January 13, 2026

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GLP-1 receptor agonists and next-generation metabolic hormone therapies in chronic kidney disease

GLP-1 receptor agonists and next-generation metabolic hormone therapies in chronic kidney disease

  • Ying, M. et al. Disease burden and epidemiological trends of chronic kidney disease at the global, regional, national levels from 1990 to 2019. Nephron 148, 113–123 (2024).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Kovesdy, C. P. Epidemiology of chronic kidney disease: an update 2022. Kidney Int. Suppl. 12, 7–11 (2022).

    Article 

    Google Scholar 

  • International Diabetes Federation. Diabetes Atlas 10th edn (International Diabetes Federation, 2021).

  • Swinburn, B. A. et al. The global syndemic of obesity, undernutrition, and climate change: the Lancet Commission report. Lancet 393, 791–846 (2019).

    Article 
    PubMed 

    Google Scholar 

  • World Health Organization (WHO). Obesity and Overweight. (2025).

  • Cameron, N. A. et al. Quantifying the sex-race/ethnicity-specific burden of obesity on incident diabetes mellitus in the United States, 2001 to 2016: MESA and NHANES. J. Am. Heart Assoc. 10, e018799 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Murray, C. J. L. et al. Global burden of 87 risk factors in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease study 2019. Lancet 396, 1223–1249 (2020).

    Article 

    Google Scholar 

  • Institute for Health Metrics and Evaluation (IHME). Global Burden of Disease Study 2019 (GBD 2019) Covariates 1980–2019, https://ghdx.healthdata.org/record/global-burden-disease-study-2019-gbd-2019-covariates-1980-2019.

  • Okunogbe, A. et al. Economic impacts of overweight and obesity: current and future estimates for 161 countries. BMJ Glob. Health 7, e009773 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Polyzos, S. A. & Mantzoros, C. S. Obesity: seize the day, fight the fat. Metab. Clin. Exp. 92, 1–5 (2019).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Boutari, C. & Mantzoros, C. S. A 2022 update on the epidemiology of obesity and a call to action: as its twin COVID-19 pandemic appears to be receding, the obesity and dysmetabolism pandemic continues to rage on. Metab. Clin. Exp. 133, 155217 (2022).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Tuttle K. R. et al. Risks of kidney failure and death in a real-world population with diabetes. Clin. J. Am. Soc. Nephrol. (2025).

  • Grams, M. E. et al. Estimated glomerular filtration rate, albuminuria, and adverse outcomes: an individual-participant data meta-analysis. JAMA 330, 1266–1277 (2023).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Jankowski, J., Floege, J., Fliser, D., Bohm, M. & Marx, N. Cardiovascular disease in chronic kidney disease: pathophysiological insights and therapeutic options. Circulation 143, 1157–1172 (2021).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Li, X. & Lindholm, B. Cardiovascular risk prediction in chronic kidney disease. Am. J. Nephrol. 53, 730–739 (2022).

    Article 
    PubMed 

    Google Scholar 

  • Ndumele, C. E. et al. Cardiovascular-kidney-metabolic health: a presidential advisory from the American Heart Association. Circulation 148, 1606–1635 (2023).

    Article 
    PubMed 

    Google Scholar 

  • Perkovic, V. et al. Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes. N. Engl. J. Med. 391, 109–212 (2024).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Parker, V. E. R. et al. Efficacy and safety of cotadutide, a dual glucagon-like peptide-1 and glucagon receptor agonist, in a randomized phase 2a study of patients with type 2 diabetes and chronic kidney disease. Diabetes Obes. Metab. 24, 1360–1369 (2022).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Nauck, M. A. et al. Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J. Clin. Invest. 91, 301–307 (1993).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Kreymann, B., Williams, G., Ghatei, M. A. & Bloom, S. R. Glucagon-like peptide-1 7-36: a physiological incretin in man. Lancet 2, 1300–1304 (1987).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Bagger, J. I. et al. Impaired regulation of the incretin effect in patients with type 2 diabetes. J. Clin. Endocrinol. Metab. 96, 737–745 (2011).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Pederson, R. A. & McIntosh, C. H. Discovery of gastric inhibitory polypeptide and its subsequent fate: personal reflections. J. Diabetes Investig. 7, 4–7 (2016).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Nauck, M. A., Bartels, E., Orskov, C., Ebert, R. & Creutzfeldt, W. Additive insulinotropic effects of exogenous synthetic human gastric inhibitory polypeptide and glucagon-like peptide-1-(7-36) amide infused at near-physiological insulinotropic hormone and glucose concentrations. J. Clin. Endocrinol. Metab. 76, 912–917 (1993).

    PubMed 
    CAS 

    Google Scholar 

  • Holst, J. J., Albrechtsen, N. J. W., Rosenkilde, M. M. & Deacon, C. F. Physiology of the incretin hormones, GIP and GLP-1-regulation of release and posttranslational modifications. Compr. Physiol. 9, 1339–1381 (2019).

