American Journal of Kidney Diseases
Volume 55, Issue 3 , Pages 426-430, March 2010

Prevention of Diabetic Kidney Disease: Negative Clinical Trials With Renin-Angiotensin System Inhibitors

  • Robert G. Nelson, MD, PhD

      Affiliations

    • National Institutes of Health, Phoenix, Arizona
    • Corresponding Author InformationAddress correspondence to Robert G. Nelson, MD, PhD, National Institutes of Health, 1550 East Indian School Rd, Phoenix, AZ 85014-4972
    • ,
  • Katherine R. Tuttle, MD

      Affiliations

    • University of Washington School of Medicine, Spokane and Seattle, Washington

published online 11 December 2009.

Article Outline

 

Commentary on Bilous R, Chaturvedi N, Sjølie AK, et al. Effect of candesartan on microalbuminuria and albumin excretion rate in diabetes: three randomized trials. Ann Intern Med. 2009;151(1):11-20; and Mauer M, Zinman B, Gardiner R, et al. Renal and retinal effects of enalapril and losartan in type 1 diabetes. N Engl J Med. 2009;361(1):40-51.

The onset of diabetic kidney disease typically is marked by the development of increased urinary albumin excretion. Microalbuminuria, the earliest detectable increase in urinary albumin levels, is defined as an albumin-creatinine ratio in the range of 30-300 mg/g.1 Although there presently is a debate about whether albuminuria is an adequate biomarker of diabetic kidney disease, it remains the test most commonly used by clinicians and researchers alike to screen for diabetic kidney disease. Because angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are proven therapies for diabetic kidney disease characterized by macroalbuminuria (albumin-creatinine ratio > 300 mg/g), by logical extension, these agents might also prevent the development of microalbuminuria. The DIRECT (Diabetic Retinopathy Candesartan Trials)–Renal Program, published in 2009 in the Annals of Internal Medicine,2 and RASS (Renin-Angiotensin System Study), published in 2009 in the New England Journal of Medicine,3 test this hypothesis.

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What Do These Important Studies Show? 

DIRECT-Renal Program 

The DIRECT-Renal Program2 pooled 3 related, randomized, double-blinded, placebo-controlled, clinical trials to assess whether the ARB candesartan prevents the onset of microalbuminuria and diminishes the rate of change in urinary albumin excretion in patients with type 1 or 2 diabetes. Of 5,231 diabetic participants in DIRECT-Renal from 309 centers in 30 countries, 3,326 had type 1 diabetes and 1,905 had type 2 diabetes; all were normoalbuminuric at baseline. Blood pressure at baseline was within the normal range for participants with type 1 diabetes and was well controlled in 62% of participants with type 2 diabetes who were treated for hypertension. Participants were randomly assigned to receive either candesartan, 16 mg/d, increasing to 32 mg/d after 1 month, or placebo and were followed up for at least 4 years. Urinary albumin excretion was measured in 2 overnight collections at baseline and annually thereafter. In the DIRECT-Renal Program, increased urinary albumin excretion was defined as a level ≥ 20 μg/min. If the albumin excretion rate in either sample was ≥ 20 μg/min, the participant was asked to submit 2 more overnight collections, and if ≥ 3 of these collections met this threshold, the participant was considered to have increased urinary albumin excretion and was counted as a case.

During a median follow-up of 4.7 years, the pooled hazard ratio for increased albuminuria in the candesartan group was 0.95 times (95% confidence interval, 0.78-1.16; P = 0.60) that of the placebo group, reflecting a nonsignificant 5% decrease in the incidence of increased urinary albumin excretion in the pooled group treated with candesartan relative to the group receiving placebo. Hazard ratios for individual studies did not differ substantially from the pooled analysis. Similarly, although treatment with candesartan significantly decreased the annual rate of change in urinary albumin excretion relative to placebo, the change was only 5.5% lower (95% confidence interval, 0.7-10.1; P = 0.024) and was not considered clinically relevant.

