{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T12:18:47Z","timestamp":1783685927150,"version":"3.55.0"},"reference-count":91,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T00:00:00Z","timestamp":1783641600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cardiometabolic residual risk in type 2 diabetes mellitus (T2D) persists despite major advances in glucose-lowering therapy, lipid management, blood pressure control, weight reduction, and organ-protective strategies. This residual burden should not be interpreted solely as the consequence of incomplete achievement of conventional therapeutic targets, but rather as the clinical expression of persistent molecular activity involving multiple interconnected organs and pathways. Insulin resistance, metaflammation, oxidative stress, mitochondrial dysfunction, lipotoxicity, endothelial impairment, hepatic metabolic dysregulation, renal inflammation, fibrotic remodeling, and metabolic memory interact within a dynamic network linking adipose tissue, liver, kidney, immune cells, and vasculature. In this review, we discuss the biochemical and molecular drivers of cardiometabolic residual risk in T2D, with particular emphasis on impaired insulin receptor substrate\/PI3K\/Akt signaling, stress-kinase activation, NLRP3 inflammasome priming and assembly, MASLD-related lipotoxicity and fibrogenesis, podocyte and tubular injury, endothelial nitric oxide synthase uncoupling, AGE-RAGE signaling, and thrombo-inflammatory vascular injury. These pathways explain why biological vulnerability may persist even when conventional clinical parameters appear adequately controlled. We also examine the role of translational biomarkers and simple clinical indices, including TyG-derived indices, adiposity markers, hepatic steatosis and fibrosis scores, albuminuria, eGFR, and lipid-related markers, as accessible windows into active biological pathways. Finally, we review how contemporary therapeutic strategies may modulate selected components of this residual-risk network. A pathway-centered interpretation of T2D may support more precise residual-risk phenotyping and help move cardiometabolic care beyond isolated target control toward mechanism-based prevention. This review further links these mechanisms to the contemporary cardiovascular\u2013kidney\u2013metabolic (CKM) framework, as defined by the 2026 AHA\/ACC\/ADA\/ASN CKM Guideline, and disaggregates the underlying molecular network into organ-specific pathway cascades that make the causal relationships between metabolic, inflammatory, hepatic, renal, and vascular injury more explicit.<\/jats:p>","DOI":"10.3390\/ijms27146170","type":"journal-article","created":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T11:43:34Z","timestamp":1783683814000},"page":"6170","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular Pathways of Cardiometabolic Residual Risk in Type 2 Diabetes: Insulin Resistance, Metaflammation, and Liver\u2013Kidney\u2013Vascular Crosstalk"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-4619-6565","authenticated-orcid":false,"given":"Antonio Maria","family":"Labate","sequence":"first","affiliation":[{"name":"SSD Diabetologia, ASST Franciacorta, Viale Mazzini 4, 25032 Chiari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Cimino","sequence":"additional","affiliation":[{"name":"SSD Diabetologia, ASST Franciacorta, Viale Mazzini 4, 25032 Chiari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Giacomelli","sequence":"additional","affiliation":[{"name":"SSD Diabetologia, ASST Franciacorta, Viale Mazzini 4, 25032 Chiari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Ettori","sequence":"additional","affiliation":[{"name":"SSD Diabetologia, ASST Franciacorta, Viale Mazzini 4, 25032 Chiari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oladayo Adigun","family":"Oladeji","sequence":"additional","affiliation":[{"name":"SSD Diabetologia, ASST Franciacorta, Viale Mazzini 4, 25032 Chiari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Agosti","sequence":"additional","affiliation":[{"name":"SSD Diabetologia, ASST Franciacorta, Viale Mazzini 4, 25032 Chiari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1606","DOI":"10.1161\/CIR.0000000000001184","article-title":"Cardiovascular-kidney-metabolic health: A presidential advisory from the American Heart Association","volume":"148","author":"Ndumele","year":"2023","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4043","DOI":"10.1093\/eurheartj\/ehad192","article-title":"2023 ESC Guidelines for the management of cardiovascular disease in patients with diabetes","volume":"44","author":"Marx","year":"2023","journal-title":"Eur. Heart J."