Diabetic nephropathy secondary prevention

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Robert G. Badgett, M.D.[2]

Overview

Once diabetic nephropathy develops, secondary prevention to halt the progression of the disease is aimed at:

  • Renin-angiotensin-aldosterone system (RAAS) with ACE inhibitors or angiotensin II receptor antagonists, the Cochrane Collaboration reported a reduction in renal outcomes[1]. This includes a regression to normoalbuminuria (in analysis 1.6 regression was found in 201/995 [20%]; risk ratio 3.06).
    • Per the Cochrane, this benefit is not affected by moderately increased albuminuria (30 to 300 mg/day; A2 or microalbuminuria) or severely increased albuminuria (>300 mg/day; A3 or microalbuminuria)[1]
    • Whether this applies to patients without hypertension is unclear:
      • The Cochrane reported, "presence (versus absence) of hypertension in the enrolled populations did not significantly impact...doubling of serum creatinine (interaction P value = 0.22)"[1] However, the Cochrane did not report the data underlying this analysis.
      • The KDIGO guideline reports that only two trials included patients without hypertension (RENAAL[2] and INNOVATION[3]). The INNOVATION trial reported significant reduction in urine microalbuminuria from telmisartan regardless of whether hypertension was present[3].

Second step:

  • Sodium-glucose co-transporter 2 inhibitors (SGLTi), which may be more effective than mineralocorticoid receptor antagonists (MRAs)[4]:
    • Canagliflozin educes the risk of kidney failure and cardiovascular events in the CREDENCE randomized control trial of patients with diabetic kidney disease (urinary albumin-to-creatinine ratio > 300) who were almost all hypertensive and already taking ACE inhibitors.[5].
    • Empagliflozin, in the EMPA-REG trial reduced renal outcomes even with patients with cardiovascular disease 80% also taking ACE inhibitors or renin inhibitors, whose urinary albumin-to-creatinine ratio < 30[6] Among patients with no albuminuria (urinary albumin-to-creatinine ratio, <30 at baseline), empagliflozin did not reduce incident albuminuria (urinary albumin-to-creatinine ratio, ≥30).
    • It is not clear why the KDIGO guidelines recommend SGLT2i for all patients with albuminuria when some patients taking ACE inhibitors only will have regression to normoalbuminuria.

Third step:

Other approaches

References

  1. 1.0 1.1 1.2 Strippoli GF, Bonifati C, Craig M, Navaneethan SD, Craig JC (2006). "Angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists for preventing the progression of diabetic kidney disease". Cochrane Database Syst Rev (4): CD006257. doi:10.1002/14651858.CD006257. PMC 6956646 Check |pmc= value (help). PMID 17054288.
  2. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH; et al. (2001). "Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy". N Engl J Med. 345 (12): 861–9. doi:10.1056/NEJMoa011161. PMID 11565518. Review in: ACP J Club. 2002 May-Jun;136(3):82-4
  3. 3.0 3.1 Makino H, Haneda M, Babazono T, Moriya T, Ito S, Iwamoto Y; et al. (2008). "Microalbuminuria reduction with telmisartan in normotensive and hypertensive Japanese patients with type 2 diabetes: a post-hoc analysis of The Incipient to Overt: Angiotensin II Blocker, Telmisartan, Investigation on Type 2 Diabetic Nephropathy (INNOVATION) study". Hypertens Res. 31 (4): 657–64. doi:10.1291/hypres.31.657. PMID 18633177.
  4. 4.0 4.1 Yang S, Zhao L, Mi Y, He W (2022). "Effects of sodium-glucose cotransporter-2 inhibitors and aldosterone antagonists, in addition to renin-angiotensin system antagonists, on major adverse kidney outcomes in patients with type 2 diabetes and chronic kidney disease: A systematic review and network meta-analysis". Diabetes Obes Metab. doi:10.1111/dom.14801. PMID 35712807 Check |pmid= value (help).
  5. Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM; et al. (2019). "Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy". N Engl J Med. 380 (24): 2295–2306. doi:10.1056/NEJMoa1811744. PMID 30990260. Review in: BMJ Evid Based Med. 2020 Apr;25(2):79-80 Review in: Ann Intern Med. 2019 Aug 20;171(4):JC15
  6. Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M; et al. (2016). "Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes". N Engl J Med. 375 (4): 323–34. doi:10.1056/NEJMoa1515920. PMID 27299675. Review in: Ann Intern Med. 2016 Oct 18;165(8):JC39 Review in: Evid Based Med. 2017 Apr;22(2):69-70
  7. Agarwal R, Kolkhof P, Bakris G, Bauersachs J, Haller H, Wada T; et al. (2021). "Steroidal and non-steroidal mineralocorticoid receptor antagonists in cardiorenal medicine". Eur Heart J. 42 (2): 152–161. doi:10.1093/eurheartj/ehaa736. PMC 7813624 Check |pmc= value (help). PMID 33099609 Check |pmid= value (help).
  8. Bakris GL, Agarwal R, Anker SD, Pitt B, Ruilope LM, Rossing P; et al. (2020). "Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes". N Engl J Med. 383 (23): 2219–2229. doi:10.1056/NEJMoa2025845. PMID 33264825 Check |pmid= value (help).
  9. Pitt B, Filippatos G, Agarwal R, Anker SD, Bakris GL, Rossing P; et al. (2021). "Cardiovascular Events with Finerenone in Kidney Disease and Type 2 Diabetes". N Engl J Med. 385 (24): 2252–2263. doi:10.1056/NEJMoa2110956. PMID 34449181 Check |pmid= value (help).
  10. Ruospo M, Saglimbene VM, Palmer SC, De Cosmo S, Pacilli A, Lamacchia O; et al. (2017). "Glucose targets for preventing diabetic kidney disease and its progression". Cochrane Database Syst Rev. 6: CD010137. doi:10.1002/14651858.CD010137.pub2. PMC 6481869. PMID 28594069. Review in: Ann Intern Med. 2017 Oct 17;167(8):JC47 Review in: Evid Based Med. 2017 Dec;22(6):219-220
  11. Chamberlain JJ, Rhinehart AS, Shaefer CF, Neuman A (2016). "Diagnosis and Management of Diabetes: Synopsis of the 2016 American Diabetes Association Standards of Medical Care in Diabetes". Ann. Intern. Med. 164 (8): 542–52. doi:10.7326/M15-3016. PMID 26928912.

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