Effektive antidiabetische Therapie zur Vorbeugung einer diabetischen Nephropathie

ZUSAMMENFASSUNG

Die chronische Nierenkrankheit (CKD: „chronic kidney disease“) stellt eine der häufigsten Folgekomplikationen bei Menschen mit Diabetes mellitus dar und erhöht exzessiv die Morbidität und Mortalität. Daher ist die Vorbeugung einer Nephropathie von klinischer Bedeutung. Im Mittelpunkt der Therapie stand in den letzten Jahren die antihypertensive und nephroprotektive Therapie mit ACE-Hemmern (ACE: „angiotensin converting enzyme“) oder ATII1-Rezeptor-Antagonisten (ATII1: Angiotensin-II-Rezeptor Subtyp-1; Blockade des Renin-Angiotensin-Systems (RAS)) in der Kombination mit einer antiglykämischen und lipidsenkenden Therapie im Rahmen eines multimodalen Therapiekonzepts. Inzwischen zeigen Antidiabetika signifikante und intrinsische nephroprotektive Effekte, die über die reine Glukosesenkung hinausgehen. Als besonders potent haben sich dabei Hemmer des Natrium-Glukose-Kotransporters 2 (SGLT-2: „sodium glucose linked transporter 2“) und GLP1-Rezeptor-Agonisten (GLP1: „glucagon-like peptide 1“) herausgestellt. GLP1-Rezeptor-Agonisten reduzieren vor allem die Albuminurie bei Menschen mit Typ-2-Diabetes. SGLT-2-Hemmer verlangsamen auch den Abfall der glomerulären Filtrationsrate (GFR) über die Zeit und konnten diesen nephroprotektiven Effekt sowohl bei Menschen mit Diabetes als auch bei jenen ohne Diabetes zeigen. Entsprechend wird in Leitlinien für Menschen mit Diabetes mellitus Typ 2 und CKD oder erhöhtem kardialen Risiko empfohlen, neben Metformin und der RAS-Blockade, die Therapie mit SGLT-2-Hemmern und – sofern zur Glykämiesenkung notwendig – additiv GLP1-Rezeptor-Agonisten anzuwenden.

Publication History

Article published online:
20 July 2023

• Literatur

• 1 Thomas MC, Brownlee M, Susztak K. et al Diabetic kidney disease. Nat Rev Dis Primers 2015; 01: 15018 DOI: 10.1038/nrdp.2015.18.
• 2 Tancredi M, Rosengren A, Svensson AM. et al Excess mortality among persons with type 2 diabetes. N Engl J Med 2015; 373: 1720-1732 DOI: 10.1056/NEJMoa1504347.
• 3 Reitzle L, Schmidt C, Du Y. et al Einschätzungen zur Prävalenz mikrovaskulärer Folgeerkrankungen bei Diabetes mellitus in Deutschland. Analyse von Versichertendaten aller gesetzlichen Krankenkassen für die Jahre 2012 und 2013. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2020; 63: 1219-1230 DOI: 10.1007/s00103-020-03211-x.
• 4 Bundesärztekammer (BÄK) KBK, Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF). Nationale VersorgungsLeitlinie Typ-2-Diabetes – Teilpublikation der Langfassung (2021). Im Internet: www.leitlinien.de/diabetes DOI: 10.6101/AZQ/000475
• 5 UK Prospective Diabetes Study (UKPDS) Group Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998; 352: 854-865 DOI: 10.1016/S0140-6736(98)07037-8.
• 6 UK Prospective Diabetes Study (UKPDS) Group Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837-853 DOI: 10.1016/S0140-6736(98)07019-6.
• 7 Group AC, Patel A, MacMahon S. et al Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008; 358: 2560-2572 DOI: 10.1056/NEJMoa0802987.
• 8 Hemmingsen B, Lund SS, Gluud C. et al Targeting intensive glycaemic control versus targeting conventional glycaemic control for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2013 DOI: 10.1002/14651858.CD008143.pub3
• 9 Busch M, Lehmann T, Wolf G. et al Antidiabetic therapy and rate of severe hypoglycaemia in patients with type 2 diabetes and chronic kidney disease of different stages – a follow-up analysis of health insurance data from Germany. Exp Clin Endocrinol Diabetes 2021; 129: 821-830 DOI: 10.1055/a-1129-6699.
• 10 Cherney DZI, Bakris GL. Novel therapies for diabetic kidney disease. Kidney Int Suppl (2011) 2018; 08: 18-25 DOI: 10.1016/j.kisu.2017.10.005.
