Comparative Efficacy of GLP-1 RAs/SGLT-2 Inhibitors in Reducing Cardiovascular Events in Type 2 Diabetes According to Baseline Use of Metformin: a Systematic Review and Meta-analysis of Randomized Controlled Trials

Overview

Journal Eur J Med Res

Publisher Biomed Central

Specialty General Medicine

Date 2025 Jan 8

PMID 39773332

Authors

Yuxin Zhang

Zhaoji Li

Yongchen Hao

Affiliations

Soon will be listed here.

Abstract

Background: Sodium-glucose transporters 2 inhibitors (SGLT-2i) and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are recommended along with metformin for the potential cardiovascular benefits among type 2 diabetes. This meta-analysis aims to evaluate whether the effects of SGLT-2i or GLP-1 RAs on cardiovascular outcomes are consistent with and without baseline metformin use.

Methods: PubMed, Cochrane, Web of Science and Embase were searched for randomized placebo-controlled trials with SGLT-2i or GLP-1 RAs as interventions of type 2 diabetes patients up to June, 2024. The main outcomes were major adverse cardiovascular events (MACE), hospitalization for heart failure (HHF) or cardiovascular death. Both random-effects model and fixed model were adopted to estimate pooled hazard ratios (HR) and 95% confidence intervals (95% CI).

Results: A total of 81,738 patients (median age: 62-66 years, 53.7-71.5% men, median follow-up: 1.3-5.4 years) from 11 studies (7 studies of SGLT-2i and 4 of GLP-1 RAs) were included in the study. The metformin-naive portions ranged from 28.90% to 81.98%. Among patients using metformin at baseline, SGLT-2i or GLP-1 RAs reduced MACE risk (HR = 0.95, 95% CI 0.91-0.99, P = 0.02). In metformin-naive patients, similar reductions were observed (HR = 0.79, 95% CI 0.65-0.95, P = 0.01). No statistically significant interaction was found between metformin users and non-users for any outcome (all P values for interaction > 0.05), indicating consistent cardiovascular benefits regardless of baseline metformin therapy.

Conclusions: SGLT-2i and GLP-1 RAs have the effects of cardiovascular benefits for T2DM patients regardless of baseline metformin use.

References

Yu J, Park S, Lee D, Kim N, Seo J . GLP-1 receptor agonists in diabetic kidney disease: current evidence and future directions. Kidney Res Clin Pract. 2022; 41(2):136-149. PMC: 8995488. DOI: 10.23876/j.krcp.22.001. View

Bakbak E, Verma S, Krishnaraj A, Quan A, Wang C, Pan Y . Empagliflozin improves circulating vascular regenerative cell content in people without diabetes with risk factors for adverse cardiac remodeling. Am J Physiol Heart Circ Physiol. 2023; 325(5):H1210-H1222. DOI: 10.1152/ajpheart.00141.2023. View

Zinman B, Wanner C, Lachin J, Fitchett D, Bluhmki E, Hantel S . Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015; 373(22):2117-28. DOI: 10.1056/NEJMoa1504720. View

ElSayed N, Aleppo G, Aroda V, Bannuru R, Brown F, Bruemmer D . 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes-2023. Diabetes Care. 2022; 46(Suppl 1):S140-S157. PMC: 9810476. DOI: 10.2337/dc23-S009. View

Mantsiou C, Karagiannis T, Kakotrichi P, Malandris K, Avgerinos I, Liakos A . 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. 2020; 22(10):1857-1868. DOI: 10.1111/dom.14108. View

Caruso I, Giorgino F . SGLT-2 inhibitors as cardio-renal protective agents. Metabolism. 2021; 127:154937. DOI: 10.1016/j.metabol.2021.154937. View

Meier J . GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol. 2012; 8(12):728-42. DOI: 10.1038/nrendo.2012.140. View

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. 2022; 13:838277. PMC: 8854770. DOI: 10.3389/fphar.2022.838277. View

Tsukagoshi-Yamaguchi A, Koshizaka M, Ishibashi R, Ishikawa K, Ishikawa T, Shoji M . Metabolomic analysis of serum samples from a clinical study on ipragliflozin and metformin treatment in Japanese patients with type 2 diabetes: Exploring human metabolites associated with visceral fat reduction. Pharmacotherapy. 2023; 43(12):1317-1326. DOI: 10.1002/phar.2884. View

10.

Samaras K, Makkar S, Crawford J, Kochan N, Wen W, Draper B . Metformin Use Is Associated With Slowed Cognitive Decline and Reduced Incident Dementia in Older Adults With Type 2 Diabetes: The Sydney Memory and Ageing Study. Diabetes Care. 2020; 43(11):2691-2701. DOI: 10.2337/dc20-0892. View

11.

ElSayed N, Aleppo G, Aroda V, Bannuru R, Brown F, Bruemmer D . 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes-2023. Diabetes Care. 2022; 46(Suppl 1):S158-S190. PMC: 9810475. DOI: 10.2337/dc23-S010. View

12.

Lam C, Ramasundarahettige C, Branch K, Sattar N, Rosenstock J, Pratley R . 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. 2021; 145(8):565-574. DOI: 10.1161/CIRCULATIONAHA.121.057934. View

13.

Visseren F, Mach F, Smulders Y, Carballo D, Koskinas K, Back M . 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J. 2021; 42(34):3227-3337. DOI: 10.1093/eurheartj/ehab484. View

14.

Beernink J, Persson F, Jongs N, Laverman G, Chertow G, McMurray J . Efficacy of Dapagliflozin by Baseline Diabetes Medications: A Prespecified Analysis From the DAPA-CKD Study. Diabetes Care. 2023; 46(3):602-607. PMC: 10020024. DOI: 10.2337/dc22-1514. View

15.

Poor S, Ettcheto M, Cano A, Sanchez-Lopez E, Manzine P, Olloquequi J . Metformin a Potential Pharmacological Strategy in Late Onset Alzheimer's Disease Treatment. Pharmaceuticals (Basel). 2021; 14(9). PMC: 8465337. DOI: 10.3390/ph14090890. View

16.

Hong J, Zhang Y, Lai S, Lv A, Su Q, Dong Y . Effects of metformin versus glipizide on cardiovascular outcomes in patients with type 2 diabetes and coronary artery disease. Diabetes Care. 2012; 36(5):1304-11. PMC: 3631843. DOI: 10.2337/dc12-0719. View

17.

Wiviott S, Raz I, Bonaca M, Mosenzon O, Kato E, Cahn A . Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2018; 380(4):347-357. DOI: 10.1056/NEJMoa1812389. View

18.

Neuen B, Arnott C, Perkovic V, Figtree G, de Zeeuw D, Fulcher G . Sodium-glucose co-transporter-2 inhibitors with and without metformin: A meta-analysis of cardiovascular, kidney and mortality outcomes. Diabetes Obes Metab. 2020; 23(2):382-390. PMC: 7821162. DOI: 10.1111/dom.14226. View

19.

Heerspink H, Stefansson B, Correa-Rotter R, Chertow G, Greene T, Hou F . Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020; 383(15):1436-1446. DOI: 10.1056/NEJMoa2024816. View

20.

Huang L, Xiong S, Liu H, Li M, Zhang R, Liu Y . Bioinformatics Analysis of the Inflammation-Associated lncRNA-mRNA Coexpression Network in Type 2 Diabetes. J Renin Angiotensin Aldosterone Syst. 2023; 2023:6072438. PMC: 9977555. DOI: 10.1155/2023/6072438. View