Preventing ESRD in Overt Nephropathy of Type 2 Diabetes
Condition: Diabetes
MeSH terms: Diabetes Mellitus
Study type: Interventional
Phase: Phase 3

Summary: 
      Nephropathy of type 2 diabetes is the leading cause of end stage renal disease (ESRD)
      world-wide and is associated with a dramatic excess cardiovascular morbidity and mortality.
      Two randomized trials found that angiotensin II receptor blockers (ARBs) reduce the incidence
      of ESRD by about 30%, but have no appreciable effects on cardiovascular mortality. Available
      data suggest that ACE inhibitors might be similarly renoprotective and even more
      cardioprotective, but large scale trials on ACE inhibitors, alone or combined with ARBs, in
      overt nephropathy of type 2 diabetes are missing.

      This study will compare the effects, at comparable blood pressure control (systolic/diastolic
      <130/80 mmHg), of dual renin-angiotensin-system (RAS) blockade by half dose of benazepril and
      valsartan combination therapy as compared to single RAS blockade by benazepril or valsartan
      alone at full dose, 20 mg and 160 mg respectively, on ESRD and cardiovascular events in
      high-risk patients with type 2 diabetes and overt nephropathy, defined as serum creatinine
      >1.8 mg/dl and < 3.2 mg/dl and spot morning urine albumin to creatinine ratio >1000mg/g for
      the patients without previous ACE inhibitor and ARB therapy and >500mg/g for the patients
      with previous ACE inhibitor or ARB therapy and no specific contraindications to the study
      drugs. The relationships between renal and cardiovascular outcomes will also be evaluated.

      102 patients will be treated for at least 3 years. At comparable blood pressure control, the
      study is expected to show a more effective reduction in ESRD and cardiovascular events with
      combined than with single drug ACE inhibitor or ARB therapy. As compared to ARB, ACE
      inhibitor therapy is expected to have a similar effect on ESRD, but a superior
      cardioprotective effect. Applied to clinical practice, the findings should help reducing
      renal and cardiovascular complications, and related treatment costs, of type 2 diabetes.
    

Detailed description: 
      Introduction Nephropathy of type 2 diabetes is the leading cause of end stage renal disease
      (ESRD). Currently, more than 50% of patients on renal replacement therapy in the US are
      diabetics. The yearly incidence of diabetics progressing to ESRD and the proportion of ESRD
      patients with diabetes is progressively increasing due to the progressively increasing
      prevalence of type 2 diabetes worldwide.

      Two large, multinational trials in overt nephropathy of type 2 diabetes found that
      interruption of the renin angiotensin system (RAS) with angiotensin II receptor blockers
      (ARBs) reduces the incidence of ESRD by about 30%, but has no appreciable effects on
      cardiovascular mortality. On the basis of these findings, ARB therapy has become standard
      treatment of patients with type 2 diabetes and nephropathy. However, despite ARB treatment,
      about 7% of patients continue to progress to ESRD and 7% continue to die every year.

      Large-scale randomized trials evaluating the nephro- and cardio-protective effects of RAS
      inhibition with angiotensin-converting enzyme (ACE) inhibitors in overt nephropathy of type 2
      diabetes are missing. However, studies in patients with type 1 diabetic nephropathy showed
      that ACE inhibitor therapy may decrease progression to ESRD by 40% and cardiovascular
      mortality by about 50%. Similar studies in non diabetic chronic nephropathies. consistently
      found a 40-50% reduction in the risk of progression to ESRD with ACE inhibitors as compared
      to non-RAS inhibitor therapy. Moreover, a meta-analysis of studies including type 2 diabetic
      patients with different degree of renal involvement showed that ACE inhibitors and ARBs
      sheared a similar renoprotective effect, but only ACE inhibitors significantly decreased the
      cardiovascular mortality.

      A recent trial in non diabetic nephropathies found that combined RAS inhibition with ARBs and
      ACE inhibitors decreases progression to ESRD by 50% as compared to ARB or ACE inhibition
      alone. Evidence that combined therapy more effectively than ACE inhibitor or ARB therapy
      alone reduces albuminuria or proteinuria in patients with type 2 diabetes, suggests that a
      similar renoprotective effect could be achieved also in overt nephropathy of type 2 diabetes.
      Indeed, short-term proteinuria reduction is a strong predictor of slower progression of renal
      disease and reduced cardiovascular mortality in the long term.

      A randomized trial powered to detect a reduced incidence of ESRD or cardiovascular mortality
      with combined ARB and ACE inhibition as compared to ACE inhibition or ARB alone would require
      several thousands of patients. However, identifying high risk patients who may benefit the
      most of nephro- and cardio-protective therapy would allow to design an adequately powered
      trial with remarkably less patients. By using a Bayesian decision-tree analysis we
      identified, among patients included in the RENAAL study, a subgroup of high risk patients
      with a baseline serum creatinine of 1.8 mg/dl or more and spot morning urine albumin to
      creatinine ratio >1000mg/g or more. Of note, over 3.5 year follow-up, 70% of these high-risk
      patients progressed to ESRD despite ARB therapy. Thus, the incidence of ESRD was three-fold
      higher in high-risk patients (20%) than in the whole study group (6.8%). High risk patients
      with these clinical characteristics are therefore the ideal target for randomized clinical
      trials aimed to evaluate the effect of novel nephro- and, possibly, cardio-protective
      treatments in overt nephropathy of type 2 diabetes.

