The effect of DPP-4 inhibitors, GLP-1 receptor agonists and SGLT-2 inhibitors on cardiorenal outcomes: a network meta-analysis of 23 CVOTs
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Abstract
BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium glucose co-transporter-2 (SGLT-2) inhibitors reduce cardiorenal outcomes. We performed a network meta-analysis to compare the effect on cardiorenal outcomes among GLP-1 RAs, SGLT-2 inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors. METHODS: We searched the PUBMED, Embase and Cochrane databases for relevant studies published up until 10 December 2021. Cardiovascular and renal outcome trials reporting outcomes on GLP-1RA, SGLT-2 inhibitors and DPP-4 inhibitors in patients with or without type 2 diabetes mellitus were included. The primary outcome was major adverse cardiovascular events (MACE); other outcomes were cardiovascular and total death, nonfatal myocardial infarction (MI), nonfatal stroke, hospitalization for heart failure (HHF), and renal outcome. RESULTS: Twenty-three trials enrolling a total number of 181,143 participants were included. DPP-4 inhibitors did not lower the risk of any cardiorenal outcome when compared with placebo and were associated with higher risks of MACE, HHF, and renal outcome when compared with the other two drug classes. SGLT-2 inhibitors significantly reduced cardiovascular (RR = 0.88) and total (RR = 0.87) death, as compared with DPP-4 inhibitors, while GLP-1 RA reduced total death only (RR = 0.87). The comparison between GLP-1RA and SGLT-2 inhibitors showed no difference in their risks of MACE, nonfatal MI, nonfatal stroke, CV and total death; SGLT-2 inhibitors were superior to GLP-1RA in reducing the risk of HHF and the renal outcome (24% and 22% lower risk, respectively). Only GLP-1RA reduced the risk of nonfatal stroke (RR = 0.84), as compared with placebo. There was no head-to-head trial directly comparing these antidiabetic drug classes. CONCLUSIONS: SGLT-2 inhibitors and GLP-1RA are superior to DPP-4 inhibitors in reducing the risk of most cardiorenal outcomes; SGLT-2 inhibitors are superior to GLP-1RA in reducing the risk of HHF and renal events; GLP-1RA only reduced the risk of nonfatal stroke. Both SGLT-2 inhibitors and GLP-1RA should be the preferred treatment for type 2 diabetes and cardiorenal diseases.
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SGLT2i and GLP-1 RA reduce adverse cardiorenal outcomes in patients with type 2 diabetes and high cardiovascular disease, chronic kidney disease, heart failure, obesity, or elevated cardiovascular disease risk.
“Sodium-Glucose Cotransporter 2 Inhibitors (SGLT2i) and Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RA) reduce adverse cardiorenal outcomes in patients with type 2 diabetes and high cardiovascular disease, chronic kidney disease, heart failure, obesity, or elevated cardiovascular disease risk.1”
From Race and ethnicity and pharmacy dispensing of SGLT2 inhibitors and GLP-1 receptor agonists in type 2 diabetes (2024) · cites this paper as [1]
The Conclusions and Discussion report reduced cardiovascular and renal outcomes with SGLT-2 inhibitors and GLP-1 receptor agonists and recommend them for patients with type 2 diabetes and cardiovascular disease, kidney disease, or heart failure. The paper mentions weight loss but does not establish reduced cardiorenal outcomes specifically in patients with obesity; it also does not substantiate every listed patient group as a separate population. (LLM, conf=0.87)
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Cites
Liberati, A., Altman, D. G., Tetzlaff, J., Mulrow, C., Gøtzsche, P. C., Ioannidis, J. P. A., Clarke, M., Devereaux, P. J., Kleijnen, J., & Moher, D. (2009) · Annals of Internal Medicine · doi:10.7326/0003-4819-151-4-200908180-00136 · Cited by 10,349 · see citing works
Einarson, T. R., Acs, A., Ludwig, C., & Panton, U. H. (2018) · Cardiovascular Diabetology · doi:10.1186/s12933-018-0728-6 · Cited by 2,312 · see citing works
Ranking treatments in frequentist network meta-analysis works without resampling methods
Rücker, G., & Schwarzer, G. (2015) · BMC Medical Research Methodology · doi:10.1186/s12874-015-0060-8 · Cited by 1,732 · see citing works
Dias, S., Sutton, A. J., Ades, A. E., & Welton, N. J. (2013) · Medical Decision Making · doi:10.1177/0272989x12458724 · Cited by 1,207 · see citing works
SGLT2 inhibitors and GLP-1 receptor agonists: established and emerging indications
Brown, E., Heerspink, H. J. L., Cuthbertson, D. J., & Wilding, J. P. H. (2021) · The Lancet · doi:10.1016/s0140-6736(21)00536-5 · Cited by 581 · see citing works
Giugliano, D., Scappaticcio, L., Longo, M., Caruso, P., Maiorino, M. I., Bellastella, G., Ceriello, A., Chiodini, P., & Esposito, K. (2021) · Cardiovascular Diabetology · doi:10.1186/s12933-021-01366-8 · Cited by 263 · cited 4× · see citing works
“Our analysis also confirms that GLP-1RA, when compared with placebo, reduce the risk of MACE, total death, HHF, and the composite renal outcome [12].”
