Skip to main content

Effects of renin–angiotensin system blockers on renal and cardiovascular outcomes in patients with diabetic nephropathy: a meta-analysis of randomized controlled trials

Abstract

Purpose

This study aimed to evaluate the effect f angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) on renal or cardiovascular outcomes in patients with diabetic nephropathy (DN).

Methods

PubMed, Embase, and Cochrane Library were searched for randomized controlled trials (RCTs) evaluating the treatment effects of ACEI and ARB on renal or cardiovascular outcomes in patients with DN until August 2017. The outcomes included end-stage renal disease (ESRD), doubling of serum creatinine levels, all-cause mortality, major cardiovascular events (MACEs), myocardial infarction (MI), stroke, and cardiac death. Relative risks (RR) with 95% confidence intervals (CIs) were used for calculating the summary results using a random-effects model.

Results

Twenty-four RCTs including 57,818 patients with DN and 891 events of ESRD, 1050 doubling of serum creatinine concentration, 4352 all-cause mortality, 6342 MACEs, 1073 MI, 2900 stroke, and 1674 cardiac deaths were reported. Overall, the summary results suggested that in patients with DN, receiving ACEI did not have a significant effect on ESRD, doubling of serum creatinine levels, all-cause mortality, MI, stroke, and cardiac death, while ACEI significantly reduced the risk of total MACEs. Furthermore, ARB therapy was associated with a low risk of ESRD and doubling of serum creatinine levels, while it did not differ significantly on all-cause mortality, MACEs, MI, stroke, and cardiac death in patients with DN.

Conclusions

Patients with DN receiving ACEI had significantly reduced the risk of total MACEs, and ARB could reduce the incidence of ESRD and the doubling of serum creatinine levels.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

References

  1. Wild S, Roglic G, Green A, Sicree R, King H (2004) Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 27:1047–1053

    PubMed  Article  Google Scholar 

  2. IDF Diabetes Atlas, 9th edition 2019. https://diabetesatlas.org/en/resources/. Retrieved 2 Dec 2019

  3. (2019) Introduction: standards of medical care in diabetes-2019. Diabetes Care 42:S1–S2. https://doi.org/10.2337/dc19-Sint01

  4. Albvr VR, Tan SH, Candasamy M, Bhattamisra SK (2019) Diabetic nephropathy: an update on pathogenesis and drug development. Diabetes Metab Syndr 13:754–762

    Article  Google Scholar 

  5. Gross JL, de Azevedo MJ, Silveiro SP, Canani LH, Caramori ML et al (2005) Diabetic nephropathy: diagnosis, prevention, and treatment. Diabetes Care 28:164–176

    PubMed  Article  Google Scholar 

  6. Levey AS, Cattran D, Friedman A, Miller WG, Sedor J et al (2009) Proteinuria as a surrogate outcome in CKD: report of a scientific workshop sponsored by the National Kidney Foundation and the US Food and Drug Administration. Am J Kidney Dis 54:205–226

    PubMed  Article  Google Scholar 

  7. Lv Y, Zou Z, Chen GM, Jia HX, Zhong J et al (2010) Amlodipine and angiotensin-converting enzyme inhibitor combination versus amlodipine monotherapy in hypertension: a meta-analysis of randomized controlled trials. Blood Press Monit 15:195–204

    PubMed  Article  Google Scholar 

  8. Wu L, Deng SB, She Q (2014) Calcium channel blocker compared with angiotensin receptor blocker for patients with hypertension: a meta-analysis of randomized controlled trials. J Clin Hypertens (Greenwich) 16:838–845

    Article  Google Scholar 

  9. Moher D, Liberati A, Tetzlaff J, Altman DG, Group P (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6:e1000097

    Article  Google Scholar 

  10. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ et al (1996) Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 17:1–12

    CAS  PubMed  Article  Google Scholar 

  11. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188

    CAS  PubMed  Article  Google Scholar 

  12. Ades AE, Lu G, Higgins JP (2005) The interpretation of random-effects meta-analysis in decision models. Med Decis Making 25:646–654

