Blutdrucksenkende pleiotrope Effekte antidiabetischer Medikamente

ZUSAMMENFASSUNG

In den letzten Jahren haben sich einige Medikamente hervorgetan, die unabhängig von ihrer primären Indikation einen protektiven Effekt auf die Nierenfunktion ausüben können. Für Nephrologen besonders interessant ist dabei der nephroprotektive Effekt, den die Inhibitoren des Natrium Glukose Kotransporters 2 (SGLT-2: „sodium glucose linked transporter 2“) wie Empagliflozin, Canagliflozin und Dapagliflozin ausüben, unabhängig von ihrem Einfluss auf den Blutzucker und wie wir seit der Studie DAPA-CKD wissen – sogar bei Patienten ohne Diabetes mellitus. Auch die modernen, nichtsteroidalen Mineralokortikoid-Rezeptor-Antagonisten wie Finerenon und Esaxerenon machten hinsichtlich ihrer Nephroprotektion auf sich aufmerksam, unabhängig von ihrer primären Indikation für die Therapie der Herzinsuffizienz und bisweilen der arteriellen Hypertonie. Ursächlich sind hierfür pharmakologische „Mehrfachwirkungen“, die pleiotrope Effekte genannt werden und einen vielschichten Eingriff in die (Patho-)Physiologie des Organismus ermöglichen. Die Therapie der arteriellen Hypertonie erfordert eine synergistische Kombination und stellt einen Angelpunkt in der kardiorenalen Achse dar. Deshalb sollen an diesem Beispiel die pleiotropen Effekte von SGLT-2-Inhibitoren, Mineralokortikoid-Rezeptor-Antagonisten und GLP-1-Agonisten (GLP-1: „glucagon-like peptide 1“) sowie deren klinische Implikationen beleuchtet werden.

