Combination therapy for kidney disease in people with diabetes mellitus – Nature Reviews Nephrology

  • de Boer, I. H. et al. Temporal trends in the prevalence of diabetic kidney disease in the United States. JAMA 305, 2532–2539 (2011).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • de Boer, I. H., Group DER. Kidney disease and related findings in the diabetes control and complications trial/epidemiology of diabetes interventions and complications study. Diabetes Care 37, 24–30 (2014).

    Article 
    PubMed 

    Google Scholar
     

  • Afkarian, M. et al. Clinical manifestations of kidney disease among US adults with diabetes, 1988-2014. JAMA 316, 602–610 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Koye, D. N., Magliano, D. J., Nelson, R. G. & Pavkov, M. E. The global epidemiology of diabetes and kidney disease. Adv. Chronic Kidney Dis. 25, 121–132 (2018).

    Article 
    PubMed 

    Google Scholar
     

  • Agrawal, L. et al. Intensive glycemic control improves long-term renal outcomes in type 2 diabetes in the Veterans Affairs Diabetes Trial (VADT). Diabetes Care 42, e181–e182 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Agrawal, L. et al. Observation on renal outcomes in the Veterans Affairs Diabetes Trial. Diabetes Care 34, 2090–2094 (2011).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lewis, E. J., Hunsicker, L. G., Bain, R. P. & Rohde, R. D. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N. Engl. J. Med. 329, 1456–1462 (1993).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lewis, E. J. et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N. Engl. J. Med. 345, 851–860 (2001).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Brenner, B. M. et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N. Engl. J. Med. 345, 861–869 (2001).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Fried, L. F. et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N. Engl. J. Med. 369, 1892–1903 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Parving, H. H. et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N. Engl. J. Med. 367, 2204–2213 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Mann, J. F. et al. Avosentan for overt diabetic nephropathy. J. Am. Soc. Nephrol. 21, 527–535 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • de Zeeuw, D. et al. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N. Engl. J. Med. 369, 2492–2503 (2013).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Packham, D. K. et al. Sulodexide fails to demonstrate renoprotection in overt type 2 diabetic nephropathy. J. Am. Soc. Nephrol. 23, 123–130 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • The E-KCG. et al. Empagliflozin in patients with chronic kidney disease. N. Engl. J. Med. 388, 117–127 (2023).

    Article 

    Google Scholar
     

  • Perkovic, V. et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N. Engl. J. Med. 380, 2295–2306 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Heerspink, H. J. L. et al. Dapagliflozin in patients with chronic kidney disease. N. Engl. J. Med. 383, 1436–1446 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Bakris, G. L. et al. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N. Engl. J. Med. 383, 2219–2229 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Heerspink, H. J. L. et al. Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial. Lancet 393, 1937–1947 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • International Diabetes Federation. IDF Diabetes Atlas, 10th edn. https://www.diabetesatlas.org (2021).

  • Menke, A., Casagrande, S., Geiss, L. & Cowie, C. C. Prevalence of and trends in diabetes among adults in the United States, 1988–2012. JAMA 314, 1021–1029 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Jager, K. J. et al. A single number for advocacy and communication-worldwide more than 850 million individuals have kidney diseases. Kidney Int. 96, 1048–1050 (2019).

    Article 
    PubMed 

    Google Scholar
     

  • Toppe, C. et al. Decreasing cumulative incidence of end-stage renal disease in young patients with type 1 diabetes in Sweden: a 38-year prospective nationwide study. Diabetes Care 42, 27–31 (2019).

    Article 
    PubMed 

    Google Scholar
     

  • Gregg, E. W., Hora, I. & Benoit, S. R. Resurgence in diabetes-related complications. JAMA 321, 1867–1868 (2019).

    Article 
    PubMed 

    Google Scholar
     

  • Narres, M. et al. Incidence and relative risk of renal replacement therapy in people with and without diabetes between 2002 and 2016 in a German region. Diabetologia 63, 648–658 (2020).

