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Should All Patients with Type 1 Diabetes Mellitus and Microalbuminuria Receive Angiotensin-Converting Enzyme Inhibitors?: A Meta-Analysis of Individual Patient Data

The ACE Inhibitors in Diabetic Nephropathy Trialist Group*
[+] Article and Author Information

From University of Birmingham, Birmingham, South Cleveland Hospital, Middlesbrough, University of Warwick, Warwick, and Imperial College of Medicine at St. Mary's, University College London, and King's College London, London, United Kingdom; University Hospital, Linkoping, Sweden; University of Padua and Sassari and National Research Centre for the Study of Aging, Padua, Italy; Austin and Repatriation Medical Centre, Heidelberg, Australia; Hôpital Broussais, Paris, France; Steno Diabetes Centre, Copenhagen, and Aarhus University Hospital, Aarhus, Denmark; and Joslin Diabetes Center, Boston, Massachusetts.


Acknowledgments: An educational grant for a meeting to plan this work was provided by Zeneca Pharmaceuticals.

Requests for Single Reprints: Nish Chaturvedi, MRCP, MD, Department of Epidemiology and Public Health, Imperial College at St. Mary's, Norfolk Place, London W2 1PG, United Kingdom; e-mail, n.chaturvedi@ic.ac.uk.


Ann Intern Med. 2001;134(5):370-379. doi:10.7326/0003-4819-134-5-200103060-00009
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Angiotensin-converting enzyme (ACE) inhibitors are recommended for all patients with type 1 diabetes and microalbuminuria, regardless of blood pressure (1). These recommendations are based on well-conducted clinical trials (2), but several questions remain unanswered. First, the range of renal disease included in studies of patients with microalbuminuria is broad, from relatively high albumin excretion rates associated with advanced renal disease to mild elevations of albumin excretion rate and relatively normal glomerular structure. Because microalbuminuria often occurs in the first 5 years after diagnosis (3), relatively young people may begin therapy with ACE inhibitors on the basis of this indication alone and would be expected to continue taking these drugs indefinitely. Furthermore, in several of these trials, change in albumin excretion rate is used as a surrogate end point, with the implicit assumption that it indicates progressive renal disease. A demonstration that ACE inhibitors reduced the risk for progression to a more definite end point, such as clinical proteinuria, would add support to intervention strategies. Although some studies have reported a statistically significant effect of ACE inhibitors on progression to macroalbuminuria (45), most were not adequately powered to do so. For example, if the risk for progression to macroalbuminuria in the placebo group is assumed to be 20% over a 2-year period, 147 patients in each group would be required to detect a relative risk of 0.33 with a power of 0.9 power and a significance of 0.05. No study has yet reported the risk for regression to normoalbuminuria, and published individual studies are not powered to do so.

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Figure 1.
Estimated difference in albumin excretion rate between placebo and treatment groups at 2 years, using 1-year data only.

ATLANTIS = ACE Inhibitor Trial to Lower Albuminuria in Normotensive Insulin-Dependent Subjects; ESPRIT = European Study of the Progression of Renal Disease in Type 1 Diabetes; EUCLID = EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes; IDDM = insulin-dependent diabetes mellitus; IMSG = Italian Microalbuminuria Study Group; MDNSG = Melbourne Diabetic Nephropathy Study Group; PRIMA = Project with Ramipril on Insulin dependent patients with MicroalbuminuriA. Error bars represent 95% CIs.

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Figure 2.
Estimated difference in albumin excretion rate between placebo and treatment groups at 2 years, using varying periods of follow-up.

Error bars represent 95% CIs.

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Figure 3.
Estimated difference in albumin excretion rate between placebo and treatment groups at 2 years, according to albuminuric status at baseline.P

Values are estimated from the regression model.  = 0.04 for treatment effect on continuous baseline albumin excretion rate.

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Figure 4.
Risk for progression to macroalbuminuria (top) and regression to normoalbuminuria (bottom).P(23)

Because the estimate of between-study variance was zero for progression to macroalbuminuria, the fixed-effects model was the same as the random-effects model (  > 0.5 for heterogeneity). *Zero events in the placebo group indicates a between-study variance of 0.22, using the Van Houwelingen method with likelihood based on confidence intervals. ATLANTIS = ACE Inhibitor Trial to Lower Albuminuria in Normotensive Insulin-Dependent Subjects; ESPRIT = European Study of the Progression of Renal Disease in Type 1 Diabetes; EUCLID = EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes; IDDM = insulin-dependent diabetes mellitus; IMSG = Italian Microalbuminuria Study Group; MDNSG = Melbourne Diabetic Nephropathy Study Group; PRIMA = Project with Ramipril on Insulin dependent patients with MicroalbuminuriA. Error bars represent 95% CIs.

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Summary for Patients

The Effect of ACE Inhibitors on Kidney Function in Patients with Type 1 Diabetes

The summary below is from the full report titled “Should All Patients with Type 1 Diabetes Mellitus and Microalbuminuria Receive Angiotensin-Converting Enzyme Inhibitors? A Meta-Analysis of Individual Patient Data.” It is in the 6 March 2001 issue of Annals of Internal Medicine (volume 134, pages 370-379). The author is the ACE Inhibitors in Diabetic Nephropathy Trialist Group.

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