    Article 
    PubMed 

    Google Scholar 

  • Alicic, R. Z., Cox, E. J., Neumiller, J. J. & Tuttle, K. R. Incretin drugs in diabetic kidney disease: biological mechanisms and clinical evidence. Nat. Rev. Nephrol. 17, 227–244 (2021).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Holt, M. K. et al. Preproglucagon neurons in the nucleus of the solitary tract are the main source of brain GLP-1, mediate stress-induced hypophagia, and limit unusually large intakes of food. Diabetes 68, 21–33 (2019).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Nauck, M. A., Quast, D. R., Wefers, J. & Pfeiffer, A. F. H. The evolving story of incretins (GIP and GLP-1) in metabolic and cardiovascular disease: a pathophysiological update. Diabetes Obes. Metab. 23, 5–29 (2021).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Gunawardene, A. R., Corfe, B. M. & Staton, C. A. Classification and functions of enteroendocrine cells of the lower gastrointestinal tract. Int. J. Exp. Pathol. 92, 219–231 (2011).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Jin, S. L. et al. Distribution of glucagonlike peptide I (GLP-I), glucagon, and glicentin in the rat brain: an immunocytochemical study. J. Comp. Neurol. 271, 519–532 (1988).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Morrow, N. M., Morissette, A. & Mulvihill, E. E. Immunomodulation and inflammation: Role of GLP-1R and GIPR expressing cells within the gut. Peptides 176, 171200 (2024).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Capozzi, M. E., D’Alessio, D. A. & Campbell, J. E. The past, present, and future physiology and pharmacology of glucagon. Cell Metab. 34, 1654–1674 (2022).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Deacon, C. F. What do we know about the secretion and degradation of incretin hormones? Regul. Pept. 128, 117–124 (2005).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Drucker, D. J. Mechanisms of action and therapeutic application of glucagon-like peptide-1. Cell Metab. 27, 740–756 (2018).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Balks, H. J., Holst, J. J., von zur Muhlen, A. & Brabant, G. Rapid oscillations in plasma glucagon-like peptide-1 (GLP-1) in humans: cholinergic control of GLP-1 secretion via muscarinic receptors. J. Clin. Endocrinol. Metab. 82, 786–790 (1997).

    PubMed 
    CAS 

    Google Scholar 

  • Muller, T. D. et al. Glucagon-like peptide 1 (GLP-1). Mol. Metab. 30, 72–130 (2019).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Grasset, E. et al. A specific gut microbiota dysbiosis of type 2 diabetic mice induces GLP-1 resistance through an enteric no-dependent and gut-brain axis mechanism. Cell Metab. 26, 278 (2017).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Ellingsgaard, H. et al. Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells. Nat. Med. 17, 1481–1489 (2011).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Lebherz, C. et al. Interleukin-6 predicts inflammation-induced increase of glucagon-like peptide-1 in humans in response to cardiac surgery with association to parameters of glucose metabolism. Cardiovasc. Diabetol. 15, 21 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Kahles, F. et al. GLP-1 secretion is increased by inflammatory stimuli in an IL-6-dependent manner, leading to hyperinsulinemia and blood glucose lowering. Diabetes 63, 3221–3229 (2014).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Kahles, F. et al. Glucose-dependent insulinotropic peptide secretion is induced by inflammatory stimuli in an interleukin-1-dependent manner in mice. Diabetes Obes. Metab. 18, 1147–1151 (2016).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Lebrun, L. J. et al. Enteroendocrine L cells sense LPS after gut barrier injury to enhance GLP-1 secretion. Cell Rep. 21, 1160–1168 (2017).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Yamada, Y. et al. Human gastric inhibitory polypeptide receptor: cloning of the gene (GIPR) and cDNA. Genomics 29, 773–776 (1995).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Thorens, B. Expression cloning of the pancreatic beta cell receptor for the gluco-incretin hormone glucagon-like peptide 1. Proc. Natl Acad. Sci. USA 89, 8641–8645 (1992).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Zheng, Z. et al. Glucagon-like peptide-1 receptor: mechanisms and advances in therapy. Signal. Transduct. Target. Ther. 9, 234 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Zhang, L., Zhang, W. & Tian, X. The pleiotropic of GLP-1/GLP-1R axis in central nervous system diseases. Int. J. Neurosci. 133, 473–491 (2023).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Meyer-Gerspach, A. C. et al. Endogenous GLP-1 alters postprandial functional connectivity between homeostatic and reward-related brain regions involved in regulation of appetite in healthy lean males: a pilot study. Diabetes Obes. Metab. 20, 2330–2338 (2018).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Ansari, S., Khoo, B. & Tan, T. Targeting the incretin system in obesity and type 2 diabetes mellitus. Nat. Rev. Endocrinol. 20, 447–459 (2024).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Sun, E. W. L., Martin, A. M., Young, R. L. & Keating, D. J. The regulation of peripheral metabolism by gut-derived hormones. Front. Endocrinol. 9, 754 (2018).

    Article 

    Google Scholar 

  • Llewellyn-Smith, I. J., Reimann, F., Gribble, F. M. & Trapp, S. Preproglucagon neurons project widely to autonomic control areas in the mouse brain. Neuroscience 180, 111–121 (2011).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Drucker, D. J. & Holst, J. J. The expanding incretin universe: from basic biology to clinical translation. Diabetologia 66, 1765–1779 (2023).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Frias, J. P. et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N. Engl. J. Med. 385, 503–515 (2021).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Jastreboff, A. M. et al. Triple-hormone-receptor agonist retatrutide for obesity — a phase 2 trial. N. Engl. J. Med. 389, 514–526 (2023).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Pyke, C. et al. GLP-1 receptor localization in monkey and human tissue: novel distribution revealed with extensively validated monoclonal antibody. Endocrinology 155, 1280–1290 (2014).

