London, UK and Odense, Denmark - Three new studies examining the role of the angiotensin receptor blocker (ARB) candesartan (Atacand, AstraZeneca/Takeda Pharmaceutical) in the prevention and treatment of diabetic retinopathy have been published online September 25, 2008 in two papers in the Lancet [1,2]. The findings are mixed, but the investigators conclude that candesartan could be of use in this indication, not least because there are very few other treatment options, and this is the first study to have shown any improvement in early retinopathy with a pharmaceutical agent.

Specifically, the results suggest a potential role of candesartan to reduce the incidence of retinopathy in type 1 diabetics who have not yet developed it and to improve the condition in type 2 diabetics who already have it.

However an accompanying comment [3], by Drs Paul Mitchell (University of Sydney, Australia) and Tien Y Wong (University of Melbourne, Australia), points out: "Although the impression suggests overall beneficial effects of candesartan in reducing retinopathy in both type 1 and 2 diabetes, neither prespecified end point was reached in the two studies."

Nevertheless, say Mitchell and Wong—who describe the two new papers as "pivotal"—the conclusions of the Diabetic Retinopathy Candesartan Trials (DIRECT), that candesartan reduces retinopathy development in type 1 diabetes and benefits its evolution in type 2, "are . . . justified, with some caveats."

The three studies reported in the two papers make up DIRECT, which randomized 5231 patients with type 1 or type 2 diabetes from 302 sites worldwide to daily placebo or 32 mg of candesartan and followed them for 4 years.

In the first paper, Dr Nish Chaturvedi (Imperial College Healthcare NHS Trust, London, UK) and colleagues for the DIRECT Programme Study Group looked at the effects of candesartan on type 1 diabetics who were normotensive and normoalbuminuric without retinopathy at baseline (DIRECT-Prevent 1, n=1421) and similar type 1 patients with existing retinopathy (DIRECT-Protect 1, n=1905). Patients were given 16 mg of candesartan daily or placebo for the first month, after which the dose of the ARB was doubled to 32 mg.

The primary end points were incidence and progression of retinopathy and were defined as at least a two-step and at least a three-step increase on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale, respectively.

In DIRECT-Prevent 1, the primary end point—incidence of retinopathy—was seen in 178 patients (25%) in the candesartan group vs 217 (31%) of placebo patients, a nonsignificant difference (hazard ratio 0.82, p=0.0508).

But further post hoc analysis of at least a three-step increase on the ETDRS scale for incidence yielded an HR of 0.65 (p=0.0034), which was attenuated but still significant after adjustment for baseline characteristics (0.71, p=0.046), Chaturvedi and colleagues say.

In DIRECT-Protect 1, the primary end point—progression of retinopathy—occurred in 127 (13%) of those taking candesartan compared with 124 (13%) of those on placebo (nonsignificant).

The take-home message for all the studies that we did was that there was a beneficial effect [of candesartan] on retinopathy.

"Although candesartan reduces the incidence of retinopathy, we did not see a beneficial effect on retinopathy progression," the researchers conclude.

Chaturvedi told heartwire: "The take-home message for all the studies that we did was that there was a beneficial effect on retinopathy. We feel that candesartan may be valuable in people with type 1 diabetes who don't currently have retinopathy but who have poor glycemic control, because clearly [the latter] is one of the strongest risk factors for retinopathy. For those kinds of individuals, one might want to consider use of candesartan to reduce the risk of onset of retinopathy."

But, she stressed, "Our study does not show a beneficial effect in people with type 1 diabetes and established retinopathy, so we can't recommend its use in that situation."

The second paper reports on the third study, in type 2 diabetics, DIRECT-Protect 2, by Dr Anne Katrin Sjølie (Odense University Hospital, Denmark) and colleagues for the DIRECT Programme Study Group. They examined whether candesartan could slow the progression and induce regression of retinopathy in 1905 people with type 2 diabetes who were normoalbuminuric and either normotensive or only mildly hypotensive randomized as before to 32 mg of candesartan or placebo daily and followed for 4 years.

Progression of retinopathy was the primary end point, and regression was a secondary end point. Candesartan reduced the progression of retinopathy by 13%, but the finding was not significant (p=0.20).

Regression on active treatment was increased by 34% (HR 1.34, p=0.009), however, and this was not attenuated by adjustment for baseline risk factors or changes in blood pressure during the trial.

The latter effects occurred only in participants with early retinopathy, however, something the editorialists stressed was "an important take-home message."

An overall change toward less severe retinopathy by the end of the trial was observed in the candesartan group (odds 1.17, p=0.003), leading the investigators to conclude, "Treatment with candesartan in type 2 diabetic patients with mild to moderate retinopathy might induce improvement of retinopathy."

Sjølie told heartwire: "In type 2 diabetes, sight-threatening retinopathy is a big problem, as the present treatment options are at a late stage and are not very effective.

DIRECT-Protect 2 is the first study showing improvement in retinopathy by pharmaceutical treatment in relatively early eye disease.

"DIRECT-Protect 2 is the first study showing improvement in retinopathy by pharmaceutical treatment in relatively early eye disease, before irreversible damage has occurred. As a large percentage of type 2 patients are also hypertensive, I would consider using candesartan in these patients with the possible additional benefit of improvement of retinopathy and decreased risk of vision-threatening eye complications. In addition, we showed that the treatment is well tolerated."

Chaturvedi, who is also a coauthor on the DIRECT-Protect 2 paper, agrees: "Candesartan can be considered in type 2 diabetics with established retinopathy and also in those who become hypertensive—if you've got to choose a blood-pressure-lowering agent, there's loads you can choose, but if candesartan has this additional beneficial effect of reverting retinopathy, then it might be worth considering it.

"Otherwise, all you've got is to wait until the patient gets quite advanced retinopathy that requires intravitreal treatment with growth factor inhibitors—which is not pleasant—or further on from that, laser therapy, which is destructive," she adds.

"The word to use is 'consider it' in people [with type 2 diabetes] and established retinopathy and in those with type 1 diabetes who are hard to control and at risk of retinopathy," she stresses.

Chaturvedi explained that no other ARB has shown any beneficial effect on diabetic retinopathy, nor has any ACE inhibitor, with the exception of "one small unpublished study."

The EUCLID trial of lisinopril in type 1 diabetes—which prompted the whole DIRECT program—did show a beneficial effect of lisinopril on progression of retinopathy over two years, she notes, but these were type 1 patients with established hypertension, and this was a secondary analysis, "so you can't make treatment recommendations based on this." Also, because the patients in DIRECT were normotensive, it is impossible to compare the two trials [EUCLID and DIRECT], she believes.

In their comment, Mitchell and Wong say EUCLID was also limited by differences between treatment groups in baseline glycemia. Furthermore, two other studies, UKPDS and the ABCD trial, did not report superiority of ACE inhibitors over other drugs that lower blood pressure for diabetic retinopathy, they note. And the ADVANCE study did not report a benefit on diabetic retinopathy with further lowering of blood pressure using a perindopril-indapamide combination compared with placebo, they add.

Other results from ADVANCE suggest that processes other than glycemia and blood pressure may contribute to the development of diabetic retinopathy, they point out, so that "specific targeting to further reduce the risk of diabetic nephropathy" might be needed.