    Article 
    PubMed 

    Google Scholar
     

  • Koye, D. N. et al. Trends in incidence of ESKD in people with type 1 and type 2 diabetes in Australia, 2002–2013. Am. J. Kidney Dis. 73, 300–308 (2019).

    Article 
    PubMed 

    Google Scholar
     

  • Wu, H. et al. Trends in kidney failure and kidney replacement therapy in people with diabetes in Hong Kong, 2002–2015: a retrospective cohort study. Lancet Reg. Health West Pac. 11, 100165 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Harding, J. L., Pavkov, M. E., Magliano, D. J., Shaw, J. E. & Gregg, E. W. Global trends in diabetes complications: a review of current evidence. Diabetologia 62, 3–16 (2019).

    Article 
    PubMed 

    Google Scholar
     

  • Afkarian, M. et al. Kidney disease and increased mortality risk in type 2 diabetes. J. Am. Soc. Nephrol. 24, 302–308 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Fox, C. S. et al. Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without diabetes: a meta-analysis. Lancet 380, 1662–1673 (2012).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wen, C. P. et al. Diabetes with early kidney involvement may shorten life expectancy by 16 years. Kidney Int. 92, 388–396 (2017).

    Article 
    PubMed 

    Google Scholar
     

  • Fioretto, P. & Mauer, M. Histopathology of diabetic nephropathy. Semin. Nephrol. 27, 195–207 (2007).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Fiorentino, M. et al. Renal biopsy in patients with diabetes: a pooled meta-analysis of 48 studies. Nephrol. Dial. Transpl. 32, 97–110 (2017).

    CAS 

    Google Scholar
     

  • Fioretto, P. et al. Patterns of renal injury in NIDDM patients with microalbuminuria. Diabetologia 39, 1569–1576 (1996).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Jin, Q. et al. Nonalbuminuric diabetic kidney disease and risk of all-cause mortality and cardiovascular and kidney outcomes in type 2 diabetes: findings from the Hong Kong Diabetes Biobank. Am. J. Kidney Dis. 80, 196–206 e1 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Nosadini, R. et al. Course of renal function in type 2 diabetic patients with abnormalities of albumin excretion rate. Diabetes 49, 476–484 (2000).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Fioretto, P., Steffes, M. W., Sutherland, D. E., Goetz, F. C. & Mauer, M. Reversal of lesions of diabetic nephropathy after pancreas transplantation. N. Engl. J. Med. 339, 69–75 (1998).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Scholtes, R. A. et al. Renal haemodynamic and protective effects of renoactive drugs in type 2 diabetes: Interaction with SGLT2 inhibitors. Nephrology 26, 377–390 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Scholtes, R. A. et al. Kidney hemodynamic effects of angiotensin receptor blockade, sodium-glucose cotransporter-2 inhibition alone, and their combination: a crossover randomized trial in people with type 2 diabetes. Circulation 146, 1895–1897 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Romero, C. A., Orias, M. & Weir, M. R. Novel RAAS agonists and antagonists: clinical applications and controversies. Nat. Rev. Endocrinol. 11, 242–252 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rayego-Mateos, S. et al. Targeting inflammation to treat diabetic kidney disease: the road to 2030. Kidney Int. 103, 282–296 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ma, T. K., Kam, K. K., Yan, B. P. & Lam, Y. Y. Renin-angiotensin-aldosterone system blockade for cardiovascular diseases: current status. Br. J. Pharmacol. 160, 1273–1292 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • van Bommel, E. J. et al. SGLT2 inhibition in the diabetic kidney-from mechanisms to clinical outcome. Clin. J. Am. Soc. Nephrol. 12, 700–710 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Persson, F. et al. Efficacy and safety of dapagliflozin by baseline glycemic status: a prespecified analysis from the DAPA-CKD trial. Diabetes Care 44, 1894–1897 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • van Bommel, E. J. M. et al. The renal hemodynamic effects of the SGLT2 inhibitor dapagliflozin are caused by post-glomerular vasodilatation rather than pre-glomerular vasoconstriction in metformin-treated patients with type 2 diabetes in the randomized, double-blind RED trial. Kidney Int. 97, 202–212 (2020).