• 11 Zhao M, Sun S, Huang Z. et al Network meta-analysis of novel glucose-lowering drugs on risk of acute kidney injury. Clin J Am Soc Nephrol 2020; 16: 70-78 DOI: 10.2215/CJN.11220720.
• 12 Li S, Vandvik PO, Lytvyn L. et al SGLT-2 inhibitors or GLP-1 receptor agonists for adults with type 2 diabetes: a clinical practice guideline. BMJ 2021; 373: n1091 DOI: 10.1136/bmj.n1091.
• 13 DeFronzo RA, Norton L, Abdul-Ghani M. Renal, metabolic and cardiovascular considerations of SGLT2 inhibition. Nat Rev Nephrol 2017; 13: 11-26 DOI: 10.1038/nrneph.2016.170.
• 14 Novikov A, Vallon V. Sodium glucose cotransporter 2 inhibition in the diabetic kidney: an update. Curr Opin Nephrol Hypertens 2016; 25: 50-58 DOI: 10.1097/MNH.0000000000000187.
• 15 van Bommel EJ, Muskiet MH, Tonneijck L. et al SGLT2 inhibition in the diabetic kidney – from mechanisms to clinical outcome. Clin J Am Soc Nephrol 2017; 12: 700-710 DOI: 10.2215/CJN.06080616.
• 16 Tsapas A, Avgerinos I, Karagiannis T. et al Comparative effectiveness of glucose-lowering drugs for type 2 diabetes: a systematic review and network meta-analysis. Ann Intern Med 2020; 173: 278-286 DOI: 10.7326/M20-0864.
• 17 Busch M, Franke S, Ruster C. et al Advanced glycation end-products and the kidney. Eur J Clin Invest 2010; 40: 742-755 DOI: 10.1111/j.1365-2362.2010.02317.x.
• 18 DeFronzo RA, Reeves WB, Awad AS. Pathophysiology of diabetic kidney disease: impact of SGLT2 inhibitors. Nat Rev Nephrol 2021; 17: 319-334 DOI: 10.1038/s41581-021-00393-8.
• 19 Vasilakou D, Karagiannis T, Athanasiadou E. et al Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med 2013; 159: 262-274 DOI: 10.7326/0003-4819-159-4-201308200-00007.
• 20 Cherney DZ, Perkins BA, Soleymanlou N. et al Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation 2014; 129: 587-597 DOI: 10.1161/CIRCULATIONAHA.113.005081.
• 21 van Bommel EJM, Muskiet MHA, van Baar MJB. 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 2020; 97: 202-212 DOI: 10.1016/j.kint.2019.09.013.
• 22 Heerspink HJL, Stefansson BV, Correa-Rotter R. et al Dapagliflozin in patients with chronic kidney disease. N Engl J Med 2020; 383: 1436-1446 DOI: 10.1056/NEJMoa2024816.
• 23 Neal B, Perkovic V, Mahaffey KW. et al Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017 DOI: 10.1056/NEJMoa1611925
• 24 Perkovic V, Jardine MJ, Neal B. et al Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019; 380: 2295-2306 DOI: 10.1056/NEJMoa1811744.
• 25 Wheeler DC, Stefansson BV, Jongs N. 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 2021; 09: 22-31 DOI: 10.1016/S2213-8587(20)30369-7.
• 26 Schork A, Saynisch J, Vosseler A. et al Effect of SGLT2 inhibitors on body composition, fluid status and renin-angiotensin-aldosterone system in type 2 diabetes: a prospective study using bioimpedance spectroscopy. Cardiovasc Diabetol 2019; 18: 46 DOI: 10.1186/s12933-019-0852-y.
• 27 Richette P, Perez-Ruiz F, Doherty M. et al Improving cardiovascular and renal outcomes in gout: what should we target?. Nat Rev Rheumatol 2014; 10: 654-661 DOI: 10.1038/nrrheum.2014.124.
• 28 Chino Y, Samukawa Y, Sakai S. et al SGLT2 inhibitor lowers serum uric acid through alteration of uric acid transport activity in renal tubule by increased glycosuria. Biopharm Drug Dispos 2014; 35: 391-404 DOI: 10.1002/bdd.1909.
• 29 Anders HJ, Davis JM, Thurau K. Nephron protection in diabetic kidney disease. N Engl J Med 2016; 375: 2096-2098 DOI: 10.1056/NEJMcibr1608564.