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"American Diabetes Association Professional Practice Committee (2026). Cardiovascular disease and risk management: Standards of Care in Diabetes-2026. Diabetes Care, 49, S216\u2013S245.","DOI":"10.2337\/dc26-S010"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"American Diabetes Association Professional Practice Committee (2026). Chronic kidney disease and risk management: Standards of Care in Diabetes-2026. Diabetes Care, 49, S246\u2013S260.","DOI":"10.2337\/dc26-S011"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1925","DOI":"10.1007\/s00125-022-05787-2","article-title":"Management of hyperglycaemia in type 2 diabetes, 2022. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)","volume":"65","author":"Davies","year":"2022","journal-title":"Diabetologia"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3075","DOI":"10.2337\/dci22-0027","article-title":"Diabetes Management in Chronic Kidney Disease: A Consensus Report by the American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO)","volume":"45","author":"Khunti","year":"2022","journal-title":"Diabetes Care"},{"key":"ref_7","unstructured":"(2024). Kidney Disease: Improving Global Outcomes CKD Work Group. KDIGO 2024 Clinical Practice Guideline for the evaluation and management of chronic kidney disease. Kidney Int., 105, S117\u2013S314."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e1889","DOI":"10.1016\/j.jacc.2026.03.056","article-title":"2026 AHA\/ACC\/ADA\/ASN Guideline for the Prevention, Detection, Evaluation, and Management of Cardiovascular-Kidney-Metabolic Syndrome: A Report of the American College of Cardiology\/American Heart Association Joint Committee on Clinical Practice Guidelines","volume":"87","author":"Ndumele","year":"2026","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"European Association for the Study of the Liver, European Association for the Study of Diabetes, and European Association for the Study of Obesity (2024). EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD): Executive Summary. Diabetologia, 67, 2375\u20132392.","DOI":"10.1007\/s00125-024-06196-3"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1542","DOI":"10.1016\/j.jhep.2023.06.003","article-title":"A multisociety Delphi consensus statement on new fatty liver disease nomenclature","volume":"78","author":"Rinella","year":"2023","journal-title":"J. Hepatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1797","DOI":"10.1097\/HEP.0000000000000323","article-title":"AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease","volume":"77","author":"Rinella","year":"2023","journal-title":"Hepatology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"15","DOI":"10.4093\/dmj.2021.0280","article-title":"Insulin resistance: From mechanisms to therapeutic strategies","volume":"46","author":"Lee","year":"2022","journal-title":"Diabetes Metab. J."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Ahn, B. (2025). Advances in insulin resistance-molecular mechanisms, therapeutic targets, and future directions. Int. J. Mol. Sci., 26, Erratum in Int. J. Mol. Sci. 2025, 26, 4171.","DOI":"10.3390\/ijms26094171"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Mir, M.M., Jeelani, M., Alharthi, M.H., Rizvi, S.F., Sohail, S.K., Wani, J.I., Sabah, Z.U., BinAfif, W.F., Nandi, P., and Alshahrani, A.M. (2025). Unraveling the mystery of insulin resistance: From principle mechanistic insights and consequences to therapeutic interventions. Int. J. Mol. Sci., 26.","DOI":"10.20944\/preprints202502.1814.v1"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1863429","DOI":"10.1155\/2022\/1863429","article-title":"Current studies on molecular mechanisms of insulin resistance","volume":"2022","author":"Pei","year":"2022","journal-title":"J. Diabetes Res."},{"key":"ref_16","first-page":"63","article-title":"Influence and treatment of insulin receptor substrate\/PI3K\/Akt-mediated insulin resistance in diabetes mellitus (Review)","volume":"33","author":"Tang","year":"2026","journal-title":"Mol. Med. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1146\/annurev-physiol-031620-093815","article-title":"Ceramides in metabolism: Key lipotoxic players","volume":"83","author":"Chaurasia","year":"2021","journal-title":"Annu. Rev. Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1016\/j.cmet.2020.08.001","article-title":"A membrane-bound diacylglycerol species induces PKC\u03b5-mediated hepatic insulin resistance","volume":"32","author":"Lyu","year":"2020","journal-title":"Cell Metab."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1038\/s41586-019-1797-8","article-title":"The integrative biology of type 2 diabetes","volume":"576","author":"Roden","year":"2019","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2133","DOI":"10.1152\/physrev.00063.2017","article-title":"Mechanisms of insulin action and insulin resistance","volume":"98","author":"Petersen","year":"2018","journal-title":"Physiol. