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Major adverse cardiovascular and limb events in patients with diabetes treated with GLP-1 receptor agonists vs DPP-4 inhibitors

Abstract

Aims/hypothesis

The safety and efficacy of glucagon-like peptide-1 receptor agonists (GLP1RAs) and dipeptidyl peptidase-4 inhibitors (DPP4is) in major cardiovascular adverse events were previously examined in cardiovascular outcome trials. However, the effects of these drugs on adverse limb outcomes were poorly examined. This study aimed to determine the real-world outcomes of patients with diabetes mellitus receiving GLP1RAs as compared with those receiving DPP4is in terms of major adverse cardiovascular and limb events.

Methods

A retrospective cohort study was conducted with data collected by the Taiwan National Health Insurance database between 1 May 2011 and 31 December 2017. Patients who were treated for type 2 diabetes with a GLP1RA or DDP4i during this period (n = 1,080,993), were identified. The primary outcome was a composite of major adverse limb events, defined as peripheral artery disease (PAD), critical limb ischaemia, percutaneous transluminal angioplasty or peripheral bypass for PAD, and amputation. The secondary cardiovascular outcome was the composite of cardiovascular death, non-fatal myocardial infarction and non-fatal ischaemic stroke. Propensity-score matching (PSM) at a 1:3 ratio between GLP1RA and DPP4i groups was done to minimise possible selection bias.

Results

A total of 948,342 individuals treated between 1 May 2011 and 31 December 2017, were identified, with 4460 in the GLP1RA group and 13,380 in the DPP4i group after PSM. The incidence of primary composite outcome events was significantly lower in those treated with GLP1RAs compared with those treated with DPP4is (2.59 vs 4.22 events per 1000 person-years; subdistribution HR [SHR] 0.63 [95% CI 0.41, 0.96]), primarily due to lower rates of amputation (1.29 events per 1000 person-years for GLP1RAs vs 2.4 events per 1000 person-years for DPP4is; SHR 0.55 [95% CI 0.30, 0.99]). Treatment with GLP1RAs was also associated with significantly lower risks of secondary composite outcome events (11.02 vs 17.95 events per 1000 person-years; HR 0.62 [95% CI 0.51, 0.76]). Moreover, the observed beneficial effects of GLP1RAs on reducing composite adverse limb outcomes were particularly noticeable in the non-cardiovascular patients and statin users (p for interaction <0.05).

Conclusions/interpretation

In individuals with diabetes, the use of GLP1RAs was associated with significantly lower risks of major adverse limb events when compared with the use of DPP4is. The reduction in risk was driven largely by reduced rate of amputations. Moreover, treatment with GLP1RAs was also associated with lower risks of cardiovascular death, non-fatal stroke, non-fatal myocardial infarction and death from any cause. However, some unexplored confounding factors may exist in this observation study and future large-scale randomised controlled trials are needed.

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

ASCVD:

Atherosclerotic cardiovascular disease

CAD:

Coronary artery disease

CANVAS:

Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes

CLI:

Critical limb ischaemia

CVOT:

Cardiovascular outcome trial

DFU:

Diabetic foot ulcers

DPP4i:

Dipeptidyl peptidase-4 inhibitor

GLP1RA:

Glucagon-like peptide-1 receptor agonist

HFH:

Hospitalisation for heart failure

LEAD:

Lower-extremity arterial disease

LEADER:

Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

MACE:

Major adverse cardiovascular events

MALE:

Major adverse limb events

NHI:

National Health Insurance

NHIRD:

National Health Insurance Research Database

PAD:

Peripheral artery disease

PSM:

Propensity-score matching

PTA:

Percutaneous transluminal angioplasty

RWD:

Real-world data

SHR:

Subdistribution HR

SGLT2i:

Sodium–glucose cotransporter 2 inhibitor

STD:

Standardised difference

TDR:

Taiwan Death Registry

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Acknowledgements

We thank A. Hsing-Fen Lin and Z. Ya-Jhu Syu, Raising Statistics Consultant Inc., for their statistical assistance.

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, data analysis and manuscript revision. JKL contributed to interpretation of data. DSHL contributed to data analysis, interpretation of data, manuscript drafting and revision. JKL is the guarantor of this work.

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Correspondence to Jen-Kuang Lee.

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Lin, D.SH., Lee, JK. & Chen, WJ. Major adverse cardiovascular and limb events in patients with diabetes treated with GLP-1 receptor agonists vs DPP-4 inhibitors. Diabetologia 64, 1949–1962 (2021). https://doi.org/10.1007/s00125-021-05497-1

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Keywords

  • Diabetes
  • Dipeptidyl peptidase-4 inhibitors
  • Glucagon-like peptide-1 receptor agonist
  • Major adverse cardiovascular events
  • Major adverse limb events