Effect of candesartan on progression and regression of retinopathy in type 2 diabetes (DIRECT-Protect 2): a randomized placebo-controlled trial

Background: The role of blockade of the renin-angiotensin system has not been studied in retinopathy in type 2 diabetes, whereas it has been shown to reduce risks for nephropathy and cardiovascular disease.

Objective: The objective of this study was to determine if the angiotensin-receptor blocker candesartan could reduce the progression of retinopathy in type 2 diabetes. 

Methods: The design of the study was parallel, randomized, double-blind, placebo-controlled experimental.  The patients were assigned to treatment groups by randomization.  Men and women 37-75 years of age, with known type 2 diabetes for between 1 and 20 years in 309 centers worldwide were screened for participation in the trial.  To be included in the trial age at onset of diabetes had to be 36 years or older, without the need for continuous insulin treatment within a year of diagnosis.  Patients were excluded from the trial if they had eye conditions that precluded capture of gradable retinal photographs; those with clinically significant macular edema or proliferative retinopathy, and those with stenotic valvular heart disease, recent stroke, or myocardial infarction.  Also excluded were pregnant and lactating women, and patients with renal impairment.   Patients were excluded if results showed that urinary albumin excretion rate in at least one of the two samples was not less than 20 µg/min, indicating normoalbuminuria.  If patients were not on antihypertensive treatment prior to the trial, they had to have a blood pressure of less than or equal to 130/85 mmHg; or if they were on antihypertensive treatment, the blood pressure had to be less than or equal to 160/90 mmHg.  Patients taking renin-angiotensin system inhibitors were excluded.  Patients also had to have mild to moderately severe non-proliferative diabetic retinopathy, assessed by a score of 20/10 or more and 47/47 or less on the severity scale used in the Early Treatment Diabetic Retinopathy Study.  Of the 1905 patients eligible for randomization, 951 were assigned to the candesartan treatment group and 954 to the placebo group.  Patients were randomized to receive either candesartan 16 mg once a day or matching placebo.  After a month of treatment, this dose was doubled to 32 mg once a day of either treatment, and all patients were followed up for at least 4 years.  The primary endpoint was progression of retinopathy, defined as an increase in three or more ETDRS levels.   An additional prespecified outcome measure was overall change in retinopathy levels from baseline to final visit, by treatment group.  Secondary endpoints were regression of retinopathy defined as reduction of at least three or more steps on the ETDRS scale from baseline to any follow-up visit, or two or more steps sustained at two consecutive follow-up visits; and development of proliferative diabetic retinopathy, clinically significant macular edema, or both.  All data was analyzed according to the intention to treat analysis, and the power of the study was estimated to be approximately 80%. 

Results: The primary outcome, defined as progression of retinopathy by three steps or more on the ETDRS scale was found to occur in 161 (17%) of 951 patients in the candesartan group and 182 (19%) of 954 in the placebo group (HR 0.87, 95% CI 0.70- 1.08, p =.20).  There were 180 (19%) of 951 patients in the candesartan group and 136 (14%) of 954 in the placebo group found to have regression of retinopathy.  This showed that candesartan was associated with a 34% increase in the relative chance of regression (p =.009).  From these data, 21 patients would need to be treated with candesartan for 4.7 years to obtain regression of retinopathy in one patient.  Proliferative diabetic retinopathy, clinically significant macular edema, or both were found in 192 (20%) of 951 patients in the candesartan group and 193 (20%) of 954 controls (HR 0.971, p =.773).  The authors concluded that treatment with candesartan over a 4 year trial reduced the primary endpoint of progression of retinopathy by 13% versus placebo in normoalbuminuric, normotensive, or controlled hypertensive patients with type 2 diabetes, although this reduction was not significant.  In addition, it was also concluded that patients given candesartan were a third more likely to experience regression of retinopathy and more likely to end the trial with a more favorable retinopathy status, due to greater regression and lesser progression.  The authors went on to state that the results of the study suggest that treatment with candesartan in type 2 diabetic patients with mild to moderate retinopathy could induce improvement of the disease. 

Strengths: The rationale behind the study objective was logical and it was appropriate to investigate candesartan treatment in this manner.  The study design was optimal and appropriate to fulfill the stated objective.  The dosing and administration was appropriate in both groups and both received treatment for a sufficient duration of time.  The results of the study were interpreted appropriately by the authors. 

Weaknesses: A main weakness in this study was the application of the results in the study to clinical practice.  The authors implied in their conclusion that candesartan should be considered in the treatment of retinopathy because of its effect on regression as well as progression.  This is an incorrect interpretation because it is likely that the positive effects on the retinopathy state of the patient were due only to the beneficial effects on the regression induced by candesartan.  In addition to this, improvement was only shown in patients with mild retinopathy, whereas in the conclusion, the authors stated it should be considered for use in patients with mild to moderate retinopathy.  These conclusions were the result of author bias due to potential conflicts of interest. 

Conclusion:  The results of this study should be considered preliminary data for the use of candesartan in the treatment of retinopathy.  Using candesartan in effort to prevent progression of retinopathy should not be the desired outcome of therapy.  Inducing regression however is a definite acceptable outcome of therapy, but more studies are needed regarding this avenue of treatment before a final conclusion can be made on the success of candesartan in treating retinopathy.   

Prepared by: Jen Curtis, Doctor of Pharmacy Candidate