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1172\/JCI77812","article-title":"The pathogenesis of insulin resistance: Integrating signaling pathways and substrate flux","volume":"126","author":"Samuel","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Michalopoulou, E., Thymis, J., Lampsas, S., Pavlidis, G., Katogiannis, K., Vlachomitros, D., Katsanaki, E., Kostelli, G., Pililis, S., and Pliouta, L. (2025). The triad of risk: Linking MASLD, cardiovascular disease and type 2 diabetes; From pathophysiology to treatment. J. Clin. Med., 14.","DOI":"10.3390\/jcm14020428"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1016\/S2468-1253(21)00308-3","article-title":"Non-alcoholic fatty liver disease and risk of fatal and non-fatal cardiovascular events: Updated systematic review and meta-analysis","volume":"6","author":"Mantovani","year":"2021","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Minetti, E.T., Hamburg, N.M., and Matsui, R. (2024). Drivers of cardiovascular disease in metabolic dysfunction-associated steatotic liver disease: The threats of oxidative stress. Front. Cardiovasc. Med., 11.","DOI":"10.3389\/fcvm.2024.1469492"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1186\/s12933-024-02434-5","article-title":"Metabolic dysfunction-associated steatotic liver disease and cardiovascular risk: A comprehensive review","volume":"23","author":"Zheng","year":"2024","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"120495","DOI":"10.1016\/j.atherosclerosis.2025.120495","article-title":"Understanding MASLD: From molecular pathogenesis to cardiovascular risk: A concise review for the clinical cardiologist","volume":"409","author":"Ratti","year":"2025","journal-title":"Atherosclerosis"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1186\/s12944-024-02108-x","article-title":"Updated mechanisms of MASLD pathogenesis","volume":"23","author":"Li","year":"2024","journal-title":"Lipids Health Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1056\/NEJMoa2401943","article-title":"Tirzepatide for metabolic dysfunction-associated steatohepatitis with liver fibrosis","volume":"391","author":"Loomba","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1056\/NEJMoa2028395","article-title":"A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis","volume":"384","author":"Newsome","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1136\/gutjnl-2023-330595","article-title":"MASLD: A systemic metabolic disorder with cardiovascular and malignant complications","volume":"73","author":"Targher","year":"2024","journal-title":"Gut"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1596","DOI":"10.1038\/s42255-021-00501-9","article-title":"Non-alcoholic fatty liver disease: The interplay between metabolism, microbes and immunity","volume":"3","author":"Tilg","year":"2021","journal-title":"Nat. Metab."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1691","DOI":"10.1136\/gutjnl-2020-320622","article-title":"NAFLD and increased risk of cardiovascular disease: Clinical associations, pathophysiological mechanisms and pharmacological implications","volume":"69","author":"Targher","year":"2020","journal-title":"Gut"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1038\/nrendo.2017.56","article-title":"Hepatokines: Linking nonalcoholic fatty liver disease and insulin resistance","volume":"13","author":"Meex","year":"2017","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_34","first-page":"28","article-title":"Role of inflammation in the progression of diabetic kidney disease","volume":"8","author":"Chatterjee","year":"2024","journal-title":"Vessel Plus"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1186\/s13098-025-01726-4","article-title":"Decoding diabetic kidney disease: A comprehensive review of interconnected pathways, molecular mediators and therapeutic insights","volume":"17","author":"Efiong","year":"2025","journal-title":"Diabetol. Metab. Syndr."