    Article 
    PubMed 

    Google Scholar
     

  • Cherney, D. Z. et al. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation 129, 587–597 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Heerspink, H. J., Perkins, B. A., Fitchett, D. H., Husain, M. & Cherney, D. Z. Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications. Circulation 134, 752–772 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Nuffield Department of Population Health Renal Studies G, Consortium SiM-AC-RT. Impact of diabetes on the effects of sodium glucose co-transporter-2 inhibitors on kidney outcomes: collaborative meta-analysis of large placebo-controlled trials. Lancet 400, 1788–1801 (2022).

    Article 

    Google Scholar
     

  • Neuen, B. L. et al. Sodium-glucose cotransporter 2 inhibitors and risk of hyperkalemia in people with type 2 diabetes: a meta-analysis of individual participant data from randomized, controlled trials. Circulation 145, 1460–1470 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Bolignano, D., Palmer, S. C., Navaneethan, S. D. & Strippoli, G. F. Aldosterone antagonists for preventing the progression of chronic kidney disease. Cochrane Database Syst. Rev. 10, CD007004 (2014).


    Google Scholar
     

  • Alexandrou, M. E. et al. Effects of mineralocorticoid receptor antagonists in proteinuric kidney disease: a systematic review and meta-analysis of randomized controlled trials. J. Hypertens. 37, 2307–2324 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kolkhof, P. et al. Finerenone, a novel selective nonsteroidal mineralocorticoid receptor antagonist protects from rat cardiorenal injury. J. Cardiovasc. Pharmacol. 64, 69–78 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Gerisch, M. et al. Biotransformation of finerenone, a novel nonsteroidal mineralocorticoid receptor antagonist, in dogs, rats, and humans, in vivo and in vitro. Drug Metab. Dispos. 46, 1546–1555 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Agarwal, R. et al. Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis. Eur. Heart J. 43, 474–484 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Agarwal, R. et al. Hyperkalemia risk with finerenone: results from the FIDELIO-DKD trial. J. Am. Soc. Nephrol. 33, 225–237 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ito, S. et al. Esaxerenone (CS-3150) in patients with type 2 diabetes and microalbuminuria (ESAX-DN): phase 3 randomized controlled clinical trial. Clin. J. Am. Soc. Nephrol. 15, 1715–1727 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Barton, M. & Yanagisawa, M. Endothelin: 30 years from discovery to therapy. Hypertension 74, 1232–1265 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Chung, E. Y. M., Badve, S. V., Heerspink, H. J. L. & Wong, M. G. Endothelin receptor antagonists in kidney protection for diabetic kidney disease and beyond? Nephrology 28, 97–108 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Weber, M. A. et al. A selective endothelin-receptor antagonist to reduce blood pressure in patients with treatment-resistant hypertension: a randomised, double-blind, placebo-controlled trial. Lancet 374, 1423–1431 (2009).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Muskiet, M. H. A. et al. GLP-1 and the kidney: from physiology to pharmacology and outcomes in diabetes. Nat. Rev. Nephrol. 13, 605–628 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

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

    Article 
    CAS 
    PubMed 

    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 
    CAS 
    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 
    CAS 
    PubMed 

    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
     

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

    Article 
    CAS 
    PubMed 

    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 
    CAS 
    PubMed 
    PubMed Central 

    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 
    CAS 
    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 
    CAS 
    PubMed 

    Google Scholar
     

  • Pichler, R., Afkarian, M., Dieter, B. P. & Tuttle, K. R. Immunity and inflammation in diabetic kidney disease: translating mechanisms to biomarkers and treatment targets. Am. J. Physiol. Renal Physiol. 312, F716–F731 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ronn, J., Jensen, E. P., Wewer Albrechtsen, N. J., Holst, J. J. & Sorensen, C. M. Glucagon-like peptide-1 acutely affects renal blood flow and urinary flow rate in spontaneously hypertensive rats despite significantly reduced renal expression of GLP-1 receptors. Physiol. Rep. 5, e13503 (2017).

