes Obes Metab 26 (2024), 2422–2430.
Zelniker, T.A., Wiviott, S.D., Raz, I., Im, K.A., Goodrich, E.L., Furtado, R.H.M., et al. Comparison of the effects of glucagon-like peptide receptor agonists and sodium-glucose cotransporter 2 inhibitors for prevention of major adverse cardiovascular and renal outcomes in type 2 diabetes mellitus. Circulation 139 (2019), 2022–2031.
Forbes, A.K., Suckling, R.J., Hinton, W., Feher, M.D., Banerjee, D., Cole, N.I., et al. Sodium-glucose cotransporter-2 inhibitors and kidney outcomes in real-world type 2 diabetes populations: a systematic review and meta-analysis of observational studies. Diabetes Obes Metab 25 (2023), 2310–2330.