Incretins and microvascular complications of diabetes: neuropathy, nephropathy, retinopathy and microangiopathy.
DPP-4 inhibitors
GLP-1
GLP-1 receptor agonists
Incretin
Mechanisms
Microvascular disease
Nephropathy
Neuropathy
Pathophysiology
Retinopathy
Review
Type 2 diabetes
Journal
Diabetologia
ISSN: 1432-0428
Titre abrégé: Diabetologia
Pays: Germany
ID NLM: 0006777
Informations de publication
Date de publication:
10 2023
10 2023
Historique:
received:
30
05
2023
accepted:
17
07
2023
medline:
4
9
2023
pubmed:
19
8
2023
entrez:
19
8
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 37597048
doi: 10.1007/s00125-023-05988-3
pii: 10.1007/s00125-023-05988-3
pmc: PMC10474214
doi:
Substances chimiques
Incretins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
1832-1845Informations de copyright
© 2023. The Author(s).
Références
Nauck MA (2020) The rollercoaster history of using physiological and pharmacological properties of incretin hormones to develop diabetes medications with a convincing benefit-risk relationship. Metabolism 103:154031. https://doi.org/10.1016/j.metabol.2019.154031
doi: 10.1016/j.metabol.2019.154031
pubmed: 31785258
White WB, Cannon CP, Heller SR et al (2013) Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 369(14):1327–1335. https://doi.org/10.1056/NEJMoa1305889
doi: 10.1056/NEJMoa1305889
pubmed: 23992602
Scirica BM, Bhatt DL, Braunwald E et al (2013) Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 369(14):1317–1326. https://doi.org/10.1056/NEJMoa1307684
doi: 10.1056/NEJMoa1307684
pubmed: 23992601
Marso SP, Bain SC, Consoli A et al (2016) Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 375(19):1834–1844. https://doi.org/10.1056/NEJMoa1607141
doi: 10.1056/NEJMoa1607141
pubmed: 27633186
Marso SP, Daniels GH, Brown-Frandsen K et al (2016) Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 375(4):311–322. https://doi.org/10.1056/NEJMoa1603827
doi: 10.1056/NEJMoa1603827
pubmed: 27295427
pmcid: 4985288
Sheng B, Truong K, Spitler H, Zhang L, Tong X, Chen L (2017) The long-term effects of bariatric surgery on type 2 diabetes remission, microvascular and macrovascular complications, and mortality: a systematic review and meta-analysis. Obes Surg 27(10):2724–2732. https://doi.org/10.1007/s11695-017-2866-4
doi: 10.1007/s11695-017-2866-4
pubmed: 28801703
Sista F, Abruzzese V, Clementi M, Carandina S, Cecilia M, Amicucci G (2017) The effect of sleeve gastrectomy on GLP-1 secretion and gastric emptying: a prospective study. Surg Obes Relat Dis 13(1):7–14. https://doi.org/10.1016/j.soard.2016.08.004
Watanabe Y, Kawai K, Ohashi S, Yokota C, Suzuki S, Yamashita K (1994) Structure-activity relationships of glucagon-like peptide-1(7–36)amide: insulinotropic activities in perfused rat pancreases, and receptor binding and cyclic AMP production in RINm5F cells. J Endocrinol 140(1):45–52. https://doi.org/10.1677/joe.0.1400045
doi: 10.1677/joe.0.1400045
pubmed: 8138751
Nauck MA, Heimesaat MM, Behle K et al (2002) Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers. J Clin Endocrinol Metab 87(3):1239–1246. https://doi.org/10.1210/jcem.87.3.8355
doi: 10.1210/jcem.87.3.8355
pubmed: 11889194
Willms B, Werner J, Holst JJ, Orskov C, Creutzfeldt W, Nauck MA (1996) Gastric emptying, glucose responses, and insulin secretion after a liquid test meal: effects of exogenous glucagon-like peptide-1 (GLP-1)-(7–36) amide in type 2 (noninsulin-dependent) diabetic patients. J Clin Endocrinol Metab 81(1):327–332. https://doi.org/10.1210/jcem.81.1.8550773
doi: 10.1210/jcem.81.1.8550773
pubmed: 8550773
