Preventing microalbuminuria with benazepril, valsartan, and benazepril-valsartan combination therapy in diabetic patients with high-normal albuminuria: A prospective, randomized, open-label, blinded endpoint (PROBE) study

Abstract

Background: Angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) prevent microalbuminuria in normoalbuminuric type 2 diabetic patients. We assessed whether combined therapy with the 2 medications may prevent microalbuminuria better than ACE inhibitor or ARB monotherapy.

Methods and findings: VARIETY was a prospective, randomized, open-label, blinded endpoint (PROBE) trial evaluating whether, at similar blood pressure (BP) control, combined therapy with benazepril (10 mg/day) and valsartan (160 mg/day) would prevent microalbuminuria more effectively than benazepril (20 mg/day) or valsartan (320 mg/day) monotherapy in 612 type 2 diabetic patients with high-normal albuminuria included between July 2007 and April 2013 by the Istituto di Ricerche Farmacologiche Mario Negri IRCCS and 8 diabetology or nephrology units in Italy. Time to progression to microalbuminuria was the primary outcome. Analyses were intention to treat. Baseline characteristics were similar among groups. During a median [interquartile range, IQR] follow-up of 66 [42 to 83] months, 53 patients (27.0%) on combination therapy, 57 (28.1%) on benazepril, and 64 (31.8%) on valsartan reached microalbuminuria. Using an accelerated failure time model, the estimated acceleration factors were 1.410 (95% CI: 0.806 to 2.467, P = 0.229) for benazepril compared to combination therapy, 0.799 (95% CI: 0.422 to 1.514, P = 0.492) for benazepril compared to valsartan, and 1.665 (95% CI: 1.007 to 2.746, P = 0.047) for valsartan compared to combination therapy. Between-group differences in estimated acceleration factors were nonsignificant after adjustment for predefined confounders. BP control was similar across groups. All treatments were safe and tolerated well, with a slight excess of hyperkalemia and hypotension in the combination therapy group. The main study limitation was the lower than expected albuminuria at inclusion.

Conclusions: Risk/benefit profile of study treatments was similar. Dual renin-angiotensin system (RAS) blockade is not recommended as compared to benazepril or valsartan monotherapy for prevention of microalbuminuria in normoalbuminuric type 2 diabetic patients.

Trial registration: EudraCT 2006-005954-62; ClinicalTrials.gov NCT00503152.

Fig 1. Trial profile.

Fig 2. Kaplan–Meier curves for the primary endpoint of progression to microalbuminuria.

Kaplan–Meier curves show the proportion of patients who reached the primary endpoint of progression to microalbuminuria in the benazepril, valsartan, and combination therapy groups during a median follow-up of 66 months. HRs, AFs, and their respective 95% confidence intervals are crude (unadjusted) and adjusted for center, age, sex, smoking habit, baseline mean BP, and log-transformed UAE. Adj, adjusted; AF, acceleration factor; BP, blood pressure; HR, hazard ratio; UAE, urinary albumin excretion; unadj, unadjusted.

Fig 3. Median albuminuria, mean BP, and HbA1c levels during the study period according to treatment groups.

Median albuminuria (A), mean systolic and diastolic BP (B), and HbA1c levels (C) during the study period according to treatment groups. BP, blood pressure.

Fig 4. Kaplan–Meier curves for fatal or nonfatal MACEs.

Kaplan–Meier curves show the proportion of patients who reached the composite endpoint of sudden cardiac death and fatal and nonfatal acute myocardial infarction or stroke in the benazepril, valsartan, and combination therapy groups during a median follow-up of 66 months. HRs and 95% confidence intervals are crude (unadjusted) and adjusted for center, age, sex, smoking habit, baseline mean BP, and log-transformed UAE. Adj, adjusted; BP, blood pressure; HR, hazard ratio; MACE, major cardiovascular event; UAE, urinary albumin excretion; unadj, unadjusted.