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(Clinical) Trial and Error in Diabetic Nephropathy

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Abstract

Patients with diabetes and nephropathy face a high risk of end-stage renal disease (ESRD) and cardiovascular disease. Trials in the past decades of nephrology research have shown the importance of lowering glucose, blood pressure, and albuminuria as a mean to lower renal and cardiovascular risk in these patients. However, despite the promising and successful results from RAAS inhibition with angiotensin receptor blockers in combination with tight glycemic and blood pressure control, many patients with diabetes and nephropathy are left with a high residual risk and still progress to ESRD. The high residual risk highlights the urgent need for additional therapies. This chapter reviews the clinical trial landscape in diabetic nephropathy and draws lessons for future clinical trials in this area.

In order to improve outcome of patients with diabetic nephropathy, novel drugs have been tested in the last decades. After numerous large and expensive trials, unfortunately only a few interventions have been shown to reduce the risk of ESRD. One of the potential explanations why many of the conducted trials failed to prove ultimate efficacy is that all interventions focused on the effect of the drug in the overall population without taking into account how the individual patient responded to the drug. In the past trials, individual patients showed a large variation in drug response: some patients benefitted, and others did not or even experienced an increased risk. Because of this variation, no benefit could be detected in the overall population. The drug response variation may thus play a much bigger and more important role than originally anticipated in clinical trial design.

The important lesson learned from a decade of clinical trial failures in nephrology is that more emphasis should be placed on the individual and how the individual responses to the drug rather than evaluating drug effects on a population level. This personalized medicine concept should be integrated in the design of future clinical trials as there are still promising therapies at the horizon for diabetic nephropathy and their potential efficacy should be tested in an appropriate fashion.

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References

  1. Waring MJ, Arrowsmith J, Leach AR, Leeson PD, Mandrell S, Owen RM, et al. An analysis of the attrition of drug candidates from four major pharmaceutical companies. Nat Rev Drug Discov. 2015;14(7):475–86.

    Article  CAS  Google Scholar 

  2. Kola I, Landis J. Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov. 2004;3(8):711–5.

    Article  CAS  Google Scholar 

  3. Strippoli GF, Craig JC, Schena FP. The number, quality, and coverage of randomized controlled trials in nephrology. J Am Soc Nephrol. 2004;15(2):411–9.

    Article  Google Scholar 

  4. Palmer SC, Sciancalepore M, Strippoli GF. Trial quality in nephrology: how are we measuring up? Am J Kidney Dis. 2011;58(3):335–7.

    Article  Google Scholar 

  5. de Zeeuw D, de Graeff PA. Clinical trial in nephrology at hard end point? J Am Soc Nephrol. 2004;15(2):506–8.

    Article  Google Scholar 

  6. Inrig JK, Califf RM, Tasneem A, Vegunta RK, Molina C, Stanifer JW, et al. The landscape of clinical trials in nephrology: a systematic review of Clinicaltrials.gov. Am J Kidney Dis. 2014;63(5):771–80.

    Article  Google Scholar 

  7. de Boer IH, Kovesdy CP, Navaneethan SD, Peralta CA, Tuot DS, Vazquez MA, et al. Pragmatic clinical trials in CKD: opportunities and challenges. J Am Soc Nephrol. 2016;27(10):2948–54.

    Article  Google Scholar 

  8. USRDS. 2016 annual data report (USRDS). 2016. Available at: https://www.usrds.org/adr.aspx. Accessed 7 Sept 2017.

  9. Ogurtsova K, da Rocha Fernandes JD, Huang Y, Linnenkamp U, Guariguata L, Cho NH, et al. IDF Diabetes Atlas: global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Res Clin Pract. 2017;128:40–50.

    Article  CAS  Google Scholar 

  10. Hill NR, Fatoba ST, Oke JL, Hirst JA, O’Callaghan CA, Lasserson DS, et al. Global prevalence of chronic kidney disease – a systematic review and meta-analysis. PLoS One. 2016;11(7):e0158765.

    Article  Google Scholar 

  11. El Nahas M. The global challenge of chronic kidney disease. Kidney Int. 2005;68(6):2918–29.

    Article  Google Scholar 

  12. Heerspink HJ, de Zeeuw D. The kidney in type 2 diabetes therapy. Rev Diabet Stud. 2011;8(3):392–402.

    Article  Google Scholar 

  13. Webster AC, Cross NB. When evidence doesn’t generalise: the case of ACE inhibition. Lancet Diabetes Endocrinol. 2016;4(4):290–2.

