Marre, M. et al. DIABHYCAR Study Investigators. Effects of low dose ramipril on cardiovascular and renal outcomes in patients with type 2 diabetes and raised excretion of urinary albumin: randomised, double blind, placebo controlled trial (the DIABHYCAR study). BMJ 328, 495

Technische Universität München, München, Bavaria, Germany
BMJ (online) (Impact Factor: 17.45). 03/2004; 328(7438):495. DOI: 10.1136/bmj.37970.629537.0D
Source: PubMed


To investigate whether a low dose of the angiotensin converting enzyme (ACE) inhibitor ramipril lowers cardiovascular and renal events in patients with type 2 diabetes who have microalbuminuria or proteinuria.
Randomised, double blind, parallel group trial comparing ramipril (1.25 mg/day) with placebo (on top of usual treatment) for cardiovascular and renal outcomes for at least three years.
Multicentre, primary care study conducted mostly by general practitioners in 16 European and north African countries.
4912 patients with type 2 diabetes aged >50 years who use oral antidiabetic drugs and have persistent microalbuminuria or proteinuria (urinary albumin excretion > or = 20 mg/l in two consecutive samples), and serum creatinine < or = 150 micromol/l.
The primary outcome measure was the combined incidence of cardiovascular death, non-fatal myocardial infarction, stroke, heart failure leading to hospital admission, and end stage renal failure.
Participants were followed for 3 to 6 (median 4) years. There were 362 primary events among the 2443 participants taking ramipril (37.8 per 1000 patient years) and 377 events among the 2469 participants taking placebo (38.8 per 1000 patient years; hazard ratio 1.03 (95% confidence interval 0.89 to 1.20, P = 0.65)). None of the components of the primary outcome was reduced. Ramipril lowered systolic and diastolic blood pressures (by 2.43 and 1.06 mm Hg respectively after two years) and favoured regression from microalbuminuria (20-200 mg/l) or proteinuria (> 200mg/l) to normal level (< 20 mg/l) or microalbuminuria (P < 0.07) in 1868 participants who completed the study.
Low dose (1.25 mg) ramipril once daily has no effect on cardiovascular and renal outcomes of patients with type 2 diabetes and albuminuria, despite a slight decrease in blood pressure and urinary albumin. The cardiovascular benefits of a daily higher dose (10 mg) ramipril observed elsewhere are not found with an eightfold lower daily dose.