• 30 Hesp AC, Schaub JA, Prasad PV. 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 2020; 98: 579-589 DOI: 10.1016/j.kint.2020.02.041.
• 31 Packer M. Mechanisms leading to differential hypoxia-inducible factor signaling in the diabetic kidney: modulation by SGLT2 inhibitors and hypoxia mimetics. Am J Kidney Dis 2021; 77: 280-286 DOI: 10.1053/j.ajkd.2020.04.016.
• 32 Marton A, Kaneko T, Kovalik JP. et al Organ protection by SGLT2 inhibitors: role of metabolic energy and water conservation. Nat Rev Nephrol 2021; 17: 65-77 DOI: 10.1038/s41581-020-00350-x.
• 33 Nuffield Department of Population Health Renal Studies Group, SGLT2 inhibitor Meta-Analysis Cardio-Renal Trialists’ Consortium 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 2022; 400: 1788-1801 DOI: 10.1016/S0140-6736(22)02074-8.
• 34 Packer M, Anker SD, Butler J. et al Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020; 383: 1413-1424 DOI: 10.1056/NEJMoa2022190.
• 35 Schulze PC, Bogoviku J, Westphal J. et al Effects of early empagliflozin initiation on diuresis and kidney function in patients with acute decompensated heart failure (EMPAG-HF). Circulation 2022; 146: 289-298 DOI: 10.1161/CIRCULATIONAHA.122.059038.
• 36 Navaneethan SD, Zoungas S, Caramori ML. et al Diabetes management in chronic kidney disease: synopsis of the KDIGO 2022 clinical practice guideline update. Ann Intern Med 2023 DOI: 10.7326/M22-2904
• 37 Wanner C, Inzucchi SE, Lachin JM. et al Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016; 375: 323-334 DOI: 10.1056/NEJMoa1515920.
• 38 Hopf M, Kloos C, Wolf G. et al Effectiveness and safety of SGLT2 inhibitors in clinical routine treatment of patients with diabetes mellitus type 2. J Clin Med 2021: 10 DOI: 10.3390/jcm10040571
• 39 Ninčević V, Omanović Kolarić T, Roguljić H. et al Renal benefits of SGLT 2 inhibitors and GLP-1 receptor agonists: evidence supporting a paradigm shift in the medical management of type 2 diabetes. Int J Mol Sci 2019: 20 DOI: 10.3390/ijms20235831
• 40 Yin W, Xu S, Wang Z. et al Recombinant human GLP-1(rhGLP-1) alleviating renal tubulointestitial injury in diabetic STZ-induced rats. Biochem Biophys Res Commun 2018; 495: 793-800 DOI: 10.1016/j.bbrc.2017.11.076.
• 41 Hendarto H, Inoguchi T, Maeda Y. et al GLP-1 analog liraglutide protects against oxidative stress and albuminuria in streptozotocin-induced diabetic rats via protein kinase A-mediated inhibition of renal NAD(P)H oxidases. Metabolism 2012; 61: 1422-1434 DOI: 10.1016/j.metabol.2012.03.002.
• 42 Gutzwiller JP, Hruz P, Huber AR. et al Glucagon-like peptide-1 is involved in sodium and water homeostasis in humans. Digestion 2006; 73: 142-150 DOI: 10.1159/000094334.
• 43 Sarafidis P, Ferro CJ, Morales E. et al SGLT-2 inhibitors and GLP-1 receptor agonists for nephroprotection and cardioprotection in patients with diabetes mellitus and chronic kidney disease. A consensus statement by the EURECA-m and the DIABESITY working groups of the ERA-EDTA. Nephrol Dial Transplant 2019; 34: 208-230 DOI: 10.1093/ndt/gfy407.
• 44 Kristensen SL, Rorth R, Jhund PS. 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 cardiovascular outcome trials. Lancet Diabetes Endocrinol 2019; 07: 776-785 DOI: 10.1016/S2213-8587(19)30249-9.
• 45 Gerstein HC, Sattar N, Rosenstock J. et al Cardiovascular and renal outcomes with efpeglenatide in type 2 diabetes. N Engl J Med 2021; 385: 896-907 DOI: 10.1056/NEJMoa2108269.
• 46 Zelniker TA, Wiviott SD, Raz I. et al Comparison of the effects of glucagon-like peptide receptor agonists and sodium-glucose cotransporter 2 inhibitors for prevention of major adverse cardiovascular and renal outcomes in type 2 diabetes mellitus. Circulation 2019; 139: 2022-2031 DOI: 10.1161/CIRCULATIONAHA.118.038868.