Mima A (2016) Incretin-based therapy for prevention of diabetic vascular complications. J Diabetes Res 2016:1379274. https://doi.org/10.1155/2016/1379274
doi: 10.1155/2016/1379274
pubmed: 26881236
Madonna R, Balistreri CR, Geng Y-J, De Caterina R (2017) Diabetic microangiopathy: pathogenetic insights and novel therapeutic approaches. Vascul Pharmacol 90:1–7. https://doi.org/10.1016/j.vph.2017.01.004
doi: 10.1016/j.vph.2017.01.004
pubmed: 28137665
Madonna R, De Caterina R (2011) Cellular and molecular mechanisms of vascular injury in diabetes — part I: pathways of vascular disease in diabetes. Vascul Pharmacol 54(3):68–74. https://doi.org/10.1016/j.vph.2011.03.005
doi: 10.1016/j.vph.2011.03.005
pubmed: 21453786
Wang R, Lu L, Guo Y et al (2015) Effect of glucagon-like peptide-1 on high-glucose-induced oxidative stress and cell apoptosis in human endothelial cells and its underlying mechanism. J Cardiovasc Pharmacol 66(2):135–140. https://doi.org/10.1097/FJC.0000000000000255
doi: 10.1097/FJC.0000000000000255
pubmed: 25815676
Oeseburg H, de Boer RA, Buikema H, van der Harst P, van Gilst WH, Silljé HHW (2010) Glucagon-like peptide 1 prevents reactive oxygen species-induced endothelial cell senescence through the activation of protein kinase A. Arterioscler Thromb Vasc Biol 30(7):1407–1414. https://doi.org/10.1161/ATVBAHA.110.206425
doi: 10.1161/ATVBAHA.110.206425
pubmed: 20448207
Mima A, Hiraoka-Yamomoto J, Li Q et al (2012) Protective effects of GLP-1 on glomerular endothelium and its inhibition by PKCβ activation in diabetes. Diabetes 61(11):2967–2979. https://doi.org/10.2337/db11-1824
doi: 10.2337/db11-1824
pubmed: 22826029
pmcid: 3478518
Ishibashi Y, Nishino Y, Matsui T, Takeuchi M, Yamagishi S (2011) Glucagon-like peptide-1 suppresses advanced glycation end product-induced monocyte chemoattractant protein-1 expression in mesangial cells by reducing advanced glycation end product receptor level. Metabolism 60(9):1271–1277. https://doi.org/10.1016/j.metabol.2011.01.010
doi: 10.1016/j.metabol.2011.01.010
pubmed: 21388644
Sell DR, Lapolla A, Odetti P, Fogarty J, Monnier VM (1992) Pentosidine formation in skin correlates with severity of complications in individuals with long-standing IDDM. Diabetes 41(10):1286–1292. https://doi.org/10.2337/diab.41.10.1286
doi: 10.2337/diab.41.10.1286
pubmed: 1397702
Pugliese G (2008) Do advanced glycation end products contribute to the development of long-term diabetic complications? Nutr Metab Cardiovasc Dis 18(7):457–460. https://doi.org/10.1016/j.numecd.2008.06.006
Piarulli F, Sartore G, Lapolla A (2013) Glyco-oxidation and cardiovascular complications in type 2 diabetes: a clinical update. Acta Diabetol 50(2):101–110. https://doi.org/10.1007/s00592-012-0412-3
doi: 10.1007/s00592-012-0412-3
pubmed: 22763581
Strain WD, Paldánius PM (2018) Diabetes, cardiovascular disease and the microcirculation. Cardiovasc Diabetol 17(1):57. https://doi.org/10.1186/s12933-018-0703-2
doi: 10.1186/s12933-018-0703-2
pubmed: 29669543
pmcid: 5905152
De Pascale MR, Bruzzese G, Crimi E et al (2016) Severe type 2 diabetes induces reversible modifications of endothelial progenitor cells which are ameliorate by glycemic control. Int J Stem Cells 9(1):137–144. https://doi.org/10.15283/ijsc.2016.9.1.137
doi: 10.15283/ijsc.2016.9.1.137
pubmed: 27426095
pmcid: 4961113
van Ark J, Moser J, Lexis CPH et al (2012) Type 2 diabetes mellitus is associated with an imbalance in circulating endothelial and smooth muscle progenitor cell numbers. Diabetologia 55(9):2501–2512. https://doi.org/10.1007/s00125-012-2590-5