    Article  Google Scholar 

  14. Perkovic V, Heerspink HL, Chalmers J, Woodward M, Jun M, Li Q, et al. Intensive glucose control improves kidney outcomes in patients with type 2 diabetes. Kidney Int. 2013;83(3):517–23.

    Article  CAS  Google Scholar 

  15. Zoungas S, Arima H, Gerstein HC, Holman RR, Woodward M, Reaven P, et al. Effects of intensive glucose control on microvascular outcomes in patients with type 2 diabetes: a meta-analysis of individual participant data from randomised controlled trials. Lancet Diabetes Endocrinol. 2017;5(6):431–7.

    Article  Google Scholar 

  16. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med. 1993;329(20):1456–62.

    Article  CAS  Google Scholar 

  17. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, 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):861–9.

    Article  CAS  Google Scholar 

  18. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, 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):851–60.

    Article  CAS  Google Scholar 

  19. de Zeeuw D, Remuzzi G, Parving HH, Keane WF, Zhang Z, Shahinfar S, et al. Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL. Kidney Int. 2004;65(6):2309–20.

    Article  Google Scholar 

  20. Atkins RC, Briganti EM, Lewis JB, Hunsicker LG, Braden G, Champion de Crespigny PJ, et al. Proteinuria reduction and progression to renal failure in patients with type 2 diabetes mellitus and overt nephropathy. Am J Kidney Dis. 2005;45(2):281–7.

    Article  Google Scholar 

  21. Holtkamp FA, de Zeeuw D, de Graeff PA, Laverman GD, Berl T, Remuzzi G, et al. Albuminuria and blood pressure, independent targets for cardioprotective therapy in patients with diabetes and nephropathy: a post hoc analysis of the combined RENAAL and IDNT trials. Eur Heart J. 2011;32(12):1493–9.

    Article  CAS  Google Scholar 

  22. Pippias M, Jager KJ, Kramer A, Leivestad T, Sanchez MB, Caskey FJ, et al. The changing trends and outcomes in renal replacement therapy: data from the ERA-EDTA registry. Nephrol Dial Transplant. 2016;31(5):831–41.

    Article  Google Scholar 

  23. Pippias M, Kramer A, Noordzij M, Afentakis N, Alonso de la Torre R, Ambuhl PM, et al. The European Renal Association – European Dialysis and Transplant Association Registry Annual Report 2014: a summary. Clin Kidney J. 2017;10(2):154–69.

    PubMed  PubMed Central  Google Scholar 

  24. de Zeeuw D, Heerspink HJ. Unmet need in diabetic nephropathy: failed drugs or trials? Lancet Diabetes Endocrinol. 2016;4(8):638–40.

    Article  Google Scholar 

  25. Keane WF, Brenner BM, de Zeeuw D, Grunfeld JP, McGill J, Mitch WE, et al. The risk of developing end-stage renal disease in patients with type 2 diabetes and nephropathy: the RENAAL study. Kidney Int. 2003;63(4):1499–507.

    Article  Google Scholar 

  26. ONTARGET Investigators, Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358(15):1547–59.

    Article  Google Scholar 

  27. Mann JF, Schmieder RE, McQueen M, Dyal L, Schumacher H, Pogue J, et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet. 2008;372(9638):547–53.

    Article  CAS  Google Scholar 

  28. Fried LF, Emanuele N, Zhang JH, Brophy M, Conner TA, Duckworth W, et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med. 2013;369(20):1892–903.

    Article  CAS  Google Scholar 

  29. Parving HH, Persson F, Lewis JB, Lewis EJ, Hollenberg NK, AVOID Study Investigators. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med. 2008;358(23):2433–46.

    Article  CAS  Google Scholar 

  30. Parving HH, Brenner BM, McMurray JJ, de Zeeuw D, Haffner SM, Solomon SD, et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med. 2012;367(23):2204–13.

    Article  CAS  Google Scholar 

  31. Heerspink HL, Greene T, Lewis JB, Raz I, Rohde RD, Hunsicker LG, et al. Effects of sulodexide in patients with type 2 diabetes and persistent albuminuria. Nephrol Dial Transplant. 2008;23(6):1946–54.

    Article  CAS  Google Scholar 

  32. Broekhuizen LN, Lemkes BA, Mooij HL, Meuwese MC, Verberne H, Holleman F, et al. Effect of sulodexide on endothelial glycocalyx and vascular permeability in patients with type 2 diabetes mellitus. Diabetologia. 2010;53(12):2646–55.

