Ganakumar V, Fernandez CJ, Pappachan JM. Antidiabetic combination therapy and cardiovascular outcomes: An evidence-based approach. World J Diabetes 2025; 16(4): 102390 [DOI: 10.4239/wjd.v16.i4.102390]
Corresponding Author of This Article
Joseph M Pappachan, MD, FRCP, Professor, Faculty of Science, Manchester Metropolitan University, Lower Ormond Street, Manchester M15 6BH, United Kingdom. drpappachan@yahoo.co.in
Research Domain of This Article
Endocrinology & Metabolism
Article-Type of This Article
Editorial
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (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: http://creativecommons.org/licenses/by-nc/4.0/
World J Diabetes. Apr 15, 2025; 16(4): 102390 Published online Apr 15, 2025. doi: 10.4239/wjd.v16.i4.102390
Antidiabetic combination therapy and cardiovascular outcomes: An evidence-based approach
Vanishri Ganakumar, Cornelius J Fernandez, Joseph M Pappachan
Vanishri Ganakumar, Department of Endocrinology, Jawaharlal Nehru Medical College, Belagavi 590010, India
Cornelius J Fernandez, Department of Endocrinology and Metabolism, Pilgrim Hospital, United Lincolnshire Hospitals NHS Trust, Boston PE21 9QS, Lincolnshire, United Kingdom
Joseph M Pappachan, Faculty of Science, Manchester Metropolitan University, Manchester M15 6BH, United Kingdom
Joseph M Pappachan, Department of Endocrinology, KMC Medical College, Manipal Academy of Higher Education, Manipal 576104, India
Author contributions: Ganakumar V and Fernandez CJ contributed to the initial drafting of the work by performing the literature search and interpretation of relevant literature and share the first authorship; Fernandez CJ also prepared the figures for the manuscript and contributed substantially in addition to the revision process; Pappachan JM conceptualized the idea and provided overall supervision to the drafting process and figure preparation; All authors contributed to the revision of the article for important intellectual content, and all authors have read and approved the final version of the manuscript.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
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: Joseph M Pappachan, MD, FRCP, Professor, Faculty of Science, Manchester Metropolitan University, Lower Ormond Street, Manchester M15 6BH, United Kingdom. drpappachan@yahoo.co.in
Received: October 16, 2024 Revised: January 8, 2025 Accepted: January 16, 2025 Published online: April 15, 2025 Processing time: 135 Days and 4.8 Hours
Abstract
Type 2 diabetes mellitus is associated with a 2-4 times increased risk of cardiovascular (CV) disease. Glucagon-like polypeptide-1 receptor agonists (GLP1RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) are two important classes of drugs with CV benefits independent of their antihyperglycemic efficacy. The CV outcome trials of both GLP1RA and SGLT2i have demonstrated CV superiority/neutrality concerning major adverse CV events (MACE). While GLP1RAs have exhibited a significant reduction in ischemic stroke and myocardial infarction (MI), SGLT2i have demonstrated a uniformly significant reduction in hospitalization for heart failure (HF) as a class effect. The unique clinical benefits and the distinct but complementary mechanisms of action make the combination of these drugs a mechanistically sound one. Recent meta-analyses suggest an independent and additive benefit of combination therapy of GLP1RA/SGLT2i vs monotherapy. Zhu et al, in a recent issue of the World Journal of Diabetes, demonstrates a numerically lower hazard ratio (HR) for CV outcomes with combination therapy vs monotherapy with either agent, with a reduction in MACE compared to GLP1RA alone [HR = 0.51, 95% confidence interval (CI): 0.16-1.65], or SGLT2i alone (HR = 0.48, 95%CI: 0.15-1.54). The CV death rate was also lower with combination therapy compared to GLP1RA alone (HR = 0.58, 95%CI: 0.08-3.39), or SGLT2i alone (HR = 0.55, 95%CI: 0.07-3.25). Fatal and non-fatal MI and fatal and non-fatal stroke were reduced with combination therapy compared to GLP1RA alone (HR = 0.45, 95%CI: 0.10-2.18 and HR = 0.86, 95%CI: 0.12-6.23, respectively), or SGLT2i alone (HR = 0.44, 95%CI: 0.09-2.10 and HR = 0.74, 95%CI: 0.10-5.47, respectively). Hospitalization for HF was prevented with combination therapy compared to GLP1RA alone (HR = 0.26, 95%CI: 0.03-1.88), or SGLT2i alone (HR = 0.33, 95%CI: 0.04-2.53). They also demonstrated that GLP1RA or SGLT2i monotherapy may not provide significant improvement in CV death and recurrent MI in patients with prior MI or HF, proposing a role for combination therapy in this subgroup. Appropriate patient selection is vital to optimize CV risk reduction as well as the cost-effectiveness of this combination therapy.
Core Tip: Glucagon-like polypeptide-1 receptor agonists (GLP1RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) are important antihyperglycemic medications with cardiovascular (CV) benefits in the form of CV superiority or neutrality, and positive effects on cardiometabolic risk factors. The divergent clinical benefits include significant reductions in hospitalization for heart failure (HF) with SGLT2i, and ischemic stroke and myocardial infarction (MI) with GLP1RA. Zhu et al, in a recent issue of the World Journal of Diabetes, suggest combination therapy with GLP1RA/SGLT2i vs monotherapy with either agent for additional improvement in CV death and recurrent MI, especially in the setting of prior MI or HF.