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.cytogfr.2025.05.007","article-title":"Exploring inflammatory and fibrotic mechanisms driving diabetic nephropathy progression","volume":"84","author":"Ansari","year":"2025","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"The EMPA-KIDNEY Collaborative Group (2023). Empagliflozin in patients with chronic kidney disease. N. Engl. J. Med., 388, 117\u2013127.","DOI":"10.1056\/NEJMoa2204233"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2252","DOI":"10.1056\/NEJMoa2110956","article-title":"Cardiovascular events with finerenone in kidney disease and type 2 diabetes","volume":"385","author":"Pitt","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1093\/eurheartj\/ehab777","article-title":"Cardiovascular and kidney outcomes with finerenone in type 2 diabetes and CKD: The FIDELITY pooled analysis","volume":"43","author":"Agarwal","year":"2022","journal-title":"Eur. Heart J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1056\/NEJMoa2403347","article-title":"Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes","volume":"391","author":"Perkovic","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1038\/s41581-020-00367-2","article-title":"Incretin drugs in diabetic kidney disease: Biological mechanisms and clinical evidence","volume":"17","author":"Alicic","year":"2021","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2219","DOI":"10.1056\/NEJMoa2025845","article-title":"Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes","volume":"383","author":"Bakris","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.2215\/CJN.02480221","article-title":"Clinical implications of an acute dip in eGFR after SGLT2 inhibitor initiation","volume":"16","author":"Heerspink","year":"2021","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1056\/NEJMoa2024816","article-title":"Dapagliflozin in patients with chronic kidney disease","volume":"383","author":"Heerspink","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2295","DOI":"10.1056\/NEJMoa1811744","article-title":"Canagliflozin and renal outcomes in type 2 diabetes and nephropathy","volume":"380","author":"Perkovic","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Yang, D.R., Wang, M.Y., Zhang, C.L., and Wang, Y. (2024). Endothelial dysfunction in vascular complications of diabetes: A comprehensive review of mechanisms and implications. Front. Endocrinol., 15.","DOI":"10.3389\/fendo.2024.1359255"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1186\/s12933-023-01965-7","article-title":"The role of oxidative stress in diabetes mellitus-induced vascular endothelial dysfunction","volume":"22","author":"An","year":"2023","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1161\/CIRCRESAHA.115.306301","article-title":"Endothelial cell dysfunction and the pathobiology of atherosclerosis","volume":"118","author":"Gimbrone","year":"2016","journal-title":"Circ. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1161\/CIRCRESAHA.116.309326","article-title":"Roles of vascular oxidative stress and nitric oxide in the pathogenesis of atherosclerosis","volume":"120","author":"Xia","year":"2017","journal-title":"Circ. Res."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Vianello, E., Beltrami, A.P., Aleksova, A., Janjusevic, M., Fluca, A.L., Corsi Romanelli, M.M., La Sala, L., and Dozio, E. (2025). The advanced glycation end-products (AGE)\u2013receptor for age system (RAGE): An inflammatory pathway linking obesity and cardiovascular diseases. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26083707"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1186\/s12933-021-01372-w","article-title":"Hypofibrinolysis in type 2 diabetes and its clinical implications","volume":"20","author":"Undas","year":"2021","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.jacbts.2022.10.004","article-title":"Coronary microvascular dysfunction: Linking inflammation and cardiac dysfunction?","volume":"8","author":"Schindler","year":"2023","journal-title":"JACC Basic. Transl. Sci."},{"key":"ref_53","first-page":"324","article-title":"Molecular mechanisms of vascular dysfunction and cardiovascular biomarkers in type 2 diabetes","volume":"4","author":"Paneni","year":"2014","journal-title":"Cardiovasc. Diagn. Ther."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1038\/414813a","article-title":"Biochemistry and molecular cell biology of diabetic complications","volume":"414","author":"Brownlee","year":"2001","journal-title":"Nature"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1161\/CIRCRESAHA.110.223545","article-title":"Oxidative stress and diabetic complications","volume":"107","author":"Giacco","year":"2010","journal-title":"Circ. Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.metabol.2017.06.002","article-title":"Current role of the NLRP3 inflammasome on obesity and insulin resistance: A systematic review","volume":"74","author":"Rheinheimer","year":"2017","journal-title":"Metabolism"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"292","DOI":"10.3892\/mmr.2025.13657","article-title":"Role of the NLRP3 inflammasome in diabetes and its complications (Review)","volume":"32","author":"Jiao","year":"2025","journal-title":"Mol. Med. Rep."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Karamitsos, K., Oikonomou, E., Theofilis, P., Ikonomidis, I., Kassi, E., Lambadiari, V., Gialafos, E., Tsatsaragkou, A., Mystakidi, V.