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Evaluation of the Lifetime Benefits of Metformin and SGLT2 Inhibitors in Type 2 Diabetes Mellitus Patients with Cardiovascular Disease: A Systematic Review and Two-Stage Meta-Analysis

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Abstract

Background

Metformin and sodium-glucose cotransporter-2 (SGLT2) inhibitors have demonstrated cardiovascular benefits but their comparative effects on mortality in type 2 diabetes mellitus (T2DM) patients with cardiovascular disease (CVD) are unknown. Hence, we evaluated and compared lifetime benefits arising from metformin or SGLT2 inhibitors in T2DM patients with CVD.

Materials and Methods

Studies published in the PubMed, EMBASE and CENTRAL databases before 28 October 2023 were retrieved. Treatment effects of metformin against US FDA-approved SGLT2 inhibitors in T2DM patients with CVD were evaluated and lifetime gains in event-free survival were estimated from our primary endpoints of all-cause and cardiovascular mortality. Risk ratios were derived to assess their impact on secondary outcomes such as major adverse cardiovascular events and hospitalizations for heart failure.

Results

Overall, 14 studies were included. Five studies published Kaplan–Meier curves for the primary outcome of all-cause mortality. Individual participant data were reconstructed from these Kaplan–Meier curves, from which we conducted our two-stage meta-analysis. Participants receiving metformin and SGLT2 inhibitors experienced a reduction in the risk for all-cause mortality as compared with those not taking metformin and placebo. However, participants receiving SGLT2 inhibitors had a higher all-cause mortality (hazard ratio 1.308, 95% confidence interval 1.103–1.550) versus metformin. Treatment with metformin was estimated to offer an additional 23.26 months of survival free from all-cause mortality versus 23.04 months with SGLT2 inhibitors.

Conclusions

In patients with T2DM and CVD, metformin and SGLT2 inhibitors were associated with substantially lower all-cause mortality rates and slightly longer life expectancies than in patients without. Metformin presented an advantage over SGLT2 inhibitors in reducing all-cause mortality.

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Author notes

  1. Hon Jen Wong and Norman H. Lin contributed equally as first authors.

Authors and Affiliations

  1. Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Hon Jen Wong, Yao Neng Teo & Ching-Hui Sia

  2. Department of Cardiology, National University Heart Centre Singapore, 1E Kent Ridge Road, NUHS Tower Block Level 9, Singapore, 119228, Singapore

    Norman H. Lin, Nicholas L. Syn, Yao Hao Teo & Ching-Hui Sia

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  1. Hon Jen Wong
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Correspondence to Ching-Hui Sia.

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Hon Jen Wong, Norman H. Lin, Yao Neng Teo, Nicholas L. Syn, Yao Hao Teo, and Ching-Hui Sia declare they have no potential conflicts of interest that might be relevant to the contents of this manuscript.

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No sources of funding were used to assist in the preparation of this study.

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This manuscript makes use of publicly available data from published studies, hence no original data are available for sharing.

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Author contributions

HJW, NHL, YNT, NLS, YHT and CHS were responsible for the conceptualization and design of the study. HJW, NHL and YNT formulated the search strategy. HJW and NHL conducted the screening for eligible studies, extracted the data and performed the risk-of-bias assessment. HJW and YNT reconstructed individual participant data. HJW, YNT and YHT performed the statistical analyses. HJW, NHL, YNT, NLS, YHT and CHS interpreted the data. HJW and NHL drafted the first manuscript. HJW, NHL, YNT, NLS, YHT and CHS critically reviewed and edited the manuscript. NLS, YHT and CHS supervised the study. All authors contributed to the article and approved the submitted version.

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Wong, H.J., Lin, N.H., Teo, Y.N. et al. Evaluation of the Lifetime Benefits of Metformin and SGLT2 Inhibitors in Type 2 Diabetes Mellitus Patients with Cardiovascular Disease: A Systematic Review and Two-Stage Meta-Analysis. Am J Cardiovasc Drugs (2024). https://doi.org/10.1007/s40256-024-00640-w

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