    Article 
    PubMed 

    Google Scholar 

  • Schlatter, P., Beglinger, C., Drewe, J. & Gutmann, H. Glucagon-like peptide 1 receptor expression in primary porcine proximal tubular cells. Regul. Pept. 141, 120–128 (2007).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Korner, M., Stockli, M., Waser, B. & Reubi, J. C. GLP-1 receptor expression in human tumors and human normal tissues: potential for in vivo targeting. J. Nucl. Med. 48, 736–743 (2007).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Crajoinas, R. O. et al. Mechanisms mediating the diuretic and natriuretic actions of the incretin hormone glucagon-like peptide-1. Am. J. Physiol. Renal Physiol. 301, F355–F363 (2011).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Farah, L. X. et al. The physiological role of glucagon-like peptide-1 in the regulation of renal function. Am. J. Physiol. Renal Physiol. 310, F123–F127 (2016).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Gutzwiller, J. P. et al. Glucagon-like peptide 1 induces natriuresis in healthy subjects and in insulin-resistant obese men. J. Clin. Endocrinol. Metab. 89, 3055–3061 (2004).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Skov, J. et al. Glucagon-like peptide-1 (GLP-1): effect on kidney hemodynamics and renin-angiotensin-aldosterone system in healthy men. J. Clin. Endocrinol. Metab. 98, E664–E671 (2013).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Gutzwiller, J. P. et al. Glucagon-like peptide-1 is involved in sodium and water homeostasis in humans. Digestion 73, 142–150 (2006).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Tonneijck, L. et al. Acute renal effects of the GLP-1 receptor agonist exenatide in overweight type 2 diabetes patients: a randomised, double-blind, placebo-controlled trial. Diabetologia 59, 1412–1421 (2016).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Tonneijck, L. et al. Renal tubular effects of prolonged therapy with the GLP-1 receptor agonist lixisenatide in patients with type 2 diabetes mellitus. Am. J. Physiol. Renal Physiol. 316, F231–F240 (2019).

    Article 
    PubMed 

    Google Scholar 

  • Rieg, T. et al. Natriuretic effect by exendin-4, but not the DPP-4 inhibitor alogliptin, is mediated via the GLP-1 receptor and preserved in obese type 2 diabetic mice. Am. J. Physiol. Ren. Physiol. 303, F963–F971 (2012).

    Article 
    CAS 

    Google Scholar 

  • Asmar, A. et al. The renal extraction and the natriuretic action of GLP-1 in Humans depend on interaction with the GLP-1 receptor. J. Clin. Endocrinol. Metab. 106, e11–e19 (2021).

    Article 
    PubMed 

    Google Scholar 

  • Thomson, S. C., Kashkouli, A., Liu, Z. Z. & Singh, P. Renal hemodynamic effects of glucagon-like peptide-1 agonist are mediated by nitric oxide but not prostaglandin. Am. J. Physiol. Renal Physiol. 313, F854–F858 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Fonseca, V. A. et al. Reductions in systolic blood pressure with liraglutide in patients with type 2 diabetes: insights from a patient-level pooled analysis of six randomized clinical trials. J. Diabetes Complications 28, 399–405 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Park, J. et al. Single-cell transcriptomics of the mouse kidney reveals potential cellular targets of kidney disease. Science 360, 758–763 (2018).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Poll, B. G., Chen, L., Chou, C. L., Raghuram, V. & Knepper, M. A. Landscape of GPCR expression along the mouse nephron. Am. J. Physiol. Renal Physiol. 321, F50–F68 (2021).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Limbutara, K., Chou, C. L. & Knepper, M. A. Quantitative proteomics of all 14 renal tubule segments in rat. J. Am. Soc. Nephrol. 31, 1255–1266 (2020).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Takeda, Y. et al. Increment of plasma glucose by exogenous glucagon is associated with present and future renal function in type 2 diabetes: a retrospective study from glucagon stimulation test. BMC Endocr. Disord. 19, 99 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Ahloulay, M., Dechaux, M., Laborde, K. & Bankir, L. Influence of glucagon on GFR and on urea and electrolyte excretion: direct and indirect effects. Am. J. Physiol. 269, F225–F235 (1995).

    PubMed 
    CAS 

    Google Scholar 

  • Mercier, O. et al. Effects of glucagon on H+-HCO3 transport in Henle’s loop, distal tubule, and collecting ducts in the rat. Am. J. Physiol. 257, F1003–F1014 (1989).

    PubMed 
    CAS 

    Google Scholar 

  • He, S. et al. Gut intraepithelial T cells calibrate metabolism and accelerate cardiovascular disease. Nature 566, 115–119 (2019).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Wong, C. K. et al. Divergent roles for the gut intraepithelial lymphocyte GLP-1R in control of metabolism, microbiota, and T cell-induced inflammation. Cell Metab. 34, 1514–1531.e1517 (2022).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Bubeck Wardenburg, J. et al. Phosphorylation of SLP-76 by the ZAP-70 protein-tyrosine kinase is required for T-cell receptor function. J. Biol. Chem. 271, 19641–19644 (1996).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Mustelin, T. & Tasken, K. Positive and negative regulation of T-cell activation through kinases and phosphatases. Biochem. J. 371, 15–27 (2003).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Kodera, R. et al. Glucagon-like peptide-1 receptor agonist ameliorates renal injury through its anti-inflammatory action without lowering blood glucose level in a rat model of type 1 diabetes. Diabetologia 54, 965–978 (2011).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Heng, T. S., Painter, M. W. & Immunological Genome Project, C The immunological genome project: networks of gene expression in immune cells. Nat. Immunol. 9, 1091–1094 (2008).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Higashijima, Y., Tanaka, T., Yamaguchi, J., Tanaka, S. & Nangaku, M. Anti-inflammatory role of DPP-4 inhibitors in a nondiabetic model of glomerular injury. Am. J. Physiol. Renal Physiol. 308, F878–F887 (2015).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Mantelmacher, F. D. et al. GIP regulates inflammation and body weight by restraining myeloid-cell-derived S100A8/A9. Nat. Metab. 1, 58–69 (2019).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Kahn, S. E. et al. Evidence of cosecretion of islet amyloid polypeptide and insulin by beta-cells. Diabetes 39, 634–638 (1990).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Inoue, K., Hisatomi, A., Umeda, F. & Nawata, H. Effects of glucagon-like peptide 1 (7-36) amide and glucagon on amylin release from perfused rat pancreas. Horm. Metab. Res. 23, 407–409 (1991).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Westermark, P., Andersson, A. & Westermark, G. T. Islet amyloid polypeptide, islet amyloid, and diabetes mellitus. Physiol. Rev. 91, 795–826 (2011).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Hay, D. L., Chen, S., Lutz, T. A., Parkes, D. G. & Roth, J. D. Amylin: pharmacology, physiology, and clinical potential. Pharmacol. Rev. 67, 564–600 (2015).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Cao, J. et al. A structural basis for amylin receptor phenotype. Science 375, eabm9609 (2022).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Lutz, T. A. Creating the amylin story. Appetite 172, 105965 (2022).