      Thus, whether dual more than single drug RAS blockade reduces the need for renal replacement
      therapy in high risk patients with type 2 diabetes and whether ACE inhibitors shear with ARBs
      a similar or even superior beneficial effect in this typology of patients is worth
      investigating. This could be of clinical relevance in these terms: 1. Effective prevention of
      ESRD in people with type 2 diabetes is expected to translate in a remarkable reduction in
      costs for renal replacement therapy by chronic dialysis or kidney transplantation; 2. A
      better definition of the cost/effectiveness profile of different study treatments may help
      optimizing the allocation of available resources in order to achieve more effective
      prevention at lower costs. 3. The definition of individual risk profiles may allows
      identifying subjects at increased risk that may benefit the most of intensified treatment,
      which should translate in a further optimization of the use of available resources at
      population level. Moreover, in addition to verify whether dual RAS blockade by combined ACE
      inhibitor and ARB treatment more effectively than single drug RAS blockade may prevent
      progression to ESRD, the present study will offer the opportunity to compare the
      renoprotective effects of equivalent doses of ACE inhibitors or ARBs.

      Aims Primary To evaluate whether, at comparable blood pressure control, dual RAS blockade
      with combined therapy with halved doses of benazepril (10 mg/day) and valsartan (160 mg/day)
      reduces the incidence of ESRD more effectively than single drug RAS blockade by full doses of
      valsartan (320 mg/day) given alone in high-risk patients with type 2 diabetes and overt
      nephropathy.

      Secondary

        -  To evaluate whether, at comparable blood pressure control, dual RAS blockade with
           combined therapy with halved doses of benazepril (10 mg/day) and valsartan (160 mg/day)
           reduces the incidence of ESRD more effectively than single drug RAS blockade by full
           doses of benazepril (20 mg/day) given alone in high-risk patients with type 2 diabetes
           and overt nephropathy.

        -  To evaluate whether, at comparable blood pressure control, the effects of benazepril and
           valsartan therapy are similar or whether, alternatively, one of the two treatments
           offers a superior protective effect against the progression to ESRD in the above study
           population.

        -  To evaluate the effects of the three study treatments on the incidence of fatal and
           non-fatal cardiovascular events, doubling of baseline serum creatinine, GFR decline and
           proteinuria,

        -  To assess the relationships, in the study group as a whole and within each treatment
           group, between renal outcome variables (ESRD, doubling serum creatinine, GFR decline,
           proteinuria) and fatal and non-fatal cardiovascular events, between achieved blood
           pressure or metabolic control and renal and/or cardiovascular outcome variables and
           between achieved proteinuria reduction or residual follow-up proteinuria and renal
           and/or cardiovascular outcome variables.

      Design This will be a multicenter, Prospective, Randomized, Open label, Blinded End point
      (PROBE) trial of 3-year treatment with halved doses of benazepril (10 mg/day) and valsartan
      (160 mg/day) given in combination, or full doses of both benazepril (20 mg/day), or valsartan
      (320 mg/day) given alone in 102 consenting patients >40 year old, with type 2 diabetes (WHO
      criteria), serum creatinine >1.8 mg/dl and < 3.5 mg/dl, spot morning urine albumin to
      creatinine ratio >1000mg/g for the patients without previous ACE inhibitor and ARB therapy
      and >500mg/g for the patients with previous ACE inhibitor or ARB therapy and no specific
      contraindications to the study drugs. Primary efficacy variable will be ESRD and primary
      comparison will be between the benazepril plus valsartan and valsartan alone groups. The
      analysis will have an 80% power to detect (p=0.05, two-side test) a 50% difference in ESRD
      incidence.
    

Intervention name(s): Benazepril; Valsartan; Benazepril/Valsartan
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Patients satisfying the inclusion/exclusion criteria will be randomly given equivalent doses (half the standard doses recommended by the manufacturer for blood pressure control) of benazepril (10 mg/day) or valsartan (160 mg/day) or one fourth of the standard doses of both agents in combination (benazepril 5 mg/day and valsartan 80 mg/day).If well tolerated, treatment will be up-titrated to full dose of benazepril (20 mg/day) or valsartan (320 mg/day) or one half of the standard doses of both agents in combination (benazepril 10 mg/day and valsartan 160 mg/day).; Patients satisfying the inclusion/exclusion criteria will be randomly given equivalent doses (half the standard doses recommended by the manufacturer for blood pressure control) of benazepril (10 mg/day) or valsartan (160 mg/day) or one fourth of the standard doses of both agents in combination (benazepril 5 mg/day and valsartan 80 mg/day).If well tolerated, treatment will be up-titrated to full dose of benazepril (20 mg/day) or valsartan (320 mg/day) or one half of the standard doses of both agents in combination (benazepril 10 mg/day and valsartan 160 mg/day).; Patients satisfying the inclusion/exclusion criteria will be randomly given equivalent doses (half the standard doses recommended by the manufacturer for blood pressure control) of benazepril (10 mg/day) or valsartan (160 mg/day) or one fourth of the standard doses of both agents in combination (benazepril 5 mg/day and valsartan 80 mg/day).If well tolerated, treatment will be up-titrated to full dose of benazepril (20 mg/day) or valsartan (320 mg/day) or one half of the standard doses of both agents in combination (benazepril 10 mg/day and valsartan 160 mg/day).
Intervention MeSH terms: Valsartan; Benazepril
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment