DIRECT: candesartan enhanced regression, reduced incidence of diabetic retinopathy

44th Annual Meeting of the EASD

ROME — Results from the DIRECT Program showed that candesartan reduced the incidence of diabetic retinopathy in patients with type 1 diabetes and enhanced the regression of retinopathy in those with type 2 diabetes. However, the study did not meet its primary endpoints.

These findings were presented at the 44th Annual Meeting of the European Association for the Study of Diabetes.

DIRECT (Diabetic Retinopathy Candesartan Trials) is a large-scale, international program comprised of three double-blind randomized, placebo-controlled studies:

DIRECT-Prevent 1 is a primary prevention study of the effect of candesartan on the incidence of new retinopathy (primary endpoint) in 1,421 patients with type 1 diabetes.
DIRECT-Protect 1 is a secondary prevention study of the effect of candesartan on the progression of retinopathy (primary endpoint) in 1,905 patients with type 1 diabetes with mild to moderate retinopathy.
DIRECT-Protect 2 is a secondary prevention study of the effect of candesartan on the progression of retinopathy (primary endpoint) in 1,905 patients with type 2 diabetes with mild to moderate retinopathy.

Researchers conducted these studies at 309 centers in 30 countries. They examined the effect of candesartan on retinopathy progression in 5,231 patients, all of whom were normoalbuminuric at baseline. Patients with type 1 diabetes were normotensive and those with type 2 were either normotensive or treated for hypertension, according to local guidelines. The researchers focused on the earlier stages of the disease and followed patients for at least four years.

In patients with type 1 diabetes and without retinopathy at baseline, candesartan reduced the incidence of retinopathy by 18%, as measured by a two-step change on the Early Treatment of Diabetic Retinopathy Study scale (P=.0508). There was a 35% reduction for the more stringent three-step change post hoc analysis (P=.003).

“There was no effect on progression of retinopathy in these patients, but there was a nonsignificant 13% reduction in type 2 patients (P=.2),” the researchers said. Furthermore, in patients with type 2 diabetes, candesartan use increased the probability of regression of retinopathy by 34% compared with placebo (P=.009).

“Treatment with candesartan may confer benefit for retinopathy in people with diabetes,” the researchers concluded. Patients were more likely to experience an overall change in retinopathy to more favorable levels at the end of the study when treated with candesartan.

More information on the results of the DIRECT Program can be viewed at www.direct-results.org. – by Tara Grassia

The level of retinopathy was more favorably affected on candesartan at the end of all three studies compared to placebo. Candesartan did not reduce the progression to microalbuminburia. The study did not meet the pre-specified endpoints, however there are a lot of interesting results. The risk of retinopathy is far less than anticipated. The study is probably too short, treatment effects only began to emerge after four years of treatment. Therefore, we need long-term studies. The simple take-home message is angiotensin receptor blockers or ACE inhibitors are indicated in patients with risk progression to retinopathy and in those with existing retinopathy in type 1 or 2 diabetes.

– Kristian F. Hanssen, MD, PhD

Professor
Department of Endocrinology and the Diabetes Research Center
Aker University Hospitals, Oslo, Norway

For more information:

Chaturvedi, N, Sjolie AK, Bilous RW, et al. Clinical trial symposium. DIRECT – Candesartan and the primary and secondary prevention of retinopathy and nephropathy. Presented at: the 44th Annual Meeting of the European Association for the Study of Diabetes; Rome; Sept. 7-11, 2008.