    Article 
    PubMed 

    Google Scholar 

  • Zakariassen, H. L., John, L. M. & Lutz, T. A. Central control of energy balance by amylin and calcitonin receptor agonists and their potential for treatment of metabolic diseases. Basic. Clin. Pharmacol. Toxicol. 127, 163–177 (2020).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Erzen, S., Tonin, G., Jurisic Erzen, D. & Klen, J. Amylin, another important neuroendocrine hormone for the treatment of diabesity. Int. J. Mol. Sci. 25, 1517 (2024).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Coester, B., Foll, C. L. & Lutz, T. A. Viral depletion of calcitonin receptors in the area postrema: a proof-of-concept study. Physiol. Behav. 223, 112992 (2020).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Lutz, T. A. Pancreatic amylin as a centrally acting satiating hormone. Curr. Drug. Targets 6, 181–189 (2005).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Mack, C. M. et al. Glucoregulatory effects and prolonged duration of action of davalintide: a novel amylinomimetic peptide. Diabetes Obes. Metab. 13, 1105–1113 (2011).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Potes, C. S. & Lutz, T. A. Brainstem mechanisms of amylin-induced anorexia. Physiol. Behav. 100, 511–518 (2010).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Roth, J. D. et al. Leptin responsiveness restored by amylin agonism in diet-induced obesity: evidence from nonclinical and clinical studies. Proc. Natl Acad. Sci. USA 105, 7257–7262 (2008).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Turek, V. F. et al. Mechanisms of amylin/leptin synergy in rodent models. Endocrinology 151, 143–152 (2010).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Liberini, C. G. et al. Amylin receptor components and the leptin receptor are co-expressed in single rat area postrema neurons. Eur. J. Neurosci. 43, 653–661 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Le Foll, C. et al. Amylin-induced central IL-6 production enhances ventromedial hypothalamic leptin signaling. Diabetes 64, 1621–1631 (2015).

    Article 
    PubMed 

    Google Scholar 

  • Ozcan, U. et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306, 457–461 (2004).

    Article 
    PubMed 

    Google Scholar 

  • Kahn, S. E., Hull, R. L. & Utzschneider, K. M. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 444, 840–846 (2006).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Mitrofanova, A., Merscher, S. & Fornoni, A. Kidney lipid dysmetabolism and lipid droplet accumulation in chronic kidney disease. Nat. Rev. Nephrol. 19, 629–645 (2023).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Saxton, S. N., Clark, B. J., Withers, S. B., Eringa, E. C. & Heagerty, A. M. Mechanistic links between obesity, diabetes, and blood pressure: role of perivascular adipose tissue. Physiol. Rev. 99, 1701–1763 (2019).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Hall, J. E., do Carmo, J. M., da Silva, A. A., Wang, Z. & Hall, M. E. Obesity, kidney dysfunction and hypertension: mechanistic links. Nat. Rev. Nephrol. 15, 367–385 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Brownlee, M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54, 1615–1625 (2005).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Weigert, C., Brodbeck, K., Lehmann, R., Haring, H. U. & Schleicher, E. D. Overexpression of glutamine:fructose-6-phosphate-amidotransferase induces transforming growth factor-beta1 synthesis in NIH-3T3 fibroblasts. FEBS Lett. 488, 95–99 (2001).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Deb, D. K., Bao, R. & Li, Y. C. Critical role of the cAMP-PKA pathway in hyperglycemia-induced epigenetic activation of fibrogenic program in the kidney. FASEB J. 31, 2065–2075 (2017).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Miller, C. G., Pozzi, A., Zent, R. & Schwarzbauer, J. E. Effects of high glucose on integrin activity and fibronectin matrix assembly by mesangial cells. Mol. Biol. Cell 25, 2342–2350 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Wright, R. J. et al. Effects of acute insulin-induced hypoglycemia on indices of inflammation: putative mechanism for aggravating vascular disease in diabetes. Diabetes Care 33, 1591–1597 (2010).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Ceriello, A. et al. Glucagon-like peptide 1 reduces endothelial dysfunction, inflammation, and oxidative stress induced by both hyperglycemia and hypoglycemia in type 1 diabetes. Diabetes Care 36, 2346–2350 (2013).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Morcos, M. et al. Activation of tubular epithelial cells in diabetic nephropathy. Diabetes 51, 3532–3544 (2002).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Wendt, T. et al. Glucose, glycation, and RAGE: implications for amplification of cellular dysfunction in diabetic nephropathy. J. Am. Soc. Nephrol. 14, 1383–1395 (2003).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Bierhaus, A. et al. Understanding RAGE, the receptor for advanced glycation end products. J. Mol. Med. 83, 876–886 (2005).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Nagareddy, P. R. et al. Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosis. Cell Metab. 17, 695–708 (2013).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Chen, T., Cao, Q., Wang, Y. & Harris, D. C. H. M2 macrophages in kidney disease: biology, therapies, and perspectives. Kidney Int. 95, 760–773 (2019).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Chow, F. Y., Nikolic-Paterson, D. J., Ozols, E., Atkins, R. C. & Tesch, G. H. Intercellular adhesion molecule-1 deficiency is protective against nephropathy in type 2 diabetic db/db mice. J. Am. Soc. Nephrol. 16, 1711–1722 (2005).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Chow, F. Y. et al. Monocyte chemoattractant protein-1-induced tissue inflammation is critical for the development of renal injury but not type 2 diabetes in obese db/db mice. Diabetologia 50, 471–480 (2007).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Zeng, L. F., Xiao, Y. & Sun, L. A glimpse of the mechanisms related to renal fibrosis in diabetic nephropathy. Adv. Exp. Med. Biol. 1165, 49–79 (2019).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Baggiolini, M. Chemokines and leukocyte traffic. Nature 392, 565–568 (1998).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Tang, S. C. W. & Yiu, W. H. Innate immunity in diabetic kidney disease. Nat. Rev. Nephrol. 16, 206–222 (2020).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Wong, C. K. et al. Central glucagon-like peptide 1 receptor activation inhibits Toll-like receptor agonist-induced inflammation. Cell Metab. 36, 130–143 e135 (2024).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Yiu, W. H., Lin, M. & Tang, S. C. Toll-like receptor activation: from renal inflammation to fibrosis. Kidney Int. Suppl. 4, 20–25 (2014).

