Chronic kidney disease in type 2 diabetics and findings from the EMPA-KIDNEY study

Česká verzia

Authors: Emil Martinka
Authors place of work: Národný endokrinologický a diabetologický ústav, n. o., Ľubochňa
Published in the journal: Forum Diab 2023; 12(1): 39-45
Category:

Summary

Chronic kidney disease (CKD) is a frequent and serious complication in patients with type 2 diabetes mellitus, affecting 38 to 68% of patients according to data in the literature. In addition, the presence of CKD is associated with significantly higher morbidity and mortality rates and it also significantly complicates therapeutic approaches. As eGF values decrease and albuminuria increases, patient mortality from cardiovascular (CV) and other causes increases. It is therefore urgent for the diabetologist to address the issue of CKD both in terms of preventing its development (primary prevention) and slowing the progression of pre-existing CKD (secondary prevention), which involves intensive collaboration with a nephrologist. The EMPA-KIDNEY study, conducted in a population of patients with different causes of CKD, estimated glomerular filtration rate (eGF) and albuminuria levels, showed that treatment with empagliflozin, compared to placebo, contributed to a 28% reduction in the risk of CKD progression or death from CV causes, with no indications of significant safety issue. The benefit of empagliflozin treatment was demonstrated regardless of the presence or absence of diabetes and baseline eGF values. The outcomes were not influenced by CKD etiology (with the exception of a less convincing result in hypertensive/renovascular CKD), baseline HbA_1c, the presence of previous CV disease or the use of RAASi at the time of randomization, which provides further support for a wider use of SGLT2i, also based on renal indication. However, the results of subgroup analyses showed that the effect of empagliflozin treatment was less evident in patients not receiving RAASi. Furthermore, the benefit of empagliflozin treatment was greater in patients with stage A3 albuminuria at the start of the study, whereas no significant difference between treatment with empagliflozin and placebo was observed in patients with normal or only mild albuminuria with a UACR of 30–300 mg/g, which was probably due to the lower risk of CKD progression in these patients. Finally, although the benefit of empagliflozin treatment was established independently of the presence / absence of diabetes mellitus, it was demonstrated to a lesser extent in patients without diabetes. These findings from the analyses of the effect of SGLT2i on CKD progression in relation to eGF, albuminuria, and the presence of diabetes, may therefore contribute to a more precise guidance on a more effective treatment as well as a better understanding of the mechanisms of renoprotection. In summary, we currently have three groups of drugs that have been proven to reduce the risk of progression of renal failure, each of them in a specific way. These groups involve the renin-angiotensin aldosterone system inhibitors (RAASi), the sodium-glucose cotransporter inhibitors (SGLT2i), and the non-steroidal mineralocorticoid receptor antagonist, finerenone. Empagliflozin is a drug from the SGLT2i group with the confirmed CV and renal benefit, making these drugs the preferred choice for the pharmacological treatment of DM2T, not only in patients with the already developed CV disease related to atherosclerosis, heart failure or CKD (secondary prevention), but also in patients receiving primary prevention. The EMPA-KIDNEY study provides further relevant evidence which significantly strengthens the preference for SGLT2i.

Keywords:

chronic kidney disease – CKD – empagliflosin – EMPA-KIDNEY

Zdroje

1. Cooper ME, Brownlee M, Susztak K et al. Diabetic kidney disease Nat Rev Dis Primers 2015; 1: 15018. Dostupné z DOI: <http://dx.doi.org/10.1038/nrdp.2015.18>.

2. Martinka E. Kardiovaskulárna morbidita a mortalita pacientov s diabetes mellitus 2. typu na Slovensku: výsledky štúdie NEFRITI II. Edukačný portál SDiA 2019. Dostupné z WWW: <http:// www.lekar.sdia.sk/sdia-lekarske-profesne-zdruzenie-aktuality/170/kardiovaskularna-morbidita-a-mortalita-pacientov-s-diabetes-mellitus-2-typu-na-slovensku-vysledky-studie-nefriti-ii/>.

3. Martinka E. CARERA (CArdiovascular and REnal Risk Assessment): prieskum kardiovaskulárneho rizika u pacientov s diabetes mellitus 2. typu na Slovensku. Dostupné z WWW: <http:// www.lekar.sdia.sk/sdia-lekarske-profesne-zdruzenie-aktuality/33/carera-cardiovascular-and-renal-risk-assessment-prieskum-kardiovaskularneho-rizika-u-pacientov-s-diabetes-mellitus-2-typu-na-lovensku/>.

4. Thomas MC, Cooper ME, Zimmet P. Changing epidemiology of type 2 diabetes mellitus and associated chronic kidney disease. Nat Rev Nephrol 2016; 12(2): 73–81. Dostupné z DOI: <http://dx.doi.org/10.1038/nrneph.2015.173>.

5. Toth-Manikowski S, Atta MG. Diabetic Kidney Disease: Pathophysiology and Therapeutic Targets. J Diabetes Res 2015; 2015: 697010. Dostupné z DOI: <http://dx.doi.org/10.1155/2015/697010>.

6. Stewart JH, McCredie MR, Williams SM et al. Trends in incidence of treated end‐stage renal disease, overall and by primary renal disease, in persons aged 20–64 years in Europe, Canada and the Asia‐Pacific region, 1998–2002. Nephrology (Carlton) 2007; 12(5): 520–527. Dostupné z DOI: <http://dx.doi.org/10.1111/j.1440–1797.2007.00830.x>.

7. Jager KJ, Kovesdy C, Langham R et al. A single number for advocacy and communication-worldwide more than 850 million individuals have kidney diseases. Nephrol Dial Transplant 2019; 34(11): 1803–1805. Dostupné z DOI: <http://dx.doi.org/10.1093/ndt/gfz174>.