    Article 
    PubMed 
    PubMed Central 

    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 
    CAS 
    PubMed 

    Google Scholar
     

  • Muskiet, M. H. et al. Acute renal haemodynamic effects of glucagon-like peptide-1 receptor agonist exenatide in healthy overweight men. Diabetes Obes. Metab. 18, 178–185 (2016).

    Article 
    CAS 
    PubMed 

    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
     

  • Rossing, P. et al. 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. Transpl. 38, 2041–2051 (2023).

    Article 

    Google Scholar
     

  • A research study to find out how semaglutide works in the kidneys compared to placebo, in people with type 2 diabetes and chronic kidney disease (the REMODEL trial) (REMODEL). ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04865770 (2024).

  • Kalantar-Zadeh, K. & Fouque, D. Nutritional management of chronic kidney disease. N. Engl. J. Med. 377, 1765–1776 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Suckling R. J., He F. J., Macgregor G. A. Altered dietary salt intake for preventing and treating diabetic kidney disease. Cochrane Database Syst. Rev. 2010:CD006763.

  • de Boer, I. H. et al. Executive summary of the 2020 KDIGO diabetes management in CKD guideline: evidence-based advances in monitoring and treatment. Kidney Int. 98, 839–848 (2020).

    Article 
    PubMed 

    Google Scholar
     

  • Kwakernaak, A. J. et al. Effects of sodium restriction and hydrochlorothiazide on RAAS blockade efficacy in diabetic nephropathy: a randomised clinical trial. Lancet Diabetes Endocrinol. 2, 385–395 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Dietary sodium intake effects on ertugliflozin-induced changes in GFR, renal oxygenation and systemic hemodynamics: the DESIGN study (DESIGN). ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05727579 (2023).

  • Yan, B., Su, X., Xu, B., Qiao, X. & Wang, L. Effect of diet protein restriction on progression of chronic kidney disease: a systematic review and meta-analysis. PLoS One 13, e0206134 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bosch, J. P. et al. Renal functional reserve in humans. Effect of protein intake on glomerular filtration rate. Am. J. Med. 75, 943–950 (1983).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Look ARG. Effect of a long-term behavioural weight loss intervention on nephropathy in overweight or obese adults with type 2 diabetes: a secondary analysis of the Look AHEAD randomised clinical trial. Lancet Diabetes Endocrinol. 2, 801–809 (2014).

    Article 

    Google Scholar
     

  • Shulman, A. et al. Incidence of end-stage renal disease following bariatric surgery in the Swedish Obese Subjects Study. Int. J. Obes. 42, 964–973 (2018).

    Article 
    CAS 

    Google Scholar
     

  • O’Hare, A. M., Tawney, K., Bacchetti, P. & Johansen, K. L. Decreased survival among sedentary patients undergoing dialysis: results from the dialysis morbidity and mortality study wave 2. Am. J. Kidney Dis. 41, 447–454 (2003).

    Article 
    PubMed 

    Google Scholar
     

  • Wilkinson, T. J., McAdams-DeMarco, M., Bennett, P. N. & Wilund, K., Global Renal Exercise N. Advances in exercise therapy in predialysis chronic kidney disease, hemodialysis, peritoneal dialysis, and kidney transplantation. Curr. Opin. Nephrol. Hypertens. 29, 471–479 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zelle, D. M. et al. Physical inactivity: a risk factor and target for intervention in renal care. Nat. Rev. Nephrol. 13, 318 (2017).

    Article 
    PubMed 

    Google Scholar
     

  • Efficacy of a high-intensity physical activity program on renal function in high risk patients with type 2 diabetes (ACTIDIANE). ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03184662 (2021).