-C., and Zisimos, K. (2025). The role of NLRP3 inflammasome in type 2 diabetes mellitus and its macrovascular complications. J. Clin. Med., 14.","DOI":"10.3390\/jcm14134606"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s00125-024-06306-1","article-title":"Targeting the NLRP3 inflammasome-IL-1\u03b2 pathway in type 2 diabetes and obesity","volume":"68","author":"Meier","year":"2025","journal-title":"Diabetologia"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Jin, J., and Zhang, M. (2024). Exploring the role of NLRP3 inflammasome in diabetic nephropathy and the advancements in herbal therapeutics. Front. Endocrinol., 15.","DOI":"10.3389\/fendo.2024.1397301"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Pellegrini, V., La Grotta, R., Carreras, F., Giuliani, A., Sabbatinelli, J., Olivieri, F., Berra, C.C., Ceriello, A., and Prattichizzo, F. (2024). Inflammatory trajectory of type 2 diabetes: Novel opportunities for early and late treatment. Cells, 13.","DOI":"10.3390\/cells13191662"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"e70014","DOI":"10.1111\/1753-0407.70014","article-title":"Overview of oxidative stress and inflammation in diabetes","volume":"16","author":"Segev","year":"2024","journal-title":"J. Diabetes"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1038\/nri2925","article-title":"Type 2 diabetes as an inflammatory disease","volume":"11","author":"Donath","year":"2011","journal-title":"Nat. Rev. Immunol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1038\/nature05485","article-title":"Inflammation and metabolic disorders","volume":"444","author":"Hotamisligil","year":"2006","journal-title":"Nature"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1038\/nrendo.2017.90","article-title":"Adapting to obesity with adipose tissue inflammation","volume":"13","author":"Reilly","year":"2017","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"100780","DOI":"10.1016\/j.lanepe.2023.100780","article-title":"Prognostic utility of Fibrosis-4 Index for risk of subsequent liver and cardiovascular events, and all-cause mortality in individuals with obesity and\/or type 2 diabetes: A longitudinal cohort study","volume":"36","author":"Anstee","year":"2024","journal-title":"Lancet Reg. Health Eur."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1002\/hep.21178","article-title":"Development of a simple noninvasive index to predict significant fibrosis in patients with HIV\/HCV coinfection","volume":"43","author":"Sterling","year":"2006","journal-title":"Hepatology"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1451","DOI":"10.1056\/NEJMoa2107038","article-title":"Empagliflozin in heart failure with preserved ejection fraction","volume":"385","author":"Anker","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1056\/NEJMoa2206286","article-title":"Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction","volume":"387","author":"Solomon","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"386","DOI":"10.4093\/dmj.2025.0220","article-title":"SGLT2 inhibitors and GLP-1 receptor agonists in diabetic kidney disease: Evolving evidence and clinical application","volume":"49","author":"Bae","year":"2025","journal-title":"Diabetes Metab. J."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Gajjar, A., Raju, A.K., Gajjar, A., Menon, M., Shah, S.A.Y., Dani, S., and Weinberg, A. (2025). SGLT2 inhibitors and GLP-1 receptor agonists in cardiovascular-kidney-metabolic syndrome. Biomedicines, 13.","DOI":"10.3390\/biomedicines13081924"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1186\/s12944-024-02412-6","article-title":"The role of the triglyceride-glucose index as a biomarker of cardio-metabolic syndromes","volume":"23","author":"Gounden","year":"2024","journal-title":"Lipids Health Dis."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1186\/s12933-024-02241-y","article-title":"Triglyceride-glucose index and health outcomes: An umbrella review of systematic reviews with meta-analyses of observational studies","volume":"23","author":"Yin","year":"2024","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"132663","DOI":"10.1016\/j.ijcard.2024.132663","article-title":"Triglyceride-glucose index (TyG) as a novel biomarker in the era of cardiometabolic medicine","volume":"418","author":"Avagimyan","year":"2025","journal-title":"Int. J. Cardiol."},{"key":"ref_75","first-page":"103834","article-title":"Is the triglyceride-glucose index ready for cardiovascular risk assessment?","volume":"34","year":"2024","journal-title":"Nutr. Metab. Cardiovasc. Dis."