SGLT2 Inhibitors and GLP-1 Agonists: A Beacon of Hope for Stroke Prevention in Diabetes

Jae-Han Jeon

doi:10.4093/dmj.2024.0079

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Editorial SGLT2 Inhibitors and GLP-1 Agonists: A Beacon of Hope for Stroke Prevention in Diabetes: Jae-Han Jeon; Diabetes & Metabolism Journal 2024;48(2):213-214.
DOI: https://doi.org/10.4093/dmj.2024.0079
Published online: March 22, 2024

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Department of Internal Medicine, Kyungpook National University Chilgok Hospital, School of Medicine, Kyungpook National University, Daegu, Korea

Corresponding author: Jae-Han Jeon https://orcid.org/0000-0002-9217-968X Department of Internal Medicine, Kyungpook National University Chilgok Hospital, School of Medicine, Kyungpook National University, 807 Hoguk-ro, Buk-gu, Daegu 41404, Korea E-mail: jeonjh@knu.ac.kr

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Diabetes mellitus is a formidable risk factor for macrovascular diseases. In modern medicine, the past decade has seen the emergence of novel pharmacological agents, notably sodiumglucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP-1) agonists, which has heralded a new era in the management of heart failure, atherosclerotic cardiovascular disease (ASCVD), and chronic kidney disease [1]. Nevertheless, the role of these new drugs in stroke prevention remains unclear.

Among these advancements, thiazolidinediones (TZDs) have shown efficacy in secondary ischemic stroke prevention [2], while a subset of clinical trials has illuminated the promising potential of GLP-1 agonists. A pivotal meta-analysis of randomized controlled trials presented the efficacy and safety of GLP-1 receptor agonists (GLP-1RAs) in mitigating nonfatal stroke, allcause or cardiovascular mortality, myocardial infarction, and major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM) [3]. The REWIND trial further emphasized this narrative, revealing a significant downturn in MACEs with the inclusion of the GLP-1RA dulaglutide in the treatment regimen of individuals with T2DM, thus broadening the protective scope of GLP-1RAs beyond mere stroke risk reduction [4]. Subsequent reviews have corroborated the strokeprotective virtues of GLP-1RAs in the T2DM populace, amplifying their potential as anti-stroke agents even in non-diabetic scenarios [5]. Furthermore, the long-term administration and higher dosages of GLP-1RAs have been linked with a reduced incidence of hospitalization for ischemic stroke among Asian patients with T2DM without established ASCVDs [6].

Conversely, the efficacy of SGLT2 inhibitors in stroke prevention has been met with skepticism. Prevailing evidence suggests a lack of significant impact on stroke incidence among T2DM patients when juxtaposed with control groups across different SGLT2 inhibitors (canagliflozin, dapagliflozin, and empagliflozin), notwithstanding a noticeable racial disparity that suggests the need for further investigation [7]. Nevertheless, a possible protective effect against hemorrhagic stroke emerges from systematic review and meta-analysis, proposing a potential reduction in this stroke subtype’s risk via SGLT2 inhibitors [8].

The findings presented by Kim et al. [9] in this issue via a systematic review and network meta-analysis suggest the stroke prevention capacity of SGLT2 inhibitors, marking a significant departure from prior studies. The inclusion of data on sotagliflozin, a dual SGLT1/2 inhibitor, in their analysis might explain this divergence. Recent clinical trials, including the SCORED and SOLOIST-WHF, have introduced mixed results, with sotagliflozin demonstrating a stroke-protective effect in the SCORED trial, which enrolled diabetic patients with chronic kidney disease [10].

It is hypothesized that sotagliflozin’s dual-inhibition mechanism might foster superior glycemic control and attenuate total stroke risk compared to other SGLT2 inhibitors, albeit at the expense of heightened risk of diarrhea and volume depletion, as noted in the SCORED trial [11]. Furthermore, the presence of SGLT1 in the brain and its overexpression in areas of brain damage could contribute to ischemia and reperfusion injury, bolstering the argument for sotagliflozin’s unique role in stroke prevention [12].

The Korean Diabetes Association has yet to provide specific guidelines on primary prevention for ischemic stroke [13], and the results of forthcoming large-scale clinical trials are highly anticipated. As the landscape of diabetes management continues to evolve, novel findings from these studies have the potential to reshape our understanding and approach to stroke prevention in diabetes.

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CONFLICTS OF INTEREST

There are no potential conflicts of interest relevant to this article to report.

REFERENCES

1. American Diabetes Association Professional Practice Committee. 9. Pharmacologic approaches to glycemic treatment: standards of care in diabetes-2024. Diabetes Care 2024;47(Suppl 1):S158-78.
2. Yaghi S, Furie KL, Viscoli CM, Kamel H, Gorman M, Dearborn J, et al. Pioglitazone prevents stroke in patients with a recent transient ischemic attack or ischemic stroke: a planned secondary analysis of the IRIS trial (Insulin Resistance Intervention After Stroke). Circulation 2018;137:455-63.Article PubMed
3. Malhotra K, Katsanos AH, Lambadiari V, Goyal N, Palaiodimou L, Kosmidou M, et al. GLP-1 receptor agonists in diabetes for stroke prevention: a systematic review and meta-analysis. J Neurol 2020;267:2117-22.Article PubMed PDF
4. Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomized placebo-controlled trial. Lancet 2019;394:121-30.PubMed
5. Goldenberg RM, Cheng AY, Fitzpatrick T, Gilbert JD, Verma S, Hopyan JJ. Benefits of GLP-1 (glucagon-like peptide 1) receptor agonists for stroke reduction in type 2 diabetes: a call to action for neurologists. Stroke 2022;53:1813-22.Article PubMed
6. Yang YS, Chen HH, Huang CN, Hsu CY, Hu KC, Kao CH. GLP-1RAs for ischemic stroke prevention in patients with type 2 diabetes without established atherosclerotic cardiovascular disease. Diabetes Care 2022;45:1184-92.Article PubMed PDF
7. Guo M, Ding J, Li J, Wang J, Zhang T, Liu C, et al. SGLT2 inhibitors and risk of stroke in patients with type 2 diabetes: a systematic review and meta-analysis. Diabetes Obes Metab 2018;20:1977-82.Article PubMed PDF
8. Tsai WH, Chuang SM, Liu SC, Lee CC, Chien MN, Leung CH, et al. Effects of SGLT2 inhibitors on stroke and its subtypes in patients with type 2 diabetes: a systematic review and metaanalysis. Sci Rep 2021;11:15364.Article PubMed PMC PDF
9. Kim JS, Lee G, Park KI, Oh SW. Comparative effect of glucoselowering drugs for type 2 diabetes mellitus on stroke prevention: a systematic review and network meta-analysis. Diabetes Metab J 2024;48:312-20.Article PubMed PMC PDF
10. Bhatt DL, Szarek M, Pitt B, Cannon CP, Leiter LA, McGuire DK, et al. Sotagliflozin in patients with diabetes and chronic kidney disease. N Engl J Med 2021;384:129-39.PubMed
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13. Choi JH, Lee KA, Moon JH, Chon S, Kim DJ, Kim HJ, et al. 2023 Clinical practice guidelines for diabetes mellitus of the Korean Diabetes Association. Diabetes Metab J 2023;47:575-94.PubMed PMC

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SGLT2 Inhibitors and GLP-1 Agonists: A Beacon of Hope for Stroke Prevention in Diabetes

Diabetes Metab J. 2024;48(2):213-214. Published online March 22, 2024

DOI: https://doi.org/10.4093/dmj.2024.0079

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