Important New Data On The Effect Of Candesartan On Diabetic Eye Complications

Main Category: Diabetes
Also Included In: Eye Health / Blindness
Article Date: 11 Sep 2008 - 9:00 PDT

email to a friend   printer friendly   view / write opinions   rate article

Data from the DIRECT Programme, the first large-scale study programme assessing the effect of treatment with an angiotensin receptor blocker (ARB) on the incidence and progression of diabetic eye complications, was presented today at the European Association of the Study of Diabetes (EASD) congress in Rome.1

The data from over 5,000 patients, published online on the Lancet website, show a strong, positive trend in favour of treatment with candesartan in reducing the incidence of diabetic retinopathy in Type 1 diabetes patients, although this result did not quite achieve statistical significance. Additionally, in Type 2 diabetes patients, a significant increase in regression of diabetic retinopathy was seen in patients treated with candesartan.

Although the programme did not meet the primary endpoints, there were some interesting clinical findings. In Type 1 patients with no signs of diabetic retinopathy at baseline, candesartan caused an 18% reduction in the incidence of diabetic retinopathy as measured by 2-step change on the Early Treatment of Diabetic Retinopathy Study (ETDRS) scale* (primary endpoint, p=0.0508), and a 35% reduction for 3-step change (post-hoc analysis, p=0.003). In the type 1 diabetic patients with existing retinopathy the results were similar in the two groups (p=0.85).

Treatment with candesartan also reduced the risk of progression of retinopathy by 13% over placebo in Type 2 diabetes patients, primary endpoint, p=0.2.1 However, importantly in these Type 2 diabetes patients with relatively early signs of diabetic retinopathy, candesartan increased the probability of regression of retinopathy by 34% compared with placebo (pre-defined secondary endpoint, p=0.009).1 In each of the three studies, levels of retinopathy over time consistently showed a statistically significant change towards less deterioration and more improvement with candesartan than with placebo.

"We broke new ground with DIRECT by focusing on the early stages of diabetic complications, with an objective to prevent the onset or protect against the worsening of these conditions. Despite the fact that the trials did not meet the primary endpoints, the data show encouraging results for candesartan treated patients with regards to reducing the incidence of retinopathy in Type 1 diabetes patients and increasing the chance of regression in Type 2 diabetes patients", said Professor Anne Katrin Sjølie, Chair of the DIRECT Steering Committee. "Diabetic retinopathy is one of the most feared2 and common complications of diabetes3 making this an important clinical finding, as the reversal of this vision threatening complication to diabetes has not been reported before in large-scale clinical trials."

Professor Rudy Bilous, DIRECT Steering Committee member and Professor of Clinical Medicine at Newcastle University and Diabetes Specialist at the James Cook University Hospital, Middlesbrough said "DIRECT is the first large scale study to show that we may prevent and in some patients reverse retinopathy using medicines that do not affect blood glucose. This information will help us plan better care for our patients and provides an additional method to treat this serious complication of diabetes"

DIRECT was an international study programme across 309 centres in 30 countries which followed 5,231 diabetes mellitus patients for at least four years. The programme comprised three double blind, randomised, placebo controlled studies. 'DIRECT-Prevent 1'(n=1,421) studied the effect of candesartan on the incidence of retinopathy (primary endpoint) in normotensive, normoalbuminuric Type 1 diabetes patients; 'DIRECT-Protect 1' (n=1,905) studied the effect of candesartan on the progression of retinopathy (primary endpoint) in normotensive, normoalbuminuric Type 1 diabetes patients already affected by retinopathy; 'DIRECT-Protect 2' (n=1,905) studied the effect of candesartan on the progression of retinopathy (primary endpoint) in normoalbuminuric, normotensive or treated hypertensive, Type 2 diabetes patients with retinopathy. The primary endpoints were measured as a predefined change in the ETDRS scale for retinopathy in each of the three studies.

The pooled data from the three studies was used to examine the effect on early onset of microalbuminuria (primary endpoint) in normotensive, normoalbuminuric diabetes patients. This is the first time that prevention of microalbuminuria with RAS blockade has been assessed in a large scale clinical study. In the DIRECT Programme, treatment with candesartan had no impact on the overall incidence of microalbuminuria.