  • Liu, J. et al. Multi-scalar data integration links glomerular angiopoietin-tie signaling pathway activation with progression of diabetic kidney disease. Diabetes 71, 2664–2676 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Stefansson, V. T. N. et al. Molecular programs associated with glomerular hyperfiltration in early diabetic kidney disease. Kidney Int. 102, 1345–1358 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Nair, V. et al. A molecular morphometric approach to diabetic kidney disease can link structure to function and outcome. Kidney Int. 93, 439–449 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Sas, K. M. et al. Tissue-specific metabolic reprogramming drives nutrient flux in diabetic complications. JCI Insight 1, e86976 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wilson, P. C. et al. The single-cell transcriptomic landscape of early human diabetic nephropathy. Proc. Natl Acad. Sci. USA 116, 19619–19625 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wu, H. et al. Mapping the single-cell transcriptomic response of murine diabetic kidney disease to therapies. Cell Metab. 34, 1064–78 e6 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hodgin, J. B. et al. Identification of cross-species shared transcriptional networks of diabetic nephropathy in human and mouse glomeruli. Diabetes 62, 299–308 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Brosius, F. C. III et al. Mouse models of diabetic nephropathy. J. Am. Soc. Nephrol. 20, 2503–2512 (2009).

    Article 
    PubMed 

    Google Scholar
     

  • Kolkhof, P. et al. Effects of finerenone combined with empagliflozin in a model of hypertension-induced end-organ damage. Am. J. Nephrol. 52, 642–652 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Vergara, A. et al. Enhanced cardiorenal protective effects of combining SGLT2 inhibition, endothelin receptor antagonism and RAS blockade in type 2 diabetic mice. Int. J. Mol. Sci. 23, 12823 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Seidu, S., Kunutsor, S. K., Topsever, P. & Khunti, K. Benefits and harms of sodium-glucose co-transporter-2 inhibitors (SGLT2-I) and renin-angiotensin-aldosterone system inhibitors (RAAS-I) versus SGLT2-Is alone in patients with type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Endocrinol. Diabetes Metab. 5, e00303 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lytvyn, Y. et al. Renal and vascular effects of combined SGLT2 and angiotensin-converting enzyme inhibition. Circulation 146, 450–462 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Phadke, G. et al. Osmotic nephrosis and acute kidney injury associated with SGLT2 inhibitor use: a case report. Am. J. Kidney Dis. 76, 144–147 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Promoting effective renoprotection in cardiac surgery patients by inhibition of SGLT-2 (MERCURI-2). ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05590143 (2023).

  • Hesp, A. C. et al. The role of renal hypoxia in the pathogenesis of diabetic kidney disease: a promising target for newer renoprotective agents including SGLT2 inhibitors? Kidney Int. 98, 579–589 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Puglisi, S. et al. Effects of SGLT2 inhibitors and GLP-1 receptor agonists on renin-angiotensin-aldosterone system. Front. Endocrinol. 12, 738848 (2021).

    Article 

    Google Scholar
     

  • Jabbour, S. A. et al. Efficacy and safety over 2 years of exenatide plus dapagliflozin in the DURATION-8 study: a multicenter, double-blind, phase 3, randomized controlled trial. Diabetes Care 43, 2528–2536 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    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 
    CAS 
    PubMed 

    Google Scholar
     

  • Lam, C. S. P. et al. Efpeglenatide and clinical outcomes with and without concomitant sodium-glucose cotransporter-2 inhibition use in type 2 diabetes: exploratory analysis of the AMPLITUDE-O trial. Circulation 145, 565–574 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • van der Aart-van der Beek, A. B. et al. Albuminuria-lowering effect of dapagliflozin, exenatide, and their combination in patients with type 2 diabetes: a randomized cross-over clinical study. Diabetes Obes. Metab. 25, 1758–1768 (2023).

    Article 
    PubMed 

    Google Scholar
     

  • van Ruiten, C. C. et al. Effect of exenatide twice daily and dapagliflozin, alone and in combination, on markers of kidney function in obese patients with type 2 diabetes: a prespecified secondary analysis of a randomized controlled clinical trial. Diabetes Obes. Metab. 23, 1851–1858 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gullaksen, S. et al. Separate and combined effects of semaglutide and empagliflozin on kidney oxygenation and perfusion in people with type 2 diabetes: a randomised trial. Diabetologia 66, 813–825 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wright, A. K. et al. Primary prevention of cardiovascular and heart failure events with SGLT2 inhibitors, GLP-1 receptor agonists, and their combination in type 2 diabetes. Diabetes Care 45, 909–918 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Pitt, B. et al. Cardiovascular events with finerenone in kidney disease and type 2 diabetes. N. Engl. J. Med. 385, 2252–2263 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Rossing, P. et al. Finerenone in patients with chronic kidney disease and type 2 diabetes by sodium-glucose cotransporter 2 inhibitor treatment: the FIDELITY analysis. Diabetes Care 45, 2991–2998 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    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 
    CAS 
    PubMed 