    Article 
    CAS 

    Google Scholar 

  • Lin, M. et al. Toll-like receptor 4 promotes tubular inflammation in diabetic nephropathy. J. Am. Soc. Nephrol.23, 86–102 (2012).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Huang, G., Zhang, Y., Zhang, Y. & Ma, Y. Chronic kidney disease and NLRP3 inflammasome: pathogenesis, development and targeted therapeutic strategies. Biochem. Biophys. Rep. 33, 101417 (2023).

    PubMed 
    CAS 

    Google Scholar 

  • Shahzad, K. et al. Nlrp3-inflammasome activation in non-myeloid-derived cells aggravates diabetic nephropathy. Kidney Int. 87, 74–84 (2015).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Schroder, K., Zhou, R. & Tschopp, J. The NLRP3 inflammasome: a sensor for metabolic danger? Science 327, 296–300 (2010).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Tschopp, J. & Schroder, K. NLRP3 inflammasome activation: the convergence of multiple signalling pathways on ROS production? Nat. Rev. Immunol. 10, 210–215 (2010).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Shahzad, K. et al. Podocyte-specific Nlrp3 inflammasome activation promotes diabetic kidney disease. Kidney Int. 102, 766–779 (2022).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Nauck, M. A., Quast, D. R., Wefers, J. & Meier, J. J. GLP-1 receptor agonists in the treatment of type 2 diabetes — state-of-the-art. Mol. Metab. 46, 101102 (2021).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Iqbal, J. et al. Effect of glucagon-like peptide-1 receptor agonists on body weight in adults with obesity without diabetes mellitus — a systematic review and meta-analysis of randomized control trials. Obes. Rev. 23, e13435 (2022).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Yao, H. et al. Comparative effectiveness of GLP-1 receptor agonists on glycaemic control, body weight, and lipid profile for type 2 diabetes: systematic review and network meta-analysis. BMJ 384, e076410 (2024).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Htike, Z. Z. et al. Efficacy and safety of glucagon-like peptide-1 receptor agonists in type 2 diabetes: a systematic review and mixed-treatment comparison analysis. Diabetes Obes. Metab. 19, 524–536 (2017).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Boyle, J. G., Livingstone, R. & Petrie, J. R. Cardiovascular benefits of GLP-1 agonists in type 2 diabetes: a comparative review. Clin. Sci. 132, 1699–1709 (2018).

    Article 
    CAS 

    Google Scholar 

  • Nauck, M. A., Meier, J. J., Cavender, M. A., Abd El Aziz, M. & Drucker, D. J. Cardiovascular actions and clinical outcomes with glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Circulation 136, 849–870 (2017).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Mann, J. F. E. et al. Potential kidney protection with liraglutide and semaglutide: Exploratory mediation analysis. Diabetes Obes. Metab. 23, 2058–2066 (2021).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Mann, J. F. E. et al. Liraglutide and renal outcomes in type 2 diabetes. N. Engl. J. Med. 377, 839–848 (2017).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Apperloo, E. M. et al. Tirzepatide associated with reduced albuminuria in participants with type 2 diabetes: pooled post hoc analysis from the randomized active- and placebo-controlled SURPASS-1-5 clinical trials. Diabetes Care 48, 430–436 (2025).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Heerspink, H. J. L. et al. Effects of semaglutide on albuminuria and kidney function in people with overweight or obesity with or without type 2 diabetes: exploratory analysis from the step 1, 2, and 3 trials. Diabetes Care 46, 801–810 (2023).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Ceriello, A. et al. Simultaneous GLP-1 and insulin administration acutely enhances their vasodilatory, antiinflammatory, and antioxidant action in type 2 diabetes. Diabetes Care 37, 1938–1943 (2014).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Chaudhuri, A. et al. Exenatide exerts a potent antiinflammatory effect. J. Clin. Endocrinol. Metab. 97, 198–207 (2012).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Sourris, K. C. et al. Glucagon-like peptide-1 receptor signaling modifies the extent of diabetic kidney disease through dampening the receptor for advanced glycation end products-induced inflammation. Kidney Int. 105, 132–149 (2024).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Ougaard, M. E. et al. Liraglutide improves the kidney function in a murine model of chronic kidney disease. Nephron 144, 595–606 (2020).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Grayson, P. C. et al. Metabolic pathways and immunometabolism in rare kidney diseases. Ann. Rheum. Dis. 77, 1226–1233 (2018).