doi: 10.1007/s00125-012-2590-5
pubmed: 22648662
pmcid: 3411291
Packer M (2018) Have dipeptidyl peptidase-4 inhibitors ameliorated the vascular complications of type 2 diabetes in large-scale trials? The potential confounding effect of stem-cell chemokines. Cardiovasc Diabetol 17(1):9. https://doi.org/10.1186/s12933-017-0648-x
doi: 10.1186/s12933-017-0648-x
pubmed: 29310647
pmcid: 5759313
De Falco E, Porcelli D, Torella AR et al (2004) SDF-1 involvement in endothelial phenotype and ischemia-induced recruitment of bone marrow progenitor cells. Blood 104(12):3472–3482. https://doi.org/10.1182/blood-2003-12-4423
doi: 10.1182/blood-2003-12-4423
pubmed: 15284120
Fadini GP, Boscaro E, Albiero M et al (2010) The oral dipeptidyl peptidase-4 inhibitor sitagliptin increases circulating endothelial progenitor cells in patients with type 2 diabetes: possible role of stromal-derived factor-1alpha. Diabetes Care 33(7):1607–1609. https://doi.org/10.2337/dc10-0187
doi: 10.2337/dc10-0187
pubmed: 20357375
pmcid: 2890368
Aronis KN, Chamberland JP, Mantzoros CS (2013) GLP-1 promotes angiogenesis in human endothelial cells in a dose-dependent manner, through the Akt, Src and PKC pathways. Metabolism 62(9):1279–1286. https://doi.org/10.1016/j.metabol.2013.04.010
doi: 10.1016/j.metabol.2013.04.010
pubmed: 23684008
pmcid: 3755020
Erdogdu O, Nathanson D, Sjöholm A, Nyström T, Zhang Q (2010) Exendin-4 stimulates proliferation of human coronary artery endothelial cells through eNOS-, PKA- and PI3K/Akt-dependent pathways and requires GLP-1 receptor. Mol Cell Endocrinol 325(1–2):26–35. https://doi.org/10.1016/j.mce.2010.04.022
doi: 10.1016/j.mce.2010.04.022
pubmed: 20452396
Qin X, Zhang Z, Xu H, Wu Y (2011) Notch signaling protects retina from nuclear factor-κB- and poly-ADP-ribose-polymerase-mediated apoptosis under high-glucose stimulation. Acta Biochim Biophys Sin 43(9):703–711. https://doi.org/10.1093/abbs/gmr069
doi: 10.1093/abbs/gmr069
pubmed: 21813561
Nauck MA, Quast DR, Wefers J, Pfeiffer AFH (2021) The evolving story of incretins (GIP and GLP-1) in metabolic and cardiovascular disease: a pathophysiological update. Diabetes Obes Metab 23(S3):5–29. https://doi.org/10.1111/dom.14496
doi: 10.1111/dom.14496
pubmed: 34310013
Lim D-M, Park K-Y, Hwang W-M, Kim J-Y, Kim B-J (2017) Difference in protective effects of GIP and GLP-1 on endothelial cells according to cyclic adenosine monophosphate response. Exp Ther Med 13(5):2558–2564. https://doi.org/10.3892/etm.2017.4279
doi: 10.3892/etm.2017.4279
pubmed: 28565879
pmcid: 5443274
Love KM, Liu J, Regensteiner JG, Reusch JEB, Liu Z (2020) GLP-1 and insulin regulation of skeletal and cardiac muscle microvascular perfusion in type 2 diabetes. J Diabetes 12(7):488–498. https://doi.org/10.1111/1753-0407.13045
doi: 10.1111/1753-0407.13045
pubmed: 32274893
Zhao M, Li CH, Liu YL (2016) Toll-like receptor (TLR)-2/4 expression in retinal ganglion cells in a high-glucose environment and its implications. Genet Mol Res GMR 15(2). https://doi.org/10.4238/gmr.15026998
Panjwani N, Mulvihill EE, Longuet C et al (2013) GLP-1 receptor activation indirectly reduces hepatic lipid accumulation but does not attenuate development of atherosclerosis in diabetic male ApoE(-/-) mice. Endocrinology 154(1):127–139. https://doi.org/10.1210/en.2012-1937
doi: 10.1210/en.2012-1937
pubmed: 23183176
Daousi C, Pinkney JH, Cleator J, Wilding JP, Ranganath LR (2013) Acute peripheral administration of synthetic human GLP-1 (7–36 amide) decreases circulating IL-6 in obese patients with type 2 diabetes mellitus: a potential role for GLP-1 in modulation of the diabetic pro-inflammatory state? Regul Pept 183:54–61. https://doi.org/10.1016/j.regpep.2013.03.004