    Google Scholar
     

  • Provenzano, M. et al. Albuminuria-lowering effect of dapagliflozin, eplerenone, and their combination in patients with chronic kidney disease: a randomized crossover clinical trial. J. Am. Soc. Nephrol. 33, 1569–1580 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • A study to learn how well the treatment combination of finerenone and empagliflozin works and how safe it is compared to each treatment alone in adult participants with long-term kidney disease (chronic kidney disease) and type 2 diabetes (CONFIDENCE). ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05254002 (2024).

  • Heerspink, H. J. L., Kohan DE & de Zeeuw, D. New insights from SONAR indicate adding sodium glucose co-transporter 2 inhibitors to an endothelin receptor antagonist mitigates fluid retention and enhances albuminuria reduction. Kidney Int. 99, 346–349 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Zibotentan and dapagliflozin for the treatment of CKD (ZENITH-CKD Trial) (ZENITH-CKD). ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04724837 (2023).

  • Zibotentan and dapagliflozin in patients with type 2 diabetes and elevated albuminuria (ZODIAC). ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05570305 (2023).

  • Rosenstock, J. et al. Empagliflozin as adjunctive to insulin therapy in type 1 diabetes: the EASE trials. Diabetes Care 41, 2560–2569 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Phillip, M. et al. Long-term efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes: pooled 52-week outcomes from the DEPICT-1 and -2 studies. Diabetes Obes. Metab. 23, 549–560 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Sands, A. T. et al. Sotagliflozin, a dual SGLT1 and SGLT2 inhibitor, as adjunct therapy to insulin in type 1 diabetes. Diabetes Care 38, 1181–1188 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Garg, S. K. et al. Effects of sotagliflozin added to insulin in patients with type 1 diabetes. N. Engl. J. Med. 377, 2337–2348 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Buse, J. B. et al. Sotagliflozin in combination with optimized insulin therapy in adults with type 1 diabetes: the North American inTandem1 study. Diabetes Care 41, 1970–1980 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • van Raalte, D. H. et al. The impact of sotagliflozin on renal function, albuminuria, blood pressure, and hematocrit in adults with type 1 diabetes. Diabetes Care 42, 1921–1929 (2019).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cherney, D. Z. I. et al. Kidney effects of empagliflozin in people with type 1 diabetes. Clin. J. Am. Soc. Nephrol. 16, 1715–1719 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Stougaard, E. B., Rossing, P., Cherney, D., Vistisen, D. & Persson, F. Sodium-glucose cotransporter 2 inhibitors as adjunct therapy for type 1 diabetes and the benefit on cardiovascular and renal disease evaluated by Steno risk engines. J. Diabetes Complications 36, 108257 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wheeler, D. C. et al. Effects of dapagliflozin on major adverse kidney and cardiovascular events in patients with diabetic and non-diabetic chronic kidney disease: a prespecified analysis from the DAPA-CKD trial. Lancet Diabetes Endocrinol. 9, 22–31 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Semaglutide effects on heart disease and stroke in patients with overweight or obesity (SELECT). ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03574597 (2024).

  • Semaglutide and albuminuria reduction trial in obese individuals without diabetes (SMART). ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04889183 (2023).

  • A trial to learn how well finerenone works and how safe it is in adult participants with non-diabetic chronic kidney disease (FIND-CKD). ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05047263 (2024).

  • Davies, M. J. et al. Management of hyperglycemia in type 2 diabetes, 2022. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 45, 2753–2786 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kidney Disease: Improving Global Outcomes Diabetes Work G. KDIGO 2022 clinical practice guideline for diabetes management in chronic kidney disease. Kidney Int. 102, S1–S127 (2022).