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Lv, C., and Huo, R. (2024). Association between visceral adiposity index, lipid accumulation product and type 2 diabetes mellitus in US adults with hypertension: A cross-sectional analysis of NHANES from 2005 to 2018. BMC Endocr. Disord., 24.","DOI":"10.1186\/s12902-024-01750-x"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"e713","DOI":"10.1002\/osp4.713","article-title":"Lipid accumulation product and visceral adiposity index for incidence of cardiovascular diseases and mortality; results from 13 years follow-up in Isfahan cohort study","volume":"10","author":"Fakhrolmobasheri","year":"2024","journal-title":"Obes. Sci. Pract."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"5","DOI":"10.17925\/EE.2024.20.2.2","article-title":"Metabolic dysfunction-associated steatotic liver disease and type 2 diabetes: A deadly synergy","volume":"20","author":"Leith","year":"2024","journal-title":"touchREV Endocrinol."},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Karagiannakis, D.S., Stefanaki, K., Petrea, F., Zacharaki, P., Giannou, A., Michalopoulou, O., Kazakou, P., Psaltopoulou, T., Vasileiou, V., and Paschou, S.A. (2024). Elevated FIB-4 is associated with higher rates of cardiovascular disease and extrahepatic cancer history in patients with type 2 diabetes mellitus. Biomedicines, 12.","DOI":"10.3390\/biomedicines12040823"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"515","DOI":"10.4314\/ahs.v23i1.54","article-title":"Atherogenic index of plasma and its cardiovascular risk factor correlates among patients with type 2 diabetes in Uganda","volume":"23","author":"Lumu","year":"2023","journal-title":"Afr. Health Sci."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"3347","DOI":"10.1210\/jc.2010-0288","article-title":"The product of triglycerides and glucose, a simple measure of insulin sensitivity. Comparison with the euglycemic-hyperinsulinemic clamp","volume":"95","year":"2010","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"920","DOI":"10.2337\/dc09-1825","article-title":"Visceral adiposity index: A reliable indicator of visceral fat function associated with cardiometabolic risk","volume":"33","author":"Amato","year":"2010","journal-title":"Diabetes Care"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Kahn, H.S. (2005). The lipid accumulation product performs better than BMI for recognizing cardiovascular risk: A population-based comparison. BMC Cardiovasc. Disord., 5, Erratum in  BMC Cardiovasc. Disord. 2005, 6, 5.","DOI":"10.1186\/1471-2261-5-26"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"2221","DOI":"10.1056\/NEJMoa2307563","article-title":"Semaglutide and cardiovascular outcomes in obesity without diabetes","volume":"389","author":"Lincoff","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1056\/NEJMoa2306963","article-title":"Semaglutide in patients with heart failure with preserved ejection fraction and obesity","volume":"389","author":"Kosiborod","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1056\/NEJMoa2206038","article-title":"Tirzepatide once weekly for the treatment of obesity","volume":"387","author":"Jastreboff","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1056\/NEJMoa2107519","article-title":"Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes","volume":"385","author":"Davies","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_88","first-page":"1811","article-title":"Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): A randomised, open-label, parallel-group, multicentre, phase 3 trial","volume":"398","author":"Kahn","year":"2021","journal-title":"Diabetes Care"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1056\/NEJMoa2108269","article-title":"Cardiovascular and renal outcomes with efpeglenatide in type 2 diabetes","volume":"385","author":"Gerstein","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/S2213-8587(24)00271-7","article-title":"Effects of GLP-1 receptor agonists on kidney and cardiovascular disease outcomes: A meta-analysis of randomised controlled trials","volume":"13","author":"Badve","year":"2025","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1812","DOI":"10.1161\/CIRCULATIONAHA.123.067584","article-title":"Cardiovascular, kidney, and safety outcomes with GLP-1 receptor agonists alone and in combination with SGLT2 inhibitors in type 2 diabetes: A systematic review and meta-analysis","volume":"149","author":"Neuen","year":"2024","journal-title":"Circulation"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/14\/6170\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T11:47:18Z","timestamp":1783684038000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/14\/6170"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,10]]},"references-count":91,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["ijms27146170"],"URL":"https:\/\/doi.org\/10.3390\/ijms27146170","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,10]]}}}