doi: 10.1016/j.regpep.2013.03.004
pubmed: 23499806
Arakawa M, Mita T, Azuma K et al (2010) Inhibition of monocyte adhesion to endothelial cells and attenuation of atherosclerotic lesion by a glucagon-like peptide-1 receptor agonist, exendin-4. Diabetes 59(4):1030–1037. https://doi.org/10.2337/db09-1694
doi: 10.2337/db09-1694
pubmed: 20068138
pmcid: 2844811
Verkman AS (2011) Aquaporins at a glance. J Cell Sci 124(13):2107–2112. https://doi.org/10.1242/jcs.079467
doi: 10.1242/jcs.079467
pubmed: 21670197
Amano H, Ito Y, Suzuki T et al (2009) Roles of a prostaglandin E-type receptor, EP3, in upregulation of matrix metalloproteinase-9 and vascular endothelial growth factor during enhancement of tumor metastasis. Cancer Sci 100(12):2318–2324. https://doi.org/10.1111/j.1349-7006.2009.01322.x
doi: 10.1111/j.1349-7006.2009.01322.x
pubmed: 19799610
Masferrer JL, Leahy KM, Koki AT et al (2000) Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res 60(5):1306–1311
pubmed: 10728691
Spektor G, Fuster V (2005) Drug insight: cyclo-oxygenase 2 inhibitors and cardiovascular risk–where are we now? Nat Clin Pract Cardiovasc Med 2(6):290–300. https://doi.org/10.1038/ncpcardio0214
doi: 10.1038/ncpcardio0214
pubmed: 16265533
Lechner J, O’Leary OE, Stitt AW (2017) The pathology associated with diabetic retinopathy. Vision Res 139:7–14. https://doi.org/10.1016/j.visres.2017.04.003
doi: 10.1016/j.visres.2017.04.003
pubmed: 28412095
Carmines PK (2010) The renal vascular response to diabetes. Curr Opin Nephrol Hypertens 19(1):85–90. https://doi.org/10.1097/MNH.0b013e32833240fc
doi: 10.1097/MNH.0b013e32833240fc
pubmed: 19770755
pmcid: 2886724
Tsapas A, Karagiannis T, Kakotrichi P et al (2021) Comparative efficacy of glucose-lowering medications on body weight and blood pressure in patients with type 2 diabetes: a systematic review and network meta-analysis. Diabetes Obes Metab 23(9):2116–2124. https://doi.org/10.1111/dom.14451
doi: 10.1111/dom.14451
pubmed: 34047443
Sun F, Wu S, Wang J et al (2015) Effect of glucagon-like peptide-1 receptor agonists on lipid profiles among type 2 diabetes: a systematic review and network meta-analysis. Clin Ther 37(1):225-241.e8. https://doi.org/10.1016/j.clinthera.2014.11.008
doi: 10.1016/j.clinthera.2014.11.008
pubmed: 25554560
Jolivalt CG, Fineman M, Deacon CF, Carr RD, Calcutt NA (2011) GLP-1 signals via ERK in peripheral nerve and prevents nerve dysfunction in diabetic mice. Diabetes Obes Metab 13(11):990–1000. https://doi.org/10.1111/j.1463-1326.2011.01431.x
doi: 10.1111/j.1463-1326.2011.01431.x
pubmed: 21635674
pmcid: 3177968
Fadini GP, Avogaro A (2018) How to interpret the role of SDF-1α on diabetic complications during therapy with DPP-4 inhibitors. Cardiovasc Diabetol 17(1):22. https://doi.org/10.1186/s12933-018-0668-1
doi: 10.1186/s12933-018-0668-1
pubmed: 29394900
pmcid: 5796514
Greco C, Santi D, Brigante G, Pacchioni C, Simoni M (2022) Effect of the glucagon-like peptide-1 receptor agonists on autonomic function in subjects with diabetes: a systematic review and meta-analysis. Diabetes Metab J 46(6):901–911. https://doi.org/10.4093/dmj.2021.0314
doi: 10.4093/dmj.2021.0314
pubmed: 35410110
pmcid: 9723196
Kim BJ, Lee JK, Schuchman EH, Jin HK, Bae J (2013) Synergistic vasculogenic effects of AMD3100 and stromal-cell-derived factor-1α in vasa nervorum of the sciatic nerve of mice with diabetic peripheral neuropathy. Cell Tissue Res 354(2):395–407. https://doi.org/10.1007/s00441-013-1689-4