BackgroundResultInfluentialSelf-citationLin, D. S.-H., Lee, J.-K., Hung, C.-S., & Chen, W.-J. (2021) · Diabetologia · doi:10.1007/s00125-021-05529-w · Cited by 108 · see citing works
Flagged first, then by citations
Research works printed but not linked: 21
- [1]IDF Diabetes Atlas 2021 – 10th edition. www.diabetesatlas.org. Accessed 15 Jan 2022.
- [2]Shah AD Langenberg C Rapsomaniki E Type 2 diabetes and incidence of cardiovascular diseases: a cohort study in 1·9 million people Lancet Diabetes Endocrinol 2015 3 105 113 10.1016/S2213-8587(14)70219-0 25466521 PMC4303913 · DOI · Paper page
- [4]Almourani R Chinnakotla B Patel R Kurukulasuriya LR Sowers J Diabetes and cardiovascular disease: an update Curr Diab Rep 2019 19 161 10.1007/s11892-019-1239-x 31828525 · DOI · Paper page
- [5]Virani SS Alonso A Benjamin EJ Heart disease and stroke statistics-2020 update: a report from the American Heart Association Circulation 2020 141 e139 e596 31992061
- [7]Cosentino F Grant PJ Aboyans V 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD Eur Heart J 2020 41 255 323 10.1093/eurheartj/ehz486 31497854 · DOI · Paper page
- [8]Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group. KDIGO Clinical practice guideline for diabetes management in chronic kidney disease Kidney Int 2020 2020 98 S1 S115 32998798
- [9]Das SR Everett BM Birtcher KK 2018 ACC Expert consensus decision pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes and atherosclerotic cardiovascular disease J Am Coll Cardiol 2018 72 3200 3223 10.1016/j.jacc.2018.09.020 30497881 PMC7560953 · DOI · Paper page
- [10]Draznin B Aroda VR Bakris G Benson G Brown FM Freeman R Green J Huang E Isaacs D Kahan S Leon J 9 Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2022 Diabetes Care 2022 45 Supplement 1 S125 S143 34964831
- [11]Abushamat LA Reusch JEB Evolving concepts of type 2 diabetes management Med Clin North Am 2021 105 955 966 10.1016/j.mcna.2021.06.003 34688420 PMC13012870 · DOI
- [13]Giugliano D Longo M Scappaticcio L SGLT-2 inhibitors and cardiorenal outcomes in patients with or without type 2 diabetes: a meta-analysis of 11 CVOTs Cardiovasc Diabetol 2021 20 236 10.1186/s12933-021-01430-3 34915880 PMC8680308 · DOI
- [14]Fei Y Tsoi M-F Cheung BMY Cardiovascular outcomes in trials of new antidiabetic drug classes: a network meta-analysis Cardiovas Diabetol 2019 18 112 10.1186/s12933-019-0916-z PMC6714383 31462224 · DOI
- [18]Higgins JP Altman DG Gøtzsche PC The Cochrane collaboration's tool for assessing risk of bias in randomised trials Br Med J 2011 343 d5928 10.1136/bmj.d5928 22008217 PMC3196245 · DOI · Paper page
- [20]Egger M Smith GD Schneider M Minder C Bias in meta-analysis detected by a simple, graphical test Br Med J 1997 315 629 634 10.1136/bmj.315.7109.629 9310563 PMC2127453 · DOI · Paper page
- [23]Maiorino MI Longo M Scappaticcio L Improvement of glycemic control and reduction of major cardiovascular events in 18 cardiovascular outcome trials: an updated meta-regression Cardiovasc Diabetol 2021 20 210 10.1186/s12933-021-01401-8 34663316 PMC8522255 · DOI · Paper page
- [24]Patil HR Al Badarin FJ Al Shami HA Meta-analysis of effect of dipeptidyl peptidase-4 inhibitors on cardiovascularrisk in type 2 diabetes mellitus Am J Cardiol 2012 110 826 833 10.1016/j.amjcard.2012.04.061 22703861 · DOI
- [28]FDA grants priority review to Boehringer-Lilly’s Jardiance for heart failure (pharmaceutical-technology.com).