• 47 Bulum T. Nephroprotective properties of the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonists. Biomedicines 2022; 10: 2586 DOI: 10.3390/biomedicines10102586.
• 48 Heerspink HJL, Sattar N, Pavo I. 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 2022; 10: 774-785 DOI: 10.1016/S2213-8587(22)00243-1.
• 49 Mikov M, Pavlovic N, Stanimirov B. et al DPP-4 Inhibitors: Renoprotective potential and pharmacokinetics in type 2 diabetes mellitus patients with renal impairment. Eur J Drug Metab Pharmacokinet 2020; 45: 1-14 DOI: 10.1007/s13318-019-00570-y.
• 50 Wolf GB, Scherberich JE, Fischer P. et al Isolation and characterization of dipeptidyl aminopeptidase IV from human kidney cortex. Clin Chim Acta 1989; 179: 61-71 DOI: 10.1016/0009-8981(89)90023-5.
• 51 Girardi AC, Knauf F, Demuth HU. et al Role of dipeptidyl peptidase IV in regulating activity of Na+/H+ exchanger isoform NHE3 in proximal tubule cells. Am J Physiol Cell Physiol 2004; 287: C1238-1245 DOI: 10.1152/ajpcell.00186.2004.
• 52 Alter ML, Ott IM, von Websky K. et al DPP-4 inhibition on top of angiotensin receptor blockade offers a new therapeutic approach for diabetic nephropathy. Kidney Blood Press Res 2012; 36: 119-130 DOI: 10.1159/000341487.
• 53 Takashima S, Fujita H, Fujishima H. et al Stromal cell-derived factor-1 is upregulated by dipeptidyl peptidase-4 inhibition and has protective roles in progressive diabetic nephropathy. Kidney Int 2016; 90: 783-796 DOI: 10.1016/j.kint.2016.06.012.
• 54 Mosenzon O, Leibowitz G, Bhatt DL. et al Effect of saxagliptin on renal outcomes in the SAVOR-TIMI 53 trial. Diabetes Care 2017; 40: 69-76 DOI: 10.2337/dc16-0621.
• 55 Zhuo M, Paik JM, Wexler DJ. et al SGLT2 inhibitors and the risk of acute kidney injury in older adults with type 2 diabetes. Am J Kidney Dis 2022; 79: 858-867e1 DOI: 10.1053/j.ajkd.2021.09.015.
• 56 De Broe ME, Kajbaf F, Lalau JD. Renoprotective effects of metformin. Nephron 2018; 138: 261-274 DOI: 10.1159/000481951.
• 57 Lalau JD, Kajbaf F, Bennis Y. et al Metformin treatment in patients with type 2 diabetes and chronic kidney disease stages 3 A, 3B, or 4. Diabetes Care 2018; 41: 547-553 DOI: 10.2337/dc17-2231.
• 58 Group GSR, Nathan DM, Lachin JM. et al Glycemia reduction in type 2 diabetes – microvascular and cardiovascular outcomes. N Engl J Med 2022; 387: 1075-1088 DOI: 10.1056/NEJMoa2200436.
• 59 Cannon CP, Pratley R, Dagogo-Jack S. et al Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med 2020; 383: 1425-1435 DOI: 10.1056/NEJMoa2004967.
• 60 Cherney DZI, Charbonnel B, Cosentino F. et al Effects of ertugliflozin on kidney composite outcomes, renal function and albuminuria in patients with type 2 diabetes mellitus: an analysis from the randomised VERTIS CV trial. Diabetologia 2021; 64: 1256-1267 DOI: 10.1007/s00125-021-05407-5.
• 61 Mosenzon O, Wiviott SD, Cahn A. et al Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: an analysis from the DECLARE-TIMI 58 randomised trial. Lancet Diabetes Endocrinol 2019; 07: 606-617 DOI: 10.1016/S2213-8587(19)30180-9.
• 62 Bhatt DL, Szarek M, Pitt B. et al Sotagliflozin in patients with diabetes and chronic kidney disease. N Engl J Med 2021; 384: 129-139 DOI: 10.1056/NEJMoa2030186. The EMPA-KIDNEY Collaborative Group
• 63 Herrington WG, Staplin N. et al Empagliflozin in patients with chronic kidney disease. N Engl J Med 2023; 388: 117-127 DOI: 10.1056/NEJMoa2204233.