Preventing Microalbuminuria in Type 2 Diabetes
Condition: Diabetes
MeSH terms: Diabetes Mellitus
Study type: Interventional
Phase: Phase 3

Summary: 
      In people with type 2 diabetes, microalbuminuria is a strong, independent risk factor for
      diabetic nephropathy and cardiovascular morbidity and mortality. ACE inhibitor therapy
      decreased the risk of microalbuminuria in hypertensive subjects with type 2 diabetes and
      normoalbuminuria by about 40%. Available data suggest that angiotensin II receptor blockers
      (ARBs) might have a similar renoprotective effect and that this effect might be increased by
      combined ACE inhibitor therapy.

      The study will evaluate the effects, at similar blood pressure control (systolic/diastolic
      <130/80 mmHg), for a period of three years, of dual renin-angiotensin-system (RAS) blockade
      by benazepril and valsartan combination therapy as compared to single RAS blockade by
      benazepril or valsartan alone on microalbuminuria and cardiovascular events in high-risk
      patients with type 2 diabetes, creatinine <1.5 mg/dl, no evidence of microalbuminuria but at
      high risk of renal disease, with hypertension and a urinary albumin excretion between 7 and
      19 microgram/min. The relationship between albuminuria and cardiovascular outcomes will also
      be evaluated.

      The study is expected to show a more effective prevention of microalbuminuria and
      cardiovascular events with combined than with single drug ACE inhibitor or ARB therapy. As
      compared to ACE inhibitor, ARB therapy is expected to have a similar effect on
      microalbuminuria, but an inferior cardioprotective effect. Applied to clinical practice, the
      findings should help preventing renal and cardiovascular complications, and related treatment
      costs, of type 2 diabetes.
    

Detailed description: 
      Nephropathy of type 2 diabetes is the leading cause of end stage renal disease (ESRD) in the
      world.According to the World Health Organization (WHO), diabetes affects over 170 million
      people, and, due to progressive aging of the population, life-style modifications and
      increasing burden of obesity, this number is expected to rise to 370 millions by 2030. About
      one third of those affected will eventually have progressive deterioration of renal function
      Untreated, these patients progress to ESRD within 10 years or die prematurely because of
      cardiovascular complications (that are 10-fold more frequent in diabetics with nephropathy
      than in those without and the general population). Costs for renal replacement therapy of
      these patients - and for treatment of related complications - are also progressively
      increasing.

      Persistent microalbuminuria is the first clinical sign of renal dysfunction in diabetic
      patients and progresses to overt proteinuria in 20 to 40 percent of cases. In 10 to 50
      percent of patients with proteinuria, chronic kidney disease develops that ultimately
      requires dialysis or transplantation. Of great concern, 40 to 50 percent of type 2 diabetic
      patients with microalbuminuria eventually die of cardiovascular disease.Thus, preventing (or
      delaying) the development of microalbuminuria is a key treatment goal for renoprotection and,
      possibly, for cardioprotection.

      A large scale randomized trial, the BErgamo NEphrologic DIabetes Complications Trial
      (BENEDICT) found that treatment with the ACE-inhibitor trandolapril (either alone or combined
      to the calcium channel blocker verapamil) significantly reduced the incidence of
      microalbuminuria in 1204 patients with type 2 diabetes and hypertension, but normal urinary
      albumin excretion, as compared with placebo. The effect of preventing microalbuminuria
      exceeded expectations based on changes in blood pressure alone and was not enhanced by
      combined calcium channel blocker therapy.

      Studies in patients with type 2 diabetes and micro- or macro- albuminuria clearly show that
      ARBs can have renoprotective effect but trials evaluating the effects of angiotensin receptor
      blockers (ARBs) on the incidence of microalbuminuria in type 2 diabetic patients with normal
      urinary albumin excretion rate are missing.

      Whether the beneficial effect against the development of microalbuminuria is enhanced when
      ACE inhibitors and ARBs are given in combination is not established so far. However, finding
      that combined ACE inhibitor and ARB therapy more effectively than single drug RAS blockade
      reduced albuminuria or proteinuria in subjects with type 2 diabetes and slowed progression to
      ESRD in those with non-diabetic chronic nephropathies, suggests that the renoprotective
      effect of combined therapy could be superior to that of single drug blockade of the RAS also
      in diabetic patients with no evidence of renal disease.

      Post hoc analyses of the BENEDICT trial found that high-normal albuminuria at baseline
      evaluation (defined as a urinary albumin excretion rate between 10 µg/min and the upper limit
      for study entry: 19 µg/min) was the strongest baseline predictor of subsequent development of
      microalbuminuria. Indeed, regardless of treatment randomization, 69 of 271 (25.5%) patients
      with high-normal albuminuria (urinary albumin excretion >10µg/min) progressed to the end
      point as compared to only 32 of 933 (3.4%) with low-normal albuminuria (<10%). Thus,
      large-part of the excess risk for microalbuminuria observed in people with type 2 diabetes is
      associated with high-normal albuminuria.

      In addition, this clinical trial might have a clinical relevance for the Italian National
      Health service (SSN): applied to clinical practice the results should help in reducing renal
      and cardiovascular complications and related treatment costs, of type 2 diabetes.

      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 microalbuminuria 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,
      hypertension and high normal albuminuria.

      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 microalbuminuria more effectively than valsartan (320 mg/day)
           given alone in high-risk patients with type 2 diabetes, hypertension and high normal
           albuminuria.

        -  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 offer
           a superior protective effect against the development of microalbuminuria in the above
           study population.

        -  To evaluate the effects of the three study treatments on the incidence of fatal and
           non-fatal cardiovascular events, regression to low-normal albuminuria (urinary albumin
           excretion <7 µg/min), albuminuria (considered as a continuous variable), serum
           creatinine, lipid profile, and GFR (in a representative subgroup);

        -  To assess the relationships, in the study group as a whole and within each treatment
           group, between renal outcome variables (including microalbuminuria and time-dependent
           changes in albuminuria) and fatal and non-fatal cardiovascular events, between achieved
           blood pressure or metabolic control and renal and/or cardiovascular outcome variables
           and between achieved albuminuria reduction or residual follow-up albuminuria 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 1020 consenting patients >40 year old, with type 2 diabetes (WHO
      criteria), serum creatinine <1.5 mg/dl, high-normal albuminuria (UAE >7 and <20 µg/min in at
      least 2 of 3 overnight urine collections), and no specific contraindications to the study
      drugs. Primary outcome variable will be microalbuminuria (UAE > 20µg /min in at least 2 of 3
      overnight urine collections in two consecutive visits 2 months apart) and primary comparison
      will be between the combined benazepril plus valsartan and the benazepril alone groups. The
      analysis will have an 80% power to detect (p=0.05, two-side test) a 40% difference in the
      incidence of microalbuminuria.
    

Intervention name(s): Benazepril; Valsartan; Benazepril/Valsartan
Intervention type(s): Drug; Drug; Drug
Intervention description(s): After one month wash-out from previous RAS (ARB or ACE) inhibitor therapy, 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).; After one month wash-out from previous RAS (ARB or ACE) inhibitor therapy, 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).; After one month wash-out from previous RAS (ARB or ACE) inhibitor therapy, 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