    Article 
    PubMed 

    Google Scholar 

  • Wang, M. Y. et al. Downregulation of the kidney glucagon receptor, essential for renal function and systemic homeostasis, contributes to chronic kidney disease. Cell Metab. 36, 575–597 e577 (2024).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Marso, S. P. et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med. 375, 311–322 (2016).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Zavattaro, M. et al. One-year treatment with liraglutide improved renal function in patients with type 2 diabetes: a pilot prospective study. Endocrine 50, 620–626 (2015).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Davies, M. J. et al. Efficacy and safety of liraglutide versus placebo as add-on to glucose-lowering therapy in patients with type 2 diabetes and moderate renal impairment (LIRA-RENAL): a randomized clinical trial. Diabetes Care 39, 222–230 (2016).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Wexler, D. J. et al. Comparative effects of glucose-lowering medications on kidney outcomes in type 2 diabetes: the grade randomized clinical trial. JAMA Intern. Med. 183, 705–714 (2023).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Neumiller, J. J. et al. Kidney outcomes with glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter 2 inhibitors, dipeptidyl peptidase-4 inhibitors, and sulfonylureas in type 2 diabetes and moderate cardiovascular risk. Clin. J. Am. Soc. Nephrol. 20, 206–217 (2024).

    Article 
    PubMed 

    Google Scholar 

  • Ndumele, C. E. et al. A synopsis of the evidence for the science and clinical management of cardiovascular-kidney-metabolic (CKM) syndrome: a scientific statement from the American Heart Association. Circulation 148, 1636–1664 (2023).

    Article 
    PubMed 

    Google Scholar 

  • Pfeffer, M. A. et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N. Engl. J. Med. 373, 2247–2257 (2015).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Muskiet, M. H. A. et al. Lixisenatide and renal outcomes in patients with type 2 diabetes and acute coronary syndrome: an exploratory analysis of the ELIXA randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 6, 859–869 (2018).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Holman, R. R. et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med. 377, 1228–1239 (2017).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Bethel, M. A. et al. Microvascular and cardiovascular outcomes according to renal function in patients treated with once-weekly exenatide: insights from the EXSCEL trial. Diabetes Care 43, 446–452 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Muskiet, M. H. A. et al. Exenatide twice-daily does not affect renal function or albuminuria compared to titrated insulin glargine in patients with type 2 diabetes mellitus: a post-hoc analysis of a 52-week randomised trial. Diabetes Res. Clin. Pract. 153, 14–22 (2019).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Gerstein, H. C. et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet 394, 121–130 (2019).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Gerstein, H. C. et al. Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial. Lancet 394, 131–138 (2019).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Tuttle, K. R. et al. Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7): a multicentre, open-label, randomised trial. Lancet Diabetes Endocrinol. 6, 605–617 (2018).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Tuttle, K. R. et al. Clinical outcomes by albuminuria status with dulaglutide versus insulin glargine in participants with diabetes and CKD: AWARD-7 exploratory analysis. Kidney360 2, 254–262 (2021).

    Article 
    PubMed 

    Google Scholar 

  • Hernandez, A. F. et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial. Lancet 392, 1519–1529 (2018).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Gerstein, H. C. et al. Cardiovascular and renal outcomes with efpeglenatide in type 2 diabetes. N. Engl. J. Med. 385, 896–907 (2021).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Marso, S. P. et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N. Engl. J. Med. 375, 1834–1844 (2016).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Tuttle, K. R. et al. Effects of once-weekly semaglutide on kidney disease outcomes by KDIGO risk category in the SUSTAIN 6 trial. Kidney Int. Rep. 9, 2006–2015 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Lincoff, A. M. et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. N. Engl. J. Med. 389, 2221–2232 (2023).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • McGuire, D. K. et al. Oral semaglutide and cardiovascular outcomes in high-risk type 2 diabetes. N. Engl. J. Med. 392, 2001–2012 (2025).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Heerspink, H. J. L. et al. Effects of tirzepatide versus insulin glargine on kidney outcomes in type 2 diabetes in the SURPASS-4 trial: post-hoc analysis of an open-label, randomised, phase 3 trial. Lancet Diabetes Endocrinol. 10, 774–785 (2022).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Heerspink, H. J. L. et al. Effects of tirzepatide versus insulin glargine on cystatin c-based kidney function: a SURPASS-4 post hoc analysis. Diabetes Care 46, 1501–1506 (2023).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Heerspink, H. J. L. et al. Kidney parameters with tirzepatide in obesity with or without type 2 diabetes. J. Am. Soc. Nephrol. 36, 2190–2200 (2025).

    Article 
    PubMed 

    Google Scholar 

  • Shaman, A. M. et al. Effect of the glucagon-like peptide-1 receptor agonists semaglutide and liraglutide on kidney outcomes in patients with type 2 diabetes: pooled analysis of SUSTAIN 6 and LEADER. Circulation 145, 575–585 (2022).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Tuttle, K. R. et al. Post hoc analysis of SUSTAIN 6 and PIONEER 6 trials suggests that people with type 2 diabetes at high cardiovascular risk treated with semaglutide experience more stable kidney function compared with placebo. Kidney Int. 103, 772–781 (2023).

    Article 
    PubMed 

    Google Scholar 

  • Apperloo, E. M. et al. Effect of semaglutide on kidney function across different levels of baseline HbA1c, blood pressure, body weight and albuminuria in SUSTAIN 6 and PIONEER 6. Nephrol. Dial. Transpl. 40, 352–359 (2025).

    Article 
    CAS 

    Google Scholar 

  • Sattar, N. et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials. Lancet Diabetes Endocrinol. 9, 653–662 (2021).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Badve, S. V. et al. Effects of GLP-1 receptor agonists on kidney and cardiovascular disease outcomes: a meta-analysis of randomised controlled trials. Lancet Diabetes Endocrinol. 13, 15–28 (2025).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Mendonca, L., Moura, H., Chaves, P. C., Neves, J. S. & Ferreira, J. P. The impact of glucagon-like peptide-1 receptor agonists on kidney outcomes: a meta-analysis of randomized placebo-controlled trials. Clin. J. Am. Soc. Nephrol. 20, 159–168 (2024).

    Article 
    PubMed 

    Google Scholar 

  • Lee, M. M. Y. et al. Cardiovascular and kidney outcomes and mortality with long-acting injectable and oral glucagon-like peptide 1 receptor agonists in individuals with type 2 diabetes: a systematic review and meta-analysis of randomized trials. Diabetes Care 48, 846–859 (2025).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Chu, L., Bradley, R. M., Auerbach, P. & Abitbol, A. Real-world impact of adding a glucagon-like peptide-1 receptor agonist compared with basal insulin on metabolic targets in adults living with type 2 diabetes and chronic kidney disease already treated with a sodium-glucose co-transporter-2 inhibitor: the impact GLP-1 CKD study. Diabetes Obes. Metab. 26, 4674–4683 (2024).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Zhang, S. et al. Healthcare utilization, mortality, and cardiovascular events following GLP1-RA initiation in chronic kidney disease. Nat. Commun. 15, 10623 (2024).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Nicholas, S. B. et al. Prescription of guideline-directed medical therapies in patients with diabetes and chronic kidney disease from the CURE-CKD Registry, 2019-2020. Diabetes Obes. Metab. 25, 2970–2979 (2023).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Lassen, M. C. H. et al. Adherence to glucagon-like peptide-1 receptor agonist treatment in type 2 diabetes mellitus: a nationwide registry study. Diabetes Obes. Metab. 26, 5239–5250 (2024).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Jung, H. et al. Clinical characteristics, treatment patterns, and persistence in individuals with type 2 diabetes initiating a glucagon-like peptide-1 receptor agonist: a retrospective analysis of the diabetes prospective follow-up registry. Diabetes Obes. Metab. 25, 1813–1822 (2023).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Sikirica, M. V. et al. Reasons for discontinuation of GLP1 receptor agonists: data from a real-world cross-sectional survey of physicians and their patients with type 2 diabetes. Diabetes Metab. Syndr. Obes. 10, 403–412 (2017).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • McEwan, P. et al. Cost-effectiveness of semaglutide in people with obesity and cardiovascular disease without diabetes. J. Med. Econ. 28, 268–278 (2025).

    Article 
    PubMed 

    Google Scholar 

  • Yang, C. T., Yao, W. Y., Ou, H. T. & Kuo, S. Value of GLP-1 receptor agonists versus long-acting insulins for type 2 diabetes patients with and without established cardiovascular or chronic kidney diseases: a model-based cost-effectiveness analysis using real-world data. Diabetes Res. Clin. Pract. 198, 110625 (2023).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Xie, Y., Choi, T. & Al-Aly, Z. Mapping the effectiveness and risks of GLP-1 receptor agonists. Nat. Med. 31, 951–962 (2025).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • van Raalte, D. H. et al. Combination therapy for kidney disease in people with diabetes mellitus. Nat. Rev. Nephrol. 20, 433–446 (2024).

    Article 
    PubMed 

    Google Scholar 

  • Fu, E. L. et al. A population-based cohort defined risk of hyperkalemia after initiating SGLT-2 inhibitors, GLP1 receptor agonists or DPP-4 inhibitors to patients with chronic kidney disease and type 2 diabetes. Kidney Int. 105, 618–628 (2024).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Fu, E. L. et al. SGLT-2 inhibitors, GLP-1 receptor agonists, and DPP-4 inhibitors and risk of hyperkalemia among people with type 2 diabetes in clinical practice: population based cohort study. BMJ 385, e078483 (2024).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Huang, T. et al. GLP-1RA vs DPP-4i use and rates of hyperkalemia and RAS blockade discontinuation in type 2 diabetes. JAMA Intern. Med. 184, 1195–1203 (2024).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Alicic, R. Z., Neumiller, J. J. & Tuttle, K. R. Combination therapy: an upcoming paradigm to improve kidney and cardiovascular outcomes in chronic kidney disease. Nephrol. Dial. Transpl. 40, i3–i17 (2025).

    Article 
    CAS 

    Google Scholar 

  • Mann, J. F. E. et al. Effects of semaglutide with and without concomitant SGLT2 inhibitor use in participants with type 2 diabetes and chronic kidney disease in the FLOW trial. Nat. Med. 30, 2849–2856 (2024).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Rossing, P. et al. Finerenone in patients across the spectrum of chronic kidney disease and type 2 diabetes by glucagon-like peptide-1 receptor agonist use. Diabetes Obes. Metab. 25, 407–416 (2023).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Cherney, D. Z. I. et al. Rationale, design and baseline characteristics of REMODEL, a mechanism-of-action trial with semaglutide in people with type 2 diabetes and chronic kidney disease. Nephrol. Dial. Transpl. 40, 2182–2192 (2025).

    Article 

    Google Scholar 

  • Wharton, S. et al. Daily oral GLP-1 receptor agonist orforglipron for adults with obesity. N. Engl. J. Med. 389, 877–888 (2023).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Rosenstock, J. et al. Orforglipron, an oral small-molecule GLP-1 receptor agonist, in early type 2 diabetes. N. Engl. J. Med. 393, 1065–1076 (2025).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Gasiorek, A. et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of the first-in-class GLP-1 and amylin receptor agonist, amycretin: a first-in-human, phase 1, double-blind, randomised, placebo-controlled trial. Lancet 406, 135–148 (2025).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Dahl, K. et al. Amycretin, a novel, unimolecular GLP-1 and amylin receptor agonist administered subcutaneously: results from a phase 1b/2a randomised controlled study. Lancet 406, 149–162 (2025).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Selvarajah, V. et al. A randomized phase 2b trial examined the effects of the glucagon-like peptide-1 and glucagon receptor agonist cotadutide on kidney outcomes in patients with diabetic kidney disease. Kidney Int. 106, 1170–1180 (2024).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Tuttle, K. R. et al. Clinical characteristics of and risk factors for chronic kidney disease among adults and children: an analysis of the CURE-CKD registry. JAMA Netw. Open. 2, e1918169 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Norris, K. C. et al. Rationale and design of a multicenter chronic kidney disease (CKD) and at-risk for CKD electronic health records-based registry: CURE-CKD. BMC Nephrol. 20, 416 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Nee, R., Yuan, C. M., Narva, A. S., Yan, G. & Norris, K. C. Overcoming barriers to implementing new guideline-directed therapies for chronic kidney disease. Nephrol. Dial. Transpl. 38, 532–541 (2023).

    Article 

    Google Scholar 

  • Exenatide injection. Prescribing information (Amneal Pharmaceuticals, 2025).

  • Liraglutide (Victoza) injection. Prescribing information (Novo Nordisk, 2025).

  • Liraglutide (Saxenda) injection. Prescribing information (Novo Nordisk, 2025).

  • Exenatide extended-release (Bydureon BCise) injectable suspension. Prescribing information (AstraZeneca Pharmaceuticals, 2025).

  • Dulaglutide (Trulicity) injection. Prescribing information (Eli Lilly, 2024).

  • Semaglutide (Ozempic) injection. Prescribing information (Novo Nordisk, 2025).

  • Semaglutide (Wegovy) injection. Prescribing information (Novo Nordisk, 2025).

  • Semaglutide (Rybelsus) tablets. Prescribing information (Novo Nordisk, 2025).

  • Tirzepatide (Mounjaro) injection. Prescribing information (Eli Lilly, 2025).

  • Tirzepatide (Zepbound) injection. Prescribing information (Eli Lilly, 2025).

  • Del Prato, S. et al. Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial. Lancet 398, 1811–1824 (2021).

    Article 
    PubMed 

    Google Scholar 

  • Holst, J. J. et al. Proglucagon processing in porcine and human pancreas. J. Biol. Chem. 269, 18827–18833 (1994).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Drucker, D. J. & Asa, S. Glucagon gene expression in vertebrate brain. J. Biol. Chem. 263, 13475–13478 (1988).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Portela-Gomes, G. M. & Stridsberg, M. Chromogranin A in the human gastrointestinal tract: an immunocytochemical study with region-specific antibodies. J. Histochem. Cytochem. 50, 1487–1492 (2002).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Mortensen, K., Christensen, L. L., Holst, J. J. & Orskov, C. GLP-1 and GIP are colocalized in a subset of endocrine cells in the small intestine. Regul. Pept. 114, 189–196 (2003).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Ugleholdt, R. et al. Prohormone convertase 1/3 is essential for processing of the glucose-dependent insulinotropic polypeptide precursor. J. Biol. Chem. 281, 11050–11057 (2006).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Baggio, L. L. & Drucker, D. J. Biology of incretins: GLP-1 and GIP. Gastroenterology 132, 2131–2157 (2007).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Cheroutre, H., Lambolez, F. & Mucida, D. The light and dark sides of intestinal intraepithelial lymphocytes. Nat. Rev. Immunol. 11, 445–456 (2011).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Martchenko, S. E. et al. Circadian GLP-1 Secretion in mice is dependent on the intestinal microbiome for maintenance of diurnal metabolic homeostasis. Diabetes 69, 2589–2602 (2020).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Yoon, H. S. et al. Akkermansia muciniphila secretes a glucagon-like peptide-1-inducing protein that improves glucose homeostasis and ameliorates metabolic disease in mice. Nat. Microbiol. 6, 563–573 (2021).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Gribble, F. M. & Reimann, F. Enteroendocrine cells: chemosensors in the intestinal epithelium. Annu. Rev. Physiol. 78, 277–299 (2016).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Vilsboll, T. et al. Incretin secretion in relation to meal size and body weight in healthy subjects and people with type 1 and type 2 diabetes mellitus. J. Clin. Endocrinol. Metab. 88, 2706–2713 (2003).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Furness, J. B., Rivera, L. R., Cho, H. J., Bravo, D. M. & Callaghan, B. The gut as a sensory organ. Nat. Rev. Gastroenterol. Hepatol. 10, 729–740 (2013).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Gribble, F. M. & Reimann, F. Function and mechanisms of enteroendocrine cells and gut hormones in metabolism. Nat. Rev. Endocrinol. 15, 226–237 (2019).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Worthington, J. J., Reimann, F. & Gribble, F. M. Enteroendocrine cells-sensory sentinels of the intestinal environment and orchestrators of mucosal immunity. Mucosal Immunol. 11, 3–20 (2018).

    Article 
    PubMed 
    CAS 

    Google Scholar 

  • Berthier, C. C. et al. Enhanced expression of Janus kinase-signal transducer and activator of transcription pathway members in human diabetic nephropathy. Diabetes 58, 469–477 (2009).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Peng, Y. et al. AGE-RAGE signal generates a specific NF-κB RelA “barcode” that directs collagen I expression. Sci. Rep. 6, 18822 (2016).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar 

  • Qi, C., Mao, X., Zhang, Z. & Wu, H. Classification and differential diagnosis of diabetic nephropathy. J. Diabetes Res. 2017, 8637138 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar 

  • Fujita, H. et al. The protective roles of GLP-1R signaling in diabetic nephropathy: possible mechanism and therapeutic potential. Kidney Int. 85, 579–589 (2014).

    Article 
    PubMed 
    CAS 

    Google Scholar 

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