doi: 10.1007/s00441-013-1689-4
pubmed: 23942895
Butler JM, Guthrie SM, Koc M et al (2005) SDF-1 is both necessary and sufficient to promote proliferative retinopathy. J Clin Invest 115(1):86–93. https://doi.org/10.1172/JCI22869
doi: 10.1172/JCI22869
pubmed: 15630447
pmcid: 539202
Broxmeyer HE, Hoggatt J, O’Leary HA et al (2012) Dipeptidylpeptidase 4 negatively regulates colony-stimulating factor activity and stress hematopoiesis. Nat Med 18(12):1786–1796. https://doi.org/10.1038/nm.2991
doi: 10.1038/nm.2991
pubmed: 23160239
pmcid: 3742313
Bae EJ (2016) DPP-4 inhibitors in diabetic complications: role of DPP-4 beyond glucose control. Arch Pharm Res 39(8):1114–1128. https://doi.org/10.1007/s12272-016-0813-x
doi: 10.1007/s12272-016-0813-x
pubmed: 27502601
Chalmoukou K, Polyzos D, Manta E et al (2022) Renal outcomes associated with glucose-lowering agents: systematic review and meta-analysis of randomized outcome trials. Eur J Intern Med 97:78–85. https://doi.org/10.1016/j.ejim.2021.12.018
doi: 10.1016/j.ejim.2021.12.018
pubmed: 34953655
Yoshiji S, Minamino H, Tanaka D, Yamane S, Harada N, Inagaki N (2022) Effects of glucagon-like peptide-1 receptor agonists on cardiovascular and renal outcomes: a meta-analysis and meta-regression analysis. Diabetes Obes Metab 24(6):1029–1037. https://doi.org/10.1111/dom.14666
doi: 10.1111/dom.14666
pubmed: 35137511
Rossing P, Baeres FMM, Bakris G et al (2023) The rationale, design and baseline data of FLOW, a kidney outcomes trial with once-weekly semaglutide in people with type 2 diabetes and chronic kidney disease. Nephrol Dial Transplant gfad009. https://doi.org/10.1093/ndt/gfad009
Rosenstock J, Perkovic V, Johansen OE et al (2019) Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: the CARMELINA randomized clinical trial. JAMA 321(1):69–79. https://doi.org/10.1001/jama.2018.18269
doi: 10.1001/jama.2018.18269
pubmed: 30418475
Mosenzon O, Leibowitz G, Bhatt DL et al (2017) Effect of saxagliptin on renal outcomes in the SAVOR-TIMI 53 trial. Diabetes Care 40(1):69–76. https://doi.org/10.2337/dc16-0621
doi: 10.2337/dc16-0621
pubmed: 27797925
Xie Y, Bowe B, Gibson AK et al (2020) Comparative effectiveness of SGLT2 inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, and sulfonylureas on risk of kidney outcomes: emulation of a target trial using health care databases. Diabetes Care 43(11):2859–2869. https://doi.org/10.2337/dc20-1890
doi: 10.2337/dc20-1890
pubmed: 32938746
Gilbert MP, Pratley RE (2020) GLP-1 analogs and DPP-4 inhibitors in type 2 diabetes therapy: review of head-to-head clinical trials. Front Endocrinol 11:178. https://doi.org/10.3389/fendo.2020.00178
doi: 10.3389/fendo.2020.00178
Saw M, Wong VW, Ho I-V, Liew G (2019) New anti-hyperglycaemic agents for type 2 diabetes and their effects on diabetic retinopathy. Eye Lond Engl 33(12):1842–1851. https://doi.org/10.1038/s41433-019-0494-z
doi: 10.1038/s41433-019-0494-z
Bethel MA, Diaz R, Castellana N, Bhattacharya I, Gerstein HC, Lakshmanan MC (2021) HbA1c change and diabetic retinopathy during GLP-1 receptor agonist cardiovascular outcome trials: a meta-analysis and meta-regression. Diabetes Care 44(1):290–296. https://doi.org/10.2337/dc20-1815
doi: 10.2337/dc20-1815
pubmed: 33444163
Andreadis P, Karagiannis T, Malandris K et al (2018) Semaglutide for type 2 diabetes mellitus: a systematic review and meta-analysis. Diabetes Obes Metab 20(9):2255–2263. https://doi.org/10.1111/dom.13361
doi: 10.1111/dom.13361
pubmed: 29756388