The DIRECT-Renal investigators concluded that candesartan had no effect on the primary prevention of increased urinary albumin excretion during 4.7 years in normoalbuminuric and normotensive patients with type 1 diabetes or normoalbuminuric patients with type 2 diabetes who were either normotensive or hypertensive. They suggested that the lack of efficacy of candesartan in DIRECT-Renal participants might be caused in part by the low prevalence of vascular disease in this relatively young cohort (mean participant age, 30-35 years in type 1 studies and 57 years in the type 2 study; pooled mean age, 40 years). Previous studies of primary prevention involving older participants with type 2 diabetes, higher blood pressure, and substantially greater risk of cardiovascular disease reported salutary effects of renin-angiotensin system (RAS) blockade on primary prevention of increased urinary albumin excretion.4, 5, 6

RASS 

RASS was a 5-year, randomized, double-blinded, placebo-controlled, clinical trial that enrolled 285 normotensive patients with type 1 diabetes and normal urinary albumin excretion from 3 centers in 3 countries.3 The trial was designed to assess whether the ACE-inhibitor enalapril or the ARB losartan would slow the development and progression of kidney disease relative to placebo. Participants were randomly assigned to receive either 10 mg/d of enalapril, 50 mg/d of losartan, or placebo. Because of emerging data that indicated a greater decrease in proteinuria with higher doses of RAS inhibitors, the amounts of study drug administered were increased midway through RASS so that participants received double the initial doses for the last 3 years. This trial is unique in that the prespecified primary study end point was change in the fraction of glomerular volume occupied by mesangium, a robust structural end point providing unequivocal evidence of kidney disease progression. Secondary renal end points included changes in other glomerular, vascular, tubular, and interstitial morphometric variables; changes in glomerular filtration rate assessed using plasma disappearance of iohexol; and changes in albuminuria. Percutaneous kidney biopsies were performed just before randomization and after 5 years of treatment.

Of 285 participants enrolled in the study, 90% completed both kidney biopsies. The change in mesangial fractional volume associated with placebo was not significantly different from that of either enalapril (P = 0.16) or losartan (P = 0.17). In addition, no differences between groups were found for other measured morphometric variables. Glomerular filtration rate decreased equivalently in all 3 groups. Of note, albumin excretion rate increased significantly from baseline only in participants who received losartan (P = 0.04), and the 5-year cumulative incidence of microalbuminuria (defined in RASS as albumin excretion of 20-200 μg/min) was 17% in this group compared with 6% in the placebo group and 4% in the enalapril group. The RASS investigators concluded that there were no structural or functional benefits to the kidney from blockade of the RAS with either an ACE inhibitor or ARB in normotensive patients with type 1 diabetes and normoalbuminuria.

Taken together, the DIRECT-Renal Program and RASS resoundingly refute the widely held belief that RAS blockade is beneficial in diabetic kidney disease prevention or management at all stages. The available evidence even suggests potential for harm from an ARB in the primary prevention setting.3

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How Do These Studies Compare With Prior Studies? 

As noted, the previously reported beneficial effect of RAS blockade on primary prevention of increased albuminuria in some older patients with type 2 diabetes4, 5, 6 may reflect increased vascular RAS activity associated with hypertension and cardiovascular disease.2 The present studies indicate that this benefit does not extend to those without these conditions. EUCLID (EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes)7 also reported a reduced incidence of increased albuminuria in normotensive patients with type 1 diabetes, although the effect was not statistically significant and this study's results therefore should be considered inconclusive. Although RAS blockade may decrease the frequency of progression to microalbuminuria in some patients with diabetes, the long-term efficacy of such a decrease is questionable given the lack of preservation of kidney structure or function in RASS participants who received these medicines.

The apparent lack of value of RAS blockade in many patients with either type 1 or type 2 diabetes who do not have increased blood pressure or urinary albumin excretion indicates that management of these patients to prevent the development of diabetic kidney disease requires other approaches. At present, intensive glycemic control has the strongest evidence base for diabetic kidney disease prevention. This evidence was first established in type 1 diabetes by the DCCT (Diabetes Control and Complications Trial),8 followed by its long-term observational follow-up study, DCCT-Epidemiology of Diabetes Interventions and Complications (EDIC).9 Subsequent studies of type 2 diabetes, the largest and most notable of which was the UKPDS (United Kingdom Prospective Diabetes Study), produced similar findings of decreased risk of diabetic kidney disease with intensive glycemic control.10, 11, 12, 13

