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Can Renin-Angiotensin Blockade Prevent Diabetic Retinopathy?

Three 5-year trials yielded negative results for candesartan.

Some evidence suggests that blockade of the renin-angiotensin system can lower the incidence and progression of retinopathy in patients with type 1 diabetes. With manufacturer support, investigators enrolled 3810 adults with nonproliferative diabetic retinopathy (half with type 1 and half with type 2 diabetes) and 1421 adults with type 1 diabetes and no retinopathy in three concurrent trials. Patients were randomized to daily candesartan (Atacand; 32 mg) or placebo and followed for about 5 years. Periodic retinal photographs were graded on a standard 11-step retinopathy scale.

Among patients with type 2 diabetes, progression of retinopathy by at least three steps was nonsignificantly less common in the candesartan group than in the placebo group (17% and 19%; P=0.2). Significantly more candesartan patients exhibited regression of retinopathy by at least three steps (a secondary endpoint; 19% vs. 14%; P=0.009).

Among patients with type 1 diabetes, incidence of new retinopathy (at least 2 steps) was marginally lower in the candesartan group than in the placebo group (25% and 31%; P=0.051) before adjustment for baseline characteristics; the difference was even less after adjustment. When the cutoff was set to three rather than two steps in a post hoc analysis, candesartan patients had a significantly lower incidence of retinopathy (10% vs. 16%; P=0.003); this difference still was significant after adjustment. Progression of preexisting retinopathy was similar in both groups.

Comment: All these trials had negative outcomes for their primary endpoints, and observed differences in retinopathy could have been confounded by slightly lower blood pressures among candesartan patients. But, candesartan had some substantial beneficial effects, most of which did not appear until late in the follow-up period. Longer studies might produce clearer results.

— Bruce Soloway, MD

Published in Journal Watch General Medicine November 20, 2008

Citation(s):

Sjølie AK et al. Effect of candesartan on progression and regression of retinopathy in type 2 diabetes (DIRECT-Protect 2): A randomised placebo-controlled trial. Lancet 2008 Oct 18; 372:1385.

• Medline abstract (Free)

Chaturvedi N et al. Effect of candesartan on prevention (DIRECT-Prevent 1) and progression (DIRECT-Protect 1) of retinopathy in type 1 diabetes: Randomised, placebo-controlled trials. Lancet 2008 Oct 18; 372:1394.

• Medline abstract (Free)