Publication History

Article published online:
16 November 2021

• Literatur

• 1 Action to Control Cardiovascular Risk in Diabetes Study Group Gerstein HC, Miller ME. et al Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358: 2545-2459 DOI: 10.1056/NEJMoa0802743.
• 2 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.
• 3 Zinman B, Wanner C, Lachin JM. et al Empagliflozin, cardio-vascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015; 373: 2117-2128 DOI: 10.1056/NEJMoa1504720.
• 4 Onishi A, Fu Y, Patel R. et al A role for tubular Na + /H + exch-anger NHE3 in the natriuretic effect of the SGLT2 inhibitor empagliflozin. Am J Physiol Renal Physiol 2020; 319: F712-F728 DOI: 10.1152/ajprenal.00264.2020.
• 5 Carraro-Lacroix LR, Malnic G, Girardi AC. Regulation of Na + /H + exchanger NHE3 by glucagon-like peptide 1 recep-tor agonist exendin-4 in renal proximal tubule cells. Am J Physiol Renal Physiol 2009; 297: F1647-F1655 DOI: 10.1152/ajprenal.00082.2009.
• 6 Inzucchi SE, Zinman B, Fitchett D. et al How does empagliflo-zin reduce cardiovascular mortality? Insights from a media-tion analysis of the EMPA-REG OUTCOME trial. Diabetes Care 2018; 41: 356-363 DOI: 10.2337/dc17-1096.
• 7 Skov J, Holst JJ, Gøtze JP. et al Glucagon-like peptide-1: effect on pro-atrial natriuretic peptide in healthy males. Endocr Connect 2014; 3: 11-16 DOI: 10.1530/EC-13-0087.
• 8 Alvarez-Alvarez B, Abad-Cardiel M, Fernandez-Cruz A. et al Management of resistant arterial hypertension: role of spiro-nolactone versus double blockade of the renin-angioten-sin-aldosterone system. J Hypertens 2010; 28: 2329-2335 DOI: 10.1097/HJH.0b013e32833d4c99.
• 9 Ito S, Itoh H, Rakugi H. et al Antihypertensive effects and safety of esaxerenone in patients with moderate kidney dys-function. Hypertens Res 2021; 44: 489-497 DOI: 10.1038/s41440-020-00585-y.
• 10 Bailey CJ. Uric acid and the cardio-renal effects of SGLT2 inhibitors. Diabetes Obes Metab 2019; 21: 1291-1298 DOI: 10.1111/dom.13670.
• 11 Novikov A, Fu Y, Huang W. et al SGLT2 inhibition and renal urate excretion: role of luminal glucose, GLUT9, and URAT1. Am J Physiol Renal Physiol 2019; 316: F173-F185 DOI: 10.1152/ajprenal.00462.2018.
• 12 Doria A, Galecki AT, Spino C. et al Serum urate lowering with allopurinol and kidney function in type 1 diabetes. N Engl J Med 2020; 382: 2493-2503 DOI: 10.1056/NEJMoa1916624.
• 13 Feig DI. Urate-lowering therapy and chronic kidney disease progression. N Engl J Med 2020; 382: 2567-2568 DOI: 10.1056/NEJMe2015886.
• 14 Griendling KK, Camargo LL, Rios FJ. et al Oxidative stress and hypertension. Circ Res 2021; 128: 993-1020 DOI: 10.1161/CIRCRESAHA.121.318063.
• 15 Spencer S, Wheeler-Jones C, Elliott J. Aldosterone and the mineralocorticoid receptor in renal injury: A potential thera-peutic target in feline chronic kidney disease. J Vet Pharma-col Ther 2020; 43: 243-267 DOI: 10.1111/jvp.12848.
• 16 Dutzmann J, Musmann RJ, Haertlé M.. et al The novel mi-neralocorticoid receptor antagonist finerenone attenuates neointima formation after vascular injury. PLoS One 2017; 12: e018-4888 DOI: 10.1371/journal.pone.0184888.
• 17 González-Blázquez R, Somoza B, Gil-Ortega M. et al Fine-renone attenuates endothelial dysfunction and albuminuria in a chronic kidney disease model by a reduction in oxidative Stress. Front Pharmacol 2018; 9: 1131 DOI: 10.3389/fphar.2018.01131.
• 18 Currie G, Taylor AH, Fujita T. et al Effect of mineralocorticoid receptor antagonists on proteinuria and progression of chronic kidney disease: a systematic review and meta-analy-sis. BMC Nephrol 2016; 17: 127 DOI: 10.1186/s12882-016-0337-0.
• 19 Morales PE, Torres G, Sotomayor-Flores C. et al GLP-1 pro-motes mitochondrial metabolism in vascular smooth muscle cells by enhancing endoplasmic reticulum-mitochondria coupling. Biochem Biophys Res Commun 2014; 446: 410-416 DOI: 10.1016/j.bbrc.2014.03.004.