    CAS  PubMed  Article  Google Scholar 

  13. Deeks JJ, Higgins JPT, Altman DG (2008) Analyzing data and undertaking meta-analyses. In: Higgins JP, Green S (eds) Cochrane Handbook for Systematic Reviews of Interventions. The Cochrane Collaboration, Oxford, p 501

    Google Scholar 

  14. Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327:557–560

    PubMed  PubMed Central  Article  Google Scholar 

  15. Altman DG, Bland JM (2003) Interaction revisited: the difference between two estimates. BMJ 326:219

    PubMed  PubMed Central  Article  Google Scholar 

  16. Tobias A (1999) Assessing the influence of a single study in meta-analysis. Stata Tech Bull 47:15–17

    Google Scholar 

  17. Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50:1088–1101

    CAS  PubMed  Article  Google Scholar 

  19. Parving HH, Hommel E, Damkjaer Nielsen M, Giese J (1989) Effect of captopril on blood pressure and kidney function in normotensive insulin dependent diabetics with nephropathy. BMJ 299:533–536

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. Bauer JH, Reams GP, Hewett J, Klachko D, Lau A et al (1992) A randomized, double-blind, placebo-controlled trial to evaluate the effect of enalapril in patients with clinical diabetic nephropathy. Am J Kidney Dis 20:443–457

    CAS  PubMed  Article  Google Scholar 

  21. Ravid M, Savin H, Jutrin I, Bental T, Katz B et al (1993) Long-term stabilizing effect of angiotensin-converting enzyme inhibition on plasma creatinine and on proteinuria in normotensive type II diabetic patients. Ann Intern Med 118:577–581

    CAS  PubMed  Article  Google Scholar 

  22. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD (1993) The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 329:1456–1462

    CAS  PubMed  Article  Google Scholar 

  23. Laffel LM, McGill JB, Gans DJ (1995) The beneficial effect of angiotensin-converting enzyme inhibition with captopril on diabetic nephropathy in normotensive IDDM patients with microalbuminuria. North American Microalbuminuria Study Group. Am J Med 99:497–504

    CAS  PubMed  Article  Google Scholar 

  24. Maschio G, Alberti D, Janin G, Locatelli F, Mann JF et al (1996) Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. The Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study Group. N Engl J Med 334:939–945

    CAS  PubMed  Article  Google Scholar 

  25. Sano T, Hotta N, Kawamura T, Matsumae H, Chaya S et al (1996) Effects of long-term enalapril treatment on persistent microalbuminuria in normotensive type 2 diabetic patients: results of a 4-year, prospective, randomized study. Diabet Med 13:120–124

    CAS  PubMed  Article  Google Scholar 

  26. Nankervis A, Nicholls K, Kilmartin G, Allen P, Ratnaike S et al (1998) Effects of perindopril on renal histomorphometry in diabetic subjects with microalbuminuria: a 3-year placebo-controlled biopsy study. Metabolism 47:12–15

    CAS  PubMed  Article  Google Scholar 

  27. (2000) Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart outcomes prevention evaluation study investigators. Lancet 355:253–259

  28. Katayama S, Kikkawa R, Isogai S, Sasaki N, Matsuura N et al (2002) Effect of captopril or imidapril on the progression of diabetic nephropathy in Japanese with type 1 diabetes mellitus: a randomized controlled study (JAPAN-IDDM). Diabetes Res Clin Pract 55:113–121

    CAS  PubMed  Article  Google Scholar 

  29. Marre M, Lievre M, Chatellier G, Mann JF, Passa P et al (2004) Effects of low dose ramipril on cardiovascular and renal outcomes in patients with type 2 diabetes and raised excretion of urinary albumin: randomised, double blind, placebo controlled trial (the DIABHYCAR study). BMJ 328:495

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. Patel A, Grop AC, MacMahon S, Chalmers J, Neal B et al (2007) Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 370:829–840

    CAS  PubMed  Article  Google Scholar 

  31. Mauer M, Zinman B, Gardiner R, Suissa S, Sinaiko A et al (2009) Renal and retinal effects of enalapril and losartan in type 1 diabetes. N Engl J Med 361:40–51

