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 2004; 328 doi: https://doi.org/10.1136/bmj.37970.629537.0D (Published 26 February 2004) Cite this as: BMJ 2004;328:495
- Michel Marre, professor ()1,
- Michel Lievre, associate professor2,
- Gilles Chatellier, professor3,
- Johannes F E Mann, professor4,
- Philippe Passa, professor5,
- Joël Ménard, professor3,
- DIABHYCAR Study Investigators
- 1Endocrinologie-Diabétologie-Nutrition, Groupe Hospitalier Bichat-Claude Bernard, Assistance Publique des Hôpitaux de Paris, 46 rue Henri Huchard, 75877 Paris Cedex 18, France
- 2Service de Pharmacologie Clinique, Faculté de Médecine Laënnec, rue Guillaume Paradin, BP 8071, 69376 Lyon Cedex 08
- 3 Département de Santé Publique, Informatique et Statistiques Médicales, 15 rue de l'Ecole de Médecine, 75270 Paris Cedex 06
- 4Schwabing General Hospital, Ludwig Maximilians University, D-80804 Munich, Germany
- 5Service de Diabétologie, Hôpital Saint-Louis, Assistance Publique des Hôpitaux de Paris, 1 avenue Claude Vellefaux, 75475 Paris Cedex 10
- Correspondence to: Professor M Marre, Service d'Endocrinologie Diabétologie Diabétologie Nutrition, Hôpital Bichat-Claude Bernard, 46, rue Henri Huchard, 75877 Paris Cedex 18, France
- Accepted 28 November 2003
Objective 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.
Design 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.
Setting Multicentre, primary care study conducted mostly by general practitioners in 16 European and north African countries.
Participants 4912 patients with type 2 diabetes aged > 50 years who use oral antidiabetic drugs and have persistent microalbuminuria or proteinuria (urinary albumin excretion 20 mg/l in two consecutive samples), and serum creatinine ≤ 150 μmol/l.
Main outcome measures 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.
Results 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.
Conclusions 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.
Funding This study was supported by a grant from Aventis (Paris) and by a Programme Hospitalier de Recherche Clinique (French health ministry) in Angers in 1996.
Competing interests During the past five years MM, ML, GC, JFEM, PP, and JM have received reimbursements for attending symposiums, for speaking, or for consulting, or have received funds for research about the renin-angiotensin system, from the following companies: AstraZeneca, Aventis, Bristol-Myers-Squibb, Merck Sharpe Dohme, Servier, and Takeda. For this study MM and ML received funds from Aventis for assaying urinary albumin and data management respectively. The following investigators are or had been employees of Aventis: Sylvie Etienne, Nathalie Genes, Daniel Vasmant, Laurent Vaur, Claude Weisselberg.
Ethical approval The study protocol was approved by the appropriate institutional review board or ethical committee in each country. The study was approved by INSERM (Institut National de la Santé et de la Recherche Médicale), France.
- Accepted 28 November 2003