• 20 Helmstädter J, Frenis K, Filippou K. et al Endothelial GLP-1 (glucagon-like peptide-1) receptor mediates cardiovascular protection by liraglutide in mice with experimental arterial hypertension. Arterioscler Thromb Vasc Biol 2020; 40: 145-158 DOI: 10.1161/atv.0000615456.97862.30.
• 21 Cai X, Yang W, Gao X. et al The association between the dosage of SGLT2 inhibitor and weight reduction in type 2 diabetes patients: a meta-analysis. Obesity (Silver Spring) 2018; 26: 70-80 DOI: 10.1002/oby.22066.
• 22 Frías JP, Guja C, Hardy E. et al Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alo-ne in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): a 28 week, multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol 2016; 4: 1004-1016 DOI: 10.1016/S2213-8587(16)30267-4. Erratum in: Lancet Diabetes Endocrinol 2017; 5: e8
• 23 Lundkvist P, Sjöström CD, Amini S. et al Dapagliflozin once-daily and exenatide once-weekly dual therapy: A 24-week randomized, placebo-controlled, phase II study examining effects on body weight and prediabetes in obese adults without diabetes. Diabetes Obes Metab 2017; 19: 49-60 DOI: 10.1111/dom.12779.
• 24 Ebrahim S, Smith GD. Lowering blood pressure: a systematic review of sustained effects of non-pharmacological interven-tions J Public Health Med 1998; 20: 441-418 DOI: 10.1093/oxfordjournals.pubmed.a024800.
• 25 Mazidi M, Rezaie P, Gao HK. et al Effect of Sodium-glucose cotransport-2 inhibitors on blood pressure in people with type 2 diabetes mellitus: a systematic review and meta-analysis of 43 randomized control trials with 22528 patients. J Am Heart Assoc 2017; 6: e004007 DOI: 10.1161/JAHA.116.004007.
• 26 Bakris GL, Agarwal R, Chan JC. et al Effect of finerenone on albuminuria in patients with diabetic nephropathy: a rando-mized clinical trial. JAMA 2015; 314: 884-94 DOI: 10.1001/jama.2015.10081.
• 27 DelOlmo-Garcia MI, Merino-Torres JF. GLP-1 receptor agonists and cardiovascular disease in patients with type 2 diabetes. J Diabetes Res 2018; 2018: 4020492 DOI: 10.1155/2018/4020492.
• 28 Sun F, Wu S, Guo S. et al Impact of GLP-1 receptor agonists on blood pressure, heart rate and hypertension among pati-ents with type 2 diabetes: a systematic review and network meta-analysis. Diabetes Res Clin Pract 2015; 110: 26-37 DOI: 10.1016/j.diabres.2015.07.015.
• 29 Neal B, Perkovic V, Mahaffey KW. et al Canagliflozin and car-diovascular and renal events in type 2 diabetes. N Engl J Med 2017; 377: 644-657 DOI: 10.1056/NEJMoa1611925.
• 30 Tikkanen I, Narko K, Zeller C. et al Empagliflozin reduces blood pressure in patients with type 2 diabetes and hyper-tension. Diabetes Care 2015; 38: 420-428 DOI: 10.2337/dc14-1096.
• 31 Wiviott SD, Raz I, Bonaca MP. et al Dapagliflozin and cardi-ovascular outcomes in type 2 diabetes. N Engl J Med 2019; 380: 347-357 DOI: 10.1056/NEJMoa1812389.
• 32 Bakris GL, Agarwal R, Anker SD. et al Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med 2020; 383: 2219-2229 DOI: 10.1056/NEJMoa2025845.
• 33 Ito S, Itoh H, Rakugi H. et al Double-blind randomized phase 3 study comparing esaxerenone (CS-3150) and eplerenone in patients with essential hypertension (ESAX-HTN Study). Hypertension 2020; 75: 51-58 DOI: 10.1161/HYPERTENSIO-NAHA.119.13569.
• 34 Ito S, Itoh H, Rakugi H. et al Antihypertensive effects and safety of esaxerenone in patients with moderate kidney dys-function. Hypertens Res 2021; 44: 489-497 DOI: 10.1038/s41440-020-00585-y.
• 35 Marso SP, Daniels GH, Brown-Frandsen K. et al Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016; 375: 311-322 DOI: 10.1056/NEJMoa1603827.
• 36 Pfeffer MA, Claggett B, Diaz R. et al Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med 2015; 373: 2247-2257 DOI: 10.1056/NEJMoa1509225.
• 37 Marsom SP, Bain SC, Consoli A. et al Semaglutide and cardio-vascular outcomes in patients with type 2 diabetes. N Engl J Med 2016; 375: 1834-1844 DOI: 10.1056/NEJMoa1607141.
• 38 Husain M, Birkenfeld AL, Donsmark M. et al Oral semaglu-tide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2019; 381: 841-851 DOI: 10.1056/NEJMoa1901118.