    Article  CAS  Google Scholar 

  33. Szelachowska M, Poplawska A, Topolska J, Kinalska I, Grimaldi M. A pilot study of the effect of the glycosaminoglycan sulodexide on microalbuminuria in type I diabetic patients. Curr Med Res Opin. 1997;13(9):539–45.

    Article  CAS  Google Scholar 

  34. Satirapoj B, Kaewput W, Supasyndh O, Ruangkanchanasetr P. Effect of sulodexide on urinary biomarkers of kidney injury in normoalbuminuric type 2 diabetes: a randomized controlled trial. J Diabetes Res. 2015;2015:172038.

    Article  Google Scholar 

  35. Gambaro G, Kinalska I, Oksa A, Pont’uch P, Hertlova M, Olsovsky J, et al. Oral sulodexide reduces albuminuria in microalbuminuric and macroalbuminuric type 1 and type 2 diabetic patients: the Di.N.A.S. randomized trial. J Am Soc Nephrol. 2002;13(6):1615–25.

    Article  CAS  Google Scholar 

  36. Lewis EJ, Lewis JB, Greene T, Hunsicker LG, Berl T, Pohl MA, et al. Sulodexide for kidney protection in type 2 diabetes patients with microalbuminuria: a randomized controlled trial. Am J Kidney Dis. 2011;58(5):729–36.

    Article  CAS  Google Scholar 

  37. Packham DK, Wolfe R, Reutens AT, Berl T, Heerspink HL, Rohde R, et al. Sulodexide fails to demonstrate renoprotection in overt type 2 diabetic nephropathy. J Am Soc Nephrol. 2012;23(1):123–30.

    Article  CAS  Google Scholar 

  38. Firth JD, Ratcliffe PJ, Raine AE, Ledingham JG. Endothelin: an important factor in acute renal failure? Lancet. 1988;2(8621):1179–82.

    Article  CAS  Google Scholar 

  39. Wenzel RR, Littke T, Kuranoff S, Jurgens C, Bruck H, Ritz E, et al. Avosentan reduces albumin excretion in diabetics with macroalbuminuria. J Am Soc Nephrol. 2009;20(3):655–64.

    Article  Google Scholar 

  40. de Zeeuw D, Coll B, Andress D, Brennan JJ, Tang H, Houser M, et al. The endothelin antagonist atrasentan lowers residual albuminuria in patients with type 2 diabetic nephropathy. J Am Soc Nephrol. 2014;25(5):1083–93.

    Article  Google Scholar 

  41. Mann JF, Green D, Jamerson K, Ruilope LM, Kuranoff SJ, Littke T, et al. Avosentan for overt diabetic nephropathy. J Am Soc Nephrol. 2010;21(3):527–35.

    Article  CAS  Google Scholar 

  42. Zeeuw D. Study of Diabetic Nephropathy with Atrasentan (SONAR). ClinicalTrials.gov no. NCT01858532. 2017. Available at: http://clinicaltrials.gov/. Accessed 7 Sept 2017.

  43. Ruiz S, Pergola PE, Zager RA, Vaziri ND. Targeting the transcription factor Nrf2 to ameliorate oxidative stress and inflammation in chronic kidney disease. Kidney Int. 2013;83(6):1029–41.

    Article  CAS  Google Scholar 

  44. Pergola PE, Raskin P, Toto RD, Meyer CJ, Huff JW, Grossman EB, et al. Bardoxolone methyl and kidney function in CKD with type 2 diabetes. N Engl J Med. 2011;365(4):327–36.

    Article  CAS  Google Scholar 

  45. de Zeeuw D, Akizawa T, Audhya P, Bakris GL, Chin M, Christ-Schmidt H, et al. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N Engl J Med. 2013;369(26):2492–503.

    Article  Google Scholar 

  46. Solomon SD, Uno H, Lewis EF, Eckardt KU, Lin J, Burdmann EA, et al. Erythropoietic response and outcomes in kidney disease and type 2 diabetes. N Engl J Med. 2010;363(12):1146–55.

    Article  CAS  Google Scholar 

  47. Cortinovis M, Perico N, Remuzzi G. Should we still believe in randomized controlled trials in nephrology? Nephron. 2017;136:281–6.

    Article  CAS  Google Scholar 

  48. Chan GC, Tang SC. Diabetic nephropathy: landmark clinical trials and tribulations. Nephrol Dial Transplant. 2016;31(3):359–68.

