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Cited by 68Diabetes Treatment and ManagementPeripheral Artery Disease ManagementDiabetes, Cardiovascular Risks, and Lipoproteins

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

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Lin, Donna Shu-Han, Lee, Jen-Kuang, Chen, Wen-Jone·2021·Diabetologia
DOI 10.1007/s00125-021-05497-1
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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.

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  • Studies noted a remarkable reduction in MACE in both sexes with GLP-1 RA, although without apparent sex-related divergence (hazard ratio of MACE occurrence 0.88 in both sexes).

    “Studies that examined the efficacy of GLP-1 RA with respect to cardiovascular outcomes noted a remarkable reduction in MACE in both sexes [67,68], although without apparent sex-related divergence (hazard ratio of MACE occurrence 0.88 in both sexes) [68].”

    From Sex Differences in Response to Treatment with Glucagon-like Peptide 1 Receptor Agonists: Opportunities for a Tailored Approach to Diabetes and Obesity Care (2022) · cites this paper as [67]

    The MACE subgroup analysis reports lower risk with GLP-1 receptor agonists than with DPP-4 inhibitors in both women and men, with no apparent sex interaction (p=0.682). But it reports hazard ratios of 0.65 for women and 0.59 for men—not 0.88 in both sexes. The overall MACE hazard ratio is 0.62. (LLM, conf=0.90)

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  • In a large retrospective cohort study of adults with T2DM, GLP-1RA treatment was associated with a 29% reduction in risk of non-fatal ischemic stroke compared with DPP-4i treatment.

    “Likewise, in a large retrospective cohort study of adults with T2DM, treatment with GLP-1RAs (N = 4,460) was associated with a 29% reduction in the risk of non-fatal ischemic stroke when compared to treatment with dipeptidyl peptidase-4 inhibitors (DPP-4i) (N = 13,380) [4].”

    From Protection against stroke with glucagon-like peptide-1 receptor agonists: a comprehensive review of potential mechanisms (2022) · cites this paper as [4]

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Authors
Lin, D. S.-H., Lee, J.-K., & Chen, W.-J.
Affiliations
  • National Taiwan University Hospital (TW)
  • National Taiwan University (TW)
Corresponding author
Lee, Jen-Kuang
ORCID
Venue
Diabetologia
Publisher
Springer Science and Business Media LLC
Published
2021-06-30
Volume
64
Issue
9
Pages
1949-1962
ISSN
  • 0012-186X (ISSN-L)
  • 1432-0428
DOI
10.1007/s00125-021-05497-1
OpenAlex
W3174357295
Cited by
68
References
51
Citations by year
2026: 5 · 2025: 15 · 2024: 20 · 2023: 12 · 2022: 15 · 2021: 1
FWCI
8.97
Type
journal article
Language
en
Open access
Licence
Locations
  • Diabetologia (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Ministry of Science and Technology, Taiwan (MOST 109, 109-2221-E, 2221-E-002, MOST108-2221-E002-163, MOST 108-, MOST109-2221-E002-083, MOST 109-2221)
  • National Taiwan University Hospital (109-EDN11, 108‐N4406, 108‐EDN02, 107-EDN11, 109-O20, 109-S4579)
  • National Taiwan University
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Surgery › Peripheral Artery Disease Management
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords
GLP-1 receptor agonists, DPP-4 inhibitors, type 2 diabetes, major adverse limb events, major adverse cardiovascular events, amputation, peripheral arterial disease, critical limb ischemia, cardiovascular mortality, real-world outcomes, drug safety and efficacy, Taiwan National Health Insurance Research Database, propensity score matching
MeSH terms
Glucagon-Like Peptide-1 Receptor, Ischemic Stroke, Glucagon-Like Peptide-1 Receptor Agonists, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Extremities, Humans, Hypoglycemic Agents, Retrospective Studies, Dipeptidyl-Peptidase IV Inhibitors

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