Wei J, Yang B, Wang R et al (2022) Risk of stroke and retinopathy during GLP-1 receptor agonist cardiovascular outcome trials: an eight RCTs meta-analysis. Front Endocrinol 13:1007980. https://doi.org/10.3389/fendo.2022.1007980
doi: 10.3389/fendo.2022.1007980
Yoshida Y, Joshi P, Barri S et al (2022) Progression of retinopathy with glucagon-like peptide-1 receptor agonists with cardiovascular benefits in type 2 diabetes - a systematic review and meta-analysis. J Diabetes Complications 36(8):108255. https://doi.org/10.1016/j.jdiacomp.2022.108255
doi: 10.1016/j.jdiacomp.2022.108255
pubmed: 35817678
Goldenberg RM (2022) Progression of retinopathy with glucagon-like peptide-1 receptor agonists with cardiovascular benefits in type 2 diabetes - a systematic review and meta-analysis. J Diabetes Complications 36(9):108285. https://doi.org/10.1016/j.jdiacomp.2022.108285
doi: 10.1016/j.jdiacomp.2022.108285
pubmed: 35998555
Qian W, Liu F, Yang Q (2021) Effect of glucagon-like peptide-1 receptor agonists in subjects with type 2 diabetes mellitus: a meta-analysis. J Clin Pharm Ther 46(6):1650–1658. https://doi.org/10.1111/jcpt.13502
doi: 10.1111/jcpt.13502
pubmed: 34355405
Wang F, Mao Y, Wang H, Liu Y, Huang P (2022) Semaglutide and diabetic retinopathy risk in patients with type 2 diabetes mellitus: a meta-analysis of randomized controlled trials. Clin Drug Investig 42(1):17–28. https://doi.org/10.1007/s40261-021-01110-w
doi: 10.1007/s40261-021-01110-w
pubmed: 34894326
Vilsbøll T, Bain SC, Leiter LA et al (2018) Semaglutide, reduction in glycated haemoglobin and the risk of diabetic retinopathy. Diabetes Obes Metab 20(4):889–897. https://doi.org/10.1111/dom.13172
doi: 10.1111/dom.13172
pubmed: 29178519
pmcid: 5888154
The Diabetes Control and Complications Trial Research Group (1998) Early worsening of diabetic retinopathy in the diabetes control and complications trial. Arch Ophthalmol 116(7):874–886. https://doi.org/10.1001/archopht.116.7.874
doi: 10.1001/archopht.116.7.874
Diabetes Control and Complications Trial Research Group, Nathan DM, Genuth S et al (1993) The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329(14):977–986. https://doi.org/10.1056/NEJM199309303291401
doi: 10.1056/NEJM199309303291401
ClinicalTrials.gov (2023) A research study to look at how semaglutide compared to placebo affects diabetic eye disease in people with type 2 diabetes (FOCUS). https://clinicaltrials.gov/ct2/show/NCT03811561 . Accessed 23 May 2023
Kolaczynski WM, Hankins M, Ong SH, Richter H, Clemens A, Toussi M (2016) Microvascular outcomes in patients with type 2 diabetes treated with vildagliptin vs. sulfonylurea: a retrospective study using german electronic medical records. Diabetes Ther Res Treat Educ Diabetes Relat Disord 7(3):483–496. https://doi.org/10.1007/s13300-016-0177-8
doi: 10.1007/s13300-016-0177-8
Chung Y-R, Park SW, Kim JW, Kim JH, Lee K (2016) Protective effects of dipeptidyl peptidase-4 inhibitors on progression of diabetic retinopathy in patients with type 2 diabetes. Retina Phila Pa 36(12):2357–2363. https://doi.org/10.1097/IAE.0000000000001098
doi: 10.1097/IAE.0000000000001098
Green JB, Bethel MA, Armstrong PW et al (2015) Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 373(3):232–242. https://doi.org/10.1056/NEJMoa1501352
doi: 10.1056/NEJMoa1501352
pubmed: 26052984
Tang H, Li G, Zhao Y et al (2018) Comparisons of diabetic retinopathy events associated with glucose-lowering drugs in patients with type 2 diabetes mellitus: a network meta-analysis. Diabetes Obes Metab 20(5):1262–1279. https://doi.org/10.1111/dom.13232
doi: 10.1111/dom.13232
pubmed: 29369494
