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Bergamo Nephrologic Diabetes Complications Trial - BENEDICT
Description:
The goal of the trial was to evaluate treatment with the angiotensin-converting enzyme (ACE) inhibitor trandolapril, the calcium channel blocker verapamil, or the combination of the two compared with placebo among patients with hypertension, type 2 diabetes, and normal urinary albumin excretion.
Study Design
Study Design:
Patients Enrolled: 1,204
Mean Follow Up: Median 3.6 years
Mean Patient Age: Mean age 63 years
Female: 47
Patient Populations:
Age ≥40 years; hypertension, defined as untreated systolic blood pressure of ≥130 mm Hg, diastolic blood pressure of ≥85 mm Hg, or need for antihypertensive therapy to attain a systolic or diastolic blood pressure under these levels; known history of type 2 diabetes mellitus not exceeding 25 years; urinary albumin excretion rate <20 µg per minute in at least two of three consecutive, sterile, overnight samples; and a serum creatinine concentration of ≤1.5 mg/dl.
Exclusions:
Glycosylated hemoglobin level ≥11%, nondiabetic renal disease, or specific indication for or contraindication to ACE inhibitor therapy or nondihydropyridine calcium channel blocker therapy
Primary Endpoints:
Development of persistent microalbuminuria (overnight albumin excretion, ≥20 µg per minute at two consecutive visits)
Secondary Endpoints:
Follow-up systolic and diastolic blood pressure
Drug/Procedures Used:
Patients were randomized to trandolapril (2 mg/day) plus verapamil (sustained-release formulation, 180 mg/day) (n=300), trandolapril alone (2 mg/day) (n=301), verapamil alone (sustained-release formulation, 240 mg/day) (n=303), or placebo (n=300). Treatment was continued for at least three years. Target blood pressure was 120/80 mm Hg. Blood pressure and randomly collected morning urine samples were performed every three months.
Principal Findings:
Persistent microalbuminuria developed in 5.7% of the trandolapril plus verapamil group, 6.0% of the trandolapril group, 11.9% of the verapamil group, and 10.0% of the placebo group. The estimated acceleration factor (which quantifies the effect of one treatment relative to another in accelerating or slowing disease progression) adjusted for predefined baseline characteristics was 0.39 for combination therapy versus placebo (p=0.01), 0.47 for trandolapril versus placebo (p=0.01), and 0.83 for verapamil versus placebo (p=0.54).
In an analysis that pooled the two trandolapril groups versus the two nontrandolapril groups, persistent microalbuminuria developed in 5.8% of the trandolapril groups versus 10.9% of the nontrandolapril groups (acceleration factor 0.44, p<0.001). In an analysis that pooled the two verapamil groups versus the two nonverapamil groups, persistent microalbuminuria developed in 8.8% of the verapamil groups versus 8.0% of the nonverapamil groups (p=NS).
Average systolic and diastolic blood pressure, respectively, was 139 and 80 mm Hg in the combination group, 139 and 81 mm Hg in the trandolapril group, 141 and 82 mm Hg in the verapamil group, and 142 and 83 in the placebo group (p<0.002 for combination group vs. placebo and trandolapril vs. placebo; p=NS for verapamil vs. placebo). Nonfatal serious adverse events were similar in all treatment groups (22.3% in the combination group, 26.6% in the trandolapril group, 22.1% in the verapamil group, and 23.3% in the placebo group).
Interpretation:
Among patients with hypertension, type 2 diabetes, and normal urinary albumin excretion, treatment with trandolapril plus verapamil and trandolapril alone was associated with a reduction in the incidence of microalbuminuria compared to placebo to a similar extent, while treatment with verapamil alone was not associated with a reduction in development of microalbuminuria compared with placebo. The reduction in microalbuminuria in the trandolapril plus verapamil and trandolapril alone groups exceeds the benefit expected, given the reduction in blood pressure.
In diabetics, microalbuminuria is often the first clinical indicator of renal dysfunction, a severe complication that can lead to the need for dialysis or transplantation. Post-hoc analyses of type 2 diabetic patients from the HOPE and LIFE trials showed a reduction in overt nephropathy associated with treatment with a renin-angiotensin system compared with controls. However, the present study is the first large-scale, randomized trial designed to evaluate the neuroprotective effects in a prespecified manner.
References:
Ruggenenti P, Fassi A, Ilieva AP, et al. Preventing microalbuminuria in type 2 diabetes. N Engl J Med 2004;351:1941-51.
Keywords: Diabetes Mellitus, Type 2, Renin-Angiotensin System, Creatinine, Calcium Channel Blockers, Renal Dialysis, Indoles, Neuroprotective Agents, Verapamil, Hypertension, Disease Progression
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