However, a note of caution is in order with regard to overly intensive glycemic control in patients with long-standing type 2 diabetes. Three recent clinical trials that sought to decrease target hemoglobin A1c (HbA1c) to levels < 7% (ie, HbA1c < 6%-6.5%) found no benefit on cardiovascular outcomes, and one study, the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial, found higher death and cardiovascular event rates with more aggressive attempts to normalize blood glucose levels.14, 15, 16 Although a companion trial, ADVANCE (Action in Diabetes and Cardiovascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation), found a decreased risk of new-onset diabetic kidney disease with a very low HbA1c goal, no cardiovascular benefits emerged.15 Safety concerns also are paramount; each of the 3 recent trials showed a dramatic increased risk of severe hypoglycemia in the groups with lower HbA1c goals. As such, the primary ACCORD results along with the increased risk of hypoglycemia raise a red flag about attempts to “normalize” glycemia in this population. Even if long-term cardiovascular and survival benefits should emerge, there may be a grave upfront cost of overly intensive glycemic control for these high-risk patients. Taken together, the current evidence does not support decreasing the HbA1c goal beyond < 7%, except possibly for younger patients with new-onset diabetes who do not have complications, comorbid conditions, or recurrent and severe hypoglycemia.

Clearly, the most effective strategy to prevent diabetic kidney disease is prevention of diabetes. The DPP (Diabetes Prevention Program) convincingly showed the remarkable benefit of lifestyle modification using diet, weight loss, and exercise.17 From a public health stand point, prevention of diabetic kidney disease and other major diabetic complications will be addressed most effectively by preventing diabetes itself.

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What Should Clinicians and Researchers Do? 

Approximately 30% of patients with type 1 diabetes and 40% of those with type 2 diabetes develop diabetic kidney disease.1 Despite the wide availability of “effective” therapies, diabetes remains the most common cause of kidney failure, with more than half (54%) the incident cases of treated kidney failure attributable to diabetic kidney disease in the United States in the most recent US Renal Data System report.18 Moreover, kidney failure is more common in older people and nonwhite populations. Perhaps most sobering is a high death rate, dominated by cardiovascular causes, of ∼20%/y in those with diabetic kidney disease when they develop macroalbuminuria or decreased kidney function.19, 20

The introduction of new and promising treatments for a disease that has such a grim prognosis is inevitably a source of optimism for clinicians and researchers alike. A risk of such optimism is that assumptions about the efficacy of the treatment in various situations are made before sufficient evidence is available. Accordingly, the decision by the work group that prepared the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (KDOQI) clinical practice guidelines and recommendations for diabetes and chronic kidney disease (CKD)1 to require a strong evidentiary basis for each clinical practice guideline was correct. Notably, no recommendation was made about the use of ACE inhibitors or ARBs for primary prevention of diabetic kidney disease. At the time the guidelines were published, this view was strongly challenged by some who believed, despite the lack of evidence, that use of ACE inhibitors and/or ARBs for diabetic kidney disease prevention or treatment across various stages was self-evident based on extrapolation from studies of treating hypertensive diabetic patients with overt nephropathy and experimental models. Findings from the studies under discussion show the importance of adhering to strict interpretation of the evidence when formulating guidelines intended to propose the best possible care within the context of presently available medical knowledge. This approach was rigorously adhered to by the work group that prepared the guidelines. It also is important to disclose that the first authors of the reports discussed in this editorial were members of this work group. Additionally, both the Joint National Committee and the American Diabetes Association recommend treatment of hypertensive diabetic patients with ACE inhibitors or ARBs, but these recommendations are based primarily on cardiovascular risk reduction, rather than prevention of diabetic kidney disease.21, 22 In contrast, the KDOQI clinical practice guidelines on hypertension and antihypertensive agents in CKD recommend ACE inhibitors or ARBs in patients with diabetic kidney disease based on their efficacy in slowing kidney disease progression.23 The KDOQI guidelines for diabetes and CKD1 appropriately note that the evidence base for this recommendation is much stronger for patients with macroalbuminuria than microalbuminuria.

