Incretins and microvascular complications of diabetes: neuropathy, nephropathy, retinopathy and microangiopathy
Open accessAbstract
Glucagon-like peptide-1 receptor agonists (GLP-1RAs, incretin mimetics) and dipeptidyl peptidase-4 inhibitors (DPP-4is, incretin enhancers) are glucose-lowering therapies with proven cardiovascular safety, but their effect on microvascular disease is not fully understood. Both therapies increase GLP-1 receptor agonism, which is associated with attenuation of numerous pathological processes that may lead to microvascular benefits, including decreased reactive oxygen species (ROS) production, decreased inflammation and improved vascular function. DPP-4is also increase stromal cell-derived factor-1 (SDF-1), which is associated with neovascularisation and tissue repair. Rodent studies demonstrate several benefits of these agents in the prevention or reversal of nephropathy, retinopathy and neuropathy, but evidence from human populations is less clear. For nephropathy risk in human clinical trials, meta-analyses demonstrate that GLP-1RAs reduce the risk of a composite renal outcome (doubling of serum creatinine, eGFR reduction of 30%, end-stage renal disease or renal death), whereas the benefits of DPP-4is appear to be limited to reductions in the risk of albuminuria. The relationship between GLP-1RAs and retinopathy is less clear. Many large trials and meta-analyses show no effect, but an observed increase in the risk of retinopathy complications with semaglutide therapy (a GLP-1RA) in the SUSTAIN-6 trial warrants caution, particularly in individuals with baseline retinopathy. Similarly, DPP-4is are associated with increased retinopathy risk in both trials and meta-analysis. The association between GLP-1RAs and peripheral neuropathy is unclear due to little trial evidence. For DPP-4is, one trial and several observational studies show a reduced risk of peripheral neuropathy, with others reporting no effect. Evidence in other less-established microvascular outcomes, such as microvascular angina, cerebral small vessel disease, skeletal muscle microvascular disease and autonomic neuropathies (e.g. cardiac autonomic neuropathy, gastroparesis, erectile dysfunction), is sparse. In conclusion, GLP-1RAs are protective against nephropathy, whereas DPP-4is are protective against albuminuria and potentially peripheral neuropathy. Caution is advised with DPP-4is and semaglutide, particularly for patients with background retinopathy, due to increased risk of retinopathy. Well-designed trials powered for microvascular outcomes are needed to clarify associations of incretin therapies and microvascular diseases.
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GLP-1 receptor agonists improve microvascular function, myocardial structure, insulin sensitivity, and vascular protection; and reduce inflammation, oxidative stress, and neurohormonal activation.
“GLP-1 receptor agonists improve microvascular function, 37 myocardial structure, 38 insulin sensitivity, 39 and vascular protection; 40,41 and reduce inflammation, 39,42 oxidative stress, 43 and neurohormonal activation 44”
From Semaglutide versus placebo in people with obesity-related heart failure with preserved ejection fraction: a pooled analysis of the STEP-HFpEF and STEP-HFpEF DM randomised trials (2024) · cites this paper as [39]
The “Microvascular disease and the potential of incretin therapies” section reports improved vascular function and reduced reactive oxygen species, and suggests an anti-inflammatory effect. It says insulin sensitivity *may* improve, rather than establishing that it does. The supplied passages do not support the claims about myocardial structure or reduced neurohormonal activation, which have separate citations in the citing sentence. (LLM, conf=0.87)
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Issar, T., Kwai, N. C. G., Poynten, A. M., Arnold, R., Milner, K., & Krishnan, A. V. (2021) · Clinical Neurophysiology · doi:10.1016/j.clinph.2021.05.033 · Cited by 21 · see citing works
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Sullivan, S. D., Alfonso‐Cristancho, R., Conner, C., Hammer, M., & Blonde, L. (2009) · Pharmacotherapy The Journal of Human Pharmacology and Drug Therapy · doi:10.1592/phco.29.11.1280 · Cited by 15 · see citing works
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Yates, T. E., Henson, J. J., Sargeant, J. A., King, J. A., Ahmad, E., Zaccardi, F., & Davies, M. J. (2021) · Translational Medicine and Exercise Prescription · doi:10.53941/tmep.v1i1.33 · Cited by 10 · see citing works
Self-citationChalmoukou, K., Polyzos, D., Manta, E., Tatakis, F., Konstantinidis, D., Thomopoulos, C., & Costas, T. (2021) · European Journal of Internal Medicine · doi:10.1016/j.ejim.2021.12.018 · Cited by 8 · see citing works
How to interpret the role of SDF-1α on diabetic complications during therapy with DPP-4 inhibitors
Fadini, G. P., & Avogaro, A. (2018) · Cardiovascular Diabetology · doi:10.1186/s12933-018-0668-1 · Cited by 6 · see citing works
Gabriel, R., Boukichou-Abdelkader, N., Gilis‐Januszewska, A., Makrilakis, K., Gómez‐Huelgas, R., Kamenov, Z. A., Paulweber, B., Satman, İ., Djordjević, P., Alkandari, A., et al. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12052035 · Cited by 6 · see citing works
Qian, W., Liu, F., & Yang, Q. (2021) · Journal of Clinical Pharmacy and Therapeutics · doi:10.1111/jcpt.13502 · Cited by 5 · see citing works
Goldenberg, R. (2022) · Journal of Diabetes and its Complications · doi:10.1016/j.jdiacomp.2022.108285 · Cited by 4 · see citing works
da Silva, G., Heise, C., Hirata, M., et al. (2015) · Diabetology & Metabolic Syndrome · doi:10.1186/1758-5996-7-s1-a59 · Cited by 3 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Butler, J., Shah, S. J., Petrie, M. C., Borlaug, B. A., Abildstrøm, S. Z., Davies, M. J., Hovingh, G. K., Kitzman, D. W., Møller, D. V., Verma, S., et al. (2024) · The Lancet · doi:10.1016/s0140-6736(24)00469-0 · Cited by 386 · see citing works
Self-citation
- Authors
- Goldney, J., Sargeant, J. A., & Davies, M. J.
- Affiliations
- University of Leicester (GB)
- Corresponding author
- Goldney, Jonathan
- Venue
- Diabetologia
- Published
- 2023-08-19
- Volume
- 66
- Issue
- 10
- Pages
- 1832-1845
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- PMC
- PMC10474214
- OpenAlex
- W4386001286
- Cited by
- 100
- References
- 98
- Citations by year
- 2026: 36 · 2025: 38 · 2024: 25 · 2023: 1
- FWCI
- 3.59
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Diabetologia (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- National Institute for Health Research (NIHR) Leicester Biomedical Research Centre, Leicester, UK
- National Institute for Health Research (NIHR) Academic Clinical Fellowship
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Keywords
- incretins, GLP-1 receptor agonists, DPP-4 inhibitors, diabetic microvascular complications, diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, albuminuria, semaglutide, SUSTAIN 6 trial, cardiovascular safety, renal outcomes, retinopathy risk, peripheral neuropathy, microvascular angina, cerebral small vessel disease
- MeSH terms
- Albuminuria, Diabetes Mellitus, Diabetic Retinopathy, Humans, Kidney Diseases, Male, Peripheral Nervous System Diseases, Retinal Diseases, Vascular Diseases, Incretins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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