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The efficacy and safety of novel classes of glucose-lowering drugs for cardiovascular outcomes: a network meta-analysis of randomised clinical trials

Abstract

Aims/hypothesis

Several cardiovascular outcome trials on sodium–glucose cotransporter 2 inhibitors (SGLT2i) have been released recently, including trials enrolling patients with congestive heart failure (CHF) and chronic kidney disease (CKD). Comparisons of the efficacy and safety of SGLT2i, glucagon-like peptide-1 receptor agonists (GLP-1RA) and dipeptidyl peptidase-4 inhibitors (DPP-4i) thus require an update. Assessments in patient subgroups, i.e., as stratified by age or the presence of CHF, CKD or atherosclerotic cardiovascular disease (ASCVD), are also currently lacking.

Methods

We searched the PubMed, Embase and Cochrane databases for relevant studies published up until 5 December 2020. RCTs comparing SGLT2i, GLP-1RA and DPP-4i with placebo (or other controls) or with each other with cardiovascular (CV) or renal outcomes were eligible for inclusion. The primary efficacy endpoint was 3-point major adverse cardiovascular events (3P-MACE), which are defined as CV death, non-fatal myocardial infarction and non-fatal ischaemic stroke. All-cause mortality, hospitalisation for heart failure (HHF) and composite renal outcomes were also analysed. Pre-specified subgroup analyses of 3P-MACE were also performed.

Results

A total of 21 trials with 170,930 participants were included in this network meta-analysis. Both GLP-1RA and SGLT2i were associated with lower risks of 3P-MACE than placebo (RR 0.89, 95% CI 0.84, 0.94 and RR 0.88, 95% CI 0.83, 0.94, respectively). GLP-1RA and SGLT2i were also associated with lower risks of 3P-MACE than DPP-4i (RR 0.89, 95% CI 0.82, 0.98 and RR 0.89, 95% CI 0.81, 0.97, respectively). A comparison between SGLT2i and GLP-1RA demonstrated no difference in their risks of 3P-MACE (RR 0.99, 95% CI 0.91, 1.08). Only GLP-1RA was associated with a lower risk of stroke compared with placebo (RR 0.85, 95% CI 0.76, 0.94). SGLT2i is superior to GLP-1RA in reducing HHF (RR 0.76, 95% CI 0.68, 0.84) and renal outcomes (RR 0.78, 95% CI 0.65, 0.93). Subgroup analyses indicated that the benefits of SGLT2i and GLP-1RA were more pronounced in elderly patients, white and Asian patients, those with established ASCVD and those with longer durations of diabetes mellitus and worse glycaemic control.

Conclusions/interpretation

SGLT2i and GLP-1RA are superior to DPP-4i in terms of CV and renal outcomes. GLP-1RA is the only drug class that reduces the risk of stroke. SGLT2i is superior in reducing HHF and renal outcomes. Therefore, the choice between SGLT2i and GLP-1RA should be individualised according to patient profiles.

PROSPERO registration number:

CRD42020206600.

Graphical abstract

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Abbreviations

3P-MACE:

3-Point major adverse cardiovascular events

ASCVD:

Atherosclerotic cardiovascular disease

CHF:

Congestive heart failure

CKD:

Chronic kidney disease

CV:

Cardiovascular

CVOT:

Cardiovascular outcome trial

DPP-4i:

Dipeptidyl peptidase-4 inhibitors

GLP-1RA:

Glucagon-like peptide-1 receptor agonists

HHF:

Hospitalisation for heart failure

IPD:

Individual patient-level data

MACE:

Major adverse cardiovascular events

MI:

Myocardial infarction

SGLT2i:

Sodium–glucose cotransporter 2 inhibitors

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Acknowledgements

We thank Alfred HF Lin, and Zoe YZ Syu, Raising Statistics Consultant Inc. New Taipei City, Taiwan, for their assistance with the statistical analysis during the completion of the manuscript.

Authors’ relationships and activities

The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.

Funding

This research was supported by the Ministry of Science and Technology of Taiwan (MOST 108-2221-E-002-163-, MOST 109-2221-E-002 -083) and National Taiwan University Hospital (107-EDN11, 108-N4406, 108EDN02, 109-O20, 109-S4579, 109-EDN11).

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All authors significantly contributed to the manuscript and approved the final version for publication. WJC and JKL contributed to the study design, data acquisition, analysis and manuscript revision. JKL and CSH contributed to data acquisition, interpretation of data and manuscript revision. DSHL contributed to data analysis, interpretation of data, manuscript drafting and revision. JKL is the guarantor of this work.

Corresponding author

Correspondence to Chi-Sheng Hung.

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Lin, D.SH., Lee, JK., Hung, CS. et al. The efficacy and safety of novel classes of glucose-lowering drugs for cardiovascular outcomes: a network meta-analysis of randomised clinical trials. Diabetologia 64, 2676–2686 (2021). https://doi.org/10.1007/s00125-021-05529-w

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Keywords

  • Cardiovascular outcome trial
  • Composite renal outcome
  • CVOT
  • DPP4
  • Meta-analysis
  • SGLT-2