Systematic Reviews
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Oct 15, 2024; 15(10): 2135-2146
Published online Oct 15, 2024. doi: 10.4239/wjd.v15.i10.2135
Combining GLP-1 receptor agonists and SGLT-2 inhibitors for cardiovascular disease prevention in type 2 diabetes: A systematic review with multiple network meta-regressions
Jing-Jing Zhu, John P H Wilding, Xiao-Song Gu
Jing-Jing Zhu, Department of Endocrinology and Metabolic Medicine, The Second Affiliated Hospital of Soochow University, Suzhou 215004, Jiangsu Province, China
Jing-Jing Zhu, John P H Wilding, Department of Cardiovascular and Metabolic Medicine, University of Liverpool, Liverpool L69 7ZX, United Kingdom
Jing-Jing Zhu, John P H Wilding, Clinical Sciences Centre, Liverpool University Hospitals NHS Foundation Trust, Liverpool L9 7AL, United Kingdom
Xiao-Song Gu, Department of Cardiovascular Medicine, The Second Affiliated Hospital of Soochow University, Suzhou 215004, Jiangsu Province, China
Co-corresponding authors: John P H Wilding and Xiao-Song Gu.
Author contributions: Wilding JPH and Gu XS contributed equally to this study as co-corresponding authors. Wilding JPH proposed to investigate cardiovascular benefit of the combination treatment of GLP-1RA and SGLT-2I; Zhu JJ and Gu XS conducted the systematic review; Zhu JJ performed all the statistics and took responsibility for the accuracy of the data analysis; Wilding JPH and Gu XS supervised the findings of this study; all the authors discussed the results, and contributed to and approved the final manuscript (including the registered protocol).
Supported by China Scholarship Council, No. 202006920018; Key Talent Program for Medical Applications of Nuclear Technology, No. XKTJ-HRC2021007; the Second Affiliated Hospital of Soochow University, No. SDFEYBS1815 and No. SDFEYBS2008; National Natural Science Foundation of China, No. 82170831; and The Jiangsu Innovation & Career Fund for PhD 2019.
Conflict-of-interest statement: Zhu JJ and Gu XS have no conflict of interest or financial disclosures that are relevant to the content of this research report. Wilding JPH reports consultancy/advisory board work for the pharmaceutical industry contracted via the University of Liverpool (no personal payment) for Altimmune, AstraZeneca, Boehringer Ingelheim, Cytoki, Lilly, Napp, Novo Nordisk, Menarini, Pfizer, Rhythm Pharmaceuticals, Sanofi, Saniona, Tern, and Shionogi & Ysopia; research grants for clinical trials from AstraZeneca and Novo Nordisk and personal honoraria/lecture fees from AstraZeneca, Boehringer Ingelheim, Medscape, Napp, Novo Nordisk, and Rhythm. Wilding JPH is past president of the World Obesity Federation, a member of the Association for the Study of Obesity, Diabetes UK, EASD, ADA, Society for Endocrinology, and the Rank Prize Funds Nutrition Committee. Wilding JPH is national lead for the Metabolic and Endocrine Speciality Group of the UK NIHR Clinical Research Network.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2020 Checklist, and the manuscript was prepared and revised according to the PRISMA 2020 Checklist.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Xiao-Song Gu, MD, PhD, Chief Physician, Associate Professor, Department of Cardiovascular, The Second Affiliated Hospital of Soochow University, No. 1055 Sanxiang Road, Suzhou 215004, Jiangsu Province, China. xiaosonggu@suda.edu.cn
Received: May 14, 2024
Revised: August 10, 2024
Accepted: September 6, 2024
Published online: October 15, 2024
Processing time: 134 Days and 20.4 Hours
Abstract
BACKGROUND

Glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose co-transporter-2 inhibitors (SGLT-2I) are associated with significant cardiovascular benefit in type 2 diabetes (T2D). However, GLP-1RA or SGLT-2I alone may not improve some cardiovascular outcomes in patients with prior cardiovascular co-morbidities.

AIM

To explore whether combining GLP-1RA and SGLT-2I can achieve additional benefit in preventing cardiovascular diseases in T2D.

METHODS

The systematic review was conducted according to PRISMA recommendations. The protocol was registered on PROSPERO (ID: 42022385007). A total of 107049 participants from eligible cardiovascular outcomes trials of GLP-1RA and SGLT-2I were included in network meta-regressions to estimate cardiovascular benefit of the combination treatment. Effect modification of prior myocardial infarction (MI) and heart failure (HF) was also explored to provide clinical insight as to when the combination treatment should be considered.

RESULTS

The estimated hazard ratios (HR)GLP-1RA/SGLT-2IvsPlacebo (0.75-0.98) and HRCombinationvsGLP-1RA/SGLT-2I (0.26-0.86) for primary and secondary cardiovascular outcomes suggested that the combination treatment may achieve additional cardiovascular benefit compared with GLP-1RA or SGLT-2I alone. In patients with prior MI or HF, the mono-therapies may not improve the overall cardiovascular outcomes, as the estimated HRMI+/HF+ (0.57-1.52) suggested that GLP-1RA or SGLT-2I alone may be associated with lower risks of hospitalization for HF but not cardiovascular death.

CONCLUSION

Considering its greater cardiovascular benefit in T2D, the combination treatment of GLP-1RA and SGLT-2I might be prioritized in patients with prior MI or HF, where the monotherapies may not provide sufficient cardiovascular protection.

Keywords: Type 2 diabetes; Glucagon-like peptide-1 receptor agonist; Sodium-glucose co-transporter-2 inhibitor; Combination treatment; Cardiovascular outcome; Systematic review; Network meta-regression

Core Tip: Major cardiovascular outcome trials suggest that patients with prior cardiovascular co-morbidities may not gain sufficient cardiovascular protection from glucagon-like peptide-1 receptor agonists (GLP-1RA) or sodium-glucose co-transporter-2 inhibitors (SGLT-2I) alone. This systematic review with network meta-regression demonstrated that the combination treatment may provide greater cardiovascular benefit compared with GLP-1RA or SGLT-2I alone. In patients with prior myocardial infarction or heart failure, the monotherapies may not be associated with consistently improved cardiovascular outcomes, hence the combination treatment might be considered for cardiovascular disease prevention.