Sango K, Takaku S, Tsukamoto M, Niimi N, Yako H (2022) Glucagon-like peptide-1 receptor agonists as potential myelination-inducible and anti-demyelinating remedies. Front Cell Dev Biol 10:950623. https://doi.org/10.3389/fcell.2022.950623
doi: 10.3389/fcell.2022.950623
pubmed: 35874814
pmcid: 9298969
Deng Y, Polley EC, Wallach JD et al (2022) Emulating the GRADE trial using real world data: retrospective comparative effectiveness study. BMJ 379:e070717. https://doi.org/10.1136/bmj-2022-070717
doi: 10.1136/bmj-2022-070717
pubmed: 36191949
pmcid: 9527635
GRADE Study Research Group, Nathan DM, Lachin JM et al (2022) Glycemia reduction in type 2 diabetes - microvascular and cardiovascular outcomes. N Engl J Med 387(12):1075–1088. https://doi.org/10.1056/NEJMoa2200436
doi: 10.1056/NEJMoa2200436
El Mouhayyar C, Riachy R, Khalil AB, Eid A, Azar S (2020) SGLT2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors in diabetes and microvascular complications: a review. Int J Endocrinol 2020:1762164. https://doi.org/10.1155/2020/1762164
doi: 10.1155/2020/1762164
pubmed: 32190049
pmcid: 7066394
Gabriel R, Boukichou-Abdelkader N, Gilis-Januszewska A et al (2023) Reduction in the risk of peripheral neuropathy and lower decrease in kidney function with metformin, linagliptin or their fixed-dose combination compared to placebo in prediabetes: A randomized controlled trial. J Clin Med 12(5):2035. https://doi.org/10.3390/jcm12052035
doi: 10.3390/jcm12052035
pubmed: 36902821
pmcid: 10004435
Spallone V (2019) Update on the impact, diagnosis and management of cardiovascular autonomic neuropathy in diabetes: what is defined, what is new, and what is unmet. Diabetes Metab J 43(1):3–30. https://doi.org/10.4093/dmj.2018.0259
doi: 10.4093/dmj.2018.0259
pubmed: 30793549
Pauza AG, Thakkar P, Tasic T et al (2022) GLP1R attenuates sympathetic response to high glucose via carotid body inhibition. Circ Res 130(5):694–707. https://doi.org/10.1161/CIRCRESAHA.121.319874
doi: 10.1161/CIRCRESAHA.121.319874
pubmed: 35100822
pmcid: 8893134
Beti C, Stratmann B, Bokman G et al (2019) Exenatide delays gastric emptying in patients with type 2 diabetes mellitus but not in those with gastroparetic conditions. Horm Metab Res 51(4):267–273. https://doi.org/10.1055/a-0818-6374
doi: 10.1055/a-0818-6374
pubmed: 30690693
Bharucha AE, Batey-Schaefer B, Cleary PA et al (2015) Delayed gastric emptying is associated with early and long-term hyperglycemia in type 1 diabetes mellitus. Gastroenterology 149(2):330–339. https://doi.org/10.1053/j.gastro.2015.05.007
doi: 10.1053/j.gastro.2015.05.007
pubmed: 25980755
MacDonald SM, Burnett AL (2021) Physiology of erection and pathophysiology of erectile dysfunction. Urol Clin North Am 48(4):513–525. https://doi.org/10.1016/j.ucl.2021.06.009
doi: 10.1016/j.ucl.2021.06.009
pubmed: 34602172
Bajaj HS, Gerstein HC, Rao-Melacini P et al (2021) Erectile function in men with type 2 diabetes treated with dulaglutide: an exploratory analysis of the REWIND placebo-controlled randomised trial. Lancet Diabetes Endocrinol 9(8):484–490. https://doi.org/10.1016/S2213-8587(21)00115-7
doi: 10.1016/S2213-8587(21)00115-7
pubmed: 34153269
Evans LE, Taylor JL, Smith CJ, Pritchard HAT, Greenstein AS, Allan SM (2021) Cardiovascular comorbidities, inflammation, and cerebral small vessel disease. Cardiovasc Res 117(13):2575–2588. https://doi.org/10.1093/cvr/cvab284
doi: 10.1093/cvr/cvab284
pubmed: 34499123
Abushamat LA, McClatchey PM, Scalzo RL et al (2020) Mechanistic causes of reduced cardiorespiratory fitness in type 2 diabetes. J Endocr Soc 4(7):bvaa063. https://doi.org/10.1210/jendso/bvaa063