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. Fried LF, Emanuele N, Zhang JH, Brophy M, Conner TA et al (2013) Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med 369:1892–1903

    CAS  PubMed  Article  Google Scholar 

  33. Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S et al (2001) The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 345:870–878

    CAS  PubMed  Article  Google Scholar 

  34. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA et al (2001) Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 345:851–860

    CAS  PubMed  Article  Google Scholar 

  35. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE et al (2001) Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 345:861–869

    CAS  PubMed  Article  Google Scholar 

  36. Yusuf S, Diener HC, Sacco RL, Cotton D, Ounpuu S et al (2008) Telmisartan to prevent recurrent stroke and cardiovascular events. N Engl J Med 359:1225–1237

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. Chaturvedi N, Porta M, Klein R, Orchard T, Fuller J et al (2008) Effect of candesartan on prevention (DIRECT-Prevent 1) and progression (DIRECT-Protect 1) of retinopathy in type 1 diabetes: randomised, placebo-controlled trials. Lancet 372:1394–1402

    CAS  PubMed  Article  Google Scholar 

  38. Bilous R, Chaturvedi N, Sjolie AK, Fuller J, Klein R et al (2009) Effect of candesartan on microalbuminuria and albumin excretion rate in diabetes: three randomized trials. Ann Intern Med 151(11–20):W13–14

    Google Scholar 

  39. Sjolie AK, Klein R, Porta M, Orchard T, Fuller J et al (2008) Effect of candesartan on progression and regression of retinopathy in type 2 diabetes (DIRECT-Protect 2): a randomised placebo-controlled trial. Lancet 372:1385–1393

    PubMed  Article  CAS  Google Scholar 

  40. Imai E, Chan JC, Ito S, Yamasaki T, Kobayashi F et al (2011) Effects of olmesartan on renal and cardiovascular outcomes in type 2 diabetes with overt nephropathy: a multicentre, randomised, placebo-controlled study. Diabetologia 54:2978–2986

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. Haller H, Ito S, Izzo JL Jr, Januszewicz A, Katayama S et al (2011) Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. N Engl J Med 364:907–917

    CAS  PubMed  Article  Google Scholar 

  42. Yamashita K, Kondo T, Muramatsu T, Matsushita K, Nagahiro T et al (2013) Effects of valsartan versus amlodipine in diabetic hypertensive patients with or without previous cardiovascular disease. Am J Cardiol 112:1750–1756

    CAS  PubMed  Article  Google Scholar 

  43. Sarafidis PA, Stafylas PC, Kanaki AI, Lasaridis AN (2008) Effects of renin-angiotensin system blockers on renal outcomes and all-cause mortality in patients with diabetic nephropathy: an updated meta-analysis. Am J Hypertens 21:922–929

    CAS  PubMed  Article  Google Scholar 

  44. Wang ZJ, Zhou YJ, Galper BZ, Gao F, Yeh RW et al (2015) Association of body mass index with mortality and cardiovascular events for patients with coronary artery disease: a systematic review and meta-analysis. Heart 101:1631–1638

    CAS  PubMed  Article  Google Scholar 

  45. Qi W, Zhang N, Korantzopoulos P, Letsas KP, Cheng M et al (2017) Serum glycated hemoglobin level as a predictor of atrial fibrillation: A systematic review with meta-analysis and meta-regression. PLoS ONE 12:e0170955

    PubMed  PubMed Central  Article  CAS  Google Scholar 

Download references

Funding

None.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Z. Li.

Ethics declarations

Conflict of interest

All authors declare that they have no conflict of interests.

Ethical approval

Not applicable.

Informed consent

Not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Liu, X., Ma, L. & Li, Z. Effects of renin–angiotensin system blockers on renal and cardiovascular outcomes in patients with diabetic nephropathy: a meta-analysis of randomized controlled trials. J Endocrinol Invest 43, 959–972 (2020). https://doi.org/10.1007/s40618-020-01179-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40618-020-01179-8

Keywords

  • Diabetic nephropathy
  • ACEI
  • ARB
  • Meta-analysis