Adjustments for blood pressure slightly attenuated the results but did not change the overall findings suggesting that the effects of candesartan in diabetic retinopathy go beyond simply lowering blood pressure in diabetes patients.

Around 80% of patients in the active treatment groups were given a 32mg dose of candesartan for between 4-6 years. This dosage was well-tolerated by both normotensive and treated-hypertensive patients. Overall incidence of adverse events were similar in both placebo and candesartan treated patients.

"Candesartan is already an established treatment for hypertension and chronic heart failure. Takeda Pharmaceutical Company Limited are proud to be involved in this innovative, large-scale study which has improved our understanding of the effects of angiotensin receptor blockers in diabetes patients and increased our knowledge of diabetic eye disease and its interactions with the RAS." said Masaomi Miyamoto, Ph.D., general manager of Pharmaceutical Development Division of Takeda.

Retinopathy, or damage to the retina, is the most common cause of blindness in people of working age in the developed world.3 Whilst strict glycaemic and blood pressure control have been shown to reduce the development and progression of retinopathy in Type 1 and 2 diabetes patients,4,5,6 previous studies have indicated that renin-angiotensin system (RAS) blockade may have additional benefits in the management of microvascular complications.7 The DIRECT Programme adds to the body of knowledge that RAS blockade is beneficial by indicating that candesartan can work at the early stage of diabetic retinopathy reducing incidence in Type 1 diabetes patients and inducing regression in Type 2 diabetes patients.

About Candesartan

Candesartan cilexetil is an angiotensin receptor blocker, indicated for the treatment of patients with hypertension and patients with CHF and left ventricular systolic dysfunction (LVEF <40%). Candesartan acts on the renin-angiotensin system, which plays an important role in regulating blood pressure. Angiotensin II, the main effector hormone in the RAS, mediates a wide range of responses such as vasoconstriction, sodium and fluid retention, cell growth, and sympathetic activation. Candesartan binds to the AT1-receptor thereby blocking its interaction with angiotensin II. This blockade leads to vasodilatation and a decrease in blood pressure. Candesartan is at least as effective as other antihypertensive drugs but with the advantage of the better tolerability profile associated with ARBs.

In November 2004, candesartan was granted EU Marketing Authorisation for the treatment of patients with heart failure and left ventricular systolic dysfunction.

In the UK, candesartan cilexetil is marketed by Takeda UK Limited under the trademark Amias®.

Please refer to the Summary of Product Characteristics enclosed in the pack or visit http://www.medicines.org.uk for more information about Amias (candesartan cilexetil).

* About the Early Treatment of Diabetic Retinopathy Study (ETDRS) scale

Within the DIRECT Programme, the presence of Diabetic Retinopathy is evaluated using the Early Treatment of Diabetic Retinopathy Study (ETDRS) scale which grades the degree of retinopathy on an 11-point scale. The lowest value on this scale is 10/10 (i.e. no retinopathy in either eye) and the highest value is 81/81 (i.e. advanced proliferative diabetic retinopathy in both eyes). At this point, new vessels cause haemorrhaging in the eye and are accompanied by severe loss of vision.

UK

About Takeda UK

Takeda UK Ltd is based in High Wycombe in Buckinghamshire, and is the UK affiliate of Takeda Pharmaceutical Company responsible for sales and marketing of the company's products in the UK.

The Takeda Pharmaceutical Company Ltd. of Osaka is a research-based global company. As the largest pharmaceutical company in Japan and one of the world leaders in its field, Takeda strives to achieve better health for individuals and progress in medicine by developing superior pharmaceutical products.

More information about Takeda in the UK is available at http://www.takeda.co.uk.

References

1. Data presented at EASD on 11 September 2008

2. Hopkins, M. Diabetic retinopathy: Seeing a difference. CPJ / RPC 2006; 139 (5): 30-31.

3. Javitt, J and Aiello, L. Cost-Effectiveness of Detecting and Treating Diabetic Retinopathy. Annals of Internal Medicine, 1996: 124 (1): 164-169

4. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998;317:703-13

5. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998; 352:854-65.

6. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352:837-53.

7. The DIRECT Programme study Group. The DIabetic REtinopathy Candesartan Trials (DIRECT) Programme: baseline characteristics. JRAAS. 2005; 6:25-32

http://www.takeda.co.uk