BMJ  2004;328:495 (28 February), doi:10.1136/bmj.37970.629537.0D (published 11 February 2004)

Primary care

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)

¹ Endocrinologie-Diabétologie-Nutrition, Groupe Hospitalier Bichat-Claude Bernard, Assistance Publique des Hôpitaux de Paris, 46 rue Henri Huchard, 75877 Paris Cedex 18, France, ² Service 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, ⁴ Schwabing General Hospital, Ludwig Maximilians University, D-80804 Munich, Germany, ⁵ Service de Diabétologie, Hôpital Saint-Louis, Assistance Publique des Hôpitaux de Paris, 1 avenue Claude Vellefaux, 75475 Paris Cedex 10

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.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

Relevant Articles

Confidence intervals illuminate absence of evidence

Doug Altman and J Martin Bland
BMJ 2004 328: 1016-1017. [Extract] [Full Text]

Low dose ramipril is not optimal in diabetes
BMJ 2004 328: 0. [Full Text]

What doesn't work and how to show it

Phil Alderson and Trish Groves
BMJ 2004 328: 473. [Extract] [Full Text] [PDF]

This article has been cited by other articles:

• Turnbull, F., Woodward, M., Neal, B., Barzi, F., Ninomiya, T., Chalmers, J., Perkovic, V., Li, N., MacMahon, S, the Blood Pressure Lowering Treatment Trialists' C, (2008). Do men and women respond differently to blood pressure-lowering treatment? Results of prospectively designed overviews of randomized trials. Eur Heart J 0: ehn427v1-12 [Abstract] [Full text]  
• Benedetto, U., Sciarretta, S., Roscitano, A., Fiorani, B., Refice, S., Angeloni, E., Sinatra, R. (2008). Preoperative Angiotensin-converting enzyme inhibitors and acute kidney injury after coronary artery bypass grafting.. Ann. Thorac. Surg. 86: 1160-1165 [Abstract] [Full text]  
• Hadjadj, S., Fumeron, F., Roussel, R., Saulnier, P.-J., Gallois, Y., Ankotche, A., Travert, F., Khalil, C. A., Miot, A., Alhenc-Gelas, F., Lievre, M., Marre, M., on behalf of the DIABHYCAR, DIAB2NEPHROGENE, and S, (2008). Prognostic Value of the Insertion/Deletion Polymorphism of the ACE Gene in Type 2 Diabetic Subjects: Results from the Non-Insulin-Dependent Diabetes, Hypertension, Microalbuminuria or Proteinuria, Cardiovascular Events, and Ramipril (DIABHYCAR), Diabete de type 2, Nephropathie et Genetique (DIAB2NEPHROGENE), and Survie, Diabete de type 2 et Genetique (SURDIAGENE) studies . Diabetes Care 31: 1847-1852 [Abstract] [Full text]  
• Cheurfa, N., Dubois-Laforgue, D., Ferrarezi, D. A.F., Reis, A. F., Brenner, G. M., Bouche, C., Le Feuvre, C., Fumeron, F., Timsit, J., Marre, M., Velho, G. (2008). The Common -866G>A Variant in the Promoter of UCP2 Is Associated With Decreased Risk of Coronary Artery Disease in Type 2 Diabetic Men. Diabetes 57: 1063-1068 [Abstract] [Full text]  
• Air, E. L., Kissela, B. M. (2007). Diabetes, the Metabolic Syndrome, and Ischemic Stroke: Epidemiology and possible mechanisms. Diabetes Care 30: 3131-3140 [Full text]  
• Porchay-Balderelli, I., Pean, F., Bellili, N., Jaziri, R., Marre, M., Fumeron, F., for the DIABHYCAR Study Group, (2007). The CETP TaqIB Polymorphism Is Associated With the Risk of Sudden Death in Type 2 Diabetic Patients. Diabetes Care 30: 2863-2867 [Abstract] [Full text]  
• Navaneethan, S. D., Querques, M., Bonifati, C., Strippoli, G. F. M. (2006). Antihypertensive Agents in Patients With Diabetes: Trade-off Between Renal and Cardiovascular Protection.. The Diabetes Educator 32: 596-602 [Abstract] [Full text]  
• Tropeano, A.-I., Boutouyrie, P., Pannier, B., Joannides, R., Balkestein, E., Katsahian, S., Laloux, B., Thuillez, C., Struijker-Boudier, H., Laurent, S. (2006). Brachial Pressure-Independent Reduction in Carotid Stiffness After Long-Term Angiotensin-Converting Enzyme Inhibition in Diabetic Hypertensives. Hypertension 48: 80-86 [Abstract] [Full text]  
• Azizi, M., Menard, J., Peyrard, S., Lievre, M., Marre, M., Chatellier, G. (2006). Assessment of Patients' and Physicians' Compliance to an ACE Inhibitor Treatment Based on Urinary N-Acetyl Ser-Asp-Lys-Pro Determination in the Noninsulin-Dependent Diabetes, Hypertension, Microalbuminuria, Proteinuria, Cardiovascular Events, and Ramipril (DIABHYCAR) Study.. Diabetes Care 29: 1331-1336 [Abstract] [Full text]  
• Rosen, A. B., Hamel, M. B., Weinstein, M. C., Cutler, D. M., Fendrick, A. M., Vijan, S. (2005). Cost-Effectiveness of Full Medicare Coverage of Angiotensin-Converting Enzyme Inhibitors for Beneficiaries with Diabetes. ANN INTERN MED 143: 89-99 [Abstract] [Full text]  
• Daly, C. A., Fox, K. M., Remme, W. J., Bertrand, M. E., Ferrari, R., Simoons, M. L., on behalf of the EUROPA investigators, (2005). The effect of perindopril on cardiovascular morbidity and mortality in patients with diabetes in the EUROPA study: results from the PERSUADE substudy. Eur Heart J 26: 1369-1378 [Abstract] [Full text]  
• Yusuf, S., Pogue, J., Myers, M. G., McCullough, C., Pfeffer, M. A., Domanski, M. J., Braunwald, E. (2005). ACE Inhibition in Stable Coronary Artery Disease. NEJM 352: 937-939 [Full text]  
• (2004). Other articles noted. Evid. Based Med. 9: e5-e5 [Full text]  
• Altman, D., Bland, J M. (2004). Confidence intervals illuminate absence of evidence. BMJ 328: 1016-1017 [Full text]  
• (2004). Does Low-Dose Ramipril Offer Cardiovascular and Renal Protection?. Journal Watch Cardiology 2004: 3-3 [Full text]  
• (2004). Low-Dose Ramipril Doesn't Prevent Cardiovascular Problems in Type 2 Diabetes. JWatch General 2004: 3-3 [Full text]  
• Azizi, M., Bissery, A., Lamarre-Cliche, M., Menard, J. (2004). Integrating Drug Pharmacokinetics for Phenotyping Individual Renin Response to Angiotensin II Blockade in Humans. Hypertension 43: 785-790 [Abstract] [Full text]  
• Alderson, P., Groves, T. (2004). What doesn't work and how to show it. BMJ 328: 473-473 [Full text]  

Rapid Responses:

Read all Rapid Responses

Citation no 18

Fredrik H. Nystrom
bmj.com, 9 Mar 2004 [Full text]