    Article  CAS  Google Scholar 

  49. Heerspink HJ, Ninomiya T, Persson F, Brenner BM, Brunel P, Chaturvedi N, et al. Is a reduction in albuminuria associated with renal and cardiovascular protection? A post hoc analysis of the ALTITUDE trial. Diabetes Obes Metab. 2016;18(2):169–77.

    Article  CAS  Google Scholar 

  50. Chin MP, Wrolstad D, Bakris GL, Chertow GM, de Zeeuw D, Goldsberry A, et al. Risk factors for heart failure in patients with type 2 diabetes mellitus and stage 4 chronic kidney disease treated with bardoxolone methyl. J Card Fail. 2014;20(12):953–8.

    Article  CAS  Google Scholar 

  51. Mix TC, Brenner RM, Cooper ME, de Zeeuw D, Ivanovich P, Levey AS, et al. Rationale--Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT): evolving the management of cardiovascular risk in patients with chronic kidney disease. Am Heart J. 2005;149(3):408–13.

    Article  CAS  Google Scholar 

  52. Petrykiv SI, Laverman GD, de Zeeuw D, Heerspink HJL. The albuminuria-lowering response to dapagliflozin is variable and reproducible among individual patients. Diabetes Obes Metab. 2017;19:1363–70.

    Article  CAS  Google Scholar 

  53. Petrykiv S, Laverman GD, de Zeeuw D, Heerspink HJL. Does SGLT2 inhibition with dapagliflozin overcome individual therapy resistance to RAAS inhibition? Diabetes Obes Metab. 2018;20:224–7.

    Article  CAS  Google Scholar 

  54. Schievink B, de Zeeuw D, Parving HH, Rossing P, Lambers Heerspink HJ. The renal protective effect of angiotensin receptor blockers depends on intra-individual response variation in multiple risk markers. Br J Clin Pharmacol. 2015;80(4):678–86.

    Article  CAS  Google Scholar 

  55. Ondra T, Dmitrienko A, Friede T, Graf A, Miller F, Stallard N, et al. Methods for identification and confirmation of targeted subgroups in clinical trials: a systematic review. J Biopharm Stat. 2016;26(1):99–119.

    Article  Google Scholar 

  56. Shah SJ. Innovative clinical trial designs for precision medicine in heart failure with preserved ejection fraction. J Cardiovasc Transl Res. 2017;10(3):322–36.

    Article  Google Scholar 

  57. Kummar S, Williams PM, Lih CJ, Polley EC, Chen AP, Rubinstein LV, et al. Application of molecular profiling in clinical trials for advanced metastatic cancers. J Natl Cancer Inst. 2015;107(4) https://doi.org/10.1093/jnci/djv003. Print 2015 Apr.

    Article  Google Scholar 

  58. Thabane L, Lancaster G. Improving the efficiency of trials using innovative pilot designs: the next phase in the conduct and reporting of pilot and feasibility studies. Pilot Feasibility Stud. 2017;4:14. https://doi.org/10.1186/s40814-017-0159-2. eCollection 2018.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Saville BR, Berry SM. Efficiencies of platform clinical trials: a vision of the future. Clin Trials. 2016;13(3):358–66.

    Article  Google Scholar 

  60. Berry SM, Connor JT, Lewis RJ. The platform trial: an efficient strategy for evaluating multiple treatments. JAMA. 2015;313(16):1619–20.

    Article  Google Scholar 

  61. Menis J, Hasan B, Besse B. New clinical research strategies in thoracic oncology: clinical trial design, adaptive, basket and umbrella trials, new end-points and new evaluations of response. Eur Respir Rev. 2014;23(133):367–78.

    Article  Google Scholar 

  62. de Zeeuw D, Heerspink HJL, Jardine M, Perkovic V. Renal trials in diabetes need a platform: time for a global approach? Lancet Diabetes Endocrinol. 2018;6:356–8.

    Article  Google Scholar 

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Authors and Affiliations

  1. Department Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

    Marjolein Y. A. M. Kroonen, Hiddo J. L. Heerspink & Dick de Zeeuw

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  1. Marjolein Y. A. M. Kroonen
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Correspondence to Hiddo J. L. Heerspink .

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  1. Department of Pathology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands

    Joris J. Roelofs

  2. Department of Internal Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands

    Liffert Vogt

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Kroonen, M.Y.A.M., Heerspink, H.J.L., de Zeeuw, D. (2019). (Clinical) Trial and Error in Diabetic Nephropathy. In: Roelofs, J., Vogt, L. (eds) Diabetic Nephropathy. Springer, Cham. https://doi.org/10.1007/978-3-319-93521-8_24

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