doi: 10.1210/jendso/bvaa063
pubmed: 32666009
pmcid: 7334033
Yates T, Henson J, Sargeant J et al (2021) Exercise, pharmaceutical therapies and type 2 diabetes: looking beyond glycemic control to whole body health and function. Transl Med Exerc Prescr 1(1):33–42. https://doi.org/10.53941/tmep.v1i1.33
doi: 10.53941/tmep.v1i1.33
Hammes H-P, Lin J, Renner O et al (2002) Pericytes and the pathogenesis of diabetic retinopathy. Diabetes 51(10):3107–3112. https://doi.org/10.2337/diabetes.51.10.3107
doi: 10.2337/diabetes.51.10.3107
pubmed: 12351455
Nyström T, Gutniak MK, Zhang Q et al (2004) Effects of glucagon-like peptide-1 on endothelial function in type 2 diabetes patients with stable coronary artery disease. Am J Physiol Endocrinol Metab 287(6):E1209–E1215. https://doi.org/10.1152/ajpendo.00237.2004
doi: 10.1152/ajpendo.00237.2004
pubmed: 15353407
Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS (2006) TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 116(11):3015–3025. https://doi.org/10.1172/JCI28898
doi: 10.1172/JCI28898
pubmed: 17053832
pmcid: 1616196
Favale NO, Casali CI, Lepera LG, Pescio LG, Fernández-Tome MC (2009) Hypertonic induction of COX2 expression requires TonEBP/NFAT5 in renal epithelial cells. Biochem Biophys Res Commun 381(3):301–305. https://doi.org/10.1016/j.bbrc.2008.12.189
doi: 10.1016/j.bbrc.2008.12.189
pubmed: 19146830
Issar T, Kwai NCG, Poynten AM, Arnold R, Milner K-L, Krishnan AV (2021) Effect of exenatide on peripheral nerve excitability in type 2 diabetes. Clin Neurophysiol 132(10):2532–2539. https://doi.org/10.1016/j.clinph.2021.05.033
doi: 10.1016/j.clinph.2021.05.033
pubmed: 34455311
Ponirakis G, Abdul-Ghani MA, Jayyousi A et al (2020) Effect of treatment with exenatide and pioglitazone or basal-bolus insulin on diabetic neuropathy: a substudy of the Qatar Study. BMJ Open Diabetes Res Care 8(1):e001420. https://doi.org/10.1136/bmjdrc-2020-001420
doi: 10.1136/bmjdrc-2020-001420
pubmed: 32576561
pmcid: 7312325
Jaiswal M, Martin CL, Brown MB et al (2015) Effects of exenatide on measures of diabetic neuropathy in subjects with type 2 diabetes: results from an 18-month proof-of-concept open-label randomized study. J Diabetes Complications 29(8):1287–1294. https://doi.org/10.1016/j.jdiacomp.2015.07.013
doi: 10.1016/j.jdiacomp.2015.07.013
pubmed: 26264399
pmcid: 4656068
Brock C, Hansen CS, Karmisholt J et al (2019) Liraglutide treatment reduced interleukin-6 in adults with type 1 diabetes but did not improve established autonomic or polyneuropathy. Br J Clin Pharmacol 85(11):2512–2523. https://doi.org/10.1111/bcp.14063
doi: 10.1111/bcp.14063
pubmed: 31338868
pmcid: 6848951
Sullivan SD, Alfonso-Cristancho R, Conner C, Hammer M, Blonde L (2009) A simulation of the comparative long-term effectiveness of liraglutide and glimepiride monotherapies in patients with type 2 diabetes mellitus. Pharmacotherapy 29(11):1280–1288. https://doi.org/10.1592/phco.29.11.1280
doi: 10.1592/phco.29.11.1280
pubmed: 19873688
da Silva GM, Heise CO, Hirata MT et al (2015) Comparative effects of a dipeptidyl peptidase-4 inhibitor and of NPH insulin on peripheral nerve conduction of patients with type 2 diabetes. Diabetol Metab Syndr 7(Suppl 1):A59. https://doi.org/10.1186/1758-5996-7-S1-A59
doi: 10.1186/1758-5996-7-S1-A59
pmcid: 4653442
Engel SS, Suryawanshi S, Stevens SR et al (2017) Safety of sitagliptin in patients with type 2 diabetes and chronic kidney disease: outcomes from TECOS. Diabetes Obes Metab 19(11):1587–1593. https://doi.org/10.1111/dom.12983
doi: 10.1111/dom.12983
pubmed: 28432745