Download full-text


Available from: Johannes F E Mann
    • "Among the BP-lowering RCTs that had rigorously excluded patients with baseline heart failure, four had BP lowering induced or initiated by a diuretic[11,13,17,18]; two by a b-blocker[15,32]; four by a calcium antagonist[9,12,22,23]; five by an ACE-inhibitor[12,32,343536and two by an angiotensin receptor blocker[43,44](Table 1, last column to the right). In meta-analyses restricted to RCTs with noto the extent of blood pressure (BP) reductions, in the 35 BP-lowering trials in which all the listed outcomes were measured. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background and objectives: Relative effectiveness of blood pressure (BP)-lowering treatment on various outcomes was evaluated by meta-analyses restricted to randomized controlled trials (RCTs) measuring all major outcomes, and the question whether BP lowering and each class of antihypertensive agents prevent new-onset heart failure by meta-analyses limited to RCTs excluding baseline heart failure from randomization. Methods: Source of these meta-analyses are our databases of BP-lowering RCTs vs placebo or less-active treatment, and head-to-head comparisons of different antihypertensive classes. Risk ratios (RRs) and 95% confidence intervals of seven outcomes were calculated by a random-effects model. The relationships of outcome reductions to BP differences were investigated by meta-regressions. Results: First, 35 BP-lowering RCTs measured all outcomes, and heart failure [RR 0.63 (0.52-0.75)] and stroke [RR 0.58 (0.49-0.68)] were the outcomes most effectively prevented. Second, heart failure and stroke reductions were significantly related to SBP, DBP and pulse pressure reductions. Third, in 18 BP-lowering RCTs excluding baseline heart failure from recruitment, heart failure reduction ('new-onset' heart failure) [RR 0.58 (0.44-0.75)] was very similar to that in the entire set of RCTs. Fourth, in meta-analyses of head-to-head comparisons of different antihypertensive classes, calcium antagonists were inferior in preventing 'new-onset' heart failure [RR 1.16 (1.01-1.33)]. However, this inferiority disappeared when meta-analysis was limited to RCTs allowing concomitant use of diuretics, β-blockers or renin-angiotensin system blockers also in the calcium antagonist group [RR 0.96 (0.81-1.12)]. Conclusion: BP-lowering treatment effectively prevents 'new onset' heart failure. It is suggested that BP lowering by calcium antagonists is effective as BP lowering by other drugs in preventing 'new-onset' heart failure, unless the trial design creates an unbalance against calcium antagonists.
    No preview · Article · Jan 2016 · Journal of Hypertension
  • Source
    • "The trial was a four-year, double-blind, parallel study. This trial showed no effect of low dose ramipril on the incidence of renal events [27]. The French Caucasian participants (3137 of the 4912 subjects) gave written informed consent for enrollment in the genetic sub-study. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Sterols, bile acids and their receptors have been involved in diabetic nephropathy. The ATP-binding cassette transporters G5 and G8 (ABCG5 and ABCG8) play an important role in intestinal sterol absorption and bile acid secretion. The aim of our study was to assess the associations between two ABCG8 coding polymorphisms, T400K and D19H, and the incidence of renal events in type 2 diabetic subjects. Participants were the 3137 French type 2 diabetic subjects with micro- or macro-albuminuria from the genetic substudy of the DIABHYCAR trial. The mean duration of follow-up was 4years. Renal events were defined as a doubling of serum creatinine concentration or end-stage renal disease at follow-up. We then used a second population (DIAB2NEPHROGENE) of 2140 type 2 diabetic patients for the purpose of validation. In DIABHYCAR, the 400K allele was significantly associated with a higher risk of incident renal events in a multiple adjusted model (HR: 1.75 [95% CI 1.20-2.56], P=0.003). This association was still significant after further adjustments for baseline values of estimated glomerular filtration rate and urinary albumin excretion. In the validation population, the 400K allele was associated with the prevalence of end-stage renal disease (OR=2.01 [95% CI 1.15-3.54], P=0.015). No significant association was found between the D19H polymorphism and the risk of diabetic nephropathy. A polymorphism of the sterol transporter ABCG8 has been associated with the prevalence of end-stage renal disease and with the incidence of new renal events in type 2 diabetic patients. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Mar 2015 · Metabolism: clinical and experimental
  • Source
    • "Increased levels of urinary albumin excretion (UAE) do not only provide an indication of early renal dysfunction, but functions also as a marker of endothelial dysfunction [3]. Many trials have reported on a high prevalence of elevated UAE not only in high risk subjects suffering from diabetes [4] [5], renal failure [6], or heart failure [7] [8], but also in subjects from the general population [9]. An increased UAE was in every cohort associated with worse outcome. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background The PREVEND IT trial reported on a high cardiovascular (CV) event rate in subjects with a baseline urinary albumin excretion (UAE) rate of ≥ 50 mg/24 h. Here, we report on the observed 10-year CV outcome of this population and compare this with the predicted Framingham Risk Score (FRS). In addition, we evaluated the effect of four years of fosinopril treatment on this relation. Methods and results From the PREVEND IT cohort, 833 subjects without history of CV disease, randomized to fosinopril (N = 412) or placebo (N = 421), were studied. The primary endpoint included CV mortality and adjudicated hospitalization for CV disease during a 10-year follow-up period. Mean age was 51 ± 12 years and 65% were males, while prevalence of diabetes (2.6%) and use of CV drugs (3.5%) was low. Subjects were categorized to high UAE (≥ 50 mg/24 h) or low UAE (< 50 mg/24 h). After 10 years of follow-up, the event rate in the high UAE group was almost twice as high as predicted by the FRS (29.5% vs. 17.2%). Treatment for four years with fosinopril reduced the event rate to comparable levels of that predicted by FRS. The addition of UAE ≥ 50 mg/24 h to the FRS improved the Integrated Discrimination Improvement (P = 0.033) and increased the area under the curve by 0.54% (P = 0.024). Conclusions The 10-year CV risk of subjects with an elevated UAE (≥ 50 mg/24 h) is substantially underestimated by the FRS. Treatment with fosinopril successfully reduced this increased event rate to FRS-predicted CV risk.
    Full-text · Article · Apr 2014 · IJC Heart and Vessels
Show more