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Effects of SGLT-2 inhibitors on mortality and cardiovascular events: a comprehensive meta-analysis of randomized controlled trials

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An Erratum to this article was published on 11 October 2016

Abstract

Aims

EMPAREG OUTCOME study showed a reduction in cardiovascular events in patients treated with the sodium-glucose transporter 2 inhibitor (SGLT2i) empagliflozin, as compared to placebo. Other drugs of the same class are currently been investigated for cardiovascular outcomes. In the meanwhile, a re-analysis of data collected in available studies can add relevant insight.

Methods

A MEDLINE search for SGLT-2 inhibitors (dapagliflozin, empagliflozin, canagliflozin, ipragliflozin, ertugliflozin, luseogliflozin) was performed, collecting all randomized trials up to November 16, 2015. All trials with a duration of treatment ≥12 weeks, enrolling patients with type 2 diabetes, comparing a SGLT2i with placebo or other comparators were included. The principal outcome was the effect of SGLT2i on all-cause and cardiovascular mortality. Secondary endpoints were myocardial infarction and stroke. Mantel–Haenszel odds ratio with 95 % confidence interval (MH-OR) was calculated.

Results

A total of 71 trials were included (31,199 and 16,088 patients in SGLT2i and comparator groups). Treatment with SGLT2i was associated with a significant reduction in all-cause mortality (MH-OR 0.70 [0.59–0.83], p < 0.001), cardiovascular mortality (MH-OR 0.43 [0.36–0.53], p < 0.001), and myocardial infarction (MH-OR 0.77 [0.63–0.94], p < 0.01), but not stroke (MH-OR 1.09 [0.86–1.38], p = 0.50), with no apparent difference across molecules (after excluding cardiovascular outcome trials).

Conclusions

Available data suggest that the beneficial action observed with empagliflozin on all-cause and cardiovascular mortality in EMPAREG OUTCOME study is a class effect. The present meta-analysis showed a significantly reduction in myocardial infarction, with no increased risk of stroke.

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Acknowledgments

This research was performed independently of any funding, as part of the institutional activity of the investigators.

Authors contribution

Matteo Monami designed the study, collected the data, performed the analysis, and wrote the manuscript. Ilaria Dicembrini collected the data and revised the manuscript. Edoardo Mannucci designed the study, collected the data, performed the analysis, and wrote the manuscript. All the authors approved the final version of this manuscript.

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Authors and Affiliations

  1. Diabetology, Azienda Ospedaliero-Universitaria Careggi, Careggi Teaching Hospital, University of Florence, Via delle Oblate 4, 50141, Florence, Italy

    Matteo Monami, Ilaria Dicembrini & Edoardo Mannucci

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  1. Matteo Monami
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Correspondence to Matteo Monami.

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Matteo Monami has received speaking fees from Bristol Myers Squibb, Eli-Lilly, Merck, Novonordisk, Merck, and Takeda; and research grants from Bristol Myers Squibb. Ilaria Dicembrini has no conflicts of interest. Edoardo Mannucci has received consultancy fees from Merck and Novartis; speaking fees from Astra Zeneca, Bristol Myers Squibb, Merck, and Novartis; and research grants from Merck, Novartis, and Takeda.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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This article does not contain any studies with animals performed by any of the authors.

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Managed by Massimo Federici.

An erratum to this article is available at http://dx.doi.org/10.1007/s00592-016-0922-5.

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Monami, M., Dicembrini, I. & Mannucci, E. Effects of SGLT-2 inhibitors on mortality and cardiovascular events: a comprehensive meta-analysis of randomized controlled trials. Acta Diabetol 54, 19–36 (2017). https://doi.org/10.1007/s00592-016-0892-7

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  • DOI: https://doi.org/10.1007/s00592-016-0892-7

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