• Diabetes & Endocrinology Clinical Trials
• Hypertension & Kidney Disease
• Diabetes & Kidney Disease
• Diabetes MellitusHypertensive Disease
• Renal Disease

Four years of candesartan, an angiotensin receptor blocker, reduced incident microalbuminuria in hypertensive patients with type 2 diabetes mellitus (T2DM) when albumin excretion was defined by a single positive urine sample but not with multiple collections. No effect was evident in normotensive T2DM subjects using either definition. Given the difference in results when multiple or single urine samples were included, the method of detection needs to be considered when evaluating studies of primary prevention of microalbuminuria in patients with T2DM.

Previously, renin-angiotensin system (RAS) blockade was shown to prevent microalbuminuria in people with T2DM who were at high cardiovascular risk. Most of these findings were based on single determinations of the albumin-to-creatinine ratio. In contrast, the pooled results of three Diabetic Retinopathy Candesartan Trials (DIRECT; NCT00252694, NCT00252720, NCT00252733), using multiple, timed overnight urine collections, failed to show a benefit of RAS blockade on the development of persistent microalbuminuria (defined as 3 of 4 consecutive samples with albumin >20 μg/min).

Rudolf Bilous, MD, James Cook University Hospital, Middlesbrough, United Kingdom, presented a reanalysis of those data with the aim of investigating whether candesartan reduced incident microalbuminuria in normotensive (blood pressure [BP] <130/85 mm Hg) and well-controlled hypertensive T2DM patients, using the less stringent definition of microalbuminuria of a single value >20 μg/min.

The three DIRECT studies involved subjects with mild to moderate retinopathy, and these pooled results are based on those populations. Overall, 1905 people with T2DM were randomized to receive either candesartan (titrated to 32 mg daily) or placebo. At study entry, all subjects had normal albumin excretion (median albuminuria 5.5 μg/min), 62% were hypertensive (mean BP 139/69 mm Hg), and 38% were normotensive (BP <130/85 mm Hg, mean 123/75 mm Hg). Each subject collected 2 timed, overnight urine specimens annually for at least 4 years. BP was measured semiannually. The two arms of the trial were well matched for gender (49% to 51% male), age (mean age 57 years), diabetes duration (mean duration 9 years), and HbA1C (mean 8.2% ± 1.6).

Candesartan lowered systolic blood pressure (SBP) as early as 6 months in both cohorts, and at 4 years of follow-up (using the last value carried forward), SBP decreased by 4.3 mm Hg in the normotensive group and by 2.9 mm Hg in the hypertensive subjects.

At 5 years of follow-up, based on a single positive sample, candesartan significantly lowered the risk of microalbuminuria by 20% when all patients were considered together (HR, 0.80; 95% CI, 0.67 to 0.96; p=0.016). The result was similar for the groups of patients who were hypertensive or normotensive at baseline but was not statistically significant for the normotensive group. However, when using the more stringent criterion of 3 of 4 positive samples, candesartan had no effect on the development of microalbuminuria.

Prof. Bilous summarized the findings by saying that candesartan 32 mg daily for 4 years was effective in reducing incident microalbuminuria in patients with T2DM who were normotensive at baseline when defined by a single positive urine sample but not by the more stringent criterion of multiple positives. He added that the drug's apparently greater efficacy in patients who were hypertensive at baseline may have been the result of the larger sample size and number of events. Overall, these results suggest that the method of detection strongly influences the results of studies that investigate the primary prevention of microalbuminuria. Furthermore, the possibility of patient benefit needs to take into account baseline vascular risk and the definition of the endpoint.

Prof. Bilous concluded that the DIRECT results do not support universal RAS blockade for T2DM patients who are at low vascular risk, and he advised developing standardized definitions of early nephropathy for intervention trials.

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The editors would like to thank the many members of the European Association for the Study of Diabetes presenting faculty who generously gave their time to ensure the accuracy and quality of the articles in this publication.

• © 2010 MD Conference Express