- [29]Li C-X Liang S Gao L Liu H Cardiovascular outcomes associated with SGLT-2 inhibitors versus other glucose-lowering drugs in patients with type 2 diabetes: A real-world systematic review and meta-analysis PLoS ONE 2021 16 e0244689 10.1371/journal.pone.0244689 33606705 PMC7895346 · DOI
- [30]Morieri ML Avogaro A Fadini GP Long-acting Injectable GLP-1 receptor agonists for the treatment of adults with type 2 diabetes: Perspectives from clinical practice Diabetes Metab Syndr Obes 2020 13 4221 4234 10.2147/DMSO.S216054 33204129 PMC7665457 · DOI
- [31]Giugliano D Longo M Maiorino MI Bellastella G Chiodini P Solerte SB Esposito K Efficacy of SGLT-2 inhibitors in older adults with diabetes: systematic review with meta-analysis of cardiovascular outcome trials Diabetes Res Clin Pract 2020 162 108114 10.1016/j.diabres.2020.108114 32165164 · DOI
- [32]Kawai Y Uneda K Yamada T Comparison of effects of SGLT-2 inhibitors and GLP-1 receptor agonists on cardiovascular and renal outcomes in type 2 diabetes mellitus patients with/without albuminuria: a systematic review and network meta-analysis Diabetes Res Clin Pract 2021 183 109146 10.1016/j.diabres.2021.109146 34780865 · DOI
- [33]Giugliano D Scappaticcio L Longo M Bellastella G Esposito K GLP-1 receptor agonists vs SGLT-2 inhibitors: the gap seems to be leveling off Cardiovasc Diabetol 2021 20 205 10.1186/s12933-021-01400-9 34641876 PMC8513211 · DOI
Cited by
Sorted by citations
Khan, S. S., Breathett, K., Braun, L. T., Chow, S. L., Gupta, D. K., Lekavich, C., Lloyd-Jones, D. M., Ndumele, C. E., Rodriguez, C. J., Allen, L. A., et al. (2025) · Circulation · doi:10.1161/cir.0000000000001307 · Cited by 75 · see citing works
Ren, Y., Chen, Y., Zheng, W., Kong, W., Liao, Y., Zhang, J., Wang, M., & Zeng, T. (2025) · Diabetes, Obesity and Metabolism · doi:10.1111/dom.16366 · Cited by 59 · see citing works
Incretins and cardiovascular disease: to the heart of type 2 diabetes?
Solini, A., Tricò, D., & Del Prato, S. (2023) · Diabetologia · doi:10.1007/s00125-023-05973-w · Cited by 32 · see citing works
Rodriguez, L. A., Finertie, H., Neugebauer, R. S., Gosiker, B., Thomas, T. W., Karter, A. J., Gilliam, L. K., Oshiro, C., An, J., Simonson, G., et al. (2024) · The Lancet Regional Health - Americas · doi:10.1016/j.lana.2024.100759 · Cited by 31 · see citing works
Wang, J., Bi, C., Xi, H., & Wei, F. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1455534 · Cited by 13 · see citing works
Glucagon-like peptide-1 receptor agonists: a review from a cardiovascular perspective
Turkistani, Y. (2025) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2025.1535134 · Cited by 10 · see citing works
- Authors
- Giugliano, D., Longo, M., Signoriello, S., Maiorino, M. I., Solerte, B., Chiodini, P., & Esposito, K.
- Affiliations
- University of Campania "Luigi Vanvitelli" (IT)
- University of Pavia (IT)
- Corresponding author
- Giugliano, Dario
- ORCID
- Venue
- Cardiovascular Diabetology
- Published
- 2022-03-16
- Volume
- 21
- Issue
- 1
- Pages
- 42-42
- ISSN
- 1475-2840 (ISSN-L)
- PMC
- PMC8925229
- OpenAlex
- W4220656413
- Cited by
- 153
- References
- 7
- Citations by year
- 2026: 26 · 2025: 32 · 2024: 42 · 2023: 37 · 2022: 16
- FWCI
- 4.56
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Cardiovascular Diabetology (publishedVersion, cc-by)
- Research Square (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Archivio Istituzionale della Ricerca - Università degli Studi della Campania "Luigi Vanvitelli" (submittedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Keywords
- DPP-4 inhibitors, GLP-1 receptor agonists, SGLT2 inhibitors, cardiorenal outcomes, major adverse cardiovascular events, heart failure hospitalization, renal outcomes, type 2 diabetes, antidiabetic drugs, cardiovascular outcomes, stroke, mortality, drug safety comparison, cardiovascular outcome trials, cardiovascular safety, nonfatal myocardial infarction
- MeSH terms
- Glucagon-Like Peptide-1 Receptor, Network Meta-Analysis, Sodium-Glucose Transporter 2 Inhibitors, Glucagon-Like Peptide-1 Receptor Agonists, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Heart Failure, Humans, Hypoglycemic Agents, Myocardial Infarction, Stroke, Glucagon-Like Peptide 1, Dipeptidyl-Peptidase IV Inhibitors
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