    Article 

    Google Scholar
     

  • Joseph, J. J. et al. Comprehensive management of cardiovascular risk factors for adults with type 2 diabetes: a scientific statement from the American Heart Association. Circulation 145, e722–e759 (2022).

    Article 
    PubMed 

    Google Scholar
     

  • Blonde, L. et al. American Association of Clinical Endocrinology clinical practice guideline: developing a diabetes mellitus comprehensive care plan — 2022 update. Endocr. Pract. 28, 923–1049 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • American Diabetes Association Professional Practice C. 11. Chronic kidney disease and risk management: standards of medical care in diabetes — 2022. Diabetes Care 45, S175–S184 (2022).

    Article 

    Google Scholar
     

  • de Boer, I. H. et al. Diabetes management in chronic kidney disease: a consensus report by the American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO). Diabetes Care 45, 3075–3090 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • van der Sande, N. G. et al. Individualized prediction of the effect of angiotensin receptor blockade on renal and cardiovascular outcomes in patients with diabetic nephropathy. Diabetes Obes. Metab. 18, 1120–1127 (2016).

    Article 
    PubMed 

    Google Scholar
     

  • Tye, S. C. et al. Initiation of the SGLT2 inhibitor canagliflozin to prevent kidney and heart failure outcomes guided by HbA1c, albuminuria, and predicted risk of kidney failure. Cardiovasc. Diabetol. 21, 194 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chertow, G. M. et al. Effects of dapagliflozin in chronic kidney disease, with and without other cardiovascular medications: DAPA-CKD trial. J. Am. Heart Assoc. 12, e028739 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Curovic, V. R. et al. Optimization of albuminuria-lowering treatment in diabetes by crossover rotation to four different drug classes: a randomized crossover trial. Diabetes Care 46, 593–601 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • A research study to see how semaglutide works compared to placebo in people with type 2 diabetes and chronic kidney disease (FLOW). ClinicalTrials.gov https://clinicaltrials.gov/study/NCT03819153 (2024).

  • Heerspink, H. J. L. et al. Design of FLAIR: a phase 2b study of the 5-lipoxygenase activating protein inhibitor AZD5718 in patients with proteinuric CKD. Kidney Int. Rep. 6, 2803–2810 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • A phase 2b diabetic kidney disease study. ClinicalTrials.gov https://clinicaltrials.gov/study/NCT04170543 (2023).

  • Frimodt-Moller, M., Persson, F. & Rossing, P. Mitigating risk of aldosterone in diabetic kidney disease. Curr. Opin. Nephrol. Hypertens. 29, 145–151 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Stasch, J. P., Schlossmann, J. & Hocher, B. Renal effects of soluble guanylate cyclase stimulators and activators: a review of the preclinical evidence. Curr. Opin. Pharmacol. 21, 95–104 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Fantus, D., Rogers, N. M., Grahammer, F., Huber, T. B. & Thomson, A. W. Roles of mTOR complexes in the kidney: implications for renal disease and transplantation. Nat. Rev. Nephrol. 12, 587–609 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    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 
    CAS 
    PubMed 

    Google Scholar
     

  • Hammoud, R. & Drucker, D. J. Beyond the pancreas: contrasting cardiometabolic actions of GIP and GLP1. Nat. Rev. Endocrinol. 19, 201–216 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • A study of tirzepatide (LY3298176) in participants with overweight or obesity and chronic kidney disease with or without type 2 diabetes (TREASURE-CKD). ClinicalTrials.gov https://clinicaltrials.gov/study/NCT05536804 (2024).

  • Ruiz-Andres, O. et al. Downregulation of kidney protective factors by inflammation: role of transcription factors and epigenetic mechanisms. Am. J. Physiol. Renal Physiol. 311, F1329–F1340 (2016).

    Article 
    PubMed 

    Google Scholar
     

  • Mora-Fernandez, C. et al. Sodium-glucose co-transporter-2 inhibitors increase Klotho in patients with diabetic kidney disease: a clinical and experimental study. Biomed. Pharmacother. 154, 113677 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar