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SGLT2 inhibitors in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials balancing their risks and benefits

Diabetologia (2022)Cite this article

Abstract

Aims/hypothesis

Cardiovascular outcome trials (CVOTs) have demonstrated the benefits of sodium–glucose cotransporter 2 inhibitors (SGLT2i). However, serious adverse drug reactions have been reported. The risk/benefit ratio of SGLT2i remains unquantified. We aimed to provide an estimation of their risk/benefit ratio in individuals with type 2 diabetes.

Methods

We conducted a systematic review (MEDLINE, up to 14 September 2021) and meta-analysis. We included randomised CVOTs assessing SGLT2i in individuals with type 2 diabetes with or without other diseases. We used the Cochrane ‘Risk of bias’ assessment tool. The primary outcomes were overall mortality, major adverse cardiovascular events (MACE), hospitalisation for heart failure (HHF), end-stage renal disease (ESRD), amputation, diabetic ketoacidosis (DKA) and reported genital infections. For each outcome, we estimated the incidence rate ratio (IRR) with a 95% CI; we then computed the number of events expected spontaneously and with SGLT2i.

Results

A total of 46,969 participants from five double-blind, placebo-controlled international trials (weighted mean follow-up 3.5 years) were included. The prevalence of previous CVD ranged from 40.6% to 99.2%. The definition of reported genital infections ranged from ‘genital mycotic infection’ to ‘genital infections that led to discontinuation of the trial regimen or were considered to be serious adverse events’. The number of included studies for each outcomes was five. The use of SGLT2i decreased the risk of all-cause death (IRR 0.86 [95% CI 0.78, 0.95]), MACE (IRR 0.91 [95% CI 0.86, 0.96]), HHF (IRR 0.69 [95% CI 0.62, 0.76]) and ESRD (IRR 0.67 [95% CI 0.53, 0.84]), and increased the risk of DKA (IRR 2.59 [95% CI 1.57, 4.27]) and genital infection (IRR 3.50 [95% CI 3.09, 3.95]) but not of amputation (IRR 1.23 [95% CI 1.00, 1.51]). For 1000 individuals treated over 3.5 years, SGLT2i are expected, on average, to decrease the number of deaths from 70 to 61, to prevent nine MACE, 11 HHF and two cases of ESRD, while inducing two DKA occurrences and 36 genital infections; 778 individuals are expected to avoid all the following outcomes: MACE, HHF, ESRD, amputation, DKA and genital infection.

Conclusions/interpretation

Our study is limited to aggregate data. In a population of individuals with type 2 diabetes and a high CVD risk, the cardiovascular and renal benefits of SGLT2i remain substantial despite the risk of DKA and even the hypothetical risk of amputation.

Trial registration

OSF Registries: https://doi.org/10.17605/OSF.IO/J3R7Y

Funding

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

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Data availability

Data, codes and other materials are available on request (please contact the corresponding author).

Abbreviations

CVOT:

Cardiovascular outcome trial

DKA:

Diabetic ketoacidosis

ESRD:

End-stage renal disease

HHF:

Hospitalisation for heart failure

IRR:

Incidence rate ratio

MACE:

Major adverse cardiovascular events

SGLT2i:

Sodium–glucose cotransporter 2 inhibitors

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Acknowledgements

We acknowledge G. Simeon, J. Corwin and P. Robinson (DRS, Hospices Civils de Lyon) for their assistance in editing the present article.

Authors’ relationships and activities

MC received consulting fees from Boehringer Ingelheim, Sanofi and AstraZeneca, and speaker honoraria from Sanofi. PM declares the following competing interests: grants from Akcea paid to his institution; advisory board fees from Akcea, Ionis and Boehringer paid to him or his institution; fees for clinical trials from Akcea, Amgen and Novo Nordisk paid to his institution; and fees for talks from Akcea, Amgen, MSD and Novo Nordisk paid to him or his institution. FG received, for his institution, fees from Portola Pharmaceuticals for central reading of ultrasound records, from Neurochlore for DSMB coordination, from EryTech Pharma for modelling projects, from RCTs and stève consultants for exploring French social security database. All other authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.

Contribution statement

EM, GG and MC designed the study. EM and GG performed the literature search, data extraction and analyses. EM and GG wrote the first draft of the report. JC, NC, CC, RB, PM, J-CL, FG and MC contributed to data interpretation of the findings and provided critical input on important intellectual content. All authors approved the final version of the manuscript. GG is the guarantor of the study.

Funding

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

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Authors and Affiliations

  1. Service Hospitalo-Universitaire de Pharmacotoxicologie, Pôle Santé Publique, Hospices Civils de Lyon, Lyon, France

    Elisa Marilly, Judith Cottin & Guillaume Grenet

  2. Laboratoire de Biométrie et Biologie Evolutive UMR 5558, CNRS, Université Lyon 1, Université de Lyon, Villeurbanne, France

    Natalia Cabrera, François Gueyffier & Michel Cucherat

  3. CIC1407 Inserm, Hospices Civils de Lyon, Lyon, France

    Catherine Cornu

  4. Département de Médecine Générale, Université de Lyon, Lyon, France

    Remy Boussageon

  5. Fédération d’endocrinologie, Maladies Métaboliques, Diabète et Nutrition, Inserm UMR 1060 CARMEN Hospices Civils de Lyon, Université Lyon 1, Lyon, France

    Philippe Moulin

  6. Service de Médecine Interne et Vasculaire, Hôpital Lyon Sud, Hospices Civils de Lyon, Lyon, France

    Jean-Christophe Lega

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  1. Elisa Marilly
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Correspondence to Guillaume Grenet.

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Marilly, E., Cottin, J., Cabrera, N. et al. SGLT2 inhibitors in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials balancing their risks and benefits. Diabetologia (2022). https://doi.org/10.1007/s00125-022-05773-8

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Keywords

  • Cardiovascular disease
  • Meta-analysis
  • Risk/benefit ratio
  • SGLT2 inhibitors
  • Systematic review
  • Type 2 diabetes