Results from the recent studies discussed illustrate the need for better biomarkers of early diabetic kidney disease. Classification of CKD stages currently uses definitions of disease severity that group patients with similar phenotypes together despite potentially different mechanisms that are inconsistently associated with progression of morphologic lesions. Further investigation into relevant molecular pathways may lead to stage-specific molecular fingerprints that can be identified easily in blood or urine. Identification of these specific metabolic pathways may form the basis of a personalized approach to CKD management using treatment strategies that interrupt disease mechanisms operative in the individual patient, in contrast to our present clinical phenotype-based management. We are entering an era of discovery for which the science of genomics, proteomics, transcriptomics, and metabolomics holds great promise that hopefully will lead to validated approaches to better characterizing patients. In the meantime, prevention and treatment of diabetic kidney disease across stages should be based on the best available clinical evidence.

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Acknowledgements 

Financial Disclosure: Dr Tuttle has received consulting fees regarding diabetes and kidney disease from Eli Lilly & Co and FibroGen Inc and has received an unrestricted research grant for a study of diabetic kidney disease from AstraZeneca, a funding source of DIRECT-Renal. Dr Nelson has no relevant financial interests to report.

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References 

  1. National Kidney Foundation. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease. Am J Kidney Dis. 2007;49(2 suppl 2):S12–S154
  2. Bilous R, Chaturvedi N, Sjølie AK, et al. Effect of candesartan on microalbuminuria and albumin excretion rate in diabetes: three randomized trials. Ann Intern Med. 2009;151(1):11–20
  3. Mauer M, Zinman B, Gardiner R, et al. Renal and retinal effects of enalapril and losartan in type 1 diabetes. N Engl J Med. 2009;361(1):40–51
  4. Ruggenenti P, Fassi A, Ilieva AP, et al. Bergamo Nephrologic Diabetes Complications Trial (BENEDICT) Investigators Preventing microalbuminuria in type 2 diabetes. N Engl J Med. 2004;351(19):1941–1951
  5. Patel A ADVANCE Collaborative Group. 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. 2007;370(9590):829–840
  6. Yusuf S, Sleight P, Pogue J, et al. Heart Outcomes Prevention Evaluation Study Investigators Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342(3):145–153
  7. EUCLID Study Group. Randomised placebo-controlled trial of lisinopril in normotensive patients with insulin-dependent diabetes and normoalbuminuria or microalbuminuria. Lancet. 1997;349(9068):1787–1792
  8. Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329(14):977–986
  9. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study Research Group. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med. 2000;342(6):381–389
  10. UK Prospective Diabetes Study Group. Intensive blood glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352(9131):837–853
  11. UK Prospective Diabetes Study Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352(9131):854–865
  12. Ohkubo Y, Kishikawa H, Araki E, et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract. 1995;28(2):103–117
  13. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HAW. 10-Year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15):1577–1589
  14. Action to Control Cardiovascular Risk in Diabetes (ACCORD) Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24):2545–2559
  15. Action in Diabetes and Cardiovascular Disease. Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24):2560–2572
  16. Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360(2):129–139
  17. Knowler WC, Barrett-Connor E, Fowler SE, et al. Diabetes Prevention Program Research Group Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6):393–403
  18. US Renal Data System. USRDS 2009 Annual Data Report; vol 2. Bethesda, MD: The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2009;
  19. Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holman RR UKPDS Group. Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int. 2003;63(1):225–232
  20. US Renal Data System. USRDS 2009 Annual Data Report; vol 1. Bethesda, MD: The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2009;
  21. Chobanian AV, Bakris GL, Black HR, et al. National High Blood Pressure Education Program Coordinating Committee Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42(6):1206–1252
  22. American Diabetes Association. Clinical practice recommendations 2009. Diabetes Care. 2009;32(suppl 1):S1–S98
  23. National Kidney Foundation. KDOQI Clinical Practice Guidelines on Hypertension and Antihypertensive Agents in Chronic Kidney Disease. Am J Kidney Dis. 2004;43(5 suppl 1):S1–S290

 Originally published online as doi:10.1053/j.ajkd.2009.10.001 on December 11, 2009.

PII: S0272-6386(09)01270-0

doi:10.1053/j.ajkd.2009.10.001

American Journal of Kidney Diseases
Volume 55, Issue 3 , Pages 426-430, March 2010

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