Effect of new glucose-lowering drugs on stroke in patients with type 2 diabetes: A systematic review and Meta-analysis

https://doi.org/10.1016/j.jdiacomp.2022.108362Get rights and content

Highlights

  • Meta-analysis studied the effect of three glucose-lowering drugs on stroke.

  • Analysis suggests that GLP-1 agonists may have a potential protective effect against stroke.

  • SGLT-2 inhibitors and DPP-4 inhibitors show a neutral effect on stroke.

Abstract

Aims

People with diabetes tend to face a higher risk of stroke. Randomized controlled trials (RCTs) have demonstrated the different outcomes of new glucose-lowering drugs marketed in recent years on cardiovascular outcome events. The effects of glucagon-like peptide-1 (GLP-1) agonists, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and dipeptidyl peptidase-4 (DPP-4) inhibitors on stroke risk were evaluated in published RCTs.

Methods

A search of Embase, Cochrane Library, and PubMed databases identified studies with stroke as an outcome event up to 3 December 2021. Risk ratios for stroke outcomes were analyzed using a fixed-effects model. I2 was used to assess the heterogeneity of the study.

Results

19 RCTs with 155,027 participants with type 2 diabetes were identified. Pooled analysis showed that compared to placebo, GLP-1 agonists reduced non-fatal stroke by 15 % (RR = 0.85, 95%CI 0.77–0.94, P = 0.002, I2 = 0 %) and total stroke (RR = 0.84, 95%CI 0.77–0.93, P = 0.000, I2 = 0 %) by 16 %. SGLT-2 inhibitors and DPP-4 inhibitors were not significantly associated with lower stroke risk.

Conclusions

This meta-analysis indicates that GLP-1 agonists have potential benefits for stroke. However, further studies are needed if GLP-1 agonists are to be used to reduce the risk of stroke in patients with type 2 diabetes. More research is also needed to investigate the effects of new glucose-lowering drugs on different stroke subtypes.

Systematic review registration

This protocol was registered on the International Prospective Register of Systematic Reviews (https://www.crd.york.ac.uk/PROSPERO/; registration number: CRD42022326382).

Introduction

Stroke is the second biggest cause of mortality worldwide (11.6 % of all deaths). About 6.55 million people died from a stroke in 2019, there were 12.2 million incident cases of stroke, 101 million prevalent cases of stroke.1., 2. Diabetes is an independent risk factor for stroke.3 The risk of stroke is twice as high in diabetics as in non-diabetics. Diabetes is also a risk factor for stroke recurrence and a high risk of adverse outcomes after stroke.4., 5., 6. Therefore, in 2008, the US FDA issued guidance that new drugs designed to improve glycemic control in patients with type 2 diabetes need to be tested for cardiovascular (CV) outcome trials (CVOTs) to assess the safety of new antidiabetic drugs.7 In recent years, new glucose-lowering drugs, such as sodium-glucose cotransporter-2 (SGLT-2) inhibitors, glucagon-like peptide-1 (GLP-1) agonists, and dipeptidyl peptidase-4 (DPP-4) inhibitors, have been proved not to increase the risk of major adverse cardiovascular events (MACE), and may have a potential cerebrovascular event benefit. The results of a meta-analysis8 suggests that, GLP-1 agonists were discovered beneficial for stroke. However, which class of new hypoglycemic drugs has a greater effect on cerebrovascular events, no direct studies are comparing the effect of the three classes of glucose-lowering drugs on stroke events. Given the aforementioned evidence, a meta-analysis was conducted to include these studies, which used SGLT-2 inhibitors, GLP-1 agonists, or DPP-4 inhibitors in the experimental group and placebo in the control group to assess the effect on the risk of stroke in patients with type 2 diabetes.

Section snippets

Methods

This study is reported following the latest PRISMA2020 (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines and registered on PROSPERO (CRD42022326382; https://www.crd.york.ac.uk/PROSPERO/).

Study selection and characteristics

Fig. 1 shows the literature search results. A total of 19 eligible studies involving 155,027 T2DM patients published were identified, which included 5 RCTs of SGLT-2 inhibitors (CANVAS,10 CREDENCE,11 DECLARE–TIMI 58,12 EMPA-REG,13 VERTIS CV14), 8 RCTs of GLP-1 agonists (AMPLITUDE-O,15 ELIXA,16 EXSCEL,17 Harmony,18 LEADER,19 PIONEER 6,20 REWIND,21 SUSTAIN-622), and 6 RCTs of DPP-4 inhibitors (CARMELINA,23 EXAMINE,24 Omarigliptin,25 SAVOR-TIMI 53,26 TECOS,27 VIVIDD28).

Baseline data for patients

Discussion

Analysis of available data from pooled RCTs suggests that treatment with GLP-1 agonists has a positive effect on non-fatal stroke and total stroke in the long term. SGLT-2 inhibitors and DPP-4 inhibitors were neutral on stroke outcome.

Studies have shown that both GLP-1 agonists and DPP-4 inhibitors have neuroprotective effects independent of glycemic control. Their effects on stroke are mediated by affecting stroke-related signaling pathways, such as reducing pro-inflammatory factor production,

CRediT authorship contribution statement

CJ and WG formed the conception and study design. JL and CJ were responsible for data collection, data analysis. JL, WZ, and LL contributed to the manuscript drafting. WZ and WG made significant revisions and supplied improvement suggestions.

Acknowledgments

This work received the following financial support: the Hospital pharmaceutical research project of Jiangsu Pharmaceutical Association Chia Tai Tianqing (TQ2021006) and Nanjing Drum Tower Hospital Clinical Research Special Fund Cultivation Project (2021-LCYJ-PY-33).

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    Conflict of interest

    No potential conflict of interest was reported by the authors.

    1

    These authors contributed equally to this work and should be considered the joint first author.

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