8. Kottgen A, Russell SD, Loehr LR et al. Reduced kidney function as a risk factor for incident heart failure: The Atherosclerosis Risk in Communities (ARIC) study. J Am Soc Nephrol 2007; 18(4): 1307–1315. Dostupné z DOI: <http://dx.doi.org/10.1681/ASN.2006101159>.

9. Damman K, Valente MA, Voors AA et al. Renal impairment, worsening renal function, and outcome in patients with heart failure: An updated meta-analysis. Eur Heart J 2014; 35(7): 455–469. Dostupné z DOI: <http://dx.doi.org/10.1093/eurheartj/eht386>.

10. House AA, Wanner C, Sarnak MJ et al. [Conference Participants]. Heart failure in chronic kidney disease: Conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int 2019; 95(6): 1304–1317. Dostupné z DOI: <http://dx.doi.org/10.1016/j.kint.2019.02.022>.

11. United States Renal Data System. 2021 USRDS Annual Data Report. 2021. Dostupné z WWW: <https://adr.usrds.org/2021>. [10–2022].

12. Zinman B, Wanner Ch, Lachin JM et al. [EMPA-REG OUTCOME Investigators]. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med 2015; 373(22): 2117–2128. Dostupné z DOI: <http://dx.doi.org/10.1056/NEJMoa1504720>.

13. Wanner C, Inzucchi SE, Lachin JM et al. [EMPA-REG OUTCOME Investigators]. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med 2016; 375(4): 323–334. Dostupné z DOI: <http://dx.doi.org/10.1056/NEJMoa1515920>.

14. Herrington WG, Preiss D, Haynes R et al. The potential for improving cardiorenal outcomes by sodium-glucose cotransporter-2 inhibition in people with chronic kidney disease: a rationale for the EMPA-KIDNEY study. Clin Kidney J 2018; 11(6):749–761 Dostupné z DOI: <http://dx.doi.org/10.1093/ckj/sfy090>.

15. Cherney DZ, Inzucchi SE, Zinman B et al. Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease: an exploratory analysis from the EMPA-REG OUTCOME randomised, placebo-controlled trial. Lancet Diabetes Endocrinol 2017; 5(8): 610–621. Dostupné z DOI: <http://dx.doi.org/10.1016/S2213–587(17)30182–1>.

16. Herrington WG, Staplin N, Wanner C et al. [EMPA-KIDNEY Collaborative Group]. Empagliflozin in Patients with Chronic Kidney Disease. N Engl J Med 2023; 388(2): 117–127. Dostupné z DOI: <http://dx.doi.org/10.1056/NEJMoa2204233>.

17. Perkovic V, Jardine MJ, Neal B et al. [CREDENCE Trial Investigators]. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019; 380(24): 2295–2306. Dostupné z DOI: <http://dx.doi.org/10.1056/NEJMoa1811744>.

18. Heerspink HJ, Stefánsson BV, CorreaRotter R et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med 2020; 383(15): 1436–46. Dostupné z DOI: <http://dx.doi.org/10.1056/NEJMoa2024816>-

19. Wheeler DC, Stefánsson 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; 9(1): 22–31. Dostupné z DOI: <http://dx.doi.dx.org/10.1016/S2213–8587(20)30369–7>.

20. Staplin N, Haynes R, Mayne K et al. [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 cotransporter-2 (SGLT2) inhibitors on kidney outcomes: collaborative meta-analysis of large placebo-controlled trials. Lancet 2022; 400(10365): 1788–1801. Dostupné z DOI: <http://dx.doi.org/10.1016/S0140–6736(22)02074–8>.

21. August P. Chronic Kidney Disease — Another Step Forward. N Engl J Med 2023; 388(2): 179–180. Dostupné z DOI: <http://dx.doi.org/10.1056/NEJMe2215286>.

22. Levey AS, Stevens LA, Schmid CH et al. A new equation to estimate glomerular filtration rate. Ann Intern Med 2009; 150(9): 604–612. Dostupné z DOI: <http://dx.doi.org/10.7326/0003–4819–150–9-200905050–00006>.

23. Herrington WG, Staplin N, Wanner C et al. [EMPA-KIDNEY Collaborative Group]. Empagliflozin in patients with chronic kidney disease. N Engl J Med 2023; 388(2): 117–127. Dostupné z DOI: <http://dx.doi.org/10.1056/NEJMoa2204233>.

24. Brenner BM, Cooper ME, de Zeeuw D et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345(12): 861–869. Dostupné z DOI: <http://dx.doi.org/10.1056/NEJMoa011161>.

25. Lewis EJ, Hunsicker LG, Clarke WR et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001; 345(12): 851–860. Dostupné z DOI: <http://dx.doi.org/10.1056/NEJMoa011303>.

26. Lewis EJ, Hunsicker LG, Bain RP et al. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med 1993; 329(20): 1456–1462. Dostupné z DOI: <http://dx.doi.org/10.1056/NEJM199311113292004>.

27. 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(23): 2219–2229. Dostupné z DOI: <http://dx.doi.org/10.1056/NEJMoa2025845>.

28. Pitt B, Filippatos G, Agarwal R et al. Cardiovascular events with finerenone in kidney disease and type 2 diabetes. N Engl J Med 2021; 385(24): 2252–2263. Dostupné z DOI: <http://dx.doi.org/10.1056/NEJMoa2110956>.

29. Fox CS, Matsushita K, Woodward M et al. Chronic Kidney Disease Prognosis Consortium. Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without diabetes: a meta-analysis. Lancet 2012; 380(9854):1662–1673. Dostupné z DOI: <http://doi: 10.1016/S0140-6736(12)61350-6>. Erratum in: Lancet 2013; 381(9864): 374. PMID: 23013602; PMCID: PMC3771350.